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- Elfving, Hedvig, et al.
(författare)
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Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer
- 2021
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Ingår i: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 151, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1-3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort.Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis.Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression.Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.
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| 2. |
- La Fleur, Linnea, et al.
(författare)
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Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
- 2019
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
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| 3. |
- Moreno-Ruiz, Pablo, et al.
(författare)
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Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation
- 2021
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Ingår i: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 155, s. 10-19
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesFibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGFβR and α-SMA fibroblast markers in a well-annotated clinical cohort of non–small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival.Materials and MethodsA well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGFβR and α-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients.ResultsHigh stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012–2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126–2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. α-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high α-SMA (p = 0.003) and FAP expression (p < 0.001).ConclusionThe study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.
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| 4. |
- Tsakonas, Georgios, et al.
(författare)
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c-MET as a biomarker in patients with surgically resected non-small cell lung cancer
- 2019
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Ingår i: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 133, s. 69-74
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Tidskriftsartikel (refereegranskat)abstract
- Background: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet. Patients and methods: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored. Results: c-MET H-score >= 20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64 - 0.97). The prognostic effect of c-MET H-score >= 20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40 - 0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43 - 0.83). Conclusion: c-MET H-score >= 20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score >= 20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.
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