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  • American Association for Cancer Research (AACR)  (36)
  • 1
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    Online Resource
    Abstract 3468: Immunoproteasome expression and checkpoint blockade response in advanced non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3468-3468
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3468-3468
    Abstract: Responders to checkpoint blockade in Non Small Cell Lung Cancer (NSCLC) often feature an inflamed microenvironment prior to therapy. However, the complete set of molecular drivers connecting this histologic observation to enhanced tumor clearance remain enigmatic. In updated analysis of the Stand Up 2 Cancer-Mark Foundation (SU2C-MARK) Cohort - a collection of 393 patients with whole exome and/or RNA sequencing along with matched checkpoint blockade response annotation - we identify a prominent predictive role for inducible components of the immunoproteasome, a non-canonical peptide processing complex upstream of antigen presentation. Notably, these subunits are enriched as predictors relative to interferon-inducible genes as well as proteasome components in general, and are consistently associated with objective response, progression-free survival and overall survival. Expression of Immunoproteasome subunits associates positively with TCR (but not BCR) burden, supporting a mechanistic model in which enhanced immunoproteasome processivity leads to superior T-cell recognition. Furthermore, although they are known to be targets of interferon gamma (IFNɣ), we demonstrate that their expression is better modeled via a combination of IFNɣ and tumor necrosis factor-α (TNFα) levels, suggesting they may act as integrators of multiple cytokine cascades. Given the fact that the immunoproteasome can alter both antigen quantity as well as quality (including peptide cleavage site preference), the enhanced expression of this complex in the setting of checkpoint blockade response may have important implications for modeling of antigen presentation. These data also suggest novel strategies to enhance immune checkpoint blockade. Citation Format: Vivek Naranbhai, Arvind Ravi, Matthew Hellmann, Monica Arniella, Mark Holton, Samuel Freeman, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron Griffin, Natalie Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick Forde, Valsamo Anagnostou, Jonathan Riess, Don Gibbons, Nathan Pennell, Vamsidhar Velcheti, Subba Digumarthy, Mari Mino-Kenudson, Andrea Califano, John Heymach, Roy Herbst, Julie Brahmer, Kurt Schalper, Victor Velculescu, Brian Henick, Naiyer Rizvi, Pasi Janne, Mark Awad, Andrew Chow, Benjamin Greenbaum, Marta Luksza, Alice Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin Gainor. Immunoproteasome expression and checkpoint blockade response in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3468.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3468
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Deep Learning to Estimate RECIST in Patients with NSCLC Treated with PD-1 Blockade
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 1 ( 2021-01-01), p. 59-67
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 1 ( 2021-01-01), p. 59-67
    Abstract: Real-world evidence (RWE), conclusions derived from analysis of patients not treated in clinical trials, is increasingly recognized as an opportunity for discovery, to reduce disparities, and to contribute to regulatory approval. Maximal value of RWE may be facilitated through machine-learning techniques to integrate and interrogate large and otherwise underutilized datasets. In cancer research, an ongoing challenge for RWE is the lack of reliable, reproducible, scalable assessment of treatment-specific outcomes. We hypothesized a deep-learning model could be trained to use radiology text reports to estimate gold-standard RECIST-defined outcomes. Using text reports from patients with non–small cell lung cancer treated with PD-1 blockade in a training cohort and two test cohorts, we developed a deep-learning model to accurately estimate best overall response and progression-free survival. Our model may be a tool to determine outcomes at scale, enabling analyses of large clinical databases. Significance: We developed and validated a deep-learning model trained on radiology text reports to estimate gold-standard objective response categories used in clinical trial assessments. This tool may facilitate analysis of large real-world oncology datasets using objective outcome metrics determined more reliably and at greater scale than currently possible. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-0419
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 3
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    Tumor Characteristics Associated with Benefit from Pembrolizumab in Advanced Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 16 ( 2019-08-15), p. 5061-5068
