W. Fraser Symmans, MD

Developing gene-based prognostics tests to guide treatment decisions for patients with estrogen receptor-positive breast cancer.

Impact

Most breast cancers are driven by hormones, particularly estrogen. These cancers, referred to as estrogen receptor (ER)-positive, are treatable with anti-hormone (endocrine) therapies. But as breast cancers progress, they often lose sensitivity to endocrine therapy. This is particularly true in breast cancers that have spread to other tissues—a process called metastasis. Dr. Symmans developed a series of gene-based tests referred to as SET (Sensitivity to Endocrine Therapy) that can be used to guide treatment decisions in patients with metastatic (stage IV) or regional (stage II-III) breast cancer. This assay employs advanced technology and has the potential to allow more precise treatment decisions compared to current assays—this is vital for the clinical management and improvement of outcomes for breast cancer patients with aggressive and advanced breast cancers.

Progress Thus Far

Dr. Symmans has demonstrated that the SET2,3 test (used to predict sensitivity to endocrine therapy for Stage 2 or 3 breast cancer) is technically accurate and reliable. Moreover, the SET2,3 test adds significant additional information to current prognostic tests such as OncotypeDX® or MammaPrint®. This is most likely due to the improved measurement of endocrine sensitivity. Building on their success with SET2,3 with endocrine therapy, Dr. Symmans expanded his focus to examine its accuracy in predicting and quantitating benefit from chemotherapy. His team showed that 86 percent of patients with high SET2,3 measures were disease-free at five years versus 69 percent of patients with low SET2,3 measures. The prognostic value of SET2,3 remained significant at 10 years with nearly 78 percent of SET2,3 high patients being disease-free versus 58 percent of SET2,3 low patients. Low SET2,3 levels, however, were found to be predictive of response to dose-dense chemotherapy—identifying patients most likely to benefit from this therapy and sparing those less likely to benefit. Other studies demonstrated that the SET4 test that combines measurements of gene expression signatures and gene mutation for Stage 4 breast cancer is highly reproducible.

What’s next

Based on promising predictive results for patients with stage 2, 3, and 4 ER-positive breast cancer, Dr. Symmans’ team will continue to determine how SET2,3 and 4 should be used to guide therapy planning. They will confirm their findings in a large cohort of tumor samples from a second independent clinical trial. Confirmation of these early findings will establish clinical validity and enhance progress toward evidence-based clinical utility of the tests, ultimately improving prediction of chemotherapy benefit. In addition, Dr. Symmans and his colleagues will determine if the duration of chemotherapy affects the sensitivity to subsequent endocrine therapy as measured by the SET assay.