TPS1117 Background: The PIK3CA oncogene mutation, seen in ~40% of patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (aBC), is associated with endocrine treatment resistance and shorter survival. Alpelisib, an α-selective PI3K inhibitor and degrader, was established as standard therapy in combination with fulvestrant for patients with HR+, HER2-, PIK3CA-mutated aBC following progression on/after endocrine-based regimen based on the phase 3 SOLAR-1 study. However, alpelisib is not yet approved in Japan. In the SOLAR-1 study, a high percentage of Japanese patients experienced dose reductions/interruptions (78.5% vs 84.4%), and/or discontinuation (56.3% vs 25.0%) of alpelisib in early stages compared with overall population, due to adverse events such as rash and hyperglycemia. Thus, it is difficult to assess the consistency of the benefit of alpelisib + fulvestrant in Japanese patients as compared to overall population due to the short duration of alpelisib exposure and low-dose intensity. The EPIK-B6 study aims to determine the recommended dose (RD) of alpelisib in Japanese patients as well as assess the efficacy and safety of alpelisib + fulvestrant in Japanese men and postmenopausal women with HR+, HER2-, PIK3CA-mutated aBC, which progressed while on/after aromatase inhibitor treatment, prior/post CDK 4/6i use. Methods: The EPIK-B6 study is designed as a phase 2, open-labelled, 2-part, multicenter study. Part 1 is to determine RD of alpelisib to be used in part 2. Part 2 is designed to assess the efficacy and safety of alpelisib (RD starting on cycle 1 day 1 [C1D1]) + fulvestrant (500 mg on C1D1 and C1D15, and D1 of subsequent cycles) after completion of part 1, in participants with/without prior CDK 4/6i use. Adult Japanese men or postmenopausal women with confirmed HR+, HER2-, PIK3CA-mutated aBC and ≥1 measurable lesion as per RECIST 1.1 criteria are eligible. Patients previously treated with fulvestrant, any PI3K, mTOR or AKT inhibitors are excluded. Use of prophylactic antihistamine is highly recommended for prevention of rash. The primary endpoint for part 2 is overall response rate based on assessments per RECIST 1.1. Secondary endpoints include progression free survival, overall survival, clinical benefit rate, duration of response, time to response, time to deterioration of ECOG performance status, safety, tolerability, and pharmacokinetics. Part 1 has been completed, and recruitment for part 2 is ongoing until August 2023 approximately. As of December 2022, 9 and 8 patients are enrolled in part 1 and 2, respectively. The study will include approximately 50 participants. Primary Analysis is planned in 2024 after at least 6 months follow-up period. Clinical trial information: NCT04524000 .
Background:Understanding of microtubule inhibitors containing neoadjuvant treatment in triple negative breast cancer (TNBC) is still limited.Methods:Targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) was carried out in TNBC tumours to examine the correlation of mutational status, tumour size, nodal status with pathological complete response (ypT0/isypN0) and differential gene expression profiles. Targeted sequencing was limited to 189 genes. Tumour samples analysed were from the JBCRG22 clinical trial.Findings: Higher mutation rates of TP53 and KMT2C were found in HRD positive (score ≥42) tumours with higher pCR rates. When stratified by tBRCA1m and tBRCA2m in HRD positive, pCR rates in tBRCA2m tumours were higher (83% vs 36%). Multivariate analysis showed significant association of the nodal status and tumour size <30.5 v ≥30.5 mm at presentation and % tumour size in largest diameter <=50%, >50% by MRI and HRD status after chemotherapy with pCR. Transcriptomic profiling resulted in identifying the downregulated FGFR2 expression (FDR p value = 2.07 x 107) in TP53 mutated tumours, and as the only common gene in A1 and B group tumours for pCR/QpCR. IL6-JAK-STAT3 signalling is enriched in TP53 wild type (p = 0.019) and post-treatment (p = 0.029) HRD high tumours. KRAS signalling down (p = 0.000), and checkpoint and mitotic spindle (p = 0.000) gene sets are enriched in the A1 and A2 post treatment tumours respectively.Interpretation: Results indicate that FGFR2 expression irrespective of the HRD score, IL-6 cytokine family genes play a role in response/resistance.Funding: This study was sponsored by the association of JBCRG and Eisai Co.,Ltd.Declaration of Interest: NM declare receiving research grants from Chugai, Eli Lilly, Astra Zeneca, Pfizer, Daiichi-Sankyo, MSD, Eisai, Novartis, Sanofi, Kyowa-Kirin, Nippon-Kayaku, Ono- Pharma. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events by Chugai, Pfizer, Astra Zeneca, Eli Lilly, Daiichi Sankyo and Eisai. Nonfinancial leadership roles at Japan Breast Cancer Research Group on the Executive Board and Japan Breast Cancer Society, Board of Directors. KK declare receiving research grants from TERUMO, Astellas, Eli Lilly, KBCRN (Kyoto Breast Cancer Research Network). Payment or honoraria from Eisai, Chugai, Takeda. MTa declare receiving research grants from Yakult, Daiichi Sankyo, AstraZeneca, KBCRN, JBCRG. Payment or honoraria from AstraZeneca, Daiichi Sankyo, Chugai, Eisai, Lilly, Pfizer. YK declare receiving payment or honoraria from Eisai, Novartis, Pfizer, Lilly, Taiho, Chugai. HB declare receiving payment or honoraria from Chugai, Eisai. RN: Payment or honoraria from Eli Lilly, AstraZeneca, Daiichi Sankyo, Chugai, Eisai, Novartis. YY declare receiving research grants from Chugai, Kyowa-Kirin, Esai, Daiichi-Sankyo, Nippon-Kayaku, Taiho, Takeda, Lilly, Pfizer, Novartis. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Chugai, Kyowa-Kirin, Novartis, Lilly, Pfizer, Daiichi-Sankyo, Nippon- Kayaku, Taiho, Esai, Takeda, MSD, Sysmex, Exact Science. Advisory Board member of AstraZeneca, Chugai, Novartis, Lilly, Pfizer, Daiichi-Sankyo. Board or advisory board of AstraZeneca, Chugai, Novartis, MSD, Lilly, Pfizer, Daiichi-Sankyo. Nonfinancial roles as Member of the Board of Directors of Japanese Breast Cancer Society and Japan Breast Cancer Research Group. TU Grants or contracts from Lilly Japan K.K. Payment or honoraria for Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., AstraZeneca, Novartis Pharma K.K. HI: Grants or contracts from Eisai Co., Ltd., Daiichi sankyo co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Payment or honoraria for lectures, presentation etc from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Inc., Kyowa Kirin Co., Ltd., JMS Co., Ltd., Daiichi sankyo co., Ltd. SM declare receiving research grant from Eisai Co., Ltd. and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca K.K, Bristol-Myers Squibb Company, Chugai Pharmaceutical Co. Ltd, Eisai Co., Ltd.,, Eli Lilly Japan K.K., Pfizer Japan Inc., MSD K.K., Novartis Pharma KK, Taiho Pharmaceutical Co. Ltd. SOh declare receiving research grant from Taiho, Eisai, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, Chugai, Lilly, Nippon Kayaku. SOg declare receiving research grants from Takeda Foundation, ChordiaTherapeutics, Inc., Sumitomo Dainippon Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd. Royalties or licenses from ASAHI Genomics Inc., Qiagen, Cordia Therapeutics; Consulting fees from Eisai Co., Ltd., ChordiaTherapeutics, Inc., Novartis Pharmaceuticals. Payment or honoraria from MSD Japan, Kyowa Hakko Kirin Co.,Ltd., Daiichi-Sankyo, Otuka Pharmaceutical Co.,Ltd., Pfizer Inc. Participation on a Data Safety Monitoring Board or Advisory Board KAN Research Institute, Inc., ChordiaTherapeutics, Inc. Stock or stock options in ASAHI Genomics Inc., Cordia Therapeutics Inc., Rebirthell Inc.. Other financial or non-financial interests as a researcher at ChordiaTherapeutics, Inc. MT declare receiving research grants from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, JBCRG assoc., Eisai, Eli Lilly, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technology, Luxonus, Shionogi, GL Science. Lecture honoraria or lecture chair from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis, Konica Minolta, Shimadzu, Yakult, Nippon Kayaku. Advisory board Kyowa-Kirin, Daiichi-Sankyo, Eli Lilly, Konica Minolta, BMS, Athenex Oncology, Bertis, Terumo, Kansai Medical Net. Non financial member of Borad of Directors at JBCRG assoc., KBCRN and OOTR. Associate editor of British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women’s Cancer, Asian Journal of Surgery, Asian Journal of Breast Surgery. Deputy Editor of International Journal of Oncology. TN, RV, SK, YM, ST, TK, RN, HY, HH declare no competing interests.Ethical Approval: The study complied with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labour and Welfare of Japan. The study protocol was reviewed and approved by the institutional review board of each participating institution. All patients provided written informed consent at primary registration. Clinical outcome of the JBCRG-22 study was published in the Breast Cancer Research and Treatment 2021 Mar 25. doi: 10.1007/s10549-021-06184-w.
