scholarly journals Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 445 ◽  
Author(s):  
David Vossen ◽  
Caroline Verhagen ◽  
Martijn van der Heijden ◽  
Paul Essers ◽  
Harry Bartelink ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Head And Neck ◽  
Genetic Alterations ◽  
Hypopharyngeal Carcinoma ◽  
Advanced Stage ◽  
Biopsy Material ◽  
Tumor Biopsy ◽  
Mutational Burden ◽  
Hpv Status ◽  
Tumor Mutational Burden

About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.

scholarly journals IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Valeria Barresi ◽  
Michele Simbolo ◽  
Andrea Mafficini ◽  
Maurizio Martini ◽  
Martina Calicchia ◽  
...  
Keyword(s):  
Giant Cells ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Molecular Profile ◽  
Wild Type ◽  
Mutational Burden ◽  
Check Point Inhibitors ◽  
Tumor Mutational Burden ◽  
Molecular Landscape ◽  
Promoter Mutations

AbstractGiant cell glioblastoma (GC-GBM) is a rare variant of IDH-wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between IDH-wt and IDH-mutant GBM. The lack of an objective definition, specifying the percentage of giant cells required for this diagnosis, may account for the absence of a definite molecular profile of this variant. This study aimed to clarify the molecular landscape of GC-GBM, exploring the mutations and copy number variations of 458 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI) in 39 GBMs dichotomized into having 30–49% (15 cases) or ≥ 50% (24 cases) GCs. The type and prevalence of the genetic alterations in this series was not associated with the GCs content (< 50% or ≥ 50%). Most cases (82% and 51.2%) had impairment in TP53/MDM2 and PTEN/PI3K pathways, but a high proportion also featured TERT promoter mutations (61.5%) and RB1 (25.6%) or NF1 (25.6%) alterations. EGFR amplification was detected in 18% cases in association with a shorter overall survival (P = 0.004). Sixteen (41%) cases had a TMB > 10 mut/Mb, including two (5%) that harbored MSI and one with a POLE mutation. The frequency of RB1 and NF1 alterations and TMB counts were significantly higher compared to 567 IDH wild type (P < 0.0001; P = 0.0003; P < 0.0001) and 26 IDH-mutant (P < 0.0001; P = 0.0227; P < 0.0001) GBMs in the TCGA PanCancer Atlas cohort. These findings demonstrate that the molecular landscape of GBMs with at least 30% giant cells is dominated by the impairment of TP53/MDM2 and PTEN/PI3K pathways, and additionally characterized by frequent RB1 alterations and hypermutation and by EGFR amplification in more aggressive cases. The high frequency of hypermutated cases suggests that GC-GBMs might be candidates for immune check-point inhibitors clinical trials.

PD-1 Blockade Elicits Ongoing Remission in Two Cases of Refractory Microsatellite-Stable Cancer Harboring a POLE Mutation

2021 ◽  
Author(s):  
Kristina Schenck ◽  
Michael Masetti ◽  
Nicole Pfarr ◽  
Sylvie Lorenzen
Keyword(s):  
Immune Checkpoint ◽  
Genetic Alterations ◽  
Chemotherapeutic Agents ◽  
Neuroendocrine Neoplasm ◽  
Cancer Drug ◽  
Standard Chemotherapy ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Cell Death Protein ◽  
The U.S

Introduction: In the last decade immune checkpoint therapy has led to a break-through in the treatment of cancer across all entities, while molecular markers have grown in importance for the choice of the appropriate chemotherapeutic agents. Accordingly, in 2017 the U.S. Food and Drug Administration (FDA) approved the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, a tissue agnostic cancer drug, for the treatment of cancer that displays microsatellite instability (MSI), regardless of histological entity and site of origin. However, a growing number of studies report that cases of microsatellite stable (MSS) tumors harboring a DNA polymerase ε (POLE) mutation, a gene associated with proofreading deficiency, leading to an increased tumor mutational burden (TMB), likewise benefit from immune checkpoint therapy. Case report: Here we present two cases - one advanced adenocarcinoma of the ileum and one mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN), both MSS and carrying a POLE mutation - that were refractory to initial chemotherapy but responded on immunotherapy with pembrolizumab. Conclusion: Colorectal cancer is a clinically and molecularly heterogenic disease which requires comprehensive genetic testing to screen for rare genetic alterations like POLE mutations to detect tumors harboring an ultramutator phenotype especially in patients that are refractory to standard chemotherapy.

