TY - JOUR
AU - Salgia, Ravi
AB - Abstract Importance Lung cancer is the leading cause of cancer deaths worldwide, with non–small-cell lung cancer (NSCLC) constituting more than 80% of all lung cancers. Non–small-cell lung cancer is a heterogenous disease, with multiple different oncogenic driver mutations representing possible therapeutic targets. The vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) represents one of the most common oncogenic driver mutations. Unfortunately, targeted therapies thus far have been unsuccessful. Objective To discuss current advancements in understanding the prognostic and predictive value of KRAS in NSCLC and explaining the treatment advancements in both the preclinical and clinical setting. Evidence Review PubMed, Cochrane Library, and Google Scholar databases were searched through February 1, 2016. English-language peer-reviewed articles published between 1964 and 2016 were found using the keywords “RAS,” “KRAS,” “NSCLC,” “synthetic lethality,” “oncogenic driver mutations,” “clinical trials,” and “phase 3 clinical trials.” Abstracts at scientific meetings were not excluded. Of 112 records idetified, 61 articles or studies were included in qualitative synthesis for this review. Findings The KRAS oncogenic driver mutation is noted in 15% to 25% of patients with NSCLC.1 While there has been limited success in inhibiting the protein directly, phase 2 and phase 3 clinical trials have demonstrated success in inhibiting downstream effectors, specifically MEK1 and/or MEK2 with selumetinib and trametinib (albeit with poor tolerability). Current clinical trials are evaluating inhibiting downstream effector pathways for improved efficacy. In the laboratory, the success of synthetic lethal approaches suggests another possible direction for future clinical trials. Conclusions and Relevance KRAS is one of the most common oncogenic driver mutations in NSCLC, with prior attempts at direct inhibition being unsuccessful. In recent years, there has been significant advancement in the understanding of the biology of KRAS and its downstream effectors. This has translated into a multitude of important preclinical studies and clinical trials that are currently underway to find effective therapeutic drugs for KRAS mutant lung cancer. Ultimately, better therapeutics need to be engineered to arrive at RAS-driven precision medicine. Introduction An oncogenic driver mutation is thought to be present in almost 64% of lung adenocarcinomas.2 The 2 most commonly mutated oncogenes in non–small-cell lung cancer (NSCLC) are the epidermal growth factor receptor (EGFR) and the vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS).3 Unfortunately, we have had minimal success targeting the RAS mutations directly for a considerable period of time.4,5 The KRAS gene, together with the rat Harvey (HRAS) and the neuroblastoma (NRAS) viral oncogenes, encode a family of guanosine triphosphate (GTP) binding proteins that play essential roles in regulating normal cellular proliferation and cell signaling.6 These RAS proteins represent the oncogenic driver mutation in over 20% of all tumors.7 Despite limited early success, a rapidly improving understanding of the KRAS mutation and its downstream effectors is now translating into improved therapeutic efficacy for KRAS mutant NSCLC. Box Section Ref ID Key Points Question What is the state of current knowledge regarding RAS in non-small cell lung cancer (NSCLC)? Findings In this systematic review, we demonstrate that KRAS is one of the most common oncogenic driver mutations but there has been limited success in inhibiting the mutation directly. Phase 2 and 3 clinical trials have demonstrated better efficacy in inhibiting downstream effector proteins, albeit with poor tolerability. Meaning There have been significant advances in the understanding of RAS in NSCLC; numerous clinical trials are currently underway attempting to improve outcomes in KRAS-mutant lung cancer. Methods This systematic review was conducted according to PRISMA guidelines. PubMed, Cochrane Library, and Google Scholar databases were searched through February 1, 2016. English-language peer-reviewed articles published between 1964 and 2016 were found using the keywords “RAS,” “KRAS,” “NSCLC,” “synthetic lethality,” “oncogenic driver mutations,” “clinical trials,” and “phase 3 clinical trials.” Abstracts at scientific meetings were not excluded. The search identified 112 records, 51 records were excluded, leaving 61 articles or studies for inclusion. The associated PRISMA flow diagram is available as an eFigure in the Supplement. RAS: Genetics and Proteomics Three RAS genes encode 4 protein isoforms (HRAS, KRAS [splice