KRAS-G12C Mutation is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma

Nadal, Ernest; Beer, David G.; Ramnath, Nithya

doi:10.1097/jto.0000000000000438

Cited by 31 publications

(39 citation statements)

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“…G12D in the present study was the most prominent subtype which was congruent with data from Caucasian and other Chinese mCRC (25)(26)(27). It had been reported that different subtypes of KRAS mutations may confer variable tumor biology (28,29). A previous study involving surgically resected lung adenocarcinoma revealed that G12C mutation was associated with poorer outcome compared with other subtypes of mutations (28).…”

Section: Discussionsupporting

confidence: 79%

“…It had been reported that different subtypes of KRAS mutations may confer variable tumor biology (28,29). A previous study involving surgically resected lung adenocarcinoma revealed that G12C mutation was associated with poorer outcome compared with other subtypes of mutations (28). Another study in Chinese patients with CRC demonstrated that KRAS codon 13 mutations, in particular G13D, were associated with significantly decreased OS rates (12).…”

Section: Discussionmentioning

confidence: 99%

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Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

et al. 2017

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Abstract. KRAS mutations serve a function in tumorigenesis of colorectal cancer (CRC) and guide the use of targeted drugs. However, the prognostic value of KRAS mutations and their subtypes remain controversial. The present study aimed to investigate the correlations between KRAS mutations and clinicopathological characteristics, and their prognostic significance in Chinese patients with metastatic CRC (mCRC). A total of 135 patients with mCRC were analyzed for KRAS mutations. Mutations in codon 12 and 13 were identified in 45 (33.3%) patients. Only 3 patients harbored a mutation of V600E. Compared with male patients, KRAS codon 12 mutations were more common in female patients (P<0.05). KRAS codon 13 mutations tended to arise in right-sided compared with left-sided colon cancer (P<0.05). Survival analysis was performed in 101 patients receiving primary tumor resection. Compared with KRAS codon 12 wild-type, codon 12 mutations were markedly correlated with a poorer survival (log-rank P= 0.002). No prognostic significance was revealed in codon 13 mutations. In univariate analysis, mortality risk was significantly increased by subtypes of G12D and G12V [hazard ratio (HR) =2.313, 95% confidence interval (CI) =1. P=0.03; HR=2.621, P=0.04, respectively]. The results of the present study suggested that codon 12 mutations, in particular G12D and G12V, predicted a negative prognosis in Chinese patients with mCRC. These findings require further confirmation via prospective studies with larger samples.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

et al. 2017

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“…Increasing evidence from several different cancers suggest that different codon-specific KRAS mutations may confer variable tumor biology. 33,34 For example, a recent study in surgically resected lung adenocarcinoma reported that patients with any KRAS mutation had significantly worse survival compared with patients who had KRAS wild-type tumors. 33 In particular, patients with a G12C mutation had worse outcomes compared with patients who harbored other types of mutations.…”

Section: Discussionmentioning

confidence: 99%

“…33,34 For example, a recent study in surgically resected lung adenocarcinoma reported that patients with any KRAS mutation had significantly worse survival compared with patients who had KRAS wild-type tumors. 33 In particular, patients with a G12C mutation had worse outcomes compared with patients who harbored other types of mutations. 33 Based on the finding that G13D tumors had a different response to chemotherapy, Tejpar et al 34 suggested that, in addition to overall KRAS status, individual genotypes should be considered as potentially important markers of prognosis.…”

