Whole Exome Sequencing of DNA in Breast Cancers Enrolled in the S0800 Trial

Purpose: The purpose of this study was to assess the somatic mutation landscape of breast tumors before and after neoadjuvant chemotherapy. The data includes whole exome sequencing of pre- and post- tissues that were collected in the context of an already published clinical trial SWOG S0800 (ZA Nahleh et al. Breast Cancer Research and Treatment. 158:485-495, 2016). The trial compared the efficacy of sequential nab-paclitaxel followed or preceded by doxorubicin/cyclophosphamide anthracycline chemotherapy with or without bevacizumab as preoperative therapy for stage II-III breast cancer. Experimental Design: 29 pre-treatment biopsies and 9 matching post-treatment surgically resected cancer tissues were available for analysis and were subjected to whole exome sequencing to identify mutational patterns associated with response to neoadjuvant chemotherapy. The 9 paired samples with residual invasive cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy. No matching normal tissues were available for germline sequencing and therefore we used n=7 post-treatment breast tissues without residual cancer (i.e. complete eradication of cancer by therapy) as a normal cohort to facilitate somatic variant calling.Conclusion: These results suggest that genomic disturbances in BRCA-related DNA repair mechanisms, reflected by a dominant mutational signature 3, confer increased chemotherapy sensitivity. Cancers that survive neoadjuvant chemotherapy, frequently have alterations in cell cycle regulating genes but different genes are affected in different patients.]]>
DISEASE CHARACTERISTICS: The clinical trial included patients with newly diagnosed, previously untreated, histologically confirmed breast cancer that was either locally advanced disease defined as stage IIIB, IIB/IIIA, or IIIC, or Inflammatory Breast Cancer defined as diffuse erythema AND edema (peau d'orange) of the breast involving at least 50% of the skin of the breast. All cancers were HER2/neu-negative as demonstrated by 0 or 1+ (weak or no staining) by immunohistochemistry OR no gene amplification by FISH. Patients may have had either estrogen receptor positive or negative disease and could have been either pre- or post-menopausal. A complete description of the clinical trial population is included in the following publication: Nahleh ZA, Barlow WE, Hayes DF, et al. SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer. Breast Cancer Research and Treatment. 2016;158:485-495 ( https://link.springer.com/article/10.1007/s10549-016-3889-6). ]]>