Associations of Age With Tumor Genomic Characteristics in Relapsed/Refractory Cancers Interrogated With the NCI-MATCH Trial Targeted Gene Panel Assay

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Abstract
PURPOSE: Motivated by the rising incidence of cancers at younger ages, this study compares tumor genomic alterations between adolescents and young adults (AYAs; 18-39 years) and non-AYAs (40 years and older) and explores the relationship with continuous age in patients with relapsed/refractory ovarian, breast, and colorectal cancers accrued to the NCI-MATCH trial. METHODS: Tumor genomic profiles generated by a next-generation sequencing 143-gene panel (NCI-MATCH assay, v2) were analyzed for association with age (AYA/total: 21/455 ovarian, 27/576 breast, 43/759 colorectal cancers). For each gene, AYA and non-AYA DNA alteration proportions were compared (Fisher exact test) and alteration association with continuous age (logistic regression) was evaluated (false discovery rate‑adjusted P value <.1 statistically significant). For colorectal cancer, sex-stratified analysis was also performed. RESULTS: No significant AYA versus non-AYA differences were observed in the prevalence of gene mutations (single nucleotide variant [SNV]/indel). A significant association of gene amplification with AYAs (odds ratio [OR], 95% CI) was CCND1 (0.2, 0.1-0.4), favoring AYAs in breast cancer. Examining age as a continuous variable, significant associations of gene mutations (SNV/indel) with older age, expressed as 5-year OR (OR [95% CI]), were observed: TP53 (1.3 [1.1 to 1.4]), ovarian cancer; CDH1 (1.4 [1.2 to 1.6]) and PIK3CA (1.1 [1.1 to 1.2]), breast cancer; and BRAF (1.4 [1.2 to 1.7]), female colorectal cancer. Associations with younger age included SMAD4 (0.8 [0.7 to 0.9]), male colorectal cancer. Significant associations of gene amplification with age (continuous) were as follows: CCNE1 (1.3 [1.1 to 1.6]), older ovarian cancer, and CCND1 (0.8 [0.8 to 0.9]), younger breast cancer. CONCLUSION: Comparing AYAs with non-AYAs among patients having relapsed/refractory disease, no significant differences in SNV/indel prevalence were observed, but CCND1 amplifications were more prevalent in AYA breast cancer. For several genes, DNA alterations were associated with continuous age and may depend on sex in colorectal cancer.

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