Long-term outcomes of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) and docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) for HER2-positive primary breast cancer: results of the randomized phase 2 JBCRG20 study (Neo-peaks).

PURPOSE: The randomized phase 2 Neo-peaks study examined usefulness of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) following docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) as compared with the standard TCbHP regimen. We previously reported that pCR rate after neoadjuvant therapy tended to be higher with TCbHP followed by T-DM1 + P. We conducted an exploratory analysis of prognosis 5 years after surgery. METHODS: Neoadjuvant treatment with TCbHP (6 cycles; group A), TCbHP (4 cycles) followed by T-DM1 + P (4 cycles; group B), and T-DM1 + P (4 cycles; group C, + 2 cycles in responders) were compared. Group C non-responders after 4 cycles were switched to an anthracycline-based regimen. We evaluated 5-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS). RESULTS: Data from 203 patients (50, 52, and 101 in groups A-C, respectively) were analyzed. No significant intergroup differences were found for DFS, DDFS, or OS. The 5-year DFS rates (95% CI) were 91.8% (79.6-96.8%), 92.3% (80.8-97.0%), and 88.0% (79.9-93.0%) in groups A-C, respectively. TCbHP followed by T-DM1 + P and T-DM1 + P with response-guided addition of anthracycline therapy resulted in similar long-term prognosis to that of TCbHP. CONCLUSIONS: In patients who achieved pCR after neoadjuvant therapy with T-DM1 + P, omission of adjuvant anthracycline may be considered, whereas treatment should be adjusted for non-pCR patients with residual disease. T-DM1 + P with response-guided treatment adjustment may be useful for minimizing toxicity. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: UMIN-CTR, UMIN000014649, prospectively registered July 25, 2014. Some of the study results were presented as a Mini Oral session at the ESMO Breast Cancer 2023 (Berlin, Germany, 11-13 May 2023).

Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study.

BACKGROUND: A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2- ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice. METHODS: Real-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2- ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival. RESULTS: Of the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9-29.4) for first-line and 14.5 months (10.2-19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1-87.7), 82.0% (70.7-89.3), and 66.0% (57.9-72.9), respectively. CONCLUSION: The addition of palbociclib to ET was effective for treating HR+/HER2- ABC in Japanese routine clinical practice.

Genomic Landscape of Circulating Tumor DNA in Patients With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Treated With Abemaciclib: Data From the SCRUM-Japan Cancer Genome Screening Project.

PURPOSE: To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET). METHODS: Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2- MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples. RESULTS: All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P < .01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA, TP53, CCND1, and RB1 (all 15%); and ESR1 (12%). CONCLUSION: We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.

Overall survival in Japanese patients with ER+/HER2- advanced breast cancer treated with first-line palbociclib plus letrozole.

BACKGROUND: An open-label, single-arm, Japanese phase 2 study (J-Ph2) investigated the efficacy and safety of first-line (1L) palbociclib (PAL) + letrozole (LET) in postmenopausal Japanese women with ER+/HER2- advanced breast cancer (ABC). In the final analysis, median progression-free survival was 35.7 months (95% CI 21.7-46.7); but overall survival (OS) data were immature. Here, we report the findings from a follow-up study of J-Ph2 (NCT04735367) evaluating OS and subsequent therapy in these Japanese women. METHODS: Patients (N = 42) who participated in J-Ph2 were enrolled in the OS follow-up study. The primary endpoint was OS and secondary endpoints included type and duration of subsequent therapy. RESULTS: Patients were a median age of 62.5 years; 48% had visceral metastases. At a median follow-up of 89.7 months, the median OS was 85.4 months (95% CI 64.3-not estimable). Median OS was longer in patients with nonvisceral versus visceral metastases (not reached vs 67.3 months), or with treatment-free interval > 12 months versus ≤ 12 months (85.4 vs 45.4 months), or with treatment duration ≥ 24 months versus < 24 months (not reached vs 47.5 months). Of patients who received a first subsequent therapy (81%), most (67%) continued endocrine-based therapy, while 7% received chemotherapy. The median duration of the first subsequent therapy was 8.3 months (95% CI 3.9-12.2), and the median chemotherapy-free survival was 69.1 months (95% CI 24.2-85.4). CONCLUSIONS: In this population of Japanese women with ER+/HER2- ABC, median OS was over 7 years with 1L PAL + LET, supporting the use of 1L PAL + endocrine therapy. TRIAL NUMBER: NCT04735367.

Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial).

BACKGROUND: Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies. METHODS: This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers. RESULTS: From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy. CONCLUSIONS: Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs. TRIAL REGISTRATION NUMBER: JapicCTI-194782, jRCT2080224706, UMIN000036970.

Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative advanced and metastatic breast cancer in Japan (KBCSG-TR-1316).

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2- mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis. METHODS: The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2- mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0-100) = - 0.45 × estrogen receptor (ER) (%) - 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38). RESULTS: Of the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients. CONCLUSIONS: The efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2- mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance.

HDR-brachytherapy for accelerated partial breast irradiation: Long-term experience from a Japanese institution.

Purpose: We investigated the long-term oncological outcome of high-dose-rate (HDR) multicatheter interstitial brachytherapy (MIB) for adjuvant accelerated partial breast irradiation (APBI) after breast conserving surgery in Japanese patients. Material and methods: Between June 2002 and October 2011, 86 breast cancer patients were treated at National Hospital Organization Osaka National Hospital (trial number of the local institutional review board, 0329). Median age was 48 years (range, 26-73 years). Eighty patients had invasive and 6 patients non-invasive ductal carcinoma. Tumor stage distribution was pT0 in 2, pTis in 6, pT1 in 55, pT2 in 22, and pT3 in one patient, respectively. Twenty-seven patients had close/positive resection margins. Total physical HDR dose was 36-42 Gy in 6-7 fractions. Results: At a median follow-up of 119 months (range, 13-189 months), the 10-year local control (LC) and overall survival rate was 93% and 88%, respectively. Concerning the 2009 Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology risk stratification scheme, the 10-year LC rate was 100%, 100%, and 91% for patients considered as low-risk, intermediate-risk, and high-risk, respectively. According to the 2018 American Brachytherapy Society risk stratification scheme, the 10-year LC rate was 100% and 90% for patients 'acceptable' and 'unacceptable' for APBI, respectively. Wound complications were observed in 7 patients (8%). Risk factors for wound complications were the omission of prophylactic antibiotics during MIB, open cavity implantation, and V100 ≥ 190 cc. No grade ≥ 3 late complications (CTCVE version 4.0) were observed. Conclusions: Adjuvant APBI using MIB is associated with favorable long-term oncological outcomes in Japanese patients for low-risk, intermediate-risk, and acceptable groups of patients.

Pembrolizumab plus chemotherapy in Japanese patients with triple-negative breast cancer: Results from KEYNOTE-355.

Pembrolizumab plus chemotherapy improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥10 in the global, phase 3, randomized controlled trial KEYNOTE-355. We report results for patients enrolled in Japan. Patients were randomized 2:1 to pembrolizumab 200 mg or placebo Q3W for 35 cycles plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin). Primary endpoints were PFS per RECIST version 1.1 by blinded independent central review and OS in patients with PD-L1 CPS ≥10, PD-L1 CPS ≥1, and the intention-to-treat (ITT) population. No alpha was assigned to this exploratory analysis. Eighty-seven patients were randomized in Japan (pembrolizumab plus chemotherapy, n = 61; placebo plus chemotherapy, n = 26), 66 (76%) had PD-L1 CPS ≥1, and 28 (32%) had PD-L1 CPS ≥10. Median time from randomization to data cutoff (June 15, 2021) was 44.7 (range, 37.2-52.9) months in the ITT population. Hazard ratios (HRs; 95% CI) for OS were 0.36 (0.14-0.89), 0.52 (0.30-0.91), and 0.46 (0.28-0.77) in the PD-L1 CPS ≥10, PD-L1 CPS ≥1, and ITT populations, respectively. HRs (95% CI) for PFS were 0.52 (0.20-1.34), 0.61 (0.35-1.06), and 0.64 (0.39-1.05). Grade 3 or 4 treatment-related adverse events occurred in 85% of patients in each group (no grade 5 events). Consistent with the global population, pembrolizumab plus chemotherapy tended to show improvements in OS and PFS with manageable toxicity versus placebo plus chemotherapy in Japanese patients and supports this combination in this setting.

Phase 1 study of the liposomal formulation of eribulin (E7389-LF): Results from the breast cancer expansion cohort.

