ABSTRACT Background Serum antibodies to the Merkel oncoprotein (AMERK) are detectable in approximately 50% of patients with Merkel cell carcinoma (MCC) and can be used to monitor for recurrence. The ...objective of this study was to characterize AMERK levels in patients receiving curative‐intent radiation therapy (RT) for MCC and identify associations between AMERK and recurrence. Methods This was a retrospective study of patients with MCC who had baseline AMERK measurements before they received curative‐intent RT from 2010 to 2020. Event‐free survival (EFS) was calculated using the Kaplan–Meier method and Cox regression. The cumulative incidence of MCC‐related recurrence (CIMR) was analyzed with death as a competing risk and the Gray test. Results The authors identified 88 patients who had baseline AMERK measurements, including 52 (59%) with detectable levels. AMERK positivity was associated with younger median age (67.8 vs. 72.0 years; p = .02) and tumor site ( p = 0.02), with lower rates for those who had disease in the head/neck region (17.3% vs. 44.4%). EFS (71.3% vs. 60.4%; p = .30) and CIMR (24.4% vs. 39.6%; p = .23) were more favorable in AMERK‐positive patients. Two patients had recurrences in the RT field, and both were AMERK‐negative at baseline. The median time to AMERK nadir after RT was 11.2 months; and, in a 6‐month post‐RT landmark analysis, the proportion of patients who were AMERK‐positive who became negative or who had levels that decreased by ≥50% were not associated with EFS (87.1% vs. 85.0%; p = .90) or CIMR (12.9% vs. 15.0%; p = .62). Conclusions Positive AMERK baseline levels were correlated with younger age at MCC diagnosis and nonhead and neck tumor location, possibly related to the distribution of viral etiology. A specific post‐RT AMERK decline correlating with EFS could not be identified.
Merkel cell oncoprotein antibodies (AMERK) positivity was correlated with other known features of Merkel cell polyomavirus‐associated Merkel cell carcinoma, including nonhead and neck site, younger age, and more favorable cancer outcomes. Among patients who had AMERK‐positive disease, male sex was associated with recurrence, but no specific decrease in AMERK levels after radiation therapy was associated with event‐free survival.
Background
Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody ...test (AMERK) has shown potential for indicating better recurrence‐free survival in a single‐institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden.
Methods
A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level.
Results
Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event‐free, overall, and MCC‐specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation.
Conclusion
Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations.
Plain Language Summary
Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited.
A blood test called anti‐Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues.
In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis.
We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages.
However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.
In this retrospective study of 261 Merkel cell carcinoma (MCC) patients, the authors found that initial anti‐Merkel cell panel (AMERK) seropositivity was linked to improved recurrence, event‐free, overall, and MCC‐specific survival, particularly in patients with localized disease. This suggests the AMERK test could be key in risk stratification and tailoring management for MCC, despite the study’s limitations due to its retrospective and exploratory nature.
Abstract The Hippo pathway, a pivotal regulator orchestrating organ size and tissue growth, has emerged as a central player in cancer biology. The downstream transcription factor YAP within this ...pathway has been implicated in diverse oncogenic processes. YAP activation contributes to drug resistance, metastasis, and poor clinical outcomes in many solid tumors. Conversely, YAP exhibits growth-suppressive effects in neuroendocrine (NE) solid cancers, a paradox that remains poorly understood. Analysis of RNAseq data from the Cancer Cell Line Encyclopedia (CCLE) revealed a distinct classification of tumors into YAP1-expressing (YAPon) and non-expressing (YAPoff) subgroups, with hematopoietic malignancies and NE solid tumors featured prominently in the latter. Merkel cell carcinoma (MCC) is a rare, high-grade, NE carcinoma of the skin with two distinct etiologies. Virus-positive MCC contains integrated Merkel cell polyomavirus that expresses the viral T antigens and virus-negative MCC caused by sunlight exposure and extensive UV damage. Bulk RNAseq performed with more than 60 MCC tumors revealed that YAP expression displayed an inverse correlation with an NE gene expression signature. To gain insight into why YAP expression is so low in MCC, we generated MCC cell lines with inducible expression of YAP. Expression of YAP led to growth arrest and cell death. We performed a genome-wide CRISPR-Cas9 screen to identify genes that when lost enable MCC cells to tolerate YAP expression. Functional enrichment analysis of the positively selected genes uncovered a variety of signaling pathways. Intriguingly, the CRISPR screen revealed a positive enrichment of non-canonical BAF complex members, including BRD9 and SMARCD1. To validate this finding, we treated MKL-1 cells with a BRD9 inhibitor, observing a substantial reduction in YAP toxicity. These findings open avenues for the development of targeted therapeutic strategies for high grade NE cancers, addressing a critical gap in our understanding of YAP biology in the context of MCC and beyond. Citation Format: Furkan Bahar, Thomas C. Frost, Varsha Ananthapadmanabhan, Julia L. Schnabel, Manisha Thakuria, James A. DeCaprio. Unraveling the mechanism of YAP toxicity in neuroendocrine solid tumors: Insights from Merkel cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3042.
