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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e21539-e21539
    Abstract: e21539 Background: Assessment of programmed death ligand-1 (PD-L1) protein expression using immunohistochemistry (IHC)-based tests is currently the only approved biomarker guiding treatment of non-small cell lung cancer (NSCLC) with checkpoint inhibitors. Robust scoring guidelines and suitable cut-offs should be defined specifically for each PD-L1 IHC assay and are critical for appropriate treatment decisions. Methods: We retrospectively applied a novel digital pathology (DP) solution that mimics the conventional tumor proportion scoring (TPS) of PD-L1. The exploratory DP solution was developed and validated using samples from 340 patients enrolled in the first- and second-line (1L and 2L) NSCLC cohorts of the avelumab phase 1 JAVELIN Solid Tumor trial (NCT01772004) and 792 patients with NSCLC enrolled in the avelumab phase 3 JAVELIN Lung 200 trial (NCT02395172). Efficacy analyses were conducted for overall survival (OS) and progression-free survival (PFS) using the full analysis set with evaluable imaging data (n = 136 and n = 544, respectively). Results: Comparison of DP and conventional, semiquantitative pathologist scoring resulted in a high correlation overall (Spearman correlation coefficient, 0.86), with comparable performance for prediction of outcome to treatment with avelumab in 2L NSCLC. Consistent with conventional scoring, median OS and median PFS in avelumab-treated patients increased with higher PD-L1 expression cut-offs: in patients with ≥1%, ≥50%, and ≥80% PD-L1 expression on tumors cells, median OS was 10.0 months (95% CI: 8.6-14.3), 13.8 months (95% CI: 9.6-20.4) and 18.5 months (95% CI: 9.6-not estimable), respectively; median PFS, 3.1 months (95% CI: 2.7-4.9), 5.5 months (95% CI: 2.8-8.3) and 5.6 months (95% CI: 2.8-9.9). Conclusions: Our results demonstrate the technical feasibility, robustness, and utility of DP in scoring PD-L1 IHC in clinical trial samples, achieving comparable performance to conventional, semiquantitative pathologist scoring. Furthermore, our study supports the manual pathologist scoring algorithm (TPS scoring) in NSCLC and the selection of higher cut-offs for the PD-L1 IHC Ab clone 73-10.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 457-457
    Abstract: Background: Automated cell-level characterization of the tumor microenvironment (TME) at scale is key to data-driven immuno-oncology. Artificial intelligence (AI)-powered analysis of hematoxylin and eosin (H & E) images scales and has recently been translated into diagnostics. However, robust TME analysis solely based on H & E data is bound by the stain's properties and by manual pathologist annotations, both in number and accuracy. In this study, we quantify the error introduced by pathologists' morphological assessment and mitigate this error by training AI-systems without manual pathologist annotations, using labels determined directly from IHC profiles. Methods: The work was carried out on 239 clinical NSCLC cases. CK-KL1, CD3+CD20, and Mum1 were used for defining carcinoma (CA), lymphocyte (LY), and plasma (PL) cells. For evaluation, representative regions were annotated by 3 trained pathologists. The workflow is based on co-registration of same-section H & E and IHC stained images with single cell precision. Cells were detected in H & E and labelled using rule-based algorithms that incorporated IHC information. This H & E data was used to train neural networks (NN). Results: (A) The inter-rater agreement of pathologists annotating on H & E is increased when information from registered IHC images is provided. (B) The concordance of pathologists on H & E-only compared to on H & E+IHC shows that pathologists miss or misclassify cells with a certain error. (C) NNs trained with IHC-based labels achieve similar performance for cell type classification on H & E as pathologists on H & E. Conclusion: This study demonstrates the value of combining histomorphological and IHC data for improved cell annotation. Our novel workflow provides a quantitative benchmark and facilitates training of accurate AI models for quantitative characterization of tumor and TME from H & E sections. A) Inter-rater agreement by metric, stain, and cell type By cell count, Pearson correlation By cell count, Pearson correlation By cell location, Krippendorff’s alpha By cell location, Krippendorff’s alpha Cell type H & E-only H & E+IHC H & E-only H & E+IHC CA 0.86 0.98 0.43 0.90 LY 0.88 0.99 0.21 0.76 PL 0.77 0.96 0.32 0.87 B) Performance of individual pathologists in H & E Against consensus in H & E+IHC Against own annotations in H & E+IHC Against own annotations in H & E+IHC Cell type By cell count, Pearson correlation By cell location, Precision By cell location, Recall CA 0.84 0.76 0.77 LY 0.78 0.70 0.60 PL 0.76 0.69 0.21 C) NN against annotator H & E+IHC consensus Cell Type By cell count, Pearson correlation CA 0.84 LY 0.92 PL 0.75 Citation Format: Thomas Mrowiec, Sharon Ruane, Simon Schallenberg, Gabriel Dernbach, Rumyana Todorova, Cornelius Böhm, Walter de Back, Blanca Pablos, Roman Schulte-Sasse, Ivana Trajanovska, Adelaida Creosteanu, Emil Barbuta, Marcus Otte, Christian Ihling, Hans Juergen Grote, Juergen Scheuenpflug, Viktor Matyas, Maximilian Alber, Frederick Klauschen. Immunohistochemistry-informed AI systems for improved characterization of tumor-microenvironment in clinical non-small cell lung cancer H & E samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 457.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
    In: Journal of Thoracic Oncology, Elsevier BV, Vol. 15, No. 8 ( 2020-08), p. 1306-1316
    Type of Medium: Online Resource
    ISSN: 1556-0864
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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  • 4
    Online Resource
    Online Resource
    S. Karger AG ; 2017
    In:  Biomedicine Hub Vol. 2, No. Suppl. 1 ( 2017-11-21), p. 1-8
    In: Biomedicine Hub, S. Karger AG, Vol. 2, No. Suppl. 1 ( 2017-11-21), p. 1-8
    Abstract: 〈 b 〉 〈 i 〉 Background/Aims: 〈 /i 〉 〈 /b 〉 Precision medicine has only been a clinical reality only since the start of the 21st century, spurred on by the coevolution of science and technologies, as well as the increasing medical needs of aging societies of industrialized countries. Its overarching objective, from the perspective of the pharmaceutical and diagnostic industry, is to develop innovative therapeutic “concepts” with increased value for patients in a global health economy context. This article analyzes the recent advances and remaining challenges from a research, medical, and regulatory perspective in the development and introduction of precision medicine in oncology, more precisely in immuno-oncology. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Analysis of the most recent scientific publications and clinical evidence. 〈 b 〉 〈 i 〉 Results and Conclusion: 〈 /i 〉 〈 /b 〉 Stakeholders need to combine efforts in order to turn scientific insights, such as those related to predictive biomarkers, into superior and affordable therapeutic concepts. Policymakers should also help to bring this about by ensuring that a suitable regulatory framework and incentive system are in place in order to encourage groundbreaking innovation, and hence the availability of new treatment options for patients.
    Type of Medium: Online Resource
    ISSN: 2296-6870
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2017
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  • 5
    In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2023-10-11)
    Abstract: The DNA damage response (DDR) pathway regulates DNA repair and cell survival, and inactivating mutations in DDR genes can increase tumour mutational burden (TMB), a predictive biomarker of treatment benefit from anti-PD-1/PD-L1 immunotherapies. However, a better understanding of the relationship among specific DDR mutations, TMB and PD-L1 expression is needed to improve translational strategies. Here, we determined genomic alteration frequencies in selected DDR genes that are clinically actionable biomarkers and investigated their association with TMB and PD-L1 in bladder, colorectal, non-small cell lung, ovarian and prostate cancers using the FoundationInsights ® web portal. Our results not only confirm known associations, such as mismatch repair and POLE gene mutations with high TMB, but also identify significant associations between mutations in the SWI/SNF chromatin remodelling genes ARID1A and SMARCA4 and high TMB in multiple tumour types. Mutations in the ATR gene were associated with high TMB in colorectal and prostate cancers; however, associations between individual DDR mutations and high PD-L1 expression were uncommon and tumour-type specific. Finally, we found that high TMB and high PD-L1 expression were poorly associated, emphasising their independence as predictive biomarkers for immune checkpoint inhibitor use.
