Keun Seok Lee

Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.

Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

Background In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer. Methods This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18–59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients. Findings Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2–not reached) in the ribociclib group compared with 13·0 months (11·0–16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44–0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient. Interpretation Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients. Funding Novartis.

The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer.In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1-21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719).Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5-14·1) in the ipatasertib group and 10·2 months (6·0-13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8-9·0) with ipatasertib versus 4·9 months (3·6-5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37-0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6-9·1) with ipatasertib versus 3·7 months (1·9-7·3) with placebo (stratified HR 0·59, 95% CI 0·26-1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group.Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer.F Hoffmann-La Roche.

Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors.BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients.Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months [95% CI 2·8-4·2] vs 1·8 months [1·5-2·8]; hazard ratio [HR] 0·67, 95% CI 0·53-0·84, one-sided p=0·00030). The most frequent grade 3-4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group).The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations.Novartis Pharmaceuticals Corporation.

Background Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer. Methods KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657. Findings From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8–34·4) for the pembrolizumab group and 31·5 months (27·8–34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9–16·3) for the pembrolizumab group and 11·6 months (8·3–13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57–1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3–12·5) for the pembrolizumab group and 10·2 months (7·9–12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69–1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3–11·4) for the pembrolizumab group and 10·8 months (9·1–12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82–1·15]). The most common grade 3–4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax). Interpretation Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer. Funding Merck Sharp & Dohme.

Abstract Purpose: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months). Patients and Methods: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods. Results: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI. Conclusions: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Purpose The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer. Patients and Methods Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes. Results Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P &lt; .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P &lt; .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032) Conclusion CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.

Brain metastases (BM) occur in up to one third of patients with metastatic breast cancer (MBC), whose incidences and prognoses by breast cancer subtypes in BM have not been well delineated.Retrospective survival analyses were performed in 126 BM patients from 805 MBC patients treated at the National Cancer Center between August 2001 and April 2006, according to clinical characteristics, breast cancer subtypes, and receipt of trastuzumab. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor-2 (HER2) statuses were tested by immunohistochemical (IHC) staining, and HER2 FISH analysis conducted for IHC 2+.The proportion of HER2+/ER- (29% vs 16%) and triple-negative (37% vs 25%) tumors was higher in the 126 BM patients than those without BM. While median survival after recurrence was longer in patients with luminal A disease (median survival of luminal A vs luminal B vs HER2+/ER- vs triple-negative: p = 0.0246; 39.6 vs 27.4 vs 20.9 vs 15.5 months), survival was shorter from BM to death in luminal A and triple negatives (median survival: p = 0.0113; 4.0 vs 9.2 vs 5.0 vs 3.4 months). Receipt of trastuzumab after BM was a significant variable for survival in HER2+ patients. Multivariate analyses identified ER-negative, HER2-negative, or triple-negative, as well as older age, presence of leptomeningeal disease, and three or more extracranial disease sites, as poor prognostic factors for survival after BM.MBC patients who developed BM had higher proportions of triple-negative and HER2+/ER- tumor status. Triple receptor status is a useful prognostic marker for predicting survival after BM in metastatic breast cancer patients.

To ascertain the attitude of cancer patients and their families toward disclosure of terminal illness to the patient.We constructed a questionnaire that included demographic and clinical information and delivered it to 758 consecutive individuals (433 cancer patients and 325 families that have a relative with cancer) at seven university hospitals and one national cancer center in Korea.380 cancer patients and one member from each of 281 families that have a relative with cancer completed the questionnaire. Cancer patients were more likely than family members to believe that patients should be informed of the terminal illness (96.1% v 76.9%; P <.001). Fifty percent of the family members and 78.3% of the patients thought that the doctor in charge should be the one who informs the patient. Additionally, 71.7% of the patients and 43.6% of the family members thought that patients should be informed immediately after the diagnosis. Stepwise multiple logistic regression indicated that the patient group was more likely than the family group to want the patient to be informed of the terminal illness (odds ratio [OR], 9.76; 95% CI, 4.31 to 22.14), by the doctor (OR, 4.00; 95% CI, 2.61 to 6.11), and immediately after the diagnosis (OR, 3.64; 95% CI, 2.45 to 5.41).Our findings indicated that most cancer patients want to be informed if their illness is terminal, and physicians should realize that the patient and the family unit may differ in their attitude toward such a disclosure. Our results also reflect the importance of how information is given to the patient.

To determine whether an Internet-based tailored education program is effective for disease-free cancer survivors with cancer-related fatigue (CRF).We randomly assigned patients who had completed primary cancer treatment within the past 24 months in any of four Korean hospitals and had reported moderate to severe fatigue for at least 1 week to participate in a 12-week, Internet-based, individually tailored CRF education program or to receive routine care. We based the program on the CRF guidelines of the National Comprehensive Cancer Network (NCCN) and incorporated the transtheoretic model (TTM). At baseline and 12 weeks, we used the Brief Fatigue Inventory (BFI) and Fatigue Severity Scale (FSS) as primary outcomes and the Hospital Anxiety and Depression Scale (HADS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) for secondary outcomes.We recruited 273 participants and randomly assigned 136 to the intervention group. Compared with the control group, the intervention group had an improvement in fatigue as shown by a significantly greater decrease in BFI global score (-0.66 points; 95% CI -1.04 to -0.27) and FSS total score (-0.49; 95% CI, -0.78 to -0.21). In secondary outcomes, the intervention group experienced a significantly greater decrease in HADS anxiety score (-0.90; 95% CI, -1.51 to -0.29) as well as global quality of life (5.22; 95% CI, 0.93 to 9.50) and several functioning scores of the EORTC QLQ-C30.An Internet-based education program based on NCCN guidelines and TTM may help patients manage CRF.

<h3>Aims</h3> The prognosis of metaplastic breast cancer (MBC) is reportedly worse than that of triple-negative invasive ductal carcinoma (TN-IDC), but the determinants of poor prognosis are not yet known. <h3>Methods</h3> Patients from two Korean cancer centres were included in this study (67 MBC and 520 TN-IDC). Characteristics of the two disease groups, including clinical parameters, histological features, chemoresponsiveness, disease recurrence and survival estimates, were evaluated. <h3>Results</h3> MBC presented with larger tumours, more frequent distant metastasis and higher histological grade compared with TN-IDC (p&lt;0.001). All but nine patients with MBC had triple-negative disease. Disease-free survival and overall survival (OS) of MBC were worse than TN-IDC (p&lt;0.001). Multivariable analysis of disease-free survival revealed MBC type as an independent prognostic factor (HR 2.53; 95% CI 1.32 to 4.84) along with lymph node metastasis and implementation of breast conserving surgery. For OS, MBC type remained a significant prognostic factor (HR 2.56; 95% CI 1.18 to 5.54). Chemoresponsiveness of MBC and TN-IDC were similar in both neoadjuvant (p=1.000) and advanced disease settings (p=0.508). For a given MBC type, risk factors for disease recurrence included the presence of a squamous component (HR 4.0; 95% CI 1.46 to 10.99) and lymph node metastasis (HR 4.76; 95% CI 1.67 to 13.60); the risk factor for OS was initial distant metastasis (HR 10.77; 95% CI 2.59 to 44.76). <h3>Conclusions</h3> MBC had worse survival outcomes compared with TN-IDC. Poor prognosis for MBC was likely caused by frequent recurrence with high initial stage and the unique biology of MBC itself.

NK105 is a novel nanoparticle drug delivery formulation that encapsulates paclitaxel (PTX) in polymeric micelles. We conducted an open-label phase III non-inferiority trial to compare the efficacy and safety of NK105 and PTX in metastatic or recurrent breast cancer.Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m2) or PTX (80 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 1.215.A total of 436 patients were randomised and 211 patients in each group were included in the efficacy analysis. The median PFS was 8.4 and 8.5 months for NK105 and PTX, respectively (adjusted hazard ratio: 1.255; 95% confidence interval: 0.989-1.592). The median overall survival and overall response rates were 31.2 vs. 36.2 months and 31.6% vs. 39.0%, respectively. The two groups exhibited similar safety profiles. The incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥Grade 3) for NK105 and PTX, respectively. The patient-reported outcomes of PSN were significantly favourable for NK105 (P < 0.0001).The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX.ClinicalTrials.gov: NCT01644890.

Genexol-PM is a Cremophor EL-free formulation of low-molecular-weight, non-toxic, and biodegradable polymeric micelle-bound paclitaxel. We conducted a phase III study comparing the clinical efficacy and toxicity of Genexol-PM with conventional paclitaxel (Genexol).Patients were randomly assigned (1:1) to receive Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 intravenously every 3 weeks. The primary outcome was the objective response rate (ORR).The study enrolled 212 patients, of whom 105 were allocated to receive Genexol-PM. The mean received dose intensity of Genexol-PM was 246.8±21.3 mg/m2 (95.0%), and that of Genexol was 168.3±10.6 mg/m2 (96.2%). After a median follow-up of 24.5 months (range, 0.0 to 48.7 months), the ORR of Genexol-PM was 39.1% (95% confidence interval [CI], 31.2 to 46.9) and the ORR of Genexol was 24.3% (95% CI, 17.5 to 31.1) (pnon-inferiority=0.021, psuperiority=0.016). The two groups did not differ significantly in overall survival (28.8 months for Genexol-PM vs. 23.8 months for Genexol; p=0.52) or progression-free survival (8.0 months for Genexol-PM vs. 6.7 months for Genexol; p=0.26). In both groups, the most common toxicities were neutropenia, with 68.6% occurrence in the Genexol-PM group versus 40.2% in the Genexol group (p < 0.01). The incidences of peripheral neuropathy of greater than grade 2 did not differ significantly between study treatments.Compared with standard paclitaxel, Genexol-PM demonstrated non-inferior and even superior clinical efficacy with a manageable safety profile in patients with metastatic breast cancer.

Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer.The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis.Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus.The primary end point was progression-free survival (PFS).Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16).The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant.ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.

Abstract Background Trastuzumab deruxtecan (T-DXd, DS-8201) is an antibody-drug conjugate with a HER2 antibody, tetrapeptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2 positive metastatic breast cancer (MBC) and supported regulatory approval in the US and Japan. Updated longer-term safety and efficacy results are presented here. Methods All patients were required to have MBC that progressed on or after T-DM1. 253 patients were enrolled and 184 received T-DXd 5.4 mg/kg, representing the primary analysis set. The primary endpoint was ORR. Additional endpoints included duration of response, PFS, and OS. Results Patients had received a median of 6 previous lines of treatment for MBC. In this updated data cutoff (8 June 2020) compared to the prior data cutoff (1 Aug 2019), median duration of follow-up has increased from 11.1 to 20.5 mo; 37 patients (20.1%) remain on treatment. Confirmed ORR was 61.4% (12 CRs) with a median duration of response of 20.8 mo; the disease control rate was 97.3% (95% CI, 93.8-99.1). The updated mPFS was 19.4 mo (95% CI, 14.1 mo-NE). Estimated OS was 85% (95% CI, 79%-90%) at 12 months and 74% (95% CI, 67%-80%) at 18 months. The preliminary mOS is 24.6 mo (estimated at 35% maturity with only 17 patients at risk at 24 months). The safety profile of T-DXd was similar as that previously reported; with an additional 9 mo follow-up, only 3 new cases of T-DXd-related interstitial lung disease (ILD) were reported. Results are summarized in the table below. Conclusion Consistent with prior results, T-DXd demonstrated high rates of durable responses in a heavily pretreated population of patients with MBC. From this single-arm, phase 2 study, the PFS and immature OS results are encouraging; these endpoints will be further evaluated in the ongoing randomized controlled studies of T-DXd. For patients who remained on treatment for this longer duration (double that of the previous report), the rate of discontinuation or ILD did not notably increase. Continued attention to pulmonary symptoms and careful monitoring is warranted. Updated Results for DESTINY-Breast011 Aug 2019 datacut8 Jun 2020 datacutPatients remaining on treatment, n/N (%)79/184 (42.9%)37/184 (20.1%)Median duration of follow-up11.1 months20.5 monthsORR60.9%61.4%CR6.0%6.5%PR54.9%54.9%SD36.4%35.9%Duration of response, median (95% CI)14.8 months (13.8-16.9)20.8 months (15.0-NE)PFS, median (95% CI)16.4 months (12.7-NE)19.4 months (14.1-NE)OSMedian (95% CI)NE (NE-NE)24.6 months (23.1-NE)Point estimate at 12 mo (95% CI)86.2% (79.8-90.7)85% (79-90)Point estimate at 18 mo (95% CI)–74% (67-80)SafetyPatients with a TEAE, n (%)183 (99.5%)183 (99.5%)Grade ≥3105 (57.1%)113 (61.4%)Associated with discontinuation28 (15.2%)34 (18.5%)Associated with death10 (5.4%)10 (5.4%)Drug-related ILD per ILD adjudication committeea25 (13.6%)28 (15.2%)Grade 5 drug-related ILD per ILD adjudication committee4 (2.2%)5 (2.7%)a1 grade 1 and 1 grade 3 event are pending adjudication and are not included. Citation Format: Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Yali Liu, Lin Zhang, Javad Shahidi, Antoine Yver, Jose Baselga, Ian E Krop. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-06.

Improving the prognosis for patients with metastatic HR+/HER2- breast cancer remains an unmet need. Patients with tumors that have progressed on endocrine therapy and/or are not eligible for endocrine therapy had limited treatment options beyond chemotherapy. Antibody-drug conjugates are a novel and promising treatment class in this setting. Datopotamab deruxtecan (Dato-DXd) consists of a TROP2-directed humanized IgG1 monoclonal antibody attached via a serum-stable cleavable linker to a topoisomerase I inhibitor payload. TROPION-Breast01 is an ongoing phase 3 study that is evaluating the efficacy and safety of Dato-DXd compared with investigator's choice of standard-of-care chemotherapy in patients with inoperable or metastatic HR+/HER2- breast cancer who have received one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. Clinical Trial Registration: NCT05104866 ( ClinicalTrials.gov )

The goal of this study was to evaluate the reliability and validity of the Korean version of the Brief Fatigue Inventory (BFI-K). One hundred seventy-eight cancer patients and the same number of age- and sex-matched control subjects completed the BFI-K, the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30), the Beck Depression Inventory (BDI), and a Brief Pain Inventory (BPI). The Cronbach's alpha coefficient for the BFI-K was 0.956 in the cancer patient group and 0.955 in the control group. The global score and nine of the single item scores for the BFI-K were significantly correlated with the fatigue and global health status/QoL subscale of the EORTC QLQ-C30, BDI, and BPI (coefficient range 0.38-0.66). Discriminant validity showed that BFI-K could distinguish significant differences of performance status between subgroups of patients, and between the cancer patient group and the control group, as expected. Our study has shown that the BFI-K is a reliable, valid self-rating instrument in terms of its psychometric properties.

Although it is believed that fish omega-3 fatty acids may decrease breast cancer risk, epidemiological evidence has been inconclusive. This study examined the association between fish and fish omega-3 fatty acids intake with the risk of breast cancer in a case-control study of Korean women.We recruited 358 incident breast cancer patients and 360 controls with no history of malignant neoplasm from the National Cancer Center Hospital between July 2007 and April 2008. The study participants were given a 103-item food intake frequency questionnaire to determine their dietary consumption of fish (fatty and lean fish) and omega-3 fatty acids derived from fish (eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)).Using a multivariate logistic regression model, high intake of fatty fish was associated with a reduced risk for breast cancer in both pre- and postmenopausal women (OR [95% CI] for highest vs. lowest intake quartiles, p for trend: 0.19 [0.08 to 0.45], p < 0.001 for premenopausal women, 0.27 [0.11 to 0.66], p = 0.005 for postmenopausal women). Similarly, reductions in breast cancer risk were observed among postmenopausal subjects who consumed more than 0.101 g of EPA (OR [95% CI]: 0.38 [0.15 to 0.96]) and 0.213 g of DHA (OR [95% CI]: 0.32 [0.13 to 0.82]) from fish per day compared to the reference group who consumed less than 0.014 g of EPA and 0.037 g of DHA per day. Among premenopausal women, there was a significant reduction in breast cancer risk for the highest intake quartiles of omega-3 fatty acids (ORs [95% CI]: 0.46 [0.22 to 0.96]), compared to the reference group who consumed the lowest quartile of intake.These results suggest that high consumption of fatty fish is associated with a reduced risk for breast cancer, and that the intake of omega-3 fatty acids from fish is inversely associated with postmenopausal breast cancer risk.

Several in vitro studies have suggested the effects of adipokines and insulin resistance on breast cancer cell proliferation and survival. However, little is known about the clinical significance of these findings.We examined associations between breast cancer recurrence and adiponectin, leptin, insulin resistance, and metabolic syndrome (MetS) in a cohort of 747 patients from 2001 to 2004.Adjusted hazard ratios showed an inverse trend across the quartiles for serum adiponectin concentration in estrogen receptor (ER)/progesterone receptor (PR) -negative patients (P for trend = 0.027) but not in ER/PR-positive patients. Compared to the highest quartile for adiponectin level, the lowest quartile showed a hazard ratio of 2.82 (1.03 to 7.68). Homeostasis model assessment for insulin resistance (HOMA-IR) showed a positive trend for recurrence in the ER/PR-negative group (P for trend = 0.087) and a negative trend in the ER/PR-positive group (P for trend = 0.081). Leptin did not show any associations (P for trend >0.05). A linear trend was observed with the number of components of MetS in ER/PR-negative patients (P for trend = 0.044). This association disappeared when adjusted for adiponectin and HOMA-IR.Adiponectin and HOMA-IR have prognostic significance in breast cancer recurrence and interventions related to these factors may protect against recurrence in ER/PR-negative patients. These findings were not observed in the case of ER/PR-positive patients. Further evaluation of these insignificant associations is needed because it might be biased by adjuvant chemotherapy or other confounders.

Purpose The primary purpose of our study was to evaluate whether maintenance chemotherapy with paclitaxel/gemcitabine (PG) was superior to observation in improving progression-free survival (PFS) in patients with metastatic breast cancer (MBC) who achieved disease control with an initial six cycles of PG as their first-line treatment. Patients and Methods The study was a prospective, randomized, multicenter, phase III trial. Patients MBC with who achieved disease control after six cycles of PG chemotherapy were randomly assigned to maintenance chemotherapy or observation until progression. Results Of 324 patients from 10 centers enrolled, 231 patients with MBC exhibited disease control (complete response + partial response + stable disease) with first-line PG and were randomly assigned to maintenance chemotherapy (n = 116) or observation (n = 115). The median age was 48 years (range, 28 to 76 years), median follow-up was 33 months, and median number of chemotherapy cycles in the maintenance group after random assignment was six. The median PFS time after random assignment was longer in the maintenance group than in the observation group (7.5 v 3.8 months, respectively; P = .026). The median overall survival (OS) time was longer in the maintenance group than in the observation group (32.3 v 23.5 months, respectively; P = .047). The rate of grade 3 or higher neutropenia after random assignment was higher in the maintenance group than in the observation group (61% v 0.9%, respectively; P &lt; .001). Conclusion In patients with MBC who achieved disease control with an initial six cycles of PG chemotherapy, maintenance PG chemotherapy resulted in better PFS and OS compared with observation.

To compare the health-related quality of life (HRQOL) of disease-free breast cancer survivors at the time of diagnosis and 1 year later with that of the general population (GP) and to examine the predictors of HRQOL change.Although studies that examine the changes HRQOL in breast cancer survivors with cohort design is increasing, few studies compared the HRQOL of breast cancer survivors from baseline (immediately after diagnosis) with that of the GP.We administered European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Quality of Life Questionnaire BR23 HRQOL immediately after diagnosis to evaluate a population-based cohort of 286 women with breast cancer. We compared HRQOL scores of subjects internally and with reference data from the GP externally.We found no significant change in HRQOL internally except for diarrhea. In the external comparison, however, breast cancer survivors reported poorer HRQOL scores than the GP at baseline and a year later; clinically meaningful detriments were found for emotional and social functioning and for the symptoms of fatigue and insomnia, financial difficulties, and most of the breast cancer-specific domains (P < 0.01 for all). Multiple linear regression analysis revealed that menopausal status and the sociodemographic characteristics of education level, employment status, and physical activity at baseline and increased symptom problems were significantly associated with functioning changes.Immediately after the diagnosis of breast cancer, patients reported a lower HRQOL than the GP, and they continued to do so a year later. Increased levels of fatigue, pain, and insomnia were the main symptoms responsible.

The immune system might influence breast cancer (BC) prognosis. However, the relationship between programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocyte (TIL) profiles remains unclear with respect to BC subtypes.We investigated the relationship between TIL profiles for CD8+ and forkhead box P3-positive (FOXP3+) and PD-L1 expression in primary tumor tissue using immunohistochemistry and the clinical outcomes in 2 patient cohorts at the National Cancer Center: 256 patients diagnosed with early-stage BC from January 2001 to December 2005 and 77 hormone receptor (HR)-negative BC patients diagnosed from January 2006 to December 2008. Clinical data were collected, including HR status, human epidermal growth factor receptor 2 expression, disease-free survival, and overall survival (OS).The median patient age was 47 years (range, 28-78), and the median follow-up period was 9.8 years. Of the 333 patients, 186 (55.9%) had HR-positive and 125 (37.5%) had node-positive BC. We found a strong positive correlation between CD8+ TILs and FOXP3+ TILs (P < .001). CD8+ TILs were more abundant in tumors with low PD-L1 expression (P < .001), although no association was found between FOXP3+ TILs and PD-L1 expression. More CD8+ TILs were present in HR-negative than in HR-positive BC (P < .001), and PD-L1 expression was more frequent in HR-positive BC (P < .001). A greater number of CD8+ TILs (increase in quartile) was strongly associated with OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.95; P = .03) only in HR-negative BC when adjusted for various clinical factors. PD-L1 expression and FOXP3+ TILs did not exhibit such associations.Higher CD8+ lymphocyte infiltration was related to lower PD-L1 expression and higher FOXP3+ TIL infiltration in BC. Higher CD8+ TIL expression was associated with prolonged survival only in those with HR-negative BC.

1013 Background: In the randomized, open-label, phase 3 KEYNOTE-119 study (NCT02555657) , OS was not significantly different with pembro monotherapy versus chemo in second- or third-line settings for mTNBC; however, the pembro treatment effect increased with increasing PD-L1 enrichment. We evaluated the association of TMB with efficacy of pembro monotherapy versus chemo in patients with previously treated mTNBC. Methods: Patients with centrally confirmed TNBC and 1 or 2 prior systemic treatments for metastatic disease were enrolled. Patients were randomly assigned 1:1 to pembro 200 mg Q3W or single-agent chemo per investigator’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine. Association of TMB, as measured by FoundationOne CDx (Foundation Medicine), with response was an exploratory objective evaluated using receiver operator characteristic (ROC) analysis, logistic regression (ORR), and Cox regression (OS; PFS) within treatment arms; estimates of efficacy based on TMB cutpoint used a prespecified cutpoint of 10 mut/Mb. Results: TMB data were available for 253/601 (42.1%) treated patients (pembro, n = 132; chemo, n = 121); baseline characteristics were similar to that of the overall study population. One-sided P values for the association of TMB and clinical outcomes in pembro-treated patients were 0.154 for ORR, 0.014 for PFS, and 0.018 for OS; the area under the ROC curve ([AUROC] 95% CI) for predicting ORR was 0.58 (0.43-0.73). Two-sided P values for the association of TMB and clinical outcomes in chemo-treated patients were 0.114 for ORR, 0.478 for PFS, and 0.906 for OS; AUROC (95% CI) was 0.43 (0.27-0.59). Twenty-six patients had TMB ≥10 mut/Mb. Thus, the prevalence of TMB ≥10 mut/Mb was ~10%. Outcomes based on TMB cutpoint are reported in the Table. Conclusions: Data from this exploratory analysis from KEYNOTE-119 suggest a potential positive association between TMB and clinical benefit with pembro but not chemo in patients with mTNBC. Although precision is limited by sample size and the number of patients with TMB ≥10 mut/Mb, ORR and HRs for OS suggested a trend towards increased benefit with pembro versus chemo in patients with TMB ≥10 mut/Mb. Clinical trial information: NCT02555657 . [Table: see text]

LBA3 Background: About 55% of mBC typically categorized as HER2 negative, express low levels of HER2 (IHC 1+ or IHC 2+/ISH− by ASCO/CAP 2018 guidelines) with poor outcomes in later lines (Tarantino 2020). T-DXd has shown promising efficacy in HER2-low mBC in a phase 1 study (NCT02564900; Modi 2020). This is the primary report from DESTINY-Breast04 (NCT03734029), the first randomized, multicenter, open-label, phase 3 study comparing efficacy and safety of T-DXd vs TPC in pts with HER2-low mBC treated with 1-2 prior lines of chemotherapy in the metastatic setting. Methods: 557 pts with centrally confirmed HER2-low mBC were randomly assigned 2:1 to T-DXd 5.4 mg/kg or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR) in pts with hormone receptor–positive (HR+) mBC. Key secondary endpoints (hierarchically tested after the primary endpoint) include PFS by BICR in the full analysis set (FAS; HR+/−) and overall survival (OS) in pts with HR+ mBC and in FAS. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of pts with HR− mBC. Results: As of Jan 11, 2022, 373 and 184 pts (88.7% and 88.6% HR+ mBC) were assigned to T-DXd and TPC, respectively. Median follow-up was 18.4 months (mo; 95% CI, 17.9-19.1). Median treatment duration was 8.2 mo (range, 0.2-33.3) with T-DXd and 3.5 mo (range, 0.3-17.6) with TPC. Efficacy results are in the Table. 52.6% of pts with T-DXd vs. 67.4% of pts with TPC had grade (G) ≥ 3 treatment-emergent adverse events (TEAEs). With T-DXd, 45 pts (12.1%; 10.0% G1/2, 1.3% G3/4, 0.8% G5) had independently adjudicated drug-related interstitial lung disease [ILD]/pneumonitis vs. 1 pt (0.6% G1) with TPC. Conclusions: DESTINY-Breast04 is the first phase 3 trial of a HER2-directed therapy in pts with HER2-low mBC to show a statistically significant and clinically meaningful benefit in PFS and OS compared to standard-of-care treatment, regardless of HR status, with a generally manageable safety profile. Funding: Daiichi Sankyo, Inc., and AstraZeneca. Clinical trial information: NCT03734029. [Table: see text]

PF-06804103 is an anti-HER2 antibody-drug conjugate with auristatin payload. We evaluated its safety, tolerability, and antitumor activity in patients with advanced/unresectable or metastatic breast and gastric cancers. This multicenter, open-label, first-in-human, phase 1 study (NCT03284723) comprised dose escalation (P1) and dose expansion (P2). In P1, adults with HER2+ breast or gastric cancer received PF-06804103 0.15-5.0 mg/kg intravenously once/21 days (Q3W); in P2, patients with HER2+ or HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer received 3.0 or 4.0 mg/kg Q3W. The primary endpoints were dose-limiting toxicities (DLT) and safety (P1), and objective response rate (ORR) assessed using RECIST v1.1 (P2). Ninety-three patients enrolled in P1 (n = 47: HER2+ gastric cancer = 22, HER2+ breast cancer = 25) and P2 [n = 46: HER2+ breast cancer = 19, hormone receptor (HR)+ HER2-low breast cancer = 27] received PF-06804103. Four patients (3.0- and 4.0-mg/kg groups, n = 2 each) had DLTs (mostly Grade 3). Safety and efficacy results showed a dose-response relationship. Adverse events (AE) leading to treatment discontinuation (44/93, 47.3%) included neuropathy (11/93, 11.8%), skin toxicity (9/93, 9.7%), myalgia (5/93, 5.4%), keratitis (3/93, 3.2%), and arthralgia (2/93, 2.2%). Two (2/79, 2.5%) patients (P1, 4.0- and 5.0-mg/kg groups, n = 1 each) achieved complete response; 21 (21/79, 26.6%) achieved partial response. In P2, ORR was higher in HER2+ compared with HR+ HER2-low breast cancer [3.0 mg/kg: 16.7% (2/12) vs. 10.0% (1/10); 4.0 mg/kg: 47.4% (9/19) vs. 27.3% (3/11)]. PF-06804103 demonstrated antitumor activity; however, AEs led to discontinuation in 47.3% of patients. Safety and efficacy were dose-dependent.

