Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non–Small-Cell Lung Cancer

Bange, Erin; Marmarelis, Melina E.; Hwang, Wei–Ting; Yang, Yu‐Xiao; Thompson, Jeffrey C.; Rosenbaum, Jason N.; Bauml, Joshua; Ciunci, Christine; Alley, Evan; Cohen, Roger B.; Langer, Corey J.; Carpenter, Erica L.; Aggarwal, Charu

doi:10.1200/po.18.00326

Cited by 60 publications

(75 citation statements)

References 26 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%

“…The current data, in a large observational genomic study among patients receiving routine clinical care, support the association of STK11m with poor treatment outcomes previously observed in smaller clinical trial cohorts [18][19][20][21][22][23][24]. Shorter OS and reduced response rates have been observed in patients with STK11m versus STK11wt non-squamous metastatic NSCLC treated with durvalumab (with or without tremelimumab) across multiple phase 1/2 trials [18].…”

Section: Plos Onesupporting

confidence: 78%

“…Our observations in patients with KRASm/STK11m were similar to those in patients with STK11m only, suggesting no additional deterioration of outcomes in the double mutants. In some retrospective studies, patients with co-mutations in KRAS and STK11 have shown a trend towards slightly poorer survival compared to patients with mutations in the individual genes (KRASm only or STK11m only), although these analyses were not conclusive [19][20][21]23].…”

Section: Plos Onementioning

confidence: 97%

“…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: Plos Onesupporting

confidence: 78%

Section: Plos Onementioning

confidence: 97%

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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“…Finally, another recent work showed that NSCLC patients with KRAS/STK11 co-mutation, treated with ICIs as second-or third-line of therapy, experienced a worse PFS and OS compared with those with STK11 mutation alone (median PFS, 2.4 months vs. 5.1 months, p = 0.048; median OS, 7.1 months vs. 16.1 months, p < 0.001) [159].…”

Section: Co-mutation Of Kras E Stk11mentioning

confidence: 96%

Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient

Rossi

Russo

Tagliamento

et al. 2020

Cancers

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In recent years, the evolution of treatments has made it possible to significantly improve the outcomes of patients with non-small cell lung cancer (NSCLC). In particular, while molecular targeted therapies are effective in specific patient sub-groups, immune checkpoint inhibitors (ICIs) have greatly influenced the outcomes of a large proportion of NSCLC patients. While nivolumab activity was initially assessed irrespective of predictive biomarkers, subsequent pivotal studies involving other PD-1/PD-L1 inhibitors in pre-treated advanced NSCLC (atezolizumab within the OAK study and pembrolizumab in the Keynote 010 study) reported the first correlations between clinical outcomes and PD-L1 expression. However, PD-L1 could not be sufficient on its own to select patients who may benefit from immunotherapy. Many studies have tried to discover more precise markers that are derived from tumor tissue or from peripheral blood. This review aims to analyze any characteristics of the immunogram that could be used as a predictive biomarker for response to ICIs. Furthermore, we describe the most important genetic alteration that might predict the activity of immunotherapy.

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The mutational landscape and prognostic indicators of pseudomyxoma peritonei originating from the ovary

Wang

Yao²,

et al. 2021

Intl Journal of Cancer

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Pseudomyxoma peritonei (PMP) is a rare disorder with unique pathological and genetic changes. Although several studies have reported the clinical features and mutational changes of PMP that originates from the appendix, few studies on PMP originating from the ovary have been reported due to its extreme rarity. In order to characterize the somatic mutational landscape and to investigate the prognosis predicting factors of ovary‐originating PMP, we examined 830 cases of PMP and identified 16 patients with PMP that originated from the ovary. Whole‐exome sequencing (WES) was performed on 12 cases using formalin‐fixed, paraffin‐embedded (FFPE) tissue samples. We found that 25% (3/12) of the patients carried mutations in cancer driver genes, including TP53, ATM and SETD2, and 16.7% (2/12) of the patients carried mutations in cancer driver genes, including ATRX, EP300, FGFR2, KRAS, NOCR1 and RB1. The MUC16 (58.33%), BSN (41.67%), PCNT (41.67%), PPP2R5A (41.67%), PRSS36 (41.67%), PTPRK (41.67%) and SBF1 (41.67%) genes presented the highest mutational frequencies. The PI3K‐Akt signaling pathway, human papillomavirus infection pathway, cell skeleton, cell adhesion, and extracellular matrix and membrane proteins were the major pathways or functions that were affected. Patients were followed up to 174 months (median: 48.26 months). The 5‐year OS rate for all patients was 71.2% and the median OS was not reached. PTPRK mutations, presurgical CA199 level, completeness of cytoreduction (CCR) and peritoneal cancer index (PCI) were identified as potential predictive factors for patient survival. In conclusion, the mutational landscape for ovary‐originating PMP was revealed and exhibited unique features distinct from appendix‐originating PMP. PTPRK, CA199, CCR and PCI may predict patient survival.

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Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non–Small-Cell Lung Cancer

Cited by 60 publications

References 26 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

Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient

The mutational landscape and prognostic indicators of pseudomyxoma peritonei originating from the ovary

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