The clinical significance of adenomatous polyposis coli (APC) and catenin Beta 1 (CTNNB1) genetic aberrations in patients with melanoma

Background Melanoma-intrinsic activated β-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). Methods We examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. Results In the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated β-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases. Conclusions APC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry

(1) Background: Immune checkpoint inhibitors have improved the prognosis of patients with advanced melanoma. Published data suggested that the objective response rates appear to be superior in patients who developed immune-related adverse events (irAEs). (2) The primary aim of this cohort study was to evaluate the association between irAEs and disease control rate in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. (3) Among 319 patients, 53% experienced at least one irAE. A higher percentage of patients with irAEs had disease control compared to those without irAEs (69.8% vs. 49.3%). In multivariate analysis, development of grade 3 and 4 irAEs was significantly associated with a protective effect for the outcome primary resistance (OR: 0.40 95% CI 0.23–0.70, p = 0.001). The presence of any grade irAEs was significantly associated with longer OS (irAEs grade 1–2 HRadj: 0.61 95% CI: 0.4–0.93, p = 0.02, irAEs grade 3–4 HRadj: 0.55 95% CI 0.31–0.99, p = 0.04), but not with PFS (irAEs grade 1–2 HRadj: 1.21 95% CI: 0.91–1.79, p = 0.16, irAEs grade 3–4 HRadj: 1.14 95% CI 0.83–2.02, p = 0.24). (4) The presence of irAEs with laboratorial expression is positively associated with response and OS, suggesting that irAEs might be a predictive factor in this setting.

591 Survival rates in Stage IV melanoma patients treated with radiation and immunotherapy differ depending on age and radiation treatment site

BackgroundMelanoma is difficult to treat due to its propensity of evading the immune system. Radiation can be combined with immune checkpoint inhibitors to potentially prolong survival. Radiation has been shown to reduce tumor sizes both at the site of radiation and at non-irradiated lesions, also known as the abscopal effect. However, the interaction of immunotherapy and radiation treatment in melanoma cancer is not well-defined. This study seeks to better characterize factors influencing survival in Stage IV melanoma patients treated with both radiation and immunotherapy.MethodsRetrospective data was collected from melanoma patients receiving both radiation and immunotherapy within 6 months of each other between 2008–2021 at our institution. Patient and treatment characteristics were examined for their influence on overall survival and progression-free survival using the log-rank test on Kaplan Meier survival curves. Radiographic response was assessed according to PERCIST/RECIST criteria and analyzed against patient/treatment characteristics using the Mann-Whitney U Test. For the abscopal effect, the percent changes both before and after radiation treatment were subtracted in non-irradiated lesions to produce a ”delta-delta” percent change to reflect the rate of change in tumor response to radiation treatment.ResultsYounger patients trended towards worse overall (p=0.141) and progression free (p=0.06) survival as well as less favorable PERCIST/RECIST response to radiation (p=.0562) compared to older patients. Combination CTLA-4 and PD-1 inhibition therapy tended to produce better PERCIST/RECIST tumor response (p=0.09), but it did not significantly affect survival times. In addition, there was some lower overall (p=0.22) and significantly lower progression free (p=0.012) survival among patients with intracranial irradiated lesions. However, no difference was found in PERCIST/RECIST response in the irradiated lesions between the intra- or extracranial groups. Non-irradiated lesions in patients with extracranial irradiated lesions had a pattern of less favorable rate of change in tumor size (p=0.16).ConclusionsLower survival times in younger patients is unexpected and may reflect differences in immunotherapy response in patients receiving both radiotherapy and immunotherapy, which requires further investigation. Combination CTLA-4 and PD-1 inhibition therapy correlating with better tumor response confirms the effect is still present in this cohort receiving radiotherapy. The lower survival times among intracranial lesion patients is most likely due to lower expectancy of brain metastasized patients; however, it could also be the brain is less responsive to immunotherapy. Further research in a larger cohort is needed for deeper analysis, but this series is still comparable in size to other published series.Ethics ApprovalThis retrospective review was approved by the University IRB, UMCIRB 15-001726. Consent of participants was waived due to the retrospective nature of this review.