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 16 ( 2019-08-15), p. 5061-5068
    Abstract: Several biomarkers have been individually associated with response to PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non–small cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the relationship between these distinct variables with response to PD-1 blockade and long-term benefit. Experimental Design: We assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4, and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of 4.5 years, range 3.8–5.5 years). Results: PD-L1 expression and CD8 infiltration correlated with each other and each significantly associated with objective response rate (ORR) and progression-free survival (PFS). TMB was independent of PD-L1 and CD8 expression, and trended towards association with ORR and PFS. There was no association between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with overall survival (OS). Among 5 patients with long-term survival & gt;3 years with no additional systemic therapy, PD-L1 expression was the only discriminating feature. The increased predictive value for PFS and OS of composite biomarker inclusive of PD-L1, CD8, CD4, and TMB was limited. Conclusions: In patients with NSCLC treated with PD-1 blockade with long-term follow up, TMB, PD-L1, and CD8 were each associated with benefit from PD-1 blockade. Pretreatment PD-L1 expression was correlated with T lymphocyte infiltration and OS, whereas models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-4275
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
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    Response to Standard Therapies and Comprehensive Genomic Analysis for Patients with Lung Adenocarcinoma with EGFR Exon 20 Insertions
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 10 ( 2021-05-15), p. 2920-2927
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 10 ( 2021-05-15), p. 2920-2927
    Abstract: EGFR exon 20 insertions (ex20ins) are an uncommon genotype in non–small cell lung cancer (NSCLC) for which targeted therapies are under development. We sought to describe treatment outcomes and genomic and immunophenotypic characteristics of these tumors. Experimental Design: We identified sequential patients with NSCLC with EGFR ex20ins and compared their clinical outcomes and pathologic features with other patients with NSCLC. Results: Among 6,290 patients with NSCLC, 106 (2%) had EGFR ex20ins. Patients with EGFR ex20ins were more likely to be Black (14% vs. 6%; P & lt; 0.001) or Asian (22% vs. 10%; P & lt; 0.001) compared with all other patients with NSCLC. Median tumor mutational burden (TMB; 3.5 vs. 5.9; P & lt; 0.001) and proportion of tumors with PD-L1 expression ≥1% (22% vs. 60%; P & lt; 0.001) were lower in EGFR ex20ins compared with other NSCLCs (TMB, n = 5,851 and PD-L1 expression, n = 282) and EGFR del 19/L858R (median TMB, 3.5; P = 0.001 and 39% PD-L1 ≥ 1%; P = 0.02). Compared with a 2:1 cohort of patients with metastatic NSCLC without targetable alterations (n = 192), EGFR ex20ins patients had longer overall survival (median 20 vs. 12 months; HR, 0.56; P = 0.007) and longer time to treatment discontinuation (TTD) for platinum chemotherapy (median, 7 vs. 4 months; HR, 0.6; P = 0.02) and no improvement in TTD for immune checkpoint inhibitors (ICI; HR, 1.75; P = 0.05). Conclusions: With better outcomes on platinum chemotherapy, patients with EGFR ex20ins NSCLC have improved prognosis, lower PD-L1 expression and TMB, and derive less benefit from ICIs compared with patients with NSCLC without targetable oncogenes. Improving molecularly targeted therapies could provide greater benefit for patients with EGFR ex20ins.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-4650
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 18 ( 2021-09-15), p. 5131-5140
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 18 ( 2021-09-15), p. 5131-5140
    Abstract: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). Experimental Design: In patients with non–small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52–0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29–1.37; AUROC = 0.6] . The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08–1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. Conclusions: Thyroid irAEs were associated with response to anti–PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-0921
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract 102: Clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS p.G12C-mutated metastatic non-small cell lung cancer (NSCLC) in the AACR Project GENIE database
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 102-102
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 102-102
    Abstract: Introduction: Mutations in the RAS family of proto-oncogenes are frequently found in NSCLC, with KRAS being the most prevalent mutated isoform. Of KRAS mutations, the most common is KRAS G12C, representing ~40% of KRAS mutations and occurring in ~13% of all lung adenocarcinoma cases. The objective of this study is to describe clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS G12C-mutated metastatic NSCLC using the AACR Project GENIE database. Methods: An observational retrospective study of adult patients ( & gt;18 years of age) with KRAS G12C-mutated metastatic NSCLC from three US academic comprehensive cancer centers in the AACR Project GENIE database was undertaken using de-identified data. Patients were eligible if their tumor tested positive for KRAS G12C mutation by next-generation sequencing at the participating institutions. Event-time distributions were estimated using the Kaplan-Meier method, and multivariable models were fitted to estimate adjusted hazard ratios (aHRs) by Cox proportional models. Patients with large panel sequencing performed up to Dec 31, 2018 were included. All available data until Aug 1, 2019 were collected. Results: Of the 416 eligible patients included in this analysis, 91.6% were white, 64.4% were female, median age at metastatic diagnosis was 68.2 years (range: 37.6-86.2), and 97.1% were former or current smokers. 65.1% of patients had stage 4 NSCLC at diagnosis, and most tumors were adenocarcinomas (85.8%). The KRAS G12C mutation was nearly mutually exclusive (≤ 1.0%) with other actionable driver mutations in EGFR, ALK, ROS1, and BRAF but was co-occurred with STK11 (23.6%) and KEAP1 (9.9%) mutations. Among patients who received PD-(L)1 monotherapy (n=110), median progression-free (mPFS) and overall survival (mOS) were 4.6 and 11.9 months, respectively, while among those who received chemotherapy only (n=133) mPFS and mOS were 4.1 and 12.1 months, respectively. When clinical outcomes were analyzed according to co-occurring genomic alterations, we found that KRAS/STK11 co-mutations were associated with significantly worse outcomes with immunotherapy (PFS: aHR 0.44, P=0.002; OS: aHR 0.42, P=0.003) but not with chemotherapy (PFS: aHR 0.82, P=0.44; OS: aHR 0.81, P=0.43). There was no significant impact of co-occurring KRAS mutations with KEAP1, SMARCA4, ATM, RBM10 and TP53 on clinical outcomes to either PD-(L)1 inhibition or chemotherapy. Conclusions: KRAS G12C mutant NSCLC represents a heterogeneous group of lung cancers and its genomic diversity is reflected in differential responses to therapy. These findings highlight the urgent clinical need for molecular biomarker-driven therapies in this subset of patients. Citation Format: Biagio Ricciuti, Chenguang Wang, Hira Rizvi, Jacklynn Egger, Michele LeNoue-Newton, Marilyn Holt, Shivani Aggarwal, Huakang Tu, Hil Hsu, Xuena Wang, Gataree Ngarmchamnanrith, Victoria Chia, Jocelyn Lee, Robert Scharpf, Valsamo Anagnostou, Christine Lovly, Greg Riely, Mark Awad. Clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS p.G12C-mutated metastatic non-small cell lung cancer (NSCLC) in the AACR Project GENIE database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 102.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-102
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract 2620: Ignoring left truncation in overall survival within real-world genomic-phenomic data leads to inflated survival estimates
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2620-2620
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2620-2620
    Abstract: Studies linking genomic and phenomic data are subject to selection biases, including delayed entry or immortal time bias. Delayed entry can be problematic for time-to-event analyses, but utilization of appropriate statistical methods to account for delayed entry are underutilized. Delayed entry commonly occurs when genomic sequencing results are obtained after the start time for survival estimation. To evaluate the impact of left truncation on overall survival (OS) estimates, we explored outcomes in patients with de novo stage IV non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) from the AACR GENIE Biopharma Collaborative, who had genomic sequencing within a specified timeframe. We analyzed OS from diagnosis and from start of the most common first-line regimen, carboplatin/pemetrexed for NSCLC (N = 212 patients) and FOLFOX for CRC (N = 369 patients). We compared median OS using standard Kaplan-Meier methods to median OS using left truncation methods to account for delayed entry. All NSCLC and CRC patients underwent genomic sequencing after their diagnosis date. Among NSCLC patients on carboplatin/pemetrexed, 41% and among CRC patients on FOLFOX, 14% had sequencing determined after starting first-line regimen. The survfit function in R package survival was used, and the absolute differences and percent