Andrew J. Spillane

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis. The first large, high-coverage whole-genome sequencing study of melanomas from cutaneous, acral and mucosal sites. Melanoma is a highly metastatic cancer with a high mutation load, and signatures in some subtypes are often associated with exposure to ultraviolet radiation. Graham Mann and colleagues report whole-genome sequencing of tumour samples from patients with melanoma, including 75 primary melanomas, 93 melanoma metastases and 15 cell lines derived from melanoma metastases. The authors compare the genomic landscapes of cutaneous, acral and mucosal subtypes of melanoma, identifying distinct mutational signatures by subtype. Cutaneous melanomas showed mutational signatures of ultraviolet radiation exposure, whereas acral and mucosal melanomas showed a lower mutation burden and more frequent complex structural rearrangements in comparison to other melanoma subtypes. Understanding the whole-genome landscapes of all melanoma subtypes is important for investigating melanoma prevention and targeted treatment.

Abstract Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2 . Significantly mutated genes are NRAS , BRAF , NF1 , KIT , SF3B1 , TP53 , SPRED1 , ATRX , HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

Abstract To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS , NF1 , NOTCH2 , PTEN and TYRP1 . Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT , CDK4 , MDM2 , CCND1 , PAK1 and GAB2 , indicating potential therapeutic options.

We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironment are associated with response to immunotherapy. No specific mutation correlates with therapy response. A multivariable model combining the TMB and IFNγ-related gene expression robustly predicts response (89% sensitivity, 53% specificity, area under the curve [AUC], 0.84); tumors with high TMB and a high IFNγ signature show the best response to immunotherapy. This model validates in an independent cohort (80% sensitivity, 59% specificity, AUC, 0.79). Except for a JAK3 loss-of-function mutation, for patients who did not respond as predicted there is no obvious biological mechanism that clearly explained their outlier status, consistent with intratumor and intertumor heterogeneity in response to immunotherapy.

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.

Cancer-associated fibroblasts (CAFs) play a role in tumour initiation and progression, possibly by inducing epithelial-to-mesenchymal transition (EMT), a series of cellular changes that is known to underlie the process of metastasis. The aim of this study was to determine whether CAFs and surrounding normal breast fibroblasts (NBFs) are able to induce EMT markers and functional changes in breast epithelial cancer cells. Matched pairs of CAFs and NBFs were established from fresh human breast cancer specimens and characterised by assessment of CXCL12 levels, α-smooth muscle actin (α-SMA) levels and response to doxorubicin. The fibroblasts were then co-cultured with MCF7 cells. Vimentin and E-cadherin expressions were determined in co-cultured MCF7 cells by immunofluorescence and confocal microscopy as well as by western blotting and quantitative PCR. Co-cultured MCF7 cells were also assessed functionally by invasion assay. CAFs secreted higher levels of CXCL12 and expressed higher levels of α-SMA compared with NBFs. CAFs were also less sensitive to doxorubicin as evidenced by less H2AX phosphorylation and reduced apoptosis on flow cytometric analysis of Annexin V compared with NBFs. When co-cultured with MCF7 cells, there was greater vimentin and less E-cadherin expression as well as greater invasiveness in MCF7 cells co-cultured with CAFs compared with those co-cultured with NBFs. CAFs have the ability to induce a greater degree of EMT in MCF7 cell lines, indicating that CAFs contribute to a more malignant breast cancer phenotype and their role in influencing therapy resistance should therefore be considered when treating breast cancer.

10002 Background: OpACIN-neo tested 3 dosing schemes of neoadjuvant (neoadj) IPI+NIVO and identified 2 cycles of IPI 1mg/kg + NIVO 3mg/kg (I1N3) as the most favorable with a pathologic (path) response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 17.6 months median FU, 1/64 (2%) patients (pts) with path response vs 13/21 (62%) of the non-responders ( > 50% viable tumor cells; pNR) had relapsed. We hypothesized that therapeutic lymph node dissection (TLND) could be omitted in pts achieving a complete or near-complete path response (≤10% viable tumor cells; major path response, MPR) in the index node (largest LN metastasis: ILN), whereas additional adjuvant (adj) therapy might improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the multi-center phase 2 OpACIN-neo study that aims to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with RECIST 1.1 measurable clinical stage III melanoma were included to receive 2 cycles of neoadj I1N3 after marker placement in the ILN. ILN resection was planned at wk 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with pPR ( > 10 – ≤50% viable tumor cells) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or targeted therapy (TT) for 52 wks +/- radiotherapy (RT). Primary endpoints were pRR in the ILN and 24-month RFS. Estimated toxicity rates at wk 12 were calculated using a Kaplan Meier based method. Results: Between Nov 16, 2018 and Jan 3, 2020, 99 of 114 screened pts were eligible and enrolled. So far, 86 pts had ≥12 wks FU. 70/99 pts achieved a path response in the ILN (pRR 71%, 95% CI 61% - 79%); 60 (61%) had MPR. TLND was omitted in 58 (97%) of the MPR pts. There were 28 non-responders; 7 developed distant metastasis before ILN resection. To date, 8 of the 21 pNR pts had adj NIVO, 7 had adj TT and 7 had adj RT. The estimated grade 3-4 irAE rate at wk 12 was 24%. Due to toxicity, 10 pts (10%) received only 1 cycle I1N3 and in 3 pts ILN resection was not performed: 2 of these pts underwent TLND at wk 9 and one pt was not evaluated for path response. At data cutoff, the surgery-related grade 1,2 and 3 AE rates were 29%, 10% and 0% in pts who underwent ILN resection only vs 21%, 30% and 9% in pts who underwent subsequent TLND (p = 0.004). At ASCO 2020 all pts will have reached ≥12 wks FU. Conclusions: Neoadj I1N3 treatment induced a high pRR with tolerable toxicity. TLND was omitted in a major subset of pts, reducing surgical morbidity. Longer FU is needed to report safety and RFS when TLND is omitted in MPR pts. Clinical trial information: NCT02977052.

Abstract Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711

Abstract Background The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. Methods EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex ® ) > 10 or change of L-Dex ® > 10 from baseline. Results Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9–62.0%], 54.1% I-IL [CI 38.0–70.1%]) and lowest at 18 months (18.8% IL [CI 5.2–32.3%], 41.4% I-IL [CI 23.5–59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6–18.7%) and L-Dex ® was 12.6 (IQR 9.0–17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. Conclusions Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study’s small sample did not have the statistical evidence to support an overall difference between the surgical groups.

<h3>Importance</h3> Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen. <h3>Objective</h3> To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population. <h3>Design, Setting, and Participants</h3> Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021. <h3>Main Outcomes and Measures</h3> Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen. <h3>Results</h3> A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted. <h3>Conclusions and Relevance</h3> The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial.

The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases.We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV melanoma with a solitary site of organ metastasis. In an independent cohort we analyzed and compared immune cell densities, subpopulations and spatial distribution in tissue from liver, lung, brain, LN or subcut sites from 130 patients with stage IV melanoma.Patients with only liver, brain or bone metastases had shorter OS compared to those with lung, LN or subcutaneous and soft tissue metastases. Liver and brain metastases had significantly lower T-cell infiltration than lung (p=0.0116 and p=0.0252, respectively) and LN metastases (p=0.0116 and p=0.0252, respectively). T cells were further away from melanoma cells in liver than lung metastases (p=0.0335). Liver metastases displayed unique T-cell profiles, with a significantly lower proportion of programmed cell death protein-1+ T cells compared to all other anatomical sites (p<0.05), and a higher proportion of TIM-3+ T cells compared to LN (p=0.0004), subcut (p=0.0082) and brain (p=0.0128) metastases. Brain metastases had a lower macrophage density than subcut (p=0.0105), liver (p=0.0095) and lung (p<0.0001) metastases. Lung metastases had the highest proportion of programmed death ligand-1+ macrophages of the total macrophage population, significantly higher than brain (p<0.0001) and liver metastases (p=0.0392).Liver and brain melanoma metastases have a significantly reduced immune infiltrate than lung, subcut and LN metastases, which may account for poorer prognosis and reduced immunotherapy response rates in patients with liver or brain metastases. Increased TIM-3 expression in liver metastases suggests TIM-3 inhibitor therapy as a potential therapeutic opportunity to improve patient outcomes.

Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients.Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models).The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated.The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10-6 and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10-4 ). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.

Background Immediate tissue expander/implant-based breast reconstruction (BR) is often avoided when post-mastectomy radiotherapy (PMRT) is planned due to concerns about high complication rates and poor aesthetic outcomes. This study evaluated surgical, aesthetic and quality of life (QoL) outcomes in women undergoing immediate implant-based BR (IIBR) followed by PMRT. Methods Participants were recruited at least six months after completing the final stage of BR. They completed validated on-line questionnaires assessing satisfaction, QoL, distress, body image and regret. Aesthetic outcomes were rated by their operating surgeon through clinical examination and assessed by an independent surgeon using photographs. Results Forty-seven participants completed questionnaires and reported good outcomes for QoL (FACT-B = 115; TOI = 73), satisfaction (Breast-Q), distress (Impact of Events scale <4.8 all subscales) and body image (Body Image scale), with a low score on the Decisional Regret scale (mean 12.1). Aesthetic outcomes were rated fair-to-good (Kroll scale). The surgical complication rate was low (expander/implant loss rate 6.4%, wound infection 10.6%, seroma 4.1%). At follow-up, 33 (70.2%) participants retained their permanent implant and 12 (25.5%) converted to a TRAM or DIEP flap; there were two LD flaps. Conclusion This study demonstrated acceptable cosmetic results, high patient satisfaction and low complication rates. It provides evidence that women are willing to accept the potential risks of IIBR in exchange for its benefits including enhanced body image during chemotherapy and PMRT and the possible avoidance of more complicated and costly delayed autologous BR. The results support the importance of access to BR, even in women with high-risk disease.

9503 Background: Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) correlates with survival, and is recognized as a path to regulatory approval in several cancers. Recent trials have reported that neoadjuvant immunotherapy (IT) and targeted therapy (TT) regimens achieve high pCR rates and impressive recurrence-free survival in stage III melanoma, however, the relationship between pCR, relapse-free (RFS) and overall survival (OS) in larger datasets of melanoma patients (pts) remains unknown. Methods: We pooled data from 6 modern NST clinical trials of anti-PD-1 based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. Pts with RECIST measurable, surgically resectable clinical stage III melanoma who underwent surgery were included. NST regimens included nivolumab (as monotherapy or in combination with ipilimumab), pembrolizumab or dabrafenib+trametinib. Baseline disease characteristics, treatment regimen, pCR and RFS were examined. Results: 184 pts with clinical stage III melanoma (AJCCv7: 100 IIIB, 84 IIIC) completed NST (133 IT, 51 TT) and underwent surgery. Median age was 57y (range 18-87). A pCR was observed in 41% of patients; 51 (38%) with IT and 24 (47%) with TT. Median follow-up post-surgery is 13 mo (95% CI 12-16); 10 mo with IT and 22 mo with TT. 44 (24%) pts have recurred (17 loco-regional, 21 distant, 6 both sites at first recurrence), 18 (14%) after IT and 26 (51%) after TT. 12-month RFS was improved with IT vs TT (83% vs 65%, p &lt; 0.001). For those with pCR, 7% have recurred, 0/51 (0%) after IT, 7/17 (41%) after TT. For those without pCR, 34% have recurred, 18/82 (22%) after IT and 19/27 (70%) after TT. 12-month RFS was improved in those with pCR vs without pCR (95% vs 62%, p &lt; 0.001), including in those with IT (100% vs 72%, p &lt; 0.001) and TT (88% vs 43%, p &lt; 0.001). 16 (9%) patients have died including two who had a pCR, both from TT. Conclusions: Neoadjuvant IT and TT are active regimens in resectable clinical stage III melanoma patients and are associated with high pCR rate. The ability to achieve pCR correlates with improved RFS and remarkably no patient with pCR from immunotherapy has recurred to date.

9503 Background: Combination anti-PD(L)1 and BRAF/MEK-targeted therapy (TT) improves PFS in stage IV melanoma vs TT. In stage IV melanoma recent data suggest immunotherapy 1st until progression, rather than BRAF-TT, improves OS, and induction TT upfront adds little benefit. NeoTrio explored the optimal combination of BRAF-TT and anti-PD1 using the NAT platform in pts with stage III melanoma (NCT02858921). Methods: 60 pts with resectable, RECIST measurable stage III (no in-transit) BRAF V600 -mutant melanoma were randomized 1:1:1 to 3 arms of 6 wks of NAT followed by complete lymph node dissection (CLND): A) Pembro ALONE (200mg Q3W x 2); B) SEQ - D+T (150mg bd + 2mg od) for 1 wk followed by pembro (200mg x 2); C) CON – D+T+pembro (doses as SEQ). Pts had 46 wks pembro post-CLND. Primary endpoint was the pathological response rate (pRR) and pathological complete response (pCR) at wk 6. Secondary endpoints; RECIST RR at wk 6, event-free survival (EFS), RFS, OS, adverse events (AE) and translational endpoints. Results: At data cutoff 2 Jan 2022, 20 pts per arm had similar baseline characteristics; overall 42% female, med age 53 yrs, 82% BRAF V600E, 62% clinical N1b. Med f/u was 20 months (95% CI 17-31). The pCR rate and pRR were highest in CON arm, and similar in ALONE and SEQ arms (Table). Events (progression before surgery, recurrence after surgery or death) were highest in ALONE arm at this 1st analysis (Table). Assessment of the durability of path response subtypes in each arm is ongoing. Most common Rx related AE were fatigue (65%, 70%, 70%, ALONE, SEQ and CON respectively), pyrexia (0%, 25%, 85%) and rash (50%, 35%, 35%). Gd 3/4 AE occurred in 30%, 25% and 55%, respectively; pyrexia and hepatitis were common in CON during NAT. Rx interruptions during NAT occurred in 0, 3 and 19 pts, respectively; 1, 0 and 8 pts permanently discontinued. Post NAT surgical operability was the same or improved in 81%. Longitudinal analysis of melanoma tissue, microenvironment and microbiome is ongoing. Conclusions: CON D+T+pembro achieved the highest pRR, pCR rate, but with greater toxicity. Recurrences were seen in those with pCR/near pCR in BRAF-TT containing arms, but not in pembro ALONE, in keeping with previous data of NAT with checkpoint inhibitors vs BRAF-TT. Short course of D+T prior to PD1 did not improve path response, despite previous translational data showing increased tumour infiltrating T-cells early-during treatment with D+T. Follow up is ongoing. Clinical trial information: NCT02858921. [Table: see text]

BackgroundHistorical studies of lymphatic drainage of the breast have suggested that the lymphatic drainage of the breast was to lymph nodes lying in the antero-pectoral group of nodes in the axilla just lateral to the pectoral muscles. The purpose of this study was to confirm this is not correct.MethodsThe hybrid imaging method of SPECT/CT allows the exact anatomical position of the sentinel lymph node (SLN) in the axilla to be documented during pre-operative lymphoscintigraphy (LS) in patients with breast cancer. We have done this in a series of 741 patients. The Level I axillary nodes were defined as anterior, mid or posterior. This was related to the anatomical location of the primary cancer in the breast.ResultsA SLN was found in the axilla in 97.8% of our patients. Just under 50% of SLNs located in the axilla were not in the anterior group and lay in the mid or posterior group of Level I axillary nodes. There was a SLN in a single node field in 460 patients (63%), two node fields in 261(36%), three node fields in 6 and four node fields in 1 patient.ConclusionAxillary lymphatic drainage from the breast is not exclusively to the anterior (or antero-pectoral) group of Level I nodes.SynopsisSPECT/CT lymphoscintigraphy shows that the breast does not always drain to the anterior group of Level I lymph nodes in the axilla but may drain to the mid axilla and/or posterior group in about 50% of patients with breast cancer regardless of the location of the cancer in the breast. These data redefine lymph drainage from the breast to axillary lymph nodes.

