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KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR. • KEYNOTE-522 evaluated neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab versus neoadjuvant chemotherapy alone in early TNBC. • Neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab significantly improved pCR/EFS versus neoadjuvant chemotherapy alone. • We explored the effect of adding pembrolizumab to chemotherapy on outcomes by RCB category. • Pembrolizumab not only increased pCR rates, but also improved EFS among many patients who do not have a pCR. • Findings support neoadjuvant pembrolizumab + chemotherapy/adjuvant pembrolizumab as a standard of care treatment in early TNBC. [ABSTRACT FROM AUTHOR]

Background: In order to clarify the safety and effectiveness of WT1 peptide vaccination for the patients with CML, we started WT1 peptide vaccination in combination with imatinib therapy for a patient with CML. Materials and Methods: A 51 years-old male with CML in CP had been treated with 400 mg imatinib for 2.5 years. Bcr-abl transcripts decreased transiently but gradually increased to more than 1, 000 copies thereafter. HLA-A*2402-restricted 9mer mutant WT1 peptides (CYTWNQMNL; a.a. 235-243), which had been identified to possess an anti-tumor immunogenicity, were administered subcutaneously at the dose of 1 mg/ day every 2 weeks in combination with 400 mg imatinib for first 5 months and thereafter every 4 weeks for 12 months. The vaccination was undertaken 22 times totally. The appearance of WT1-specific CTLs in PB was confirmed by evaluating the frequency of MHC/WT1 tetramer + CD8+ T cells by using mixed lymphocyte peptide culture (MLPC). Results: Although bcr-abl transcripts increased up to more than 2,000 copies after the the initiation of WT1 vaccination every 2 weeks, the transcripts have decreased to less than 500 copies by the administration of WT1 peptides every 4 weeks. After seven months from the cessation of WT1 peptide vaccination bcr-abl transcripts decreased to the level of major molecular response (MMR), which is lasting thereafter for nearly 4 years. While WT1-specific CTLs were not detected in PB before WT1 peptide vaccination, the CTLs appeared after the second vaccination and remained at the level of nearly 15/106 CD8+ cells thereafter. The MHC/WT1 tetramer+ cells showed cytotoxicity against only leukemia cells expressing WT1 and HLA-A*2402. Conclusions: The present study showed that WT1 peptide vaccination for an imatinib-pretreated CML patient is feasible and effective, which is due to the long-lasting amplification of WT1-specific CTLs with cytotoxicity against WT1-expressing leukemia cells. [ABSTRACT FROM AUTHOR]

[Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody drug conjugate comprised of a humanized HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload (MAAA-1181a; exatecan derivative). MAAA-1181a is a substrate for CYP3A enzymes and OATP1B. T-DXd demonstrated antitumor activity and manageable safety in HER2-expressing/mutated solid tumors (NCT02564900). This study (NCT03383692) assessed the effect of concomitant ritonavir (OATP1B/CYP3A inhibitor) or itraconazole (CYP3A strong inhibitor) on the PK profile of T-DXd and MAAA-1181a. Eligible subjects had HER2-expressing (IHC ≥1+ and/or ISH+) unresectable/metastatic solid tumors. T-DXd 5.4 mg/kg was administered IV in 3-week cycles. Ritonavir 200 mg BID (cohort 1) or itraconazole 200 mg QD/BID (cohort 2) were administered from day 17 of cycle 2 to end of cycle 3. Primary endpoints were C max and AUC 17d. TEAEs and objective tumor response rate (ORR) were secondary endpoints. Forty subjects were enrolled (17 in cohort 1; 23 in cohort 2). Breast cancer was the most common cancer (42.5%). In the PK analysis set (n = 26; majority of exclusions due to inhibitor drug noncompliance), there was a small increase in AUC 17d for MAAA-1181a and T-DXd with concomitant ritonavir or itraconazole (Table). In the safety analysis set (n = 40), 39 (97.5%) had a TEAE, 5 (12.5%) reported ≥1 serious TEAE, and 2 had ILD/pneumonitis (grade ≤3). The most common TEAEs included nausea (80.0%), decreased appetite (55.0%), and constipation (37.5%). TEAE incidence