Prevalence of NTRK1/3 fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15537-e15537
Author(s):  
Magali Svrcek ◽  
Raphael Colle ◽  
Anne Cayre ◽  
Pierre Bourgoin ◽  
Romain Cohen ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Methylation Status ◽  
Cell Of Origin ◽  
Primary Resistance ◽  
Paired Samples ◽  
Repair Deficiency ◽  
Innovative Therapies ◽  
Radiological Response ◽  
Negative Tumor

e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAFV600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.

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

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.

scholarly journals 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

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.

scholarly journals Unexpected tumor response to palliative pelvic radiotherapy in mismatch repair-deficient advanced prostate cancer: a case report

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Giovanni Aluisio ◽  
Ercole Mazzeo ◽  
Frank Lohr ◽  
Federica Fiocchi ◽  
Stefania Bettelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Computed Tomography ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Computed Tomography Scan ◽  
Altered Expression ◽  
First Case ◽  
Repair Deficiency ◽  
Tomography Scan

Abstract Background Mismatch-repair-deficiency resulting in microsatellite instability (MSI) may confer increased radiosensitivity in locally advanced/metastatic tumors and thus radiotherapy (RT) potentially might have a changing role in treating this subset of patients, alone or in combination with checkpoint inhibitors. Case presentation We report a 76 year-old Italian male patient presenting with locally advanced undifferentiated prostate cancer (LAPC), infiltrating bladder and rectum. Molecular analysis revealed high-MSI with an altered expression of MSH2 and MSH6 at immunohistochemistry. Two months after 6 chemotherapy cycles with Docetaxel associated to an LHRH analogue, a computed tomography scan showed stable disease. After palliative RT (30 Gy/10 fractions) directed to the tumor mass with a 3D-conformal setup, a follow-up computed tomography scan at 8 weeks revealed an impressive response that remained stable at computed tomography after 9 months, with sustained biochemical response. To our knowledge, this is the first case of such a sustained response to low dose RT alone in high-MSI LAPC. Conclusions Routine evaluation of MSI in patients with locally problematic advanced tumors might change treatment strategy and treatment aim in this setting, from a purely palliative approach to a quasi-curative paradigm.

scholarly journals Universal Screening of Gastrointestinal Malignancies for Mismatch Repair Deficiency at Stanford

2020 ◽  
Vol 4 (5) ◽  
Author(s):  
Aser Abrha ◽  
Navika D Shukla ◽  
Rachel Hodan ◽  
Teri Longacre ◽  
Shyam Raghavan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Pancreatic Cancer ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Gastrointestinal Malignancies ◽  
Pathogenic Variants ◽  
Repair Deficiency ◽  
Common Etiology ◽  
Significant Pathway ◽  
Tumor Material

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.

scholarly journals (Not-so) Unexpected Tumor Response to Palliative Pelvic Radiotherapy in Mismatch Repair-Deficient Advanced Prostate Cancer

2020 ◽  
Author(s):  
Giovanni Aluisio ◽  
Ercole Mazzeo ◽  
Frank Lohr ◽  
Federica Fiocchi ◽  
Stefania Bettelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ct Scan ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Altered Expression ◽  
First Case ◽  
Repair Deficiency ◽  
Changing Role

Abstract Mismatch-repair-deficiency resulting in microsatellite instability (MSI) may confer increased radiosensitivity in locally advanced/metastatic tumors and thus radiotherapy (RT) potentially might have a changing role in treating this subset of patients, alone or in combination with checkpoint inhibitors. We report a 76year-old patient presenting with locally advanced undifferentiated prostate cancer (LAPC), infiltrating bladder and rectum. Molecular analysis revealed high-MSI with an altered expression of MSH2 and MSH6 at immunohistochemistry. Two months after 6 chemotherapy cycles with Docetaxel associated to an LHRH analogue, a CT scan showed stable disease. After palliative RT (30Gy/10 fractions) directed to the tumor mass with a 3D-conformal setup, a follow-up CT scan at 8 weeks revealed an impressive response, that remained stable at CT after 9 months, with sustained biochemical response. To our knowledge, this is the first case of such a sustained response to low dose RT alone in H-MSI LAPC.Routine evaluation of MSI in patients with locally problematic advanced tumors might change treatment strategy and treatment aim in this setting, from a purely palliative approach to a quasi-curative paradigm.

scholarly journals Correlation of Mismatch Repair Deficiency with Clinicopathological Features and Programmed Death-Ligand 1 Expression in Thyroid Carcinoma

2022 ◽  
Author(s):  
Xiao-Ping Chen ◽  
Pei-pei Qiao ◽  
Kai-Sai Tian ◽  
Li-Tao Han ◽  
Ma Ben ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Clinicopathological Characteristics ◽  
Clinicopathologic Characteristics ◽  
Dna Mismatch ◽  
Asian Populations ◽  
Repair Deficiency ◽  
Poorly Differentiated

