Brief Summary

This project aims to investigate racial heterogeneity in triple negative breast cancer (TNBC) and ovarian cancer, focusing on its implications for PARP inhibitor treatment response and clinical trial design. The study proposes to develop a transcriptional profile using an African American (AA) diversity-enriched sample to better characterize tumor PARP inhibitor response and improve prediction across diverse populations. By addressing both the scientific opportunities and ethical imperatives of diversity inclusion, the project seeks to enhance the generalizability of clinical trial results while discouraging racial profiling in medical decision-making.

Expanded Summary

Background and Objectives

The project addresses the critical issue of racial heterogeneity in cancer biology, particularly in triple negative breast cancer (TNBC) and ovarian cancer, and its potential impact on PARP inhibitor treatment response. Despite the higher incidence of TNBC among African American (AA) women and the persistent disparities in ovarian cancer survival rates, clinical trials often lack adequate representation from diverse populations.

Key objectives include:

1. Evaluating racial heterogeneity in TNBC and ovarian cancer tumor biology.
2. Developing a transcriptional profile using AA diversity-enriched samples to improve PARP inhibitor response prediction.
3. Investigating the impact of diversity-focused trial designs on physician referral practices and racial profiling in treatment decision-making.

Scientific Rationale

The study is based on several key observations:

1. AA women are twice as likely to develop TNBC compared to European American (EA) women.
2. Preliminary data suggests that within TNBC, AAs are more likely to have a specific subtype with greater involvement of the homologous recombination (HR) pathway, which is targeted by PARP inhibitors.
3. BRCA mutation status, while important, is not a sufficiently sensitive biomarker for PARP inhibitor response.
4. The genetic diversity represented in the AA population may capture biological variation that is underrepresented in current clinical trials.

Proposed Approach

The project consists of two main aims:

1. Transcriptional Profiling:
   • Analyze genome-wide expression data from 100 AA TNBC and 100 AA Ovarian Cancer tumors.
   • Identify and validate transcriptional subtypes using hierarchical clustering.
   • Compare subtypes to those generated in EA populations and evaluate their relevance to PARP inhibitor response.