Complete response to anti-PD-L1 antibody in a metastatic bladder cancer associated with novel MSH4 mutation and microsatellite instability

BackgroundMicrosatellite instability (MSI) occurs in 3% of urothelial carcinomas as a result of germline or somatic loss of function mutation in mismatch repair (MMR) proteins.1 Although MSH4 is a member of the DNA MMR mutS family, the association of MSH4 mutation with MSI has not been described. We report a complete responder to PD-L1 blockade who had MSH4 mutated metastatic bladder cancer with mixed histology and MSI. The genomics of urothelial, plasmacytoid and squamous histology was characterized individually through microdissection.Case presentationAn 81-year-old man was diagnosed with metastatic urothelial carcinoma 8 months after a cystectomy for muscle invasive bladder cancer. His disease was primary refractory to first-line platinum-based chemotherapy but attained complete response to second-line atezolizumab. PCR-based assay revealed MSI high. The tumor mutational burden was elevated to 36.7 mut/Mb. However, immunohistochemistry of MLH1, MSH2, MSH6 and PMS2 was intact. Whole exome sequencing confirmed that the above mentioned four classic MMR genes were wild type but revealed a deleterious MSH4 L359I mutation with variant allele fraction of 30% and Polyphen2 score of 0.873. The association of MSH4 alterations and MSI-H was independently verified in two publicly available MSI-H colorectal cancer datasets.ConclusionsThe novel MSH4 L359I mutation is associated with MSI and high mutational burden leading to remarkable response to PD-L1 blockade. More studies are warranted to establish the causality relationship between MSH4 and MSI.

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Complete Response With Immunotherapy: A Case of Metastatic Bladder Cancer

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/23247096211035603 ◽

2021 ◽

Vol 9 ◽

pp. 232470962110356

Author(s):

Balraj Singh ◽

Parminder Kaur ◽

Sachin Gupta ◽

Nirmal Guragai ◽

Michael Maroules

Keyword(s):

Bladder Cancer ◽

Cancer Immunotherapy ◽

Locally Advanced ◽

Complete Response ◽

First Line ◽

Novel Therapy ◽

Metastatic Bladder Cancer ◽

Metastatic Urothelial Cancer ◽

Platinum Based Chemotherapy ◽

Broad Variety

Bladder cancer is the most common urinary tract malignancy. Platinum-based chemotherapy is the first line of treatment in locally advanced or metastatic bladder cancer. Immunotherapy has become a novel therapy option in a broad variety of malignancies including bladder cancer. Immunotherapy is approved as first line of treatment in patients who are ineligible for platinum-based chemotherapy and second-line treatment for metastatic urothelial cancer who progressed after platinum-based treatments. We present the case of an 83-year-old female with metastatic bladder cancer who was chemotherapy ineligible and had complete response with immune checkpoint inhibitor pembrolizumab.

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Selective organ preservation with neoadjuvant chemotherapy in the treatment of muscle invasive transitional cell carcinoma (TCC) of the bladder.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.310 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 310-310

Author(s):

Shaista Hafeez ◽

Robert Anthony Huddart

Keyword(s):

