Using data from The Cancer Genome Atlas (TCGA), Alhalabi et al. determined that 26% of muscle-invasive urothelial cancer cases harbored a homozygous deletion of MTAP, which was consistent with immunohistochemistry analysis of patient-derived tumor tissues. Importantly, there was no difference in MTAP loss between early- and late-stage cancers, therefore suggesting that this is an early event. Next, the investigators analyzed data from 21 pemetrexed-treated patients with urothelial cancer in a historical cohort and an ongoing cohort. In the former, four patients had MTAP deficiency while ten were MTAP proficient, and in the latter, all seven patients had MTAP deficiency. Cisplatin-based chemotherapy had been given to 76% of patients prior to the study and 47% had received at least two lines of prior therapy. In the historical cohort analysis, all MTAP deficient patients showed an objective response to pemetrexed while only one of MTAP proficient patients showed an objective response. The prospective study by Alhalabi et al. was terminated early in favor of the patients starting treatment in another trial with pemetrexed and anti-PD-L1. The overall response rate to pemetrexed was 42%. In terms of safety, there were no grade 4 or 5 adverse effects from treatment and the most common adverse effect was anemia.
Alhalabi et al. then tested the effect of pemetrexed on MTAP deficient or proficient urothelial cancer cell lines showing significantly lower cell viability in MTAP deficient cell compared to MTAP proficient cell lines. Pemetrexed increased DNA double-strand breaks in MTAP deficient cell lines compared to MTAP proficient cell lines. In vivo experiments using xenograft models of urothelial cancer also showed that MTAP deficient xenografts were more sensitive to pemetrexed. To examine whether these findings could be extended to other tumor types. Alhalabi et al. examined the clinical and RNA expression data from 72 patients with lung adenocarcinoma who were treated with pemetrexed-based chemotherapy in the BATTLE-2 trial. Objective responses were significantly higher in the MTAP deficient (and CDKN2A deficient) patients compared to other patients (54% versus 24%, respectively). In a generalized linear model, none of the assessed genes showed a significant effect on response to treatment except MTAP.
These findings highlight the interplay between MTAP status and response to pemetrexed treatment in patients with urothelial cancer. While the sample size in the present study was small and there were various confounding factors in patients from the historical cohort, planned follow up studies by the investigators aim to validate these findings and will explore combinations of pemetrexed and anti-PD-L1 blockade in MTAP deficient urothelial cancers.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York
References:
- Alhalabi O, Chen J, Zhang Y, et al. MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers. Nat Commun. 2022;13(1):1797. Published 2022 Apr 4. doi:10.1038/s41467-022-29397-z
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