Genetic Profiling Can Identify “Actionable” Mutations in Tumors That Are Missed by Traditional Tests

VBCC - December 2014, Vol 5, No 10 - Personalized Medicine
Wayne Kuznar

San Francisco, CA—Comprehensive genetic profiling can identify clinically meaningful alterations in 85% of patients with cancer, said Juliann Chmielecki, PhD, Senior Scientist of Cancer Genomics at Foundation Medicine, at the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative.

As more cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies.

The number of clinically relevant genes across solid tumors is high. Clinically relevant alteration is defined as an alteration for which an FDA-approved targeted therapy is available for that tumor type or for another tumor type.

In 2012, researchers found at least 1 clinically relevant genomic alteration in 59% of colorectal cancer (CRC) and non–small-cell lung cancer (NSCLC) tissue specimens, and revealed 2 gene fusions, C2orf44-ALK in CRC and KIF5B-RET in lung adenocarcinoma. Further screening of 561 lung adenocarcinomas showed RET fusions in 2% of tissue samples.

The pace of targeted therapy discovery is rapid; by 2014, RET fusion–positive NSCLC was found to respond to the RET inhibitor cabozantinib (Cometriq).

Multiple diagnostic tests for the myriad genetic alterations in cancers may exhaust precious biopsy material, said Dr Chmielecki.

In a study of clinically relevant somatic mutations in NSCLC specimens, the fraction of mutations with an allele frequency under the limit of detection by capillary Sanger sequencing was 55%. “Next-generation sequencing–based tests miss most of the actionable alterations within a given patient,” Dr Chmielecki said.

New Genetic-Profiling Test
To address the challenges presented by small biopsies, the multiple classes of genetic alterations, and the tumor samples that may have small tumor content, “we developed a test that has all 4 classes of alterations, with very high sensitivity and positive predictive value,” Dr Chmielecki stated.

The new genetic-profiling test is based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions, copy number alterations, and selected fusions across 314 cancer-related genes from formalin-fixed paraffin-embedded specimens.

Of more than 13,000 patients who had undergone genetic profiling, 97% had 1 genetic mutation reported and 85% of samples had at least 1 clinically relevant alteration.

“When we look at the 314 cancer-­related genes, we’re not finding a huge number of alterations per patient,” Dr Chmielecki said. “A higher number is usually cancers that are associated with carcinogens, such as lung cancer and melanoma.” Alterations per sample ranged from 0 to 57, and clinically relevant alterations per sample ranged between 0 and 28.

The solid tumor types that were represented in the >13,000 specimens included lung (19%), breast (14%), colon (9%), brain (5%), ovarian (5%), pancreatic (4%), soft tissue (4%), and other (32%, mainly rare tumors).

The investigators found a huge number of low-frequency alterations that could be linked to targeted therapies “that may be clinically relevant, even though they’re not occurring in hot spots of high-frequency genes,” Dr Chmielecki said.

Novel Alterations
A novel KIF5B-RET fusion was identified and was later discovered to be present in 1% to 2% of patients with NSCLCs; KIF5B-RET–transformed cells are sensitive to RET inhibitors, suggesting that RET kinase inhibitors should be tested in prospective trials of patients with NSCLC with RET fusions. Multiple patients with KIF5B-RET fusion are known to have responded to a RET inhibitor, she indicated.

HER2/ERBB2 alterations were observed across 27 tumor types. “This phenomenon may extend well beyond the gastric and breast cancer field, and into areas that have not been looked at,” said Dr Chmielecki.

“There are clinical case reports showing sensitivity of HER2 amplification outside of breast and gastric cancers, as well as some of these newer mutations being discovered.” Nearly 50% of all HER2/ERBB2 alterations are missed by current tests, she noted.

EGFR alterations were identified in 151 cases (6.8% of total cases) across 13 different tumor types, including breast cancer. An EGFR mutation is not usually tested for in a person with breast cancer. By site of organ, EGFR alterations occurred in glial, lung, brain, head and neck, bladder, kidney, uterine, breast, bone, colorectal, esophageal, skin, and stomach tumors.

Fusions were identified in 13 kinases across multiple tumor types. Of the 248 kinase fusions that were identified, many with novel 5’ fusion partners were identified (2.2% of total cases).

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Last modified: December 23, 2014
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