Survivorship care plans (SCPs) have been proposed for universal use with the aim of addressing the many unmet needs of cancer survivors. Trials have failed to find a significant impact of SCPs on quality of life outcomes. This study evaluated quality of life, unmet needs, satisfaction with health care and perception of cancer care coordination at the end of treatment in a cohort of women at the end of treatment for early breast cancer. The aim was to identify specific needs to assist in the design of a tailored SCP.Women completed patient-reported measures of health-related quality of life (FACT-B [ES]), unmet needs (CaSUN), satisfaction with medical care and cancer care coordination. Total scores and subscale scores for the whole cohort and results of analysis comparing three age groups were reported.Sixty-eight women (mean age 56) participated. Mean score for FACT-B = 108 and FACT-B (ES) = 167.4. Younger women (<51 years) reported a significantly lower quality of life (P = 0.001 for FACT-B, TOI and FACT-B [ES]). Using CaSUN, 76.1% of participants reported at least one unmet need; mean number of unmet needs = 6.2. Younger women reported more unmet needs than older women. The most frequently reported unmet need was fear of cancer recurrence. Overall, participants were very satisfied with medical care and cancer care coordination.Younger women reported poorer quality of life and more unmet needs. SCPs should specifically target younger women and must include strategies to address fear of cancer recurrence if they are to lead to a measureable difference in outcomes.

Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, >4 mm in thickness and those with nodal micrometastases at diagnosis, have few options for adjuvant treatment. Recent studies have suggested a role for vitamin D to delay melanoma recurrence and improve overall prognosis. This is a pilot placebo-controlled randomised phase II trial to assess the feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients who have been treated for cutaneous melanoma by wide excision of the primary. Patients aged 18 – 79 years who have completed primary surgical treatment and have Stage IIb, IIc, IIIa (N1a, N2a) or IIIb (N1a, N2a) disease are eligible for randomisation 2:1 to active treatment or placebo. The primary endpoints are sufficiency of dose, adherence to study medication and safety of the drug. The secondary endpoints are participation and progression free survival. The study has been approved by the Ethics Review Committee (RPAH Zone) of the Sydney Local Health District, protocol number X09-0138. Effective, non-toxic adjuvant therapy for high risk primary melanoma is not currently available. Favorable outcomes of this phase II study will form the basis for a multi-centre phase III study to assess whether the addition of oral high-dose vitamin D therapy in patients who have completed primary treatment for melanoma and are at high risk of recurrence will: 1. prolong time to recurrence within 5 years 2. improve overall survival at 5 years and 3. be both safe and tolerable. Target accrual for the study has been met with 75 patients randomised between December 2010 and August 2014. The Mel-D trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG 02.09). Australia and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000351213

<h2>Abstract</h2> Ductal carcinoma in situ (DCIS) is a pre-invasive breast cancer with excellent prognosis but with potential adverse impacts of diagnosis and treatment on quality of life and other patient-reported outcomes (PROs). We undertook a systematic review to synthesise current evidence about PROs following diagnosis and treatment for DCIS. We searched five electronic databases (from database inception to November 2015), cross-referenced and contacted experts to identify studies that reported PROs after DCIS treatment. Two reviewers independently applied inclusion and quality criteria, and extracted findings. Of 2130 papers screened, 23 were eligible, reporting 17 studies. Short- and long-term PRO evidence about differences between DCIS treatment options was lacking. Evidence pooled across treatments indicated core aspects of quality of life (physical, role, social, emotional function, pain, fatigue) and psychological distress (anxiety, depression) were impacted significantly initially, with most aspects returning to population norms by 6–12 months, and all by 2 years post-operatively. Fears of recurrence and dying from breast cancer were exaggerated, occurred early and persisted for many years. Sexuality and body image impacts were generally low and resolved within 1–3 months after surgery. A minority of women experienced considerable impact, including depression and sexual issues associated with body image problems. Well-powered PRO studies are required to track recovery trajectories and long-term impacts of the range of contemporary and emerging local and systemic treatments for DCIS. PRO data would enable care providers to prepare patients for short-term sequelae and enable patients who have treatment options to exercise preferences in choosing among them.

Detection of melanoma-associated mutations using circulating tumor DNA (ctDNA) from plasma is a potential alternative to using genomic DNA from invasive tissue biopsies. In this study, we developed a custom melanoma next-generation sequencing (NGS) panel which includes 123 amplicons in 30 genes covering driver and targetable mutations and alterations associated with treatment resistance. Analysis of a cohort of 74 stage III and IV treatment-naïve melanoma patients revealed that sensitivity of ctDNA detection was influenced by the amount of circulating-free DNA (cfDNA) input and stage of melanoma. At the recommended cfDNA input quantity of 20 ng (available in 28/74 patients), at least one cancer-associated mutation was detected in the ctDNA of 84% of stage IV patients and 47% of stage III patients with a limit of detection for mutant allele frequency (MAF) of 0.2%. This custom melanoma panel showed significant correlation with droplet digital PCR (ddPCR) and provided a more comprehensive melanoma mutation profile. Our custom panel could be further optimized by replacing amplicons spanning the TERT promoter, which did not perform well due to the high GC content. To increase the detection rate to 90% of stage IV melanoma and decrease the sensitivity to 0.1% MAF, we recommend increasing the volume of plasma to 8 mL to achieve minimal recommended cfDNA input and the refinement of poorly performing amplicons. Our panel can also be expanded to include new targetable and treatment resistance mutations to improve the tracking of treatment response and resistance in melanoma patients treated with systemic drug therapies.

9501 Background: In the OpACIN-neo study, 2 cycles neoadjuvant (neoadj) IPI 1mg/kg + NIVO 3mg/kg (I1N3) have been identified as most favorable dosing scheme with a pathologic response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 24.6 months median follow-up (FU), the 2-year (2y) RFS was 96.9% for patients (pts) with pathologic response versus 35.5% for non-responders (&gt;50% viable tumor; pNR). These data raised the question whether therapeutic lymph node dissection (TLND) could be safely omitted in pts achieving a major pathologic response (MPR; ≤10% viable tumor) in their index node (ILN; largest LN metastasis at baseline), and if additional adjuvant (adj) therapy could improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the phase 2 OpACIN-neo study aiming to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with stage III melanoma were included to receive 2 cycles neoadj I1N3 after marker placement in the ILN. ILN resection was planned at week 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with partial response (pPR; &gt;10 – ≤50% viable tumor) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or dabrafenib plus trametinib (D+T) for 52 weeks ±radiotherapy (RT). Primary endpoints were pRR in the ILN and RFS at 2y. The 2y RFS rates were calculated using a Kaplan Meier based method. Results: Between Nov 2018 and Jan 2020, 99 patients were enrolled and treated with at least 1 cycle of neoadj I1N3. We previously showed a pRR of 72% (95% CI 62 - 80), including 60 (61%) pts with MPR and 11 (11%) pts with pPR. TLND omission in MPR pts resulted in significant reduced surgical morbidity and improved quality of life. There were 27 non-responders of whom 6 developed distant metastasis before ILN resection. Of the other 21 pNR pts, 7 received adj NIVO, 10 adj D+T, 3 no adj therapy, and 1 was lost to FU. After a median FU of 27.9 months (data cutoff Jan 31, 2022), the estimated 2y RFS rate for MPR pts was 93.3% (95% CI 87.2 – 99.9), with 4/60 pts developing a regional relapse. Distant metastasis-free survival (DMFS) was 100%. Of the 11 pPR pts, 4 developed a relapse (all distant), resulting in a 2y RFS and DMFS rate of 63.6% (95% CI 40.7 – 99.5). The 2y RFS rate of the pNR pts was 71.4% (95% CI 54.5 – 93.6), and DMFS 76.2%. At data cutoff, relapse occurred in 2/7 pNR pts with adj NIVO and 3/10 with adj D+T. Final data cutoff is planned mid Feb, 2022. Conclusions: MPR pts in whom TLND was omitted showed a 2y RFS rate of 93.3% and DMFS of 100%, indicating that the ILN procedure and omitting adj therapy could become a safe approach in these pts. Adj systemic therapy in pNR pts seems to improve RFS as compared to historic control (OpACIN-neo), thus should be considered in this unfavorable pNR group. The DMFS rate of 63.6% observed in the pPR group advocates the consideration of adj therapy also for this subgroup in the future. Clinical trial information: NCT02977052.

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P < 0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

Targeted therapy directed at driver oncogenic mutations offers an effective treatment option for select patients with metastatic melanoma. The aim of this study was to assess the prevalence of clinically significant somatic mutations, specifically BRAF, NRAS and KIT, in a large cohort of Australian patients with metastatic melanoma. We performed a cross-sectional cohort study of consecutive patients with American Joint Committee on Cancer (AJCC) stage IIIc unresectable or stage IV melanoma managed at Melanoma Institute Australia, and affiliated sites, that underwent molecular testing between 22 June 2009 and 19 July 2013. Additionally, we examined the change in BRAF testing methodology and patient population over time, and how this influenced the prevalence of mutations. A total of 767 molecular tests were conducted for 733 patients. BRAF V600 mutation testing was performed for 713 patients (97.2%), with an overall mutation prevalence of 37.7% (269/713); 74.3% (200/269) were the V600E genotype and 22.3% (60/269) V600K. The BRAF mutation prevalence and proportion of BRAF V600E and V600K genotypes varied across the study period, as did testing methodology and the median age of the cohorts. Of 222 patients who underwent NRAS testing, 58 (26.1%) had a mutation identified. The overall prevalence of KIT mutations was 3.7% (11/296). In Australia the prevalence of BRAF mutations is lower than initially reported, although this remains the most common mutation identified in metastatic melanoma and an important therapeutic target. NRAS mutations are more prevalent than initially described; however, other mutations reported in melanoma, including KIT, are rare in an unselected population of patients.

Background: Combination D+T improves the overall survival (OS) of patients (pts) with BRAF V600 mutant advanced melanoma, and an adjuvant trial is in progress (NCT01682083). We sought to explore neoadjuvant D+T for pts with bulky but resectable stage III melanoma.

•The extent and composition of the pathological response after neoadjuvant DT in BRAFV600E/K melanoma correlates with RFS.•Patients achieving pCR had longer RFS compared with patients who did not.•Hyalinized fibrosis correlated with longer RFS, while necrosis and proliferative fibrosis correlated with shorter RFS.•Absence of pCR or presence of immature fibrosis independently predicted shorter RFS.•Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS. BackgroundRecent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse.MethodsSurgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes.ResultsFifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035).ConclusionsThe extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy. Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

10015 Background: Early results of the OpACIN-neo study testing 3 different dosing schedules of neoadjuvant IPI + NIVO demonstrated that 2 cycles IPI 1mg/kg + NIVO 3mg/kg (IPI1NIVO3, arm B) was the most favorable schedule with 20% grade 3-4 immunotherapy-related adverse events (irAEs) and a pathologic response rate (pRR) of 77%. After a median follow-up (FU) of 8.3 months, none of the 64 patients (pts) with a pathologic (path) response ( &lt; 50% viable tumor cells) versus 9/21 (43%) without a path response had relapsed. Here, we present the updated 2-year RFS, EFS and long-term toxicity data. Methods: In the phase 2 multi-center OpACIN-neo trial, 86 stage III melanoma pts with resectable and RECIST 1.1 measurable lymph node metastasis were randomized between 3 different dosing schedules of neoadjuvant IPI + NIVO: arm A: 2x IPI3+NIVO1 Q3W (n = 30), arm B: 2x IPI1+NIVO3 Q3W (n = 30), and arm C: 2x IPI3 Q3W followed by 2x NIVO3 Q2W (n = 26). Lymph node dissection was scheduled at week 6. Primary endpoints were toxicity, radiologic RR and pRR; RFS and EFS were secondary endpoints. Results: After a median FU of 24.6 months, the median RFS and EFS was not reached in any of the 3 arms. In total, 2 pts progressed before surgery, 12 pts relapsed (11 pts without path response and 1 pt with pCR) and 5 pts died (4 due to melanoma and one pt due to toxicity). Estimated 24-months RFS was 84% (95% CI 76-92%) for the total population, 97% (95% CI 93-100%) for pts with a path response and 36% (95% CI 17-74%) for pts without a path response. Estimated 24-months EFS for the total population was 82% (95% CI 74-91%). RFS and EFS did not differ between the arms. Of the 81 pts alive, 55 (68%) have ongoing irAEs; only 2 (3%) pts have ≥ grade 3 irAEs. Most frequent ongoing irAEs were vitiligo (35%), fatigue (14%), sicca syndrome (11%), rash (10%), arthralgia (7%) and endocrine toxicities (20%). 17 pts need hormone replacement therapy: 11 (14%) thyroid hormone and 7 (9%) hydrocortisone. No difference between treatment arms was observed. Ongoing surgery-related AEs were observed in 31 (38%) pts of which lymphedema was seen most frequently (17 pts; 21%). Conclusions: Extended follow-up data shows that 2 cycles of neoadjuvant IPI + NIVO without adjuvant therapy induces durable RFS. While almost no ongoing high-grade irAEs were observed, the majority of pts have low-grade ongoing toxicities. These outcomes strongly support the need to test 2 cycles of neoadjuvant IPI1+NIVO3 versus adjuvant anti-PD-1 in a randomized phase 3 trial. Clinical trial information: NCT02977052.

Triple-negative breast cancer (TNBC) is a group of breast cancers which neither express hormonal receptors nor human epidermal growth factor receptor. Hence, there is a lack of currently known targeted therapies and the only available line of systemic treatment option is chemotherapy or more recently immune therapy. However, in patients with relapsed disease after adjuvant or neoadjuvant therapy, resistance to chemotherapeutic agents has often developed, which results in poor treatment response. Multidrug resistance (MDR) has emerged as an important mechanism by which TNBCs mediate drug resistance and occurs primarily due to overexpression of ATP-binding cassette (ABC) transporter proteins such as P-glycoprotein (Pgp). Pgp overexpression had been linked to poor outcome, reduced survival rates and chemoresistance in patients. The aim of this mini-review is to provide a topical overview of the recent studies and to generate further interest in this critical research area, with the aim to develop an effective and safe approach for overcoming Pgp-mediated chemoresistance in TNBC.