Biomarkers of Chinese advanced cancer patients based on real-world data: Actionable genomic alterations and tumor mutational burden.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14280-e14280
Author(s):  
HaiTao Wang ◽  
Huina Wang ◽  
Rongyun Guo ◽  
Mingwei Li ◽  
Yanrui Zhang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Real World ◽  
Cell Cancer ◽  
Objective Response ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tumor Type ◽  
Mutational Burden ◽  
Esophagogastric Cancer ◽  
Tumor Mutational Burden

e14280 Background: Biomarkers would enrich patients(pts) with responsiveness to both targeted treatments and immunotherapy which have become a priority. However, molecular heterogeneous in actionable gene alterations and mutational loads need to be explored. In this study, based on a real world setting, Cancer Gene Panel (CGP） analysis was performed in a series samples of Chinese pts with advanced solid tumors, to delineate the landscape of actionable mutations and tumor mutational burden (TMB). Methods: 176 advanced pts were enrolled encompassing 19 common tumor types. All tissue samples were analyzed using next-generation sequencing with Acornmed panel including 808 genes. Results: The frequencies of genetic alterations among the most common driver genes were comparable to those reported by MSK-IMPACT (2018) ( TP53: 51.7% vs 44.8%; APC: 9.7% vs 9.8%; EGFR: 12.5% vs 7.7%; KRAS: 16.5% vs 13.6%; PIK3CA: 4.6% vs 12.0%; VHL: 4.0% vs 6.7%). 58.3% of pts with refractory solid tumors had at least one actionable mutation. Among those pts, 16.7% of them including CDK4, CDK6 or CDKN2A/B could benefit from palbociclib, and 32.1% of them including mTOR, PIK3CA, PTEN or STK11 could benefit from everolimus, and 61.9% of them including BRCA2, ARID1A, MSH1/2/6 or ATM could benefit from olaparib. Across all the specimens, the top 20% of TMB was 17.23 mutations/Mb, with a range of 0-48 mutations/Mb. The top 20% of TMB for each tumor type was 21.67(Bladder cancer), 17.23(Lung cancer), 16.45(Colorectal cancer), 11.04 (Renal cell cancer), 16.25 (Prostate cancer) , 19.70 (Hepatobiliary cancer), 14.78 (Esophagogastric cancer), 7.80 (Pancreatic cancer), 25.31 (undefined tumor) mutations/Mb respectively. Conclusions: This study indicates that most of pts with advanced refractory solid tumors have at least one actionable mutation, and matched therapies may confer clinical benefit. TMB fluctuated wildly across different cancer types, illustrating the unequal objective response rate of immunotherapy across various cancer type. Furthermore, CGP analysis in advanced pan-cancer pts can provide opportunities for targeted therapies and immunotherapy, especially in those with refractory cancer.

scholarly journals Case Report: Sequential Chemotherapy and Immunotherapy Produce Sustained Response in Osteosarcoma With High Tumor Mutational Burden

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuier Zheng ◽  
Fenglin Wang ◽  
Jin Huang ◽  
Yan Zhou ◽  
Quanjun Yang ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Lower Lobe ◽  
Genetic Alterations ◽  
Primary Lesion ◽  
Pathway Enrichment Analysis ◽  
Significant Heterogeneity ◽  
Sequential Chemotherapy ◽  
Good Tolerance ◽  
Mutational Burden ◽  
Tumor Mutational Burden

BackgroundImmunotherapy has provided an effective method for the treatment of many cancers. However, its efficacy in osteosarcoma is not satisfactory so far.Case PresentationHere, we presented a case of osteosarcoma treated with sequential chemotherapy and immunotherapy and showed promising therapeutic potential. The 29-year-old female patient presented 9th rib osteosarcoma with suspected right lung lower lobe metastasis. Surgery was performed to remove the primary lesion, and a series of chemotherapies were given afterward in consideration of the response and tolerance. The right lung lower lobe metastasis was under control first but progressed (PD) 9 months after the initiation of therapy. The lesion was surgically removed and subsequent chemotherapy was implemented. The patient had good tolerance with chemotherapy and maintained well for approximately 11 months before the discovery of 11th rib and right lung upper lobe metastases. Surgery was then performed on both lesions and achieved complete response. Post-surgical brief chemotherapy and subsequent long-term immunotherapy (pembrolizumab) maintained continuous remission for 33 months. The patient survived for 60 months with well-controlled disease from the time of confirmed diagnosis. Genetic alterations of all primary and metastatic lesions were investigated by whole-exome sequencing (WES). Substantial similarity in mutational landscape between the primary lesion and 11th rib metastasis and between the two lung metastases were revealed, while substantial heterogeneity was found between the rib lesions and lung metastases. The tumor mutational burden (TMB) for the 9th rib primary lesion, the metastatic 11th rib lesion, and the metastatic right upper and lower lobe nodule tissues was 8.02, 2.38, 4.61, and 0.14 mutations/Mb, respectively. The primary lesion exhibited the most diverse copy number variation (CNV) changes among all lesions. Furthermore, pathway enrichment analysis also suggested significant heterogeneity among the lesions.ConclusionsSurgery with sequential chemotherapy and maintenance immunotherapy was shown to have good response for the first time on osteosarcoma patient who had high TMB tumor lesions and good tolerance for chemotherapy and immunotherapy.

