Abstract 752: Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden

2019 ◽  
Author(s):  
Kadoaki Ohashi ◽  
Go Makimoto ◽  
Shuta Tomida ◽  
Kazuya Nishii ◽  
Shinichi Toyooka ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Tumor Mutation Burden ◽  
Lung Cancers ◽  
Mutation Burden ◽  
Alk Positive

Abstract 752: Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden

2019 ◽  
Author(s):  
Kadoaki Ohashi ◽  
Go Makimoto ◽  
Shuta Tomida ◽  
Kazuya Nishii ◽  
Shinichi Toyooka ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Tumor Mutation Burden ◽  
Lung Cancers ◽  
Mutation Burden ◽  
Alk Positive

scholarly journals Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden

2019 ◽  
Vol 14 (11) ◽  
pp. 2009-2018 ◽  
Author(s):  
Go Makimoto ◽  
Kadoaki Ohashi ◽  
Shuta Tomida ◽  
Kazuya Nishii ◽  
Takehiro Matsubara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Mutation Burden ◽  
Rapid Acquisition ◽  
Mutation Burden ◽  
Alk Positive

High spatiotemporal heterogeneity, clonal selection and neoantigen evolution in acquired sorafenib-resistant patient-derived xenograft models of hepatocellular carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15641-e15641
Author(s):  
Xin-Rong Yang ◽  
Bo Hu ◽  
Jian Zhou ◽  
Jia Fan
Keyword(s):  
Drug Resistance ◽  
Clonal Selection ◽  
Acquired Resistance ◽  
Tumor Mutation Burden ◽  
Acquired Drug Resistance ◽  
Patient Derived Xenograft ◽  
Mutation Burden ◽  
Spatiotemporal Heterogeneity ◽  
Pdx Models ◽  
Syngeneic Tumors

e15641 Background: Patient-derived xenograft (PDX) models have been regarded as valuable preclinical models for oncology drug development and exploring underlying mechanism of drug resistance. As the standard treatment option for advanced hepatocellular carcinoma (HCC), the survival benefit of sorafenib is modest. Even among those who initially responded well to sorafenib treatment, most patients ultimately develop progressive disease owing to acquired drug resistance. Understanding how selective pressure from sorafenib directs the evolution of HCC and shapes its clonal architecture is a central biological question with important clinical implications to combat acquired drug resistance. Methods: Three sorafenib-resistant PDX models were generated by continuous sorafenib treament for more than six months. Whole exome sequencing (WES) and RNA sequencing were performed. The subclone of mutation, fusion genes, and the evolving landscape of tumor neoantigens were further explored. Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was evaluated in sorafenib resistance syngeneic tumors model by immune-competent C57BL/6J mice with Hepa 1-6. Results: High spatiotemporal heterogeneity was observed in engraftment among pre- and post- sorafenib resistance in established acquired-resistance PDX models. Clonal selection on engraftment was observed in established acquired-resistance PDX models. There are many high expressed genes, which showed subclone expansion with the emergence of sorafenib resistance. There is vary difference of neoantigens between pre- and post-resistance engraftment as well as sampling points in same tissues. It was presented that a high burden of clonal neoantigens in sorafenib resistant tissues (P < 0.05), while there has no difference in tumor mutation burden. Moreover, the intra-tumor heterogeneity upon the neoantigen landscape was much bigger than that upon tumor mutation burden. We found that fusion subclone sizes were increased significantly after sorafenib resistance (P < 0.05). Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was confirmed in sorafenib resistance syngeneic tumors mice model (P < 0.001). Conclusions: High spatiotemporal heterogeneity, clonal selection and neoantigen evolution was observed in acquired sorafenib-resistant PDX model of HCC. Immunotherapy such as immune checkpoint inhibitors might be a promising strategy for HCC patients with acquired sorafenib resistance. .

Genomic profiling of squamous malignancies across anatomic sites.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11512-11512 ◽  
Author(s):  
Christine H. Chung ◽  
Garrett Michael Frampton ◽  
Zachary Rockow Chalmers ◽  
Jon Chung ◽  
Saad A. Khan ◽  
...  
Keyword(s):  
Clinical Care ◽  
Acquired Resistance ◽  
Therapy Response ◽  
Subsequent Development ◽  
Genomic Profiling ◽  
Tumor Mutation Burden ◽  
Genomic Features ◽  
Mutation Burden ◽  
Hpv Status ◽  
Allelic Deletion

