Real-world patterns on tumor mutation burden testing in a pan-tumor population

Background: There is limited real-world information on use of tumor mutational burden (TMB) testing and characteristics of patients receiving it. Materials & methods: Patients ≥18 years old and diagnosed with advanced solid tumors between 1 January 2015 and 31 January 2019 with TMB testing (TMB cohort) and without it (non-TMB) were included in this retrospective, observational study. Results: The TMB cohort (n = 202) was younger than non-TMB (n = 212) (mean age 62.1 vs 65.6 at diagnosis; p = 0.005). There were more Black patients in the TMB cohort (21.3 vs 11.8% in non-TMB; p = 0.004). Clinical characteristics were comparable between the two cohorts; however, systemic anticancer treatment was higher among TMB cohort (91.6 vs 77.8% in non-TMB). Conclusion: Notable differences were observed between patients receiving TMB test and those not receiving it.

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DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden

PLoS ONE ◽

10.1371/journal.pone.0244558 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244558

Author(s):

McKayla J. Riggs ◽

Nan Lin ◽

Chi Wang ◽

Dava W. Piecoro ◽

Rachel W. Miller ◽

...

Keyword(s):

Endometrial Cancer ◽

Microsatellite Instability ◽

Information Exchange ◽

P Value ◽

Tumor Mutation Burden ◽

Prognostic Features ◽

Oncology Research ◽

Mutational Burden ◽

Mutation Burden ◽

Tumor Mutational Burden

Objective DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. Methods We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). Conclusions DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.

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Prolonged Response to Anti–PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2019.7304 ◽

2019 ◽

Vol 17 (6) ◽

pp. 644-648 ◽

Cited By ~ 2

Author(s):

Olumide Gbolahan ◽

Neda Hashemi-Sadraei ◽

Bert O’Neil

Keyword(s):

Overall Survival ◽

Clinical Symptoms ◽

Checkpoint Inhibitors ◽

Antibody Therapy ◽

Tumor Mutation Burden ◽

Mutational Burden ◽

Mutation Burden ◽

Tumor Mutational Burden ◽

Tumor Genome ◽

Prolonged Response

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

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PD-L1 expression landscape and its relationship with tumor mutation burden in Chinese cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15267 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15267-e15267

Author(s):

Haihua Yang ◽

Longgang Cui ◽

Yuzi Zhang ◽

Zhengyi Zhao ◽

Yuezong Bai ◽

...

Keyword(s):

Cancer Patients ◽

Expression Profiles ◽

Chinese Patients ◽

Cancer Type ◽

Tissue Samples ◽

Tumor Mutation Burden ◽

Mutational Burden ◽

Mutation Burden ◽

Tumor Mutational Burden ◽

Chinese Cancer Patients

e15267 Background: Little is known about the pan-cancer PD-L1 expression landscape in Chinese patients although PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer. We did a cross-sectional analysis to assess the PD-L1 expression landscape in Chinese patients and its relationship with Tumor mutation burden (TMB). Methods: Tissue samples were collected from more than 8,000 consecutive cases in China between January, 2017, and August, 2019 and were analyzed by 3D Medicines, a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The method for NGS sequencing and tumor mutational burden (TMB) measurement were described previously. Clinical data and PD-L1 expression profiles were obtained from 8,063 patients whose tissue samples assed quality control. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay (Dako North America, Carpentaria, CA, U.S.) or Ventana PD-L1 SP263 assay (Ventana Medical Systems, Tucson, AZ, U.S.). PD-L1 expression was determined using Tumor Proportion Score (TPS), the percentage of viable tumor cells stained. Results: PD-L1 expression was examined for 8,063 tissue samples collected from more than 18 different types of solid tumors. There were 4,866 (60%) male and 3,197 (40%) female patients. Their median age was 59 (IQR range, 50-66) years. Given the significance of different cut-points of PD-L1 expression in predicting clinical outcomes, expression levels of PD-L1 were arranged into the following intervals: < 1%, 1%-5%, 5%-50% and ≥50% for each cancer type. Small cell lung cancer (SCLC) had the lowest and Squamous Carcinoma of Head and Neck (HNSC) had the highest levels of PD-L1 expression. Spearman correlation analysis indicated no correlation between PD-L1 and tumor mutational burden (TMB) for Chinese cancer patients (R = 0.1, P < 0.01), which is in line with the previous reports that PD-L1 and TMB were two independent predictors in immunotherapy. Conclusions: The landscape of PD-L1 expression among Chinese cancer population in this study will further assist the utilization of PD-L1 as a predictive biomarker in clinical practice.

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The landscape of POLE variants in colorectal and endometrial tumors: Correlation with microsatellite instability (MSI) and tumor mutation burden (TMB).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13538 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13538-e13538

Author(s):

Sanjeevani Arora ◽

Joanne Xiu ◽

Davendra Sohal ◽

Emil Lou ◽

Richard M. Goldberg ◽

...

