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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. In this study, we addressed potent genetic variants related with anthracycline induced cardiotoxicity in Korean early breast cancer patients adjusting various clinical factors with a long follow‐up period. The results of our study showed that in anthracycline treatments with a cumulative dose not exceeding 300 mg/m2, clinical factors were more associated with cardiotoxicity than genetic factors. Several possible genetic variants found in this study may require further study.

In this single-group, phase 2 study, the use of trastuzumab deruxtecan resulted in a response in 60% of women with HER2-positive advanced breast cancer who had received a median of six previous lines of therapy. The drug was associated with myelosuppression and gastrointestinal toxicity; interstitial lung disease was reported in 13.6% of the patients.

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. 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. 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). 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. Merck Sharp & Dohme.

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. 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. 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. 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. Novartis.

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.

The phase 2 randomised Young-PEARL study demonstrated that palbociclib plus exemestane with ovarian function suppression significantly prolonged progression-free survival compared with capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Here, we report results of the protocol-specified secondary endpoint of overall survival. Young-PEARL was a multicentre, randomised, open-label, phase 2 study conducted at 14 institutions in South Korea. Premenopausal women aged 19 years or older with histologically confirmed hormone receptor-positive, HER2-negative metastatic breast cancer that recurred or progressed during or after previous tamoxifen treatment, who were aromatase inhibitor naive, and had an Eastern Cooperative Oncology Group performance status of 0–2 were eligible. One previous line of chemotherapy was permitted in the metastatic setting. Eligible patients were randomly assigned (1:1), using block randomisation (block size of two) stratified by previous chemotherapy for metastatic breast cancer and presence of visceral metastasis, to receive either palbociclib (orally, 125 mg per day on a 3-weeks-on, 1-week off schedule) plus exemestane (orally 25 mg daily) with leuprorelin (subcutaneously 3·75 mg on day 1 of each 28-day cycle) or capecitabine (orally, 1250 mg/m2 twice a day on a 2-weeks-on, 1-week-off schedule) until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival. Overall survival was a secondary endpoint. All analyses were done in the modified intention-to-treat population (ie, included all patients randomly assigned to treatment who had at least one post-baseline CT scan and excluded those who did not receive study medication and who had any major violation of the eligible criteria). Safety was assessed in all patients who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02592746, and is now complete. Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled. 184 patients were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92), of whom 174 were included in the modified intention-to-treat population (n=90 in the palbociclib plus endocrine therapy group and n=84 in the capecitabine group). All patients were female and ethnicity data were not collected. As of data cutoff (Feb 29, 2024), median follow-up was 54·0 months (IQR 34·1–74·4). Median progression-free survival was 19·5 months (90% CI 14·3–22·2) for palbociclib plus endocrine therapy and 14·0 months (11·7–18·7) for capecitabine (hazard ratio 0·74 [90% CI 0·57–0·98]; one-sided log-rank p=0·036). 52 (58%) of 90 patients in the palbociclib plus endocrine therapy group and 48 (57%) of 84 in the capecitabine group died, with a median overall survival of 54·8 months (95% CI 48·9–77·1) in the palbociclib plus endocrine therapy group versus 57·8 months (46·3–89·2) in the capecitabine group (hazard ratio 1·02 [95% CI 0·69–1·51]; p=0·92). The most common grade 3 or worse adverse event was neutropenia (59 [64%] of 92 in the palbociclib plus endocrine therapy group vs 15 [18%] of 85 in the capecitabine group) . No treatment-related deaths occurred. With extended follow-up, palbociclib plus exemestane with ovarian function suppression continued to show a significant benefit in progression-free survival compared with capecitabine in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had been previously treated with tamoxifen; however, no improvement in overall survival was seen. Given the progression-free survival benefit, the upfront use of palbociclib plus endocrine therapy is the preferred option for premenopausal women, although a capecitabine-first strategy might be an alternative treatment strategy for maintaining overall survival in resource-limited settings. Pfizer and Ministry of Health & Welfare, South Korea.