    Type of Medium: Online Resource
    ISSN: 2397-768X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 6
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 5 ( 2021-11), p. 1802-1812
    Abstract: MET exon 14 skipping alterations ( METex14) comprise a diverse set of actionable oncogene drivers in non–small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. MATERIALS AND METHODS METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. RESULTS Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. CONCLUSION METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 9012-9012
    Abstract: 9012 Background: In the VISION study, tepotinib in METex14 skipping NSCLC pts (Cohort A) had robust and durable clinical activity. Serial LBx samples were collected for biomarker analyses, presented herein. Methods: LBx samples taken at baseline (BL), Week 6, 12, & end of treatment (EOT) were analyzed using Guardant360 ® CDx (73 genes). Investigator (INV)-assessed clinical outcome was evaluated per BL biomarker profiles and by molecular response (MR; defined as 〉 75% depletion from BL in METex14 variant allele frequency [VAF] ctDNA confirmed in 2 consecutive samples) or molecular progression (MP; defined as VAF increase 〉 0 from BL). Acquired resistance was investigated in EOT samples, following progression per INV. Results: LBx pts (n = 99) had a median age of 72 yrs (range 49–88), 53% were male, 44% never smokers, 85% had adenocarcinoma. INV ORR was 53% (95% CI 42, 63); ORR in 1L (n = 44) was 59% (43, 74) & ≥2L (n = 55) was 47% (33, 61). 94 pts had BL biomarker profiles; these were similar in 1L and ≥2L pts, except EGFR amp: 1/43 1L [2%] vs 8/51 ≥2L [16%] . Outcomes were not impacted by location/type of METex14 alteration. 1 pt with concomitant MET M1250T mutation had a PFS of 17.3 months. A trend towards better efficacy was seen in pts with concomitant MET amp (6 responses in 8 pts). Response to tepotinib occurred both in pts with wt or mutant TP53; however, there was a trend for longer mDOR in pts with wt TP53 (18.3 [95% CI 9.7, ne] vs 7.1 [4.7, 10.9] months) and mPFS (9.5 [6.7, 19.7] vs 5.1 [2.8, 6.9] months). Concomitant oncogenic mutations were rare, with no responses in 3 pts with KRAS, NRAS alterations and 3 responses in 5 pts with PI3K/AKT alterations. 65 pts had 2 consecutive on-treatment samples: 46 (71%) had confirmed MR, 5 (8%) had confirmed MP, 14 (22%) had no change in VAF or lacked confirmation. MR was associated with clinical response and MP was associated with no response/short PFS (Table). 52 pts with progression had EOT LBx samples. Emerging MET resistance mutations (Y1230H/C & D1228H/N) occurred in 7 (13%) pts, all responders and 5/7 had PFS 〉 10 months. Analyses on non-MET-driven resistance mechanisms will be presented. Conclusions: LBx biomarker analysis from the largest on-treatment data set for a MET inhibitor in METex14 skipping NSCLC, showed that ctDNA depletion in METex14 VAF is associated with improved clinical response in pts treated with tepotinib. This suggests serial LBx could help us to monitor response/non-response, understand resistance, and guide trials that test escalation/de-escalation strategies to improve outcomes and maximize QOL. Clinical trial information: NCT02864992. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4704-4704
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4704-4704
    Abstract: Background: It has been recognized that gut microbiome has impact on the cancer immunotherapy efficacy and Cancer Microbiome-Immune Axis is reported. Also, it is important to discover and identify clinically translatable predictive biomarker in gut microbiome to inform the treatment selections. Multiple pre-analytical and analytical steps & factors including the sample collection, DNA extraction, library preparation, sequencing and bioinformatics analysis are associated with the microbiome data interpretation as well as its potential clinical application. 