Date of Award

January 2017

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard P. Lifton

Abstract

Triple Negative Breast Cancer (TNBC) encompasses a wide range of treatment responses, however there are no predictive biomarkers approved for clinical use to target therapy. With a novel exome analysis method, we discovered that the overall proportion of the homologous recombination repair (HRR) genes affected by structural variation can accurately predict both positive and negative chemotherapy response prior to initiation of therapy in the large majority of patients in our cohort.

We analyzed exome sequences of unpaired tumor samples, collected prior to ACT chemotherapy, in 17 TNBC patients who exhibit complete pathologic response to neoadjuvant chemotherapy (pCR) and 15 patients who had extensive residual disease (RD).

In the process, we created one of the first analytical pipelines capable of performing comprehensive integrated analysis of somatic point mutations and structural variation in unpaired tumor exome samples. Validation on tumor-normal matched samples demonstrated >95% specificity for point mutations, LOH, and CNV calling compared to standard tumor-normal somatic analysis.

When applied to the TNBC cohort, our somatic mutation caller identified multiple damaging somatic mutations in genes linked to EMT. LOH analysis showed significantly greater LOH in pCR (Complete Response) than RD patients (Residual Disease) (p=6.5E-12). The five regions with greatest LOH difference between pCR and RD subgroups each contained a HRR gene locus. Overall high LOH burden was associated with the presence of TP53 point mutations (p=0.002).

By integrating data from all three methods, we found significantly more pCR patients with high mutation burden (including CNV and LOH) in homologous recombination repair genes than RD patients (83% vs 20%). With this metric, we can predict 83% of positive response and 80% of negative response based on our patients’ genomic profiles prior to chemotherapy initiation (OR=18.7, 95% CI= 3.2 to 110.3, p=0.0012).

This result offers a potential significant improvement in our ability to personalize therapy in TNBC and may facilitate development of targeted PARP inhibitor therapeutics.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 06/12/2019

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