Background The National Institute of Standards and Technology (NIST) Reference Material RM 8366 was developed to improve the quality of gene copy measurements of EGFR (epidermal growth factor receptor) and MET (proto-oncogene, receptor tyrosine kinase), important targets for cancer diagnostics and treatment. The reference material is composed of genomic DNA prepared from six human cancer cell lines with different levels of amplification of the target genes. Methods The reference values for the ratios of the EGFR and MET gene copy numbers to the copy numbers of reference genes were measured using digital PCR. The digital PCR measurements were confirmed by two additional laboratories. The samples were also characterized using Next Generation Sequencing (NGS) methods including whole genome sequencing (WGS) at three levels of coverage (approximately 1 ×, 5 ×  and greater than 30 ×), whole exome sequencing (WES), and two different pan-cancer gene panels. The WES data were analyzed using three different bioinformatic algorithms. Results The certified values (digital PCR) for EGFR and MET were in good agreement (within 20%) with the values obtained from the different NGS methods and algorithms for five of the six components; one component had lower NGS values. Conclusions This study shows that NIST RM 8366 is a valuable reference material to evaluate the performance of assays that assess EGFR and MET gene copy number measurements.

/pdf/development-and-interlaboratory-evaluation-of-a-nist-48dpnqskz2.pdf

Development and interlaboratory evaluation of a NIST Reference Material RM 8366 for EGFR and MET gene copy number measurements.

Background MET amplification or METex14 skipping mutations are uncommon oncogenic events in NSCLC patients. Clinicopathological characteristics, concurrent gene alterations, and prognosis of MET TKIs in these patients are yet to be elucidated. Methods We retrospectively analyzed the genomic profiles of 43 MET amplifications or 31 METex14 skipping mutations in NSCLC patients with no previous treatment with EGFR TKIs. Survival outcomes were analyzed in evaluable patients receiving MET TKI treatment: MET amplification cohort (n = 29) and METex14 skipping mutation cohort (n = 29). Results Among evaluable patients, a shorter PFS was observed in the MET amplification cohort than in the METex14 skipping mutation cohort (7.0 months vs. 11.0 months, P = 0.043). Concurrent mutations in both cohorts resulted in a statistically significant shorter PFS (MET amplification: 3.5 months versus 8.0 months, P = 0.038, METex14 skipping mutation: 7.0 versus NR months, P = 0.022). However, a statistically significant OS (17.0 months versus 20.0 months, P = 0.044) was only observed in the MET amplification cohort. TP53, the most common concurrent mutation in both cohorts, was associated with worse survival outcomes as compared to the wild type. The MET amplification cohort with a concurrent PIK3CA mutation exhibited primary resistance to MET TKIs and showed disease progression (80%). Conclusion MET TKIs could be a better treatment option for patients with METex14 skipping mutations. Concurrent mutations may deteriorate the PFS of MET TKIs in NSCLC patients with MET amplification or METex14 skipping mutations. PIK3CA mutations may confer primary resistance to MET TKIs in patients with MET amplification.

/pdf/prognosis-and-concurrent-genomic-alterations-in-patients-13pckolu2b.pdf

Prognosis and Concurrent Genomic Alterations in Patients With Advanced NSCLC Harboring MET Amplification or MET Exon 14 Skipping Mutation Treated With MET Inhibitor: A Retrospective Study.

Lung cancer (LC) is one of the most incident malignancies and a leading cause of cancer mortality worldwide. Common tumorigenic drivers of LC mainly include genetic alterations of EGFR, ALK, KRAS, BRAF, ROS1, and MET. Small inhibitory molecules and antibodies selectively targeting these alterations or/and their downstream signaling pathways have been approved for treatment of LC. Unfortunately, following initial positive responses to these targeted therapies, a large number of patients show dismal prognosis due to the occurrence of resistance mechanisms, such as novel mutations of these genes and activation of alternative signaling pathways. Over the past decade, it has become clear that there is no possible cure for LC unless potent antitumor immune responses are induced by therapeutic intervention. Immunogenic cell death (ICD) is a newly emerged concept, a form of regulated cell death that is sufficient to activate adaptive immune responses against tumor cells. It transforms dying cancer cells into a therapeutic vaccine and stimulates long-lasting protective antitumor immunity. In this review, we discuss the key targetable genetic aberrations and the underlying mechanism of ICD in LC. Various agents inducing ICD are summarized and the possibility of harnessing ICD in LC immunotherapy is further explored.

