Stanford Cancer Institute Breakthroughs in Cancer: John Heymach, MD, PhD

In this seminar, Dr. John Heymach, a leading lung cancer researcher, discusses the evolution of personalized therapy for lung cancer, moving beyond simple driver oncogenes. He begins by contrasting the chemotherapy era, where median survival improved by only 0.4 months over 25 years, with the current era of targeted therapy, where identifying driver mutations like EGFR can lead to median overall survival exceeding 8 years. However, he emphasizes that the simple paradigm of one driver, one drug is insufficient due to the vast heterogeneity within oncogene-driven cancers. Focusing on EGFR, he notes that there are over 100 different mutations, many without approved targeted therapies. He proposes a novel structure-function classification of EGFR mutations based on drug sensitivity patterns, dividing them into four groups: classical-like, T790-like, PACK (P-loop and alpha-C helix compressing), and exon 20 loop insertions. This classification better predicts drug response than traditional exon-based grouping. For example, PACK mutations, which constitute about 12% of lung cancers, respond better to second-generation TKIs like afatinib than to third-generation drugs like osimertinib. He also discusses the role of tumor suppressors, transcriptional programs, and epigenetic modifications in driving heterogeneity. The talk concludes with a Q&A session.