Titles and Affiliations
Chief, Breast Medicine Service
Professor of Medicine,
Weill Cornell Medical College
Research area
Understanding how genes influence breast cancer risk to guide personalized screening and risk reduction strategies.
Impact
Most breast cancers are not the result of inherited mutations in cancer causing genes. For families with a high incidence of breast cancer, however, a genetic component may underlie an increased risk. The BRCA genes (BRCA1 and BRCA2) are the most common heritable risk genes, but scientists have uncovered many more genes that may be implicated in an increased risk of breast cancer. Testing for mutations in BRCA1, BRCA2, and other susceptibility genes has become nearly routine, and will become more so in the years to come. Despite this, there is little guidance available to doctors in how to provide the best care for women with a genetic susceptibility to breast cancer. Dr. Robson and his team employ advanced technologies that incorporate information from genetic tests to enhance the precision of genetic risk assessment in women with mutations in BRCA or other susceptibility gene. This includes utilizing genomic markers to create a risk modifying panel, called polygenic risk score (PRS) to help women gain a better understanding of their breast cancer risk which can lead to more informed decisions about their preventive and screening care. Dr. Robson is also working to develop a non-invasive blood test for early cancer detection and monitoring, and to understand why some BRCA-associated tumors stop responding to targeted therapies.
Progress thus far
Over the past year, Dr. Robson has continued to develop the use of PRS to provide more specific, personalized risk estimates for women with inherited mutations in BRCA1/BRCA2 and other breast cancer risk genes. In a prospective study conducted with fellow BCRF investigators Susan Domchek and Judy Garber, the team utilized PRS along with BRCA mutation status to personalize risk assessment in 353 women. Those who received these personalized estimates felt less conflicted about decisions like risk-reducing mastectomy. The team is now ready to modify the test in other genes, including CHEK2, ATM, and PALB2, where individual risk varies even more widely and precise estimates may be especially valuable.
Dr. Robson and his team are using liquid biopsy to detect tiny amounts of circulating tumor DNA (ctDNA)—fragments of DNA shed by tumors that circulate in the blood. This tumor-naïve approach successfully detected cancer DNA before surgery and confirmed it had cleared afterward in all ten patients tested in early studies. The team also identified a new detection signal, based on the pattern of how tumor DNA fragments break, sensitive enough to trace a single cancer DNA molecule among a million healthy ones in controlled testing. Early results from this innovative test show promise in detecting early-stage breast cancer and monitoring how well treatment works, particularly in women with BRCA mutations.
Dr. Robson’s team, in collaboration with BCRF investigator Dr. Andrew Tutt, is also investigating why some BRCA-associated cancers stop responding to PARP inhibitor therapy. The team has assembled 79 paired tumor samples taken before and after treatment and has fully sequenced the first 49, with analysis now underway to identify the genomic mechanisms driving this resistance.
What’s next
In the coming year, Dr. Robson plans to significantly advance the PRS research by expanding participant recruitment to include women with mutations in moderate-risk genes such as CHEK2, ATM, and PALB2, with enrollment opening in late 2026 and all participants followed through one- and six-month outcomes. Using their tumor-naïve ctDNA platform, the team will now combine their new fragment-based detection signal with additional measures into a single model, validated across tumor subtypes, with a particular focus on early-stage ER-positive/HER2-negative breast cancer, a subtype that is challenging to monitor with current diagnostic tools. The team will also complete sequencing and analysis of the remaining PARP inhibitor-resistance tumor samples.
Biography
Mark E. Robson, MD is an Associate Attending Physician of the Clinical Genetics and Breast Medicine Service in the Department of Medicine at Memorial Sloan Kettering Cancer Center. He received his BSc from Washington and Lee University and his MD from the University of Virginia. He performed residency and fellowship training at Walter Reed Army Medical center before coming to Memorial Sloan Kettering in 1996. He is currently the Clinic Director of the Clinical Genetics Service and the chair of the Cancer Genetics Subcommittee of the American Society of Clinical Oncology.
Dr. Robson’s research is directed toward the improving the integration of genetic information into the clinical management of women with breast cancer. He and his colleagues have conducted a number of studies examining outcomes in women with hereditary breast cancer to better define the risks and benefits of treatments such as breast conserving therapy and adjuvant chemotherapy in this group. He and his coworkers have also conducted a number of studies examining the effectiveness of screening interventions such as breast MRI or ovarian cancer screening in women at hereditary risk. He is currently conducting studies to evaluate the impact of intensive screening or surgical prevention upon women’s quality of life, and to develop new screening tools, such as serum peptide profiling.