variants K4A- and K4B-], and NRAS).8 These proteins are closely related, sharing 85% identical amino acid sequences. RAS activity is initiated by binding to GTP, with activity being halted when the enzyme is bound to guanosine diphosphate (GDP). In normal cells, the activity of RAS and its ability to activate downstream pathways is dependent on the ratio of GTP to GDP.9Quiz Ref ID The most common RAS mutations lead to RAS proteins that have impaired GTPase activity, and thus permanent activation of RAS signaling occurs.7 Prior to activation, KRAS undergoes a multistep posttranslational modification including farnesylation, geranylgeranylation, and palmitoylation. Earlier attempts with treatment with farnesyl transferase inhibitors showed little clinical success and excessive toxic effects.10,11 The significance of the RAS enzyme is due to its ability to activate a multitude of effector proteins leading to the activation of a complex, important network of pathways vital for cell proliferation and survival (Figure 1).12-16 RAS in Lung Cancer KRAS mutations account for 90% of RAS mutations in lung adenocarcinomas, and approximately 97% of KRAS mutations in NSCLC involve substitution mutations on exon 2 or 3 (G12, G13, and Q61) (Figure 2). It had been assumed that KRAS mutations are mutually exclusive from EGFR mutations and EML4-ALK translocations. However, more recent data demonstrates concomitant mutations can occur—in an evaluation of 282 cases of NSCLC, 3 cases (1.1%) showed a concomitant EGFR and KRAS mutation and 7 cases (2.5%) showed a concomitant EML4-ALK and KRAS alteration.17 Histology KRAS mutations are rare in lung squamous cell carcinoma (approximately 5%).18 In an analysis of 1532 NSCLC samples, KRAS mutations were detected in 303 cases (19.7%) (adenocarcinoma 206 of 602 [34%]; squamous 44 of 705 [6%]; and other histology 53 of 229 [23%]). Quiz Ref IDMutations were more frequent in women, younger patients, and patients with early stage cancer, but in multivariate analysis, only age (P = .04) and histology (P < 0.001) remained significant.19 Smoking Status Quiz Ref IDKRAS mutations are more common in smokers. In one study of 106 patients with adenocarcinoma, KRAS mutations were noted exclusively in smokers (40 of 92 smokers [43%] vs 0 of 14 nonsmokers [0%]).20 However, KRAS mutations can appear in nonsmokers; when they do, specific mutation types correlate with smoking status. In a series of 482 patients with KRAS-mutated lung adenocarcinoma, transversion mutations (G →T or G →C) were more common in patients with a smoking history (22%), while transition mutations (G →A) occurred more frequently in patients who had never smoked (15%).1 Metastatic Disease There is currently limited information evaluating patterns of metastatic disease and metastatic frequency in KRAS-mutant lung cancer. One small study found no difference in the sites of metastatic disease or number of metastatic sites in patients with KRAS-mutant disease vs KRAS wild-type disease.21 Another study of 174 patients (22 [12.9%] with KRAS mutations) found that KRAS was an independent risk factor for the development of brain metastases (P = .007).22 Prognostic Value of KRAS The significance of the KRAS mutant status as a prognostic marker remains controversial, though it does appear to be dependent both on (1) which specific KRAS codon is mutated and (2) disease stage at the time of diagnosis. In one study of 677 patients, Yu et al23 demonstrated that there was no difference in overall survival when comparing specific amino acid substitutions on codon 12. Interestingly, however, patients with KRAS codon 13 mutant tumors had inferior survival compared with patients with codon 12 tumors, with a median 13 months and 16 months survival, respectively (P = .009).23 Staging also appears to be important. For resectable disease, the prognostic value of KRAS appears to be minimal. Data from a combined analysis of 4 trials of adjuvant chemotherapy after resection demonstrated no statistically significant difference in overall survival in 300 patients with KRAS mutant status compared with 1243 KRAS wild-type.24 Of note, the codon on which the mutation occurred again appeared to be significant—in the small number of patients with a codon 13 mutation, adjuvant chemotherapy appeared to be deleterious and patients had significantly worse overall survival. On the other hand, in stage IV NSCLC, the presence of KRAS mutant status appears to be associated with poor prognosis, with 1 large multivariate analysis demonstrating that the presence of a KRAS mutation was associated with shorter survival (hazard ratio [HR], 1.21; P = .048).25 Predictive Value of KRAS There have been