did not increase in cycle 3 vs 2. Confirmed ORR was 15/36 (41.7%) in subjects with measurable tumors at baseline (n = 36). Table 330P Pharmacokinetics of T-DXd and MAAA-1181a without (cycle 2) and with (cycle 3) concomitant ritonavir (CYP3A/OATP1B inhibitor) or itraconazole (CYP3A strong inhibitor) Table Ritonavir Parameters LS Means Ratio 90% CI C2 C3 C3/C2 Lower Upper MAAA-1181a AUC 17d (d*ng/mL) a 30.2 36.6 1.215 1.078 1.370 C max (ng/mL) b 8.49 8.38 0.987 0.854 1.140 T-DXd AUC 17d (d*ug/mL) a 623 742 1.192 1.140 1.246 C max (ug/mL) b 131 138 1.049 0.976 1.128 Itraconazole Parameters LS Means Ratio 90% CI C2 C3 C3/C2 Lower Upper MAAA-1181a AUC 17d (d*ng/mL) c 28.8 33.9 1.178 1.108 1.252 C max (ng/mL) c 8.43 8.78 1.042 0.917 1.184 T-DXd AUC 17d (d*ug/mL) c 617 685 1.110 1.073 1.147 C max (ug/mL) c 137 140 1.025 0.963 1.091 a N = 8; b N = 12; c N = 14. AUC 17d , area under the concentration-time curve from cycle day 1–17; CI, confidence interval; C max , maximum plasma concentration; C2, cycle 2; C3, cycle 3; LS, least squares; MAAA-1181a, topoisomerase I inhibitor payload (exatecan derivative) that is released from T-DXd; T-DXd, [fam-] trastuzumab deruxtecan. There was a small increase in AUC 17d for T-DXd and its payload with concomitant ritonavir and itraconazole that did not appear to be clinically meaningful. Efficacy and safety of T-DXd were consistent with previous trials. NCT03383692. Medical writing and editorial support was provided by Alicia Salinero, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC, and funded by Daiichi Sankyo, Co., Ltd. Daiichi Sankyo, Co., Ltd. Daiichi Sankyo, Co., Ltd. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Merck Serano; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Taiho; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy, Research grant / Funding (institution): Green Cross; Advisory / Consultancy: Samyang Biopharm; Advisory / Consultancy: Hanmi; Advisory / Consultancy, Research grant / Funding (institution): Genexine; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boeringer-Ingelheim; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): FivePrime; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Ono; Research grant / Funding (institution): CKD Pharma. M. Takahashi: Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Kyowa Hakko-Kirin; Honoraria (self): Eisai; Honoraria (self): Eli Lilly; Honoraria (self): Taiho; Honoraria (self): Daiichi Sankyo. J. Watanabe: Honoraria (self): Daiichi Sankyo. H. Minami: Honoraria (self), Research grant / Funding (institution), clinical trial: Novartis; Research grant / Funding (institution): Asahi-Kasei Pharma; Research grant / Funding (institution): Astellas; Research grant / Funding (institution), clinical trial: AstraZeneca; Honoraria (self), Research grant / Funding (institution), clinical trial: Bayer; Honoraria (self), Research grant / Funding (institution): Behringer; Honoraria (self), Research grant / Funding (institution), clinical trial: Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self), Research grant / Funding (institution), clinical trial: Chugai; Research grant / Funding (institution), clinical trial: Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): DaiNihonSumitomo; Honoraria (self), Research grant / Funding (institution): Eizai; Honoraria (self): Janssen; Honoraria (self): Kowa; Honoraria (self), Research grant / Funding (institution): Kyowa-Kirin; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self), Research grant / Funding (institution), clinical trial: MSD; Research grant / Funding (institution): Nihon Shinyaku; Honoraria (self), Research grant / Funding (institution): Nippon Chemiphar; Honoraria (self), Research grant / Funding (institution), clinical trial: Ono Yakuhin; Honoraria (self): Ohtsuka; Honoraria (self), Research grant / Funding (institution), clinical trial: Pfizer; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self): Shire Japan; Honoraria (self), Research grant / Funding (institution), clinical trial: Taiho; Research grant / Funding (institution): Taisho-Toyama; Honoraria (self), Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Teijin Pharma; Research grant / Funding (institution): Yakult; Honoraria (self): Genomic Health; Research grant / Funding (institution): CSL Behring; Research grant / Funding (institution): Nihon Kayaku; Research grant / Funding (institution): Shionogi. N. Yamamoto: Honoraria (self), Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Taiho; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Quintiles; Research grant / Funding (institution): Astellas; Honoraria (self), Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Kyowa-Hakko Kirin; Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): ONO PHARMACEUTICAL CO., LTD; Honoraria (self): Chugai; Honoraria (self): AstraZeneca; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy: Cimic; Research grant / Funding (institution): Janssen Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (self): Merck. C. Lin: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Research grant / Funding (institution): Daiichi Sankyo; Travel / Accommodation / Expenses: BeiGene. T. Fujiki: Full / Part-time employment: Daiichi Sankyo. I. Achiwa: Full / Part-time employment: Daiichi Sankyo. E. Kamiyama: Full / Part-time employment: Daiichi Sankyo. Y. Okuda: Full / Part-time employment: Daiichi Sankyo. C. Lee: Full / Part-time employment: Daiichi Sankyo. S. Takahashi: Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Quintiles. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA -mutated, HR+, HER2− ABC. Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA -mutant cohort was evaluated by Kaplan–Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien–Fleming efficacy boundary of P ≤ 0.0161. In the PIK3CA -mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA -mutated, HR+, HER2− ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. NCT02437318. • In SOLAR-1, the key secondary endpoint of OS was evaluated in patients with HR+, HER2−, PIK3CA -mutated ABC. • Adding alpelisib to fulvestrant numerically improved mOS by 7.9 months, though the result was not statistically significant. • OS was numerically improved in hard-to-treat disease, including a 14-month median improvement in those with lung/liver metastases. • Median time to first chemotherapy was delayed by 8.5 months with the addition of alpelisib to fulvestrant. • With longer follow-up the alpelisib plus fulvestrant safety profile was similar to prior reports with no new safety signals. [ABSTRACT FROM AUTHOR]

Background: Capecitabine (X) and docetaxel (T) have demonstrated a synergistic effect in preclinical models and a survival benefit in metastatic breast cancer. This study's purpose was to determine the efficacy of X and T followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) in the preoperative setting. [ABSTRACT FROM PUBLISHER]

CLEOPATRA study demonstrated the efficacy and safety of pertuzumab (P) + trastuzumab (T) + docetaxel (D) but efficacy results of Japanese subgroup weren't consistent with the whole study results. A phase IV, multicenter, prospective, COMACHI study was conducted in Japan to re-confirm the efficacy and safety of P+T+D demonstrated in the CLEOPATRA study. Patients (pts) with HER2-positive breast cancer who were diagnosed as Stage IV or recurred more than a year after (neo)adjuvant taxane chemotherapy completion were enrolled. Pts were administered study drugs intravenously every 3 weeks. Discontinuation of D was allowed after cycle 6. After discontinuation of D, pts were given maintenance by T+P, however not allowed to receive hormonal therapy for HR positive pts. We defined PFS as the primary endpoint. To demonstrate a median PFS of 12.4 months (mos) or more, which was observed in the placebo arm in the CLEOPATRA study. From November 2013 to September 2015, 132 pts were enrolled and all pts were treated with T+P at least once. The median age was 56.5 years old and 102 pts (77.3%) had not received prior HER2 therapy. Median cycles of T and P were both 24.0 (range 2.0-71.0) and that of D was 6.0 (range 0.0-65.0). Pts characteristics and subgroup analysis results are shown in the Table below. Table 353P Table Name Level Patients Events Time to event [n (%)] [n (%)] [Median (95% CI)] All n/a 132 (100.0%) 66 (50.0%) 22.8 (16.9, 34.8) Prior (neo) adjuvant therapy(Excluding