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Article

A Novel Three-Gene Score as a Predictive Biomarker for Pathologically Complete Response after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

1
Department of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
2
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
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Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu 501-1193, Japan
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Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
5
Department of Surgery, University at Buffalo, The State University of New York Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14263, USA
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Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 113-8654, Japan
7
Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 700-8558, Japan
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Department of Breast Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Theodoros Foukakis
Cancers 2021, 13(10), 2401; https://doi.org/10.3390/cancers13102401
Received: 29 April 2021 / Accepted: 14 May 2021 / Published: 16 May 2021
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
Neoadjuvant chemotherapy is now a standard of care not only to decrease tumor size for breast conserving operation but also to assess drug response of an in situ cancer. Although the triple-negative subtype typically responds better compared to the other subtypes, a pathological complete response, which is a surrogate of survival, is achieved in less than half of the cases. For the most efficient patient selection, and avoiding unnecessary side effects and financial toxicity, an accurate predictive biomarker is urgently needed. We developed a novel three-gene score that associated with immune cell infiltration and pathological complete response not only in the training cohort but also in the validation triple-negative cohort. High-score TNBC was significantly associated with better survival in patients who received chemotherapy but not in patients who did not receive chemotherapy. Our score is a predictive and prognostic biomarker of response to neoadjuvant chemotherapy in triple-negative breast cancer patients.
Although triple-negative breast cancer (TNBC) typically responds better to neoadjuvant chemotherapy (NAC) compared to the other subtypes, a pathological complete response (pCR) is achieved in less than half of the cases. We established a novel three-gene score using genes based on the E2F target gene set that identified pCR after NAC, which showed robust performance in both training and validation cohorts (total of n = 3862 breast cancer patients). We found that the three-gene score was elevated in TNBC compared to the other subtypes. A high score was associated with Nottingham histological grade 3 in TNBC. Across multiple cohorts, high-score TNBC enriched not only E2F targets but also G2M checkpoint and mitotic spindle, which are all cell proliferation-related gene sets. High-score TNBC was associated with homologous recombination deficiency, high mutation load, and high infiltration of Th1, Th2, and gamma-delta T cells. However, the score did not correlate with drug sensitivity for paclitaxel, 5-fluorouracil, cyclophosphamide, and doxorubicin in TNBC human cell lines. High-score TNBC was significantly associated with a high rate of pCR not only in the training cohort but also in the validation cohorts. High-score TNBC was significantly associated with better survival in patients who received chemotherapy but not in patients who did not receive chemotherapy. The three-gene score is associated with a high mutation rate, immune cell infiltration, and predicts response to NAC in TNBC. View Full-Text
Keywords: three gene; predictive biomarker; prognosis; neoadjuvant chemotherapy; triple-negative breast cancer; tumor immune microenvironment three gene; predictive biomarker; prognosis; neoadjuvant chemotherapy; triple-negative breast cancer; tumor immune microenvironment
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MDPI and ACS Style

Oshi, M.; Angarita, F.A.; Tokumaru, Y.; Yan, L.; Matsuyama, R.; Endo, I.; Takabe, K. A Novel Three-Gene Score as a Predictive Biomarker for Pathologically Complete Response after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. Cancers 2021, 13, 2401. https://doi.org/10.3390/cancers13102401

AMA Style

Oshi M, Angarita FA, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K. A Novel Three-Gene Score as a Predictive Biomarker for Pathologically Complete Response after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. Cancers. 2021; 13(10):2401. https://doi.org/10.3390/cancers13102401

Chicago/Turabian Style

Oshi, Masanori, Fernando A. Angarita, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, and Kazuaki Takabe. 2021. "A Novel Three-Gene Score as a Predictive Biomarker for Pathologically Complete Response after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer" Cancers 13, no. 10: 2401. https://doi.org/10.3390/cancers13102401

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