Purpose To evaluate the efficacy and safety of preoperative chemoradiation with cetuximab, irinotecan, and capecitabine in patients with rectal cancer. Methods and Materials Forty patients with locally advanced, nonmetastatic, and mid- to lower rectal cancer were enrolled. Radiotherapy was delivered at a dose of 50.4 Gy/28 fractions. Concurrent chemotherapy consisted of an initial dose of cetuximab of 400 mg/m2 1 week before radiotherapy, and then cetuximab 250 mg/m2/week, irinotecan 40 mg/m2/week for 5 consecutive weeks and capecitabine 1,650 mg/m2/day for 5 days a week (weekdays only) from the first day during radiotherapy. Total mesorectal excision was performed within 6 ± 2 weeks. The pathologic responses and survival outcomes were evaluated as study endpoints, and an additional KRAS mutation analysis was performed. Results In total, 39 patients completed their planned preoperative chemoradiation and underwent R0 resection. The pathologic complete response rate was 23.1% (9/39), and 3 patients (7.7%) showed near total regression of tumor. The 3-year disease-free and overall survival rates were 80.0% and 94.7%, respectively. Grade 3/4 toxicities included leukopenia (4, 10.3%), neutropenia (2, 5.1%), anemia (1, 2.6%), diarrhea (2, 5.1%), fatigue (1, 2.6%), skin rash (1, 2.6%), and ileus (1, 2.6%). KRAS mutations were found in 5 (13.2%) of 38 patients who had available tissue for testing. Clinical outcomes were not significantly correlated with KRAS mutation status. Conclusions Preoperative chemoradiation with cetuximab, irinotecan, and capecitabine was active and well tolerated. KRAS mutation status was not a predictive factor for pathologic response in this study. To evaluate the efficacy and safety of preoperative chemoradiation with cetuximab, irinotecan, and capecitabine in patients with rectal cancer. Forty patients with locally advanced, nonmetastatic, and mid- to lower rectal cancer were enrolled. Radiotherapy was delivered at a dose of 50.4 Gy/28 fractions. Concurrent chemotherapy consisted of an initial dose of cetuximab of 400 mg/m2 1 week before radiotherapy, and then cetuximab 250 mg/m2/week, irinotecan 40 mg/m2/week for 5 consecutive weeks and capecitabine 1,650 mg/m2/day for 5 days a week (weekdays only) from the first day during radiotherapy. Total mesorectal excision was performed within 6 ± 2 weeks. The pathologic responses and survival outcomes were evaluated as study endpoints, and an additional KRAS mutation analysis was performed. In total, 39 patients completed their planned preoperative chemoradiation and underwent R0 resection. The pathologic complete response rate was 23.1% (9/39), and 3 patients (7.7%) showed near total regression of tumor. The 3-year disease-free and overall survival rates were 80.0% and 94.7%, respectively. Grade 3/4 toxicities included leukopenia (4, 10.3%), neutropenia (2, 5.1%), anemia (1, 2.6%), diarrhea (2, 5.1%), fatigue (1, 2.6%), skin rash (1, 2.6%), and ileus (1, 2.6%). KRAS mutations were found in 5 (13.2%) of 38 patients who had available tissue for testing. Clinical outcomes were not significantly correlated with KRAS mutation status. Preoperative chemoradiation with cetuximab, irinotecan, and capecitabine was active and well tolerated. KRAS mutation status was not a predictive factor for pathologic response in this study.

Although the introduction of human epidermal growth factor receptor (HER)2‐directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T‐DM1) in the treatment of HER2‐positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2‐positive mBC will eventually progress. Poziotinib is an oral pan‐HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open‐label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2‐positive mBC who had progressed from more than two HER2‐directed therapies. Patients received 12 mg poziotinib once daily on a 14‐day on/7‐day off schedule. Progression‐free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30–76) and had received a median of four prior therapies including two HER2‐directed therapies for advanced or metastatic cancers. The median follow‐up duration was 12 months. The median PFS was 4.04 months (95% confidence interval [CI], 2.94–4.40 months), and median overall survival has not been reached. The most common treatment‐related adverse events were (total/grade ≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2‐positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases.

Purpose The purpose of this study is to determine whether breast cancer subtype can affect locoregional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) after neoadjuvant chemotherapy (NAC) and breast-conserving therapy (BCT). Materials and Methods We evaluated 335 consecutive patients with clinical stage II-III breast cancer who received NAC plus BCT from 2002 to 2009. Patients were classified according to six molecular subtypes: luminal A (hormone receptor [HR]+/HER2–/Ki-67 < 15%, n=113), luminal B1 (HR+/HER2–/Ki-67 ≥ 15%, n=33), luminal B2 (HR+/HER2+, n=83), HER2 with trastuzumab (HER2[T+]) (HR–/HER2+/use of trastuzumab, n=14), HER2 without trastuzumab (HER2[T–]) (HR–/HER2+, n=31), and triple negative (TN) (HR–/HER2–, n=61). Results After a median follow-up period of 7.2 years, 26 IBTRs and 37 LRRs occurred. The 5-year LRR-free survival rates were luminal A, 96.4%; B1, 93.9%; B2, 90.3%; HER2(T+), 92.9%; HER2(T–), 78.3%; and TN, 79.6%. The 5-year IBTR-free survival rates were luminal A, 97.2%; B1, 93.9%; B2, 92.8%; HER2(T+), 92.9%; HER2(T–), 89.1%; and TN, 84.6%. In multivariate analysis, HER2(T–) (IBTR: hazard ratio, 4.2; p=0.04 and LRR: hazard ratio, 7.6; p < 0.01) and TN subtypes (IBTR: hazard ratio, 6.9; p=0.01 and LRR: hazard ratio, 8.1; p < 0.01) were associated with higher IBTR and LRR rates. A pathologic complete response (pCR) was found to show correlation with better LRR and a tendency toward improved IBTR controls in TN patients (IBTR, p=0.07; LRR, p=0.03). Conclusion The TN and HER2(T–) subtypes predict higher rates of IBTR and LRR after NAC and BCT. A pCR is predictive of improved IBTR or LRR in TN subtype. Key words: Breast neoplasms, Molecular subtype, Neoadjuvant chemotherapy, Ipsilateral breast tumor recurrence, Local neoplasm recurrence

This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer.Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review.The risk ratio for ORR was 0.940 (95% CI: 0.842-1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80-1.25. ORR was 62.5% (95% CI: 57.2-67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3-71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups.When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR.ClinicalTrials.gov, NCT01989676.

BackgroundWe assessed the effect of chemotherapy regimens beyond first-line agents on the clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC).Patients and MethodsWe included 240 patients who were prospectively enrolled into various clinical trials and were receiving cytotoxic chemotherapy for HER2-negative MBC at the National Cancer Center, Korea, from October 2002 to September 2012. Clinicopathologic data were collected for the analysis.ResultsA total of 240, 209, and 166 patients received first-, second-, and third-line chemotherapy, respectively. The median age was 49 years (range, 28-77 years), and most had hormone receptor-positive cancer (n = 177; 73.8%). The median progression-free survival (PFS) was 7.6 months for first-line (PFS1) versus 5.1 months for second-line (PFS2) versus 3.6 months for third-line (PFS3) chemotherapy. The PFS from previous chemotherapy significantly affected subsequent PFS: PFS1 for PFS2, PFS1 ≥ 7.6 months, hazard ratio (HR) 0.647; 95% confidence interval (CI), 0.0.484-0.864 (P = .003); PFS2 for PFS3, PFS2 ≥ 5.1 months, HR 0.676; 95% CI, 0.0.484-0.944; P = .022). The median overall survival was 31.2 months (95% CI, 26.4-36.0 months). Hormone receptor positivity (HR 0.548; 95% CI, 0.261-0.499; P < .001) and PFS1 ≥ 7.6 months (HR 0.361; 95% CI, 0.393-0.765; P < .001) were significant factors for survival on multivariate analysis.ConclusionThe efficacy of previous treatment significantly affected the outcomes of subsequent treatment. We have confirmed that the succession of chemotherapy is justified in patients with MBC who benefited from previous chemotherapy.

Purpose The aim of this study was to develop a combined statistical model using both clinicopathological factors and texture parameters from 18 F-FDG PET/CT to predict responses to neoadjuvant chemotherapy in patients with breast cancer. Materials and Methods A total of 435 patients with breast cancer were retrospectively enrolled. Clinical and pathological data were obtained from electronic medical records. Texture parameters were extracted from pretreatment FDG PET/CT images. The end point was pathological complete response, defined as the absence of residual disease or the presence of residual ductal carcinoma in situ without residual lymph node metastasis. Multivariable logistic regression modeling was performed using clinicopathological factors and texture parameters as covariates. Results In the multivariable logistic regression model, various factors and parameters, including HER2, histological grade or Ki-67, gradient skewness, gradient kurtosis, contrast, difference variance, angular second moment, and inverse difference moment, were selected as significant prognostic variables. The predictive power of the multivariable logistic regression model incorporating both clinicopathological factors and texture parameters was significantly higher than that of a model with only clinicopathological factors ( P = 0.0067). In subgroup analysis, texture parameters, including gradient skewness and gradient kurtosis, were selected as independent prognostic factors in the HER2-negative group. Conclusions A combined statistical model was successfully generated using both clinicopathological factors and texture parameters to predict the response to neoadjuvant chemotherapy. Results suggest that addition of texture parameters from FDG PET/CT can provide more information regarding treatment response prediction compared with clinicopathological factors alone.

Purpose We investigated whether irinotecan plus capecitabine improved progression-free survival (PFS) compared with capecitabine alone in patients with human epidermal growth factor 2 (HER2) negative and anthracycline and taxane pretreated metastatic breast cancer (MBC). Materials and Methods A total of 221 patients were randomly assigned to irinotecan (80 mg/m2, days 1 and 8) and capecitabine (1,000 mg/m2 twice a day, days 1-14) or capecitabine alone (1,250 mg/m2 twice a day, days 1-14) every 3 weeks. The primary endpoint was PFS. Results There was no significant difference in PFS between the combination and monotherapy arm (median, 6.4 months vs. 4.7 months; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63 to 1.11; p=0.84). In patients with triple-negative breast cancer (TNBC, n=90), the combination significantly improved PFS (median, 4.7 months vs. 2.5 months; HR, 0.58; 95% CI, 0.37 to 0.91; p=0.02). Objective response rate was numerically higher in the combination arm, though it failed to reach statistical significance (44.4% vs. 33.3%, p=0.30). Overall survival did not differ between arms (median, 20.4 months vs. 24.0 months; p=0.63). While grade 3 or 4 neutropenia was more common in the combination arm (39.6% vs. 9.0%), hand-foot syndrome was more often observed in capecitabine arm. Quality of life measurements in global health status was similar. However, patients in the combination arm showed significantly worse symptom scales especially in nausea/vomiting and diarrhea. Conclusion Irinotecan plus capecitabine did not prove clinically superior to single-agent capecitabine in anthracycline- and taxane-pretreated HER2 negative MBC patients. Toxicity profiles of the two groups differed but were manageable. The role of added irinotecan in patients with TNBC remains to be elucidated. Key words: Metastatic breast cancer, Irinotecan, Capecitabine, Clinical trial, Progression free survival

Abstract Purpose: This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). Patients and Methods: This study enrolled premenopausal women with HR+, HER2− ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n = 16) or buparlisib (100 mg once daily; n = 13) in 28-day cycles until MTD was observed. Results: The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group. Conclusions: The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2− ABC. See related commentary by Clark et al., p. 371

Importance Addition of immune checkpoint inhibitors to anti- ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects. Objective To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2 -positive early breast cancer warrants continuation to the next phase. Design, Setting, and Participants This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2 -positive breast cancer (primary tumor size &amp;gt;2 cm or pathologically confirmed lymph node–positive cancer, without distant metastases) with a clinical stage of II or III. Interventions Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m 2 ), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks. Main Outcomes and Measures The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes. Results A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor–negative disease vs hormone receptor–positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1–positive expression vs programmed cell death 1–negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase. Conclusions and Relevance In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2 -positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2 -positive early breast cancer is warranted. Trial Registration ClinicalTrials.gov Identifier: NCT03881878

This study aimed to evaluate the Korean version of the M. D. Anderson Symptom Inventory (MDASI-K) as a tool for assessing multiple symptoms in Korean cancer patients. Participants (178 cancer patients and 178 age and sex-matched community-dwelling adults) completed the MDASI-K and the Korean version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30. The MDASI-K exhibited substantial reliability and validity. Cronbach alpha coefficients were 0.91 and 0.93 in the cancer patients, and 0.96 and 0.96 in the normal group for both symptom and interference, respectively. MDASI-K summary scores correlated significantly with those of the EORTC QLQ-C30. Discriminant validity of the MDASI-K was demonstrated by its ability to clearly distinguish significant differences within different Eastern Cooperative Oncology Group performance statuses and those between the patient and normal groups in the mean scores of both symptom and interference. The MDASI-K is a valid and reliable measure for assessing multiple symptoms in Korean cancer patients.