multiple studies evaluating the predictive value of KRAS-mutant lung cancer for chemotherapy. In the TRIBUTE trial26 comparing first-line carboplatin or paclitaxel plus erlotinib or placebo, response rates in the chemotherapy-alone arm were 23% and 26% for patients with KRAS mutant status and KRAS wild-type status, respectively. No significant difference in overall survival between the 2 groups was noted.27 Eastern Cooperative Oncology Group (ECOG) study 3590,28 a study that randomly assigned patients with completely resected stage II to IIIa NSCLC to receive adjuvant radiotherapy with or without etoposide or cisplatin, showed that KRAS mutation was neither prognostic of survival nor predictive of a differential benefit from chemotherapy28; contradicting this, however, is data that shows patients with dual KRAS and p53 mutations have a deleterious response to chemotherapy compared with observation (HR, 2.49; 95% CI, 1.10-5.66; P = .03).29 Predictive Value for Response to EGFR Tyrosine Kinase Inhibitor Therapy As KRAS is located downstream from the EGFR receptor, it was hypothesized that the KRAS mutation would invalidate therapy with an EGFR tyrosine kinase inhibitor (TKI). However, evidence from multiple large phase 3 trials have been mixed. Evidence suggesting the KRAS mutation to be a negative predictive factor in TKI therapy includes data from the TRIBUTE27 and BR.2129 trials. In the phase 3 TRIBUTE trial, patients with KRAS mutations had significantly worse response rates when treated with chemotherapy plus erlotinib as compared with standard carboplatin and paclitaxel (8% compared with 53%, respectively).27 Similar outcomes were seen in the second line Br.21 trial comparing erlotinib vs placebo, where a significant survival benefit from erlotinib therapy was observed in patients with KRAS wild-type disease (HR, 0.69; P = .03) but not for patients with mutant KRAS (HR, 1.67; P = .31).29 Contradicting this is data from the phase 3 TRUST trial30 that evaluated erlotinib therapy in patients with stage IIIB and stage IV NSCLC. In this study, the difference in survival for KRAS mutant vs KRAS wild-type was not found to be significant (albeit, there were only 17 patients with KRAS mutant disease). Additionally, the phase 3 SATURN trial31 showed a marginal trend toward benefit from maintenance erlotinib in 90 patients with KRAS mutant disease, though the confidence intervals were wide (HR, 0.77; 95% CI, 0.50-1.19). This led the authors to conclude that KRAS mutant status should not be used as a criterion for excluding patients from treatment with erlotinib. The small sample size in the TRUST trial and the wide confidence interval in SATURN trial are clear weaknesses in these studies, however. KRAS and Immunotherapy Quiz Ref IDProgrammed cell death protein 1 (PD-1) expression has been found to be significantly associated with the presence of KRAS mutations (P = .006).32 It has been demonstrated that PD-L1 (programmed cell death 1 ligand 1) expression is elevated in premalignant KRAS cells, and that ERK activation mediated constitutive KRAS mutation driver up-regulation of PD-L1 in these cells. From these findings, it was suggested that KRAS mutation may directly up-regulate the PD-1/PD-L1 immune checkpoint pathway.33 Brahmer et al34 observed durable responses and an encouraging survival profile with nivolumab monotherapy in NSCLC, regardless of KRAS or EGFR mutations. Subgroup analysis demonstrated no apparent association between types of target mutations and response to immunotherapy.34 Further studies are needed to better understand the relationship between KRAS oncogenes and immunotherapy. Therapeutic Options for KRAS Mutant Lung Cancer Targeting the KRAS protein itself has been previously unsuccessful owing to its high affinity for GTP/GDP and the absence of known allosteric regulatory sites.26 However, some success in being seen in the preclinical setting. These have mostly been seen with novel small molecule fragments that covalently modify the mutant KRAS G12C thiol by forming an allosteric bond to KRAS and locking the protein in its inactive state.35 More recently, Lito and colleagues36 used a novel compound, ARS853, to bind to the KRAS G12C binding site and block nucleotide exchange factors from activating KRAS. This led to inhibition of KRAS in 95% in KRAS G12C-mutant lung cancer cell lines.36 While these methods have shown success, these drugs are likely years away from being used clinically.37 Thus, many of the prior clinical trials up to this point have evaluated inhibition of downstream effectors. Two of the most extensively studied effectors for inhibition have been MEK1 and MEK2, which are located downstream in the