Retesting for biomarkers with liquid biopsy in the third-line setting is crucial. It can uncover new, actionable mutations that have emerged during treatment or confirm the absence of resistance mutations, potentially allowing patients to benefit from re-challenging with a previously used targeted therapy.
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A key conceptual shift is viewing ctDNA not as a statistical risk marker, but as direct detection of molecular residual disease (MRD). This framing, similar to how a CT scan identifies metastases, explains its high positive predictive value and justifies its use in making critical treatment decisions.
ctDNA testing (liquid biopsy) is more effective than tissue biopsy for identifying ESR1 mutations. It samples DNA from all metastatic sites, capturing the disease's genetic heterogeneity and reflecting the most active resistance mechanisms, unlike a single-site needle biopsy which can miss them.
Historically, discussing adjuvant therapy for Stage III colon cancer was quick and straightforward, while Stage II was complex. The advent of ctDNA testing has reversed this dynamic. Stage II decisions are now clearer (treat if positive), while Stage III discussions have become much longer and more nuanced as clinicians integrate ctDNA data with patient preferences.
A study switching therapy based on ctDNA-detected ESR1 mutations revealed patients felt significantly better after the switch, even without visible tumor progression on scans. This counterintuitive finding suggests molecular progression has a subclinical impact on quality of life, supporting proactive, biomarker-driven treatment changes before patients clinically deteriorate.
Dr. Bardia emphasizes that ESR1 is an 'acquired alteration,' meaning the mutation can develop during treatment. This necessitates a shift from one-time diagnostic testing to a dynamic, serial testing model. Repeat testing is critical to identify these actionable mutations as they arise, allowing patients to access newly approved targeted therapies.
The InVigor11 study was the first to show that detecting recurrence via a ctDNA test before it's visible on scans is not just a prognostic sign, but an actionable clinical state. Intervening with therapy at this early stage was proven to improve patient outcomes, establishing a new paradigm for cancer surveillance.
In late-stage metastatic colorectal cancer, the goal shifts from achieving significant tumor shrinkage to stabilizing the disease. This recalibration of 'success' focuses on maintaining quality of life and managing symptoms for patients who have undergone multiple prior therapies.
In third-line mCRC, drug selection is heavily guided by a patient's accumulated toxicities. For instance, a patient with bone marrow issues from prior chemotherapy might receive a VEGF inhibitor instead of another chemotherapy agent, prioritizing tolerability and quality of life.
As more effective targeted therapies move into first- and second-line treatment, patients live longer. A paradoxical outcome is that more patients will survive long enough to become candidates for third-line therapy, potentially expanding this patient population rather than shrinking it.
ctDNA testing does more than identify targetable mutations. The mutant allele fraction provides a quasi-volumetric measure of tumor burden, and its early clearance on therapy (as seen in MONALEESA-3) is a strong prognostic indicator for survival, adding value beyond standard radiographic assessment.