ALCMI Study Finds New Targetable Genetic Alteration in NSCLC

Posted by ALCF Staff on August 8th, 2016

The Genomics of Young Lung Cancer (GoYLC) study has identified a unique and targetable new genetic alteration that drives a subset of lung cancer, as reported this month in the prestigious scientific journal, Cancer Discovery.

This alteration is a gene fusion, an abnormality whereby a gene fuses with another, and together this gene fusion drives cancer cells to grow and replicate. This newly identified gene fusion; EGFR-RAD51 entails the incorrect fusion of the EGFR (Epidermal Growth Factor Receptor) gene with the RAD51 gene, which causes the highly undesirable activation of pro-cancer signaling pathways from the EGF receptor.

Mutations in the EGFR gene have previously been known to play a role in driving a subset of non-small cell lung cancer (NSCLC) tumors. These EGFR mutations, such as those in exon 19 or exon 21, are currently targetable by medicines known as TKIs or Tyrosine Kinase Inhibitors, such as erlotinib, afatinib, gefitinib, etc. The newly identified genetic alteration is different from previously known EGFR mutations in that it is not an alteration within the EGFR gene itself, rather, it is an abnormal fusion of the EGFR gene to another gene.

Encouraging findings emerging from the GoYLC study and reported in the Cancer Discovery article demonstrate that these newly identified EGFR gene fusions are clinically actionable, in that these can be treated with targeted therapies, and patients presenting with tumors harboring EGFR fusions respond to therapy with known TKIs such as erlotinib.

In the study published in Cancer Discovery, the EGFR-RAD51 gene fusions were identified in 4 patients who presented with metastatic lung cancer. These gene fusions were identified by comprehensive next-generation sequencing (NGS), highlighting the need for genetic testing of all newly diagnosed cancers to identify targetable alterations that typically produce better, and durable responses compared to chemotherapy. Such gene fusions are not detected in standard genetic testing, and so crucially these patients may not have been offered targeted drugs to their specific mutation if not for the NGS testing they received. All four patients that presented with the EGFR-RAD51 fusion had clinical and radiographic responses to EGFR inhibition through targeted agents such as erlotinib (Tarceva).

The researchers leading the effort further investigated the specific factors contributing to the tumorigenic (capable of causing tumors) activity of EGFR-RAD51 in the lab, and identified that this abnormal gene fusion drives pro-cancer gene signaling through the MAPK and PI3K-AKT pathways that are known drivers of tumor growth.

Although EGFR fusions have been known to occur in one other cancer type (glioma), this report in Cancer Discovery is the first ever documentation of lung cancer patients with EGFR fusion–positive tumors that derived significant and sustained antitumor responses from treatment with the EGFR TKI erlotinib (Tarceva).

This study highlights the need for, and importance of comprehensive genomic testing of all tumors to identify actionable alterations that can potentially be treated with targeted therapies, which provide patients increased likelihood of sustained, durable anti-tumor responses, and typically a better quality of life. Therefore, Don’t Guess, Test!

The GoYLC is being run through the Addario Lung Cancer Medical Institute, or ALCMI, a patient-founded international research consortium that develops and directly facilitates research studies and clinical trials. Dr. Barbara Gitlitz from the University of Southern California (USC) Keck School of Medicine is leading the GoYLC study along with investigators at Dana-Farber Cancer Institute (Dr. Geoffrey Oxnard), as well as University of Torino, Italy (Drs. Tiziana Vavala nd Silvia Novello). Funding support for GoYLC has come from the Bonnie J. Addario Lung Cancer Foundation, Peter Barker Foundation, Genentech, Beth Longwell Foundation, Pfizer, Schmidt Legacy Foundation, and Upstage Lung Cancer. For more details on the Genomics of Young Lung Cancer study, click here.

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