Goserelin and letrozole in premenopausal patients can result in clinical outcomes comparable to those obtained by letrozole alone in postmenopausal patients with metastatic breast cancer (MBC).A total of 73 patients with hormone-responsive MBC were included. Of those, 35 premenopausal patients received goserelin (3.6 mg subcutaneously every 28 days) plus letrozole (2.5 mg orally daily), and 38 postmenopausal patients received letrozole alone as their first-line endocrine therapy in a metastatic setting.Baseline characteristics were similar in the two groups, except for a younger age (median, 41 v 53.5 years; P < .001) and a shorter disease-free interval (median, 1.8 v 3.3 years; P = .03) in the premenopausal group. Clinical benefit rates were comparable between the two groups (77% v 74%; P = .77). With the median follow-up of 27.4 months, there was no statistical difference in the median time to progression between the two groups (9.5 months [95% CI, 6.4 to 12.1 months] v 8.9 months [95% CI, 6.4 to 13.3 months]). In patients who did not receive bisphosphonate, letrozole +/- goserelin caused a greater loss of bone mineral density at 6 months compared with that of patients receiving bisphosphonate treatment (premenopausal group, -16.7% v 53.9%; P = .002 and postmenopausal group, -13.3% v 17.4%; P = .04 at the lumbar spine).Clinical efficacies in premenopausal MBC patients with combined letrozole and goserelin therapy were comparable to those in postmenopausal patients treated with letrozole alone. Although letrozole +/- goserelin resulted in a modest increase in bone resorption, concurrent treatment with bisphosphonate could prevent bone loss at 6 months.

We tested whether a decision aid explaining how to discuss the approach of death with a family member with cancer would help family caregivers decide to discuss a terminal prognosis.We randomly assigned caregivers of terminally ill patients with cancer to a group that received a video and a companion workbook that showed either how they can discuss the prognosis with their patient (experimental arm) or how cancer pain can be controlled (control arm). At baseline and 1 month, we evaluated the decision to discuss terminal prognosis as the primary outcome. At 0, 1, 3, and 6 months, we assessed the caregivers' decisional conflict and satisfaction as secondary outcomes using a Decision Conflict Scale (DCS).We found no difference in changes in the decision to discuss terminal prognosis between the two groups. Conflict (P = .003), uncertainty (P = .019), and value clarity (P = .007) subscale scores and total DCS score (P = .008) improved from baseline to 1 month significantly more in the experimental arm than in the control arm. Over 6 months, the significant between-group differences continued for the conflict (P = .031), uncertainty (P = .014), and value clarity (P = .039) subscale scores and total DCS score (P = .040).Decision aids can help caregivers, with the aid of trained professionals, to communicate with patients about their terminal illness.

Purpose The aim of this study was to examine molecular subtype conversions in patients who underwent neoadjuvant chemotherapy (NAC) and analyze their clinical implications. Materials and Methods We included consecutive breast cancer patients who received NAC at the National Cancer Center, Korea, between August 2002 and June 2011, and had available data on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) receptor status prior to NAC. Molecular subtypes, hormone receptor (HR) status, and ER and PR Allred scores before and after NAC were compared, and the long-term outcomes were analyzed. Results Of 322 patients, 32 (9.9%) achieved a pathologic complete response after NAC. HR+/HER2– tumors tended to convert into triple negative (TN) tumors (10.3%), whereas 34.6% of TN tumors gained HR positivity to become HR+/HER2– tumors. Clinical outcomes of molecular subtype conversion groups were compared against patients who remained as HR+/HER2– throughout. The HR+/HER2– to TN group had significantly poorer recurrence-free survival (RFS) (hazard ratio, 3.54; 95% confidence interval [CI], 1.60 to 7.85) and overall survival (OS) (hazard ratio, 3.73; 95% CI, 1.34 to 10.38). Patients who remained TN throughout had the worst outcomes (for RFS: hazard ratio, 3.70; 95% CI, 1.86 to 7.36; for OS: hazard ratio, 5.85; 95% CI, 2.53 to 13.51), while those who converted from TN to HR+/HER2–showed improved comparable survival outcomes. Conclusion Molecular subtypes of breast cancers changed frequently after NAC, resulting in different tumor prognostication. Tumor subtyping should be repeated after NAC in patients with breast cancer. Key words: Breast neoplasms, Molecular subtype, Receptor status, Neoadjuvant chemotherapy

Abstract Background: MONALEESA-7 (NCT02278120), the first large randomized phase III clinical trial dedicated to investigating a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus ET vs ET + placebo (PBO) in pre- or perimenopausal patients with HR+/HER2− ABC, previously demonstrated a statistically significant improvement in OS with the addition of ribociclib (RIB) to ET vs PBO + ET (median, not reached vs 40.9 months; HR, 0.71 [95% CI, 0.54-0.95]; P = .00973; Im SA, et al. N Engl J Med. 2019). This concluded the protocol-defined final analysis of OS and the patients and investigators were unblinded to their treatment assignment allowing patients on the PBO arm to cross-over to RIB treatment. Longer follow-up allows for more events to further characterize the long-term survival benefits. Here we report an exploratory update of OS after a minimum of ~ four years of follow-up, an additional 20 months since the last report. Methods: Pre- or perimenopausal patients with HR+/HER2− ABC were randomized 1:1 to receive RIB or PBO plus goserelin with either a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) or tamoxifen. RIB is approved in combination with an NSAI in pre- or perimenopausal patients. Patients who had received a prior CDK4/6i or ET in the advanced setting were excluded. Patients who received ET in the (neo)adjuvant setting or ≤ 1 prior line of chemotherapy for advanced disease were eligible to enroll. Updated OS were evaluated by Cox proportional hazards model and summarized using Kaplan-Meier methods. Additional post-progression endpoints such as progression-free survival 2 (PFS2), time to chemotherapy (CT) and CT-free survival were also evaluated and summarized. Results: The data cutoff for this updated OS analysis was 29 June 2020, and the median follow-up was 53.5 mo (min, 46.9 mo). These updated results with extended follow-up demonstrated an OS benefit with RIB + ET vs PBO + ET (median, 58.7 vs 48.0 mo; HR, 0.76 [95% CI, 0.61-0.96]). In patients receiving an NSAI, a similar OS benefit was observed with RIB + NSAI vs PBO + NSAI (median, 58.7 vs 47.7 mo; HR, 0.80 [95% CI, 0.62-1.04]). The survival benefit shown in subgroup analyses was consistent with the intent-to-treat (ITT) population. PFS2, time to chemotherapy (CT), and CT-free survival for the ITT and NSAI populations are in the Table. Among the patients who discontinued study treatment, 77.3% and 78.1% in the RIB + ET vs PBO + ET arms received a subsequent antineoplastic therapy, respectively, and 12.9% and 26.1% received a subsequent line of CDK4/6i. Additionally there were 15 patients in the PBO arm that crossed over to the RIB arm following unblinding and prior to disease progression. Conclusions: With an extended follow-up of more than 4 years, RIB + ET continued to demonstrate a clinically relevant OS benefit compared with ET alone in pre- or perimenopausal patients with a median OS ~5 years with RIB +ET in HR+/HER2− ABC. A similar benefit with RIB was observed for PFS2, time to CT, and CT-free survival. ITTNSAI cohortRIB + ETn=335PBO + ETn=337RIB + NSAIn=248PBO + NSAIn=247PFS2Events, n (%)177 (52.8)221 (65.6)131 (52.8)159 (64.4)Median, mo44.231.043.630.4HR (95% CI)0.68 (0.56-0.83)0.69 (0.55-0.87)Time to first CTEvents, n (%)144 (43.0)173 (51.3)107 (43.1)129 (52.2)Median, mo50.936.850.936.0ITT HR(95% CI)0.69 (0.56-0.87)0.66 (0.51-0.85)CT-free survivalEvents, n (%)190 (56.7)236 (70.0)139 (56.0)169 (68.4)Median, mo42.426.442.525.9HR (95% CI)0.67 (0.55-0.81)0.64 (0.51-0.81) Citation Format: Debu Tripathy, Seock-Ah Im, Marco Colleoni, Fabio Franke, Aditya Bardia, Nadia Harbeck, Sara Hurvitz, Louis Chow, Joohyuk Sohn, Keun Seok Lee, Saul Campos-Gomez, Rafael Villanueva Vazquez, Kyung Hae Jung, K Govind Babu, Paul Wheatley-Price, Michelino De Laurentiis, Young-Hyuck Im, Sherko Kümmel, Nagi El-Saghir, Mei-Ching Liu, Sharonjeet Kaur, Claudia Gasch, Craig Wang, Yongyu Wang, Arunava Chakravartty, Yen-Shen Lu. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-04.

In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice.This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor-positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events.Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93-8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67-11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%).Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842.

Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) are reliable ways to identify overexpression or amplification of the HER-2/neu (HER2, symbol ERBB2) gene, but each technique requires a high-quality tissue sample, which may not be available. We investigated whether serum concentrations of the HER2 extracellular domain (ECD) can be used as an alternative to tissue HER2 status in metastatic breast cancer, and we defined an optimal decision-level concentration of serum HER2 for prediction of tissue HER2 status.In 195 patients with metastatic breast cancer, we determined HER2 expression by IHC and performed FISH analysis on tumors for which IHC staining was graded as 2+. We measured serum HER2 by immunoassay and used ROC curve analysis to determine optimal serum HER2 ECD concentrations for differentiation between positive and negative HER2 status.IHC results were 0/1+ for 30 (15%) of the patients, 2+ for 89 (46%), and 3+ for 76 (39%). FISH revealed HER2 amplification in 19 (21%) of the IHC 2+ tumors. Mean (SE) serum HER2 ECD was 22.2 (5.1) microg/L in the tissue HER2-negative group, significantly lower than the concentration of 363 (96) microg/L in the tissue HER2-positive group (P<0.0001). ROC curve analysis showed 95% specificity and 62% sensitivity for tissue HER2 positivity at 37 microg/L of serum HER2.To use serum HER2 concentration as an alternative to direct determination of tissue HER2 status, we suggest 37 microg/L as a cutoff for predicting positive tissue HER2 with 95% specificity. Sensitivity, however, is low.

The risk for lymphedema (LE) after neoadjuvant chemotherapy (NCT) in breast cancer patients has not been fully understood thus far. This study is conducted to investigate the incidence and time course of LE after NCT.A total of 313 patients with clinically node-positive breast cancer who underwent NCT followed by surgery with axillary lymph node (ALN) dissection from 2004 to 2009 were retrospectively analyzed. All patients received breast and supraclavicular radiation therapy (SCRT). The determination of LE was based on both objective and subjective methods, as part of a prospective database.At a median follow-up of 5.6 years, 132 patients had developed LE: 88 (28%) were grade 1; 42 (13%) were grade 2; and two (1%) were grade 3. The overall 5-year cumulative incidence of LE was 42%. LE first occurred within 6 months after surgery in 62%; 1 year in 77%; 2 years in 91%; and 3 years in 96%. In a multivariate analysis, age (hazard ratio [HR], 1.66; p < 0.01) and the number of dissected ALNs (HR, 1.68; p < 0.01) were independent risk factors for LE. Patients with both of these risk factors showed a significantly higher 5-year cumulative incidence of LE compared with patients with no or one risk factor (61% and 37%, respectively; p < 0.001). The addition of adjuvant chemotherapy did not significantly correlate with LE.LE after NCT, surgery, and SCRT developed early after treatment, and with a high incidence rate. More frequent surveillance of arm swelling may be necessary in patients after NCT, especially during the first few years of follow-up.

Although the invasive lobular carcinoma (ILC) is the second most frequent histologic subtype in Western countries, its incidence is much lower in Asia, and its characteristics are less well known.We assessed the clinical characteristics and outcomes of 83 Korean patients (2.8%) with ILC for comparison with 2,833 (97.2%) with the invasive ductal carcinoma (IDC), including 1,088 (37.3%) with the luminal A subtype (LA-IDC).The mean age of all patients was 48.2 years, with no significant differences among the groups. Compared to IDC, ILC showed a larger tumor size (≥ T2, 59.8% vs. 38.8%, P = 0.001), a lower histologic grade (HG 1/2, 90.4% vs. 64.4%, P < 0.001), more frequent estrogen receptor positive (90.4% vs. 64.4%, P < 0.001), progesterone receptor positive (71.1% vs. 50.1%, P < 0.001) and HER2 negative (97.5% vs. 74.6%, P < 0.001) status, and lower Ki-67 expression (10.3% ± 10.6% vs. 20.6% ± 19.8%, P < 0.001), as well as being more likely to be of the luminal A subtype (91.4% vs. 51.2%, P < 0.001). Six (7.2%) ILC and 359 (12.7%) IDC patients developed disease recurrence, with a median follow-up of 56.4 (range 4.9-136.6) months. The outcome of ILC was close to LA-IDC (HR 0.77 for recurrence, 95% CI 0.31-1.90, P = 0.57; HR 0.75 for death, 95% CI 0.18-3.09, P = 0.70) and significantly better than for the non-LA-IDC (HR 1.69 for recurrence, 95% CI 1.23-2.33, P = 0.001; HR 1.50 for death, 95% CI 0.97-2.33, P = 0.07).ILC, a rare histologic type of breast cancer in Korea, has distinctive clinicopathological characteristics similar to those of LA-IDC.

