KRAS Mutation as the Biomarker of Response to Chemotherapy and EGFR-TKIs in Patients With Advanced Non–Small Cell Lung Cancer

Campos‐Parra, Alma D.; Zuloaga, Carlos; Manríquez, María Eugenia Vázquez; Avilés, Alejandro; Borbolla-Escoboza, José R.; Cardona, Andrés Felipe; Meneses, Abelardo; Arrieta, Óscar

doi:10.1097/coc.0b013e318287bb23

Cited by 34 publications

(32 citation statements)

References 23 publications

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“…Another explanation may be that the results of the nonrandomized components of a CT are not valid because of unknown confounding and selection mechanisms. In our study, we observe a longer OS compared to another CT, which is possibly secondary to a higher prevalence of EGFR mutations and a lower prevalence of KRAS mutations in our population and may be partly explained by different risk factors [2,28,29] and ethnicity differences from Caucasian populations [30,31,32]. …”

Section: Discussionmentioning

confidence: 66%

Survival of Patients with Advanced Non-Small Cell Lung Cancer Enrolled in Clinical Trials

et al. 2016

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Background: Up-to-date oncological therapy has been accomplished through the results of clinical trials (CTs). We analyzed the overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and its relation to CT enrollment. Methods: The study included 1,042 patients with advanced NSCLC treated at the Instituto Nacional de Cancerología. All patients received treatment according to the national and international guidelines. Data were collected from medical records. Patients were subgrouped on the basis of their CT enrollment as follows: participants in any CT (ACT), exclusively intervention CTs (ICT) or exclusively pharmaceutical-sponsored CTs (PCT). Results: The CT enrollment effect was assessed through a multivariate Cox proportional hazards model. Thirty percent of the patients were in ACT, 28.3% in ICT and 13.7% in PCT. Female gender (p = 0.001), adenocarcinoma histology (p = 0.018), positive EGFR mutation (p = 0.006), and better ECOG performance status (<2) (p ≤ 0.0001) were more frequent in patients enrolled in CT; further, tobacco smoking (p ≤ 0.0001) and KRAS mutation (p = 0.001) were more frequent in patients who were not enrolled in a CT. Conclusion: Enrollment in ACT was associated with a better OS (hazard ratio: 0.47-0.74). NSCLC patients enrolled in a CT have an improved survival in an independent manner to other prognostic factors.

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Section: Discussionmentioning

confidence: 66%

Survival of Patients with Advanced Non-Small Cell Lung Cancer Enrolled in Clinical Trials

et al. 2016

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“…In our population, 9.0% of cases were FISH positive, probably due to a high prevalence of patients without a positive smoking history at the time of diagnosis. In our institution only 50% to 55% NSCLC patients have a positive smoking history, [36][37][38] unlike the white population. The low frequency of tobacco exposure suggests that other risk factors are associated with lung cancer in Mexico.…”

Section: Discussionmentioning

confidence: 99%

“…3,6,14,25,[35][36][37][38][39][40][41][42][43] Some reports suggest that patients with ALK-rearranged NSCLC do not exhibit significant ethnic differences in contrast to NSCLC harboring EGFR mutations. 3,4,6,7,14 Consistent with our findings, ALK-rearranged NSCLC patients are usually young (approximately 50 y of age at diagnosis), show no sex predilection, are most often never/ light smokers, and tumors have adenocarcinoma histology with a mucinous component.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of EML4 - ALK Translocation With FISH, Immunohistochemistry, and Real-time Polymerase Chain Reaction in Patients With Non–Small Cell Lung Cancer

Cruz‐Rico¹,

Avilés‐Salas

Segura-González³

et al. 2017

American Journal of Clinical Oncology

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“…[31][32][33] TICs exhibit the unique capacity to both selfrenew, and form a more differentiated, but highly proliferative tumor cell population, driving both tumor initiation and maintenance. 34,35 Tumors harboring mutant KRAS exhibit enhanced chemoresistance, 36 radiation resistance, 37 and poor survival; 38 all properties associated with the TIC phenotype, suggesting that KRAS is an important driver of the LADC TIC phenotype. 39,40 We have identified PKCɩ as a key mediator of the KRAS LADC TIC phenotype.…”

Section: Pkci Is Required For Kras Ladcmentioning

confidence: 99%

Targeting oncogenic protein kinase Cι for treatment of mutantKRASLADC

et al. 2016

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Lung cancer is the leading cause of cancer death in the US with »124,000 new cases annually, and a 5 y survival rate of »16%. Mutant KRAS-driven lung adenocarcinoma (KRAS LADC) is a particularly prevalent and deadly form of lung cancer. Protein kinase Ci (PKCi) is an oncogenic effector of KRAS that activates multiple signaling pathways that stimulate transformed growth and invasion, and maintain a KRAS LADC tumor-initiating cell (TIC) phenotype. PKCi inhibitors used alone and in strategic combination show promise as new therapeutic approaches to treatment of KRAS LADC. These novel drug combinations may improve clinical management of KRAS LADC.KEYWORDS lung adenocarcinoma; oncogenic Kras; Protein Kinase Ciota; therapeutic targeting KRAS mutation is an oncogenic driver required for LADC tumor initiation and maintenance Activating KRAS mutations are detected in approximately 33% of LADC. KRAS mutations are also present in preneoplastic lesions of the lung (atypical alveolar hyperplasias, AAH), suggesting early acquisition during lung neoplasia.1 Genomic sequencing of lung adenomas in situ revealed both regional histological and genomic heterogeneity; however, KRAS mutations were observed uniformly throughout individual lesions, indicating that mutant KRAS drives early tumor cell transformation, selection and evolution. 2Expression of mutant KrasG12D in the mouse lung is sufficient to drive LADC initiation, providing in vivo evidence that KRAS is a key oncogenic driver of LADC initiation.3,4 Interestingly, systemic delivery of KRAS siRNA significantly inhibited tumor growth and metastasis of mutant KRAS LADC tumors, demonstrating a continued dependency on mutant KRAS signaling for tumor maintenance.

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KRAS Mutation as the Biomarker of Response to Chemotherapy and EGFR-TKIs in Patients With Advanced Non–Small Cell Lung Cancer

Abstract: KRAS mutation status is a good biomarker for response to EGFR-TKIs in patients with NSCLC. KRAS mutational status could impact the decision to give CT or EGFR-TKIs as a second line of treatment to patients with NSCLC, particularly in patients with WT-EGFR.

Cited by 34 publications

References 23 publications

Survival of Patients with Advanced Non-Small Cell Lung Cancer Enrolled in Clinical Trials

Survival of Patients with Advanced Non-Small Cell Lung Cancer Enrolled in Clinical Trials

Diagnosis of EML4 - ALK Translocation With FISH, Immunohistochemistry, and Real-time Polymerase Chain Reaction in Patients With Non–Small Cell Lung Cancer

Targeting oncogenic protein kinase Cι for treatment of mutantKRASLADC

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