Gene abnormalities discovered in a subpopulation of lung and colorectal tumors could identify patients with a heightened response to highly specific drugs used for other cancers, according to study results published in the journal Nature Medicine.
After the discovery of a unique fusion gene in a DNA tumor sample removed from a 44-year-old never-smoker with non–small cell lung cancer, researchers from Foundation Medicine Inc. found that the gene was composed of a cell growth gene, RET, and part of another gene, KIF5B — a gene combination which appeared to stimulate uncontrolled cell division.
To determine the frequency of this gene fusion, labeled KIF5B-RET, researchers analyzed genomic DNA from 40 colorectal cancer and 24 NSCLC formalin-fixed paraffin-embedded specimens using an assay that captures and sequences 2,574 coding exons representing 145 cancer-relevant genes, in addition to 37 introns from 14 genes that are commonly reorganized in cancer.
“We looked for the RET fusion gene in a larger collection of lung tumor samples to determine how common it is, and if it is acting as an oncogene (a gene that drives cancer)” researcher Pasi A. Jänne, MD, PhD, a thoracic oncologist at Dana-Farber Cancer Institute, said in a press release.
The researchers searched samples from 121 white patients and 405 Asian patients who had never smoked or had rarely smoked in the past, and detected the RET fusion gene in one of the white samples (0.8%) and nine of the Asian patient samples (2%).
Researchers also sequenced DNA samples from 40 patients with colorectal cancer and identified another novel gene alteration, C2orf44-ALK, which stimulated overexpression of the ALK protein leading to cancerous proliferation. Additional screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2%; 95% CI 0.8–3.1).
The researchers observed that when multikinase inhibitors — sorafenib (Nexavar, Bayer), sunitinib (Sutent, CPPI CV) and vandetanib (Caprelsa, IPR Pharmaceuticals) — were tested on cultured cells containing the newly discovered RET mutation, each of the drugs killed the designated cells, indicating sensitivity to specific multikinase inhibitors, which inhibit RET. According to the researchers, this discovery suggests that the same drugs also may be effective against lung and colorectal tumors driven by the newly found gene fusions.
“This is a textbook example of personalized medicine for lung cancer — a genetic alteration found in a subset of patients that we can now look for and use as a means to select particular therapies,” Jänne said. “In the past, although these targeted drugs were available, they were not chosen for a particular subset, but instead given to everybody. This will increase the likelihood of those therapies being more successful.”
Disclosure: The researchers report employment and consulting funding from Foundation Medicine Inc.
The work from Doron Lipson and colleagues published in Nature Medicine identifying new ALK and RET gene fusions from colorectal and lung cancer biopsies marks the arrival of an era of clinical next-gen sequencing in personalized cancer care. This report highlighted the feasibility and clinical impact of the application of a single, multiplex targeted cancer gene sequencing that requires minimal DNA from archival formalin-fixed paraffin-embedded (FFPE) tumor samples. At least one clinically relevant genomic alteration was identified in 59% of the FFPE tumor samples analyzed, and two novel gene fusions were uncovered, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Clinical relevance of the novel gene fusion finding was demonstrated by the in vitro inhibitory sensitivity of the KIF5B-RET transfected cells by multitargeted kinase inhibitors sunitinib, sorafenib and vandetanib, but not gefitinib (Iressa, AstraZeneca).
Today, the question regarding “clinical genomic sequencing” is no longer about “when” and “if” it should be done, but really is already about “how” it should be done. Regulatory progress in clinical cancer sequencing needs to catch up with the immensely rapid technologic advances. While the price tag of whole-genome sequencing continues to drop with time, the debate likely will go on for now regarding the best way to sequence: getting part of the genome (targeted sequencing of selected coding exons and introns) with higher certainty as in this study vs. getting the whole picture (whole-genome/exome sequencing) with perhaps lesser certainty. It all still comes down to depth of sequencing coverage and cost. It is also time to rethink our targeted therapeutics development strategies to match up with the rapid ongoing cancer genomic discoveries, as the need for more targeted drugs and more flexible indications of use.
Patrick C. Ma, MD, MS
Director of Aerodigestive Oncology Translational Research
Taussig Cancer Institute
The Cleveland Clinic
Disclosure: Dr. Ma reports no relevant financial disclosures.