Purpose To evaluate the treatment outcome and efficacy of regional lymph node irradiation after neoadjuvant chemotherapy (NCT) and surgery in positron emission tomography (PET)–positive clinical N3 (cN3) breast cancer patients. Methods and Materials A total of 55 patients with ipsilateral infraclavicular (ICL), internal mammary (IMN), or supraclavicular (SCL) lymph node involvement in the absence of distant metastases, as revealed by an initial PET scan, were retrospectively analyzed. The clinical nodal stage at diagnosis (2002 AJCC) was cN3a in 14 patients (26%), cN3b in 12 patients (22%), and cN3c in 29 patients (53%). All patients were treated with NCT, followed by mastectomy or breast-conserving surgery and subsequent radiotherapy (RT) with curative intent. Results At the median follow-up of 38 months (range, 9–80 months), 20 patients (36%) had developed treatment failures, including distant metastases either alone or combined with locoregional recurrences that included one ipsilateral breast recurrence (IBR), six regional failures (RF), and one case of combined IBR and RF. Only 3 patients (5.5%) exhibited treatment failure at the initial PET-positive clinical N3 lymph node. The 5-year locoregional relapse-free survival, disease-free survival (DFS), and overall survival rates were 80%, 60%, and 79%, respectively. RT delivered to PET-positive IMN regions in cN3b patients and at higher doses (≥55 Gy) to SCL regions in cN3c patients was not associated with improved 5-year IMN/SCL relapse-free survival or DFS. Conclusion NCT followed by surgery and RT, including the regional lymph nodes, resulted in excellent locoregional control for patients with PET-positive cN3 breast cancer. The primary treatment failure in this group was due to distant metastasis rather than RF. Neither higher-dose RT directed at PET-positive SCL nodes nor coverage of PET-positive IMN nodes was associated with additional gains in locoregional control or DFS. To evaluate the treatment outcome and efficacy of regional lymph node irradiation after neoadjuvant chemotherapy (NCT) and surgery in positron emission tomography (PET)–positive clinical N3 (cN3) breast cancer patients. A total of 55 patients with ipsilateral infraclavicular (ICL), internal mammary (IMN), or supraclavicular (SCL) lymph node involvement in the absence of distant metastases, as revealed by an initial PET scan, were retrospectively analyzed. The clinical nodal stage at diagnosis (2002 AJCC) was cN3a in 14 patients (26%), cN3b in 12 patients (22%), and cN3c in 29 patients (53%). All patients were treated with NCT, followed by mastectomy or breast-conserving surgery and subsequent radiotherapy (RT) with curative intent. At the median follow-up of 38 months (range, 9–80 months), 20 patients (36%) had developed treatment failures, including distant metastases either alone or combined with locoregional recurrences that included one ipsilateral breast recurrence (IBR), six regional failures (RF), and one case of combined IBR and RF. Only 3 patients (5.5%) exhibited treatment failure at the initial PET-positive clinical N3 lymph node. The 5-year locoregional relapse-free survival, disease-free survival (DFS), and overall survival rates were 80%, 60%, and 79%, respectively. RT delivered to PET-positive IMN regions in cN3b patients and at higher doses (≥55 Gy) to SCL regions in cN3c patients was not associated with improved 5-year IMN/SCL relapse-free survival or DFS. NCT followed by surgery and RT, including the regional lymph nodes, resulted in excellent locoregional control for patients with PET-positive cN3 breast cancer. The primary treatment failure in this group was due to distant metastasis rather than RF. Neither higher-dose RT directed at PET-positive SCL nodes nor coverage of PET-positive IMN nodes was associated with additional gains in locoregional control or DFS.

Abstract Background: Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is a hallmark of hormone receptor-positive (HR+) breast cancer (BC) resistant to endocrine therapy (ET). Preclinical and clinical data suggest that adding a PI3K inhibitor (PI3Ki) to ET may overcome resistance. In BELLE-2, a Phase III randomized study, buparlisib (BUP; BKM120; pan-PI3Ki) + fulvestrant (FULV) demonstrated clinical activity and manageable safety in patients (pts) with HR+, human epidermal growth factor receptor 2-negative advanced BC, with the greatest treatment effect in pts with PIK3CA mutation in circulating tumor DNA (ctDNA). Here, we report results from the final progression-free survival (PFS) analysis of the BELLE-3 study. Methods: Pts (N=432) were randomized 2:1 to BUP (100mg/day) or placebo (PBO) + FULV (500mg per standard of care) and stratified by visceral disease status. Key inclusion criteria: prior aromatase inhibitor therapy; disease progression ≤30 days from combination therapy of ET + mTOR inhibitor as last regimen. Key exclusion criteria: &amp;gt;1 chemotherapy regimen for advanced BC; prior PI3Ki, AKT inhibitor, or FULV; history of/active mood disorders. Primary and key secondary endpoints were PFS (local assessment; Response Evaluation Criteria In Solid Tumors v1.1) and overall survival (OS), respectively. Other secondary endpoints included: overall response rate (ORR); clinical benefit rate (CBR); efficacy by PIK3CA status in ctDNA (BEAMing technology); safety. Results: BELLE-3 met its primary endpoint with a statistically significant improvement in PFS per investigator assessment in favor of BUP + FULV (BUP arm) vs PBO + FULV (PBO arm; hazard ratio [HR] 0.67; 95% confidence interval [CI]: 0.53–0.84; p&amp;lt;0.001). Median PFS (mPFS) in the BUP vs PBO arm was 3.9 vs 1.8 months. The 6-month PFS rate was 30.6% vs 20.1%. PFS per central assessment was consistent with these findings (HR 0.57; 95% CI: 0.44–0.74; p&amp;lt;0.001). PIK3CA status in ctDNA was available for 349 pts; 147 (42.1%) pts had PIK3CA-mutant (mut) status and 202 (57.9%) had PIK3CA-wildtype (wt) status. PFS improvement in the BUP vs PBO arm was greater in the PIK3CA-mut (mPFS 4.7 vs 1.6 months; HR 0.50; 95% CI: 0.33–0.76) than the PIK3CA-wt group (mPFS 3.7 vs 2.7 months; HR 0.73; 95% CI: 0.52–1.01). A similar treatment effect was seen in 321 pts with PIK3CA status based on PCR in tissue samples (PIK3CA-mut HR 0.39; 95% CI: 0.23–0.65. PIK3CA-wt HR 0.83; 95% CI: 0.60–1.14). ORR was 7.6% (95% CI: 4.8–11.3) vs 2.1% (95% CI: 0.4–6.0) in the BUP vs PBO arm, and CBR at 24 weeks was 24.6% (95% CI: 19.7–29.9) vs 15.4% (95% CI: 9.9–22.4). Most common (&amp;gt;10%; BUP vs PBO arm) Grade 3/4 AEs were increased alanine aminotransferase (21.9% vs 2.9%), increased aspartate aminotransferase (17.7% vs 2.9%), and hyperglycemia (12.2% vs 0). Conclusions: BELLE-3 met its primary endpoint in the full population. PFS improvement in the BUP vs PBO arm was greater in pts with PIK3CA-mut than PIK3CA-wt tumors, based on ctDNA and PCR. Secondary endpoints showed improved clinical benefit with BUP + FULV vs PBO + FULV. Safety was in line with that previously seen with the combination. Keywords: Breast cancer; PI3K inhibitor; Fulvestrant; Buparlisib. Citation Format: Di Leo A, Seok Lee K, Ciruelos E, Lønning P, Janni W, O'Regan R, Mouret Reynier M-A, Kalev D, Egle D, Csoszi T, Bordonaro R, Decker T, Tjan-Heijnen VC, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T. BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S4-07.

<h2>Abstract</h2><h3>Background</h3> Paclitaxel plus gemcitabine (PG) combination chemotherapy is a preferred chemotherapeutic regimen for patients with metastatic breast cancer (MBC). Eribulin mesylate is a halichondrin non-taxane inhibitor of microtubule dynamics. A recent pooled analysis with eribulin showed improved overall survival (OS) in various MBC patient subgroups pretreated with anthracycline and taxane. Furthermore, eribulin may have less neurotoxicity than paclitaxel. <h3>Patients and methods</h3> This study was a prospective randomised phase II, open-label, two-arm, multicentre study comparing eribulin plus gemcitabine (EG) with PG chemotherapy as a first-line treatment for patients with human epidermal growth factor receptor 2-negative MBC. We hypothesised that EG chemotherapy would not be inferior to PG chemotherapy. The primary end-point was progression-free survival (PFS), which was estimated to be 70% at 6 months for each arm. The secondary end-points were as follows: OS, neuropathic scale, toxicity and clinical benefit rate. <h3>Results</h3> A total of 118 patients (median age: 50, 24–66) were enrolled between March 2015 and March 2016 and were randomly assigned to PG (<i>n</i> = <i>59</i>) or EG (<i>n</i> = <i>59</i>) chemotherapy. The mean number of metastatic sites was 3 (range 1–8). The 6-month PFS rates for both arms were 72% for EG and 73% for PG (<i>P</i> = <i>0.457</i>). There was no significant difference in OS between the two groups (not reached versus 21.2 months, <i>P</i> = <i>0.2234</i>). The median number of chemotherapy cycles for both groups was 10 for EG and 8 for PG (range 2–32). Clinical benefit rates were 44% for EG and 49% for PG. Major toxicities were neutropenia and neurotoxicity. Grade II or above neurotoxicity was more common with PG than with EG (13.6% for EG versus 45.8% for PG, <i>P</i> < <i>0.0001</i>). <h3>Conclusion</h3> EG chemotherapy had similar clinical benefits to PG chemotherapy in terms of PFS but less neurotoxicity. <h3>Trial registration</h3> KCSG BR13-11; ClinicalTrials.gov, NCT02263495.

LBA1008 Background: The phase III MONALEESA-7 study (NCT02278120) is the first dedicated trial of endocrine therapy (ET) ± a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in premenopausal patients (pts) with hormone receptor–positive (HR+)/HER2− ABC. The study met its primary endpoint of significantly longer progression-free survival (PFS) with ribociclib (RIB; a CDK4/6 inhibitor) + ET vs placebo (PBO) + ET (median, 23.8 vs 13.0 mo; HR, 0.55; P &lt; 0.0001; Tripathy D, et al. Lancet Oncol. 2018). Methods: Premenopausal pts (N=672) with HR+/HER2− ABC were treated with RIB or PBO + goserelin and either a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) or tamoxifen. This is the 2nd of 3 protocol-specified OS analyses (scheduled to occur after ≈ 189 deaths [75% of the planned total events]). OS was evaluated by Kaplan-Meier methods, and statistical comparison was made by 1-sided stratified log-rank test, with a protocol-defined Lan-DeMets (O’Brien-Fleming) stopping boundary of p &lt; 0.01018 for superior efficacy. Results: The data cutoff for this prespecified interim analysis was Nov 30, 2018, and the median follow-up was 34.6 mo (min, 28.0 mo). At cutoff, 173 pts were continuing study treatment (RIB, n=116; PBO, n=57), and OS was evaluated after 192 deaths (RIB, n=83; PBO, n=109). RIB + ET demonstrated a significantly longer OS than PBO + ET (median, not reached vs 40.9 mo [95% CI, 37.80 mo-not evaluable]; HR, 0.712 [95% CI, 0.54-0.95]; p = 0.00973). The result crossed the prespecified stopping boundary for superior efficacy. Estimated OS rates with RIB + ET vs PBO + ET at 42 mo were 70.2% vs 46.0%, respectively. In pts who received an NSAI (n=495), RIB + ET demonstrated a consistent OS improvement vs PBO + ET (HR, 0.699 [95% CI, 0.50-0.98]). Posttreatment therapy use was balanced between treatment arms (RIB, 68.9%; PBO, 73.2%). Conclusions: RIB + ET demonstrated a clinically and statistically significant longer OS than ET alone in premenopausal pts with HR+/HER2− ABC. This is the first time that a CDK4/6 inhibitor or any targeted agent + ET has demonstrated significantly longer OS vs ET alone as initial endocrine-based therapy. Clinical trial information: NCT02278120.

Abstract The heterogeneity of triple-negative breast cancer (TNBC) poses difficulties for suitable treatment and leads to poor outcome. This study aimed to define a consensus molecular subtype (CMS) of TNBC and thus elucidate genomic characteristics and relevant therapy. We integrated the expression profiles of 957 TNBC samples from published datasets. We identified genomic characteristics of subtype by exploring the pathway activity, microenvironment, and clinical relevance. In addition, drug response (DR) scores (n = 181) were computationally investigated using chemical perturbation gene signatures and validated in our own patient with TNBC (n = 38) who received chemotherapy and organoid biobank data (n = 64). Subsequently, cooperative functions with drugs were also explored. Finally, we classified TNBC into four CMSs: stem-like; mesenchymal-like; immunomodulatory; luminal-androgen receptor. CMSs also elucidated distinct tumor-associated microenvironment and pathway activities. Furthermore, we discovered metastasis-promoting genes, such as secreted phosphoprotein 1 by comparing with primary. Computational DR scores associated with CMS revealed drug candidates (n = 18), and it was successfully evaluated in cisplatin response of both patients and organoids. Our CMS recapitulated in-depth functional and cellular heterogeneity encompassing primary and metastatic TNBC. We suggest DR scores to predict CMS-specific DRs and to be successfully validated. Finally, our approach systemically proposes a relevant therapeutic prediction model as well as prognostic markers for TNBC. Implications: We delineated the genomic characteristic and computational DR prediction for TNBC CMS from gene expression profile. Our systematic approach provides diagnostic markers for subtype and metastasis verified by machine-learning and novel therapeutic candidates for patients with TNBC.

Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC).Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS).MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]).Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136).ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.

PURPOSE This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial. METHODS Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib. RESULTS Baseline circulating tumor DNA was sequenced in 565 patients; 477 evaluable patients had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (29%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (18%), and the Chr8p11.23 locus (13%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.44 [95% CI, 0.32 to 0.61]) and altered (HR 0.56 [95% CI, 0.36 to 0.89]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.22 [95% CI, 0.08 to 0.55]) or wild-type (HR 0.50 [95% CI, 0.38 to 0.67]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status. CONCLUSION In this study—to our knowledge, the first large study of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer—multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

Purpose This study investigated pathological complete response (pCR) according to androgen receptor (AR) in breast cancer patients undergoing neoadjuvant chemotherapy and estimated the relationship between AR expression and clinicopathological factors.Materials and Methods We identified 624 breast cancer patients who underwent surgery after neoadjuvant chemotherapy at the National Cancer Center in Goyang, Korea from April 2016 to October 2019. We retrospectively collected the clinicopathologic information and AR expression results and analyzed the data according to cancer stage, hormonal receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status, tumor subtype, and pCR.Results Among the 624 breast cancer patients, 529 (84.8%) were AR-positive (AR+) patients and 95 (15.2%) were AR-negative (AR–) patients. AR+ patients showed more estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, HER2-positivity, and HR-positive and HER2-negative (HR+/HER2–) subtype. The rate of pCR was 31.4% (196/624). AR– patients had a significantly higher rate of pCR than AR+ patients (AR– 43.2% vs. AR+ 29.3%, p=0.007). The tumor factors associated with pCR were early stage, histologic grade 3, ER-negative, PR-negative, AR-negative, HER2-positive, and high Ki-67 values. In univariable analysis, AR+ significantly decreased the state of pCR (odds ratio, 0.546; 95% confidence interval, 0.349 to 0.853; p=0.008). According to tumor subtype, AR– tumor showed higher pCR rate in HR+/HER2– subtype (AR– 28.6% vs. AR+ 7.3%, p=0.022).Conclusion AR expression is predominant in the HR+/HER2– subtype. AR– is significantly associated with the pCR rate in breast cancer patients, especially within HR+/HER2– subtype. When determining neoadjuvant chemotherapy for the HR+/HER2– subtype, AR expression can be considered as a pCR predictive marker.

1020 Background: DESTINY-Breast04 (NCT03734029) showed improved progression-free survival (PFS) and overall survival for T-DXd vs TPC in pts with HER2-low (IHC 1+ or 2+/ISH-negative) mBC. We present exploratory biomarker analysis in pts with HER2-low, HR+ mBC. Methods: Biopsy specimens collected from 326 pts after prior treatment were analyzed using RNA-sequencing and intrinsic subtypes estimated by PAM50 gene expression. ESR1 and PIK3CA mutations and known gene alterations associated with resistance to CDK4/6 inhibitors (CDK4/6i) were assessed in baseline (BL) circulating tumor DNA (ctDNA) samples from 414 pts by Guardant OMNI. Association with objective response rate (ORR) and PFS was evaluated. Results: Frequencies of BL intrinsic subtypes in the T-DXd and TPC arms were 41.3% and 46.6% for Luminal A, 48.0% and 37.9% for Luminal B, and 9.0% and 11.7% for HER2 enriched, respectively. According to ctDNA results in the T-DXd and TPC arms, respectively, ESR1 mutations were observed in 51.3% and 54.0% of pts, PIK3CA mutations in 36.1% and 41.6% of pts, and at least one CDK4/6i resistance marker (pts with prior CDK4/6i) was detected in 71.5% and 70.2% of pts. Improved T-DXd efficacy was seen regardless of intrinsic subtype (Luminal A, Luminal B, HER2-enriched), ESR1 mutation, PIK3CA mutation, or CDK4/6i resistance markers (Table). Conclusions: Greater clinical benefit was consistently observed with T-DXd vs TPC independent of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known CDK4/6i resistance marker status. Clinical trial information: NCT03734029 . [Table: see text]

Purpose Breast conservation surgery (BCS) and radiotherapy (RT) following neoadjuvant chemotherapy (NCT) have been linked with high locoregional recurrence (LRR) rates and ipsilateral breast tumor recurrence (IBTR) rates. The purpose of this study was to analyze clinical outcomes in patients who exhibited LRR and IBTR after being treated by BCS and RT following NCT. Methods and Materials In total, 251 breast cancer patients treated with BCS and RT following NCT between 2001 and 2006 were included. All patients had been shown to be clinically node-positive. Clinical stage at diagnosis (2003 AJCC) was II in 68% of patients and III in 32% of patients. Of those, 50%, 35%, and 15% of patients received anthracycline-based, taxane-based, and combined anthracycline-taxane NCT, respectively. All patients received RT. Results During follow-up (median, 55 months), 26 (10%) patients had LRR, 19 of these patients had IBTR. Five-year actuarial rates of IBTR-free and LRR-free survival were 91% and 89%, respectively. In multivariate analyses, lack of hormone suppression therapy was found to increase both LRR and IBTR rates. Hazard ratios were 7.99 (p < 0.0001) and 4.22 (p = 0.004), respectively. Additionally, pathology stage N2 to N3 increased LRR rate (hazard ratio, 4.22; p = 0.004), and clinical AJCC stage III IBTR rate (hazard ratio, 9.05; p = 0.034). Achievement of pathological complete response and presence of multifocal tumors did not affect LRR or IBTR. Conclusions In patients with locally advanced disease, who were clinically node-positive at presentation, BCS after NCT resulted in acceptably low rates of IBTR and LRR. Mastectomy should be considered as an option in patients who present with clinical stage III tumors or who are not treated with adjuvant hormone suppression therapy, because they exhibit high IBTR rates after NCT and BCS. Breast conservation surgery (BCS) and radiotherapy (RT) following neoadjuvant chemotherapy (NCT) have been linked with high locoregional recurrence (LRR) rates and ipsilateral breast tumor recurrence (IBTR) rates. The purpose of this study was to analyze clinical outcomes in patients who exhibited LRR and IBTR after being treated by BCS and RT following NCT. In total, 251 breast cancer patients treated with BCS and RT following NCT between 2001 and 2006 were included. All patients had been shown to be clinically node-positive. Clinical stage at diagnosis (2003 AJCC) was II in 68% of patients and III in 32% of patients. Of those, 50%, 35%, and 15% of patients received anthracycline-based, taxane-based, and combined anthracycline-taxane NCT, respectively. All patients received RT. During follow-up (median, 55 months), 26 (10%) patients had LRR, 19 of these patients had IBTR. Five-year actuarial rates of IBTR-free and LRR-free survival were 91% and 89%, respectively. In multivariate analyses, lack of hormone suppression therapy was found to increase both LRR and IBTR rates. Hazard ratios were 7.99 (p < 0.0001) and 4.22 (p = 0.004), respectively. Additionally, pathology stage N2 to N3 increased LRR rate (hazard ratio, 4.22; p = 0.004), and clinical AJCC stage III IBTR rate (hazard ratio, 9.05; p = 0.034). Achievement of pathological complete response and presence of multifocal tumors did not affect LRR or IBTR. In patients with locally advanced disease, who were clinically node-positive at presentation, BCS after NCT resulted in acceptably low rates of IBTR and LRR. Mastectomy should be considered as an option in patients who present with clinical stage III tumors or who are not treated with adjuvant hormone suppression therapy, because they exhibit high IBTR rates after NCT and BCS.

Lapatinib plus capecitabine is an effective treatment option for trastuzumab-refractory HER2-positive metastatic breast cancer. We have investigated the correlation between quantitative measures of HER2, p95HER2, and HER3 and treatment outcomes using lapatinib and capecitabine.Total HER2 (H2T), p95HER2 (p95), and total HER3 (H3T) expression were quantified in formalin-fixed paraffin-embedded samples using the VeraTag assays. Patients received lapatinib and capecitabine treatment following trastuzumab failure according to the Lapatinib Expanded Access Program. The association between the protein expression levels and clinical outcomes was analyzed.A total of 52 patients were evaluable. H2T level was significantly higher in responders (median 93.49 in partial response, 47.66 in stable disease, and 17.27 in progressive disease; p = 0.020). Longer time-to-progression (TTP) was observed in patients with high H2T [p = 0.018, median 5.2 months in high (>14.95) vs. 1.8 in low (<14.95)] and high H3T [p = 0.017, median 5.0 months in high (>0.605) vs. 2.2 in low (<0.605)]. Patients having both high H2T and high H3T had significantly longer TTP [adjusted hazard ratio (HR) 0.38 (95% CI 0.20-0.73), p = 0.004] and overall survival [adjusted HR 0.46 (95% CI 0.24-0.89), p = 0.020]. No significant association between p95 and response or survival was observed.These data suggest a correlation between high HER2 and high HER3 expression and treatment outcome, while no significant difference was observed between clinical outcome and p95 expression level in this cohort of HER2-positive, trastuzumab-refractory metastatic breast cancer patients treated with lapatinib and capecitabine.

The insulin-like growth factor (IGF) signaling pathway plays an important role in cancer biology. The IGF 1 receptor (IGF1R) overexpression has been associated with a number of hematological neoplasias and solid tumors including breast cancer. However, molecular mechanism involving IGF1R in carcinogenic developments is clearly not known. We investigated the genetic variations across the IGF1R polymorphism and the risk of breast cancer risk in Korean women. A total of 1418 individuals comprising 1026 breast cancer cases and 392 age-matched controls of Korean were included for the analysis. Genomic DNA was extracted from whole blood and single nucleotide polymorphisms (SNPs) were analyzed on the GoldenGate Assay system by Illumina's Custom Genetic Analysis service. SNPs were selected for linkage disequilibrium (LD) analysis by Haploview. We genotyped total 51 SNPs in the IGF1R gene and examined for association with breast cancer. All the SNPs investigated were in Hardy-Weinberg equilibrium. These SNPs tested were significantly associated with breast cancer risk, after correction for multiple comparisons by adjusting for age at diagnosis, BMI, age at menarche, and age at first parturition. Among 51 IGF1R SNPs, five intron located SNPs (rs8032477, rs7175052, rs12439557, rs11635251 and rs12916884) with homozygous genotype (variant genotype) were associated with decreased risk of breast cancer. Fisher's combined p-value for the five SNPs was 0.00032. Three intron located SNPs with heterozygous genotypes also had decreased risk of breast cancer. Seven of the 51 IGF1R SNPs were in LD and in one haplotype block, and were likely to be associated with breast cancer risk. Overall, this case-control study demonstrates statistically significant associations between breast cancer risk and polymorphisms in IGF1R gene.

Background:The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC).This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC.Methods: In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients.Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity.In addition, we investigated the mutational status of PIK3CA (E542K, E545K, H1047R) in tumor tissues (n=14) and cell-free DNA (cfDNA) from blood samples (n=23) using droplet digital PCR.Results: In phase I (n=9), we found that the MTD of GPE was gemcitabine 800 mg/m 2 and cisplatin 30 mg/m 2 on days 1 and 8 every 3 weeks along with everolimus 5 mg daily.Phase II was terminated early after 14 patients had been enrolled because of slow recruitment and concerns about efficacy.Results of the combined analysis of phases I and II showed the objective response rate (ORR) of GPE (n=16) was 31.3% and the median PFS was 5.5 months (95% CI, 3.5-7.5).Stomatitis and hematologic toxicities were observed most frequently in the GPE arm.PIK3CA mutations were identified in 8 (57.1%) tumor samples and 17 (73.9%)cfDNA samples; there was no significant association between PIK3CA mutation status and response to GPE treatment.Conclusions: Although the majority of patients with metastatic TNBC demonstrated PIK3CA mutations in cfDNA, the addition of everolimus to gemcitabine/cisplatin did not have a synergistic effect in these patients.Further studies are needed to determine the most effective way to target the PI3K/AKT/mTOR pathway in TNBC patients.

Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein.621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety.104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity.Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted.NCT01808573.

The purpose of the study was to evaluate the methylation status of the interleukin-10 (IL-10) gene in breast cancer tissues compared with normal and benign breast disease tissues. Between 2000 and 2001, we used paraffin-embedded specimens of 30 normal, 31 benign and 72 breast cancer tissues from the National Cancer Center, Korea. The methylation patterns of the IL-10 gene were evaluated using bisulfite DNA sequencing and the expression levels of IL-10 mRNA were evaluated using real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) and reverse transcriptase-polymerase chain reaction (RT-PCR). The methylation rates of the IL-10 gene were significantly lower in malignant tumors than in benign and normal tissues (normal; 63.3%, benign; 74.2%, cancer; 45.8%, p = 0.02). The methylation density rates of the IL-10 gene were also significantly lower in malignant tumors (normal; 59.68 ± 7.12%, benign; 48.89 ± 7.45%, cancer; 30.56 ± 4.18%, p = 0.001). Tissues with aberrant methylation of the IL-10 gene showed significantly lower rates of mRNA expression compared with unmethylated cases (12.5% vs. 68.0%, p = 0.012). The mRNA expression of tissues with unmethylated IL-10 was upregulated approximately ten thousand-fold compared to those with IL-10 methylation in the real-time RT-PCR experiment. IL-10 methylation demonstrated a significant association with lower expression of Ki-67 (9.36 ± 2.43 vs. 19.68 ± 3.42, p = 0.02). IL-10 methylation in cancer tissues is lower than that in normal and benign breast tissues, and DNA hypomethylation in the gene influences gene activation. Our data suggest that hypomethylation of the IL-10 gene can be involved in the process of breast carcinogenesis.

