Low Tumor Mitochondrial DNA Content Is Associated with Better Outcome in Breast Cancer Patients Receiving Anthracycline-Based Chemotherapy.

Abstract

<b>Purpose:</b> In this study, we aimed to explore whether low levels of mitochondrial DNA (mtDNA) content in the primary tumor could predict better outcome for breast cancer patients receiving anthracycline-based therapies. We hypothesized that tumor cells with low mtDNA content are more susceptible to mitochondrial damage induced by anthracyclines, and thus are more susceptible to anthracycline treatment.<b>Experimental Design:</b> We measured mtDNA content by a qPCR approach in 295 primary breast tumor specimens originating from two well-defined cohorts: 174 lymph node-positive patients who received adjuvant chemotherapy and 121 patients with advanced disease who received chemotherapy as first-line palliative treatment. The chemotherapy regimens given were either anthracycline-based (FAC/FEC) or methotrexate-based (CMF).<b>Results:</b> In both the adjuvant and advanced settings, we observed increased benefit for patients with low mtDNA content in their primary tumor, but only when treated with FAC/FEC. In multivariable Cox regression analysis for respectively distant metastasis-free survival and progression-free survival, the HR for the FAC/FEC-treated mtDNA low group in the adjuvant setting was 0.46 [95% confidence interval (CI), 0.24-0.89; <i>P</i> = 0.020] and in the advanced setting 0.49 (95% CI, 0.27-0.90; <i>P</i> = 0.022) compared with the FAC/FEC-treated mtDNA high group. We did not observe these associations in the patients treated with CMF.<b>Conclusions:</b> In our two study cohorts, breast cancer patients with low mtDNA content in their primary tumor had better outcome from anthracycline-containing chemotherapy. The frequently observed decrease in mtDNA content in primary breast tumors may be exploited by guiding chemotherapeutic regimen decision making. <i>Clin Cancer Res; 23(16); 4735-43. ©2017 AACR</i>.