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Characterization of genetics in patients with mucosal melanoma treated with immune checkpoint blockade
Elizabeth I Buchbinder1,2,3, Jason L Weirather1, Michael Manos1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract:
Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana-Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor-genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population.
Insights
Mucosal melanoma (MM) has lower response rates to immune checkpoint blockade (ICB) than other melanomas. This study found low tumor mutational burden in MM and no significant correlation between common gene mutations and ICB response.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Mucosal melanoma (MM) is a rare subtype of melanoma with distinct genetic profiles.
- While immune checkpoint blockade (ICB) is a treatment for MM, response rates are suboptimal compared to cutaneous melanoma.
- Understanding the genomic landscape of MM is crucial for improving treatment strategies.
Purpose of the Study:
- To investigate the genomic alterations in mucosal melanoma.
- To correlate tumor genotype with response to immune checkpoint blockade (ICB) in MM patients.
- To compare the genetic profile of MM with that of cutaneous melanoma.
Main Methods:
- Targeted sequencing (OncoPanel) of 447 genes was performed on 46 MM tumors from patients treated with ICB.
- Tumor genotypes were analyzed alongside clinical response data, including durable clinical benefit (DCB).
- Comparative genomic analysis was conducted on additional MM and cutaneous melanoma cohorts.
Main Results:
- The average mutational burden in MM was low (6.23 mut/Mb) and did not correlate with ICB response.
- SF3B1, KIT, and NF1 were the most frequent mutations in MM, differing from cutaneous melanoma profiles.
- Patients with KIT aberrations showed a trend towards higher DCB rates (71% vs. 28%), but this was not statistically significant.
Conclusions:
- Mucosal melanoma exhibits a distinct genetic profile with low mutational burden.
- Current genetic markers, including KIT aberrations, do not reliably predict response to ICB in MM.
- Further research is needed to identify predictive biomarkers for ICB efficacy in mucosal melanoma.
