<i>KRAS</i> Codon 12 and 13 Mutations in Relation to Disease-Free Survival in <i>BRAF</i>–Wild-Type Stage III Colon Cancers from an Adjuvant Chemotherapy Trial (N0147 Alliance)

Yoon, Harry H.; Tougeron, David; Shi, Qian; Alberts, Steven R.; Mahoney, Michelle R.; Nelson, Garth D.; Nair, Suresh; Thibodeau, Stephen N.; Goldberg, Richard M.; Sargent, Daniel J.; Sinicrope, Frank A.

doi:10.1158/1078-0432.ccr-13-3140

Cited by 141 publications

(116 citation statements)

References 48 publications

(64 reference statements)

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“…The most common mutant alleles for KRAS are 12D, 12C, 12V, 12R, and 13D [144,145]. Evidence has shown that different KRAS mutant alleles may have different clinical impacts on the prognosis of lung [146,147], colon [148][149][150], and pancreatic [151] cancers, although the alleles associated with poor clinical outcomes are not consistent in these studies. Molecular characterization of clinical specimens from patients who participated in prospective phase II biomarker-integrated approaches of targeted therapy for lung cancer elimination revealed that the expressions of cell cycle regulators PLK1, CCNB1, and CCNE1 were lower in KRAS 12C and KRAS 12V mutant tumors, but were higher in the remaining KRAS mutant tumors, when compared with KRAS wild-type cancer [146].…”

Section: Studies On Clinical Specimens and Clinical Trialsmentioning

confidence: 85%

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Fang¹

2016

ABBS

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Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine.

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Section: Studies On Clinical Specimens and Clinical Trialsmentioning

confidence: 85%

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Fang¹

2016

ABBS

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“…In the Alliance N0147 trial, patients with KRAS exon 2 mutations experienced a shorter disease-free survival than patients without such mutations. 148 At this time, however, the test is not recommended for prognostic reasons.…”

Section: The Role Of Kras Nras and Braf Statusmentioning

confidence: 99%

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Benson¹,

Venook²,

Cederquist³

et al. 2017

J Natl Compr Canc Netw

745

515

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OverviewColorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2016, an estimated 95,270 new cases of colon cancer and approximately 39,220 cases of rectal cancer will occur. During the same year, an estimated 49,190 people will die of colon and rectal cancer combined. AbstractThis portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, KRAS/NRAS mutational status, and patient comorbidities and preferences. Location of the primary tumor, the BRAF mutation status, and tumor microsatellite stability should also be considered in treatment decisions. J Natl Compr Canc Netw 2017;15(3): 370-398 NCCN Categories of Evidence and ConsensusCategory 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

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“…Furthermore, Yoon et al [10] found that RCC was significantly associated with a shorter DFS compared with LCC when patients with BRAF-wild-type stage Ⅲ…”

Section: Adjuvant Chemotherapymentioning

confidence: 99%

Different treatment strategies and molecular features between right-sided and left-sided colon cancers

Shen¹

2015

WJG

179

183

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The colon is derived from the embryological midgut and hindgut separately, with the right colon and left colon having different features with regards to both anatomical and physiological characteristics. Cancers located in the right and left colon are referred to as right colon cancer (RCC) and left colon cancer (LCC), respectively, based on their apparent anatomical positions. Increasing evidence supports the notion that not only are there differences in treatment strategies when dealing with RCC and LCC, but molecular features also vary between them, not to mention the distinguishing clinical manifestations. Disease-free survival after radical surgery of both RCC and LCC are similar. In the treatment of RCC, the benefit gained from adjuvant FOLFIRI chemotherapy is superior, or at least similar, to LCC, but inferior to LCC if FOLFOX regimen is applied. On the other hand, metastatic LCC exhibits longer survival than that of RCC in a palliative chemotherapy setting. For KRAS wild-type cancers, LCC benefits more from cetuximab treatment than RCC. Moreover, advanced LCC shows a higher sensitivity to bevacizumab treatment in comparison with advanced RCC. Significant varieties exist at the molecular level between RCC and LCC, which may serve as the cause of all apparent differences. With respect to carcinogenesis mechanisms, RCC is associated with known gene types, such as MMR, KRAS, BRAF, and miRNA-31, while LCC is associated with CIN, p53, NRAS, miRNA-146a, miRNA-147b, and miRNA-1288. Regarding protein expression, RCC is related to GNAS, NQO1, telomerase activity, P-PDH, and annexin A10, while LCC is related to Topo I, TS, and EGFR. In addition, separated pathways dominate progression to relapse in RCC and LCC. Therefore, RCC and LCC should be regarded as two heterogeneous entities, with this heterogeneity being used to stratify patients in order for them to have the optimal, current, and novel therapeutic strategies in clinical practice. Additional research is needed to uncover further differences between RCC and LCC.

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KRAS Codon 12 and 13 Mutations in Relation to Disease-Free Survival in BRAF–Wild-Type Stage III Colon Cancers from an Adjuvant Chemotherapy Trial (N0147 Alliance)

Cited by 141 publications

References 48 publications

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Different treatment strategies and molecular features between right-sided and left-sided colon cancers

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