Molecular Epidemiology of EGFR and KRAS Mutations in 3,026 Lung Adenocarcinomas: Higher Susceptibility of Women to Smoking-Related KRAS-Mutant Cancers

Doğan, Snjezana; Shen, Ronglai; Ang, Daphne; Johnson, Melissa L.; D’Angelo, Sandra P.; Paik, Paul K.; Brzostowski, Edyta B.; Riely, Gregory J.; Kris, Mark G.; Zakowski, Maureen F.; Ladanyi, Marc

doi:10.1158/1078-0432.ccr-11-3265

Cited by 556 publications

(492 citation statements)

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“…While KRAS mutations were associated with a smoking history greater than 20 pack-years, the tumors resected from almost 10% of patients with smoking histories of 10 pack-years or less had KRAS mutations. DOGAN et al (42) 241 of 2,198); KRAS mutations were found in 34% of former or current smokers (627 of 1,860) and 6% (43 of 669) of never-smokers. EGFR mutations among smokers were most common for those with less than a 10 pack-year smoking history.…”

Section: Driver Mutationsmentioning

confidence: 96%

“…A typical tumor contains two to eight driver mutations that can affect as many as 12 key cellular signaling pathways. Reported genetic alterations for lung adenocarcinoma include: EGFR (32,(42)(43)(44)(45)(46)(47), KRAS (42,(48)(49)(50)(51)(52), BRAF (53)(54)(55)(56), and ERBB2 (formerly HER2) (45, 56-60) driver mutations; ROS1 (32,(61)(62)(63), KIF5b-RET (32,64,65), and EML4-ALK rearrangements (20,45,57,61,(66)(67)(68)(69)(70); and other gene amplifications (20). An estimated 50% of lung adenocarcinomas in patients in Western populations have either an EGFR or KRAS driver mutation (42).…”

Section: Clinical Issuesmentioning

confidence: 99%

“…This approach, which recognizes the possible etiologic diversity represented by different histologic and molecular subtypes, has recently been termed molecular pathological epidemiology." The studies of LI et al (77) and DOGAN et al (42) characterize the frequency of driver mutations in two distinct populations: Chinese and Western patients, respectively. Most studies conducted to date have demonstrated a higher rate of EGFR mutations among Asian patients than Western patients, and these studies are consistent with those findings.…”

Section: Driver Mutationsmentioning

confidence: 99%

“…Most studies conducted to date have demonstrated a higher rate of EGFR mutations among Asian patients than Western patients, and these studies are consistent with those findings. Nonetheless, the LI and DOGAN studies, among others (42,45,57,77,85,86), establish that a significant number of smoking patients harbor EGFR mutations in their tumor specimens. These findings stand in contrast to those reported in some of the early EGFR studies (47,(71)(72)(73), which seemed to indicate that an EGFR mutation occurred exclusively in nonsmokers.…”

Section: Driver Mutationsmentioning

confidence: 99%

“…Such statements appear to be based on early trials of EGFR mutations and tyrosine kinase inhibitor treatment that seemed to indicate that these mutations occurred almost exclusively in never-smokers (47,(71)(72)(73), while KRAS mutations are more common in current and former smokers. Smoking status is not, however, the important distinguishing factor in these cases, as EGFR and KRAS mutations commonly occur in both smokers (42,48,77) and nonsmokers and are at the same time mutually exclusive (52). The key distinction is that EGFR mutations, even when identified in current or former smokers, are not caused by smoking (20,87), while two different KRAS mutations -one associated with smoking, the other not associated with smoking -have been identified in the published literature.…”

Section: Lung Cancer In a Smoker Is Not Inherently Different From Lunmentioning

confidence: 99%

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Implications of Evolving Medical Science for Proof of Lung Cancer Causation

Frarey¹,

Martínez²

2015

Beiträge Zur Tabakforschung International/Contributions to Tobacco Research

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SummaryCausal determination in cases of diseases involving multiple risk factors and long development time poses formidable challenges to judges and juries. Numerous scientific, medical and legal questions are involved. For example, is the mere presence of a factor known to be associated with elevated disease risk sufficient for a causal determination? If not, what level of exposure should be deemed sufficient, and how can that exposure be measured with adequate confidence over an extended period? In the presence of two or more factors associated with elevated disease risk, how can causation be demonstrated and apportioned among these factors, particularly when the potential effects of their interaction are unknown? With increasing knowledge of the molecular and genetic changes involved in disease development, what level of comprehension and proof is sufficient to implicate a specific risk factor in the complex causal mechanism of an individual’s disease? Lung cancer, notwithstanding its strong association with cigarette smoking, represents a group of diseases associated with both a variety of risk factors and relatively long development time. Both the published scientific literature and current clinical practice for the treatment of lung cancer, particularly lung adenocarcinoma, reflect the rapid changes that have occurred in this field over the past decade. These medical advances, in addition to promising better prognosis for some lung cancer patients, have implications for the proof of lung cancer causation in litigation in which plaintiffs contend that tobacco smoke exposure caused their disease. This is particularly true in cases arising in many European countries and other jurisdictions in which little or no histological or cytological information has been produced by plaintiffs. This paper examines the rapidly evolving science underpinning lung cancer diagnosis and treatment and its forensic implications. [Beitr. Tabakforsch. Int. 26 (2015) 298-311]

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Section: Driver Mutationsmentioning

confidence: 96%

Section: Clinical Issuesmentioning

confidence: 99%

Section: Driver Mutationsmentioning

confidence: 99%

Section: Driver Mutationsmentioning

confidence: 99%

Section: Lung Cancer In a Smoker Is Not Inherently Different From Lunmentioning

confidence: 99%

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Implications of Evolving Medical Science for Proof of Lung Cancer Causation

Frarey¹,

Martínez²

2015

Beiträge Zur Tabakforschung International/Contributions to Tobacco Research

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Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

Kris

Johnson

Berry

et al. 2014

JAMA

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1,468

1,136

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IMPORTANCE Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. OBJECTIVES To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. DESIGN, SETTING, AND PARTICIPANTS From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. INTERVENTIONS Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. MAIN OUTCOMES AND MEASURES Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. RESULTS From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006). CONCLUSIONS AND RELEVANCE Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.

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Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

Arbour

Riely

2019

JAMA

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868

697

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IMPORTANCE Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.OBSERVATIONS Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of Ն50%) and 40% among patients with ALK-positive tumors.CONCLUSIONS AND RELEVANCE Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.

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Molecular Epidemiology of EGFR and KRAS Mutations in 3,026 Lung Adenocarcinomas: Higher Susceptibility of Women to Smoking-Related KRAS-Mutant Cancers

Cited by 556 publications

References 50 publications

Implications of Evolving Medical Science for Proof of Lung Cancer Causation

Implications of Evolving Medical Science for Proof of Lung Cancer Causation

Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

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