BACKGROUND: A liposomal formulation of eribulin, E7389-LF, may provide improved pharmacokinetics and allow increased access to tumour tissues. This expansion of a phase 1 study assessed the safety and efficacy of E7389-LF in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. METHODS: Patients received E7389-LF 2.0 mg/m2 every three weeks. Tumour assessments were conducted every six weeks by the investigator by Response Evaluation Criteria in Solid Tumours v1.1. All adverse events were monitored and recorded. Serum biomarker assessments were conducted. RESULTS: Of 28 patients included, 75.0% had hormone receptor-positive breast cancer (HR+ BC) and 25.0% had triple-negative breast cancer (TNBC). The most common grade ≥3 treatment-related treatment-emergent adverse events included neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), and febrile neutropenia (25.0%). Rates of neutropenia and febrile neutropenia were lower among patients who received prophylactic pegfilgrastim. Objective response rate was 35.7% (95% confidence interval [CI]: 18.6-55.9) for all patients and 42.9% (95% CI: 21.8-66.0) for patients with HR+ BC. Median progression-free survival was 5.7 months (95% CI: 3.9-8.3). The median overall survival was 18.3 months (95% CI: 13.2-not estimable). Among the 54 biomarkers assessed, 27, including 5 of 7 vascular markers, were significantly altered by E7389-LF treatment from baseline to any time point. CONCLUSION: E7389-LF was tolerable and favourable antitumour activity was observed, particularly in patients with HR+ BC. Prophylactic pegfilgrastim can be considered in patients at high risk for neutropenia and febrile neutropenia. GOV NUMBER: NCT03207672.

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer.

BACKGROUND: Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients. METHODS: This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points. RESULTS: Twelve patients were enrolled. No DLTs or grade 3-5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9-not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months. CONCLUSIONS: Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation. TRIAL REGISTRATION: JAPIC Clinical Trial Information, JapicCTI-153066 . Registered 12 November 2015. ClinicalTrials.gov, NCT02623751 . Registered 8 December 2015.

Capecitabine in Combination with Endocrine Therapy as Maintenance Therapy after Bevacizumab Plus Paclitaxel Induction Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: KBCSG-TR1214.

Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab-paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m2/day on days 1-21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab-paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0-11.8} months) than in group E (4.3 {3.6-6.0} months) (hazard ratio, 0.53; p < 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41; p = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.

Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917).

BACKGROUND: Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post-T-DM1 treatments is currently lacking. We evaluated the effectiveness of post-T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. METHODS: In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post-T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken. RESULTS: Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8-6.9) months, 5.6 (4.6-6.4) months, and 22.8 (18.2-32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8-56.7) and 23% (15.1-31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months. CONCLUSIONS: In the real-world setting in Japan, several post-T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings. TRIAL REGISTRATION: UMIN000038296 ; registered on 15 October 2019.

Meta-analysis of nanoparticle albumin-bound paclitaxel used as neoadjuvant chemotherapy for operable breast cancer based on individual patient data (JBCRG-S01 study).

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX), a novel taxane formulation, was developed to avoid cremophor/ethanol-associated toxicities including peripheral neuropathy and hypersensitivity. At least 35 phase II studies using combined nab-PTX and anthracycline in neoadjuvant settings are registered in Japan. We analyzed the efficacy and safety of nab-PTX based on patient characteristics in these studies. METHODS: We conducted a meta-analysis using individual patient data (IPD) to investigate the average efficacy of nab-PTX-containing regimens as neoadjuvant chemotherapy for operable breast cancer. IPD were provided by principal investigators who agreed to participate. The primary endpoint was pathological complete response (pCR) rate of each breast cancer subtype. RESULTS: We analyzed the data of 16 studies involving 753 patients. The overall crude frequencies of pCR (ypT0 ypN0, ypT0/is ypN0, and ypT0/is ypNX) were 18.1, 26.0, and 28.6%, respectively. Specifically, the frequencies were 6.7, 10.2, and 13.4% for luminal (n = 343); 40.5, 63.5, and 68.9% for human epidermal growth factor receptor 2 (HER2)-rich, (n = 74); 21.9, 40.6, and 42.7% for luminal/HER2 (n = 96); and 26.3, 31.5, and 32.3% for triple-negative breast cancers (TNBC) (n = 232). The multivariate analyses indicated that HER2 positivity, TNBC, high Ki-67, high nuclear grade, and weekly nab-PTX administration were significantly associated with the pCR. The proportion of hematological toxicities (neutropenia (39.7%) and leukopenia (22.5%)), peripheral sensory neuropathy (9.7%), myalgia (5.7%), and arthralgia (4.7%) was higher than grade 3 adverse events, but most patients recovered. CONCLUSIONS: Nab-PTX is a safe and acceptable chemotherapeutic agent in neoadjuvant settings, particularly for aggressive cancers. UMIN-CTR#: UMIN000028774.

Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial.

PURPOSE: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. METHODS: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety. RESULTS: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively. CONCLUSIONS: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

Current Status of Advance Care Planning and End-of-life Communication for Patients with Advanced and Metastatic Breast Cancer.

BACKGROUND: Advance care planning (ACP) is a process that supports adults in understanding and sharing their personal values, life goals, and preferences regarding future medical care. We examined the current status of ACP and end-of-life (EOL) communication between oncologists and patients with metastatic breast cancer. MATERIALS AND METHODS: We conducted a survey among 41 institutions that specialize in oncology by using an online tool in October 2019. Participants (118 physicians) from 38 institutions completed a 39-item questionnaire that measured facility type and function; physicians' background and clinical approach, education about EOL communication, and understanding about ACP; and the current situation of ACP and EOL discussions. RESULTS: Ninety-eight responses concerning physicians' engagement in ACP with patients were obtained. Seventy-one (72%) answered that they had engaged in ACP. Among these, 23 (33%) physicians used a structured format to facilitate the conversation in their institutions, and only 6 (8%) settled triggers or sentinel events for the initiation of ACP. In the multivariable analysis, only the opportunity to learn communication skills was associated with physicians' engagement with ACP (odds ratio: 2.8, 95% confidence interval: 1.1-7.0). The frequency and timing of communication about ACP and EOL care with patients substantially varied among the oncologists. Communication about patients' life expectancy was less frequent compared with other topics. CONCLUSION: The opportunity to improve EOL communication skills promoted physicians' engagement with ACP among patients with metastatic/advanced breast cancer. However, there were still substantial variabilities in the method, frequency, and timing of ACP and EOL communication among the oncologists. IMPLICATIONS FOR PRACTICE: This study found that the opportunity to improve end-of-life (EOL) communication skills promoted physicians' engagement in advance care planning (ACP) among patients with metastatic/advanced breast cancer. All oncologists who treat said patients are encouraged to participate in effective education programs concerning EOL communication skills. In clinical practice, there are substantial variabilities in the method, frequency, and timing of ACP and EOL communication among oncologists. As recommended in several clinical guidelines, the authors suggest a system that identifies patients who require conversations about their care goals, a structured format to facilitate the conversations, and continuous measurement for improving EOL care and treatment.

Rechallenge of anti-PD-1/PD-L1 antibody showed a good response to metastatic breast cancer: a case report.

Rechallenge of immune checkpoint inhibitors has been reported for neoplasms other than breast cancer. Reported here is a case of a 55-year old woman diagnosed as having triple-negative right breast cancer with multiple metastases including lung. Atezolizumab and nab-paclitaxel were administered followed by epirubicin-cyclophosphamide. With subsequent eribulin, the overall best response was progressive disease, and curative surgical resection was performed. Three months after surgery (1.5 years after initial response of lung metastasis), right lung metastasis emerged at a site different from baseline. Based on the microsatellite instability-high status, pembrolizumab was administered and showed a good response. The patient has been treated with pembrolizumab, maintaining partial response, for over 9 months, which suggests the benefit of immune checkpoint inhibitors rechallenge in breast cancer.

A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer.

