Dr Stockhammer on Gene Alterations and Poor Outcomes in EGFR-Mutant Lung Cancer

Paul Stockhammer, MD, PhD, academic hospital resident, Smilow Cancer Center, Yale New Haven Hospital, Yale Medicine, discusses research into the association between alterations in multiple tumor suppressor genes and poorer outcomes in patients with EGFR-mutant lung cancer, which was presented at the 2023 ASCO Annual Meeting.

In this study, investigators first validated that TP53 mutations are prognostic and that these mutations are associated with worse outcomes, he says. Upon stratification, patients with TP53 mutations who have additional mutations in at least 1 of 5 tumor suppressor genes evaluated in the study have poor outcomes with standard-of-care EGFR TKIs, Stockhammer explains. These patients have inferior progression-free and overall survival outcomes compared with patients who have only TP53 mutations and those with TP53 wild-type disease.

The investigators hypothesized that upon stratification by additional tumor suppressor gene alterations, TP53mutation status is no longer prognostic, Stockhammer shares. Overall, this study confirmed that hypothesis and found that patients with multiple tumor suppressor gene alterations have poorer outcomes with EGFR TKIs, he expands. Additionally, these cases are associated with a more aggressive clinical disease phenotype. Investigators also found that these cases lead to patients’ disease being more refractory to TKIs. Approximately 25% of patients with additional tumor suppressor gene mutations in this study did not respond to treatment with EGFR TKIs.

Upon disease progression, the pattern of disease progression in these patients was also more disseminated than the disease progression in patients with only TP53 mutations or TP53 wild-type disease, Stockhammer explains. At progression, patients with TP53 mutations and additional tumor suppressor gene mutations had disease involvement in a significantly higher number of involved sites than that in the other 2 groups, Stockhammer continues. Overall, investigators showed that patients with mutations in TP53 and additional tumor suppressor genes have worse outcomes with EGFR TKIs, have a more aggressive disease phenotype with earlier disease progression, and are more refractory to EGFR TKIs, he explains. The investigators hypothesized that upon identification of these mutations, certain tumors may benefit from alternative therapies, he concludes.