Top

International Journal of Clinical Oncology

Published in:

01-04-2016 | Original Article

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

Authors: Yukie Enomoto, Takashi Morimoto, Arisa Nishimukai, Tomoko Higuchi, Ayako Yanai, Yoshimasa Miyagawa, Keiko Murase, Michiko Imamura, Yuichi Takatsuka, Takashi Nomura, Masashi Takeda, Takahiro Watanabe, Seiichi Hirota, Yasuo Miyoshi

Published in: International Journal of Clinical Oncology | Issue 2/2016

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.

Wolmark N, Wang J, Mamounas E et al (2001) Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 30:96–102CrossRefPubMed

Rouzier R, Pusztai L, Delaloge S et al (2005) Nomograms to predict pathologic complete response and metastasis-free survival after preoperative chemotherapy for breast cancer. J Clin Oncol 23:8331–8339CrossRefPubMed

Chaturvedi S, McLaren C, Schofield AC et al (2005) Patterns of local and distant disease relapse in patients with breast cancer treated with primary chemotherapy: do patients with a complete pathological response differ from those with residual tumour in the breast? Breast Cancer Res Treat 93:151–158CrossRefPubMed

Abrial SC, Penault-Llorca F, Delva R et al (2005) High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer. Breast Cancer Res Treat 94:255–263CrossRefPubMed

Guarneri V, Broglio K, Kau SW et al (2006) Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 24:1037–1044CrossRefPubMed

Mazouni C, Kau SW, Frye D et al (2007) Inclusion of taxanes, particularly weekly paclitaxel, in preoperative chemotherapy improves pathologic complete response rate in estrogen receptor-positive breast cancers. Ann Oncol 18:874–880CrossRefPubMed

von Minckwitz G, Blohmer JU, Costa SD et al (2013) Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 31:3623–3630CrossRef

Symmans WF, Peintinger F, Hatzis C et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422CrossRefPubMed

Romero A, García-Sáenz JA, Fuentes-Ferrer M et al (2013) Correlation between response to neoadjuvant chemotherapy and survival in locally advanced breast cancer patients. Ann Oncol 24:655–661CrossRefPubMed

10.

Cockburn A, Yan J, Rahardja D et al (2014) Modulatory effect of neoadjuvant chemotherapy on biomarkers expression; assessment by digital image analysis and relationship to residual cancer burden in patients with invasive breast cancer. Hum Pathol 45:249–258CrossRefPubMed

11.

Miller M, Ottesen RA, Niland JC et al (2014) Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol 21:3317–3323CrossRefPubMed

12.

Bottini A, Berruti A, Bersiga A et al (2001) Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer. Br J Cancer 85:1106–1112CrossRefPubMedPubMedCentral

13.

Makris A, Powles TJ, Allred DC et al (1999) Quantitative changes in cytological molecular markers during primary medical treatment of breast cancer: a pilot study. Breast Cancer Res Treat 53:51–59CrossRefPubMed

14.

Chang J, Ormerod M, Powles TJ et al (2000) Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma. Cancer 89:2145–2152CrossRefPubMed

15.

Burcombe R, Wilson GD, Dowsett M et al (2006) Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer. Breast Cancer Res 8:R31CrossRefPubMedPubMedCentral

16.

von Minckwitz G, Schmitt WD, Loibl S et al (2013) Ki67 measured after neoadjuvant chemotherapy for primary breast cancer. Clin Cancer Res 19:4521–4531CrossRef

17.

Zhang N, Moran MS, Huo Q et al (2011) The hormonal receptor status in breast cancer can be altered by neoadjuvant chemotherapy: a meta-analysis. Cancer Investig 29:594–598CrossRef

18.

Pagani O, O’Neill A, Castiglione M et al (1998) Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 34:632–640CrossRefPubMed

19.

Swain SM, Jeong JH, Geyer CE Jr et al (2010) Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 362:2053–2065CrossRefPubMedPubMedCentral

20.

Japanese Breast Cancer Society (2012) General rules for clinical and pathological recording of breast cancer, 17th edn. Kanehara & Co., Ltd, Tokyo

21.

Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMed

22.

Jones RL, Salter J, A’Hern R et al (2009) The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 116:53–68CrossRefPubMed

23.

Tanei T, Shimomura A, Shimazu K et al (2011) Prognostic significance of Ki67 index after neoadjuvant chemotherapy in breast cancer. Eur J Surg Oncol 37:155–161CrossRefPubMed

24.

Miller TW, Balko JM, Fox EM et al (2011) ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 1:338–351CrossRefPubMedPubMedCentral

25.

Guix M, Granja Nde M, Meszoely I et al (2008) Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers. J Clin Oncol 26:897–906CrossRefPubMed

26.

Dave B, Migliaccio I, Gutierrez MC et al (2011) Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol 29:166–173CrossRefPubMedPubMedCentral

27.

Ellis MJ, Suman VJ, Hoog J et al (2011) Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031. J Clin Oncol 29:2342–2349CrossRefPubMedPubMedCentral

28.

Navolanic PM, Steelman LS, McCubrey JA (2003) EGFR family signaling and its association with breast cancer development and resistance to chemotherapy. Int J Oncol 22:237–252PubMed

29.

Lewis-Wambi JS, Jordan VC (2009) Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res 11:206CrossRefPubMedPubMedCentral

Title: Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers
Authors: Yukie Enomoto
Takashi Morimoto
Arisa Nishimukai
Tomoko Higuchi
Ayako Yanai
Yoshimasa Miyagawa
Keiko Murase
Michiko Imamura
Yuichi Takatsuka
Takashi Nomura
Masashi Takeda
Takahiro Watanabe
Seiichi Hirota
Yasuo Miyoshi
Publication date: 01-04-2016
Publisher: Springer Japan
Published in: International Journal of Clinical Oncology / Issue 2/2016
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-015-0897-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2016

Predictive markers, including total lesion glycolysis, for the response of lymph node(s) metastasis from head and neck squamous cell carcinoma treated by chemoradiotherapy

Prognostic relevance of stromal CD26 expression in rectal cancer after chemoradiotherapy

Clinical trials of antiangiogenic therapy for hepatocellular carcinoma

A prospective study of XELOX plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer (KSCC 0902)

Tumor angiogenesis—characteristics of tumor endothelial cells

Optimal strength and timing of steroids in the management of erlotinib-related skin toxicities in a post-marketing surveillance study (POLARSTAR) of 9909 non-small-cell lung cancer patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer