PD-1 blockade in deficient mismatch repair mixed adenoneuroendocrine carcinoma of the stomach: new hope for an orphan disease

Riccò, B.; Salati, Massimiliano; Bonetti, Luca Reggiani; Dominici, Massimo; Luppi, Gabriele

doi:10.1177/0300891620952845

Cited by 5 publications

(3 citation statements)

References 10 publications

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“…Tumour MSI-H/dMMR status as well as high-TMB (≥10 mut/Mb) are known predictive biomarkers of response to CPIs, leading to tissue agnostic FDA approvals of CPIs for progressing solid tumours [44][45][46]. In terms of PDNECs specifically, beyond our clinical trial, there are anecdotal reports of response to CPIs in high-TMB and/or MSI-H EP-PDNECs [47][48][49][50][51][52]. A subset of treated tumours (N = 28) in this study were tested for MSI and dMMR, and no tumours were MSI-H/dMMR.…”

Section: Discussionmentioning

confidence: 99%

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas

et al. 2023

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BACKGROUND:To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarkerunselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. Primary endpoint: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.

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Section: Discussionmentioning

confidence: 99%

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas

et al. 2023

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“…However, adjuvant treatments for these two components are largely different ( 31 ). In addition, although some molecular targeted drugs and immunotherapies have been preliminary used to treat MiNENs, the evidence of efficacy is limited, and therefore, their roles in MiNENs need further exploration which is beyond the scope of this study ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs): A SEER database analysis of 767 cases

et al. 2023

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BackgroundMixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is an extremely rare entity, consisting of neuroendocrine and non-neuroendocrine components. It can occur in various organs throughout the body, with a rising incidence. Its clinical management is a rapidly growing field of interest; however, large-scale patient cohorts are still missing to guide clinical practice.Patients and methodsThe demographic, clinicopathological, and survival information of all patients diagnosed with MiNEN in the national Surveillance, Epidemiology, and End Results (SEER) program database (2000–2017) were extracted and further analyzed. The information of the patients before and after 2010 was compared to understand the epidemiological changes of MiNEN. The characteristics of MiNEN originating in different organs were compared. The clinical significance of surgical resection for metastatic MiNENs was also analyzed.ResultsA total of 1081 patients were screened, and after applying the exclusion criteria, 767 patients were finally analyzed. There was no obvious sex preference (49.2% vs 50.8%, p>0.05) and the majority of the patients were Caucasians (n=627, 81.7%). A total of 88.3% of the patients were older than 50 years old, and the median age was 60 years. 79.3% of the tumors are located in the distal digestive tract, and 67.7% were grade 3/4. Distant metastasis was presented in 33.9% of the patients at diagnosis. A total of 88% of the patients underwent surgical treatments. The number of patients increased 10-fold between 2000 and 2017. There was no significant difference in sex, race, stage, or surgical treatments among the patients diagnosed before and after 2010. More patients older than 60 years were diagnosed after 2010 (p=0.009). The median survival was 61.0 ± 9.8 months for the whole cohort. After multivariate analysis, older age (>60 years, p<0.01), more advanced stage (p<0.01), grade 3/4 (p<0.01), and non-surgical treatment (p<0.01) were independent risk factors for poorer survival. The appendiceal MiNENs showed the best prognosis. A total of 260 metastatic MiNENs were further analyzed. Only patients with metastatic MiNENs originating from the appendix had a potential benefit from surgical resection, compared to other sites (p=0.05).ConclusionThis study provides the epidemiological, clinicopathological, and survival information of the largest number of MiNEN patients. Although MiNEN is an extremely rare malignant neoplasm, its incidence increases rapidly. The majority of the patients suffered from advanced-stage disease, which highlights the need for improvement of early detection in the future. The appendix is the most common primary site of MiNEN, and surgical resection for selected metastatic MiNEN originating in the appendix has favorable survival outcomes.

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“…Currently, MSI and MMR protein deficiency have been explored in different malignancies, particularly to address an indication of ICPI [82][83][84][85][86][87][88]. Exploring the MMR/MSI status should become the new standard in poorly differentiated NEN, regardless of germline mutations consistent with LS [85][86][87][88].…”

Section: Nen and Mmr/msi Assessmentmentioning

confidence: 99%

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes–Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond

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Turturea

Turturea³

et al. 2023

Diagnostics

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DNA damage repair pathways, including mismatch repair (MMR) genes, are prone to carcinoma development in certain patients. The assessment of the MMR system is widely recognized as part of strategies concerning solid tumors (defective MMR cancers), especially MMR proteins (through immunohistochemistry), and molecular assays for microsatellite instability (MSI). We aim to highlight the status of MMR genes–proteins (including MSI) in the relationship with ACC (adrenocortical carcinoma) according to current knowledge. This is a narrative review. We included PubMed-accessed, full-length English papers published between January 2012 and March 2023. We searched studies on ACC patients for whom MMR status was assessed, respectively subjects harboring MMR germline mutations, namely Lynch syndrome (LS), who were diagnosed with ACC. MMR system assessments in ACCs involve a low level of statistical evidence. Generally, there are two main types of endocrine insights: 1. the role of MMR status as a prognostic marker in different endocrine malignancies (including ACC)—which is the topic of the present work, and 2. establishing the indication of immune checkpoint inhibitors (ICPIs) in selective, mostly highly aggressive, non-responsive to standard care forms upon MMR evaluation (which belongs to the larger chapter of immunotherapy in ACCs). Our one-decade, sample-case study (which, to our knowledge, it is the most comprehensive of its kind) identified 11 original articles (from 1 patient to 634 subjects per study diagnosed with either ACC or LS). We identified four studies published in 2013 and 2020 and two in 2021, three cohorts and two retrospective studies (the publication from 2013 includes a retrospective and a cohort distinct section). Among these four studies, patients already confirmed to have LS (N = 643, respective 135) were found to be associated with ACC (N = 3, respective 2), resulting in a prevalence of 0.0046%, with a respective of 1.4% being confirmed (despite not having a large amount of similar data outside these two studies). Studies on ACC patients (N = 364, respective 36 pediatric individuals, and 94 subjects with ACC) showed that 13.7% had different MMR gene anomalies, with a respective of 8.57% (non-germline mutations), while 3.2% had MMR germline mutations (N = 3/94 cases). Two case series included one family, with a respective four persons with LS, and each article introduced one case with LS-ACC. Another five case reports (between 2018 and 2021) revealed an additional five subjects (one case per paper) diagnosed with LS and ACC (female to male ratio of 4 to 1; aged between 44 and 68). Interesting genetic testing involved children with TP53-positive ACC and further MMR anomalies or an MSH2 gene-positive subject with LS with a concurrent germline RET mutation. The first report of LS-ACC referred for PD-1 blockade was published in 2018. Nevertheless, the use of ICPI in ACCs (as similarly seen in metastatic pheochromocytoma) is still limited. Pan-cancer and multi-omics analysis in adults with ACC, in order to classify the candidates for immunotherapy, had heterogeneous results, and integrating an MMR system in this larger and challenging picture is still an open issue. Whether individuals diagnosed with LS should undergo surveillance for ACC has not yet been proven. An assessment of tumor-related MMR/MSI status in ACC might be helpful. Further algorithms for diagnostics and therapy, also taking into consideration innovative biomarkers as MMR-MSI, are necessary.

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PD-1 blockade in deficient mismatch repair mixed adenoneuroendocrine carcinoma of the stomach: new hope for an orphan disease

Cited by 5 publications

References 10 publications

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas

Comprehensive analysis of mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs): A SEER database analysis of 767 cases

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes–Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond

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