Refining eligibility guidelines may identify more appropriate patients to undergo useful medical procedures.To improve cost-effectiveness in selecting patients with melanoma for sentinel lymph node biopsy (SLNB).This hybrid prognostic study/decision analytical model was conducted among patients with melanoma who were eligible for SLNB at 2 melanoma centers from Australia and the US from 2000 to 2014. Participants consisted of 2 cohorts of patients with melanoma undergoing SLNB and a cohort of eligible patients without SLNB. Individualized probabilities of SLNB positivity generated by a patient-centered methodology (PCM) were compared with those generated by conventional multiple logistic regression analysis investigating 12 prognostic factors. Prognostic accuracy was assessed by the area under the receiver operating characteristic curve (AUROC) for each methodology and by matched-pair analyses.Triaging appropriate patients to undergo SLNB.Total number of SLNBs performed (giving total cost) vs number of SLNB-positive outcomes (a measure of effectiveness) was evaluated. Improved cost-effectiveness through judicious patient selection was interpreted as increased numbers of SLNB-positive outcomes achieved, decreased numbers of SLNBs performed, or both outcomes simultaneously.Among 7331 patients with melanoma, SLNB outcomes were assessed in 3640 Australian patients (2212 males [60.8%]; 2447 aged >50 years [67.2%]) and 1342 US patients (774 males [57.7%]; 885 aged >50 years [66.0%]); 2349 patients eligible for SLNB who did not undergo the procedure were included in the simulation. PCM-generated probabilities achieved an AUROC of 0.803 in predicting SLNB positivity in the Australian cohort and 0.826 in the US cohort, higher than corresponding AUROCs generated by conventional logistic regression analysis. In simulation, adopting many SLNB-positive probabilities as minimally acceptable patient-selection criteria resulted in fewer procedures performed or increased the expected numbers of positive SLNBs. A minimally acceptable PCM-generated probability of 8.7% elicited the same number of SLNBs as historically performed (3640 SLNBs), with 1066 positive SLNBs (29.3%), constituting an improvement of 287 additional positive SLNBs compared with 779 actual positive SLNBs (36.8% improvement). In contrast, adopting a 23.7% PCM-generated minimum cutoff probability resulted in performing 1825 SLNBs, or 1815 fewer SLNBs than the actual experience (49.9%). It resulted in the same expected number of positive results (779 SLNBs), for a 42.7% positivity rate.This prognostic study/decision analytical model found that the PCM approach outperformed conventional multiple logistic regression analysis in predicting which patients would have positive results on SLNB. These findings suggest that systematically producing and exploiting more accurate SLNB-positivity probabilities could improve the selection of patients with melanoma for SLNB compared with using established guidelines, thus improving the cost-effectiveness of the selection process. Eligibility guidelines to undergo SLNB should include a context-tailored minimum cutoff probability.

TPS9605 Background: Adjuvant (adj) immune checkpoint inhibition (ICI) improves relapse free survival (RFS) in stage III melanoma patients (pts). However, preclinical and translational data suggest that neo-adjuvant (neoadj) treatment might be favorable due to broader immune activation. The phase 1b OpACIN study comparing neoadj to adj IPI plus NIVO demonstrated a high pathological response rate (pRR) of 78% complicated by 90% gr 3-4 immune-related adverse events (irAEs). The phase 2 OpACIN-neo trial tested safety and efficacy of three different schemes of neoadj IPI+NIVO and identified two cycles of IPI 1mg/kg + NIVO 3mg/kg as well tolerated (20% gr 3-4 irAEs), with a high pRR of 77%. In both trials, none of the pts with a pathologic response have relapsed after a median follow-up of 30 and 8.3 months. In stage IV melanoma, long-term benefit is observed in patients achieving CR with ICI, even after cessation of therapy. This raises the question of whether a therapeutic lymph node dissection (TLND) can be omitted when a deep pathologic response with neoadj IPI+NIVO is achieved. Methods: The aim of this international multi-center investigator-initiated phase 2 PRADO extension study is to confirm the pRR and toxicity of 2 cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg (the preferred OPACIN-neo regimen) and to test response-driven subsequent therapy i.e. omitting surgery and adjuvant ICI based on the pathological response. 100-110 pts with stage IIIB/C melanoma and a measurable lymph node (≥15mm according to RECIST 1.1) will receive two cycles of IPI 1mg/kg + NIVO 3mg/kg after marker placement into the largest lymph node metastasis. After six weeks, pts will undergo resection of the index lymph node. For pCR/near pCR, pts will not undergo TLND; For pPR, pts will undergo TLND; and for pNR, pts will undergo TLND and start adjuvant NIVO or targeted therapy +/- radiotherapy for 52 weeks. Primary endpoints are pRR of marked lymph node and RFS at 24 months. Baseline biopsies, blood samples (week 0, 6, 12) and faeces (week 0, 6) will be collected for translational research analyses. The first patient in this trial was included in October 2018; 22 patients have been enrolled. Clinical trial information: NCT02977052.

The use of circulating tumor DNA (ctDNA) to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing (WES) of ctDNA could accurately profile the mutation landscape of metastatic melanoma. We used WES to identify variants in matched, tumor-derived genomic DNA (gDNA) and plasma-derived ctDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and ctDNA. The mutant allele frequency of common single nucleotide variants was lower in ctDNA, reflecting the lower read depth and minor fraction of ctDNA within the total circulating free DNA pool. There was also variable concordance between gDNA and ctDNA based on the total number and identity of detected variants and this was independent of the tumor biopsy site. Nevertheless, established melanoma driver mutations and several other melanoma-associated mutations were concordant between matched gDNA and ctDNA. This study highlights that WES of ctDNA could capture clinically relevant mutations present in melanoma metastases and that enhanced sequencing sensitivity will be required to identify low frequency mutations.

Gene expression profiling is increasingly being utilised as a diagnostic, prognostic and predictive tool for managing cancer patients. Single-sample scoring approach has been developed to alleviate instability of signature scores due to variations from sample composition. However, it is a challenge to achieve comparable signature scores across different expressional platforms.The pre-treatment biopsies from a total of 158 patients, who have received single-agent anti-PD-1 (n = 84) or anti-PD-1 + anti-CTLA-4 therapy (n = 74), were performed using NanoString PanCancer IO360 Panel. Multiple immune-related signature scores were measured from a single-sample rank-based scoring approach, singscore. We assessed the reproducibility and the performance in reporting immune profile of singscore based on NanoString assay in advance melanoma. To conduct cross-platform analyses, singscores between the immune profiles of NanoString assay and the previous orthogonal whole transcriptome sequencing (WTS) data were compared through linear regression and cross-platform prediction.singscore-derived signature scores reported significantly high scores in responders in multiple PD-1, MHC-1-, CD8 T-cell-, antigen presentation-, cytokine- and chemokine-related signatures. We found that singscore provided stable and reproducible signature scores among the repeats in different batches and cross-sample normalisations. The cross-platform comparisons confirmed that singscores derived via NanoString and WTS were comparable. When singscore of WTS generated by the overlapping genes to the NanoString gene set, the signatures generated highly correlated cross-platform scores (Spearman correlation interquartile range (IQR) [0.88, 0.92] and r2 IQR [0.77, 0.81]) and better prediction on cross-platform response (AUC = 86.3%). The model suggested that Tumour Inflammation Signature (TIS) and Personalised Immunotherapy Platform (PIP) PD-1 are informative signatures for predicting immunotherapy-response outcomes in advanced melanoma patients treated with anti-PD-1-based therapies.Overall, the outcome of this study confirms that singscore based on NanoString data is a feasible approach to produce reliable signature scores for determining patients' immune profiles and the potential clinical utility in biomarker implementation, as well as to conduct cross-platform comparisons, such as WTS.

Introduction Neoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored to minimise morbidity and optimise oncological outcomes and quality of life. Accurate information about locoregional treatments following neoSACT is vital to allow the translation of downstaging benefits into practice and facilitate meaningful interpretation of oncological outcomes, particularly locoregional recurrence. Reporting of locoregional treatments in neoSACT studies, however, is currently poor. The development of a core outcome set (COS) and reporting guidelines is one strategy by which this may be improved. Methods and analysis A COS for reporting locoregional treatment (surgery and radiotherapy) in neoSACT trials will be developed in accordance with Core Outcome Measures in Effectiveness Trials (COMET) and Core Outcome Set-Standards for Development guidelines. Reporting guidance will be developed concurrently. The project will have three phases: (1) generation of a long list of relevant outcome domains and reporting items from a systematic review of published neoSACT studies and interviews with key stakeholders. Identified items and domains will be categorised and formatted into Delphi consensus questionnaire items. (2) At least two rounds of an international online Delphi survey in which at least 250 key stakeholders (surgeons/oncologists/radiologists/pathologists/trialists/methodologists) will score the importance of reporting each outcome. (3) A consensus meeting with key stakeholders to discuss and agree the final COS and reporting guidance. Ethics and dissemination Ethical approval for the consensus process will be obtained from the Queen’s University Belfast Faculty Ethics Committee. The COS/reporting guidelines will be presented at international meetings and published in peer-reviewed journals. Dissemination materials will be produced in collaboration with our steering group and patient advocates so the results can be shared widely. Registration The study has been prospectively registered on the COMET website ( https://www.comet-initiative.org/Studies/Details/2854 ).

Metastatic breast cancer in the internal mammary nodes (IMN) indicates a poor prognosis. Several recent epidemiological surveys have determined a reduction in survival for patients with medial compared to lateral sector tumors attributing this to a higher rate of unrecognized IMN metastasis and hence these patients are undertreated with adjuvant therapy.(1-6)Through mathematical modeling based on large datasets we aim to quantify the impact on survival of IMN metastases at different tumor and axillary stages.Mathematical models were created to estimate the survival of patients with and without IMN metastasis. It was assumed that the different rate of survival between medial and lateral sector breast cancers was a result of the differential rate of unrecognized IMN metastases with resultant under-staging and under treatment. We applied these models on a retrospective database analysis from the Surveillance, Epidemiology and End-Results (SEER) registries from 1994 to 2003.The 10-year odds of death (OOD) from breast cancer for patients with medial compared with lateral sector tumors ranged from 1.2 to 1.5 depending on stage. The predicted odds of breast cancer death for patients with unrecognized IMN metastases ranged from 2.4 to 20, with the highest OOD in the groups with small tumors and no axillary node metastasis.Through modeling we have been able to predict and quantify the significantly worse survival outcomes for patients with undiagnosed IMN metastasis.

Neoadjuvant anti-PD-1 (PD1) induces a pathological complete response (pCR) in 20% and any pathological response (pRR) in 34% of stage III pts, with durable survival in responders. Improvements are needed to overcome primary resistance. NeoPele sought to determine if additional clinical benefit can be achieved by adding lenva to pembro using the NAT platform in pts with stage III melanoma (NCT04207086). 20 pts with resectable, RECIST measurable stage III nodal melanoma received 6 wks of NAT with pembro (200mg, IV, Q3W) and lenva (20mg, po, od), then a lymph node dissection (LND), then 46 wks pembro. CT + PET scans were performed at baseline and wk 6; CT was continued 12 wkly to 2 yrs. Primary endpoint was pCR and pRR at wk 6. Secondary endpoints; RECIST RR at wk 6, event-free survival (EFS), relapse free survival (RFS), OS, toxicity and translational endpoints. At data cut off 31 Mar 2022, 20 pts analysed: 30% female, med age 64.7 yrs, 3 (15%) BRAF V600E, 8 (40%) NRAS, 10 (50%) clinical N1b. Med f/u was 11.2 months (95% CI 10.2 - 13.8). 8/20 (40%) pts had pCR and 15/20 (75%) had any path response (Table). Events occurred in 4 pts; 1 had brain metastasis prior to LND with pPR, and 3 post surgery with pNR. Most common toxicities were fatigue (9, 45%), hypertension (8, 40%), headache (6, 30%) and anorexia (5, 25%) due to lenva; 45% were gd 3/4, most commonly hypertension (5, 25%). Most common surgical events were seroma (4, 20%) and lymphoedema (7, 35%), with no DVTs. 4 pts interrupted lenva and 0 permanently discontinued during NAT. Post NAT surgical operability was the same or improved in 13 (65%) pts, and harder in 7 (35%). Longitudinal analysis of melanoma tissue, microenvironment and microbiome is ongoing.Table: 793PPembro+Lenva (n=20)pRR pCR Near pCR pPR pNR15 (75%) 8 (40%) 3 (15%) 4 (20%) 5 (25%)RECIST ORR/CR35% / 5%No. Events4 (20%)No. Recurred/Progressed by pCR/near-pCR/pPR/pNR0/0/1ˆ/3No. Death11-yr EFS (95% CI)80% (95% CI 64-99%)ˆ1 pt progressed in brain prior to surgery but had LND. Open table in a new tab ˆ1 pt progressed in brain prior to surgery but had LND. A high pCR and pRR rate was observed with NAT pembro+lenva, higher than previous studies of PD1 alone. The trial and translational investigations are ongoing, and RFS and OS data will be collected.

To examine the impact of breast reconstruction on women's perceptions of body image over time and to assess the influence of sociodemographic variables on body image.A prospective, longitudinal cohort study, using validated breast cancer-specific questionnaires, to compare patient-reported outcomes in women choosing immediate (n = 61), delayed (n = 16) or no (n = 23) breast reconstruction.One hundred women completed baseline questionnaires that included items on body image; 30 women completed all four annual follow-up sets, while 20 women completed baseline only. The three groups were well matched at baseline and similar trajectories in body image measures were identified over 48 months in all groups. At 12 months post-mastectomy, significant changes were seen in eight of the 10 subscales; this reduced to seven subscales at 24 months and four at 36 months. By 48 months, only three subscales remained significantly different to baseline scores: women remained less vulnerable and had fewer limitations (improved outcomes); the one worse outcome was persistently higher levels of arm concern. Three of the sociodemographic variables (health insurance, age and employment status) showed significant inter-group differences at some time points.These findings suggest women recover from the negative impact of mastectomy on body image within four years of surgery, whether they have immediate, delayed or no reconstruction. Our results provide some indirect evidence that having a choice of BR options is important, regardless of the choice made. Four years appears to be a suitable follow-up period for future studies in this area.

572 Background: Selective use of radiotherapy (RT) after surgery for early breast cancer (EBC) has been an elusive goal. The role of breast MRI in localised EBC is controversial. We aimed to determine if preoperative MRI could identify patients with EBC in whom the ipsilateral invasive recurrence (IIR) rate was sufficiently low without RT, such that RT might be safely omitted. Here we report primary and secondary outcomes, and imaging/biopsy findings for occult lesions. Methods: PROSPECT is a prospective single-arm study. Criteria for omission of RT included age at least 50, nil/minimal or mild Background Parenchymal Enhancement (BPE) on MRI, unifocal pT1N0 cancer, not Triple Negative (TNBC), no LVI. All patients who underwent PROSPECT MRI were included in the analysis. Imaging findings on MMG, US and MRI were documented and all biopsies were recorded. Pathology of lesions identified by MRI was described. The primary outcome was the IIR at 5 years of those treated without RT. An IIR rate of 5% or less was considered acceptable. The protocol specified primary analysis occurred after the 100 th patient reached 5 years follow up in May 2021. Results: Between 9/2011 and 5/2019, 443 patients had MRI after diagnosis. BPE was nil/minimal or mild in 344 patients. MRI detected 194 occult lesions in 144 (33%) patients; 139 (72%) were ipsilateral. 61 MMG/US occult malignant lesions - 36 invasive and 25 DCIS - were identified in 48 patients (11% of total cohort). Of 38 ipsilateral lesions in 32 patients (7% of total cohort), 23 were DCIS, 4 were T1a, 7 T1b and 4 T1c. 201 patients were treated on trial without RT. The median age was 63 years (range: 50 to 84), median tumour size 11 mm (range: 2 to 20), grade 1 (104), grade 2 (86) or grade 3 (11). The rate of IIR at 5 years was 1% (1/101). There were 2 IIRs at 4.6 and 7.7 years follow up, 1 regional recurrence, and 1 patient with both a regional and distant recurrence with 1 breast cancer death. There was 1 contralateral (CL) breast cancer, 1 CL DCIS, 2 other cancer diagnoses and 1 death from other causes. Of 242 patients undergoing MRI but not in the main study, median age was 63 range: 50-80, median tumour size, 13mm (range: 4-145). 9 underwent mastectomy (2% of total cohort). Followup is complete for 235. There was 3 IIR, 3 CL primary and no distant metastases or breast cancer deaths. Conclusions: Breast MRI in selected, low risk patients identified occult malignancy in 11% of patients. At a median of 5 years follow up the IIR and other breast cancer events was very low. This suggests that local recurrences may be due to occult breast cancers, and MRI may allow the identification of truly localised cancers for which radiation may be safely omitted. The event rate for the entire cohort was very low, suggesting that identification of occult malignancy in apparently unifocal EBC is beneficial. Confirmatory trials are needed. Clinical trial information: 12610000810011.

