Identifying mismatch repair‐deficient colon cancer: near‐perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population‐based series

Loughrey, Maurice B.; McGrath, J. P.; Coleman, Helen; Bankhead, Peter; Maxwell, Perry; McGready, Claire; Bingham, Victoria; Humphries, Matthew P.; Craig, Stephanie G.; McQuaid, Stephen; Salto-Tellez, Manuel; James, Jacqueline

doi:10.1111/his.14233

Cited by 66 publications

(67 citation statements)

References 62 publications

(162 reference statements)

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“…The majority of the cases presented here were offered immunotherapy due to an MSI phenotype. It is important to note that while dMMR is largely associated with MSI in Lynch syndrome colorectal (98%) 50 and endometrial (94%) 51 cancers, the concordance is much lower for other Lynch syndrome cancer types such as urothelial cancer (23%) 52 and brain tumors (0%). 53 In accordance with this, an MSS phenotype has been found in 36% of Lynch syndrome tumors, with associations to noncolorectal, nonendometrial tumors and MSH6 and PMS2 gene variants.…”

Section: Discussionmentioning

confidence: 99%

An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

Therkildsen¹,

Jensen

Rasmussen³

et al. 2021

CEG

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During the recent years, immune checkpoint-based therapy has proven highly effective in microsatellite instable (MSI) solid tumors irrespective of organ site. MSI tumors are associated with a defective mismatch repair (MMR) system and a highly immune-infiltrative tumor microenvironment—both characteristics of Lynch syndrome. Lynch syndrome is a multi-tumor syndrome that not only confers a high risk of colorectal and endometrial cancer but also cancer in, eg the upper urinary tract, ovaries, and small bowel. Since the genetic predisposition for Lynch syndrome are pathogenic variants in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2 , most of the Lynch syndrome cancers show MMR deficiency, MSI, and activation of the immune response system. Hence, Lynch syndrome cancer patients may be optimal candidates for immune checkpoint-based therapies. However, molecular differences have been described between sporadic MSI tumors (developed due to MLH1 promoter hypermethylation) and Lynch syndrome tumors, which may result in different treatment responses. Furthermore, the response profile of the rare Lynch syndrome cases may be masked by the more frequent cases of sporadic MSI tumors in large clinical trials. With this review, we systematically collected response data on Lynch syndrome patients treated with FDA- and EMA-approved immune checkpoint-based drugs (pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, and nivolumab) to elucidate the objective response rate and progression-free survival of cancer in Lynch syndrome patients. Herein, we report Lynch syndrome-related objective response rates between 46 and 71% for colorectal cancer and 14–100% for noncolorectal cancer in unselected cohorts as well as an overview of the Lynch syndrome case reports. To date, no difference in the response rates has been reported between Lynch syndrome and sporadic MSI cancer patients.

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Section: Discussionmentioning

confidence: 99%

An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

Therkildsen¹,

Jensen

Rasmussen³

et al. 2021

CEG

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“…The pathological identification of dMMR breast cancers has proven to be extremely challenging due to the constraints of the existing methods, and the absence of CDx tests and/or tumor-specific guidelines [ 12 ]. So far, the variety of currently available locally developed laboratory tests have been shaped on those approved for colorectal and endometrial carcinomas [ 59 , 60 ]. For a long time, there has been a nihilistic view of the actual clinical utility of MMR screening for HR+ breast cancer, probably because of the relatively low frequency of the dMMR phenotype in these patients.…”

Section: Mismatch Repair Testing: Focus On Hr+ Breast Cancermentioning

confidence: 99%

Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

et al. 2021

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The clinical outcome of patients with a diagnosis of hormone receptor (HR)+ breast cancer has improved remarkably since the arrival of endocrine therapy. Yet, resistance to standard treatments is a major clinical challenge for breast cancer specialists and a life-threatening condition for the patients. In breast cancer, mismatch repair (MMR) status assessment has been demonstrated to be clinically relevant not only in terms of screening for inherited conditions such as Lynch syndrome, but also for prognostication, selection for immunotherapy, and early identification of therapy resistance. Peculiar traits characterize the MMR biology in HR+ breast cancers compared to other cancer types. In these tumors, MMR genetic alterations are relatively rare, occurring in ~3 % of cases. On the other hand, modifications at the protein level can be observed also in the absence of gene alterations and vice versa. In HR+ breast cancers, the prognostic role of MMR deficiency has been confirmed by several studies, but its predictive value remains a matter of controversy. The characterization of MMR status in these patients is troubled by the lack of tumor-specific guidelines and/or companion diagnostic tests. For this reason, precise identification of MMR-deficient breast cancers can be problematic. A deeper understanding of the MMR biology and clinical actionability in HR+ breast cancer may light the path to effective tumor-specific diagnostic tools. For a precise MMR status profiling, the specific strengths and limitations of the available technologies should be taken into consideration. This article aims at providing a comprehensive overview of the current state of knowledge of MMR alterations in HR+ breast cancer. The available armamentarium for MMR testing in these tumors is also examined along with possible strategies for a tailored pathological characterization.

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“…Both cases showed loss of MLH1 and PMS2 nuclear expression but were considered MSS by PCR testing. Possible explanations for the discordant results include tumoral heterogeneity [ 50 ] and/or underrepresentation of tumor cells in the sample [ 51 , 52 ]. We have a higher frequency of MSI-high cases in this series than reported in the literature (15–20%) [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of Thomsen–Friedenreich Antigen in Colorectal Cancer and Association with Microsatellite Instability

Leão

Wen

Duarte

et al. 2021

IJMS

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Microsatellite instability (MSI) is a molecular phenotype due to a deficient DNA mismatch repair (dMMR). In colorectal cancer (CRC), dMMR/MSI is associated with several clinical and histopathological features, influences prognosis, and is a predictive factor of response to therapy. In daily practice, dMMR/MSI profiles are identified by immunohistochemistry and/or multiplex PCR. The Thomsen–Friedenreich (TF) antigen was previously found to be a potential single marker to identify MSI-high gastric cancers. Therefore, in this study, we aimed to disclose a possible association between TF expression and MSI status in CRC. Furthermore, we evaluated the relationship between TF expression and other clinicopathological features, including patient survival. We evaluated the expression of the TF antigen in a cohort of 25 MSI-high and 71 microsatellite stable (MSS) CRCs. No association was observed between the expression of the TF antigen and MSI-high status in CRC. The survival analysis revealed that patients with MSI-high CRC showed improved survival when the TF antigen was expressed. This finding holds promise as it indicates the potential use of the TF antigen as a biomarker of better prognosis in MSI-high CRCs that should be validated in an independent and larger CRC cohort.

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Identifying mismatch repair‐deficient colon cancer: near‐perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population‐based series

Cited by 66 publications

References 62 publications

An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

Expression of Thomsen–Friedenreich Antigen in Colorectal Cancer and Association with Microsatellite Instability

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