Abstract P1-07-11: Tumor genomic profiling of triple negative breast cancer during neoadjuvant chemotherapy: Results from a prospective trial of carboplatin and docetaxel
Authors: Ademuyiwa FO , Miller CA , Li T , Sanati S , Ma CX , Weilbaecher K , Ellis MJ , Mardis ER 
Published: May 2019

Background-The clonal evolution and effect of neoadjuvant chemotherapy on the mutational landscape of triple negative breast cancer (TNBC) is unknown. Inability to eradicate TNBC may be due to clonal progression and selection of cells fundamentally resistant to chemotherapy.In this study, we sought to decipher the genomic architecture of TNBC serially during neoadjuvant chemotherapy to distinguish pre- versus post-chemotherapy genotypes.

Methods-Tumor specimens were obtained from patients with stages II and III TNBC enrolled on an ongoing prospective neoadjuvant co-clinical trial (NCT02124902). Patients have a research biopsy at baseline, cycle 1 day 3 (optional), and at definitive surgery for those with residual disease. Patients are treated with docetaxel 75mg/m2 and carboplatin AUC6 cycled every 3 weeks X six cycles. Definitive surgery is 3-5 weeks after chemotherapy. The primary endpoint is pathologic complete response rate. Correlative studies include development of patient derived xenografts, evaluation of genomic signatures of resistance and response, and comparison of chemotherapy responses between xenografts and host patients. Five patients' serial tumor samples and germline DNA were studied by exome and transcriptome sequencing. Three of these patients had an additional on-treatment sample at cycle 1 day 3. Two patients lacked residual disease samples- one was not banked and the other could not be accurately genotyped due to low cellularity. The median sequencing depth was 90.13x. Sequencing was performed on either fresh frozen or formalin-fixed paraffin-embedded samples with high cellularity (≥50%). After identifying somatic mutations in each tumor series, we evaluated whether each mutation was persistent, emergent, or cleared by comparing pre- and post-treatment (and when possible, on-treatment) samples.

Results-All five patients had response to neoadjuvant chemotherapy based on caliper-based and pathologic (residual cancer burden I or II) measurements. All residual disease remained TNBC by standard immunohistochemistry and all samples were basal-like from PAM50 gene expression analysis. We identified 908 somatic mutations, including the expected variants in TP53 which persisted in all post-treatment samples. Non-silent somatic variants were identified in other breast cancer-related genes, including GATA1, FBXO11, PIK3R1, AXIN2, ARID1B, BRCA2, and RBCC1. In spite of the clinico-pathologic evidence of response, we observed little change in clonal architecture, as derived from the purity-corrected variant allele fractions between baseline, cycle 1 day 3, and post-chemotherapy samples. Copy number alterations were likewise stable and transcriptional-based assessment indicated that patterns of mutant allele expression in driver genes were retained throughout the course of treatment.

Conclusion-In TNBC patients undergoing neoadjuvant platinum-based chemotherapy, there were no apparent shifts in the prevalence of known breast cancer specific somatic variants during or after chemotherapy. Despite pathologic response, core genomic features appear to be preserved in TNBC patients with residual disease following chemotherapy, likely accounting for high rates of relapse in these patients.

Citation Format: Ademuyiwa FO, Miller CA, Li T, Sanati S, Ma CX, Weilbaecher K, Ellis MJ, Mardis ER. Tumor genomic profiling of triple negative breast cancer during neoadjuvant chemotherapy: Results from a prospective trial of carboplatin and docetaxel [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-11.