Survivorship care after breast cancer treatment is increasingly complex as it aims to manage the long term effects of cancer and its treatment, including psychosocial needs. While survivorship care is traditionally delivered by surgeons and specialist oncologists in Australia, general practitioners are ideally placed to manage these issues.This study explored the attitudes of 20 breast cancer survivors to GP involvement in follow up care through semi-structured telephone interviews, which were analysed using qualitative methods.Women were reluctant to change from specialist based care but identified many potential benefits of GP involvement in long term cancer care. They expressed an interest in shared care programs between specialists and GPs. Some participants thought that additional training may be required if GPs were to deliver this care.This study shows cautious interest from breast cancer survivors for increasing GP involvement in follow up care. These views should be considered as alternative models of care are developed.

Background: Neoadjuvant systemic therapy (NAST) is an increasingly used treatment option for women with large operable or highly proliferative breast cancer.With equivalent survival outcomes between NAST and up-front surgery, the situation-specific preference-sensitive nature of the decision makes it suitable for a decision aid (DA).This study aimed to develop and evaluate a DA for this population.Methods: A DA booklet was developed according to international standards, including information about adjuvant and neoadjuvant treatment, outcome probabilities, and a values clarification exercise.Eligible women, considered by investigators as candidates for NAST, were enrolled in a multi-institutional, single-arm, longitudinal study.Patient-reported outcome measure questionnaires were completed preand post-DA, between chemotherapy and surgery, and at 12 months.Outcomes were feasibility (percentage of eligible patients accessing the DA); acceptability to patients (percentage who would recommend it to others) and clinicians (percentage who would use the DA in routine practice); and decision-related outcomes.Results: From 77 eligible women, 59 were enrolled, of whom 47 (79.7%; 95% CI, 69.4-89.9)reported having read the DA; 51 completed the first post-DA questionnaire.Of these 51, 41 participants (80.4%; 95% CI, 69.5-91.3)found the DA useful for their decision about NAST.Of 18 responding investigators, 16 (88.9%;95% CI, 74.4-103.4)indicated they would continue to use the DA in routine practice.Post-DA, decisional conflict decreased significantly (P<.01); anxiety and distress decreased significantly; and 86.3% (95% CI, 73.7-94.3)achieved at least as much decisional control as they desired.Conclusions: This DA was feasible and acceptable to patients and clinicians, and improvement in decision-related outcomes was demonstrated when used in combination with clinical consultations.This DA could safely be implemented into routine practice for women considering NAST for operable breast cancer.

TPS10087 Background: Previous OpACIN and OpACIN-neo studies, investigating neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO), demonstrated high pathologic response rates (74-78%) and favorable long-term outcomes in patients (pts) achieving pathologic response; at 36 and 18 months follow-up, respectively, only 1/71 (1.4%) pts with response has relapsed. In contrast, pts without pathologic response (pNR) have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline interferon-gamma (IFN-γ) signature low pts were less likely to respond to neoadjuvant IPI plus NIVO. The DONIMI study tests the combination of NIVO +/- IPI with domatinostat (DOM), a class 1 histone deacetylase inhibitor, according to the IFN-γ signature in the tumor. Based on the signature previously described by Ayers et al. we have developed a neoadjuvant IFN-γ signature algorithm that will be used for the first time to classify pts in this prospective trial. Methods: The aim of this two-center investigator-initiated phase 1b study is to assess the safety and feasibility of neoadjuvant NIVO +/- DOM +/- IPI in 45 stage III melanoma pts with RECIST 1.1 measurable de-novo or recurrent disease. IFN-γ signature high pts (n = 20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240mg q3wk) or Arm B (2 cycles NIVO 240mg q3wk + DOM 200mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n = 25) will be randomized to Arm C (2 cycles NIVO 240mg q3wk + DOM 200mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240mg q3wk + IPI 80mg q3wk + DOM 200mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 pts cannot adhere to the preplanned time of surgery (week 6 +/- 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. The first patient was enrolled on January 23 th , 2020. Clinical trial information: NCT04133948.

BackgroundDuctal carcinoma in situ (DCIS) is an in-situ (pre-cancerous) breast malignancy whereby malignant cells are contained within the basement membrane of the breast ducts. Increasing awareness that some low-risk forms of DCIS might remain indolent for many years has led to concern about overtreatment, with at least 3 clinical trials underway internationally assessing the safety of active monitoring for low-risk DCIS. This study aimed to understand healthcare professionals’ (HCPs) views on the management options for patients with DCIS.MethodsQualitative study using semi-structured interviews with HCPs involved in the diagnosis and management of DCIS in Australia and New Zealand. Interviews were audio-recorded, transcribed and analysed thematically using Framework Analysis method.ResultsTwenty-six HCPs including 10 breast surgeons, 3 breast physicians, 6 radiation oncologists, and 7 breast care nurses participated. There was a strong overall consensus that DCIS requires active treatment. HCPs generally felt uncomfortable recommending active monitoring as a management option for low-risk DCIS as they viewed this as outside current standard care. Overall, HCPs felt that active monitoring was an unproven strategy in need of an evidence base; however, many acknowledged that active monitoring for low-risk DCIS could be appropriate for patients with significant co-morbidities or limited life expectancy. They believed that most patients would opt for surgery wherever possible.ConclusionsThis study highlights the important need for robust randomised controlled trial data about active monitoring for women with low-risk DCIS, to provide HCPs with confidence in their management recommendations and decision-making.

Many studies have demonstrated the positive impact of breast reconstruction (BR) on women following mastectomy for breast cancer. However, women's preferences for BR are not always considered by surgeons prior to mastectomy. The aim of this research is threefold: to document the negative impact lack of choice has had on some Australian women; to explore potential reasons for the absence of informed discussion; and to develop a prompt list of discussion topics to aid informed decision making.This research is part of a larger study using semistructured telephone or face-to-face interviews with women with breast cancer, surgeons, and health professionals to explore ways of improving access to BR. This article focuses on responses from all 22 women who reported negative BR experiences and seven of 31 surgeons who had made comments relevant to limiting BR discussion and choice.The impact of a lack of information or choice at the time of mastectomy was often extreme and long-term. Breast surgeons are the gate keepers to accessing BR but too often appeared to limit women's choices. Interviews revealed cases where BR was not offered prior to mastectomy, even though it was available locally; where BR was not available locally, but patients were not informed about BR options available in other locations; where only delayed BR options were discussed; and where the type of BR being offered did not match patient preferences.We have suggested essential BR discussion points to be raised with all clinically eligible women interested in considering BR.

9583 Background: Combination D+T improves the overall survival (OS) of patients (pts) with V600 BRAF-mutation positive advanced melanoma. D+T is currently being explored in an adjuvant study of pts with resected stage III melanoma (NCT01682083). We sought to explore neoadjuvant D+T for pts with bulky but resectable stage III melanoma (NCT01972347). Methods: In this phase 2 study, all pts received D (150 mg twice daily) + T (2 mg once daily) for 12 wks prior to complete resection of the pre-therapy tumour bed (RES), then 40 wks of further D+T. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1 with histologically confirmed resectable bulky stage IIIB/C BRAF V600E/K mutant melanoma. CT and PET scans were performed at baseline and 12 wks just prior to RES for RECIST and metabolic complete response (rCR and mCR respectively). CT monitoring was continued 12 wkly thereafter to 2 yrs then 6 mnthly to 3 yrs. Biopsies were taken at baseline and wk 1. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints were surgical morbidity, mCR, relapse free survival (RFS), OS, toxicity and translational endpoints. Results: At data cut 4 Jan 2016, 19 had commenced D+T. 14 had reached RES (10 stage IIIC [2 in-transit only], 4 IIIB; 12 V600E, 1 V00K, 1 V600). At RES, 6/14 (43%) had pCR, 5/14 (36%) had rCR (rRR 93%), and 7/14 (50%) had mCR. All 6 pts with pCR had mCR, but 2 did not have rCR. No pt progressed during neoadjuvant treatment. 2/14 pts recurred in the resected field 12 and 36 wks after RES on D+T. These pts had the highest ctDNA at baseline. 8/14 (57%) had ≥ 1 surgical complication post RES; 8 had a wound infection requiring antibiotics, 5 had a seroma, 2 bled (1 wound evacuation). 11/14 had a post RES drain (median drain time 27d). 12/14 (86%) interrupted D+T in the first 12 wks for a median of 7d, 9 due to pyrexia ( ≥ 38.5oC). 1 pt ceased D+T at wk 28 due to renal failure. Conclusions: A high rate of pCR was observed with neoadjuvant D+T for resectable stage III melanoma. pCR correlated with mCR, but not rCR. Surgical complication rates were consistent with historic controls and stage of disease. The trial and translational research is ongoing, and ease of resection, RFS and OS data are being collected. Clinical trial information: NCT01972347.

Abstract Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

Abstract Introduction The outcome of high-risk stage III melanoma patients was poor with a 5-year overall survival (OS) rate of &amp;lt;50%. Adjuvant ipilimumab (IPI) improved the relapse-free survival (RFS) and OS, and adjuvant anti-PD-1 improved the RFS further. Preclinical data suggested that neoadjuvant therapy may be more effective than adjuvant therapy due to broader immune activation. The OpACIN trial compared neoadjuvant IPI plus nivolumab (NIVO) versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO only. Neoadjuvant IPI plus NIVO induced high pathologic response rates of 74-78%. Here, we present the 36- and 18-months RFS update of the OpACIN and OpACIN-neo trial, respectively. Methods The phase 1b OpACIN trial randomized 20 stage IIIB/IIIC melanoma patients to receive either 4 cycles of adjuvant IPI 3 mg/kg plus NIVO 1 mg/kg or 2 cycles of neoadjuvant IPI plus NIVO at the same dose followed by 2 cycles adjuvant IPI plus NIVO. In the OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), and arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as &amp;lt;50% viable tumor cells and centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method. Results After a median follow-up of 36 months for the OpACIN and 18 months for the OpACIN-neo trial, only 1 of 71 patients (1.4%) with a pathologic response on neoadjuvant therapy had relapsed, versus 15 of 23 patients (65.2%) without a pathologic response. The estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm in the OpACIN trial. The median RFS was not reached in any of the arms within the OpACIN-neo trial. Estimated 18-months RFS rate was 85% (95% CI: 78%-93%) for all patients; for arm A 90% (95% CI: 80%-100%), for arm B 82% (95% CI: 70%-98%) and for arm C 83% (95% CI: 70%-100%). Translational analyses showed that tumor mutational burden and interferon-γ gene expression score at baseline, both separate and combined, can function as predictors of response. Conclusions OpACIN showed for the first time a potential benefit of neoadjuvant versus adjuvant immunotherapy, while OpACIN-neo confirmed the high pathologic response rates which can be achieved by neoadjuvant IPI plus NIVO. Both trials argue for pathologic response as a surrogate markers for RFS. Clinical trial information: NCT02437279, NCT02977052 Citation Format: Christian U. Blank, Judith M. Versluis, Elisa A. Rozeman, Alexander M. Menzies, Irene L. Reijers, Oscar Krijgsman, Esmée P. Hoefsmit, Bart A. van de Wiel, Karolina Sikorska, Carolien Bierman, Petros Dimitriadis, Maria Gonzalez, Annegien Broeks, Ron M. Kerkhoven, Andrew J. Spillane, John B. Haanen, Winan J. van Houdt, Robyn P. Saw, Hanna Eriksson, Alexander C. van Akkooi, Richard A. Scolyer, Ton N. Schumacher, Georgina V. Long. 36-months and 18-months relapse-free survival after (neo)adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma patients - update of the OpACIN and OpACIN-neo trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3412.

The optimal time interval between diagnostic excision of a primary cutaneous melanoma and sentinel node (SN) biopsy is unknown. The current study sought to determine whether this interval influenced the SN-positivity rate, recurrence or survival.Data collected from 2004 to 2014 for a Dutch population-based cohort of patients with melanoma who underwent SN biopsy (SNB) within 100 days of initial diagnosis (n = 7660) and for a similarly specified cohort from a large Australian melanoma treatment centre (n = 3478) were analysed. Time to SNB was analysed continuously (in weeks) and categorically (per month). The effects of SNB timing on SN-positivity were assessed using multivariable logistic regression, and its effects on recurrence-free survival (RFS) and overall survival (OS) were assessed using Cox proportional hazard regression analyses. Advanced modelling using a multivariable Cox model with penalised splines for modelling the continuous effects of time to SNB on RFS and OS was also performed.In neither the Dutch nor the Australian cohort was there a significant association between time to SNB and SN-positivity in either cohort, nor was there an impact of time to SNB on RFS or OS in either cohort. The spline-based HR curves for RFS and OS confirmed these findings.The time interval between diagnostic excision of a primary melanoma and SNB did not influence the SN-positivity rate or survival outcomes. This provides reassurance that neither early nor delayed definitive wide excision and SNB will adversely affect prognosis.

Abstract Background and Objectives Adjuvant radiotherapy (RT) can be given to melanoma patients following salvage surgery for node field recurrence after a previous regional node dissection, but the value of this treatment strategy is poorly documented. This study evaluated long‐term node field control and survival of patients treated in this way in an era before effective adjuvant systemic therapy became available. Methods Data for 76 patients treated between 1990 and 2011 were extracted from an institutional database. Baseline patient characteristics, treatment details and oncological outcomes were analysed. Results Adjuvant RT with conventional fractionation (median dose 48 Gy in 20 fractions) was given to 43 patients (57%) and hypofractionated RT (median dose 33 Gy in 6 fractions) to 33 patients (43%). The 5‐year node field control rate was 70%, 5‐year recurrence‐free survival 17%, 5‐year melanoma‐specific survival 26% and 5‐year overall survival 25%. Conclusions Salvage surgery with adjuvant RT achieved node field control in 70% of melanoma patients with node field recurrence following a prior node dissection. However, disease progression at distant sites was common and survival outcomes were poor. Prospective data will be required to assess outcomes for contemporary combinations of surgery, adjuvant RT and systemic therapy.

Objectives Non-mortality benefits of breast cancer screening are rarely considered in assessments of benefits versus harms. This study aims to estimate the rate of overdiagnosis in women with screen-detected breast cancer (SDBC) by allocating cases to either possibly overdiagnosed (POD) or not overdiagnosed categories and to compare treatment recommendations for surgery and adjuvant treatments by category, age at diagnosis and cancer stage. Methods and analysis Retrospective secondary analysis of 10 191 women diagnosed with breast cancer in Australia and New Zealand in 2018. Treatment recommendations for 5226 women with SDBC and 4965 women with non-SDBC (NSDBC) were collated and analysed. Descriptive statistics were used to calculate proportions and risk ratios (RRs). Results The POD rate was 15.8%. Screening detected 66.3% of stage 0 tumours, 59% of stage 1, 40% of stage 2 and 27.5% of stage 3 tumours. Women with SDBC were less likely than their NSDBC counterparts to receive chemotherapy (RR 0.60 Aus/0.53 NZ), immunotherapy (mostly human epidermal growth factor 2 receptor therapy) (RR 0.58 Aus/0.82 NZ), mastectomy (RR 0.55 Aus/0.63 NZ) and axillary lymph node dissection (RR 0.49 Aus/0.52 NZ), or to require both mastectomy and radiotherapy (RR 0.41 Aus/0.34 NZ). Less than 1% of POD women were recommended chemotherapy, 9.5% radiotherapy, 6.4% endocrine therapy, 2.2% mastectomy and 0.5% axillary lymph node dissection. Conclusions Women with SDBCs required less intensive treatment; rates of possible overtreatment of SDBCs are relatively low and may be minimised through multidisciplinary discussion and shared decision-making. Reduced treatment intensity should be considered when balancing the potential benefits and harms of screening.

