A phase 2 evaluation of pembrolizumab for recurrent Lynch‐like versus sporadic endometrial cancers with microsatellite instability

Bellone, Stefania; Roque, Dana M.; Siegel, Eric; Buza, Natália; Hui, Pei; Bonazzoli, Elena; Guglielmi, Adele; Zammataro, Luca; Nagarkatti, Nupur; Zaidi, Samir; Lee, Jungsoo; Silasi, Dan‐Arin; Huang, Gloria S.; Andikyan, Vaagn; Damast, Shari; Clark, Mitchell; Azodi, Masoud; Schwartz, Peter E.; Tymon‐Rosario, Joan; Harold, Justin; Mauricio, Dennis; Zeybek, Burak; Menderes, Gulden; Altwerger, Gary; Ratner, Elena; Alexandrov, Ludmil B.; Iwasaki, Akiko; Kong, Yong; Song, Eric; Dong, Weilai; Elvin, Julia A.; Choi, Jungmin; Santin, Alessandro D.

doi:10.1002/cncr.34025

Cited by 42 publications

(38 citation statements)

References 42 publications

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“…Response to the checkpoint inhibitor pembrolizumab was shown in a few cases with APOBEC and MMR-associated hypermutated breast cancers [ 29 ]. However, even the same mutation signature does not lead to uniform responsiveness to immunotherapy, and variation of the produced total mutation number may still be critical, as shown in the variability of response to pembrolizumab in endometrial cancers with mismatch repair due to Lynch syndrome as compared with sporadic mismatch repair defects [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

High Mutation Burden in ER-Positive/HER2-Negative/Luminal Breast Cancers

Voutsadakis

2022

JCM

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Background: Tumor mutation burden (TMB) is arising as a useful marker of checkpoint inhibitors’ effectiveness in cancer patients in general and has been proposed as predictive in breast cancers. Despite the initial success of checkpoint inhibitors in triple-negative breast cancer, ER-positive breast cancers are less amenable to immunotherapy treatments due to the lower immunogenicity of this subset, associated with lower TMB and less pronounced inflammatory cell infiltration. However, a minority of ER-positive breast cancers do have a higher TMB and could be targets of immune checkpoint inhibitors. Methods: This investigation uses publicly available genomic data to examine ER-positive/HER2-negative or luminal breast cancers with high mutation numbers and compare them with cancers of the same subtype and low mutation numbers. Clinical characteristics and molecular correlates according to mutation numbers are described. Results: ER-positive/HER2-negative and luminal breast cancers with high mutation numbers have a higher prevalence of PIK3CA mutations and in some of the series examined mutations in TP53 and CDH1. A significant proportion of cancers with high mutation numbers carry mutations in microsatellite instability genes and genes involved in DNA damage response. Despite these differences, the prognosis of ER-positive/HER2-negative and luminal breast cancers with high mutation numbers is not significantly different compared to counterparts with lower mutation counts. Conclusions: These data may inform the potential suitability of these cancers for immunotherapy and could guide the development of rational combination therapies based on immune checkpoint inhibitors with other targeted drugs.

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Section: Discussionmentioning

confidence: 99%

High Mutation Burden in ER-Positive/HER2-Negative/Luminal Breast Cancers

Voutsadakis

2022

JCM

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“…Similarly, the scientific understanding of biomarkers predictive of responses is constantly evolving. In endometrial cancers, it is likely in the future that biomarkers will guide further subclassifications by therapeutic agent; recent publications have explored differential responses between patients across the spectrum of MMR deficiencies with pembrolizumab [ 108 , 109 ]. For those who are less likely to have deep, prolonged responses to immunotherapy, KEYNOTE-775 [ 8 ] suggests that lenvatinib may be more useful in this situation, but this needs to be explored further.…”

Section: Angiogenesis Inhibitors In Gynecologic Cancers: Carving a Ne...mentioning

confidence: 99%

Angiogenesis: A Pivotal Therapeutic Target in the Drug Development of Gynecologic Cancers

Kasherman

Liu

Karakasis

et al. 2022

Cancers

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Since the discovery of angiogenesis and its relevance to the tumorigenesis of gynecologic malignancies, a number of therapeutic agents have been developed over the last decade, some of which have become standard treatments in combination with other therapies. Limited clinical activity has been demonstrated with anti-angiogenic monotherapies, and ongoing trials are focused on combination strategies with cytotoxic agents, immunotherapies and other targeted treatments. This article reviews the science behind angiogenesis within the context of gynecologic cancers, the evidence supporting the targeting of these pathways and future directions in clinical trials.

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“…This study by Bellone and colleagues 15 highlights the need for a transition to tumor sequencing-based detection of the dMMR status. The assessment of multiple tumor-based features as evidence of defective MMR, namely microsatellite instability, tumor mutational signatures, and TMB, has the potential to improve dMMR detection accuracy, and when it is considered together with the ability to classify a tumor's etiology as either double somatic MMR mutations or germline MMR pathogenic variants from the same assay, it has significant potential for precision ICI therapy.…”

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confidence: 94%

Mismatch repair and clinical response to immune checkpoint inhibitors in endometrial cancer

Antill

Buchanan

Scott

2021

Cancer

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Endometrial cancer is common, and a subset recurs and requires additional treatment.• Some of these are recognized as being susceptible to immune therapies and are said to have mismatch repair deficiency (dMMR). • However, this clinical trial highlights which cases are more likely to respond well: those containing mutations in genes known as Lynch genes and also some with mutations in POLE/POLD1 ("ultra-hypermutation" genes).• In contrast, the majority of dMMR endometrial cancers have silencing or DNA methylation of one of these genes, MLH1, and do not seem to be as responsive to single-agent immune therapy.• The availability of combination therapies may be important to consider for these women.Endometrial cancer (EC), the most common gynecological cancer affecting women in developed countries, is rising in incidence, partly because of increasing obesity and our aging population. 1 On the basis of genomic, proteomic, and epigenomic evaluations, 4 distinct molecular subtypes of EC have been defined: polymerase ε (POLE)-hypermutated, microsatellite instability, copy number-low/p53 wild type, and copy number-high/p53-mutated. 2 Up to 30% of all ECs are associated with DNA mismatch repair deficiency (dMMR). 3 As for other tumor types, dMMR in EC may be either acquired or due to inherited defects in 1 of 4 DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) or in EPCAM (causing downstream silencing of MSH2). [4][5][6][7][8][9] The majority of dMMR in ECs (~75% of dMMR and ~20% of all ECs) is caused by acquired hypermethylation of the MLH1 gene promoter. 3 The remaining causes of dMMR in ECs are attributed to either double somatic MMR mutations or germline MMR pathogenic variants. 10 Cancers with dMMR typically have a microsatellite instability-high (MSI-H) phenotype due to uncorrected errors that occur in repetitive DNA sequence during DNA replication, which results in a high somatic mutation frequency. When these dMMR-related mutational events occur in coding regions, the generation of high levels of novel frameshift peptide antigens occurs. The abundance and "foreign" nature of these frameshift peptide neoantigens in dMMR cancers likely explain the strong CD3+ and CD8+ T-cell responses, which are predictive of sensitivity to immune checkpoint inhibitor (ICI) therapy. 11 Most patients are diagnosed at an early stage and cured with surgery and/or local therapies. Chemotherapy (carboplatin combined with paclitaxel) has remained the first-line systemic therapy beyond endocrine therapy for women with advanced or recurrent EC. Therapeutic options after this are associated with poor outcomes with response rates of 20% or less. 12 Chemotherapy resistance has been reported in dMMR tumors, and this may explain the worse prognosis in the advanced setting in comparison with MMR-proficient tumors. 3,12,13 Immunotherapy using a single-agent ICI may be a highly effective treatment for dMMR/MSI-H ECs with reported overall tumor response rates (ORRs) between 27% and 57%. 12 However, these studies are small and include single...

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A phase 2 evaluation of pembrolizumab for recurrent Lynch‐like versus sporadic endometrial cancers with microsatellite instability

Cited by 42 publications

References 42 publications

High Mutation Burden in ER-Positive/HER2-Negative/Luminal Breast Cancers

High Mutation Burden in ER-Positive/HER2-Negative/Luminal Breast Cancers

Angiogenesis: A Pivotal Therapeutic Target in the Drug Development of Gynecologic Cancers

Mismatch repair and clinical response to immune checkpoint inhibitors in endometrial cancer

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