Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas

Shoushtari, Alexander N.; Chatila, Walid K.; Arora, Arshi; Sánchez-Vega, Francisco; Kantheti, Havish S.; Zamalloa, Jorge A. Rojas; Krieger, Penina; Callahan, Margaret K.; Warner, Allison Betof; Postow, Michael A.; Momtaz, Parisa; Nair, Suresh; Ariyan, Charlotte E.; Barker, Christopher A.; Brady, Mary Susan; Coit, Daniel G.; Rosen, Neal; Chapman, Paul B.; Busam, Klaus J.; Solit, David B.; Panageas, Katherine S.; Wolchok, Jedd D.; Schultz, Nikolaus

doi:10.1158/1078-0432.ccr-20-4189

Cited by 35 publications

(31 citation statements)

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“…Moreover, a treatment with MEK inhibitors could lead to a survival benefit of NRAS -mutant patients [ 16 ]. Shoushtari et al showed an inferior response of NRAS p.Q61 mutant melanoma to anti-PD-1 monotherapy and a trend towards inferior response to a combination of ipilimumab and nivolumab in cutaneous melanoma [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma

Freiberger

Turko

Hüllner

et al. 2021

Cancers

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Mucosal melanoma can be driven by various driver mutations in genes such as NRAS, KIT, or KRAS. However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in JAK1/2, B2M, or STK11, a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the NRAS clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to NRAS in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging NRAS mutant clones and immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma

Freiberger

Turko

Hüllner

et al. 2021

Cancers

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“…The hazard ratio (HR) of PFS in 2 studies ( 16 , 17 ) and overall survival (OS) in 2 studies ( 14 , 17 ) were 0.73 (95% CI: 0.58-0.93, I 2 = 0%, P=0.930; Figure 2C ) and 1.01 (95% CI: 0.52-1.96, I 2 = 89.3%, P=0.002; Figure 2D ), respectively. However, studies with opposite results were not included because of different objectives, such as TTF ( 18 ). As a result, no confirmatory conclusion can be drawn from this meta-analysis, which demonstrated the controversial results of different published studies.…”

Section: Resultsmentioning

confidence: 99%

“…In the Asian population predominantly with acral and mucosal melanoma, the ORR of NRAS mutant patients was only 6.1% (1/16) to anti-PD-1 monotherapy (7). In a recent study of MAPK pathway alteration in cutaneous and unknown primary melanomas, time to treatment failure (TTF) was shorter for patients with NRAS Q61 mutations (18). We performed a systemic meta-analysis based on the relevant studies.…”

Section: Discussionmentioning

confidence: 99%

“…Six retrospective studies and 1 randomized clinical trial were relevant to our analyses (11)(12)(13)(14)(16)(17)(18). Study design, drug, number of patients, efficacy of immunotherapy (ORR, DCR, PFS, OS, TTF, et al) for NRAS mutant and wild-type advanced melanoma patients, and univariate and multivariate factors analyzed along with NRAS status were listed in Supplementary Table S1.…”

Section: Meta-analysismentioning

confidence: 99%

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Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

et al. 2021

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BackgroundAnti-PD-1 monotherapy is the standard therapy for advanced melanoma patients, including those with NRAS mutations. The influence of NRAS mutation on immunotherapy, especially in noncutaneous melanoma, is largely uncharacterized.Materials and MethodsWe analyzed clinical data of four clinical trials for advanced melanoma patients treated with anti-PD-1 monotherapy between 2016 and 2019. The impact of NRAS mutation on efficacy and outcome of immunotherapy were analyzed in cutaneous and noncutaneous groups separately.ResultsA total of 206 patients were assessed, including 92 cutaneous melanoma patients with 12 NRAS mutations and 114 noncutaneous melanoma patients with 21 NRAS mutations. In cutaneous melanoma, the response rates of NRAS mutant patients were lower than patients without NRAS mutations (9.5% vs. 23.9%), the median progression-free survival (PFS) and median overall survival (OS) were shorter for patients with NRAS mutations, although without significant difference for OS (P=0.081). In noncutaneous melanoma, the response rates were 0 and 13.7% for NRAS mutant and wild-type patients, the median PFS were 3.6 months (95% CI: 0.9-6.3) and 4.3 months (95%CI: 2.9-5.7) (P=0.015), and the median OS were 10.8 months (95% CI: 1.5-20.1) and 15.3 months (95% CI: 13.2-17.4) (P=0.025), respectively. In multivariate analysis, NRAS mutation, along with ECOG performance score and LDH level, was negatively associated with both PFS (HR 1.912, P=0.044) and OS (HR 2.210, P=0.025) in noncutaneous melanoma.ConclusionIn advanced Asian melanoma treated with anti-PD-1 monotherapy, NRAS mutant patients had lower response rates and poorer prognoses compared to wild-type patients, especially in noncutaneous subtypes.

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“…A total of 4,859 patients (22.5%) with metastatic sites extracted through manual chart review and previously published were available (Abida et al, 2017; Jones et al, 2021; Razavi et al, 2018; Shoushtari et al, 2021; Yaeger et al, 2018). Ten tumor types were represented including the most frequent (prostate, lung, breast, colorectal, and melanoma).…”

Section: Methodsmentioning

confidence: 99%

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Nguyen

Fong

Luthra

et al. 2021

Preprint

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Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.

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Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas

Cited by 35 publications

References 31 publications

Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma

Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma

Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

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