Abstract Background: Immunotherapies targeting PD-1/PD-L1 and CTLA4 have revolutionized the treatment of advanced melanoma. Combining the two therapeutics increases the response rates compared to either treatment alone. However, this increased efficacy is accompanied by a higher incidence of severe immune-related adverse events (irAEs). Metrics of the intestinal microbiome are associated with cancer patients’ responses to immunotherapy but the value of microbiome metrics as predictors for irAEs, are unknown. In an effort to reduce irAEs during combination neoadjuvant therapy, the OpACIN-neo trial (Rozeman et al. ESMO 2018) was initiated wherein Stage III melanoma patients were treated with 2 doses each of ipilimumab and nivolumab in the neoadjuvant setting, according to three dosing regimen. Involved lymph nodes were resected after 6 weeks. Aims: (1) To determine whether intestinal microbial components are associated with response to antiPD1/anti-CTLA4 immunotherapy in the neoadjuvant setting or with the development of severe irAEs. (2) To determine the effects of antiPD1/anti-CTLA4 immunotherapy on the microbiome over the 6 week course of treatment. Methods: Of Melanoma Institute Australia patients enrolled in the OpACIN-neo trial (n=38), 68% of patients experienced complete, or near complete pathological responses and 61% experienced at least one irAE of grade 3 or more. Faecal microbiomes at baseline, and at resection (6 weeks immunotherapy), were analyzed using 16S ribosomal gene and metagenomic sequencing and the results compared with patient response and development of G3-G5 irAEs. Results: In baseline samples, Inverse Simpson’s diversity index indicated significantly lower overall microbial diversity in non-responders (p=.014), as well as those who went on to experience severe irAEs (p=.002). Importantly, the group of patients who were both non-responders and experienced severe irAEs had the lowest microbial diversity of all patients (p=.0033). Specific taxa associated with irAEs are distinct from those described for response. The 6 week course of immunotherapy led to a slight increase in microbial diversity but few specific taxa were observed to be significantly altered between the timepoints. Conclusions: The findings suggest that not only are patients with extremely low microbial diversity predisposed to develop severe irAEs but they are also unlikely to respond to combination immunotherapy. Thus, microbial diversity may delineate patients who are likely to have poor outcomes and would benefit from microbial modulation. Citation Format: Marcel Batten, Erin R. Shanahan, Ines P. Silva, Chandra Adhikari, Jordan Conway, Annie Tasker, Alexander M. Menzies, James S. Wilmott, Robyn P. Saw, Andrew J. Spillane, Kerwin F. Shannon, Christian U. Blank, Andrew J. Holmes, Richard A. Scolyer, Georgina V. Long. Low intestinal microbial diversity is associated with severe immune-related adverse events and lack of response to neoadjuvant combination antiPD1, anti-CTLA4 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2822.

Introduction Sentinel lymph node biopsy (SLNB) is a diagnostic procedure developed in the 1990s. It is currently used to stage patients with primary cutaneous melanoma, provide prognostic information and guide management. The Australian Clinical Practice Guidelines state that SLNB should be considered for patients with cutaneous melanoma &gt;1 mm in thickness (or &gt;0.8 mm with high-risk pathology features). Until recently, sentinel lymph node (SLN) status was used to identify patients who might benefit from a completion lymph node dissection, a procedure that is no longer routinely recommended. SLN status is now also being used to identify patients who might benefit from systemic adjuvant therapies such as anti-programmed cell death 1 (PD1) checkpoint inhibitor immunotherapy or BRAF-directed molecular targeted therapy, treatments that have significantly improved relapse-free survival for patients with resected stage III melanoma and improved overall survival of patients with unresectable stage III and stage IV melanoma. Australian and international data indicate that approximately half of eligible patients receive an SLNB. Methods and analysis This mixed-methods study seeks to understand the structural, contextual and cultural factors affecting implementation of the SLNB guidelines. Data collection will include: (1) cross-sectional questionnaires and semistructured interviews with general practitioners and dermatologists; (2) semistructured interviews with other healthcare professionals involved in the diagnosis and early definitive care of melanoma patients and key stakeholders including researchers, representatives of professional colleges, training organisations and consumer melanoma groups; and (3) documentary analysis of documents from government, health services and non-government organisations. Descriptive analyses and multivariable regression models will be used to examine factors related to SLNB practices and attitudes. Qualitative data will be analysed using thematic analysis. Ethics and dissemination Ethics approval has been granted by the University of Sydney. Results will be disseminated through publications and presentations to clinicians, patients, policymakers and researchers and will inform the development of strategies for implementing SLNB guidelines in Australia.

Abstract Background The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. Objective To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. Methods We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P &lt; 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. Results Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90). Conclusion We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

Background Neoadjuvant systemic therapy (NAST) is used for large operable or highly proliferative breast cancers. It is not known whether psychological outcomes differ according to the treatment sequence (chemotherapy or surgery first) or tumour response. Methods This was a planned analysis of a multi-institutional single arm longitudinal study of patients considering NAST for operable breast cancer. Participants completed patient reported outcome questionnaires before and after the decision about NAST, between chemotherapy and surgery, and 12 months after diagnosis. Results Fifty-nine women enrolled. Fourteen of 51 (28%) who received NAST experienced pathological complete response (pCR). Patients who had surgery first (n = 7) had higher baseline anxiety, and a greater decrease in anxiety at 12 months follow up, compared with patients who received NAST (n = 50) (a decrease from baseline of 34 pts vs 17 points; p = 0.033). Distress declined at a similar rate in surgery first and NAST groups. Mean satisfaction with decision score post-decision was significantly lower in the adjuvant group compared with NAST (22 vs 26, p = 0.02). No differences were seen between patients with pCR vs residual cancer in: distress, anxiety, satisfaction with decision, fear of progression, and decision regret. Conclusion Most patients in this study proceeded with NAST when their surgeon offered it as an option. This exploratory analysis suggests that patients who chose surgery first tended to be more anxious, and had lower satisfaction with their decision, than those who had NAST. In patients who had NAST, lack of pCR does not appear to correlate with adverse psychological outcomes.

SUMMARY Aim: This study evaluated the use and impact of a survivorship care plan (SCP) in breast cancer survivors. Methods: An SCP was implemented at the end of treatment in a cohort of 68 Australian breast cancer survivors. Utility, cancer care coordination, satisfaction with medical care, quality of life and unmet needs were measured at baseline, 6 and 18 months. Results: In total, 56% of participants at 6 months and 51% at 18 months reported continued use of the SCP during follow-up consultations. Younger women were more likely to use the SCP. Overall quality of life improved over time, however, endocrine symptoms worsened significantly, especially in younger women. Conclusion: Younger women, who frequently suffer from debilitating endocrine symptoms, may be the group most likely to benefit from an SCP.

The benefits of patient-reported feedback, using questionnaires that allow patients to report how they feel and function without any interpretation from healthcare professionals, are well established. However, patient-reported outcomes measures (PROMs) are not routinely collected in patients with melanoma in Australia. The aim of this study is to evaluate the feasibility and acceptability of implementing electronic PROMs (ePROMs) into routine care from the perspectives of patients with stage III melanoma and their treating clinical team.A minimum of 50 patients and 5 clinicians will be recruited to this prospective, longitudinal pilot study (ePROMs-MELanoma). The study uses a mixed-methods approach (quantitative PROMs questionnaires and end-of-study surveys with qualitative interviews) and commenced in May 2021 in surgical and medical melanoma clinics at two sites in metropolitan Sydney, Australia. The primary outcomes are measures of feasibility and acceptability, comprising descriptive questionnaire completion statistics, and proportion of patients who reported that these PROMs were easy to complete and measured items they considered important. Clinician and clinic staff views will be canvassed on the appropriateness of these PROMs for their patients, change in referral practice and uptake and incorporation into routine practice. Secondary aims include measurement of improvements in patients' emotional and physical health and well-being, and utility of real-time data capture and clinician feedback. All participants will complete the Distress Thermometer and EQ-5D-5L questionnaires in the clinic using a tablet computer at baseline and two to three subsequent follow-up appointments. Participants who report a score of 4 or higher on the Distress Thermometer will be triaged to complete an additional three questionnaires: the QLQ-C30, Depression, Anxiety and Stress Scale and Melanoma Concerns Questionnaire-28. Results will be generated in real time; patients with psychosocial distress or poor quality of life will discuss possible referral to appropriate allied health services with their clinician. Thematic analysis of interviews will be conducted.Ethics approval obtained from St Vincent's Hospital Human Research Ethics Committee on 19 September 2019 (2019/ETH10558), with amendments approved on 8 June 2022. Patient consent is obtained electronically prior to questionnaire commencement. Dissemination strategies will include publication in peer-reviewed journals and presentation at international conferences, tailored presentations for clinical societies and government bodies, organisational reporting through multidisciplinary meetings and research symposia for local clinicians and clinic staff, and more informal, lay reports and presentations for consumer melanoma representative bodies and patient participants and their families.ACTRN12620001149954.

9511 Background: Several factors have been proposed as biomarkers for response to PD1 therapy, including tumor mutational burden (TMB), immune gene expression, PD-L1 expression and TILs, while few specific mechanisms of resistance have been identified. The relative importance of these factors or detailed examination of biomarkers of response to combination immunotherapy have yet to be explored. Methods: Cutaneous metastatic melanoma (MM) patients (pts) treated with anti-PD-1 (PD1) +/- anti-CTLA-4 (CTLA4) were selected. Pre-treatment tumors underwent whole genome sequencing (WGS), RNA sequencing (RNAseq) and immunohistochemistry (IHC; TILs and PD-L1). Results: Tumors from 77 pts treated with PD1 (n = 53) or PD1+CTLA4 (n = 24) underwent WGS. Higher TMB (p = 0.0001), lower structural variant (SV) burden (p = 0.001) and higher neoantigen load (p = 0.001) were associated with response. There was no difference in the expression of specific genes reported to confer resistance (JAK1/2, PTEN or BAF/PBAF complex members) or response (SERPINB3/4, ARID) in responders vs non-responders. RNAseq was performed on 53/77 samples; IFN and TCR signalling pathways were enriched in responders. Cytolytic activity (CYT, p = 0.002), T cell proportion estimated by CIBERSORT (p = 0.002) and confirmed by IHC (p = 0.033), and PD-L1 expression (IHC, p = 0.026) were also higher in responders. Multivariate analysis including DNA (TMB, SV count), RNA (six gene IFN expression signature - IFNG.6; effector T cell gene expression signature; chemokine gene expression; CYT), IHC (PD-L1, TILs) and clinical factors (sex, age, RECIST Sum of diameters, LDH) identified TMB and IFNG.6 as independent predictors of response (AUC = 0.83). 15 outliers with discordant molecular features and clinical outcomes had varying profiles, including 5 non-responders with high TMB, but low IFNG.6 expression, suggestive of a failure of immune activation. Conclusions: Comprehensive clinical and genomic analysis demonstrated that TMB and IFNG expression independently predict response, suggesting defects in both immune recognition or activation in non-responders.

Abstract Window of opportunity therapies, which involve short‐term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone‐receptor positive breast cancer, a 2‐week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision‐making regarding treatment options. Changes in short‐term biomarker endpoints such as cell proliferation measured by Ki‐67 can act as surrogate markers of long‐term outcomes. Paired tissues obtained pre‐ and post‐investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.

TPS10088 Background: Recent clinical trials of neoadjuvant (neo-adj) ipilimumab combined with nivolumab (OpACIN &amp; OpACIN-neo) in resectable stage III melanoma show that a pathological response ( &lt; 50% viable tumour at the tumour bed as determined by histopathological analysis) is associated with a prolonged relapse-free survival compared to no pathological response. Furthermore, recurrences seldom occur in those who have a pathological response following neo-adj immunotherapy with only 1/71 pts (1.4%) having recurred. In contrast, 15/23 (65.2%) pts with no pathological response have relapsed to date. The NeoPeLe trial will test the hypothesis that the synergistic combination of PD-1 blockade (pembrolizumab) with anti-angiogenic/multiple RTK inhibitor (lenvatinib) will result in a high rate of pathological response in the resected surgical specimen with a low rate of toxicity. Tissue and blood biomarkers are drawn at several timepoints and correlated to clinical and pathological endpoints to explore mechanisms of response and resistance. We will compare pathological response rate, and other clinical outcomes in this study, with previously published neo-adj clinical trials to select the best schedules for larger-scale clinical testing. Across neo-adj studies, we will also analyse the tissue collected to explore determinants of the optimal therapy for individual pts, whilst minimising toxicity. Methods: Eligible pts with stage IIIB/C/D, resectable and measurable (RECIST 1.1) nodal metastatic melanoma will be enrolled to this phase II single-centre trial (n = 20). All pts undergo complete nodal resection (RES) at wk 6 following neo-adj therapy with pembrolizumab (200mg, IV, 3 wkly) and lenvatinib (20mg, oral, daily). Adjuvant therapy with pembrolizumab is given for 46 wks after RES. After 52 wks of the study treatment, pts will be followed for relapse and survival for 5 years. CT and FDG PET/CT are used to measure response and exclude progression in the neo-adj phase, and to monitor for recurrence during adj and post treatment phases. Blood and tumour samples are collected at baseline, day 8, RES and at relapse if feasible. Faecal samples are collected at baseline and before RES. The primary endpoint is the complete pathological response rate at RES following 6 wks of neo-adj therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, and biomarker analyses. Clinical trial information: NCTNCT04207086.