In clinical trials, preoperative immune checkpoint inhibitors (ICIs) have shown clinical activity in advanced cutaneous squamous cell carcinoma (cSCC). However, these studies excluded patients with ...relevant comorbidities.
To evaluate radiologic and pathologic response rates to neoadjuvant-intent programed cell death protein 1 (PD-1) ICIs in a clinical population.
This cohort study of patients who were treated with neoadjuvant cemiplimab or pembrolizumab for advanced cSCC from January 2018 to January 2023 was conducted at 2 academic institutions in Boston, Massachusetts. Median follow-up was 9.5 months (range, 1.2-40.5).
Cemiplimab or pembrolizumab.
Primary outcomes were radiologic and pathologic response rates. Secondary outcomes were 1-year recurrence-free survival, progression-free survival, disease-specific survival, and overall survival.
This cohort study included 27 patients (including 9 patients 33.3% with a history of lymphoma). Most patients were male (18 of 27 66.7%), with a median age of 72 years (range, 53-87 years). Most primary tumors were located on the head/neck (21 of 27 77.8%). There were no unexpected delays in surgery. The median number of doses before surgery was 3.5 (range, 1.0-10.0). Five patients (18.5%) ultimately declined to undergo planned surgery due to clinical responses or stability, and 1 (3.7%) did not undergo surgery due to progressive disease. The overall pathologic response rate (pathological complete response pCR or major pathological response) was 47.4% (9 of 19), and the overall radiologic response rate (radiologic complete response or partial response) was 50.0% (8 of 16). The pCR rate (7 of 19 36.8%) was higher than the radiologic complete response rate (2 of 16 12.5%). The pCR rate among patients with cSCC and concomitant lymphoma was 25.0%. The 1-year recurrence-free survival rate was 90.9% (95% CI, 50.8%-98.7%), progression-free survival was 83.3% (95% CI, 27.3%-97.5%), disease-specific survival was 91.7% (95% CI, 53.9%-98.8%), and overall survival was 84.6% (95% CI, 51.2%-95.9%).
The results of this cohort study support the reproducibility of neoadjuvant-intent immunotherapy for cSCC in the clinical setting, including for patients with a history of lymphoma. Outside of clinical trials, it is not infrequent for patients to opt out of surgery for regressing tumors. The inclusion of higher-risk patients and preference for nonsurgical treatment are 2 factors that might explain the numerically lower pathologic response rate in this institutional experience.
Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer ...phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling.
Merkel Cell Carcinoma: A Population Analysis on Survival Sridharan, Vishwajith; Muralidhar, Vinayak; Margalit, Danielle N ...
Journal of the National Comprehensive Cancer Network,
10/2016, Letnik:
14, Številka:
10
Journal Article
Recenzirano
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy. However, factors associated with disease presentation and outcomes remain uncertain, especially in light of recent changes in ...workup, such as sentinel lymph node biopsy. Therefore, this study used the SEER database to examine factors that could affect stage at presentation and treatment.
We identified 4,543 patients and evaluated associations between sex, race, age, primary disease site, disease presentation, and treatment. We also used univariate and multivariate analyses to examine the effect of these factors on disease-specific survival (DSS) and overall survival (OS). We specifically conducted subgroup analyses on a more modern cohort of patients with MCC treated between 2006 and 2012.
Male sex, older age, larger tumor size, and primary tumors of the scalp, neck, or trunk were associated with a higher burden of nodal disease. Multivariate predictors of worse DSS/OS in both the recent and overall cohort included age older than 75 years, number of lymph nodes involved, tumors greater than 5 cm, metastatic disease, or lack of radiation therapy. The number of involved nodes was the best predictor of DSS/OS. Associations with radiation therapy were most pronounced in patients with nodal disease and those not undergoing surgery.
Sex, age, tumor size, and primary site of disease correlated with burden of nodal disease in MCC. Associations between disease presentation and treatment strategies such as radiation and DSS and OS have remained relatively constant in the modern era from 2006 to 2012 compared with findings from prior studies.
Merkel cell carcinomas (MCCs) are rare but highly malignant skin cancers associated with a recently described polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory, ...and regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T-cell activation, proliferation, enhanced cytokine production, and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes showed TCR repertoire skewing and upregulation of CD137. MCC tumors implanted into immunodeficient mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting that tumor-specific T cells capable of controlling tumor growth were present in MCC. Both CD4+ and CD8+ FOXP3+ regulatory T cells were frequent in MCC. Fifty percent of nonactivated T cells in MCC-expressed PD-1, a marker of T-cell exhaustion, and PD-L1 and PD-L2 were expressed by a subset of tumor dendritic cells and macrophages. In summary, we observed tumor-specific T cells with suppressed activity in MCC tumors. Agents that stimulate T-cell activity, block regulatory T cell function, or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer.
