LKB1/STK11  mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic value

Facchinetti, Fabio; Bluthgen, M.V.; Tergemina-Clain, Gabrielle; Faivre, Laurence; Pignon, Jean-Pierre; Planchard, David; Remón, Jordi; Soria, Jean‐Charles; Lacroix, Ludovic; Besse, Benjamin

doi:10.1016/j.lungcan.2017.08.002

Cited by 94 publications

(80 citation statements)

References 35 publications

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“…patients with STK11m had a co-mutation in KRASm, which is largely consistent with the comutation frequencies reported previously [20,21,24,33].…”

Section: Plos Onesupporting

confidence: 91%

“…PD-L1 expression on tumor cells has been used to guide treatment selection, and more recently tumor mutational burden (TMB) has shown potential as a predictive biomarker for IO benefit [12][13][14][15]. Mutations in individual genes and co-mutation patterns have also been linked to patient response to standard chemotherapy and/or IO in advanced NSCLC [16][17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

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STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

et al. 2020

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Background Mutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/ STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting. Methods This retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated firstline immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS). Results Of 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9-2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3-2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2-1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/ STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings. Conclusions This large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or

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“…patients with STK11m had a co-mutation in KRASm, which is largely consistent with the comutation frequencies reported previously [20,21,24,33].…”

Section: Plos Onesupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

et al. 2020

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“…Indeed, we could not confirm a significant prognostic impact of TP53 after adjustment for adjuvant therapy in multivariate analysis. The finding that mutations in STK11 conferred poor prognosis is supported by a trend for a worse survival in one study [37], while another paper showed poor prognosis for patients with mutations in exon 1 and 2 of STK11 in comparison to mutations in exon 3-9 [38]. SMARCA4, a subunit in the SWI/SNF chromatin remodeling complex, is frequently mutated in lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 92%

“…Our results were further supported by data from the MSK-IMPACT study. Other studies looking at the prognostic impact of co-occurring mutations in TP53 or STK11 together with KRAS have been inconclusive [37,44]. Gene expression analysis in lung adenocarcinoma has shown that TP53 mutations enhance signatures related to cell proliferation in contrast to STK11 mutations that boost expression of genes induced by KRAS mutations and suppress signatures related to immune function [45].…”

Section: Discussionmentioning

confidence: 99%

Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11

et al. 2019

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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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“…A functional coordination between STK11 with ERBB2 in mediating these effects in mammary tumorigenesis was also demonstrated 62 – 64 . The STK11 is also one of the most frequently inactivated genes in non-small cell lung cancer 65 . Loss of STK11 copy in multiple NTM-BCa subjects also suggests association with malignant transformation in these women.…”

Section: Discussionmentioning

confidence: 99%

Sputum Detection of Predisposing Genetic Mutations in Women with Pulmonary Nontuberculous Mycobacterial Disease

Philley

Hertweck

Kannan

et al. 2018

Sci Rep

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Nontuberculous mycobacterial lung disease (NTM), including Mycobacterium avium complex (MAC), is a growing health problem in North America and worldwide. Little is known about the molecular alterations occurring in the tissue microenvironment during NTM pathogenesis. Utilizing next generation sequencing, we sequenced sputum and matched lymphocyte DNA in 15 MAC patients for a panel of 19 genes known to harbor cancer susceptibility associated mutations. Thirteen of 15 NTM subjects had a diagnosis of breast cancer (BCa) before or after NTM infection. Thirty three percent (4/12) of these NTM-BCa cases exhibited at least 3 somatic mutations in sputa compared to matched lymphocytes. Twenty four somatic mutations were detected with at least one mutation in ATM, ERBB2, BARD1, BRCA1, BRCA2, AR, TP53, PALB2, CASP8, BRIP1, NBN and TGFB1 genes. All four NTM-BCa patients harboring somatic mutations also exhibited 15 germ line BRCA1 and BRCA2 mutations. The two NTM subjects without BCa exhibited twenty somatic mutations spanning BRCA1, BRCA1, BARD1, BRIP1, CHEK2, ERBB2, TP53, ATM, PALB2, TGFB1 and 3 germ line mutations in BRCA1 and BRCA2 genes. A single copy loss of STK11 and AR gene was noted in NTM-BCa subjects. Periodic screening of sputa may aid to develop risk assessment biomarkers for neoplastic diseases in NTM patients.

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LKB1/STK11 mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic value

Cited by 94 publications

References 35 publications

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11

Sputum Detection of Predisposing Genetic Mutations in Women with Pulmonary Nontuberculous Mycobacterial Disease

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