ANZ Journal of SurgeryVolume 83, Issue 12 p. 893-893 EDITORIAL Why the results of the American College of Surgeons Oncology Group Z0011 Trial are so important Andrew Spillane MD, FRACS, Andrew Spillane MD, FRACS Sydney Medical School, The University of Sydney, Sydney Department of Breast and Surgical Oncology, The Mater Hospital, North Sydney Department of Surgical Oncology, Royal North Shore Hospital, St. Leonards, New South Wales, AustraliaSearch for more papers by this author Andrew Spillane MD, FRACS, Andrew Spillane MD, FRACS Sydney Medical School, The University of Sydney, Sydney Department of Breast and Surgical Oncology, The Mater Hospital, North Sydney Department of Surgical Oncology, Royal North Shore Hospital, St. Leonards, New South Wales, AustraliaSearch for more papers by this author First published: 02 December 2013 https://doi.org/10.1111/ans.12385Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Giuliano AE, McCall L, Beitsch P et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases. Ann. Surg. 2010; 252: 426–432. 2 Giuliano AE, Hunt KK, Ballman KV et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011; 305: 569–575. 3 Galimberti V, Cole BF, Zurrida S et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol. 2013; 14: 297–305. 4 Nguyen PL, Taghian AG, Katz MS et al. Breast cancer subtype approximated by estrogen receptor progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J. Clin. Oncol. 2008; 26: 2373–2378. 5 Ngui NK, Elder EE, Jayasinghe UW, French J. Relevance of the American College of Surgeons Oncology Group Z0011 Trial to breast cancer in the Australian setting. ANZ J. Surg. 2013; 83: 924–928. 6 Caudle AS, Hunt KK, Tucker SL et al. American College of Surgeons Oncology Group (ACOSOG) Z0011: impact on surgeon practice patterns MD. Ann. Surg. Oncol. 2012; 19: 3144–3151. 7 Güth U, Myrick ME, Viehl CT, Schmid SM, Obermann EC, Weber WP. The post ACOSOG Z0011 era: does our new understanding of breast cancer really change clinical practice? Eur. J. Surg. Oncol. 2012; 38: 645–650. Citing Literature Volume83, Issue12December 2013Pages 893-893 ReferencesRelatedInformation

Differentiating between metastatic melanoma and malignant perivascular epithelioid cell tumour (malignant PEComa; also known as malignant epithelioid angiomyolipoma) may present a difficult diagnostic challenge due to the presence of overlapping histological and immunohistochemical features, particularly when occurring in patients with a history of melanoma. Given the marked differences in their natural history, prognosis and management (including systemic therapy options), distinguishing between them is critical for optimal patient care. Herein, we present a case of a high grade epithelioid malignancy associated with a conventional angiomyolipoma/PEComa of the kidney, in a patient with a history of melanoma, in which the ultimate diagnosis was established by analysing the primary melanoma and the two distinct areas of the kidney tumour using a next generation sequencing (NGS) panel. The case highlights the utility of DNA sequencing to establish the correct diagnosis when the results of routine clinical, morphological, immunohistochemical and molecular evaluation remain inconclusive. A 58-year-old female presented with abdominal pain. An abdominal positron emission tomography-computed tomography (PET-CT) scan identified a biphasic, PET-avid left renal mass. No other suspicious lesions were apparent on clinical examination or imaging. She had a history of primary cutaneous melanoma of the thigh resected 3 years previously, which showed high risk features including a Breslow thickness of 10 mm and an elevated mitotic rate (5 mitoses/mm2), although no metastatic disease was identified in three sentinel lymph nodes from the right inguinal and iliac crest regions at that time. The melanoma was predominantly intradermal, with a growth pattern reminiscent of a deep penetrating naevus but with atypical spindled cytomorphology, prominent nuclear pleomorphism and frequent mitotic activity (Fig. 1A–D). It was positive with melanocyte markers (SOX10, S100, Melan-A and HMB45) and PRAME, while p16 expression was lost. It was negative for desmin, CD31, ERG, CD10, cytokeratin and p63. The left renal mass was removed with a radical nephrectomy. No extrarenal disease was identified intraoperatively. On macroscopic pathological examination, the upper pole of the kidney contained an exophytic, 44×35×23 mm tumour with a mainly solid, lobulated, focally nodular appearance. The cut surface was heterogeneous, with cream, pale tan and brown areas, with focal necrosis and haemorrhage (Fig. 1E). Histologically, the tumour had a biphasic appearance, with one region showing features of a classical angiomyolipoma/PEComa, and the other showing overt features of malignancy. The two regions were discretely separated in some areas, and more intimately admixed elsewhere (Fig. 1H,I). The low grade region (Fig. 1F,G) contained bland spindle cells with myoid features, some with cytoplasmic clearing, arranged in short fascicles. Focal adipocytes and variably sized vessels were identified. No mitoses or necrosis were seen in this area. The second component consisted of large, epithelioid cells with eosinophilic cytoplasm and prominent nucleoli, showing solid and pseudopapillary growth, with some areas showing perivascular condensation, areas of necrosis, and up to 18 mitoses per 10 high power fields (Fig. 1J,K). The immunohistochemical findings are summarised in Fig. 2. The low grade region of the kidney tumour showed diffuse positivity with SMA, patchy staining with desmin and HMB45, and focal weak positivity with Melan-A (Fig. 3). It was negative for S100, SOX10, PRAME and p16. There was focal, weak cytoplasmic positivity for WT1, patchy positivity for CD56, and occasional cells were positive for CCNB3. The high grade region showed patchy staining for S100 and moderate staining for PRAME and Cyclin D1, with focal HMB45 positivity and focal weak Melan-A positivity (Fig. 3). SOX10 was negative across multiple blocks of the high grade component. CD56 and CCNB3 were positive, WT1 showed cytoplasmic positivity, there was non-specific cytokeratin uptake in the necrotic areas, and p16 showed patchy positive staining. BRAFVE1, TFE3, GATA3, CD57, MyoD1 and Myogenin were negative in both components, and INI1 was retained. In both components MiTF was weakly positive.Fig. 3Immunohistochemical profile of the two regions in the kidney tumour. (A,B) HMB45 showing patchy positivity in both low grade (A) and high grade (B) regions. (C) Melan-A showed very focal weak staining in both regions; image from interface between zones. (D,E) Smooth muscle actin (SMA) stain, with the intermingled interface (D) and the abrupt interface (E) between zones. SMA showed diffuse positivity in the spindled, low grade region (left half of each image) and focal, very weak positivity in high grade region (right half). (F) S100 showed focal positivity in the high grade region (right half of image). (G) CD56 showed patchy positivity in both regions. (H) PRAME showed nuclear positivity in the high grade region (top right of image). (I) WT1 showed diffuse cytoplasmic/membrane staining in the high grade region (right half of image) and focal positivity in low grade region.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Differential diagnoses based on the morphology and immunoprofile included an angiomyolipoma/PEComa with malignant transformation, or a benign angiomyolipoma involved by metastatic melanoma. Initially it was considered that, despite the negativity with SOX10, the malignant component was morphologically more in keeping with metastatic melanoma than a malignant PEComa. Routine molecular analysis for metastatic melanoma was performed on the primary melanoma and the kidney tumour at that time using a PCR-based DNA sequencing assay (Illumina technology), which showed no hotspot mutations in BRAF, NRAS or KIT in either tumour. The key pathological features are summarised in Fig. 2. In light of the prognostic and treatment implications of the two differential diagnoses, additional DNA sequencing was performed on tissue from the patient's primary melanoma and separately on each component of the renal tumour using a customised next generation sequencing panel (ArcherDX), which incorporated a total of 54 recurrently mutated coding and non-coding melanoma-related genes discovered in our previous whole genome sequencing of a large cohort of melanomas.1Hayward N.K. Wilmott J.S. Waddell N. et al.Whole-genome landscapes of major melanoma subtypes.Nature. 2017; 545: 175-180Crossref PubMed Scopus (855) Google Scholar This revealed abnormalities in the primary melanoma that were absent in both zones of the kidney lesion, including a CDKN2A mutation and a TERT promoter mutation. In contrast, the two components of the kidney tumour harboured an identical TP53 mutation, which was absent from the melanoma (Fig. 2). These findings indicated that the malignant renal tumour was molecularly more similar to the adjacent angiomyolipoma/PEComa than to the melanoma. Consequently, the kidney tumour was diagnosed as a malignant PEComa arising in association with an angiomyolipoma/PEComa. Within 12 months of diagnosis the patient developed metastatic PEComa in retroperitoneal lymph nodes, as well as a cerebellar dysfunction syndrome that was considered to be paraneoplastic in nature. Angiomyolipoma, a member of the family of perivascular epithelioid cell neoplasms (PEComa), represents a rare mesenchymal neoplasm with an unusual immunoprofile, expressing both smooth muscle markers (SMA, desmin and caldesmon) and melanocytic markers (usually Melan-A and HMB45 and sometimes S100).2WHO Classification of Tumours Editorial BoardWHO Classification of Tumours: Soft Tissue and Bone Tumours.5th ed. IARC, Lyon (France)2020Google Scholar Most cases are sporadic, however a subset arises in association with tuberous sclerosis complex.3Rakowski S.K. Winterkorn E.B. Paul E. et al.Renal manifestations of tuberous sclerosis complex: incidence, prognosis, and predictive factors.Kidney Int. 2006; 70: 1777-1782Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar ‘Classical’ angiomyolipoma is considered benign, and has characteristic histological features that allow diagnosis on routine histology. However, the epithelioid variant has malignant potential and can occasionally demonstrate histological features similar to melanoma including large polygonal or spindled cells with atypical nuclei, prominent nucleoli, intranuclear inclusions, multinucleated giant cells, mitoses and necrosis.4Holger M. Humphrey P.A. Ulbright T.M. et al.WHO Classification of Tumours of the Urinary System and Male Genital Organs.4th ed. IARC, Lyon2016Google Scholar While it is not often that malignant PEComa of the kidney occurs in a patient with a history of melanoma, distinguishing between these entities is of significant clinical importance due to the implications for both prognosis and ongoing management. A diagnosis of resected American Joint Committee on Cancer (AJCC) stage IV metastatic melanoma would result in consideration of adjuvant immune checkpoint inhibitor therapy, and possible enrolment into a clinical trial. Malignant PEComa often shows resistance to chemotherapy and radiotherapy, and thus the mainstay of treatment is radical resection and close observation, with long-term follow-up due to the risk of late recurrence.5Sobiborowicz A. Switaj T. Teterycz P. et al.Feasibility and long-term efficacy of PEComa treatment-20 years of experience.J Clin Med. 2021; 10: 2200Crossref PubMed Scopus (11) Google Scholar Immunohistochemistry does not necessarily help differentiate these entities. Melan-A and HMB45, markers that are otherwise considered relatively specific for melanocyte differentiation, are positive in angiomyolipoma/PEComa. While SOX10 and S100 positivity would favour a diagnosis of melanoma, absence of staining does not exclude this entity: the capacity of melanoma to dedifferentiate and lose expression of one or more melanocyte markers is well known.6Agaimy A. Stoehr R. Hornung A. et al.Dedifferentiated and undifferentiated melanomas: report of 35 new cases with literature review and proposal of diagnostic criteria.Am J Surg Pathol. 2021; 45: 240-254Crossref PubMed Scopus (31) Google Scholar In addition, while expression of smooth muscle markers may be more suggestive of a PEComa, melanoma may also show divergent differentiation, aberrantly expressing other markers (including muscle markers).6Agaimy A. Stoehr R. Hornung A. et al.Dedifferentiated and undifferentiated melanomas: report of 35 new cases with literature review and proposal of diagnostic criteria.Am J Surg Pathol. 2021; 45: 240-254Crossref PubMed Scopus (31) Google Scholar Routine melanoma-related molecular testing may be useful if a common melanoma-associated driver mutation (such as a BRAF or NRAS mutation) is identified, however almost 50% of melanomas are negative for these mutations, thus, if absent/wild-type, melanoma still remains a possibility.7Lyle M. Haydu L.E. Menzies A.M. et al.The molecular profile of metastatic melanoma in Australia.Pathology. 2016; 48: 188-193Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar A subset of PEComas harbour translocations in TFE3,2WHO Classification of Tumours Editorial BoardWHO Classification of Tumours: Soft Tissue and Bone Tumours.5th ed. IARC, Lyon (France)2020Google Scholar which can be identified using immunohistochemistry and with fluorescent in situ hybridisation (FISH). If positive, this may assist in recognising a PEComa, however it was negative in our case and thus did not assist in the diagnosis. The most common molecular event in angiomyolipoma/PEComa is deletion and/or loss of heterozygosity in TSC2 or TSC1; genes which were not included in our customised melanoma NGS panel.8Agaram N.P. Sung Y.S. Zhang L. et al.Dichotomy of genetic abnormalities in PEComas with therapeutic implications.Am J Surg Pathol. 2015; 39: 813-825Crossref PubMed Scopus (140) Google Scholar A subgroup of PEComa is characterised by rearrangements of the TFE3 gene, an abnormality that is mutually exclusive with TSC2 mutations.8Agaram N.P. Sung Y.S. Zhang L. et al.Dichotomy of genetic abnormalities in PEComas with therapeutic implications.Am J Surg Pathol. 2015; 39: 813-825Crossref PubMed Scopus (140) Google Scholar TERT promoter mutations occur in about 80% of cutaneous melanomas,1Hayward N.K. Wilmott J.S. Waddell N. et al.Whole-genome landscapes of major melanoma subtypes.Nature. 2017; 545: 175-180Crossref PubMed Scopus (855) Google Scholar but have not, to our knowledge, been identified in PEComa. Loss of function of cyclin-dependent kinase inhibitor 2A (CDKN2A), also a frequent event in primary invasive melanoma,1Hayward N.K. Wilmott J.S. Waddell N. et al.Whole-genome landscapes of major melanoma subtypes.Nature. 2017; 545: 175-180Crossref PubMed Scopus (855) Google Scholar appears to be an uncommon occurrence in PEComa.9Groisberg R. Hong D.S. Holla V. et al.Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas.Oncotarget. 2017; 8: 39254-39267Crossref PubMed Scopus (55) Google Scholar On the other hand, mutations in TP53 are a recognised event in many PEComas9Groisberg R. Hong D.S. Holla V. et al.Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas.Oncotarget. 2017; 8: 39254-39267Crossref PubMed Scopus (55) Google Scholar,10Groisberg R. Subbiah V. Sequencing PEComas: viewing unicorns through the molecular looking glass.Oncology. 2021; 99: 62-64Crossref PubMed Scopus (4) Google Scholar but are relatively rare in melanoma.11Hodis E. Watson I.R. Kryukov G.V. et al.A landscape of driver mutations in melanoma.Cell. 2012; 150: 251-263Abstract Full Text Full Text PDF PubMed Scopus (1935) Google Scholar The NGS results thus provided the evidence needed to demonstrate the molecular similarity between the malignant renal component and the classical angiomyolipoma, and exclude metastatic melanoma. This case highlights the utility of deep sequencing molecular analysis to establish a correct diagnosis in cases where results of clinical, morphological, immunohistochemical and standard molecular evaluation remain inconclusive, particularly where the findings will have an immediate impact on patient management. RAS has received fees for professional services from F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Merck Sharpe & Dohme, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics, Regeneron.

Abstract Background: While immune checkpoint inhibitors (ICI) have become the standard-of-care for advanced melanoma patients, only half of treated patients will survive beyond 5-years and many develop significant toxicity. The PIP study is combining pre-treatment clinical, molecular, and immunological profiles of melanoma patients to provide accurate prediction of response to ICI therapies. Methods: 504 patients with advanced melanoma who received anti-PD-1±CTLA-4 ICI were studied to develop predictive models of resistance to ICI. Resistance was defined as patients with progressive disease as best response, or partial response/stable disease with &amp;lt;6 months progression-free survival (RECIST 1.1). Machine learning models were developed using clinicopathological characteristics, tumor mutation burden (TMB, Qiaseq TMB IO), gene expression profiling ((GEP), Nanostring Pancancer 360 IO) and spatial quantitative pathology immune profiling (multiplex immunofluorescence, (MIF)) of baseline melanoma biopsies. Models were developed in a discovery cohort (n=247), validated in an independent cohort (n=97), with an accruing prospective cohort (n=160). Model predictive performance was assessed using the area under the curve (AUC). Results: Models were developed and validated using sequential addition of omics features to relevant clinical factors. Baseline clinical data alone achieved an AUC of 68%. Clinical plus three-tier TMB (&amp;lt;10, 10-20, &amp;gt;20 mut/mb) achieved an AUC of 78%. Clinical data plus GEP achieved 79% AUC, inclusive of tumor inflammation, antigen presentation and T-cell related signatures. Clinical and MIF spatial pathology achieved an 82% AUC including the distances between T-cells, CD16+ cells and melanoma cells as features in the model. Finally, the combination of TMB and GEP achieved an 83% AUC. Prospective validation of the models is awaiting follow-up milestones. Conclusion: Multi-omic models using pre-treatment tissue and clinicopathology can significantly improve the accuracy of predicting patient outcomes to ICI treatments compared to baseline clinical data alone. Several models may be required based on different omic combinations to account for the reality of biopsy suitability and assay failures. These findings prove personalized precision treatment of patients with immunotherapies is possible in the clinical setting and such approaches should become routine care. Citation Format: Tuba N. Gide, Nurudeen A. Adegoke, Yizhe Mao, Monica Lennox, Saurab Raj, Camelia Quek, Ismael A. Vergara, Nigel Maher, Alison Potter, Robyn P. Saw, John F. Thompson, Andrew J. Spillane, Kerwin F. Shannon, Matteo S. Carlino, Maria Gonzalez, Serigne N. Lo, Alexander M. Menzies, Inês Pires da Silva, Richard A. Scolyer, Georgina V. Long, James S. Wilmott. Predictive biomarker models of immunotherapy response in patients with metastatic melanoma: genomic, transcriptomic, and immune profiles from the Personalised Immunotherapy Program (PIP). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5701.

