James M. Ford, MD, FASCO

Improving breast cancer genetic risk assessment and screening.

Impact

Genetic tests for breast cancer risk can be immensely helpful for families carrying mutations in known breast cancer susceptibility genes, like the BRCA1 and BCRCA2 genes. However, for patients whose inherited risks are not explained by well-known gene mutations, currently available tests provide limited information, do not allow for nuanced genetic counseling on exact levels of risk, and may result in an over-application of prophylactic interventions—such as preventative mastectomies. Researchers have identified approximately 300 potential genetic alterations (known as single nucleotide polymorphisms, SNPs) associated with breast cancer. These are present at varying frequencies in the population and could be used to further refine the percent lifetime risk. Dr. Ford and his team will analyze these SNPs, and how well they coordinate with known risk genes, to potentially improve risk assessments. They are also working to develop new early detection blood-based tools for breast cancer and to uncover genetic bases of treatment resistance.

Progress Thus Far

Dr. Ford and his team are expanding the ability to accurately predict genetic breast cancer risk by incorporating Polygenic Risk Scores (PRS) into the analysis of multigene cancer panels. A PRS is an individualized risk assessment calculated by looking at over 300 SNPs. Dr. Ford and his team are applying PRS to samples from carriers of breast cancer susceptibility genes from their biobank, as well as collecting prospective samples from new patients undergoing genetic testing. Using new diagnostic techniques developed at Stanford, they are analyzing cell-free DNA in blood—“liquid biopsies”—as a cancer screening tool to detect cancers at an early and curable stage. The team found that R-loops, RNA-DNA hybrid structures, a product resulting from inefficient DNA repair in BRCA mutated cells, are detectable in blood and show high sensitivity as a potential biomarker for early cancer detection in women at high genetic risk. Dr. Ford and his team continue to advance our understanding of breast cancer genetic risk in the overall population and develop new screening tools for individual women at high genetic risk.

In a newly launched second line of research, the team is addressing resistance to PARP inhibitors, targeted drugs approved for BRCA-mutant breast and other cancers. Although many tumors initially respond well to these drugs, resistance commonly develops over time, limiting their long-term benefit. The team has developed four stable triple-negative breast cancer cell models resistant to the PARP inhibitors talazoparib or olaparib that do not appear to rely on any previously known resistance mechanisms. Gene expression sequencing of these models revealed hundreds of changes, and the team has narrowed this down to about 20 prioritized candidate genes for further study.

What’s next

Next, Dr. Ford’s team will expand their ongoing PRS studies, continuing follow-up from their completed PRS trial and launching a new prospective PRS study in Stanford’s high- and moderate-risk patients with the goal of quantifying how strongly PRS can refine risk estimates. For their new PARP inhibitor resistance initiative, the team will validate their candidate genes at the protein level and functionally test each one to determine whether altering these genes can restore drug sensitivity or, conversely, induce resistance. Together, these studies aim to deliver more precise inherited-risk counseling and to identify actionable targets for reversing PARP inhibitor resistance, accelerating progress toward improved surveillance and treatment for patients with inherited breast cancer risk.

Biography