Abstract 355: Tumor mutational burden, microsatellite instability (MSI) status and mutational frequency of 30 DDR genes in Chinese patients with gastric or gastroesophageal junction (GEJ) cancers with different levels of PD-L1 expression

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

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PD-L1 expression, tumor mutational burden, and microsatellite instability status in 746 pancreas ductal adenocarcinomas.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.757 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 757-757

Author(s):

Amanda Hemmerich ◽

Claire I. Edgerly ◽

Daniel Duncan ◽

Richard Huang ◽

Natalie Danziger ◽

...

Keyword(s):

Microsatellite Instability ◽

Mutational Burden ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Positive Score ◽

Combined Positive Score ◽

High Level ◽

Positive Groups

757 Background: Pancreas ductal adenocarcinomas (PDA) has a 5-year survival rate of 6% with a need for new therapeutic options. The approval of pembrolizumab for some gastrointestinal cancers shows the potential of immunotherapy (IMT) in PDA. We evaluated the IMT-associated biomarkers of PD-L1 expression, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 amplification in PDAs. Methods: 746 formalin-fixed paraffin embedded samples were evaluated for PD-L1 IHC using the Dako 22C3 pharmDx assay and scored using tumor proportion score (TPS). The cases had comprehensive genomic profiling (CGP) via DNA sequencing, using a hybrid-capture next-generation sequencing assay (FoundationOne and FoundationOneCDx) for genomic alterations (GAs), TMB, and MSI. Results: PD-L1 was positive (TPS ≥ 1%) in 29% (214/746) and negative in 71% (532/746). 43/214 (20%) of positive cases were high positive (TPS ≥ 50%). TMB (590 cases) had a mean of 3.20, 3.46, and 3.61 mutations/Mb for PD-L1 negative, positive, and high positive groups. 3 hypermutated (TMB ≥ 20) were negative for PD-L1 expression. 3/581 cases were MSI-high with a high TMB score (average 23.53 mutations/Mb). 2 MSI-high cases were negative for PD-L1 and 1 was high positive. PD-L1 amplification was not detected (0/746). Only BCOR was significantly different between PD-L1 high positive and PD-L1 negative tumors (Table). Conclusions: Of 729 PDA cases, 29% were positive (TPS ≥ 1%) for PD-L1 expression while only 6% of all cases showed a high level of PD-L1 expression on tumor cells. TMB high (3/729) and MSI-High (3/729) cases were rare. Only 2 of the TMB high cases were also MSI-high. PD-L1 amplification was not detected. Comparing GAs in PD-L1 high positive vs negative cases was only significantly different for BCOR. Further investigation is needed to see if a combined positive score of PD-L1 expression may identify a subset of patients with PDA who are more likely to respond to IMT. [Table: see text]

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Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.426 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 426-426

Author(s):

Joseph Jacob ◽

Oleg Shapiro ◽

Andrea Necchi ◽

Petros Grivas ◽

Ethan Sokol ◽

...

Keyword(s):

Microsatellite Instability ◽

Metastatic Disease ◽

Clear Cell ◽

High Status ◽

Genomic Profiling ◽

Hybrid Capture ◽

Mutational Burden ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Histologic Subtypes

426 Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 126 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (27%) adenocarcinomas (UrthAC) and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Ages were similar in all groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher TMB and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. MSI high status was absent throughout. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials.[Table: see text]

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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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Landscape of somatic alterations in large-scale solid tumors from an Asian population

10.21203/rs.3.rs-916644/v1 ◽

2021 ◽

Author(s):

Kai Wang ◽

Qun Wu ◽

Herui Yao

Keyword(s):

Large Scale ◽

Asian Population ◽

Chinese Patients ◽

Mutational Burden ◽

American Patient ◽

Tumor Tissues ◽

Tumor Mutational Burden ◽

Somatic Alterations ◽

Comprehensive Comparison ◽

Blood Specimens

Abstract Extending the benefits of tumor molecular profiling for all cancer patients will require comprehensive analysis of tumor genomes across distinct patient populations world-wide. In this study, we performed deep next-generation DNA sequencing (NGS) from tumor tissues and matched blood specimens from over 10,000 patients in China by using a 450-gene comprehensive assay, developed and implemented under international clinical regulations. We performed a comprehensive comparison of somatically altered genes, the distribution of tumor mutational burden (TMB), gene fusion patterns and the spectrum of various somatic alterations between Chinese and American patient populations. In total, 64% of cancers from Chinese patients in this study were found to have clinically actionable genomic alterations, which may affect clinical decisions related to targeted therapy or immunotherapy. These findings describe the similarities and differences between tumors from Chinese and American patients, providing valuable information for personalized medicine.

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Using target capture sequencing detect microsatellite instability(MSI), tumor mutational burden(TMB) and POLE/POLD1 mutations in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e15012 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e15012-e15012

Author(s):

Jing Wang ◽

Dan Liu ◽

Huanwen M. Wu ◽

Yuting Yi ◽

Yan-Fang Guan ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Mutational Burden ◽

Target Capture ◽

Tumor Mutational Burden ◽

Target Capture Sequencing ◽

Capture Sequencing

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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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