Abstract Purpose Patients with melanoma liver metastases have significantly reduced overall response and survival when treated with immune checkpoint inhibitors (ICI) compared to those without liver metastases. Melanoma liver metastases are less likely to respond to ICI compared to other sites of metastases, and the presence of liver metastases has also been associated with reduced responses to ICI at other metastatic sites. We aimed to profile circulating and tumor immune profiles of melanoma patients with versus without liver metastases to elucidate the factors behind this observation. Methods Pre-treatment PBMCs from 37 advanced melanoma patients (Cohort A) were profiled using mass cytometry (CyTOF) spanning 46 markers. Expression of specific immune cells were compared between those with (n = 8) vs without (n = 29) liver metastases. In a separate independent cohort of 93 untreated metastatic melanoma patients (Cohort B), FFPE tumour samples comprised of subcutaneous, lymph node (LN) and brain metastases were stained for myeloid and T cell markers using multiplex IHC. Immune cell populations in cohort B tissues were compared between patients with (n=40) vs without (n=53) liver metastases. Results PBMCs from patients in Cohort A with liver metastases had an increased proportion of a myeloid population characterised as HLA-DR+CD14+CD16- compared to patients without liver metastases (p = 0.035). However, a difference in CD68+CD14+CD16- myeloid cells was not seen in cohort B melanoma tissues (subcut, LN, brain metastases) between patients with vs without liver metastases. In subcutaneous tissues, there was a significantly reduced density of T cells in patients with liver metastases (median = 59 cells/mm2) compared to those without (median = 217 cells/mm2; p = 0.037). This trend was also observed in LN and brain metastases but did not reach significance. In brain metastases, a higher proportion of FoxP3+ T cells was observed in patients with liver metastases (p = 0.003). An increase in this population was also observed in the LN and subcutaneous metastases in the presence (vs absence) of liver metastases, however this did not reach significance. LN metastases also showed a reduced proportion of both TIM3+ (p = 0.049) and CD103+ (p = 0.048) T cells in patients with liver metastases (vs absence), and a similar trend was observed in subcutaneous metastases. In contrast, brain metastases showed the opposite trend as well as higher proportion of PD1+ T cells in patients with liver metastases vs those without (p = 0.033). Conclusion These data provide insights into the differences in the anti-tumor immune profiles of patients with versus without liver metastases; the presence of liver metastases may have a specific impact at different metastatic sites. This highlights the need for further validation and investigation into the mechanism by which the presence of liver metastases may exert this effect. Citation Format: Jordan W. Conway, Felix Marsh-Wakefield, Kazi J. Nahar, Serigne N. Lo, Ismael A. Vergara, Tuba N. Gide, Grace H. Attrill, Jorja Braden, Matteo S. Carlino, Robyn P. Saw, John F. Thompson, Andrew J. Spillane, Kerwin F. Shannon, Brindha Shivalingam, Alexander M. Menzies, Umaimainthan Palendira, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Ines Pires Da Silva. The association between melanoma liver metastases (mets) and the systemic anti-tumor immune profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 81.

&lt;div&gt;Abstract&lt;p&gt;Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes.&lt;/p&gt;Significance:&lt;p&gt;This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank"&gt;This article is highlighted in the In This Issue feature, p. 2711&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

&lt;div&gt;Abstract&lt;p&gt;Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes.&lt;/p&gt;Significance:&lt;p&gt;This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank"&gt;This article is highlighted in the In This Issue feature, p. 2711&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

TPS9610 Background: Patients diagnosed with stage II melanoma account for ~50% of those who develop metastatic disease and die (Poklepovic et al., 2020). Neoadjuvant therapy (NAT) is a powerful treatment platform to rapidly assess drug activity in resectable cancers using the International Neoadjuvant Melanoma Consortium (INMC) path response criteria (Tetzlaff et al., 2018), wherein a major path response (≤10% viable tumor) correlates with low risk of recurrence in resectable stage III melanoma (Menzies et al., 2021). Other benefits include early insight into response, feedback to pts regarding their individual response and prognosis, ability to tailor subsequent management, and collection of translational specimens to explore mechanisms of response and resistance (Amaria et al., 2019). NAT for stage II melanoma is an opportunity to improve survival rates beyond the gains achieved with adjuvant therapy, as illustrated by the phase II SWOG 1801 trial (Patel et al., 2022) for pts with stage III melanoma. The NeoReNi II trial will examine whether combination PD-1 blockade plus lymphocyte-activation 3 (LAG3) checkpoint inhibition will achieve a high rate of path response with manageable toxicity. Methods: Pts with histologically confirmed AJCC (8 th ed.) clinical stage IIA (T2b, T3A), IIB (T3b, T4a), or IIC (T4b) primary cutaneous melanoma from a partial biopsy, with residual macroscopic disease at study entry, are eligible (N = 20). Pts with IIA disease must have an estimated ≥20% risk of recurrence at 5 years, according to the Melanoma Institute Australia stage II risk calculator (melanomarisk.org.au). All pts undergo wide excision and sentinel lymph node resection (RES) at wk 6 following NAT with 2 doses of nivo (480 mg, IV) plus rela (160 mg, IV). Pts with no ( &gt; 50% viable tumor) or partial path response ( &gt; 10% - ≤50% viable tumor) receive a further 11 cycles (Q4W) of adjuvant nivo (480 mg) plus rela (160 mg), and radiological and clinical surveillance. Pts with complete (pCR; 0% viable tumor) or near-complete (≤10% viable tumor) path response will undergo radiological and clinical surveillance after RES. All pts will be followed for recurrence (6 monthly CT) and survival for 10 years. Lymphatic mapping, dermoscopy, in vivo confocal microscopy, CT, and FDG PET/CT will be performed at baseline (BL) and prior to RES to measure response to NAT. Tumour and fecal samples are collected at BL, RES, and recurrence. Blood samples are collected at BL, wk 4, RES, and recurrence. The primary endpoint is the rate of pCR at RES after 6 wks of NAT using INMC response criteria (Tetzlaff et al., 2018). Secondary endpoints include assessing the feasibility of NAT in a stage II pt population, RFS, OS, safety/tolerability, surgical outcomes, changes in confocal microscopy and dermoscopy, rate of sentinel node positivity and changes in lymphatic mapping, QOL, and biomarker analyses. Clinical trial information: NCT05418972 .

Targeted axillary dissection (TAD) is a relatively new tool for axillary management in patients with breast cancer. It is performed selectively in node-positive cases after neoadjuvant systemic therapy (NAST), as a less invasive alternative to axillary lymph node dissection (ALND).1, 2 It involves the removal of the biopsy-proven positive lymph node (clipped at the time of core biopsy) and associated sentinel lymph nodes. Depending on breast cancer molecular sub-type, NAST can involve chemotherapy, targeted therapy, and/or immunotherapy. In the past, all patients with positive lymph nodes were recommended to undergo a Level 2 ALND. With NAST there are increasingly higher rates of axillary pathological complete responses (pCR), up to ≥60% for some HER2+ tumours.3 This has challenged the need to perform ALND with its associated morbidities. Since its initial description in the mid-2010s, TAD's ability to determine axillary status post NACT, whilst being less invasive and less morbid than an ALND, has led to its international uptake.1, 2, 4 The recently updated German Gynaecological Oncology Group (AGO) guidelines are the first to list TAD as standard of care for cN+ converting to ycN0 post NAST.5 The National Comprehensive Cancer Network have also identified TAD, listing it as an optional technique.6 The international opinion has been further ratified by the recent European Breast Cancer Research Association of Surgical Trialists (EUBREAST) survey that identified TAD as the preferred surgical technique for patients with cN1 disease and/or up to 3 clinically suspicious nodes converting to ycN0 (150 of 277 respondents, 54.2%) post NAST.7 There are concerns regarding the oncological safety of TAD given the lack of long-term data. The Oncoplastic Breast Consortium and EUBREAST initiative created a list of uncertainties and controversies in axillary management, with TAD's applicability and oncologic safety the second most important question to be answered.8 Yet, when the 61 members were asked, ‘Should targeted axillary dissection (TAD versus SLN only or ALND) be standard care in initially cN+ converting to ycN0 and is TAD oncologically safe compared to ALND?’ a consensus of 89% agreed. International registry studies are currently underway evaluating TAD safety, i.e., AXSANA and MINI-MAX, however long-term results are pending.9, 10 The recently published SenTa 3-year outcomes have shown non-inferiority when comparing TAD to ALND for survival outcomes and recurrence rates.11 The Australian and New Zealand (ANZ) acceptance of TAD has been evident with institutional experiences published, recent integration into the Breast Quality Audit (BQA) recordable fields, and it being incorporated into the University of Sydney Graduate Certificate of Advanced Breast Surgery course.12, 13 It is hypothesised that TAD is predominantly performed at specialist Breast Oncology institutions – including those with BreastSurgANZ Post Fellowship Trainees (PFTs). However, the extent of TAD acceptance across ANZ is unknown. Currently, there is no ANZ data available regarding the accepted indications for TAD, the technique performed, nor its pathological interpretation. Given the dynamic landscape of neoadjuvant treatment in breast cancer, an Australian and New Zealand survey supported by Breast Cancer Trials, was constructed by the authors to understand current surgical practices and trends, with 7 of the 41 questions specifically about TAD. This bi-national survey was distributed to all BreastSurgANZ PFTs, representing 21 institutions (18 in Australia and 3 in New Zealand), with a total of 109 associated breast surgeons (95 from Australia, 14 from New Zealand). These 109 surgeons represent 31.14% of all full BreastSurgANZ members (n = 350). The initial question posed was whether a TAD would be considered in a cN+ patient prior to NAST: 19 of 21 institutions stated it would (90.48%). The PFTs in the two centres not performing TAD were in New Zealand. For those centres performing TAD, 12 of 19 (63.2%) institutions stated phenotype (e.g., HER2+ and triple negative breast cancer) did not influence TAD decision-making. An important consideration for TAD is the indication, with the predominance of the literature focusing on low volume disease, classified usually as 1–2 positive nodes or cN1. We gave scenarios to determine when the PFTs thought a TAD would be considered, and it was noted that no institutions would offer it for either 4 or more suspicious nodes prior to NAST or in cN2. The most common indication was for ≤2 radiologically suspicious nodes prior to NAST for 10 of 19 institutions (52.63%), with the remaining 9 finding ≤3 radiologically suspicious nodes an acceptable indication. When asked whether clinical and/or radiological findings at completion of NACT influenced choosing TAD, 17 of 19 (89.47%) stated it did. The TAD technique has been thoroughly discussed in the literature, with multiple modalities described for identifying the biopsy-proven involved and clipped node(s). Institutions were questioned regarding their choice for localisation techniques, allowing them to select the multiple options they may employ at their institutions. Hookwire was the most used technique, deployed in 13 of 19 institutions (68.42%). Magnetic seeds (e.g., MagSEED®) was second most common, used in 8 institutions (42.11%). Less commonly used were Radioactive seeds (e.g., I-125), Reflectors (e.g., Savi Scout) and Carbon tattooing in two centres each. Radio-isotope occult lesion localisation (ROLL) was used in one institution. A point of contention in the literature is how to manage the pathological outcome after a TAD. The terminology of a ‘positive TAD’ is controversial, with the recent AGO treating micro-metastasis and greater as a positive TAD, with isolated tumour cells (ITC) as needed to be discussed case-by-case. Of the 18 centres that responded, 1 or more macrometastases was defined as a positive TAD in 9 (50%). A micrometastasis or greater were deemed a positive TAD in 4 centres (22.22%), with 5 centres deeming the presence of ITCs or greater as positive (27.78%). The uncertainty about how to manage the positive TAD was evident, with 13 of the 19 centres stating that the case would be ‘Discussed at the MDM with case-by-case decision making’. The remaining six centres all stated that an axillary clearance would be offered for a positive TAD (31.58%), with one of those institutions stating axillary clearance and regional nodal irradiation (5.26%). In conclusion, axillary management post NAST is a dynamically evolving field, with the aim being progress towards less morbid treatment without compromising oncological outcome. This survey has identified that TAD is becoming well integrated into ANZ surgical management, mirroring international trends. Limitations of the survey include that not all surgeons at an institution may have the same approach to TAD and the PFT is interpreting their practice. Notably, there is a lack of information on the evolving practice of TAD in ANZ, due to limited data reported in the BQA. This has led to the development of a joint Breast Cancer Trials and BreastSurgANZ TAD Registry, a 12-month database that aims to collect all information pertaining to TAD cases to allow greater understanding of the indications, techniques, and adjuvant therapy decisions post-TAD. The TAD Registry will be affiliated with all BreastSurgANZ PFT-associated institutions, however individual surgeons are able to apply to contribute to the registry by submitting an expression of interest at https://www.breastsurganz.org/tad-registry/. By obtaining these data we hope to better understand current post-NAST axillary management and identify areas of further research with the aim to improve patient outcomes. Adam Ofri: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; validation; writing – original draft; writing – review and editing. Andrew J. Spillane: Conceptualization; formal analysis; methodology; project administration; supervision; writing – original draft; writing – review and editing. Caroline Baker: Conceptualization; data curation; writing – review and editing. G. Bruce Mann: Conceptualization; data curation; writing – review and editing. Melanie Walker: Conceptualization; data curation; writing – review and editing. Sanjay Warrier: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; supervision; writing – review and editing. Professor Andrew Spillane is an Editorial Board member of ANZJS and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication. Dr. Adam Ofri is a recipient of the Breast Cancer Trials Clinical Research Fellowship stipend. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians.

9580 Background: Neoadjuvant D+T has a high pathologic response rate and impressive short-term survival. The NeoCombi trial (NCT01972347) enrolled 35 patients with resectable stage III melanoma, with last patient commencing treatment April 19th 2017. We report 5-year outcomes from this trial. Methods: Pts received 12 wks neoadjuvant standard dose D+T, then 40 wks adjuvant D+T. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1 with clinical stage III BRAF V600E/K melanoma. CT and PET scans were performed at baseline and prior to surgery. Pathologic response was determined as per International Neoadjuvant Melanoma Consortium (INMC) criteria and defined as complete (pCR), near complete, partial (pPR) or no response (pNR). CT monitoring was continued 12 wkly thereafter to 2 yrs, then 6 monthly to 3 yrs, then as standard care. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints included relapse free survival (RFS), OS, and toxicity. Results: 35 pts were enrolled, 6 with IIIB, 29 IIIC (7 ITM only) disease (clinical AJCCv7). At data cut August 17th 2021, median F/U was 60 mo (95% CI 56-72). No patients progressed in the neoadjuvant phase, and (49%) had a pCR, 1 near pCR, 6 pPR, 11 pNR. 5-year RFS, DMFS and OS data are shown in the Table. The majority of recurrences occurred within the first 2 years, with no recurrences beyond 3y. 21 patients recurred; 12 (57%) had first recurrence locoregional (6/12 subsequent distant recurrence) and 9 (43%) had first recurrence in distant sites (3/9 in brain). Locoregional recurrence was managed with surgery alone in 4/12, systemic therapy alone in 2/12, or both surgery and systemic therapy in 5/12 (4/5 had adjuvant systemic therapy), 1 pt was observed until distant recurrence. Subsequent systemic therapy in the 15 patients with a distant recurrence included PD-1 based immunotherapy (N=14) and BRAF targeted therapy (N=10). Conclusions: Neoadjuvant D+T in clinical stage III melanoma has impressive early activity, however patients remain at high risk of recurrence. Pathologic response can identify patients at the highest risk of recurrence, offering a chance of alternative adjuvant therapy in non-responders. Clinical trial information: NCT01972347. [Table: see text]

Introduction: Women with locally extensive breast cancer requiring mastectomy and post-mastectomy radiotherapy (PMRT) face many conflicting issues affecting their choice of immediate versus delayed versus no breast reconstruction (BR). This study assessed women’s reasons and priorities in choosing the timing and type of BR in a setting where all options were discussed with all women.