Genexol-PM is a novel Cremophor EL-free polymeric micelle formulation of paclitaxel. This single arm, multicenter phase II study was designed to evaluate the efficacy and safety of Genexol-PM in patients with histologically confirmed metastatic breast cancer (MBC). Forty-one women received Genexol-PM by intravenous infusion at 300 mg/m 2 over 3 h every 3 weeks without premedication until disease progression or intolerability. A total of 331 chemotherapy cycles were administered, with a median of 8 cycles per patient (range, 1–16). Overall response rate was 58.5% (95% CI: 43.5–72.3) with 5 complete responses and 19 partial responses. Thirty-seven patients who received Genexol-PM as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI: 43.5–73.7), and two responses were reported in four patients treated in the second-line setting for their metastatic disease. The median time to progression (TTP) for all patients was 9.0 months (range, 1.0–17.0+ months). Grade 3 non-hematologic toxicities included sensory peripheral neuropathy (51.2%), and myalgia (2.4%). Eight patients (19.5%) experienced hypersensitivity reactions, with grade 3 in two patients. Hematologic toxicities were grade 3 and 4 neutropenia (51.2 and 17.1%, respectively), and grade 1 and 2 thrombocytopenia (22.0%). Notably, no febrile neutropenia was observed. Genexol-PM appears a promising new paclitaxel in view of significant efficacies. Further trials with different dosing schedules, durations of delivery, or in combination with other drugs are warranted.

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis, especially in patients with residual disease post-neoadjuvant chemotherapy. This phase II MIRINAE trial (KCSG-BR18-21) evaluates the efficacy and safety of atezolizumab combined with capecitabine versus capecitabine monotherapy as adjuvant treatment in TNBC patients with residual invasive cancer. The primary endpoint is the 5-year invasive disease-free survival (IDFS) rate. Secondary endpoints include IDFS in PD-L1 positive patients, distant relapse-free survival (DRFS), and overall survival (OS). This study addresses the limitations of KEYNOTE-522 by providing data on post-neoadjuvant therapies, potentially establishing a new standard of care for TNBC. Trial registration This trial is registered at ClinicalTrials.gov (NCT03756298).

AimsThe 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.MethodsPatients 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.ResultsMBC presented with larger tumours, more frequent distant metastasis and higher histological grade compared with TN-IDC (p<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<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).ConclusionsMBC 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.

IntroductionInfertility resulting from cancer treatment is known to be a major factor that reduces the quality of life of young cancer survivors. However, discussions and decision-making about fertility preservation before cancer treatment have been insufficient owing to barriers in the clinical field. In addition, selecting a fertility preservation option requires a complex decision-making process that considers not only medical information but also the patient’s values and preferences. Hence, an environment that more easily supports patient decision-making about fertility preservation needs to be created. Therefore, this protocol will develop and test a web-based decision aid (DA) for fertility preservation among young patients with cancer, considering patient preferences and values, evaluate acceptability and usability of the developed DA and assess its effectiveness.Methods and analysisThis protocol outlines the development of a web-based DA for fertility preservation targeting females of reproductive age diagnosed with cancer. It includes alpha testing to evaluate the usability and acceptability of the DA, as well as beta testing to assess its effectiveness outside of clinical settings, both based on an online survey. The web-based DA for fertility preservation consists of three modules: 1) an information collection module, 2) an option suggestion module and 3) a value communication module. The information collection module collects information essential to select appropriate fertility preservation options. The option suggestion module returns all applicable fertility preservation options based on the patient’s characteristics, which are essential for determining the appropriate option, such as menarche status and desire for pregnancy. The value communication module provides information on the extent to which each fertility preservation option satisfies the patient’s values and preferences. After the development of the DA, a small group of young patients with cancer (n=10) and health providers (n=5) will be asked to use this web-based DA for fertility preservation and assess the acceptability and usability of this DA based on a survey (alpha-testing). By reflecting the feedback of acceptability and usability testing, the DA will be updated for improvement, and clinical field testing (beta-testing pilot trial) will be performed using the updated DA. Beta-testing will be conducted on young patients with cancer (aged 18–40 years) before they receive any curative cancer treatment (n=32). These patients with cancer will be randomly allocated to the DA group (intervention group) or the usual care group (control group). The DA group will use the web-based DA before treatment, and the control group will not have access to the web-based DA and will be asked to decide whether to consult a fertility preservation specialist. The primary outcome of the beta testing will be the level of decisional conflict, and the secondary outcomes will include knowledge, decision self-efficacy, decision readiness, depression severity, quality of life, counselling on fertility preservation and decision-making about fertility preservation. Outcomes, including decisional conflict, knowledge, decision self-efficacy, quality of life and depression severity, will be measured before the intervention (T0), 1 week after the intervention (T1) and 1 month after the intervention (T2). The readiness for decision-making will be assessed at T1 for the intervention group only. Counselling on fertility preservation and decision-making about fertility preservation will be assessed once after testing (T2) for both the intervention and control groups.Ethics and disseminationThe study will be conducted in accordance with ethical standards and was approved by the Institutional Review Board at the National Cancer Centre, Korea (IRB No. NCC2024-0050). All study participants will provide written informed consent before participation. The results generated from this study will be presented at conferences or scientific meetings and disseminated through publication in a peer-reviewed journal.Trial registrationNCT07038174 (beta-testing phase).