Staging, ctDNA, and the Art of Personalizing Metastatic Breast Cancer Therapy: Hayley Knollman, MD

Hayley M. Knollman, MD, assistant professor of clinical medicine, University of Pennsylvania, explored current challenges and evolving strategies in the diagnosis and treatment of estrogen receptor–positive (ER-positive) breast cancer, with a particular focus on the role of circulating tumor DNA (ctDNA) and genomic testing, during an interview at an Institute for Value-Based Medicine^® event of The American Journal of Managed Care^® on April 9 in Philadelphia.

Knollman explained that at initial diagnosis, breast cancer staging still relies primarily on standard methods: blood work, imaging scans, and biopsy-based testing for ER, progesterone receptor (PR), and HER2. While HER2 status clearly guides therapy in HER2-positive disease, the emerging categories of HER2-low and HER2–ultra-low currently have limited impact on frontline treatment in patients with potentially curable disease. Instead, she said, these distinctions become more relevant if and when the cancer progresses to metastatic disease, making it important to characterize tumors comprehensively at the outset.

A major theme of the discussion is the gap between technological capability and clinical guidance. In metastatic ER-positive breast cancer, ctDNA and broader genomic assays are now widely accessible, but there remains considerable uncertainty about how often they should be performed, at which time points, and how best to act on the results. Knollman’s personal approach is to obtain molecular or genomic testing at initial metastatic diagnosis and again at a site of progression, with intermittent ctDNA or genomic assessments over the course of what can be a many-year disease trajectory.

The complexity of treatment sequencing is highlighted as the therapeutic arsenal expands. Decisions increasingly hinge on factors such as ESR1 mutations (linked to resistance to aromatase inhibitors), PIK3CA mutations, prior therapies, duration of response, and the pattern and tempo of progression. While first-line treatment for metastatic ER-positive disease—typically an aromatase inhibitor plus a CDK4/6 inhibitor—remains relatively standardized, subsequent lines are far more nuanced. Knollman characterized the management of metastatic breast cancer as “more of an art than a strict science,” emphasizing individualized decision-making guided by tumor genomics, disease behavior, and patient history.