DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted November 1, 2017
Geoffrey Oxnard, M.D., Dana Farber Cancer Institute

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Cloud Paweletz (left) and Geoffrey Oxnard (right)

Recent years have seen the development and advancement of numerous targeted treatments for lung cancer, and more are expected to become available to patients in the coming years. These treatments take advantage of a cancer patient’s specific driver mutation in their tumor cells and target the affected pathways. The therapies are highly effective when matched with the right mutation and are gaining in popularity for certain difficult-to-treat lung cancers. Unfortunately, the process of identifying the genetic mutations that match these targeted therapies is often challenging. A biopsy must be recovered from the tumor site—a process which, in and of itself, involves some risk and is not always feasible, depending on a patient’s condition.

To solve this problem, researchers are looking into less-invasive approaches to identify and test the genetic code of cancer cells in lung cancer patients. Dr. Geoffrey Oxnard, at the Dana Farber Cancer Institute, applied a fiscal year 2013 Lung Cancer Research Program (LCRP) Career Development Award to validate a droplet digital polymerase chain reaction (ddPCR) approach to genotype tumors using cell free-DNA in the patient’s blood. During his award period, Dr. Oxnard was able to successfully confirm that his method detects and sequences tumor DNA floating in a patient’s bloodstream. His method was highly sensitive and was able to identify 64-83% of patients’ tumor genome for KRAS and EGFR mutations (common cancer mutations). As might be expected, the sensitivity of this test was highest for patients with the greatest number of metastases. This assay was 100% specific for these same EGFR and KRAS mutations, meaning it was able to distinguish cancer-causing EGFR and KRAS mutations from normal DNA 100% of the time.

Interestingly, Dr. Oxnard’s assay showed no significant correlation between tumor size and the levels of mutation detectable in a patient’s bloodstream. There was, however, a notable improvement (as measured by a decrease) in the amount of cell free-tumor DNA in the bloodstream post-treatment that correlated with tumor shrinkage, suggesting this assay has the potential to be used as an early marker of treatment effectiveness, in addition to its prognostic applications. Dr. Oxnard has follow-on studies of this new potential use for ddPCR underway and hopes to see success as this assay is used in practice to guide clinical care.

Since the start of Dr. Oxnard’s award, he has significantly expanded assay development and is currently enrolling patients in a clinical trial to investigate his ddPCR assay in early and drug-resistant cancer. He is also enrolling patients and working with pharmaceutical companies to test approaches that use his ddPCR assay as a launching point, including the validation of next-generation sequencing of cell free-DNA to get a better picture of the cancer genotype.

Thanks to LCRP funding, Dr. Oxnard successfully confirmed the utility of his ddPCR method for identification of genomic modifications in cancer and has started implementing it as a prognostic and care guidance tool in the clinic on a trial basis. Once this method gains widespread acceptance and Food and Drug Administration approval as a prognostic biomarker, it will provide lung cancer patients with an alternative to invasive biopsies as a means of determining their best treatments and lead to quicker, more successful applications of targeted treatments, resulting in improved survival of lung cancer patients.

Publications:

Sacher AG, Paweletz CP, Dahlberg SE, et al. 2016. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Onco 2(8):1014-22.

Paweletz CP, Sacher AG, Raymond CK, Alden RS, O'Connell A, Mach SL, Kuang Y, Gandhi L, Kirschmeier P, English JM, Lim LP, Jänne PA and Oxnard GR. 2016. Bias-corrected targeted next-generation sequencing for rapid, multiplexed detection of actionable alterations in cell-free DNA from advanced lung cancer patients. Clin Cancer Res (22):(4)915-922 DOI: 10.1158/1078-0432.CCR-15-1627-T.

Link:

Public and Technical Abstracts: Noninvasive Personalization of Lung Cancer Therapy Using a New, Clinical-Grade Assay for Plasma-Based Measurement and Monitoring of Tumor Genotype

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Last updated Wednesday, November 1, 2017