The current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in the Asian subset of patients in the BOLERO-1 trial.Postmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR-) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety.In the Asian subset, median PFS was similar in the everolimus (n = 198) and placebo (n = 105) arms in the full analysis set (hazard ratio = 0.82 (95% CI 0.61-1.11)). In the HR- subpopulation, everolimus prolonged median PFS by 10.97 months vs placebo (25.46 vs 14.49 months; hazard ratio = 0.48 (95% CI 0.29-0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm.The efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population.ClinicalTrials.gov, NCT00876395 . Registered on 2 April 2009.

Cancer-associated microRNAs have been stably detected in blood. The objective of this study was to identify a panel of circulating microRNAs with the potential to serve as biomarkers for estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2)− breast cancer. We used microarray-based expression profiling to compare the levels of circulating microRNAs in blood samples from 11 ER+/HER2− advanced breast cancer patients plus 5 age-matched controls. MicroRNA levels were validated by reverse transcription quantitative polymerase chain reaction in 40 control subjects, 187 early breast cancer patients, and 45 metastatic breast cancer patients. Then, we assessed the association between the levels of microRNA and clinical outcomes of ER+/HER2− metastatic breast cancer. Initially, we found that miR-1280, miR-1260, and miR-720 were up-regulated in blood from breast cancer patients (P < 0.05). In validation, miR-1280 levels significantly increased in breast cancer patients and reflected tumor status (control<<early cancer<metastatic cancer). Among 37 metastatic breast cancer patients, miR-1280 levels significantly decreased after treatment in patients who responded to systemic treatment (P < 0.001). We confirmed that miR-1280 was not a classic microRNA, but a tRNALeu-derived fragment. These findings suggest that a circulating tRNA-derived microRNA, miR-1280, is differently expressed in breast cancer patients and may serve as a biomarker for ER-positive breast cancer.

This study evaluated the association of serum HER2 (sHER2) levels at diagnosis with clinicopathologic parameters and disease free survival (DFS) in operable breast cancer patients according to intrinsic subtype.The sHER2 levels were measured using a chemiluminescence immunoassay. The HER2 status in all tumor tissues was determined by immunohistochemistry, and confirmed in equivocal cases by fluorescence in situ.There were 436 consecutive stage I-III breast cancer patients with sHER2 result at diagnosis between Nov 2004 and Dec 2011. High sHER2 levels (≥ 15 ng/ml) were reported in 52 patients (11.9%) and HER2 overexpression in tumor tissue was observed in 111 patients (25.5%). High sHER2 levels were associated significantly with advanced stage (P < 0.001), mastectomy (P = 0.012), neoadjuvant chemotherapy (P < 0.001), anti-HER2 therapy (P < 0.001) and hormone therapy (P = 0.022). The patients with high sHER2 levels had a worse DFS (P < 0.001). In multivariate analysis, high sHER2 levels were associated significantly with worse DFS (HR = 2.25, 95% CI 1.27-3.99, P = 0.005). High sHER2 levels were associated with worse DFS in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subtypes (P = 0.043, 0.003 and 0.041, respectively).These results show that the sHER2 level at diagnosis is a useful prognostic factor in patients with operable breast cancer, especially in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subtypes.

&lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; This retrospective study was undertaken to assess the incidence of and risk factors for febrile neutropenia (FN) during adjuvant chemotherapy for early-stage breast cancer (ESBC). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A multicenter survey of three tertiary hospitals was conducted, with data extracted from the records of ESBC patients treated with adjuvant chemotherapy containing AC (doxorubicin, 60 mg/m&lt;sup&gt;2&lt;/sup&gt; and cyclophosphamide, 600 mg/m&lt;sup&gt;2&lt;/sup&gt; every 21 days). Assessments included clinical characteristics, chemotherapy dose modifications, and incidence of FN. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A total of 610 patients were included for analysis. The incidence of grade 4 neutropenia and FN was 44.6 and 8.5%, respectively. Reduced relative dose intensity (RDI) less than 85% occurred in 11.0% of patients, and there were treatment delays in 12.6% of patients. Multivariate analysis identified several independent predictors for FN, including the presence of grade 4 neutropenia and pretreatment calculated estimated glomerular filtration rate less than 60 ml/min. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Patients with ESBC are at substantial risk for FN and reduced RDI when treated with adjuvant AC chemotherapy. Predictive models based on risk factors identified in this study should enable the selective application of supportive measures in an effort to deliver the full dose of chemotherapy.

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), BRD2, BRD4, and AR; effectively suppressing the expression of AR associated targets. In addition, JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. Taken together, our results showed that the BET inhibitor JQ1 is a promising therapeutic agent for the treatment of AR-positive TNBC.

We performed a genome-wide association study to investigate the association between single nucleotide polymorphisms and anthracycline-induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m2 -300 mg/m2 ) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty-seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m2 [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23-4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11-5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E-06), rs11894115 (MPP4, P = 4.71E-06), rs58328254 (RPL7, P = 6.09E-06), and rs117299725 (PRUNE2, P = 8.53E-06), although none of these variants reached the Bonferroni-corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E-07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.

PF-05280014 was compared with trastuzumab sourced from the European Union (trastuzumab-EU), each plus paclitaxel, as first-line treatment for human epidermal growth factor receptor 2-positive metastatic breast cancer in a phase III study. Equivalence between treatment groups was demonstrated. The aim of this study was to report long-term safety and overall survival (OS) over 6 years after the first patient was screened. Randomized patients received intravenous PF-05280014 or trastuzumab-EU, each plus paclitaxel, until objective disease progression. OS, long-term safety, subgroup safety (patients ongoing after day 378), and time-to-treatment discontinuation (TTD) were assessed based on the final statistical analysis plan amended for the ad-hoc analyses. Of 707 randomized patients (n = 352, PF-05280014; n = 355, trastuzumab-EU), 252 (71.6%) in the PF-05280014 and 251 (70.7%) in the trastuzumab-EU group discontinued treatment due to objective progression. Overall, 451 (63.8%) patients completed the study. Between groups (PF-05280014; trastuzumab-EU), estimated median TTDs were 12.25 and 12.06 months (p = 0.692); 61 (17.3%) and 67 (18.9%) patients died; stratified hazard ratio for OS was 0.929 (95% confidence interval 0.656–1.316; p = 0.339); estimated survival rates were 82.3 and 77.4% at 2 years and 77.2 and 75.3% at 3 years. The incidences of treatment-emergent adverse events (TEAEs) overall (98.6%; 96.6%) and for grades ≥3 (41.0%; 43.1%) were comparable between groups. In patients (n = 265; n = 264) ongoing after day 378, the incidences of any TEAEs, grade ≥3 TEAEs, and serious TEAEs were comparable between the treatment groups. Long-term safety and OS were consistent with previous results and demonstrated no clinically meaningful differences between treatment groups. ClinicalTrials.gov: NCT01989676 (21 November 2013); and EudraCT: 2013-001352-34 (18 December 2013).

This single-arm phase II trial investigate the efficacy and safety of S-1 plus oxaliplatin (SOX) in patients with metastatic breast cancer.Patients with metastatic breast cancer previously treated with anthracyclines and taxanes were enrolled. Patients received S-1 (40-60 mg depending on patient's body surface area, twice a day, day 1-14) and oxaliplatin (130 mg/m2, day 1) in 3 weeks cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumor 1.1. Secondary endpoints included time-to-progression (TTP), duration-of-response (DoR), overall survival (OS), and adverse events.A total of 87 patients were enrolled from 11 institutions in Korea. Hormone receptor was positive in 54 (62.1%) patients and six (6.9%) had human epidermal growth factor receptor 2-positive disease. Forty-eight patients (85.1%) had visceral metastasis and 74 (55.2%) had more than three sites of metastases. The ORR of SOX regimen was 38.5% (95% confidence interval [CI], 26.9 to 50.0) with a median TTP of 6.0 months (95% CI, 5.1 to 6.9). Median DoR and OS were 10.3 months (95% CI, 5.5 to 15.1) and 19.4 (95% CI, not estimated) months, respectively. Grade 3 or 4 neutropenia was reported in 28 patients (32.1%) and thrombocytopenia was observed in 23 patients (26.6%).This phase II study showed that SOX regimen is a reasonable option in metastatic breast cancer previously treated with anthracyclines and taxanes.

Patient-derived tumor cells can be a powerful resource for studying pathophysiological mechanisms and developing robust strategies for precision medicine. However, establishing organoids from patient-derived cells is challenging because of limited access to tissue specimens. Therefore, we aimed to establish organoids from malignant ascites and pleural effusions.Ascitic or pleural fluid from pancreatic, gastric, and breast cancer patients was collected and concentrated to culture tumor cells ex vivo. Organoids were considered to be successfully cultured when maintained for five or more passages. Immunohistochemical staining was performed to compare the molecular features, and drug sensitivity was assayed to analyze the clinical responses of original patients.We collected 70 fluid samples from 58 patients (pancreatic cancer, n=39; gastric cancer, n=21; and breast cancer, n=10). The overall success rate was 40%; however, it differed with types of malignancy, with pancreatic, gastric, and breast cancers showing 48.7%, 33.3%, and 20%, respectively. Cytopathological results significantly differed between successful and failed cases (p=0.014). Immunohistochemical staining of breast cancer organoids showed molecular features identical to those of tumor tissues. In drug sensitivity assays, pancreatic cancer organoids recapitulated the clinical responses of the original patients.Tumor organoids established from malignant ascites or pleural effusion of pancreatic, gastric, and breast cancers reflect the molecular characteristics and drug sensitivity profiles. Our organoid platform could be used as a testbed for patients with pleural and peritoneal metastases to guide precision oncology and drug discovery.

<h2>Abstract</h2><h3>Introduction</h3> Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. <h3>Methods</h3> This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. <h3>Results</h3> Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, <i>p</i> < 0.001). The combination arm had higher disease control rate (76.8% vs<i>.</i> 45.9%, <i>p</i> = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, <i>p</i> = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3–4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs<i>.</i> 19.5%, <i>p</i> = 0.066). <h3>Conclusions</h3> This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable.

Purpose: This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC). Methods: We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC. Results: In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (&lt;65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (&lt;10 months). Common grade 3–4 adverse events were thrombocytopenia ( n = 107, 13.2%), neutropenia ( n = 23, 2.8%), anemia ( n = 21, 2.6%), and elevated liver enzyme ( n = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively. Conclusion: This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy.

The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment.Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive.One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status.Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.

Abstract Background: PALB2, located on chromosome 16, plays a vital role in DNA damage repair as a partner and localizer of BRCA2. PALB2 germline pathogenic variant has been known to increase the risks of breast cancer, pancreatic cancer, and ovarian cancer. However, the prevalence of PALB2 germline variants in Korean patients has not been thoroughly investigated. This study aimed to evaluate the prevalence of PALB2 germline variants and the risk factors in Korean population. Methods: We analyzed the data of 3755 patients who performed hereditary cancer germline next generation sequencing (NGS) panels, including PALB2, at the National Cancer Center in Korea between 2008 and 2022. Genetic variants were classified using a five-tier system following the American College of Medical Genetics and Genomics guidelines as follows: pathogenic (PV), likely pathogenic (LPV), variants of uncertain significance (VUS), likely benign, and benign. We retrospectively reviewed 102 individuals who were confirmed to have the PALB2 germline variant with PV, LPV and VUS. Also, we analyzed the clinical characteristics of patients with PALB2 heterozygous PV or LPV. Results: A total of 102 patients (2.7%, 102/3755) represented PALB2 germline variants with 81 (79.4%) VUS, 14 (13.7%) LPV, and 7 (6.9%) PV. Detected twelve germline PALB2 LPV or PV were as followings; c.3350+5G&amp;gt;A (n=6), c.454A&amp;gt;T (n=3), c.1048C&amp;gt;T (n=2), c.2016dup (n=2), c.1424C&amp;gt;G (n=1), c.1976_1977del (n=1), c.2095dup (n=1), c.2834+2T&amp;gt;C (n=1), c.2920_2921delAA (n=1), c.3317delT (n=1), c.902delA (n=1), and exon 11 deletion (n=1). 35 PALB2 VUS were detected in 81 patients. Among 21 female patients with LPV or PV (median diagnosis age 50 years; 25-69), 18 carriers (85.7%) and 3 carriers (14.3%) were diagnosed with breast cancer and ovarian cancer, respectively. For 18 breast cancer patients, 3 patients had bilateral breast cancer and 3 patients had multi-organ cancers (ovary, thyroid, or colorectal and gastric cancer).Also, 15 carriers (71.4%) have first-degree relatives with breast, ovarian, pancreatic, lung, gastric, liver, thyroid, and colorectal cancer and 10 carriers (47.6%) have second-degree relatives with breast, pancreatic, lung, gastric, liver, prostate, lymphoma, laryngeal, and uterine cancer. Conclusion: In our study, PALB2 germline PV or LPV were detected at a low frequency of 0.56% in Korean cancer patients. Family history was an important risk factor for suspected germline pathogenic variants, and bilateral breast cancer was observed in 16.7% of breast cancer patients who harbored PALB2 PV or LPV. This study was supported by grant from the National Cancer Center. (grant number HA23C0419; NCC- 23F1850; NCC-2110181). Citation Format: Min-Chae Kang, Ye-Ryeong Jung, Seeyoun Lee, Han-Sung Kang, So-Youn Jung, Myong Cheol Lim, Keun Seok Lee, Eun-Gyeong Lee, Sun-Young Kong. Prevalence and risk factors of PALB2 germline pathogenic variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7338.