MAPK (BRAF and RAF1) pathway.23 There are currently 2 US Food and Drug Administration-approved MEK1 and MEK2 inhibitors: selumetinib and trametinib.38 Quiz Ref IDIn a randomized phase 2 trial, second-line selumetinib plus docetaxel was compared with docetaxel plus placebo in patients with KRAS-mutated disease and was found to have a significant survival advantage (median survival, 9.4 months vs 5.2 months, respectively; HR, 0.80; P = .21), albeit with more clinical adverse effects. An objective partial response was observed in 16 of 43 patients (37%) treated with docetaxel plus selumetinib compared with 0 of 43 patients receiving docetaxel plus placebo.39 The effectiveness of trametinib appears to be unrelated to KRAS status. In a phase 2 trial of 47 patients with advanced NSCLC, patients treated with docetaxel plus trametinib had a 30% response rate. There was no difference in response rates between patients with KRAS wild-type disease and KRAS mutant disease.40 Many present studies are now focusing on inhibition of multiple pathways for improved efficacy. This is based off preclinical data demonstrating a significant response rate when the MEK and PI3k/mTOR (mammalian target of rapamycin) pathways were dually inhibited.41 Engelman et al42 have demonstrated that dual inhibition of PI3k/mTOR and MEK pathways in mice led to marked tumor regression; inhibition of solely the PI3K pathway showed no clinical response.42 RAS: Synthetic Lethality In addition to the methods we previously identified, the strategy of synthetic lethality has become popular when considering future therapeutic strategies in KRAS mutant lung cancer. Synthetic lethality is the concept of targeting gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele.43 Targeting a gene that is synthetic lethal should kill only malignant cells (in this case RAS-mutant cells), and have no effect on normal cells (KRAS wild-type cells). Table 1 summarizes the most well-understood synthetic lethal approaches to date.44-60 RAS: Clinical Trials In the era of personalized medicine, clinical trials are vital to establishing successful treatment methods with targeted therapies. This success has been seen most notably in EGFR- and ALK-mutated lung cancer. While similar effectiveness has lagged behind in KRAS mutant lung cancer, success in the clinical setting is beginning to be seen, particularly with the MEK1 and MEK2 inhibitors. There are currently a multitude of clinical trials under way focusing on KRAS mutant NSCLC (Table 2).61 A continued challenge has been unacceptable adverse effects from the drugs. For instance, in a recently completed phase 1 study with the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib, only intermittent dosing was considered tolerable owing to significant adverse effects.62 Conclusions Non–small-cell lung cancer is a heterogeneous disease. KRAS represents one of the most commonly mutated genes in NSCLC; it is critical we continue working to understand KRAS mutations and to investigate drugs to inhibit the effects of KRAS mutation. With improving abilities to identify possible synthetic lethal targets and a multitude of clinical trials under way, the exciting potential for personalized, effective treatment in KRAS mutant NSCLC is just beginning to be realized. Back to top Article Information Corresponding Author: Ravi Salgia, MD, PhD, City of Hope, 1500 E Duarte Rd, Duarte, CA 91010 (rsalgia@coh.org). Accepted for Publication: February 9, 2016. Published Online: April 21, 2016. doi:10.1001/jamaoncol.2016.0405. Author Contributions: Dr Salgia had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Wood, Hensing, Salgia. Acquisition, analysis, or interpretation of data: Wood, Malik, Salgia. Drafting of the manuscript: Wood, Hensing, Malik, Salgia. Critical revision of the manuscript for important intellectual content: Wood, Salgia. Obtained funding: Salgia. Administrative, technical, or material support: Salgia. Study supervision: Hensing, Salgia. Conflict of Interest Disclosures: None reported. References 1. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res. 2008;14(18):5731-5734.PubMedGoogle ScholarCrossref 2. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. 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TI - Prognostic and Predictive Value in KRAS in Non–Small-Cell Lung Cancer: A Review
JF - JAMA Oncology
DO - 10.1001/jamaoncol.2016.0405
DA - 2016-06-01
UR - https://www.deepdyve.com/lp/american-medical-association/prognostic-and-predictive-value-in-kras-in-non-small-cell-lung-cancer-NFnKk5rfFF
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EP - 812
VL - 2
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DP - DeepDyve
ER -