Abstract Background In the multi-center investigator-initiated OpACIN-neo trial, patients (pts) with macroscopic stage III melanoma were randomized (stratified by center) to 3 different dosing schemes of neoadjuvant (neoadj) IPI+NIVO. Two cycles IPI 1mg/kg + NIVO3mg/kg was identified as the most favorable regimen with 20% grade 3-4 adverse events and a pathological response rate (pRR) of 77%. After a median follow-up (FU) of 8.3 months (mo) none (0/86) of the pts with a pathologic (path) response had relapsed, while 9/21 (43%) without a path response relapsed. Post-hoc analyses were conducted to investigate potential differences between pts treated in Europe (EU) and in Australia (AUS). Methods Baseline patient characteristics, safety and efficacy in terms of path response were evaluated in pts treated in EU (n=48) and AUS (n=38). Multivariate analyses were performed using logistic regression method. Median FU was 9.3mo for EU pts and 6.9mo for AUS pts. Results Baseline characteristics (AUS vs EU) differed in age (median 60 vs 53 year [yr], p=0.017) and AUS pts were more likely to be male (65.8 vs 50.0%, p=0.142) and have an unknown primary melanoma (36.8 vs 20.8%, p=0.100); no difference in PD-L1 expression was observed. There was a trend to a higher pRR for AUS pts than for EU pts (84.2% vs 68.1%, OR 2.50, p=0.092). pRR was also higher for pts >60yr compared to £60yr (91.2% vs 64.7%, OR 5.64, p=0.010) and males vs females (83.7% vs 63.9%, OR 2.90, p=0.041). Multivariate analysis including continent, age and gender showed an adjusted OR for path response of 1.85 (p=0.289) for AUS vs EU pts, an OR of 4.89 (p=0.021) for pts >60yrs vs £60yrs and an OR of 2.50 (p=0.095) for males vs females. The frequency of high grade toxicity was the same in pts 60yr (42.3% vs 32.4%, p=0.353). Conclusions The continental difference in path response appears mostly driven by differences in age and gender. It remains to be elucidated whether the higher pRRs in elderly pts and pts from AUS can be explained by differences in mutational burden (analysis in progress and will be presented). Our data also indicate that neoadj IPI+NIVO is safe and highly effective in the elderly. Clinical trial identification NCT02977052. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. A.M. Menzies: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. R.A. Scolyer: Advisory / Consultancy: MSD; Advisory / Consultancy: Neracare; Advisory / Consultancy: Novartis. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. J. Hansson: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GSK; Advisory / Consultancy: GenMab; Research grant / Funding (institution): NanoString. All other authors have declared no conflicts of interest.

Abstract Background In the multicenter investigator-initiated OpACIN-neo trial, patients (pts) with macroscopic stage III melanoma were randomized (stratified by center) to three different dosing schemes of neoadjuvant ipilimumab (IPI) + nivolumab (NIVO). Two cycles IPI 1 mg/kg + NIVO 3 mg/kg was identified as the most favorable regimen with 20% grade 3-4 adverse events and a pathologic response rate (pRR) of 77%. After a median follow-up of 17.7 months, relapses were observed in 1/64 (2%) of the pts with a pathologic response, and in 13/21 (62%) of the non-responders. Post-hoc analyses according to continent of study inclusion were conducted to investigate potential differences between pts treated in Europe (EU) and in Australia (AUS). Methods We evaluated baseline patient characteristics, safety and efficacy in terms of pathologic response in pts treated in EU (n=48) and AUS (n=38). Mutational (mut) load of baseline biopsies was assessed using whole exome sequencing. Multivariate analyses were performed using the logistic regression method. Median follow-up was 18.2 months for EU pts and 16.6 months for AUS pts. Results Baseline characteristics (AUS vs EU) differed in age (median 60 vs 53 year [yr], p=0.017). There were numerically more male pts in the Australian cohort (65.8 vs 50.0%, p=0.142) and more pts with unknown primary melanoma (36.8 vs 20.8%, p=0.100). A numerical higher pRR was observed in AUS pts vs EU pts (84.2% vs 64.7%, OR 2.50, p=0.092). The pRR was significantly higher for older pts (OR per yr 1.059, p=0.003), males (83.7% vs 63.9%, OR 2.90, p=0.041), and pts with higher mut load (OR per mutation 1.002, p=0.014). Mut load was higher in pts with pathologic response (p=0.0013) and in AUS pts (p=0.0003). There was a positive correlation between age and mut load (R=0.26, p=0.043). Multivariate analysis including continent, age, gender and mut load revealed that only mut load was significantly associated with response (OR 1.002, p=0.037).The frequency of grade 3-5 toxicities was the same in pts &amp;lt;60 compared to pts &amp;gt;60 yr (42.3% vs 32.4%, p=0.353). Conclusion The numerical higher pRR in AUS vs EU melanoma pts upon neoadjuvant IPI + NIVO appears mostly driven by a higher mut load found in the melanomas of AUS pts. AUS pts were older and there was a positive correlation between age and mut load, indicating that the higher mut load in AUS pts might be explained by higher age. It remains to be elucidated if continental variance in sun exposure also contributed to the difference in mut load. The fact that older pts achieve a higher response rate in absence of increased toxicity rates indicates that older pts should not be withheld neoadjuvant IPI + NIVO. Citation Format: Irene L. Reijers, Elisa A. Rozeman, Alexander M. Menzies, Judith M. Versluis, Bart A. van de Wiel, Karolina Sikorska, Hanna Eriksson, Kerwin Shannon, Carolien Bierman, Harm van Tinteren, Maria Gonzalez, Andrew J. Spillane, Robyn P. Saw, Alexander C. van Akkooi, Richard A. Scolyer, Johan Hansson, Georgina V. Long, Christian U. Blank. Different pathologic response rates between Australia and Europe in macroscopic stage III melanoma patients upon neoadjuvant ipilimumab plus nivolumab in the phase II OpACIN-neo trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3271.

ANZ Journal of SurgeryVolume 84, Issue 10 p. 699-700 EDITORIAL Intraoperative molecular sentinel node analysis: the way of the future or great technology with limited indication? Kylie L. Snook FRACS, Kylie L. Snook FRACS Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia Department of Breast and Surgical Oncology, The Mater Hospital North Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorAndrew J. Spillane MD, FRACS, Andrew J. Spillane MD, FRACS Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia Department of Breast and Surgical Oncology, The Mater Hospital North Sydney, Sydney, New South Wales, Australia Department of Surgical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, AustraliaSearch for more papers by this author Kylie L. Snook FRACS, Kylie L. Snook FRACS Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia Department of Breast and Surgical Oncology, The Mater Hospital North Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorAndrew J. Spillane MD, FRACS, Andrew J. Spillane MD, FRACS Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia Department of Breast and Surgical Oncology, The Mater Hospital North Sydney, Sydney, New South Wales, Australia Department of Surgical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, AustraliaSearch for more papers by this author First published: 30 September 2014 https://doi.org/10.1111/ans.12714Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume84, Issue10October 2014Pages 699-700 RelatedInformation

ANZ Journal of SurgeryVolume 84, Issue 7-8 p. 586-586 MEDIA REVIEW Management of Soft Tissue Sarcoma. Edited by M. F. Brennan, C. R. Antonescu and R. G. Maki. New York, NY: Springer, 2013. 358 pages. ISBN 978-1-4614-5003-0. Price: $159. Andrew John Spillane MD, FRACS, Andrew John Spillane MD, FRACS Surgical Oncology, The University of Sydney Breast and Surgical Oncology at the Poche Centre Melanoma Institute Australia, Sydney, New South Wales, AustraliaSearch for more papers by this author Andrew John Spillane MD, FRACS, Andrew John Spillane MD, FRACS Surgical Oncology, The University of Sydney Breast and Surgical Oncology at the Poche Centre Melanoma Institute Australia, Sydney, New South Wales, AustraliaSearch for more papers by this author First published: 25 July 2014 https://doi.org/10.1111/ans.12636Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume84, Issue7-8July-August 2014Pages 586-586 RelatedInformation

ANZ Journal of SurgeryVolume 86, Issue 9 p. 633-634 EDITORIAL Perceptions of increasing the complexity and commitment required for training breast surgeons Andrew Spillane MD, FRACS, Andrew Spillane MD, FRACS Surgical Oncology Department, Northern Clinical School, The University of Sydney, Sydney, New South Wales, Australia Breast and Surgical Oncology at the Poche Centre, Sydney, New South Wales, Australia Melanoma Institute Australia, Sydney, New South Wales, Australia Mater Hospital North Sydney, Sydney, New South Wales, Australia Royal North Shore Hospital, Sydney, New South Wales, Australia BreastSurgANZ, Sydney, New South Wales, AustraliaSearch for more papers by this author Andrew Spillane MD, FRACS, Andrew Spillane MD, FRACS Surgical Oncology Department, Northern Clinical School, The University of Sydney, Sydney, New South Wales, Australia Breast and Surgical Oncology at the Poche Centre, Sydney, New South Wales, Australia Melanoma Institute Australia, Sydney, New South Wales, Australia Mater Hospital North Sydney, Sydney, New South Wales, Australia Royal North Shore Hospital, Sydney, New South Wales, Australia BreastSurgANZ, Sydney, New South Wales, AustraliaSearch for more papers by this author First published: 01 September 2016 https://doi.org/10.1111/ans.13635Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume86, Issue9September 2016Pages 633-634 RelatedInformation

Background: Women diagnosed with large or highly proliferative operable breast cancer may be offered neoadjuvant systemic therapy (NAST) for reasons including downstaging, prognostication or expanding surgical options. We aimed to systematically develop, and evaluate a DA for women who had been offered NAST. Methods: Eligible women who were considered candidates for NAST, from four Australian recruiting centres were enrolled in a single arm longitudinal study. Participants completed online questionnaires prior to accessing the DA, and on three occasions post-DA. Primary outcomes were feasibility of use, and acceptability to patients and clinicians. Secondary outcomes were patient reported measures relevant to patient decision-making. Results: Seventy-nine women were offered study participation and 59 enrolled. Patients were typically well educated, married, had health insurance and were information seekers (mean information needs: 7.5/10; SD 1.84). 59/79 (74.7%) patients who were offered study participation accessed the DA and 49 (79.7%) of those 59 participants reported having read it. 41/51 (80.4%) participants who completed the post-DA assessment reported that the DA helped them with their decision about NAST. 51/59 (86%) participants elected to receive NAST. 16/18 (88.9%) investigators would continue to use the DA in routine practice. Post-DA, decisional conflict decreased significantly across all subscales (p < 0.01); anxiety and distress decreased significantly; 86.3% achieved at least as much decisional control as they desired; a high level of knowledge was demonstrated; and 39/51 (76.5%) patients had a high (≥24) Satisfaction with Decision score (mean 25.5, SD 3.6). 84.4% reported that they shared responsibility for the decision about NAST. Investigators reported that the DA was able to be integrated into patient care. Conclusions: Study primary outcomes were positive, showing the DA was feasible and acceptable to patients and clinicians. Improvements in decision-related outcomes were demonstrated, and the DA could be included in routine workflow. This DA can be implemented into routine clinical practice for women with operable breast cancer who are candidates for NAST. Clinical trial identification: Registration: Australia and New Zealand Clinical Trials Registry (www.anzctr.org.au): ACTRN12614001267640 Legal entity responsible for the study: Australia and New Zealand Breast Cancer Trials Group Funding: HCF Research Foundation Australia and New Zealand Breast Cancer Trials Group Disclosure: All authors have declared no conflicts of interest.

Purpose: Sentinel node biopsy (SNB) is standard of care for node negative, early breast cancer. There is debate as to the role of SNB in cases presenting with locally recurrent cancer or new ipsilateral cancer after breast conservation surgery or mastectomy in patients who have had a prior axillary dissection or prior SNB. The role of re‐operative SNB is evolving as is its place in staging and management. Methodology: Illustrative case histories and English language literature review. Results: High rates of ipsilateral axillary lymphatic drainage still occur in patients where only prior SNB has been performed in the axilla. When prior axillary dissection has been performed there is approximately 33–38% chance of demonstrating axillary sentinel nodes and a 28–58% chance of demonstrating non‐ipsilateral axillary / extra‐axillary drainage. The more extensive the axillary intervention the greater the chance of extra‐axillary lymphatic drainage. Common sites of non‐ipsilateral axillary lymphatic drainage include – internal mammary nodes and the contralateral axilla. Less common sites include intramammary lymph nodes both in the ipsilateral and the contralateral breast, interpectoral nodes and supraclavicular nodes. Information from the redo SNB alters management in the majority of cases. Re‐operative SNB has been reported after prior mastectomy but there is very little data available. Conclusions: Lymphatic mapping is possible in the majority of ipsilateral local recurrent and new primary breast cancer patients. Re‐operative SNB is technically feasible in the majority of cases where lymphatic drainage is demonstrated. When performed the results change management in the majority of cases.

ABSTRACT Background Although there are well-known prognostic factors for survival from cutaneous melanoma (CM) such as primary tumour thickness and stage of the tumour at diagnosis, the role of germline genetic factors in determining survival is not well understood. Objective To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. Methods We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia (MIA; 5,762 patients with melanoma; 800 deaths from melanoma) and UK Biobank (UKB: 5,220 patients with melanoma; 241 deaths from melanoma). The GWAS were adjusted for age, sex and the first ten genetic principal components, and combined in a fixed-effects inverse-variance-weighted meta-analysis. Significant (P&lt;5×10 −8 ) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts, with replication in the LMC. Results Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, hazard ratio [HR] 2.09, 95% confidence interval [CI] 1.61-2.71, P=2.08×10 −8 ) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR=2.38, 95% CI=1.77—3.21, P=1.07×10 −8 ) on chromosome 7. While neither SNP replicated (P&gt;0.05) in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets and requires confirmation in additional cohorts. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR=0.88, 95% CI=0.83—0.94, P=6.93×10 −5 ; I 2 =88%). The association with the PRS was not replicated (P &gt; 0.05) in LMC, but remained significantly associated with MSS in the meta-analysis of the discovery and replication results. Conclusion We found two loci potentially associated with MSS, and evidence that increased germline genetic susceptibility to develop CM may be associated with improved MSS.

Background: We aimed to determine if preoperative MRI could identify patients in whom the ipsilateral invasive recurrence (IIR) rate was sufficiently low without RT, such that RT might be safely omitted. Here we report primary analysis, and imaging/biopsy findings for occult lesions.