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Clinicopathological analysis of homologous recombination-deficient breast cancers with special reference to response to neoadjuvant paclitaxel followed by FEC

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Abstract

Purpose

This study aimed to elucidate the clinicopathological characteristics of breast tumors with homologous recombination deficiency (HRD) and the sensitivity to neoadjuvant paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide (P-FEC).

Methods

Tumor biopsy samples obtained before P-FEC from 141 patients with stages II–III breast cancer including the luminal (n = 76), luminal-HER2 (n = 13), HER2 (n = 17), and triple-negative (TNBC, n = 35) subtypes were subjected to assay for HRD score using the OncoScan CNV FFPE Assay Kit. HRD score was a simple sum of NtAI, LOH, and LST (cutoff, 42). TNBCs were also subjected to the gene expression assay using the Affymetrix microarray (U133 plus 2.0) and to the BRCA1 promoter methylation assay using the methylation-specific real-time PCR.

Results

Of the 141 breast tumors, 45 samples (32%) had high HRD scores and were associated with high histological grade (P = 0.001), negative progesterone receptor (P = 0.018), high Ki67 index (P = 0.032), and BRCA1 promoter methylation (P = 3.6e−07). The proportion of tumors with high HRD scores was significantly higher in the TNBC subtype than the others (P = 0.006). In the TNBC subtype, but not the others, high HRD scores were significantly (P = 0.001) associated with a low pathological complete response rate to P-FEC. Among the molecular TNBC subtypes, a majority of tumors belonging to the basal-like 1, immunomodulatory, mesenchymal, mesenchymal stem-like, but not luminal androgen receptor (LAR), subtypes had high HRD scores.

Conclusions

Approximately one-third of sporadic breast tumors show a high HRD score, indicating the presence of homologous recombination dysfunction, and they are characterized by biologically aggressive phenotypes, most commonly in the TNBC subtype, and less sensitive to P-FEC.

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Abbreviations

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor receptor 2

TNBC:

Triple-negative breast cancer

TILs:

Tumor-infiltrating lymphocytes

HG:

Histological grade

IHC:

Immunohistochemistry

pCR:

Pathologic complete response

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Acknowledgements

The authors would like to express special thanks to Dr. Nicolai Juul Birkbak for valuable advice on the determination of HRD scores. This study was supported in part by AstraZeneca Externally Sponsored Research [Tracking Number NCR-16-12580] and Affymetrix Japan.

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Authors and Affiliations

  1. Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, 2-2-E10 Yamadaoka, 565-0871, Suita-shi, Osaka, Japan

    Seiichi Imanishi, Yasuto Naoi, Kenzo Shimazu, Masafumi Shimoda, Naofumi Kagara, Tomonori Tanei, Tomohiro Miyake, Seung Jin Kim & Shinzaburo Noguchi

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  1. Seiichi Imanishi
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Correspondence to Yasuto Naoi.

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Conflict of interest

Shinzaburo Noguchi has been an adviser for Taiho, AstraZeneca, and Novartis and has received research funding for this study from AstraZeneca and for other studies from Sysmex, Novartis, Chugai, Daiichi-Sankyo, Kyowa-Kirin, Takeda, Pfizer, Ono, Taiho, and Eisai and honoraria from AstraZeneca, Novartis, Pfizer, Chugai, Takeda, Sysmex, Nippon Kayaku, and Ono. Yasuto Naoi has received research funding for this study from AstraZeneca and honoraria from Sysmex. Naofumi Kagara has received honoraria from AstraZeneca and Novartis. Masafumi Shimoda has received research funding for other studies from Novartis and AstraZeneca and honoraria from Chugai, Eisai, Novartis, and Takeda. Kenzo Shimazu has received honoraria from AstraZeneca, Chugai, and Sysmex. Seung Jim Kim has received honoraria from AstraZeneca, Chugai, Eisai, Kyowa-Kirin, Novartis, Pfizer, Shimadzu, Taiho, and Takeda. The other authors declare no conflicts of interest.

Ethical approval

This study complies with the current relevant laws of and guidelines for Japan.

Informed consent

The study protocol was approved by the Ethical Review Board of Osaka University Hospital, and informed consent was obtained from each patient before tumor biopsy.

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Imanishi, S., Naoi, Y., Shimazu, K. et al. Clinicopathological analysis of homologous recombination-deficient breast cancers with special reference to response to neoadjuvant paclitaxel followed by FEC. Breast Cancer Res Treat 174, 627–637 (2019). https://doi.org/10.1007/s10549-018-05120-9

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