Abstract Background Mutations in DNA mismatch repair (MMR) genes associated with thyroid carcinoma (TC) have rarely been reported, especially in East Asian populations. Methods We examined tumor tissue from a cohort of 241 patients diagnosed with TC between 2008 and 2020. MMR proteins were detected using tissue microarray-based immunohistochemistry in order to identify MMR-protein-deficient (MMR-D) and MMR-protein-intact (MMR-I) tumors. We retrospectively summarized the clinicopathologic characteristics of patients with MMR-D TC, measured the expression of PD-L1, and recorded overall survival (OS) and other clinical outcomes. Results In our cohort, there were 18 (7.5%) MMR-D (MLH1, MSH2, MSH6, and PMS2) patients, including 12 with papillary TC (PTC) (6.7%), 2 with poorly differentiated TC (PDTC) (4.7%), and 4 with anaplastic TC (ATC) (22.2%). Half of them (9/18) showed a specific deletion in MSH6, and 6 of them also carried variants in the MSH6 and PMS2 gene. Survival was significantly better in patients with MMR-D ATC than in those with MMR-I tumors (p=0.033). Four of the 18 MMR-D patients (22%) were found to be PD-L1 positive. Their OS was much shorter than that of PD-L1-negative patients. Conclusions MMR-D and PD-L1 positivity appear to be associated with clinicopathological characteristics and prognosis in TC. The results indicate that MMR status may have important prognostic significance in TC. Therefore, immune checkpoint inhibitors that target the PD-1/PD-L1 pathway may be a treatment option for TCs.

scholarly journals PATH-45. DIFFERENT TYPES OF HYPERMUTATOR PHENOTYPE OF GLIOBLASTOMA ACCORDING TO MUTATION PATTERNS OF MISMATCH REPAIR GENES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi153-vi153 ◽  
Author(s):  
Kuniaki Saito ◽  
Saki Shimizu ◽  
Eriko Nozaki ◽  
Keiichi Kobayashi ◽  
Nobuyoshi Sasaki ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Routine Care ◽  
Insertion Mutation ◽  
Mismatch Repair Genes ◽  
Target Sequencing ◽  
Msh6 Mutation ◽  
Repair Deficiency ◽  
Mutation Pattern ◽  
Repair Genes

Abstract BACKGROUND Although precision medicine has been widely applied to routine care, only few molecular targeted drugs have been developed for glioma. Immune checkpoint inhibitors hold a potential promise to improve outcome of malignant glioma especially with the hypermutator phenotype. Mismatch repair deficiency could induce hypermutation during temozolomide (TMZ) treatment, but the mechanism of mutation acquisition is not well understood. METHODS We present the results of target sequencing of 57 longitudinal specimens from 27 individuals with glioblastoma (GBM). We used Ion AmpliSeq Cancer Hotspot Panel v2 (CHP) and/or Ion AmpliSeq Comprehensive Cancer Panel (CCP) for target sequencing. RESULTS Acquired mutations with G:C >A:T transition at non-CpG sites were found in 70% of recurrent MGMT methylated samples, whereas only 8% in MGMT unmethylated cases (p< 0.001). Two cases of hypermutator phenotype were identified in MGMT methylated, IDH wild type recurrent GBMs after TMZ chemotherapy. One case gained mutations in mismatch repair genes of MLH1, MSH2, MSH6, and PMS1. Most of the acquired mutations were G:C >A:T mutations typical to TMZ-induced hypermutation. The recurrent tumor was highly aggressive with overall survival after recurrence of 3.7 months. The other case gained mutations in mismatch repair genes of MLH1 and PMS1 only. Most of the acquired mutations were insertion mutations. The prognosis after recurrence was much longer. CONCLUSIONS We identified two types of hypermutator phenotype according to mutation pattern of mismatch repair genes. It has been suggested that MSH2-MSH6 complex deficient tumor cannot repair TMZ-induced mismatch mutation, thereby causing hypermutation. Conversely, MLH1-PMS1 complex deficient tumor with intact MSH2-MSH6 complex can repair mismatch mutation but is susceptible to insertion mutation. Taken together, MSH6 mutation plays a key role in TMZ-induced hypermutation, while MLH1 and PMS1 mutations might cause insertion-based hypermutation. Larger and prospective studies are warranted to clarify the mechanism, outcome, and effectiveness of checkpoint inhibitors.

scholarly journals Mismatch Repair Deficiency as a Predictive Biomarker for Immunotherapy Efficacy

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Giulia Viale ◽  
Dario Trapani ◽  
Giuseppe Curigliano
Keyword(s):  
Clinical Trials ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Mismatch Repair Deficiency ◽  
Durable Response ◽  
Repair Deficiency ◽  
Cancer Types ◽  
Therapeutic Decision Making

Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in different cancer types. No predictive biomarker has been validated thus far to select patients who would benefit from therapy. Among the candidate predictive biomarkers, mismatch repair status of the tumor is currently one of the most promising. Indeed, tumors displaying mismatch repair deficiency or microsatellite instability showed remarkable response to immunotherapy in clinical trials. This correlation has been first reported in colorectal cancers, but similar results have been observed also in other cancer types. The possible mechanism behind this correlation may be the higher mutational load observed in mismatch repair deficient tumors, leading to neoantigens formation, recruitment of immune cells, and release of proinflammatory factors in the microenvironment. These results support an approach to treatment based on assessment of the genomic stability of the tumor besides its biologic characteristics and may change our therapeutic decision making process. However, due to the small percentage of patients with tumors displaying mismatch repair deficiency, data from clinical trials should not be considered definitive and need further confirmation.

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