The efficacy of pembrolizumab monotherapy versus chemotherapy increased with increasing programmed death ligand 1 (PD-L1) expression, as quantified by combined positive score (CPS; PD-L1 expression on both tumour cells and immune cells) in patients with previously treated metastatic triple-negative breast cancer (mTNBC) in the phase 3 KEYNOTE-119 study. This exploratory analysis was conducted to determine whether the expression of PD-L1 on tumour cells contributes to the predictive value of PD-L1 CPS in mTNBC. PD-L1 expression in tumour samples was assessed using PD-L1 IHC 22C3 pharmDx and quantified using both CPS and tumour proportion score (TPS; PD-L1 expression on tumour cells alone). Calculated immune cell density (CID) was defined as CPS minus TPS. The ability of each scoring method (CPS, TPS, and CID) to predict clinical outcomes with pembrolizumab was evaluated. With pembrolizumab, the area under the receiver operating characteristic curve was 0.69 (95% CI = 0.58-0.80) for CPS, 0.55 (95% CI = 0.46-0.64) for TPS, and 0.67 (95% CI = 0.56-0.77) for CID. After correction for cutoff prevalence, CPS performed as well as, if not better than, CID with respect to predicting objective response rate, progression-free survival, and overall survival. Data from this exploratory analysis suggest that, although PD-L1 expression on immune cells alone is predictive of response to programmed death 1 blockade in mTNBC, adding tumour PD-L1 expression assessment (i.e. CPS, which combines immune cell and tumour cell PD-L1 expression) may improve prediction. PD-L1 CPS thus remains an effective and broadly applicable uniform scoring system for enriching response to programmed death 1 blockade with pembrolizumab in mTNBC as well as other tumour types.

Abstract Background: Overweight/obesity has been known as a prognostic factor for breast cancer recurrence and breast cancer related death. However, weight control is hard in breast cancer survivors because of menopause, chemotherapy, anti-hormonal therapy, and psychologic issues. This study aimed to develop 24-week mobile application based human coaching program with Noom and evaluate its efficacy in overweight/obese breast cancer survivors. Methods In this single-arm prospective cohort study, 130 breast cancer survivors with BMI ≥25 were enrolled and received 24-week program including diet-,exercise-, and psychology-based contents with trained human coach in Noom during 2019-2021. For hyperactive group who joined more than 16 weeks, we evaluated weight, BMI, lipid level, bioimpedance, and Quality of Life (QoL) at baseline, 6 month and 12month follow-up. Results Among 130 breast cancer survivor, 101 participants (77.7%) and 93 participants (71.5%) completed 6 month and 12 month follow-up, respectively. In hyperactive group (68/101, 67%), body weight and BMI reduced significantly (mean difference: -1.97 kg, 95% CI (confidence interval):-2.65- -1.26, P&amp;lt; 0.001 and -0.86, 95% CI:-1.15- -0.56, P&amp;lt; 0.001, respectively) at 6 month and maintained at 12 month without the yo-yo effect. Among the lipid panel, triglycerides level decreased significantly (-34.13, 95% CI:-58.09- -10.17, P=0.006) and maintained at 12 month. In the aspect of bioimpedance components, skeletal muscle mass (SMM, kg), body fat mass (BFM, kg), percent body fat (PBF, %), waist-hip ratio (WHR), and visceral fat area (VFA, cm2) were improved for first 6 months. However, WHR and VFA increased during next 6months. Based on the EORTC QLQ C30 and BR 23, nausea/vomiting, constipation, body image, arm and breast symptoms showed significant improvement during the first 6monts. Conclusions This study demonstrated that 24-week mobile application based human coaching program is beneficial for controlling body weight, BMI, TG and body composition in bioimpedance for overweigh/obsess breast cancer survivors. ClinicalTrials.gov NCT05506189; https://clinicaltrials.gov/ct2/show/ NCT05506189. IRB: NCC2019-0098 Citation Format: So-Youn Jung, Eun-Gyeong Lee, Dong-Eun Lee, Jeongseon Kim, Jai Hong Han, Seeyoun Lee, Han-Sung Kang, Eun Sook Lee, Heejung Chae, Sung Hoon Sim, Keun Seok Lee, Jungeun Lee. Effectiveness of 24-week mobile application based human coaching program for controlling weight, BMI and body composition in overweight/obese breast cancer survivors: Single-arm prospective cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-07.

Abstract BACKGROUND Endocrine therapy (ET) is the mainstay of treatment for metastatic hormone receptor-positive breast cancer (HR+ BC). ET resistance and disease progression are expected, thus novel therapies, like cancer immunotherapy, are needed. Prior data suggest that abemaciclib (abema), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has immunomodulatory activity. In the MORPHEUS HR+ BC study (NCT03280563), atezolizumab (atezo; anti–programmed death-ligand 1 [PD-L1]) was tested in combination with fulvestrant (FUL), with and without abema, in patients (pts) with HR+ metastatic BC. We present 24-week interim analyses. METHODS Pts with measurable disease progression during first- or second-line therapy for metastatic or inoperable locally advanced HR+ BC and prior treatment with a CDK4/6 inhibitor were randomized to receive FUL (control) or FUL + atezo (1200 mg intravenous every 3 weeks) or FUL + atezo + abema (150 mg twice a day); prior FUL was not permitted. Pts were treated until loss of clinical benefit or unacceptable toxicity. Primary endpoints were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and safety. Progression-free survival (PFS) was a secondary endpoint. Baseline tumor samples were analyzed for PD-L1 expression (SP263), CD8 T cell infiltration, and gene expression by RNAseq. RESULTS As of Dec 2022, 40, 31, and 25 pts (38, 30, and 20 evaluable pts) were randomized to atezo + abema + FUL, atezo + FUL, and FUL, respectively. Pts were followed for ≥ 24 weeks. Demographics were similar among the groups, with most pts receiving prior palbociclib (palbo) as part of their only prior metastatic therapy. Details and best confirmed ORRs are shown in the table. Median PFS was 6.34 months (95% confidence interval [CI] 5.52, 16.03) in the atezo + abema + FUL arm, 3.15 months (95% CI 1.51, 7.79) in the atezo + FUL arm, and 1.95 months (95% CI 1.45, 4.93) in the FUL arm. The hazard ratio of atezo + abema + FUL vs FUL was 0.43 (95% CI 0.24, 0.78). Safety data are shown in the table. Mild/moderate (grade 1/2) interstitial lung disease (ILD)/pneumonitis (7.7%) was observed in the atezo + abema + FUL arm. At baseline, tumors exhibited low prevalence of PD-L1 (median immune cells: 0.5%, tumor cells: 0%) and CD8 infiltration (12% inflamed phenotype), which did not associate with response in any arm. RNAseq analysis indicated that response to atezo + abema + FUL was strongly associated with low baseline expression levels of proliferation and metabolism signatures and trended with high expression of some immune signatures. CONCLUSIONS The triplet therapy of atezo + abema + FUL showed improved ORR and PFS compared with FUL monotherapy in the second- or third-line setting post-CDK4/6 inhibitor. This combination of atezo + abema + FUL was tolerable, with no unexpected safety signals, including no high-grade ILD/pneumonitis. Efficacy and safety Data are number of patients (%), unless otherwise specified. * Patient was treated in the second line and incorrectly included in this group. Abema, abemaciclib; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; atezo, atezolizumab; CDK4/6, cyclin-dependent kinase 4/6; CI, confidence interval; ful, fulvestrant; irAE, immune-related adverse event; L, line; ORR, objective response rate; PFS, progression-free survival; TRAE, treatment-related adverse event. Citation Format: Kyung Hae Jung, Seock-Ah Im, Denise Yardley, Sara Hurvitz, Keun Seok Lee, Amir Sonnenblick, Shlomit Shachar, Antoinette Tan, Elizabeth Comen, Einav Gal-Yam, Adam Brufsky, Hope Rugo, Jing Zhu, Kelly DuPree, Vanessa Breton, Fiona Young, Richard Schwab, Edward Cha, Melinda Telli. MORPHEUS Hormone Receptor-Positive Breast Cancer: interim analysis of a Phase Ib/II, study of fulvestrant ± atezolizumab and abemaciclib triplet treatment in patients metastatic disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-08.

Aim: To investigate factors that affect the place of death (POD) of terminal cancer patients. Materials and Methods: We recruited 702 consecutive patients (<TEX>${\geq}18$</TEX> years) from 12 centers during July 2005 to October 2006, and 481 completed the questionnaire. In April 2011, we linked the data for 96.0% (n=462) of the deceased patients to the POD using the 2005-2009 death certificate data of Korea's National Statistical Office. The primary outcome variable was POD, and the predictive value of variables pertaining to patients and caregivers was evaluated using univariate and multivariate analyses. Results: Most patients died in a hospital (91.5%, n=441) and age, education, preference for place of terminal care, wish to use hospice/palliative care services, terminal cancer awareness, time between diagnosis and death, and global quality-of-life subscale of the EORTC QLQ-C30 of patients, and education and preference for place of terminal care of caregivers were significant predictors in univariate analyses. On multivariate analysis, patients and caregivers who preferred hospital/palliative care as the terminal care option over home care [adjusted odds ratio (aOR), 2.68; 95% confidential interval (CI), 1.18-7.04 and aOR: 2.65; 95%CI: 1.15-6.09 for patient and caregiver preferences, respectively] and caregivers who were highly educated (aOR, 3.19; 95%CI, 1.44-7.06) were predictors of POD. Conclusions: Most of the terminal cancer patients died in a hospital. Our findings indicate that major predictors of hospital deaths are preference of both the patient and caregiver for hospital/palliative care as the terminal care option and higher education of the caregiver.

To report a phase 2 trial of accelerated, hypofractionated whole-breast irradiation (AH-WBI) delivered as a daily dose of 3 Gy to the whole breast followed by a tumor bed boost.Two hundred seventy-six patients diagnosed with breast cancer (pT1-2 and pN0-1a) who had undergone breast-conserving surgery in which the operative margins were negative were treated with AH-WBI delivered as 39 Gy in 13 fractions of 3 Gy to the whole breast once daily over 5 consecutive working days, and 9 Gy in 3 sequential fractions of 3 Gy to a lumpectomy cavity, all within 3.2 weeks.After a median follow-up period of 57 months (range: 27-75 months), the rate of 5-year locoregional recurrence was 1.4% (n=4), whereas that of disease-free survival was 97.4%. No grade 3 skin toxicity was reported during the follow-up period. Qualitative physician cosmetic assessments of good or excellent were noted in 82% of the patients at 2 months after the completion of AH-WBI. The global cosmetic outcome did not worsen over time, and a good or excellent cosmetic outcome was reported in 82% of the patients at 3 years. The mean pretreatment percentage breast retraction assessment was 12.00 (95% confidence interval [CI]: 11.14-12.86). The mean value of percentage breast retraction assessment increased to 13.99 (95% CI: 12.17-15.96) after 1 year and decreased to 13.54 (95% CI: 11.84-15.46) after 3 years but was not significant (P>.05).AH-WBI consisting of 39 Gy in 13 fractions followed by a tumor bed boost sequentially delivering 9 Gy in 3 fractions can be delivered with excellent disease control and tolerable skin toxicity in patients with early-stage breast cancer after breast-conserving surgery.

Recently, we reported cytoskeleton-associated protein2 (CKAP2) as a possible new prognostic breast cancer marker. However, it has not yet been applied in clinic. Therefore, clinical significance of CKAP2 was evaluated in comparison with that of Ki-67 in a cohort of breast cancer patients, and the expression difference was analyzed in cell cycle-arrested cancer and fibroblast cells.A total of 579 early breast cancer patients who underwent surgery at the National Cancer Center Hospital in Korea between 2001 and 2005 were accrued. CKAP2-positive cell count (CPCC) and Ki-67 labeling index (Ki-67LI) were evaluated by immunohistochemcal staining. The immunocytochemical staining patterns of CKAP2 and Ki-67 were analyzed in HeLa and human fibroblast cells after synchronization by double thymidine block.Although there was a significant correlation (R = 0.754, P < 0.001) between CPCC and Ki-67LI, only CPCC was correlated with DFS in overall population (HR, 2.029; 95% CI, 1.012-4.068; P = 0.046) and HER2-negative luminal subgroup (HR, 3.984; 95% CI, 1.350-11.762; P = 0.012) by multivariate analysis. In immunocytochemical staining, more than 50% of serum-starved or non-mitotic cell phase HeLa cells were positive for Ki-67, in comparison to the low CKAP2-positivity, which might explain the prognostic difference between CPCC and Ki-67LI.The current study showed that CPCC but not Ki-67LI is an independent prognostic indicator in early breast cancer, more specifically in HER2-negative luminal breast cancer. The difference between two markers may be related to the lower background expression of CKAP2 in cancer cells.

Metastasis of a phyllodes tumor to the stomach is an extremely rare condition with important clinical implications. A 44-year-old woman was initially diagnosed with a phyllodes tumor in her right breast in 2008, and subsequently presented to an outpatient clinic with dizziness on December 16, 2013. We found that she had severe anemia (hemoglobin levels, 6.7 g/dL), and we quickly performed esophagogastroduodenoscopy to identify the cause. This procedure revealed large ulcerofungating masses with active bleeding in the stomach. Histopathological examination revealed that the masses were consistent with phyllodes tumor metastases. In patients with a metastatic phyllodes tumor presenting as anemia, gastric metastasis should be considered as one of the differential diagnoses because overlooking the possibility might have dire consequences if cytotoxic chemotherapy were administered.