PURPOSE Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, ...observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 95% CI, 2.7 to 20). CONCLUSION ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.
•Efficacy of hypofractionated radiotherapy for Stage I-III Merkel cell carcinoma is not well-described.•There was no difference in cumulative incidence of in-field locoregional relapse or ...MCC-specific survival between hypofractionated and conventionally-fractionated radiotherapy.•On multivariable analysis, immunosuppression, clinical stage III disease, and lymphovascular invasion were associated with any recurrence when controlling for sex, age, and hypo-RT.
Limited data exists regarding the efficacy of curative hypofractionated radiotherapy (hypo-RT) regimens compared to conventionally-fractionated radiotherapy (conv-RT) for Merkel cell carcinoma (MCC).
A retrospective analysis of 241 patients diagnosed with non-metastatic MCC from 2005-2021 and who received RT at Dana-Farber/Brigham & Women’s Cancer Center. The primary outcome was cumulative incidence of in-field locoregional relapse using Gray’s test with competing risks of death and isolated out-of-field recurrence. Secondary outcomes included overall survival (OS) and MCC-specific survival using log-rank tests, and risk factors of recurrence using Cox-proportional hazards regression.
There were 50 (20.6 %) and 193 (79.4 %) courses of hypo-RT and conv-RT, respectively. The hypo-RT cohort was older (≥73 years at diagnosis: 78.0 % vs 41.5 %, p < 0.01), and received a lower equivalent total RT dose in 2 Gy per fraction (<50 Gy: 58.0 % vs 5.2 %, p < 0.01). Median follow-up was 65.1 months (range: 1.2–194.5) for conv-RT and 25.0 months (range: 1.6–131.3) for hypo-RT cohorts. Two-year cumulative incidence of in-field locoregional relapse was low in both groups (1.1 % conv-RT vs 4.1 % hypo-RT, p = 0.114). While two-year OS was lower for the hypo-RT group (62.6 % vs 84.4 %, p = 0.0008), two-year MCC-specific survival was similar (84.7 % vs 86.6 %, p = 0.743). On multivariable analysis, immunosuppression, clinical stage III disease, and lymphovascular invasion were associated with any-recurrence when controlling for sex, age, and hypo-RT.
There was no difference in cumulative incidence of in-field locoregional relapse or MCC-specific survival between hypo-RT and conv-RT. Prospective studies are needed to confirm hypo-RT as an efficacious treatment option for MCC.
Background
This study sought to determine the efficacy and safety profile of cabozantinib in patients with advanced Merkel cell carcinoma (MCC).
Experimental Design
This prospective, phase II, ...single‐institution trial enrolled patients with platinum‐failure, recurrent/metastatic MCC to receive cabozantinib 60 mg orally daily until disease progression, withdrawal from study, or severe toxicity. The primary endpoint was disease control rate. Secondary endpoints included overall survival (OS), progression‐free survival (PFS), and toxicity. Immunohistochemistry for VEGFR‐2, MET, and HGF expression and next‐generation sequencing of tumor tissue were performed and correlated with outcome.
Results
Eight patients were accrued from January 24, 2014, to June 8, 2016. The study was closed prematurely because of toxicity and lack of responses. The most frequent adverse events were grades 1 and 2 and included anorexia, fatigue, nausea, hypothyroidism, and dysgeusia. Two patients developed nonhealing, painful ulcers and tumor‐skin fistula. One patient had stable disease for 8 months. One patient withdrew from the study after 2 weeks of therapy because of adverse events. Three patients required dose reduction because of toxicity. Median PFS and OS were 2.1 and 11.2 months, respectively. No expression of MET, HGF, or VEGFR‐2 was identified in tumor cells by immunohistochemistry of patients’ tissue samples.
Conclusion
Cabozantinib was poorly tolerated and did not demonstrate activity in patients with recurrent/metastatic, platinum‐failure MCC. It is unclear whether preselection of patients with the specific upregulation or genetic alteration in the targets for cabozantinib would have changed the results of this study. (Clinical trial identification number: NCT02036476)
Implications for Practice
This phase II study demonstrated poor tolerability and lack of activity of cabozantinib in an unselected group of patients with advanced Merkel cell carcinoma. Although it is unclear whether preselection of patients with the specific upregulation and genetic alterations in targets for cabozantinib would have changed the results of this study, this would have likely led to an extremely rare patient population that would take many years to accrue.
Merkel cell carcinoma is a rare and aggressive neuroendocrine skin cancer, with a rising incidence. This article evaluates the feasibility of using cabozantinib in patients with advanced Merkel cell carcinoma whose disease failed platinum‐based therapy.
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