Section: Discussionmentioning

confidence: 99%

Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases

Margonis

Kim

Sasaki

et al. 2016

Cancer

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BACKGROUND:Investigations regarding the impact of tumor biology after surgical management of colorectal liver metastasis have focused largely on overall survival. We investigated the impact of codon-specific KRAS mutations on the rates and patterns of recurrence in patients after surgery for colorectal liver metastasis (CRLM). METHODS: All patients who underwent curative-intent surgery for CRLM between 2002 and 2015 at Johns Hopkins who had available data on KRAS mutation status were identified. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were assessed using univariable and multivariable analyses. RESULTS: A total of 512 patients underwent resection only (83.2%) or resection plus radiofrequency ablation (16.8%). Although 5-year overall survival was 64.6%, 284 (55.5%) patients recurred with a median RFS time of 18.1 months. The liver was the initial recurrence site for 181 patients, whereas extrahepatic recurrence was observed in 162 patients. Among patients with an extrahepatic recurrence, 102 (63%) had a lung recurrence. Although overall KRAS mutation was not associated with overall RFS (P 5 0.186), it was independently associated with a worse extrahepatic (P 5 0.004) and lung RFS (P 5 0.007). Among patients with known KRAS codon-specific mutations, patients with codon 13 KRAS mutation had a worse 5-year extrahepatic RFS (P 5 0.01), whereas codon 12 mutations were not associated with extrahepatic (P 5 0.11) or lung-specific recurrence rate (P 5 0.24). On multivariable analysis, only codon 13 mutation independently predicted worse overall extrahepatic RFS (P 5 0.004) and lung-specific RFS (P 5 0.023). CONCLUSIONS: Among patients undergoing resection of CRLM, overall KRAS mutation was not associated with RFS. KRAS codon 13 mutations, but not codon 12 mutations, were associated with a higher risk for overall extrahepatic recurrence and lung-specific recurrence. Cancer 2016;122:2698-707. V C 2016 American Cancer Society.KEYWORDS: codon-specific mutation, KRAS mutation, colorectal liver metastasis, recurrence patterns, hepatectomy. INTRODUCTIONColorectal cancer (CRC) is one of the most common malignancies and is the fourth most common cause of cancer-related death worldwide.1 Distant metastasis is the main cause of death in CRC patients, and less than 5% of patients with unresectable metastatic CRC are alive after 5 years.2,3 The most common site of distant metastasis is the liver, with approximately 25% of patients presenting with synchronous disease and an additional 30% to 40% developing colorectal liver metastases (CRLM) during the course of their disease. 4,5 Surgical intervention remains the mainstay of treatment for liver-limited metastatic disease, with overall 5-year survival reported to be as high as 47% to 58% after curative intent surgery. [6][7][8] Although overall survival has improved over the last several decades, the incidence of recurrence has remained relatively constant, with contemporary 5-year recurrence rates reported to range from 57% to 77%.

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“…Indeed, in colorectal cancer, it seems that codon 13 mutation is associated with better prognosis following lung metastasectomy (15), with different prognosis according to the amino-acid substitution (16). In NSCLC, little evidence suggests that the type aminoacid substitution might impact survival following surgery (17,18). More particularly, in the largest published cohort on the impact of KRAS amino-acid substitution on survival after NSCLC surgery, our team has showed that G12V mutation was associated with worse overall survival and time to recurrence (19).…”

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confidence: 99%

MicroRNAs: a new tool in the complex biology of KRAS mutated non-small cell lung cancer?

Renaud¹,

Seitlinger

Massard

2017

J. Thorac. Dis.

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Despite several advances in the last decades in both medical and surgical management, with a 5-year overall survival (OS) not exceeding 15%, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide (1). The past few years have seen an increased understanding in the molecular alterations of several cancers, helping clinicians to guide medical treatment and offer more accurate prognosis to patients. NSCLC was not left behind (2). Indeed, the recent discovery of oncogenic drivers such as activating mutations in the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR) has led to a dramatic increase in survival of patients harboring these mutations (3). Meanwhile, the prognostic and predictive values of EGFR mutations seem to be largely established in metastatic NSCLC (4), only a fleeting glimpse of clinical implications of many other mutations has been offered so far by the published literature, and might need further researches. One of the most promising molecular markers seems to rely in the mutations of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. KRAS encodes for RAS proteins which are small GTPases bounding between inactive guanosine diphosphate (GDP) and active guanosine triphosphate (GTP) forms. RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. Approximately 15% to 25% of NSCLC adenocarcinomas exhibit KRAS mutations (5). In the very large majority of the cases, these mutations are missense mutations introducing an aminoacid substitution at codon 12, 13 or 61 of the exon 2 of the gene (6). This confers a constitutive activation of KRAS signaling pathways, including the PI3K-AKT-mTOR pathway, involved in cell survival, and the RAS-RAF-MEK-ERK pathway, involved in cell proliferation. The complexity of KRAS mutations is reflected by the difficulty to develop effective therapies for patients with NSCLC harboring such mutations, and so far KRAS mutations are related to a poor prognosis in both locally and advanced NSCLC patients (7,8).A promising area of research seems to be focused on microRNAs (miRNAs). miRNAs are small noncoding RNAs which act as post-translational regulator of genes. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer. They are well-known key player in downstream oncogenic pathways, behaving as oncogenes or oncosuppressors in different types of cancer. Their central role in tumorogenesis and their stable and long-lasting presence in tissues and body fluids underlie the increased efforts and interest in defining their role as possible next-generation biomarkers and targets for novel therapeutic approaches (9).The recently published paper of Langsch and co-workers offers a promising insight of the place of miRNAs in the molecular biology of KRAS-driven non-small cell lung cancer, and the possibility to use them as molecular Editorial MicroRNAs: a new tool in the co...

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KRAS-G12C Mutation is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma

Cited by 31 publications

References 2 publications

Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases

MicroRNAs: a new tool in the complex biology of KRAS mutated non-small cell lung cancer?

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