DNA Damage and Repair Biomarkers of Immunotherapy Response

Mouw, Kent W.; Goldberg, Michael S.; Konstantinopoulos, Panagiotis A.; D’Andrea, Alan D.

doi:10.1158/2159-8290.cd-17-0226

Cited by 538 publications

(492 citation statements)

References 185 publications

(190 reference statements)

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“…Of note, tumors that harbor MDM2 amplification had significantly lower rates of high TMB than MDM2 wild-type tumors (2.9% [105 of 3,650] v 6.5% [6,492 of 99,228]; P < .001). Because high TMB correlates with checkpoint blockade responsiveness, 44,45 this observation may partially explain resistance to PD-1/PD-L1 inhibitors in MDM2 -amplified tumors but does not clarify the mechanism that underlies the correlation between MDM2 amplification and hyperprogression. Furthermore, how patients whose tumors have high TMB as well as MDM2 amplification would fare on checkpoint inhibitors is unclear; however, one of our previously reported patients with MDM2 amplification who demonstrated hyperprogression with anti–PD-L1 immunotherapy had a high TMB.…”

Section: Discussionmentioning

confidence: 99%

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Kato

Ross

Gay

et al. 2018

JCO Precision Oncology

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Purpose MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. Methods We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). Results MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. Conclusion MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.

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Section: Discussionmentioning

confidence: 99%

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Kato

Ross

Gay

et al. 2018

JCO Precision Oncology

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“…Other potential biomarkers of response have also been proposed, including immune-related gene signatures [43,96], and baseline hematological measures, such as neutrophil-lymphocyte ratio [97]. Notably, TMB and neoantigen formation are increased in tumors with DNA repair deficiencies caused by, for example, loss-of-function mutations in homologous recombination and mismatch repair (MMR) genes [98]. In tumors with deficient mismatch repair (dMMR) and microsatellite instability (MSI), a high mutational and neoantigen burden is associated with a favorable response to ICI [99].…”

Section: Future Perspectivementioning

confidence: 99%

Patient Selection for Anti-PD-1/PD-L1 Therapy in Advanced Non-Small-Cell Lung Cancer: Implications for Clinical Practice

et al. 2018

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Immune checkpoint inhibitors targeting PD-1 or PD-L1 represent a standard treatment option for patients with advanced non-small-cell lung cancer. However, a substantial proportion of patients will not benefit from these treatments, and robust biomarkers are required to help clinicians select patients who are most likely to benefit. Here, we discuss the available evidence on the utility of clinical characteristics in the selection of patients with advanced non-small-cell lung cancer as potential candidates for single-agent anti-PD-1/PD-L1 therapy, and provide practical guidance to clinicians on identifying those patients who are most likely to benefit. Recommendations on the use of immune checkpoint inhibitor in clinically challenging populations are also provided.

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“…15, 2018; subtype. The DNA repair defects thus drive genomic instability and dysregulate tumor microenvironment [32]. loss has been shown to define a distinct molecular subtype of clear cell renal cell carcinoma (ccRCC) and UM [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

Shrestha

Nabavi

Lin

et al. 2018

Preprint

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DNA Damage and Repair Biomarkers of Immunotherapy Response

Cited by 538 publications

References 185 publications

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Patient Selection for Anti-PD-1/PD-L1 Therapy in Advanced Non-Small-Cell Lung Cancer: Implications for Clinical Practice

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

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