hormone therapy) YES 38 (28.8%) 18 (47.4%) 27.7 (12.4, NE) NO 94 (71.2%) 48 (51.1%) 20.8 (16.9, 38.8) Age < 65 96 (72.7%) 49 (51.0%) 22.8 (16.5, NE) >- 65 36 (27.3%) 17 (47.2%) 33.1 (18.7, NE) Disease Type at Screening VISCERAL DISEASE 81 (61.4%) 49 (60.5%) 18.4 (13.8, 33.7) NON-VISCERAL DISEASE 51 (38.6%) 17 (33.3%) NE (20.7, NE) ER/PgR Status POSITIVE 72 (54.5%) 39 (54.2%) 18.9 (14.7, 33.1) NEGATIVE 60 (45.5%) 27 (45.0%) 33.7 (20.6, NE) HER2 Status IHC/ISH IHC < = 2+ and ISH POSITIVE 21 (15.9%) 13 (61.9%) 16.5 (10.4, 34.8) IHC 3+ 111 (84.1%) 53 (47.7%) 22.9 (18.9, NE) Stage < STAGE IV 61 (46.2%) 24 (39.3%) 28.4 (22.8, NE) STAGE IV 71 (53.8%) 42 (59.2%) 18.9 (14.3, 33.7) Median PFS was 22.8 mos [95% CI, 16.9-34.8], and thereby a median PFS of 12.4 mos or more was confirmed. The incidence of typical Grade 3/4 adverse events were febrile neutropenia (31.1%), neutropenia (24.2%), leukopenia (10.6%), and diarrhea (4.5%), and these findings are consistent with the CLEOPATRA study except for febrile neutropenia. Febrile neutropenia lead to only one case of treatment discontinuation and it was manageable. The efficacy and safety of P+T+D in Japanese pts were consistent with those of the CLEOPATRA study and we confirmed this treatment as a standard care at 1st line therapy for HER2-positive metastatic breast cancer. Chugai Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd. N. Masuda: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli-Lilly; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Officer / Board of Directors: Japan Breast Cancer Research Group Association. S. Ohtani: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: AstraZeneca. S. Nagai: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli-Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd. Y. Komoike: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eli-Lilly; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Taiho; Speaker Bureau / Expert testimony, the publisher, for writing atricle: Nikkei Business Publications, Inc. Y. Ito: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli-Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eisai; Research grant / Funding (institution): Covance; Research grant / Funding (institution): IQVIA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): A2healthcare; Research grant / Funding (institution): Parexel; Research grant / Funding (institution): Kyowa-Kirin. M. Ikeda: Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Asahi Kasei Pharma Corporation; Speaker Bureau / Expert testimony: Kyowa-Kirin; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Mundipharma; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Nippon Kayaku; Research grant / Funding (institution): Hisamitsu; Officer / Board of Directors, engaged in the project of medical practice guidline: Japanese Breast cancer society; Officer / Board of Directors, the leader of clinical trial comittee: Setouchi Breast Project Comprehensive Support Organization. K. Ishida: Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Nippon Kayaku. T. Nakayama: Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eli-Lilly; Speaker Bureau / Expert testimony: Novartis. T. Takashima: Speaker Bureau / Expert testimony, Officer / Board of Directors: Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony, Officer / Board of Directors: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Kyowa-Kirin; Speaker Bureau / Expert testimony: Eli-Lilly. T. Asakawa: Full / Part-time employment: Chugai Pharmaceutical Co., Ltd. S. Matsumoto: Full / Part-time employment: Chugai Pharmaceutical Co., Ltd. D. Shimizu: Full / Part-time employment: Chugai Pharmaceutical Co., Ltd. M. Takahashi: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Eli-Lilly; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Kyowa-Kirin; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Daiichi Sankyo; Speaker Bureau / Expert testimony: Allergan; Speaker Bureau / Expert testimony, Research grant / Funding (institution): FUJIFILM Toyama Chemical; Speaker Bureau / Expert testimony: Nihon Medi-Physics; Honoraria (self), for wrtitin article: The Asahi Shimbun Company. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]