16S amplicon-sequencing coupled with bioinformatics approach for advance analysis provides end-to-end solution. It is therefore essential to develop a clinical-grade assay for targeting & characterization of taxa at genus and species level microbes in stool samples, which is designed as two-phase approach: firstly, identification the optimal sample preparation reagents using pre-mixed bacteria and healthy donor stool samples coupled with proprietary bioinformatics solution; secondly, exploratory analysis of patient samples. Methods: Healthy stool samples (n = 30, gender ratio 1:1, 10 from US west coast, 10 from US mid-west, 10 from US east coast) were extracted across extraction kits (kit A, B and C). Following isolation, bacterial 16S rRNA amplicons were generated and sequenced using a 2 × 300 bp paired-end configuration on the Illumina MiSeq. FASTQ files were analyzed using the Sigma-Aldrich® M-CAMPTM web platform1. Results: We previously compared 5 kits using ATCC® microbiome standards (MSA 2002 and MSA 2003). Kit A, B & C were identified as high yield DNA with the similar relative abundance of microbial family. In current study, we performed the taxonomical classification, diversity analysis and comparative analysis of 16S amplicon-seq using 30 healthy stool samples. The beta diversity showed all 3 kits clustered closely together which indicated the relative abundance of microbial families were similar across the extraction kits. The Weighted Unifrac showed significant difference among the kits (P = 0.046). Kit C species abundance is significantly difference than that of Kit A & Kit B (Pairwise Permanova P = 0.027 (Kit A vs C); P = 0.017 (Kit B vs C); P = 0.991 (Kit A vs B)). Relative frequency-based group-sample level composition at phylum and species level show high level similarity. Conclusion: The comprehensive qualification approaches including the analytically optimized extraction condition and post-analytically implement the bioinformatics solution assures the characterization of microbiota for enabling biomarker driven precision oncology. Analytical performance assessment using colorectal cancer patients’ samples is ongoing for further exploring its potential clinical utilities. Citation Format: Danyi Wang, Brajendra Kumar, Aaron Tenney, Ravi Kiron, Yang Liu, Fei Zhong, Juergen Scheuenpflug, Zheng Feng. Characterizing and developing the clinical grade next generation sequencing based gut microbiome assay with the bioinformatics solution. [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 4704.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5748-5748
    Abstract: Introduction: The patient-centric liquid biopsy approach to detect changes in ctDNA provides an early indication of treatment response to therapies and is an emerging tool to aid clinicians in treatment decision making. We investigated this approach in the mCRC palliative treatment setting by exploring the potential clinical utility of the validated Guardant Health Molecular Response (MR) algorithm. Methods: Longitudinal plasma samples (70) were collected from 14 patients with mCRC and treated using chemotherapy alone or combined with one or more targeting agents. All patients were clinically stable or had clinical benefit over the course of plasma collection. 6 patients had radiological response by RECISTv1.1 and 10 had tumor RAS/RAF mutation status. Baseline and longitudinal plasma samples (27-276 days post treatment) were tested by GuardantOMNI® 500-gene liquid biopsy assay. Selection of qualifying alterations and generation of MR scores were pursued using the Guardant Health MR algorithm. Results: Thirteen patients were evaluable for MR by having somatic alterations at each timepoint that exceeded the molecule threshold required for reliable MR score calculation. Mean variant allele fraction (mVAF) of all plasma samples outside the 4-10 week on-treatment window trended in the same direction as the early on-treatment plasma samples when compared to baseline. Eleven patients experienced a consistent reduction in mVAF compared to baseline. One outlier showed a mVAF increase at the earliest on-treatment timepoint, followed by molecular clearance at all subsequent timepoints. GuardantOMNI® detected a frameshift APC alteration at the baseline of this patient, which may have limited the tumor response to the chemotherapy. The second outlier patient was originally diagnosed as RAS/RAF wild-type and treated with anti-EGFR and anti-PD-L1. MR scores for this patient across all timepoints reflected an increase in mVAF compared to baseline. Notably, GuardantOMNI® detected a low level KRAS alteration in the baseline plasma sample of this patient, indicating this patient’s disease had elements of KRAS