Yukie Enomoto1, Takashi Morimoto2, Arisa Nishimukai1, Tomoko Higuchi1, Ayako Yanai1, Yoshimasa Miyagawa1, Keiko Murase1, Michiko Imamura1, Yuichi Takatsuka1, Takashi Nomura2, Masashi Takeda3, Takahiro Watanabe4, Seiichi Hirota4, Yasuo Miyoshi5. 1. Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. 2. Department of Breast Surgery, Yao Municipal Hospital, 1-3-1 Ryuka-cho, Yao, Osaka, 581-0069, Japan. 3. Department of Pathology, Yao Municipal Hospital, 1-3-1 Ryuka-cho, Yao, Osaka, 581-0069, Japan. 4. Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. 5. Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. ymiyoshi@hyo-med.ac.jp.
Abstract
BACKGROUND: Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined. METHODS: A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically. RESULTS: Ki67 expression levels after NAC (median 5 %, range 0-70 %) were significantly reduced compared with before NAC (25, 1-80 %, P < 0.0001), but only in patients who attained clinical response. This significant suppression of Ki67 in clinical responders was consistently observed in breast cancers from the ER-positive subset, but not the ER-negative subset in the total test set (n = 120). These observations were also made in the validation set (n = 63). Among premenopausal, but not postmenopausal patients, a significant decrease in PgR expression levels was detected in breast cancers of patients who attained clinical response (pre-NAC 50, 0-100 %, post-NAC 5, 0-20 %; P = 0.0003). CONCLUSION: The impact of Ki67 suppression on clinical response seems to be restricted to ER-positive breast cancers. Since PgR expression levels of premenopausal ER-positive cancers were significantly reduced in clinical responders, inhibition of estrogen signaling due to chemotherapy-induced amenorrhea may be involved in this association.
BACKGROUND: Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined. METHODS: A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically. RESULTS: Ki67 expression levels after NAC (median 5 %, range 0-70 %) were significantly reduced compared with before NAC (25, 1-80 %, P < 0.0001), but only in patients who attained clinical response. This significant suppression of Ki67 in clinical responders was consistently observed in breast cancers from the ER-positive subset, but not the ER-negative subset in the total test set (n = 120). These observations were also made in the validation set (n = 63). Among premenopausal, but not postmenopausal patients, a significant decrease in PgR expression levels was detected in breast cancers of patients who attained clinical response (pre-NAC 50, 0-100 %, post-NAC 5, 0-20 %; P = 0.0003). CONCLUSION: The impact of Ki67 suppression on clinical response seems to be restricted to ER-positive breast cancers. Since PgR expression levels of premenopausal ER-positive cancers were significantly reduced in clinical responders, inhibition of estrogen signaling due to chemotherapy-induced amenorrhea may be involved in this association.
Entities:
Keywords:
Breast cancer; Ki67; Neoadjuvant chemotherapy; Progesterone receptor
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: A Makris; T J Powles; D C Allred; S E Ashley; P A Trott; M G Ormerod; J C Titley; M Dowsett Journal: Breast Cancer Res Treat Date: 1999-01 Impact factor: 4.872
Authors: Valentina Guarneri; Kristine Broglio; Shu-Wan Kau; Massimo Cristofanilli; Aman U Buzdar; Vicente Valero; Thomas Buchholz; Funda Meric; Lavinia Middleton; Gabriel N Hortobagyi; Ana M Gonzalez-Angulo Journal: J Clin Oncol Date: 2006-03-01 Impact factor: 44.544
Authors: C Mazouni; S-W Kau; D Frye; F Andre; H M Kuerer; T A Buchholz; W F Symmans; K Anderson; K R Hess; A M Gonzalez-Angulo; G N Hortobagyi; A U Buzdar; L Pusztai Journal: Ann Oncol Date: 2007-02-10 Impact factor: 32.976
Authors: Marian Miller; Rebecca A Ottesen; Joyce C Niland; Laura Kruper; Steven L Chen; Courtney Vito Journal: Ann Surg Oncol Date: 2014-07-25 Impact factor: 5.344
Authors: W Fraser Symmans; Florentia Peintinger; Christos Hatzis; Radhika Rajan; Henry Kuerer; Vicente Valero; Lina Assad; Anna Poniecka; Bryan Hennessy; Marjorie Green; Aman U Buzdar; S Eva Singletary; Gabriel N Hortobagyi; Lajos Pusztai Journal: J Clin Oncol Date: 2007-09-04 Impact factor: 44.544
Authors: Gunter von Minckwitz; Wolfgang D Schmitt; Sibylle Loibl; Berit M Müller; Jens U Blohmer; Bruno V Sinn; Holger Eidtmann; Wolfgang Eiermann; Bernd Gerber; Hans Tesch; Jörn Hilfrich; Jens Huober; Tanja Fehm; Jana Barinoff; Thomas Rüdiger; Erhard Erbstoesser; Peter A Fasching; Thomas Karn; Volkmar Müller; Christian Jackisch; Carsten Denkert Journal: Clin Cancer Res Date: 2013-06-27 Impact factor: 12.531
Authors: A Bottini; A Berruti; A Bersiga; M P Brizzi; P Bruzzi; S Aguggini; A Brunelli; G Bolsi; G Allevi; D Generali; E Betri; G Bertoli; P Alquati; L Dogliotti Journal: Br J Cancer Date: 2001-10-19 Impact factor: 7.640
Authors: Lena Haeberle; Andrea Cacciato Insilla; Anne-Christine Kapp; Katja Steiger; Anna Melissa Schlitter; Björn Konukiewitz; Ihsan Ekin Demir; Helmut Friess; Irene Esposito Journal: Histol Histopathol Date: 2021-03-26 Impact factor: 2.303
Authors: Laura Rey-Vargas; Juan Carlos Mejía-Henao; María Carolina Sanabria-Salas; Silvia J Serrano-Gomez Journal: BMC Cancer Date: 2020-07-18 Impact factor: 4.430
Authors: Xiaoyu Li; Takashi Eguchi; Rania G Aly; Navin K Chintala; Kay See Tan; Marjorie G Zauderer; Francine R Dembitzer; Mary Beth Beasley; Berhane Ghebrehiwet; Prasad S Adusumilli; Ellinor I B Peerschke Journal: Front Oncol Date: 2019-10-11 Impact factor: 6.244