Chemotherapy Modulates Endocrine Therapy-Related Resistance Mutations in Metastatic Breast Cancer

Dabo Zhou; Quchang Ouyang; Liping Liu; Jingyu Liu; Yu Tang; Mengjia Xiao; Yikai Wang; Qiongzhi He; Zhe-Yu Hu

doi:10.1016/j.tranon.2019.02.014

Chemotherapy Modulates Endocrine Therapy-Related Resistance Mutations in Metastatic Breast Cancer

Transl Oncol. 2019 May;12(5):764-774. doi: 10.1016/j.tranon.2019.02.014. Epub 2019 Mar 17.

Authors

Dabo Zhou¹, Quchang Ouyang², Liping Liu¹, Jingyu Liu¹, Yu Tang¹, Mengjia Xiao¹, Yikai Wang³, Qiongzhi He⁴, Zhe-Yu Hu⁵

Affiliations

¹ The Affiliated Cancer Hospital of Xiangya Medical School, Central South University / Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China.
² The Affiliated Cancer Hospital of Xiangya Medical School, Central South University / Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China. Electronic address: oyqc1969@126.com.
³ Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, 33022, USA.
⁴ Geneplus Beijing Institute, Beijing 102206, China.
⁵ The Affiliated Cancer Hospital of Xiangya Medical School, Central South University / Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013, China; Department of Breast Cancer Medical Oncology, the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China. Electronic address: huzheyu@hnszlyy.com.

Abstract

Purpose: Accumulation of PIK3CA, ESR1, and GATA3 mutations results in resistance to endocrine therapy in breast cancer patients; however, the response of these genes to chemotherapy is unclear. Therefore, we sought to evaluate the genetic response of circulating tumor DNA (ctDNA) to chemotherapy in metastatic breast cancer patients.

Methods: The mutation frequency of 1021 genes was examined prior to chemotherapy in ctDNA of 44 estrogen receptor-positive metastatic breast cancer patients. These genes were evaluated again in a subset of patients (n=24) following chemotherapy. Mutation frequency was defined as the percentage of mutations found in ctDNA compared to total cell-free DNA.

Results: Prior to chemotherapy, PIK3CA was the most commonly mutated gene, with mutation found in 22 of the metastatic breast cancer patients. Following chemotherapy, 16 patients exhibited progressive disease (PD), and 8 patients experienced no progression (non-PD). PIK3CA mutation frequency increased in 56.25% (9/16) of the PD patients but decreased in 62.5% (5/8) of the non-PD patients. As a result, more PD patients exhibited increased PIK3CA mutation frequency than non-PD patients (56.25% vs 0%, P=.002). Further, ESR1 and GATA3 mutations correlated with PIK3CA mutation. Interestingly, patients receiving the mTOR inhibitor everolimus exhibited a lower progression rate (0% vs 62.5%, P=.001), and the combination of everolimus and chemotherapy effectively suppressed PIK3CA, ESR1, and GATA3 gene mutations.

Conclusion: Together, these results suggest that mTOR inhibition may be a useful chemotherapy adjuvant to suppress chemotherapy-induced gene mutations that render tumors resistant to endocrine therapy in metastatic breast cancer patients with PD.