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Findings from an oncogene overlap study in NSCLC support the potential clinical impact of high-level amplification of MET, HER2, and KRAS defined by NGS.
Clinically relevant amplified subgroups with altered genetic profiles and decreased survival were identified using tissue-based next-generation sequencing (NGS) HER2, KRAS, and MET copy number gain thresholds in non–small cell lung cancer (NSCLC) adenocarcinoma samples (n = 13,702), according to findings from a retrospective analysis published in Clinical Lung Cancer.1
The copy number gain thresholds were set by oncogene overlap and dataset size (at least 6 for HER2 and KRAS, and at least 4 for MET), and tumors that were considered relevantly amplified for MET, HER2, and KRAS were significantly less likely to be driver-positive (P < .001). As copy number gain increased, the frequency of driver-positive tumors decreased.
“[Based on the] first part of the results, using NGS and oncogene overlap, we can define a threshold that isn’t just based on us picking a number of what copy number gain we think is clinically meaningful for a cancer. But based on biological mutual exclusivity this copy number gain seems to define a subgroup of meaningfully HER2-, KRAS-, and MET-amplified cancers that then could be studied in targeted therapy trials,” Alexander Watson, MD, DPhil, FRCPC, said in an interview with OncLive®. Watson, a coauthor of the study and an advanced fellow in Thoracic Oncology and Investigational Cancer Therapeutics at University of Colorado Anschutz Medical Campus in Denver, detailed the implications of findings from the study in another article.
Additionally, findings revealed that when driver-positivity overlapped with amplified status, same-gene alterations—mutation and copy number gain—were significantly enriched for all 3 HER2, KRAS, and MET genes; however, BRAF and EGFR mutations were more common in MET-amplified tumors than in HER2- or KRAS-amplified.
Furthermore, a negative overall survival association with amplified status was seen independent of driver-positive status in the HER2 and MET groups. For MET, amplified tumors were associated with an increased HR for death vs tumors that were not amplified regardless of oncogene driver co-occurrence; the HR for driver-positive tumors was 1.62 and the HR was 1.47 for driver-negative tumors. This was also observed in the HER2 group with respective HRs of 1.3 and 1.71. In the KRAS group, an increased HR for death for amplified tumors vs tumors that were not amplified was observed in KRAS driver-positive tumors (HR, 1.5), but not in driver-negative tumors (HR, 0.92).
Copy number gain is a continuous variable, and investigators conducted this study to test the hypothesis that high copy number amplification is a “primary driver and an acquired mechanism of therapeutic resistance to targeted therapy across a range of same- and different-pathway driver oncogenes in NSCLC.”
Study authors noted that approximately 1% to 21% of patients with NSCLC have copy number gain of the MET protooncogene as a potential primary oncogenic driver, and approximately 2% to 22% of patients with NSCLC have copy number gain of the HER2 gene. Although KRAS has been implicated in TKI resistance in several driver mutation subtypes of NSCLC, it has not been shown to be actionable or a primary driver. As copy number gain assessment by NGS can vary by assay and application, and unique confounding factors are also a consideration, it is key to develop better methods to define relevant copy number thresholds by NGS.
Thus, investigators used an oncogene overlap approach to determine meaningful copy number gain thresholds. The NSCLC tumors were sequenced at Caris Life Sciences and the overall cohort of tumors were broken down into analysis groups by the presence or absence of an amplified HER2, KRAS, or MET gene and the presence or absence of an oncogenic driver mutation.
Data on stage and line of therapy/prior treatments received were not available for the cohort, representing a limitation of the study. In the overall cohort, 65% of tumors had oncogenic driver mutations. Notably, driver-positive groups were more likely to be female overall (P < .001), but KRAS-amplified and driver-positive tumors were distributed evenly between both sexes, according to investigators.
Data also revealed that the gene copy number for HER2, KRAS, and MET ranged from 2 to greater than 7 copies; the frequency of co-occurring driver oncogenes also decreased at high copy numbers for each gene.
Regarding HER2 copy number gain, irrespective of same-gene mutation inclusion or exclusion, tumors had a significant decrease in oncogene mutation overlap starting at copy numbers greater than 4. When the copy number gain threshold was 6 or greater, 26.7% of HER2 tumors were oncogenic driver-positive. When the copy number gain was less than 6, 65.2% of tumors were driver-positive.
When examining KRAS, 44.0% of tumors with a copy number gain of at least 6 were oncogenic driver-positive vs 65.0% in tumors with a copy number gain less than 6; however, this represented tumors that had KRAS mutations, which comprised the vast majority of co-occurring mutations for the KRAS copy number gain tumors. “Excluding KRAS mutations substantially altered concurrent oncogene mutation frequency, and the relationship to oncogene mutation frequency became more linear; 8.8% of tumors were driver-positive when excluding KRAS mutations,” investigators wrote. “Overall, the decrease in driver overlap frequency with increasing copy number gain was lowest for KRAS (vs HER2 or MET) when excluding same-gene (KRAS) mutations.”
Furthermore, when MET tumors were evaluated, the relationship between copy number gain and co-occurrence of oncogenic drivers decreased semi-linearly above a copy number gain greater than 2.4 and then plateaued at approximately greater than 4. Among tumors with a MET copy number gain of at least 4, 33.2% were oncogenic driver-positive; 26.3% were driver-positive when excluding MET mutations. Additionally, 65.4% of MET copy number gain less than 4 tumors were driver positive.
“[The] frequency of most driver mutations were numerically decreased in the amplified group (vs no [amplification group]), with significance limited by the rarity in certain alterations when adjusting for multiple comparisons,” investigators wrote. “KRAS mutations (36.87% no amplification vs 6.35% amplified, P < .001) and MET mutations (2.81% vs 0.79%, P < .001) were significantly decreased among HER2-amplified tumors, while EGFR mutations were nonsignificantly decreased (17.87% no amplification vs 10.19% amplified, P = .051).”
Investigators concluded that prospective research surrounding the benefit of targeted therapy in these groups should be encouraged.
Watson AS, Krause HB, Elliott A, et al. Use of oncogene overlap by tissue-based next-generation sequencing to explore the mutational landscape and survival impact of HER2, KRAS and MET copy-number gain in nonsmall cell lung cancer. Clin Lung Cancer. 2024;25(8):712-722.e1. doi:10.1016/j.cllc.2024.09.001
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