https://www.frontiersin.org/articles/10.3389/fmed.2022.1102550/pdf

From targeted therapy to a novel way: Immunogenic cell death in lung cancer

Background MET exon 14 skipping mutation (METex14) is observed in ~3% of non-small cell lung cancer (NSCLC) cases and has been shown to be an independent poor prognostic factor associated with shorter overall disease-specific survival. Broad molecular testing can identify this biomarker in patients with advanced NSCLC (aNSCLC) and allow patients to be matched with the appropriate targeted therapy. This study examines biomarker testing patterns and clinical outcomes of chemotherapy and immuno-oncology (IO) monotherapy in aNSCLC patients with METex14. Methods A descriptive retrospective study was conducted using the Flatiron Health–Foundation Medicine Inc. (FMI) clinico-genomic database. Patients with METex14 aNSCLC treated with systemic therapies were included in the biomarker testing analysis. The duration from specimen collection to reported results was assessed for PD-L1– and METex14-tested patients. Clinical outcomes were assessed in patients treated with chemotherapy or IO monotherapy. First-line (1L) and second-line (2L) real-world progression-free survival (rw-PFS) were estimated using Kaplan-Meier analysis. Results Of 91 METex14 patients eligible for the biomarker testing analysis, 77% and 60% received PD-L1 and FMI next-generation sequencing (NGS) testing within 3 months post aNSCLC diagnosis. Of those assessed for both PD-L1 and METex14 (n=9), the median duration between specimen collection and reporting was 1 week shorter for PD-L1 than for FMI NGS. Median 1L rw-PFS was 5.7 months (95% CI, 4.6-7.1) and 2.4 months (95% CI, 1.4-3.2) in patients receiving 1L chemotherapy (n=59) and IO monotherapy (n=18), with 3-month 1L rw-PFS rates of 78% and 33%. Median 2L rw-PFS was 3.5 months (95% CI, 1.9-11.1) and 4.7 months (95% CI, 2.8-12.9) in patients receiving 2L chemotherapy (n=16) and IO monotherapy (n=23), with 3-month 2L rw-PFS rates of 54% and 67%. Conclusions The median time from biopsy to test results appears 1 week shorter for PD-L1 than for FMI NGS. Chemotherapy and IO monotherapy were the most common regimens utilized but with limited PFS.

/pdf/biomarker-testing-patterns-and-treatment-outcomes-in-28x53stb.pdf

Biomarker Testing Patterns and Treatment Outcomes in Patients With Advanced Non-Small Cell Lung Cancer and MET Exon 14 Skipping Mutations: A Descriptive Analysis From the US

Das Lungenkarzinom hat sich zu einem beeindruckenden Beispiel fur den Erfolg molekular zielgerichteter Therapien entwickelt. Eine optimale Therapiestratifizierung des Patienten setzt aber eine umfassende Molekulardiagnostik voraus. Sehr unterschiedliche, teils komplexe Biomarker mussen an meist limitiertem diagnostischem Material bei hoher Sensitivitat getestet werden und stellen die Molekularpathologie damit vor neue Herausforderungen. Das Verstandnis pradiktiver Biomarker im Bereich der Immunonkologie wird ebenfalls wichtiger werden. Neben PDL1 sind derzeit weitere mogliche Kandidaten wie z. B. die Tumormutationslast (TMB, „tumor mutational burden“) Gegenstand von Untersuchungen. In Zukunft wird eine komplexere pathologische Befundung notig sein, um negativ und positiv pradiktive sowie prognostische Gensignaturen in einen aussagekraftigen und verstandlichen Befund zu integrieren. Dies wird weitgehend uber Next-Generation-Sequencing(NGS)-Panels erfolgen, die alle therapierelevanten Genalterationen („single nucleotide variants“, SNV; „copy number variation“, CNV; Translokationen, ggf. TMB) zeitgleich an einer Probe abdecken konnen. Ziel wird dabei sein, Patienten zu ermitteln, die aufgrund eines bestimmten Tumorgenotyps mit hoher Wahrscheinlichkeit auf eine zielgerichtete bzw. Immuntherapie ansprechen. Ebenso wichtig wird es sein, Patienten aufgrund negativ pradiktiver Tumormarker von einer Therapie auszuschliesen. Die Autoren geben im vorliegenden Beitrag einen Uberblick uber den aktuellen Stand therapierelevanter Genalterationen beim Lungenkarzinom.

Molekularpathologie des Lungenkarzinoms: aktuelle Standards und weitere Entwicklungen

Abstract 1118: Activation of MET via diverse exon 14 skipping mutations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors

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Abstract 1118: Activation of MET via diverse exon 14 skipping mutations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors