Lung Oligometastasis of Breast Cancer: Prospective Cohort Study of Treatment Strategies (SBP-06).

While local treatment of metastases is considered to be unrelated to prognosis, previous studies have suggested that local treatment of isolated lung metastases may have positive prognostic impact. We designed this prospective cohort study to investigate the clinical situation and its outcomes. We enrolled patients with fewer than 3 lung nodules suspected of being oligometastases after curative breast cancer surgery. Treatments, including local and systemic therapy, were selected by the physician and patient in consultation. The primary outcome was overall survival (OS); secondary outcomes were the efficacy and the safety of the surgery for lung oligometastases. Between May 2015 and May 2019, 14 patients were enrolled. Resection of lung nodules (metastasectomy) was performed in 11 (78.6%) of 14 patients, and one of these cases was diagnosed as primary lung cancer. Metastasectomies were all performed employing video-assisted thoracic surgery (VATS) without perioperative complications. Systemic therapies were administered to all patients except one. The respective 3-year and 5-year OS rates of patients with lung oligometastases were 91.6% and 81.5%, respectively. Progression occurred in 6 patients: 3 of the 10 with metastasectomy and all 3 without this surgical procedure. Lung metastasectomy was worthwhile as a diagnostic evaluation and may provide long-term benefit in some patients.

Phase II trial of biweekly administration with eribulin after three cycles of induction therapy in hormone receptor-positive, HER2-negative metastatic breast cancer (JACCRO BC-03).

PURPOSE: Metastatic breast cancer (MBC) is usually incurable; treatment aims to maximize patients' function and quality of life (QOL). Eribulin is a standard treatment in patients with MBC pretreated with anthracycline and taxane; however, the best administration schedule is unknown. METHODS: In this prospective phase II trial of patients with luminal MBC, we administered biweekly eribulin to patients who completed a three-cycle induction treatment. RESULTS: Sixty patients with hormone-receptor-positive and HER2-negative MBC were enrolled; 40 obtained stable disease (SD) or better efficacy after induction therapy, after which they were switched to biweekly maintenance administration. The median progression-free survival (PFS) in patients who switched to maintenance therapy was 15.21 weeks (95% CI 9.71-22.14), starting on the first day of maintenance therapy. Overall survival (OS) in patients who switched to maintenance therapy was 21.39 months (95% CI 18.89-32.89). PFS and OS in the whole population starting from the registration date were 19.00 weeks (95% CI 17.00-25.00) and 21.52 months (95% CI 16.23-24.25), respectively. PFS from the enrollment date for patients who received maintenance therapy was 25.29 weeks (95% CI 19.14-32.14). Patients who achieved complete response or partial response during induction therapy had significantly longer PFS compared to patients with SD. CONCLUSION: The efficacy of biweekly administration of eribulin at maintenance was nonsignificant. However, less frequent visits are convenient, and reduced dose intensity improves safety. Biweekly administration, besides dose reduction, could be an acceptable option for patients who are unable to maintain a standard regimen.

Phase III study of long-term prognosis of estrogen receptor-positive early breast cancer treated with neoadjuvant endocrine therapy with/without adjuvant chemotherapy.

PURPOSE: Neoadjuvant endocrine therapy (NET) is a treatment option for estrogen receptor-positive (ER+) postmenopausal early breast cancer (EBC). This phase III trial evaluated the prognosis of EBC patients treated with/without chemotherapy (CT) following NET. METHODS: ER+/HER2-, T1c-2, and clinically node-negative EBC patients were enrolled in 2008-2013 and treated with endocrine therapy (ET) in weeks 24-28. All patients, excluding those with progressive disease (PD) during NET or ≥ 4 positive lymph nodes after surgery, were randomized to ET for 4.5-5 years with/without CT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant DFS (DDFS), overall survival (OS), and DFS/DDFS/OS according to clinical response to NET. RESULTS: Of 904 patients, 669 were randomized to CT+ET (n = 333) or ET alone (n = 336). The median follow-up was 7.8 years. DFS (CT+ET, 47 events; ET alone, 70 events) and DDFS did not reach the planned numbers of events. Eight-year DFS/DDFS rates were 86%/93% and 83%/92%, respectively. DFS was significantly better in CT+ET than ET alone in subgroups aged < 60 years (P = 0.016), T2 (P = 0.013), or Ki67 > 20% (P = 0.026). Progesterone receptor and histological grade were predictive markers for clinical responses to NET. CONCLUSION: NET may be used as standard treatment for patients with ER+EBC. Although it is difficult to decide whether to administer adjuvant CT based solely on the effect of NET, the response to NET may help to inform this decision. TRIAL REGISTRATION: This study was registered at the UMIN Clinical Trials Registry under UMIN000001090 (registered 20 March 2008).

Retrospective study on the effectiveness of medroxyprogesterone acetate in the treatment of ER-positive/HER2-negative post-menopausal advanced breast cancer: an additional analysis of the JBCRG-C06 Safari study.

BACKGROUND: Only old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment. METHODS: This was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan-Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate. RESULTS: From the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer. CONCLUSION: In actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents.

Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR.

BACKGROUND: Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC. METHODS: Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. RESULTS: This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8+ T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4+ T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4+ T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4+ T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2). CONCLUSIONS: Intratumoral and stromal CD4+ T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results. TRIAL REGISTRATION: UMIN000023162.

Eribulin improved the overall survival from the initiation of first-line chemotherapy for HER2-negative advanced breast cancer: a multicenter retrospective study.

BACKGROUND: Eribulin methylate (eribulin) improved the overall survival (OS) of eribulin-treated patients with HER2-negative advanced breast cancer (ABC) in prospective and retrospective studies. However, the effect of eribulin on OS as first-line chemotherapy and the characteristics of the patients who benefited from eribulin remain unclear. METHODS: Between January 2011 and December 2016, 301 patients with HER2-negative ABC who started first-line chemotherapy at 3 institutions were retrospectively evaluated for OS from the initiation of first-line chemotherapy. RESULTS: We identified 172 patients (119 estrogen receptor-positive [ER+], 47 ER-, 6 unknown) who received eribulin (eribulin group) and 129 patients (92 ER+, 31 ER-, 6 unknown) who did not receive eribulin (non-eribulin group). The median OS from the initiation of first-line chemotherapy in the two groups was not statistically significant (869 vs. 744 days, P = 0.47, log-rank); however, in patients who received eribulin in later lines (≥3rd-line) and who had a history of perioperative chemotherapy with anthracycline- and/or taxane-based regimens, the median OS improved (1001 vs. 744 days, P = 0.037; and 834 vs. 464 days, respectively P = 0.032, respectively; Wilcoxon). Multivariate analyses revealed that a history of perioperative chemotherapy with anthracycline- and/or taxane-based regimens was a predictive factor (hazard ratio, 0.39; 95% confidence interval, 0.21-0.70) for OS. CONCLUSIONS: This study successfully identified subgroups of HER2- ABC patients with improved OS by eribulin therapy. Selecting patients according to their background and line of treatment will maximize the efficacy of eribulin therapy.

Factors associated with overall survival after recurrence in patients with ER-positive/HER2-negative postmenopausal breast cancer: an ad hoc analysis of the JBCRG-C06 Safari study.

BACKGROUND: The Safari study (UMIN000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive advanced breast cancer treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure in patients with estrogen receptor-positive advanced breast cancer. The current study is an ad hoc analysis that focused on the relationship between the patient factors and overall survival after recurrence by adding factors generally associated with overall survival after recurrence. METHODS: The overall survival after recurrence in patients with estrogen receptor-positive human epidermal growth factor receptor 2 negative recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. RESULTS: A total of 598 cases were used for the analysis of overall survival after recurrence. Multivariate analysis revealed that favorable overall survival (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥3 years), low nuclear or histological grade (G3 vs. G1), long time to treatment failure of initial palliative endocrine therapy (≥12 months) and long time to initial palliative chemotherapy (≥2 years). CONCLUSION: The results of this study indicate that sequential endocrine monotherapy may be a useful treatment option for patients with estrogen receptor-positive/human epidermal growth factor receptor 2 negative recurrent breast cancer who have been successfully treated with initial long-term palliative endocrine therapy.

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial.

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.

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.

The efficacy and safety of pertuzumab plus trastuzumab and docetaxel as a first-line therapy in Japanese patients with inoperable or recurrent HER2-positive breast cancer: the COMACHI study.

PURPOSE: In the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did not demonstrate the improved progression-free survival (PFS) of pertuzumab plus trastuzumab and docetaxel vs. placebo that was seen in the overall population. Therefore, COMACHI was conducted to confirm the efficacy and safety of this treatment regimen in this patient subgroup. METHODS: This was a phase IV study of pertuzumab plus trastuzumab and docetaxel in Japanese patients with histologically/cytologically confirmed inoperable or recurrent HER2-positive breast cancer. All patients received pertuzumab, trastuzumab, and docetaxel intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), investigator-assessed objective response rate, and duration of response (DoR). Safety was also assessed. RESULTS: At final analysis, median investigator-assessed PFS was 22.8 months (95% CI 16.9-37.5). From first dose, OS rate at 1 year was 97.7%; and at 2 and 3 years were 88.5% and 79.1%, respectively. Of the 118 patients with measurable disease at baseline, response rate was 83.9% (95% CI 77.3-90.5) and median investigator-assessed DoR was 26.3 months (95% CI 17.1-not evaluable). Treatment was well tolerated, with no new safety signals detected. CONCLUSIONS: Our results suggest similar efficacy and safety for pertuzumab plus trastuzumab and docetaxel in Japanese patients compared with the overall population of CLEOPATRA, providing further support for this combination therapy as standard of care for Japanese patients with inoperable or recurrent HER2-positive breast cancer.

A phase II study of sequential treatment with anthracycline and taxane followed by eribulin in patients with HER2-negative, locally advanced breast cancer (JBCRG-17).

PURPOSE: The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC. METHODS: In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative. RESULTS: A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%). CONCLUSION: Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.

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.

Risk factors of local recurrence following implant-based breast reconstruction in breast cancer patients.

BACKGROUND: The number of patients desiring implant-based breast reconstruction has been increasing. While local recurrence is observed in patients with breast reconstruction, only a few reports have focused on the risk factors for local recurrence and the prognosis after developing local recurrence. METHODS: We analyzed 387 patients who underwent implant-based breast reconstruction during the period from 2004 to 2017 in Hiroshima City Hospital. We retrospectively examined the risk factors for local recurrence and the outcomes of patients developing such recurrence after implant-based breast reconstruction. RESULTS: The median follow-up time was 59 months. The local recurrence rate was 3.1% (n = 12). The most common reason for detecting local recurrence was a palpable mass. Four patients with local recurrence had recurrence involving the skin just above the primary lesion and needle biopsy tract. All patients with local recurrence received surgery and systemic therapy and most patients received radiation therapy, all have remained free of new recurrence to date. Multivariate analysis showed lymphatic vessel invasion (HR, 6.63; 95% CI, 1.40-31.36; p = 0.017) and positive or < 2 mm vertical margin (HR, 9.72; 95%CI, 1.23-77.13; p = 0.047) to be associated with significantly increased risk of local recurrence. CONCLUSIONS: The risk factors for local recurrence following implant-based breast reconstruction were lymphatic vessel invasion and positive or < 2 mm vertical margin. Removal of the skin just above the primary lesion and needle biopsy tract and adjuvant radiation therapy might improve local outcomes. Patients with local recurrence following implant-based breast reconstruction appear to have good outcomes with appropriate treatment.

Clinical usefulness of eribulin as first- or second-line chemotherapy for recurrent HER2-negative breast cancer: a randomized phase II study (JBCRG-19).

BACKGROUND: Anthracycline (A) or taxane T-based regimens are the standard early-line chemotherapy for metastatic breast cancer (BC). A previous study has shown a survival benefit of eribulin in heavily pretreated advanced/recurrent BC patients. The present study aimed to compare the benefit of eribulin with treatment of physician's choice (TPC) as first- or second-line chemotherapy for recurrent HER2-negative BC. METHODS: Patients with recurrent HER2-negative BC previously receiving anthracycline and taxane AT-based chemotherapy in the adjuvant or first-line setting were eligible for this open-label, randomized, parallel-group study. Patients were randomized 1:1 by the minimization method to receive either eribulin (1.4 mg/m2 on day one and eight of each 21-day cycle) or TPC (paclitaxel, docetaxel, nab-paclitaxel or vinorelbine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure (TTF), overall response rate (ORR), duration of response, and safety (UMIN000009886). RESULTS: Between May 2013 and January 2017, 58 patients were randomized, 57 of whom (26 eribulin and 31 TPC) were analyzed for efficacy. The median PFS was 6.6 months with eribulin versus 4.2 months with TPC (hazard ratio: 0.72 [95% confidence interval (CI), 0.40-1.30], p = 0.276). Median TTF was 6.0 months with eribulin versus 3.6 months with TPC (hazard ratio: 0.66 [95% CI, 0.39-1.14], p = 0.136). Other endpoints were also similar between groups. The most common grade ≥ 3 adverse event was neutropenia (22.2% with eribulin versus 16.1% with TPC). CONCLUSIONS: Eribulin seemed to improve PFS or TTF compared with TPC without statistical significance. Further validation studies are needed.

