Zihan Wei

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.

Subprotocol C1: Adverse Events Related to Treatment.

Subprotocol C1 co-occurring mutation plot

Subprotocol C1: Details on Cases with Confirmed PR or PFS >6 months

Subprotocol C2 co-occurring mutation plot

Subprotocol C2: Adverse Events Related to Treatment

Purpose:The NCI-MATCH trial enrolled patients to subprotocols C1 and C2 to evaluate the METtyrosine kinase inhibitor crizotinib for efficacy in patients with MET amplification (METamp; C1) or MET exon 14 skipping mutation (METex14; C2).Patients and Methods:Tumors harboring METamp or METex14 were confirmed by Oncomine assay, RNA sequencing, and anchored multiplex PCR. Patients received 250 mg crizotinib orally daily until disease progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS).Results:C1 efficacy analysis comprised 28 of 44 enrolled patients (17 gastrointestinal, seven lung, and four other tumor types). Four patients had a partial response (PR), 10 had stable disease (SD), and 13 had progressive disease (PD); one was unevaluable. The ORR was 14% [four of 28; 90% confidence interval (CI), 5%–29.8%]. The median PFS (mPFS) was 3.4 months (90% CI, 1.8–3.7), and the median OS (mOS) was 7.1 months (90% CI, 5–11.5). C2 included 14 of 20 patients (five gastrointestinal, six lung, and three other). Two patients had PR, four SD (2 > 6 months), and four PD were observed. The ORR was 14% (two of 14; 90% CI, 2.6%–38.5%). mPFS and mOS were 2 months (90% CI, 1.4–4.1) and 10.2 months (90% CI, 2.3–19.6). METex14 cases with read count ≥50,000 had mPFS 8.8 months [90% CI, 2.1–NR(not reached)] versus 1.7 months (90% CI, 1.1–3.7).Conclusions:Crizotinib demonstrated clinical activity across tumors with METamp and METex14. Subprotocol C1, but not C2, met its primary endpoint. In METex14 disease, a read count cutoff >50,000 may help distinguish true pathogenic variants from low-level splice transcripts and enable more accurate classification.

Representativeness of Study Participants