The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies. Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed. The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876-16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2- subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group. The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ST reports honoraria from Ono, Chugai, Yakult Honsha, Taiho, Asahi Kasei Pharma, Eisai, Bristol-Myers Squibb and Eli Lilly; Prof. NM reports grants from Chugai, Eli Lilly, Astra Zeneca, Pfizer, Daiichi-Sankyo, MSD, Eisai, Novartis, Sanofi, Kyowa-Kirin, Nippon-Kayaku, Ono and Gilead Science, and honoraria from Chugai, Pfizer, Astra Zeneca, Eli Lilly and Daiichi-Sankyo, and Representative of a board of directors of JBCRG and Board of Directors of JBCS; MK reports honoraria from Pfizer, Daiichi-Sankyo, Astra Zeneca, Eli Lilly, Taiho, Kyowa-Kirin and Chugai; HI reports grants from Chugai, Daiichi-Sankyo and Astra Zeneca, and consulting fee from Daiichi-Sankyo, Chugai, Astra Zeneca, Eli Lilly, MSD, Pfizer and Gilead Science, and honoraria from Daiichi-Sankyo, Chugai, Astra Zeneca, Eli Lilly, MSD, Pfizer, Taiho and Kyowa-Kirin; TI reports honoraria from Pfizer, Kyowa-Kirin, Chugai, Daiichi-Sankyo, Astra Zeneca and Eli Lilly; TU reports grant from Eli Lilly, and honoraria from Chugai, Eisai, Astra Zeneca and Novartis; SO reports honoraria from Chugai, MSD, Nippon-Kayaku and Eli Lilly; HY reports grants from Eli Lilly and Eiken Kagaku; ET reports honoraria from Daiichi-Sankyo, Eli Lilly and Astra Zeneca; KA reports grants from Chugai, Eisai and Takeda, and consulting fee from Taiho, and honoraria from Chugai, Eisai, Astra Zeneca, Taiho, Novartis, Daiichi-Sankyo, Mochida, Ono, Pfizer, Eli Lilly, Terumo and Becton Dickinson; TT reports grants from Eli Lilly, Chugai, Eisai, Takeda, Kyowa-Kirin, Daiichi-Sankyo and Nippon-Kayaku, and honoraria from Daiichi-Sankyo, Pfizer, Novartis, Astra Zeneca, Chugai and Takeda; YY reports grants from Chugai, Kyowa-Kirin, Eisai, Daiichi-Sankyo, Nippon-Kayaku, Taiho, Takeda, Eli Lilly, Pfizer and Novartis, and honoraria from Astra Zeneca, Chugai, Kyowa-Kirin, Novartis, Eli Lilly, Pfizer, Daiichi-Sankyo, Nippon-Kayaku, Taiho, Eisai, Takeda, MSD, Sysmex and Exact Science, and participation on Advisory Board of Astra Zeneca, Chugai, Novartis, MSD, Eli Lilly, Pfizer and Daiichi-Sankyo, and member of the Board of Directors of JBCS and JBCRG; TY reports grants from Chugai, Taiho, Nippon-Kayaku and Kyowa-Kirin, and honoraria from Chugai, Eisai, Novartis, Taiho, Nippon-Kayaku, Astra Zeneca, Kyowa-Kirin, Pfizer, Eli Lilly and Daiichi-Sankyo; TY reports honoraria from Pfizer, Eli Lilly and Eisai; MT reports grants from Chugai, Takeda, Pfizer, JBCRG assoc., KBCRN assoc., Eisai, Eli Lilly, Daiichi-Sankyo, Astra Zeneca, Astellas, Shimadzu, Yakult, Nippon-Kayaku, AFI technology, Luxonus, Shionogi, GL Science and Sanwa Shurui, and honoraria from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, Astra Zeneca, Eli Lilly, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon-Kayaku, Devicore Medical Japan and Sysmex, and advisory board of Daiichi-Sankyo, Eli Lilly, BMS, Athenex Oncology, Bertis Terumo and Kansai Medical Net, and a member of the board of directors of JBCRG, KBCRN and OOTR, and chairman of the board of directors of JBCS, and 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 and Asian Journal of Breast Surgery; TY reports grants from AC Medical, A2 Healthcare, ClinChoice, Japan Tabacco, Japan Media, Medidata Solutions, Ono, Kyowa-Kirin, Tsumura, Daiichi-Sankyo, Otsuka, Eisai, Solasia Pharma, Asahi Intecc, 3H Clinical Trial, Medrio, Nipro, Intellim, Welby, 3H Medi Solution, Baseconnect, Nobori, Puravida Technologies and Hemp Kitchen, and consulting fee from Public Health Research Foundation, EPS, Japan Tabacco, Medidata Solutions, Ono, Kowa, Chugai, Daiichi-Sankyo, Eisai, 3H Clinical Trial, Intellim, Astra Zeneca, Sonire Therapeutics, Seikagaku, Merck, Mebix and Nippon Boehringer Ingelheim, and advisory board of Incyte Bioscience; CI reports grants from Chugai, Asahi Kasei Pharma, Ono, Eli Lilly, Shionogi, Yakult, Otsuka, Sanofi, Merck, Astra Zeneca, Nippon Boehringer Ingelheim, Yansen, MSD, Sonia-Therapy, Taiho, Takeda, Daiichi-Sankyo, Bayer, Nippon-Kayaku, Tsumura, Kyowa-Kirin, Hitachi, Incyte, Ascent, Eisai, PRA Health Science, Novartis and Riken Genesis, and honoraria from Taiho, Merck, Eli Lilly, Bristol-Myers Squibb, Daiichi-Sankyo, Nippon-Kayaku, Nihon-Servier, M3, MSD, Novartis, Astra Zeneca, Ono, Sanofi, Chugai, Terumo, Asahi Kasei Pharma, Pfizer, Bayer, Incyte, Takeda and Kyowa-Kirin. All remaining authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)