alteration that were not detected by tissue-based testing. All 6 patients with RECIST 1.1 information had partial responses (PR) and 5 showed a decrease in the MR score. The one patient whose MR score did not align with radiographic assessment was the mis-genotyped KRAS mutation-positive patient, who is under further investigation. Conclusions: We demonstrate that ctDNA analysis of plasma samples taken at early timepoints (4-10 weeks) after treatment initiation are sufficient to support MR assessments and highlight the advantage of the patient-centric liquid biopsy approach over genetic testing of diagnostic tumor samples in detecting potential resistance mutations prior to therapy. Citation Format: Neil R. Smith, Jean-Christophe Pignon, Scott A. Shell, Arialle Yablonovitch, Juergen Scheuenpflug, Zheng Feng. Longitudinal evaluation of ctDNA molecular response for monitoring clinical benefit and investigating treatment related impacts in metastatic colorectal cancer patients treated with different drug regimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5748.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5737-5737
    Abstract: Background: Following MET inhibitor and checkpoint inhibitor approvals, it is essential to identify cancer indications that harbor molecular alterations of interest and a thorough real-world molecular genomics based characterization of those tumors would allow to expand cancer specific indications that might benefit from MET and checkpoint inhibitors and shed light on exploring clinically efficacious combo strategies. Importantly, such an approach provides the end-to-end solutions that shall significantly contribute to clinical translation and/or back translation strategies for innovative cancer therapies. Methods: We systemically interrogated FoundationInsights®, a dataset of real-world molecular genomic tumor profiling from North American patients, and investigated the prevalence of MET amplifications, METex14 skipping and MET fusions prevalence in 62110 unique patient samples across five indications (lung adenocarcinoma [LUAD], esophageal/gastroesophageal-junction/stomach adenocarcinoma [Eso/GEJ/Sto] , papillary renal cell carcinoma, hepatocellular carcinoma [HCC] and glioblastoma). MET alteration prevalence was further categorized based on tumor cell PD-L1 IHC status (22C3 pharmDx) and TMB status. Additionally, comprehensive text mining from clinicaltrials.gov and landscape overview were conducted. Results: MET amplification was the most frequent MET alteration examined with a prevalence ranging from 1.4% in HCC to 4.8% in Eso/GEJ/Sto. In HCC and LUAD, MET amplification prevalence was higher in tumors with high TMB (≥10 mutations/megabase, P & lt;0.05). In Eso/GEJ/Sto and LUAD, MET amplification occurrence was higher in PD-L1-high tumor vs. PD-L1-low or PD-L1-neg tumors (P & lt;0.05). METex14 skipping mutations were observed in LUAD (2.3%), rarely in the other five tumor types analyzed (≤0.1%). Lastly in LUAD, METex14 skipping mutations were more frequent in PD-L1 high tumors but not those with high TMB (P & lt;0.05). Text mining results indicate that- while most trials use MET amplification for patient stratification- there is a distinct tendency for MET inhibitor trials to increasingly include METex14 skipping as a major selection criterion as well. Conclusions: Real world genomics corroborated MET amplification as a predominant MET alteration across various indication. The potential clinical benefit to combine MET inhibitors with PD-1/PD-L1 blockades in specific indications and specific subsets of patients is further recognized. Collectively, the comprehensive molecular profiling & text mining approaches will continue to guide application of precision medicine in clinical trial design based on appropriate biomarker selection. Citation Format: Zheng Feng, Jean-Christophe Pignon, Radwa Sharaf, Natalie Romanov, Julien Doudement, Lee A. Albacker, Noriaki Kurata, Neil R. Smith, Nobutoshi Matsushita, Juergen Scheuenpflug. Precision oncology driven real world clinical genomics data mining of MET alterations, TMB, and PDL-1 to empower indication agnostic patient enrollment and combination strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5737.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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