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Partial Response ◽

Poor Response ◽

Complete Response ◽

Radical Radiotherapy ◽

Bladder Preservation ◽

Platinum Based Chemotherapy ◽

Muscle Invasive

310 Background: Radiotherapy has been previously associated with high treatment failure for those with muscle invasive bladder cancer. Evidence suggests modern organ sparing approaches may have favourable outcome in appropriately selected patients. We investigate whether response to neo-adjuvant chemotherapy can guide selection for bladder preservation and identify those patients likely to have greater success with radical radiotherapy treatment. Methods: Retrospective analysis of 94 patients with T2-T4aN0M0 bladder TCC treated between January 2000 and June 2011. Patients received platinum based chemotherapy following transuretheral resection of bladder tumour, with repeat cystoscopy (+biopsy) performed to guide subsequent management. Poor responders were advised to proceed with surgery. We report on the outcome of 79 individuals who received radiotherapy. Results: 56 (60%) patients achieved complete response following chemotherapy (72% with stage T2). 15 (16%) patients achieved partial pathological response. 12 patients had radiological assessment of partial response made. 11 patients had poor response. All patients achieving complete response, 22 with partial response and 1 with poor response proceeded to radical radiotherapy. Median time to disease progression following radiotherapy was 17months (range 8-91). 5 patients developed invasive recurrence, 17 developed superficial recurrence, 4 developed local nodal disease and 7 developed metastasises. After median follow-up of 36 months (range 6-114), 50 patients were alive with no disease, 24 had died (14 from metastatic bladder cancer and 10 from other causes). 5 patients were alive with active disease (4 with localized and 1 with metastatic disease). 13 required cystectomy (9 for superficial disease, 3 for invasive recurrence, and 1 for treatment related toxicity). Of those alive and disease free 84% had an intact bladder. 82% had an intact bladder at last follow-up or death. Conclusions: Neoadjuvant chemotherapy followed by radical radiotherapy allows bladder preservation in over 80% of selected patients with survival rates comparable to contemporary surgical series.

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Tumor mutational burden (TMB), intratumoral genetic heterogeneity (ITGH) and BCG responsiveness in high-risk non-muscle invasive bladder cancer (NMIBC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e16516 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e16516-e16516 ◽

Cited By ~ 1

Author(s):

Diogo Assed Bastos ◽

Mariana Lima ◽

Romulo Loss Mattedi ◽

Carlos Dzik ◽

Leopoldo Ribeiro-Filho ◽

...

Keyword(s):

Bladder Cancer ◽

High Risk ◽

Genetic Heterogeneity ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Muscle Invasive

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Complete Response To Tislelizumab In A Muscle-Invasive Urothelial Carcinoma After Surgery Associated With Tumor Mutational Burden High: A Case Report

10.21203/rs.3.rs-1226643/v1 ◽

2022 ◽

Author(s):

Jing Jin ◽

Qidong Yang ◽

Yangyang Yu ◽

Lin Chen ◽

Shouhua Pan

Keyword(s):

Urothelial Carcinoma ◽

Adjuvant Treatment ◽

Muscularis Propria ◽

Progression Free Survival ◽

Complete Response ◽

Regional Lymph Nodes ◽

Metastatic Recurrence ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Muscle Invasive

Abstract Muscle-invasive urothelial carcinoma (MIUC) is a highly aggressive urothelial carcinoma. Radical cystectomy (RC) is standard of treatment, but still more than 50% patients with cancer invading the muscularis propria or involving the regional lymph nodes will have metastatic recurrence. In CheckMate274 study, programmed cell death-1 (PD-1) inhibitor nivolumab as adjuvant treatment has shown effective for patients with MIUC. Tislelizumab is an anti-human PD-1 monoclonal IgG4 antibody which was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. But there is no report of tislelizumab as adjuvant treatment in MIUC currently. Here, we report a case of MIUC in a patient with PD-L1-negative, microsatellite stable (MSS), high tumor mutational burden (TMB-H) obtained complete response (CR) receiving tislelizumab therapy after surgery. Progression-free survival (PFS) exceeded 6 months since tislelizumab treatment. To our knowledge, this is the first reported case of MIUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as adjuvant treatment. However, we still need more studies to assess the efficacy of tislelizumab as adjuvant treatment in MIUC and to confirm that TMB is a predicted biomarker of tislelizumab for efficacy.

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NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.528 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii126-ii126

Author(s):

Amber Ruiz ◽

Jerome Graber

Keyword(s):

Treatment Response ◽

Mismatch Repair ◽

Case Series ◽

Germline Mutations ◽

Molecular Characteristics ◽

Loss Of Function ◽

Dna Mismatch ◽

Mutational Burden ◽

Increased Risk ◽

Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

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