e12576 Background: From the results of ACOSOG Z0011, IBCSG23-01 and AMAROS trials, axilla surgery in node-positive breast cancer (BC) tends to be less invasive with sentinel node biopsy (SNB) followed by adjuvant therapy and regional node irradiation (RNI). However, optimized axilla treatment including SNB without RNI is still debated. The Japanese Society for Sentinel Node Navigation Surgery conducted a multi-institutional prospective cohort study to compare SNB with SNB followed by axillary lymph node dissection (ALND) in cases with positive-sentinel lymph nodes (SLN)(UMIN No. 000011782, Jpn J Clin Oncol, p.876-9, 2014). Methods: Female BC patients with cT1-3N0-1M0 were eligible. When 1 to 3 positive micrometastases or macrometastases in SLN were confirmed by histological or molecular diagnosis, SNB alone or additional ALND had been decided by physician’s discretion. Primary chemotherapy before or after SNB was acceptable for registration. Lymph node sampling was also allowed in the SNB group. Cases with bilateral BC, isolated tumor cells only in SLN, past history of invasive cancer within 5 years at the registration were ineligible. The primary endpoint was the 5-year recurrence rate of regional node (RN) in the SNB group. The secondary endpoint was overall survival (OS). We planned to collect 240 patients to reject that the 5-year recurrence rate of RN was more than 10% assuming the rate 5%. To compare the SNB group and ALND group, the propensity score matching (PSM) was performed. Matching variables were initial treatment, metastatic size and numbers of SLN, clinical stage, age, body mass index, menopausal status, family history, past history of invasive cancer, breast surgery. Results: Eight-hundred eighty cases had been registered between 2013 and 2016. In the 871 eligible cases, 308 cases were the SNB group. At the median follow-up of 6.3 years, 5-year recurrence rate of RN was 2.7% [95% confidence interval, 1.4% to 5.4%] and 5-year OS was 97.6% [94.9% to 98.8%]. After PSM, 209 cases were matched in the SNB and ALND group. Among them, 343 cases (82%) received operation at initial treatment. Partial and total mastectomy was performed in 225 (54%) and 193 cases (46%), respectively. One-positive SLN was recorded in 366 cases (88%), 2 in 48 (11%) and 3 in 4 (1%). Macrometastases and micrometastases in SLN were diagnosed in 271 (65%) and 147 cases (35%), respectively. Three-hundred seventy-six cases (90%) belonged to luminal-like subtype. RNI was underwent in 42 cases (20%) of the SNB group and 13 cases (6%) of the ALND group. Five-year recurrence rate of RN was 2.1% [0.8% to 5.5%] and 2.0% [0.8% to 5.3%] for the SNB and ALND group, respectively. Conclusions: Our series suggests that RNI is not necessary for regional control in cases with 1 to 3 positive SLN. In conclusion, SNB alone is acceptable in cases with fewer metastatic SLN. Clinical trial information: UMIN No. 000011782.
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.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]).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.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.
Abstract Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.
BackgroundA 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.MethodsPatients 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.ResultsOf 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.ConclusionE7389-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.Clinicaltrials.gov numberNCT03207672.
Patients with estrogen receptor (ER)-positive breast cancer are less likely to achieve a pathological complete response (pCR) with neoadjuvant chemotherapy. Neoadjuvant endocrine therapy may be more appropriate than neoadjuvant chemotherapy in these hormone-sensitive patients. Most patients with ER-positive breast cancer are postmenopausal, and therefore, generally older and less able to tolerate chemotherapy. We aimed to investigate the efficacy and safety of tailored neoadjuvant endocrine and chemoendocrine therapy for postmenopausal breast cancer patients. Untreated patients with primary invasive ER-positive, HER2-negative, stage I-IIIA breast cancer, and Ki67 index ≤30% were enrolled. Patients received exemestane 25 mg/d for 12 weeks. Based on clinical response and change in Ki67 index, assessed at 8-12 weeks, patients with complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% before and after treatment were defined as responders. For the subsequent 24 weeks, responders continued exemestane monotherapy (group A), and nonresponders received exemestane 25 mg/d plus cyclophosphamide 50 mg/d (group B). The primary endpoint was clinical response at weeks 24 and 36. A total of 59 patients (median age, 69 years) started initial exemestane monotherapy. After exclusion of three patients who discontinued during this period, 56 remained enrolled to receive subsequent treatment. Clinical response rates (CR and PR) and 95% CI at weeks 24 and 36 were 85% (12/14; 57.2%-98.2%) and 71% (10/14; 41.9%-91.6%), respectively, in group A; and 54% (23/42; 38.7%-70.2%) and 71% (30/42; 55.4%-84.3%), respectively, in group B. At week 36, no significant difference was found in median Ki67 index between the groups (3.5% and 4.0%). There were no treatment-related deaths. We found that clinical response comparable to that of responders was achieved in nonresponders after addition of cyclophosphamide to the initial endocrine therapy.
