Universal Screening of Gastrointestinal Malignancies for Mismatch Repair Deficiency at Stanford

Abstract Background In light of recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for mismatch repair deficient (dMMR) malignancies, identifying patients with dMMR malignancies has become increasingly important. Although screening for dMMR in colorectal cancer (CRC) is recommended, it is less common for extracolonic gastrointestinal (GI) malignancies. At Stanford Comprehensive Cancer Institute (SCCI), all GI malignancies have been screened for dMMR via immunohistochemistry since January 2016. Methods In this study, we conducted a retrospective review of all patients with GI malignancies screened for dMMR between January 2016 and December 2017. Tumor sequencing was performed on cases negative for germline pathogenic variants where tumor material was available. Results A total of 1425 consecutive GI malignancies were screened for dMMR at SCCI during the study period, and 1374 were included for analysis. dMMR was detected in 7.2% of all GI malignancies. We detected the highest prevalence of dMMR in gastric (15 of 150, 10.0%) followed by colorectal (63 of 694, 9.1%), pancreatic (13 of 244, 5.3%), and gastroesophageal malignancy (6 of 132, 4.5%) patients. Lynch syndrome was the most common etiology for dMMR in colorectal cancer (41.5%), double somatic (confirmed or possible) pathogenic variants the most common etiology in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation the most common etiology in gastric (73.3%) and gastroesophageal cancer (83.3%). Conclusions Given the relatively high incidence of dMMR in GI malignancies, we recommend screening all GI malignancies. Our results suggest that although a rare occurrence, double somatic pathogenic variants may be a biologically significant pathway causing dMMR in pancreatic cancer.

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Prevalence and molecular etiology of mismatch repair deficiency among gastrointestinal cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.215 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 215-215 ◽

Cited By ~ 2

Author(s):

Navika Shukla ◽

Aser Abrha ◽

Teri A. Longacre ◽

Rachel Koff ◽

James M. Ford ◽

...

Keyword(s):

Pancreatic Cancer ◽

Esophageal Cancer ◽

Cancer Patients ◽

Mismatch Repair ◽

Patient Characteristics ◽

Gi Cancer ◽

Fda Approval ◽

Repair Deficiency ◽

Common Etiology ◽

Significant Pathway

215 Background: In light of recent FDA approval of anti-PD-1 therapy for microsatellite unstable (MSI-H) or mismatch repair deficient (dMMR) solid tumors, identifying patients with dMMR tumors has become increasingly important. While screening for dMMR and MSI-H in colorectal cancer (CRC) is recommended, this screening is less commonly done for extracolonic gastrointestinal (GI) tumors. At Stanford Comprehensive Cancer Institute (SCCI), all GI cancer patients have been universally screened for dMMR via immunohistochemistry since January 2016. Methods: In this study, we undertook a retrospective review of all GI cancer patients screened for dMMR between January 2016 to December 2017. Data on patient characteristics, germline and tumor sequencing, and tumor characteristics were collected and reported. Results: A total of 1543 GI malignancies were screened for dMMR at SCCI during the study period. Colorectal (n = 711), pancreatic (n = 264), gastric (n = 159), and gastro-esophageal (n = 137) cancer were amongst the most frequently screened tumors. dMMR was detected in 7.1% of all GI malignancies. We detected the highest prevalence of dMMR in colorectal (69/711, 9.7%), followed by gastric (15/159, 9.4%), pancreatic (18/264, 6.8%), and gastro-esophageal cancer (6/137, 4.4%). Lynch syndrome was the most common etiology for dMMR in CRC patients (39.4%), double somatic (confirmed or possibly) mutations were most common in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation was the most common etiology in gastric (73.3%) and gastro-esophageal cancer (100%). Conclusions: Given the relatively high incidence of dMMR in GI malignancies, we strongly recommend screening all GI malignancies. Of note, we found higher than previously reported rates of dMMR within pancreatic cancer. Our results also suggest that while rare, double somatic mismatch repair mutations may be a significant pathway causing dMMR in pancreatic cancer.

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Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status

JAMA Oncology ◽

10.1001/jamaoncol.2018.4942 ◽

2019 ◽

Vol 5 (4) ◽

pp. 551 ◽

Cited By ~ 39

Author(s):

Romain Cohen ◽

Elisabeth Hain ◽

Olivier Buhard ◽

Agathe Guilloux ◽

Armelle Bardier ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Mismatch Repair Deficiency ◽

Primary Resistance ◽

Repair Deficiency

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Immune checkpoint inhibitors for patients with colorectal cancer: mismatch repair deficiency and perspectives

Colorectal Cancer ◽

10.2217/crc-2017-0004 ◽

2017 ◽

Vol 6 (1) ◽

pp. 23-31

Author(s):

Romain Cohen ◽

Magali Svrcek ◽

Alex Duval ◽

Yann Parc ◽

Pia P Österlund ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Mismatch Repair Deficiency ◽

Repair Deficiency

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Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

Current Treatment Options in Oncology ◽

10.1007/s11864-021-00870-z ◽

2021 ◽

Vol 22 (8) ◽

Author(s):

Federica Pecci ◽

Luca Cantini ◽

Alessandro Bittoni ◽

Edoardo Lenci ◽

Alessio Lupi ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Cancer Progression ◽

Checkpoint Inhibitors ◽

Tnm Classification ◽

Standard Of Care ◽

First Line Therapy ◽

Combination Strategies ◽

The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

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Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00165-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Tong Xie ◽

Qin Feng ◽

Zhongwu Li ◽

Ming Lu ◽

Jian Li ◽

...

Keyword(s):

Mismatch Repair ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Combined Therapy ◽

Dual Therapy ◽

Circulating Tumor Dna ◽

Targeted Sequencing ◽

Dna Mismatch ◽

Repair Deficiency ◽

Mutation Burden

Abstract Background Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs). Case presentation We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib. Conclusion Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.

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RARE-55. CHALLENGES AND SPECIFIC STRATEGIES FOR CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME IN LOW RESOURCE SETTINGS. ON BEHALF OF THE INTERNATIONAL RRD CONSORTIUM IN LOW RESOURCE SETTINGS PANEL

Neuro-Oncology ◽

10.1093/neuonc/noaa222.765 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii454-iii454

Author(s):

Rejin Kebudi ◽

Nisreen Amayiri N ◽

Malak Abedalthagafi ◽

Asim Noor Rana ◽

Slman Kirmani ◽

...

Keyword(s):

Mismatch Repair ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Malignant Gliomas ◽

Mismatch Repair Deficiency ◽

Term Survival ◽

Low Resource Settings ◽

Low Resource ◽

Repair Deficiency ◽

Constitutional Mismatch Repair Deficiency

Abstract Germline biallelic mutations in one of the mismatch repair genes (MSH2/MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency (CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood. The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD. Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing the many challenges associated with this condition. To address specific issues surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, colon cancers and T cell lymphomas should be stained routinely as the prevalence of CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be used in the management of malignant glioma. By contrast, preclinical studies have suggested increased sensitivity to nitrosoureas. For the management of CMMRD related lymphoma and leukemia, mercaptopurines should not be avoided or discontinued as a part of the standard of care before more data are collected. 3) Management with checkpoint inhibitors should be limited to centers with intensive care units and expertise in complex supportive care to manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

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Cost-effectiveness of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer

Cancer ◽

10.1002/cncr.31795 ◽

2018 ◽

Vol 125 (2) ◽

pp. 278-289 ◽

Cited By ~ 12

Author(s):

Jacqueline N. Chu ◽

Jin Choi ◽

Sassan Ostvar ◽

James A. Torchia ◽

Kerry Lynn Reynolds ◽

...

Keyword(s):

Colorectal Cancer ◽

Cost Effectiveness ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors

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Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers14020406 ◽

2022 ◽

Vol 14 (2) ◽

pp. 406

Author(s):

Quang Loc Bui ◽

Léo Mas ◽

Antoine Hollebecque ◽

David Tougeron ◽

Christelle de la Fouchardière ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Control ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Immune Checkpoints ◽

Repair Deficiency ◽

Improved Outcomes ◽

Number Of Patients ◽

Tumor Types

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

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