Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer

Schrock, Alexa B.; Ouyang, Ching; Sandhu, Jaideep; Sokol, Ethan S.; Jin, Dexter X.; Ross, Jeffrey S.; Miller, Vincent A.; Lim, Dean; Amanam, Idoroenyi; Chao, Joseph; Catenacci, Daniel V.T.; Cho, M.; Braiteh, Fadi; Klempner, Samuel J.; Ali, Siraj M.; Fakih, Marwan

doi:10.1093/annonc/mdz134

Cited by 510 publications

(441 citation statements)

References 24 publications

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“…Growing evidence suggests such mechanisms include the high expression of PD-L1, DNA mismatch-repair deficiency, a high tumor mutational burden, an interferon (IFN)-γ signature and the presence of CD8+ T cells. [10][11][12][13][14] In our case, plausible mechanisms for the dramatic response to pembrolizumab may include PD-L1 overexpressed in tumors and the dysfunction of PBAF associated with the loss of SMACA4. The loss of PBAF function may induce the upregulation of IFN-γ-responsive genes and secretion of T cell chemoattractants to recruit effector T cells to tumors.…”

Section: Discussionmentioning

confidence: 75%

“…The mechanisms that determine sensitivity to anti‐PD‐1 blockade remain to be fully elucidated. Growing evidence suggests such mechanisms include the high expression of PD‐L1, DNA mismatch‐repair deficiency, a high tumor mutational burden, an interferon (IFN)‐γ signature and the presence of CD8+ T cells . In our case, plausible mechanisms for the dramatic response to pembrolizumab may include PD‐L1 overexpressed in tumors and the dysfunction of PBAF associated with the loss of SMACA4.…”

Section: Discussionmentioning

confidence: 76%

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Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

et al. 2019

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SMARCA4‐deficient thoracic sarcoma (SMARCA4‐DTS) is a new clinical entity characterized by SMARCA4 inactivation and has a dismal prognosis because of rapid growth. Effective treatments for SMARCA4‐DTS have not yet been developed. Most recently, anti‐programmed cell death 1 receptor (PD‐1) blockade has been effective for SMARCA4‐deficient lung cancer and malignant rhabdoid tumor‐like tumors. Here, we describe a patient with SMARCA4‐DTC who experienced a marked response to the administration of pembrolizumab. A 70‐year‐old female was referred to our department for treatment of SMARCA4‐DTC. Positron emission tomography‐computed tomography had revealed a left mediastinal tumor, peritoneal dissemination and multiple cutaneous metastases at diagnosis. Immunohistochemical analyses revealed 60% of tumor cells expressed programmed cell death ligand 1 (PD‐L1). The patient was given pembrolizumab as first‐line treatment. Pembrolizumab suppressed tumor growth dramatically, with only one dose leading to a partial response. Our case suggests the immunohistochemical analysis of PD‐L1 expression be undertaken for patients with SMARCA4‐DTS and that pembrolizumab treatment may be a promising strategy for PD‐L1‐positive SMARCA4‐DTS.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 76%

Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

et al. 2019

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“…Further studies in PDAC should also address whether better response to immunotherapy could be reached where there is co-existence of MSI/ dMMR and high TMB, such as in colorectal cancer. 54 We also found additional potential driver genes typically involved in MSI/ dMMR PDAC: JAK (JAK1 and JAK3) and KMT2 (KMT2C and KMT2D). JAK genes code for a homonymous family of kinases, which are required for the signalling of a host of immune modulators in tumour, stromal and immune cells; alterations in this family have been associated with an immune evasion by tumour cells.…”

Section: Discussionmentioning

confidence: 62%

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications

Luchini

Brosens

Wood

et al. 2020

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ObjectiveRecently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC).DesignPubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project).ResultsOverall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%–2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a KRAS/TP53 wild-type molecular background (p<0.01), with more common JAK genes mutations. Data on survival are still unclear.ConclusionPDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.

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“…The genetic modifications in tumors can include non-synonymous mutations comprising mainly missense mutations, as well as synonymous mutations, insertions or deletions, splice site mutations and copy number gains and losses. Tumor mutational burden (TMB), represents the number of somatic mutations in a tumor, but there is no consensus as to which mutations should be included in the calculation: some authors report all mutations (8,9), others use only non-synonymous mutations (10), and yet others (11)(12)(13) consider only mutations that alter the sequence of a protein (i.e., missense and indels within exons). The former vary in prevalence between 0.01 mutations/megabase pair (Mbp) and 400 mutations/Mbp.…”

Section: Introductionmentioning

confidence: 99%

“…This hypothesis has some clinical data in its favor. For instance, tumors known, through DNA sequencing, to harbor multiple acquired mutations, such as microsatellite unstable tumors, melanoma and non-small-cell lung cancer, are those with the best response to ICPI (8). Furthermore, studies have shown improved response rates (RRs) and progression free survival (PFS) in patients with tumors deemed to have high tissue TMB (9,11).…”

Section: Introductionmentioning

confidence: 99%

Tissue-Plasma TMB Comparison and Plasma TMB Monitoring in Patients With Metastatic Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitors

et al. 2020

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Immuno-oncology is an ever growing field that has seen important progress across the spectrum of cancers. Responses can be deep and durable. However, as only a minority of patients respond to checkpoint inhibition, predictive biomarkers are needed. Cancer is a genetic disease arising from the accumulation of somatic mutations in the DNA of affected cells. Tumor mutational burden (TMB), represents the number of somatic mutations in a tumor that form neoantigens, responsible for the immunogenicity of tumors. Randomized controlled trials have so far failed to show a survival benefit when stratifying patients by tissue TMB. TMB has also been evaluated in plasma (PTMB). PTMB is anticipated to represent the biology of the entire cancer, whereas obtaining tissue of an amenable primary or a metastatic lesion may be prone to sampling bias because of tumor heterogeneity. For this reason, we are evaluating the correlation between TMB and PTMB, and prospectively evaluating the impact of these biomarkers on clinical outcomes. We also discuss the technical difficulties inherent to performing and comparing these analyses. Furthermore, we evaluate the correlation between the evolution of PTMB during an immunotherapy treatment and response at 3 and 6 months, as we believe PTMB may be a dynamic biomarker. In this paper, we present results from the first 4 patients in this project.

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Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer

Cited by 510 publications

References 24 publications

Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications

Tissue-Plasma TMB Comparison and Plasma TMB Monitoring in Patients With Metastatic Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitors

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