Abstract Background: Nab-paclitaxel(nab-PTX) is improved taxane in terms of solubility, alcohol-free and reduced incidence of anaphylaxis. On the other hand, chemotherapy-induced peripheral neuropathy (PN) is known as a major adverse event which was failed to suppress by many medications. Recently, some reports describe about cooling and compression of extremities of patients treated by taxane can reduce the incidence and severity of PN. The efficacies of interventions with frozen groves and compression stockings to prevent nab-PTX-induced PN was examined.Methods: The patients with HER2 negative primary breast cancers treated by four cycles of nab-PTX pre-/post- operative chemotherapies were randomized to two groups (interventions with frozen groves (FG) and compression stockings (CS), and with standard care (SD)). Primary endpoint was frequency and time to onset of >Grade 2 PN by CTCAE ver.4.0, and secondary endpoints are frequency of >Grade2 PN at the end of four cycles of nab-PTX, HRQOL, recovery of PN for 5 years from the end of nab-PTX and safety. Also, we requested to keep diary with several questions for patient reported outcomes (PRO).Results: Of the 124pts enrolled, 123(62 FG/CS, 61 SD) were included in the intent-to-treat analysis. There were no significant differences in clinicopathological findings between two groups. As a primary endpoint, frequency and time to onset of >Grade 2 motor-PN /sensory-NP of hands comparing FG and SD showed p=0.162/0.599, and of foots comparing CS and SD showed p=0.525/0.933 (Log-rank test with one sided significant level of 10%). Conversely, the worst Grade of sensory-PN is statistically significant difference at Cycle 2 (p=0.021; Mann-Whitney’s U-test with two-sided significant level of 5%), >Grade3 of motor-PN was statistically significant low in all cycles (p=0.022; Log-rank test with one sided significant level of 10%), >Grade1 of sensory-PN was statistically significant low (p=0.022; Log-rank test with one sided significant level of 10%), and >Grade3 of sensory-PN was statistically significant low in all cycles (p=0.072; Log-rank test with one sided significant level of 10%) with FG in detail. In addition, Grade3 of motor-PN was statistically significant low in all cycles (p=0.022; Log-rank test with one sided significant level of 10%), >Grade1 of sensory-PN was statistically significant low (p=0.015; Log-rank test with one sided significant level of 10%), and >Grade3 of sensory-PN was statistically significant low in all cycles (p=0.089; Log-rank test with one sided significant level of 10%)in all cycles (p=0.022; Log-rank test with one sided significant level of 10%) with CS in detail. Moreover, PRO indicated by patients’ diary showed interesting patterns of increase and decrease in sense of pain and paralyzed which might be corresponding to efficacy of interventions with FG and CS.Conclusion: Although primary endpoints were not met by the interventions with FG and CS, this trial revealed the detail of PN caused by nab-PTX, and these interventions might delay beginning of sensory and motor PN and reduce the worst grade of PN. The adverse events grading according to CTCAE and PRO indicated by patients’ diary seems to be not completely matched, the usefulness of FG and CS are investigating with more questionnaire. (UMIN: UMIN000016902) Citation Format: Masahiro Kashiwaba, Takahiro Nakayama, Takafumi Sangai, Takashi Morimoto, Hiroyuki Yasojima, Yutaka Yamamoto, Shinji Ohno, Norikazu Masuda. A randomized phase II trial of interventions with frozen groves and compression stockings to prevent nab-paclitaxel induced chemotherapy-induced peripheral neuropathy (SPOT trial) [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 PS9-52.