11512 Background: Primary squamous cell carcinomas (SCCs) have diverse etiologies, but can share genomic features. We reviewed the genomic profiles of a series of SCC cases of differing anatomic origin. Methods: Hybrid-capture based genomic profiling of 182 or 236 or 315 genes was performed on 4783 squamous malignancies in the course of clinical care, with baits for HPV6, 11, 16, and 18, and assessment of tumor mutation burden (TMB; mutations/Mb) and microsatellite instability. Results: Sites of origin were head and neck (HNSCC, n = 1300), cervical (cSCC; n = 318), anal (aSCC, n = 248), esophageal (n = 242), lung (lSCC, n = 2386), and cutaneous (sSCC, n = 289) SCC cases. For HNSCC, cSCC, and aSCC (collectively termed HCA SCC), 395 (30%), 215 (68%), and 211 (83%) were HPV positive, respectively. For HCA SCC, the most common GA were in TP53 (45%), CDKN2A (29%), PIK3CA (24%), TERT (21%), and FAT1 (14%). The most frequent GA differentially associated with HPV status were in PIK3CA (34.9% versus 16.0%), CYLD (11.4% versus 1.4%) and PTEN (14.8% versus 6.1%) for HPV+ cases, and TP53 (3.8% versus 76.5%), CDKN2A ()1.4% versus 49.8%), and TERT (4.3% versus 33.0%) for HPV- cases. Mean TMB for HPV+ and HPV- cases were 6.6 (STDEV 7.3) and 13.7 (STDEV 29.7), respectively. TMB of all SCC cases was significantly different (p < 10-12) when stratified by HPV status. For lSCC and eSCC, the most common GA were found in TP53 (86%) CDKN2A (40%), and PIK3CA (26%) and mean TMB was 11.6 with HPV found in 3.1% of cases. In sSCC, the most common GA were in TP53 (85.5%), CDKN2A (54.3%), and TERT(44.0%), and mean TMB was 59.5 with HPV in 3.1% of cases. Subsets of SCC cases had defining and targetable GA including bi-allelic deletion of SMARCB1 ( < 0.3%), amplification of PD-L1 (~2% ), and various kinase fusions. Cases demonstrating radiologic response to immunotherapy and matched targeted therapies, as well as subsequent development of multiple mechanisms of acquired resistance, will be presented. Conclusions: HPV driven SCC have similar genomic profiles regardless of of site origin, and have a significantly lower median TMB than HPV negative SCC. Early consistency of responses of SCC to matched therapies may strengthen the case for site independent genomic predictors of therapy response.

PD-L1 expression, tumor mutation burden and response to immune checkpoint blockade in patients with HER2-mutant lung cancers.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 9060-9060 ◽  
Author(s):  
Wei-Chu Victoria Lai ◽  
Daniel L. Feldman ◽  
Darren J. Buonocore ◽  
Edyta B. Brzostowski ◽  
Hira Rizvi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Tumor Mutation Burden ◽  
Lung Cancers ◽  
Mutation Burden

Tumor mutation burden and efficacy of targeted therapy in patients with EGFR mutant lung cancers.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 9042-9042
Author(s):  
Michael David Offin ◽  
Hira Rizvi ◽  
Megan Tenet ◽  
Ai Ni ◽  
Francisco Sanchez Vega ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tumor Mutation Burden ◽  
Lung Cancers ◽  
Mutation Burden ◽  
Egfr Mutant

scholarly journals Effects of tumor mutation burden on the antigen presentation pathway

2021 ◽  
Author(s):  
Enrique M. Garcia-Rivera ◽  
Jiho Park ◽  
Aakash Desai ◽  
Romain Boidot ◽  
Sandy Chevrier ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Free Survival ◽  
Tumor Mutation Burden ◽  
Lung Cancers ◽  
Antigen Presentation Pathway ◽  
Mutation Burden ◽  
Presentation Pathway ◽  
Antigen Presenting ◽  
To Receive

AbstractTumor mutation burden (TMB) is used to select patients to receive immune checkpoint inhibitors (ICIs) but has mixed predictive capabilities. We hypothesized that inactivation of antigen presenting genes (APGs) that result from increased TMBs would result in inherent resistance to ICIs. We observed that somatic mutations in APGs were associated with increasing TMBs across 9,418 tumor samples of 33 different histological subtypes. In adenocarcinomas of the lung, ITGAX and CD1B were some of the most commonly mutated APGs. In 62 patients with non-small cell lung cancers treated with a PD-1 inhibitor in second or later lines of therapy, there was an association of increased TMB with mutations in APGs; however, mutations in one or more APGs were associated with improved progression-free survival. Contrary to our hypothesis, mutations in APGs were associated with improved progression-free survival with nivolumab, possibly due to the involvement of single alleles rather than complete loss.

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