Keyword(s):

Life Sciences ◽

Mutation Rates ◽

Chi Square ◽

Tumor Mutation Burden ◽

Pathogenic Variants ◽

Mutational Burden ◽

Mutation Burden ◽

Tumor Mutational Burden ◽

Polymerase Epsilon ◽

Very High

e13538 Background: Polymerase epsilon (POLE) is a major replicative DNA polymerase. Somatic POLE pathogenic variants (PV) are prevalent in endometrial cancer (EC) and in germline predispose to colorectal cancer (CRC), EC, and possibly other cancers (CA). PVs in the exonuclease domain (ExoD) [amino acid (AA) 268-471] lead to CAs with exceptionally high TMB. PV and uncertain variants (VUS) outside ExoD are sometimes concurrent with an ExoD PV and/or MSI. We hypothesized that the presence of non-ExoD variants may further increase POLE-associated mutation rate and tumor mutational burden. Methods: We retrospectively examined 1870 CRC and 4481 EC genomic profiles conducted by Caris Life Sciences (6/2016-6/2019). All patients had a 592-targeted gene somatic panel. Profiles with a POLE variant (PV or VUS) were analyzed. Median TMB (TMB, in mutations/megabase) was dichotomized to low/intermed ( < 17) vs high (>17). Tumors were grouped by: single ExoD PV, ExoD PV plus another variant (PV or VUS), or no ExoD PV. Known CRC/EC ExoD PV drivers were identified (Campbell et al, Cell 2017): D275G, P286R, S297F/Y, F367C/L/V, V411L, L424F, P436R/S/Y, M444K/L, A456P, S459F/Y, S461L/P, A465V. Kruskal-Wallis and chi-square tests were used. Results: Overall 4.5% CRC (80/1870) and 6.5% EC (303/4481) samples had POLE variants (Table). High TMB was seen in 56.3% CRC and 53.3% EC. In both CRC/ECs, TMB was higher in tumors with an ExoD PV and a 2nd variant compared to those with a solitary ExoD PV or no ExoD PV (both p < 0.001). MSI was more prevalent in CRC and EC with high TMB but no ExoD PV vs those with either high TMB and an ExoD PV, or low/intermed TMB and no ExoD PV (both p < 0.001). In both CRC/ECs, several ExoD PV associated with very high TMB when non-ExoD regions of POLE contained recurrent variant clusters: AA 1906 (TMB 225); AA 1826-7 (TMB 243); AA 1380-2 (TMB 229). Conclusions: In CRC/ECs, POLE ExoD PV and MSI appear to drive TMB in distinct and largely non-overlapping ways. Non-ExoD POLE variants may synergize with ExoD PVs to further increase mutation rates. [Table: see text]

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Fewer actionable mutations but higher tumor mutational burden characterizes NSCLC in black patients at an urban academic medical center

Oncotarget ◽

10.18632/oncotarget.27212 ◽

2019 ◽

Vol 10 (56) ◽

pp. 5817-5823 ◽

Cited By ~ 1

Author(s):

Noura J. Choudhury ◽

Mansooreh Eghtesad ◽

Sabah Kadri ◽

John Cursio ◽

Lauren Ritterhouse ◽

...

Keyword(s):

Medical Center ◽

Academic Medical Center ◽

Mutational Burden ◽

Academic Medical ◽

Black Patients ◽

Tumor Mutational Burden

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Abstract CT194: Exploratory subgroup analysis of atezolizumab (atezo) clinical characteristics in patients (pts) with low circulating tumor DNA (ctDNA) in B-F1RST—a Phase II trial evaluating blood-based tumor mutational burden (bTMB) in NSCLC

10.1158/1538-7445.am2019-ct194 ◽

2019 ◽

Author(s):

Mark A. Socinski ◽

Sarah M. Paul ◽

Cindy Yun ◽

Sylvia Hu ◽

Vincent Shen ◽

...

Keyword(s):

Phase Ii ◽

Subgroup Analysis ◽

Clinical Characteristics ◽

Phase Ii Trial ◽

Circulating Tumor Dna ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Tumor Dna

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Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4086 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4086-4086 ◽

Cited By ~ 2

Author(s):

Apurva Jain ◽

Rachna T. Shroff ◽

Mingxin Zuo ◽

Jacqueline Weatherly ◽

Funda Meric-Bernstam ◽

...

Keyword(s):

Dna Repair ◽

Biliary Tract ◽

Checkpoint Inhibitors ◽

Repair Pathway ◽

Biliary Tract Cancers ◽

Mutational Burden ◽

Study Results ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Brca1 Brca2

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.

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Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000147 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000147 ◽

Cited By ~ 24

Author(s):

Diana M Merino ◽

Lisa M McShane ◽

David Fabrizio ◽

Vincent Funari ◽

Shu-Jen Chen ◽

...

Keyword(s):

Linear Regression ◽

Predictive Biomarker ◽

Regression Analyses ◽

Reference Standard ◽

Bioinformatics Pipeline ◽

Mutational Burden ◽

Study Results ◽

Tumor Mutational Burden ◽

Cancer Types ◽

Prediction Limits

BackgroundTumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms.MethodsEleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits.ResultsStudy results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers.ConclusionsIncreasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

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