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Multiple Genetic Alterations Uncovered in Advanced EGFR-Mutant Lung Cancer Patients

NEW YORK (GenomeWeb) – Most patients with advanced EGFR-mutant lung cancer also harbor key secondary mutations within their tumors, according to a new study.

Rather than focus on single gene mutations that might be driving lung cancer, researchers from the University of California, San Francisco, examined whether additional oncogene mutations might occur alongside ones in EGFR and affect patient outcomes.

In conjunction with Guardant Health researchers, the UCSF-led team analyzed liquid biopsy samples isolated from more than 1,000 patients with advanced non-small-cell lung cancer with EGFR mutations, and about 1,000 patients without EGFR mutations. As they reported in Nature Genetics today, the researchers found co-occurring mutations in most of the patients with EGFR mutations, and that these extra mutations commonly appeared in genes in the WNT/beta-catenin and cell-cycle pathways. They further linked these mutations to patients' treatment response and clinical outcomes.

"If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment," senior author Trever Bivona, an oncologist at UCSF Medical Center, said in a statement.

The researchers examined the cell-free DNA they isolated for mutations in 73 known oncogenes using Guardant's exome analysis platform. Among the 1,122 patients with EGFR-mutant tumors, 92.9 percent had at least one other cancer-related variant. On average, they reported that patients with EGFR-mutant tumors had two to three additional altered genes.

In particular, about half the patients had mutations in the TP53 gene while alterations in the CTNNB1, CDK6, and AR genes were also enriched among those patients. At the pathway level, alterations affecting WNT/CTNNB1 and hormone signaling protein pathways were enriched among patients with EGFR-mutant tumors. Additionally, they noted that alterations in genes involved in cell division, epigenetic modifications, DNA repair, and cellular signaling pathways were also affected in 10 percent to 25 percent of tumors.

For 97 of the patients in the study, the researchers also had clinical and treatment response data. This subset included patients who were tyrosine kinase inhibitor treatment-naïve as well as those who showed progression on first-line tyrosine kinase inhibitors or on second-line drugs. The researchers noted that, with each line of therapy, the number of somatic mutations in the patients' samples increased.

Patients who progressed after receiving second-line treatments tended to have an increased number of co-mutations in CCNE1, NF1, and PIK3CA, and increased alterations in the TP53, receptor tyrosine kinase, MAPK, and cell-cycle pathways.

Additionally, the researchers noted that alterations within the cell-cycle and MAPK pathways were markers of shorter progression-free survival during EGFR tyrosine kinase inhibitor treatment, and patients with CDK4 or CDK6 alterations had lower overall survival than those who did not have them.

Bivona and his colleagues also analyzed tumor exome and cfDNA samples that had been collected from an NSCLC patient over the course of six years. Within this patient, they uncovered multiple co-alterations that cropped up early on. For instance, early-stage disease samples harbored alterations in CTNNB1, SMAD4, and CDKN2A, while mutations arose in PRKCA and PIK3CA, among others, after metastasis. Progression on tyrosine kinase inhibitor treatment then occurred following acquisition of the EGFR p.Thr790Met mutation.

This indicated to the researchers that co-occurring genetic mutations might drive metastasis and treatment resistance. They argued that new treatment approaches that target multiple genetic pathways at once are needed.

Co-first author Collin Blakely from UCSF noted in a statement that there are already approved breast cancer treatment drugs that target cell-cycle genes that those could be combined with other therapies to "improve these patients' chance of responding to therapy and avoiding drug resistance."

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