Optimizing antiemetic treatment for chemotherapy-induced nausea and vomiting in Japan: Update summary of the 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis.

Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).

Optimizing the timing of 3.6 mg Pegfilgrastim Administration for Dose-Dense Chemotherapy in Japanese Patients with Breast Cancer.

Perioperative dose-dense chemotherapy (DDCT) with pegfilgrastim (Peg) prophylaxis is a standard treatment for high-risk breast cancer. We explored the optimal timing of administration of 3.6 mg Peg, the dose approved in Japan. In the phase II feasibility study of DDCT (adriamycin+cyclophosphamide or epirubicin+cyclophosphamide followed by paclitaxel) for breast cancer, we investigated the feasibility, safety, neutrophil transition, and optimal timing of Peg treatment by administering Peg at days 2, 3, and 4 post-chemotherapy (P2, P3, and P4 groups, respectively). Among the 52 women enrolled, 13 were aged > 60 years. The anthracycline sequence was administered to P2 (n=33), P3 (n=5), and P4 (n=14) patients, and the taxane sequence to P2 (n=38) and P3 (n=6) patients. Both sequences showed no interaction between Peg administration timing and treatment discontinuation, treatment delay, or dose reduction. However, the relative dose intensity (RDI) was significantly different among the groups. The neutrophil count transition differed significantly among the groups receiving the anthracycline sequence. However, the neutrophil count remained in the appropriate range for both sequences in the P2 group. The timing of Peg administration did not substantially affect the feasibility or safety of DDCT. Postoperative day 2 might be the optimal timing for DDCT.

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.

BACKGROUND: Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS: We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. RESULTS: The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer.

PURPOSE: Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC. METHODS: We randomized patients with stage I-III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2. RESULTS: We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years. CONCLUSIONS: Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC. TRIAL REGISTRATION: UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

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.

Multicenter study of primary systemic therapy with docetaxel, cyclophosphamide and trastuzumab for HER2-positive operable breast cancer: the JBCRG-10 study.

BACKGROUND: The original aim of this study was to evaluate the treatment sequence and anthracycline requirement in docetaxel, cyclophosphamide and trastuzumab therapy. After one death in the anthracycline-containing arm, the protocol was amended to terminate the randomization. The single-docetaxel, cyclophosphamide and trastuzumab arm was continued to examine the efficacy and safety of the anthracycline-free regimen. METHODS: Women with human epidermal growth factor receptor-2-positive, operable and primary breast cancer were randomized to receive 5-fluorouracil, epirubicin and cyclophosphamide (four cycles) followed by docetaxel, cyclophosphamide and trastuzumab (four cycles), or docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide, or docetaxel, cyclophosphamide and trastuzumab (six cycles). After the protocol amendment, patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm alone. The primary endpoint was a pathological complete response. RESULTS: In total, 103 patients were enrolled between September 2009 and September 2011: 21, 22 and 24 patients in the 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel, cyclophosphamide and trastuzumab; docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide and docetaxel, cyclophosphamide and trastuzumab arms, respectively, and 36 patients in the docetaxel, cyclophosphamide and trastuzumab arm after the protocol amendment. In total, 60 patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm, in which the pathological complete response rate was 45.8%, and disease-free survival at 3 years was 96.6%. Patients with stage I or IIA in the docetaxel, cyclophosphamide and trastuzumab arm showed good disease-free survival (100% at 3 years). The comparison of efficacy among the three arms was statistically underpowered. Left ventricular ejection fraction decreased significantly after 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel-docetaxel, cyclophosphamide and trastuzumab (P = 0.017), but not after docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide or docetaxel, cyclophosphamide and trastuzumab. CONCLUSIONS: The pathological complete response rate for docetaxel, cyclophosphamide and trastuzumab was similar to previous reports of anthracycline-containing regimens. Docetaxel, cyclophosphamide and trastuzumab might be an option for primary systemic therapy in human epidermal growth factor receptor-2-positive early breast cancer. A larger confirmatory study is necessary.