differences in median OS estimates were calculated. Failure to account for delayed entry leads to an overestimation of OS, regardless of cohort and start date. Adjusting survival outcomes using left truncation methods reduces the influence of some aspects of selection bias and results in better estimates of time to event outcomes. Analyses from these cohorts can provide meaningful insights about survival outcomes outside the clinical trial setting and may support trial design and reliable selection of control arms. As such, it is imperative that analytic methods to account for the inflated survival estimates are incorporated. EstimateCRC Stage IV (N = 658)NSCLC Stage IV (N = 722)Unadjusted Median (IQR) Overall Survival from Diagnosis (Years)3.2 (2.9, 3.4)2.3 (2.0, 2.5)Median (IQR) Overall Survival from Diagnosis in Years, Adjusting for Delayed Entry2.1 (1.9, 2.4)1.3 (1.1, 1.6)Difference in Medians (Years)1.11.0% Difference in Medians34%44%EstimateCRC Stage IV (N = 369)NSCLC Stage IV (N = 212)Unadjusted Median (IQR) Overall Survival from Most Common First-Line Regimen (Years)2.9 (2.6, 3.4)1.3 (1.0, 1.6)Median (IQR) Overall Survival from Most Common First-Line Regimen in Years, Adjusting for Delayed Entry2.1 (1.8, 2.5)0.9 (0.7, 1.2)Difference in Medians (Years)0.80.4% Difference in Medians28%31% Citation Format: Samantha Brown, Jessica A. Lavery, Eva M. Lepisto, Caroline McCarthy, Hira Rizvi, Celeste Yu, Kenneth L. Kehl, Shawn M. Sweeney, Julia E. Rudolph, Nikolaus Schultz, Ritika Kundra, Brooke Mastrogiacomo, Phillipe Bedard, Jeremy L. Warner, Gregory J. Riely, Deborah Schrag, Katherine S. Panageas, The AACR Project GENIE Consortium. Ignoring left truncation in overall survival within real-world genomic-phenomic data leads to inflated survival estimates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2620.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2620
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 21 ( 2022-11-02), p. 4058-4078
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 21 ( 2022-11-02), p. 4058-4078
    Abstract: The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non–small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non–small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage–specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy. Significance: The complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage–specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-22-1731
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR -Mutant Lung Cancers
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 3 ( 2019-02-01), p. 1063-1069
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 3 ( 2019-02-01), p. 1063-1069
    Abstract: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. Experimental Design: We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. Results: Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P & lt; 0.0001) with a broad range (0.82–17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). Conclusions: TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy. See related commentary by Cheng and Oxnard, p. 899
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-1102
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Abstract 5666: A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5666-5666
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5666-5666
    Abstract: Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICI) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we analyze 211 samples from 99 patients and demonstrate that pre-treatment circulating tumor DNA (ctDNA) and circulating immune profiles are independently associated with DCB. We further show that ctDNA dynamics after a single ICI infusion can identify the majority of patients who will achieve DCB. Integrating these determinants, we describe an entirely noninvasive multi-analyte assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA- On-treatment) that robustly predicted DCB, and that was validated in two independent cohorts (AUC = 0.89-0.93, PPV = 92-100%, HR = 0.04-0.11). Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICI. Citation Format: Barzin Y. Nabet, Mohammad S. Esfahani, Emily G. Hamilton, Jacob J. Chabon, Everett J. Moding, Hira Rizvi, Chloe B. Steen, Aadel A. Chaudhuri, Chih Long Liu, Angela B. Hui, Henning Stehr, Linda Goljenola, Michael C. Jin, Young-Jun Jeon, Diane Tseng, Taha Merghoub, Joel W. Neal, Heather A. Wakelee, Sukhmani K. Padda, Kavitha J. Ramchandran, Millie Das, Rene F. Bonilla, Christopher Yoo, Emily L. Chen, Ryan B. Ko, Aaron M. Newman, Matthew D. Hellmann, Ash A. Alizadeh, Maximilian Diehn. A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5666.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5666
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 410466-3
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