PURPOSE: The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists. METHODS: Neopeaks, a randomized, phase 2 study, compared docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) followed by trastuzumab emtansine + pertuzumab (T-DM1+P; 4 cycles; group B), and T-DM1+P (4 cycles; group C) regimens in HER2-positive primary breast cancer patients; concurrent hormone therapy with T-DM1+P was administered in case of estrogen receptor positivity (ER+). Based on tumor shrinkage, nonresponders in group C were switched to 5-fluorouracil + epirubicin + cyclophosphamide (FEC; 4 cycles). Primary endpoint was pCR (comprehensive pCR ypN0 [ypT0-TisypN0]). RESULTS: Of 236 patients enrolled, 204 were randomized to groups A (n = 51), B (n = 52), and C (n = 101). In group C, 80 (79%) patients continued T-DM1+P following favorable response, whereas 21 (21%) nonresponders switched to FEC. pCR rate was numerically higher with the TCbHP → T-DM1+P regimen (71%) versus the standard TCbHP (57%) and T-DM1+P (57%) regimens. The rate in group C was higher among responders continuing T-DM1+P (63%) versus nonresponders who switched to FEC (38%). pCR rates after initial 4 cycles of T-DM1+P (group C; 57%) and standard TCbHP regimen (57%) were equivalent. pCR rate in patients with ER+ was significantly higher in group B (69%) than groups A (43%) and C (51%), but was comparable in patients with ER- (67-76%). Compared with the T-DM1-based arm, the incidence of adverse events was higher in the taxane-based arms. CONCLUSION: In the neoadjuvant setting, the pCR rate with the standard TCbHP → T-DM1+P regimen was numerically better than the TCbHP regimen alone and significantly better in patients with ER+. Personalization of the T-DM1+P regimen could serve as a reasonable approach to minimize toxicity while maintaining efficacy. Trial registration ID: UMIN-CTR: UMIN000014649.

Distinct gene expression profiles between primary breast cancers and brain metastases from pair-matched samples.

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy.

BACKGROUND: We conducted a phase I/II clinical trial to evaluate the efficacy of eribulin and olaparib in a tablet form (EO study) for triple-negative breast cancer (TNBC) patients. We hypothesized that somatic BRCA mutations and homologous recombination repair (HRR)-related gene alterations might affect efficacy. METHODS: Our analyses identified mutations in HRR-related genes and BRCA1/2, and we subsequently evaluated their association to response by the EO study participants. Tissue specimens were obtained from primary or metastatic lesion. Tissue specimens were examined for gene mutations or protein expression using a Foundation Medicine gene panel and immunohistochemistry. RESULTS: In the 32 tissue specimens collected, we detected 33 gene mutations, with the most frequent nonsynonymous mutations found in TP53. The objective response rates (ORRs) in patients with and without HRR-related gene mutation were 33.3% and 40%, respectively (P = .732), and the ORRs in patients with and without somatic BRCA mutations were 60% and 33.3%, respectively (P = .264), with the ORR numerically higher in the somatic BRCA-mutation group but not statistically significant. There was no correlation between immunohistochemistry status and response or between BRCA status or HRR-related gene mutation and survival. Immunohistochemical analysis indicated that EGFR-negative patients had a tendency for better progression-free survival (log-rank P = .059) and significantly better overall survival (log-rank P = .046); however, there was no correlation between the status of other immunohistochemistry markers and survival. CONCLUSION: These findings suggested somatic BRCA mutation and EGFR-negativity as a potential biomarker for predicting the efficacy of eribulin/olaparib combination therapy. (UMIN000018721).

Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 12 weeks' exemestane exposure in patients with estrogen receptor-positive breast cancer: A multicenter, open-label, phase II study.

Our aim was to investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane alone followed by tailored treatment, either continued exemestane monotherapy or exemestane plus docetaxel-cyclophosphamide (TC) combination therapy, in postmenopausal patients with primary invasive estrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I-IIIA breast cancer and Ki67 labeling index ≤30%. In this open-label phase II study, patients initially received exemestane 25 mg/d for 12 weeks. Responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 labeling index ≤5% after treatment, or stable disease with Ki67 labeling index ≤5% both before and after treatment. For the subsequent 12 weeks, exemestane monotherapy was continued for responders (group A), whereas nonresponders received exemestane plus four cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (group B). Clinical response rate (ie the proportion of patients with CR or PR) at 24 weeks was the primary endpoint. Of 64 patients provisionally enrolled between December 2010 and May 2016, 58 (median age 60 years) started the study treatment. Five patients discontinued treatment in the initial exemestane monotherapy period, and 39 completed the study treatment. Clinical response rates at 8-12 and 24 weeks were 71% (10/14, 95% confidence interval [CI] 41.9%-91.6%) and 57% (8/14, 95% CI 28.9%-82.3%), respectively, in group A, and 16% (4/25, 95% CI 4.5%-36.1%) and 56% (14/25, 95% CI 34.9%-75.6%), respectively, in group B. Grade ≥3 adverse events were reported in 8% (1/15) and 53% (20/38) in group A and group B, respectively. The tailored treatment maintained the favorable clinical response to exemestane alone in responders and improved clinical response in nonresponders. TRIAL NUMBER: UMIN000004752 (UMIN Clinical Trials Registry).