Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers.
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).


CONCLUSIONS
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.
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Yukie
Y
Enomoto
Department of Breast Surgery, Yao Municipal Hospital, 1-3-1 Ryuka-cho, Yao, Osaka, 581-0069, Japan.
Takashi
T
Morimoto
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Arisa
A
Nishimukai
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Tomoko
T
Higuchi
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Ayako
A
Yanai
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Yoshimasa
Y
Miyagawa
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Keiko
K
Murase
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Michiko
M
Imamura
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Yuichi
Y
Takatsuka
Department of Breast Surgery, Yao Municipal Hospital, 1-3-1 Ryuka-cho, Yao, Osaka, 581-0069, Japan.
Takashi
T
Nomura
Department of Pathology, Yao Municipal Hospital, 1-3-1 Ryuka-cho, Yao, Osaka, 581-0069, Japan.
Masashi
M
Takeda
Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Takahiro
T
Watanabe
Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
Seiichi
S
Hirota
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.
Yasuo
Y
Miyoshi
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017697:Premenopause; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
Breast cancer; Ki67; Neoadjuvant chemotherapy; Progesterone receptor