Adapting to Tumor Evolution: Resistance Mechanisms and Sequencing After Progression

Dr. Singhi frames the discussion around why tumors progress and how to reassess resistance mechanisms through repeat molecular testing. Dr. Jani walks through two patient scenarios.

For patients who began with actionable alterations—using EGFR as an example, with frontline options such as FLAURA2-based, Mariposa-based, or osimertinib monotherapy—repeat testing at progression is essential. If tissue is obtainable, it is preferred because it can capture histologic shifts, including transformation to small cell lung cancer. Dr. Jani notes a specific clinical clue: when a patient presents with significant sudden acute progression that does not appear consistent with non-small cell biology, tissue biopsy is particularly important. Whether or not tissue is obtained, liquid biopsy provides valuable information about on-target, off-target, or entirely new resistance alterations to guide next-line sequencing.

For patients without actionable alterations at baseline, Dr. Jani again recommends repeat comprehensive NGS—tissue if possible, liquid biopsy if not. IHC testing for HER2 and MET is increasingly important in this group to identify emerging resistance pathways. In both scenarios, he recommends performing both tissue and liquid biopsy to inform sequencing strategy.

Dr. Singhi closes with a teaching point: "The tumor you treated last year may not be the same tumor that you're treating today," underscoring the need for current molecular profiling to guide optimal care.

In the next episode, "Access to Molecular Testing Across Institutions: Barriers, Resources, and Real-World Solutions," the panel explores how testing access varies and what institutions can do to streamline biomarker-driven care.