scholarly journals Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer

2021 ◽  
pp. 817-826
Author(s):  
Ajaratu Keshinro ◽  
Chad Vanderbilt ◽  
Jin K. Kim ◽  
Canan Firat ◽  
Chin-Tung Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Structural Changes ◽  
Transforming Growth Factor ◽  
Tumor Infiltrating Lymphocytes ◽  
Genetic Alterations ◽  
High Power Field ◽  
Colon Tumors ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Infiltrating Lymphocytes

PURPOSE To characterize the relationship between tumor-infiltrating lymphocytes (TIL), tumor mutational burden (TMB), and genetic alterations in microsatellite stable (MSS), microsatellite instability (MSI), or mutant POLE/POLD1 colon cancer. MATERIALS AND METHODS Four hundred ninety-nine resected stage I-III colon tumors treated between 2014 and 2019 were assessed for TIL; somatic mutations, copy number alterations, and structural changes in > 400 oncogenes; and MSI status. RESULTS Of the 499 tumors analyzed, 313 were MSS, 175 were MSI, and 11 had POLE/POLD1 pathogenic mutations. Both the percentage of tumors with a high level of TIL (≥ 4 lymphocytes per high-power field) and the median TMB differed significantly between the three phenotypes: MSS, 4.5% and 6 mutations/Mb; MSI, 68% and 54 mutations/Mb; POLE/POLD1, 82% and 158 mutations/Mb ( P < .05). Within each phenotype, TMB did not vary significantly with TIL level. Among MSI tumors, the median number of frameshift indels was significantly higher in tumors with high levels of TIL (20 v 17; P = .018). In the MSS group, significantly higher proportions of tumors with high levels of TIL had mutations in the transforming growth factor-β (36% v 12%; P = .01), RAS (86% v 54%; P = .02), and Hippo (7% v 1%; P = .046) pathways; in contrast, TP53 alterations were associated with low levels of TIL (74% v 43%; P = .01). CONCLUSION The association between TIL, TMB, and genetic alterations varies significantly between MSI, MSS, and mutant POLE/POLD1 colon tumors. These differences may help explain tumoral immunity and lead to predictors of response to immunotherapy.

scholarly journals The Clinical Implications of Tumor Mutational Burden in Osteosarcoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Lu Xie ◽  
Yufei Yang ◽  
Wei Guo ◽  
Dongxue Che ◽  
Jie Xu ◽  
...  
Keyword(s):  
Cox Regression ◽  
White Blood Cells ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Tissue Samples ◽  
Mutational Burden ◽  
Kaplan Meier ◽  
Whole Exome ◽  
Tumor Mutational Burden ◽  
Somatic Alterations

BackgroundOsteosarcoma (OTS) is aggressive bone malignancy without well-recognized prognosis biomarker. Tumor mutational burden (TMB) has been proved as effective biomarker in predicting clinical outcomes in several cancer types. However, its prognostic value in OTS remains unknown. In this study, we aim to evaluate the implication of TMB in OTS patients.MethodsTo depict the landscape of somatic mutations in OTS, we performed Whole-Exome Sequencing (WES) on 31 OTS tissue samples and corresponding White Blood Cells (WBCs) as matched control. TMB was calculated as the total number of somatic alterations in coding regions normalized to the per sequenced genomic megabase (~30.4Mb in WES). The prognostic values of TMB were evaluated by Kaplan-Meier methods and Cox regression models.ResultsThe median age was 16.0 years at diagnosis, and 54.8% of patients were male. The most common genetic alterations were mainly involved in cell cycle and DNA damage response and repair, including H3F3A, TP53, MYC, and CDKN2A/B. The median progression-free survival (PFS) was 775.5 days in TMB-High (defined as third quartile of TMB value, &lt;2.565) versus 351 days in TMB-Low (&lt;2.565). All patients with TMB-High are PFS-Long (&gt;400 days), while 36.4% of all patients with TMB-Low were PFS-Long (P=0.003). TMB were significantly greater in PFS-Long than in PFS-Short (&lt;400 days) (P=0.002). Moreover, the median overall survival (OS) was 1,307 days in TMB-High versus 672.5 days in TMB-Low. Furthermore, TMB-High group had significantly improved PFS (P=0.04) and OS (P=0.03).ConclusionsTMB-High can be used as prognostic marker for OTS. Our findings demonstrate that TMB may be helpful in combination with traditionally clinicopathologic risk factors to optimize risk stratification and guide treatment decisions.

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