Abstract 1394: Comprehensive clinical and genomic analysis for patients with MYC, MYCN, and MYCL amplified solid tumors

Abstract

Introduction: The MYC gene family (MYCf), which includes MYC, MYCN, and MYCL, is deregulated in ~70% of cancers and is associated with treatment resistance. Whereas older investigational therapies for MYC amplified tumors were unsuccessful, promising novel targeted therapies are in early phase clinical trials. Unfortunately, it remains unclear how to select patients whose cancers may harbor true MYC addiction. We thus sought to characterize factors such as amplification level, focality, and clonality that may correlate with increased MYC dependence. Methods: Utilizing a center-wide next generation sequencing (NGS) program of >71,000 sequenced patients, genomic and clinical data from pediatric and adult patients with MYC, MYCN, and MYCL amplifications were identified between 2014 and 2022. Patients were characterized as harboring MYC, MYCN, and MYCL amplification based on a read-depth methodology using a DNA-based hybrid-capture NGS (MSK-IMPACT) and Fraction and Allele-Specific Copy Number Estimates from the Tumor Sequencing (FACETS). All cases underwent clinical data curation including baseline demographic, tumor characteristics, and treatment histories. Results: We identified 3911 cancers with MYCf amplification (n=3257 (82%) MYC; n=364 (9%) MYCL; n=330 (8%) MYCN) across 40 malignancies, for an overall 5.5% incidence. The most frequent tumor types with MYCf amplification were breast (22%), non-small cell lung (NSCLC) (11%), colorectal (8%), ovarian (8%), prostate (7%), brain (5%), and small cell lung cancers (SCLC) (2%). Cancers with MYC amplification had longer segment lengths than MYCL and MYCN amplification, which appeared more focal (median = 19, 4.3 and 4.5 MB, respectively, p < 0.001). MYCN amplified cancers had higher total copy number than MYC and MYCL amplified cancers (median = 19, 8, 9, respectively, p < 0.001). MYC, MYCN, and MYCL samples were predominantly clonal (median clonal fraction > 99% for all genes). Most NSCLC, squamous cell lung cancers, and pulmonary carcinoids had MYC amplifications (93%, 70%, and 67% respectively). Conversely, SCLCs most often had MYCL amplifications (49%). No concurrent targetable driver alterations were found in 33% of metastatic NSCLCs with MYC, 75% of MYCN, and 6% of MYCL amplifications. Conclusions: While MYCf amplification is observed across a broad range of cancer types, factors such as gene type (MYC, MYCN, MYCL), focality, total copy number, clonality, and concurrent oncogenic drivers vary widely. Novel MYC-directed trials may consider enrichment for a subpopulation of cancers with higher-level, focal, and clonal MYCf amplifications without concurrent other drivers. Citation Format: Monica F. Chen, Allison Richards, Patrick Evans, Patrick Lee, Adam Price, Matteo Repetto, Soo Ryum Yang, Jason Chang, Rose Brannon, Ezra Rosen, David Brown, Charles Rudin, Nitya Raj, Mark G. Kris, Jorge Reis-Filho, Mark Donoghue, Alexander E. Drilon, Noura J. Choudhury. Comprehensive clinical and genomic analysis for patients with MYC, MYCN, and MYCL amplified solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1394.