KRAS insertions in colorectal cancer: What do we know about unusual KRAS mutations?

Macedo, Mariana Petaccia de; Lima, Luciana; Begnami, Maria D.; Melo, Fernanda Machado de; Brot, Louise De; Lisboa, Bianca Cristina Garcia; Soares, Luisa M.; Soares, Fernando Augusto; Carraro, Dirce Maria; Cunha, Isabela Werneck da

doi:10.1016/j.yexmp.2014.02.014

Cited by 11 publications

(7 citation statements)

References 24 publications

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“…Consequently, the estimated 30% reduction in risk of death with addition of tivantinib did not reach statistical significance. Additional RAS testing should be conducted in these tumors; the presence of rare RAS mutations can confer resistance to EGFR inhibitors . Finally, adequate tissue samples for evaluation of MET expression were only available from 67 patients (55%) in phase 2.…”

Section: Discussionmentioning

confidence: 99%

“…Additional RAS testing should be conducted in these tumors; the presence of rare RAS mutations can confer resistance to EGFR inhibitors. 55,56 Finally, adequate tissue samples for evaluation of MET expression were only available from 67 patients (55%) in phase 2. Evidence suggests that MET overexpression is a later event in tumor growth/metastasis; therefore, MET may be a predictive biomarker in advanced disease.…”

Section: Discussionmentioning

confidence: 99%

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A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

Eng

Bessudo

Hart

et al. 2016

Intl Journal of Cancer

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Cetuximab in combination with an irinotecan‐containing regimen is a standard treatment in patients with KRAS wild‐type (KRAS WT), metastatic colorectal cancer (mCRC). We investigated the addition of the oral MET inhibitor tivantinib to cetuximab + irinotecan (CETIRI) based on preclinical evidence that activation of the MET pathway may confer resistance to anti‐EGFR therapy. Previously treated patients with KRAS WT advanced or mCRC were enrolled. The phase 1, open‐label 3 + 3, dose‐escalation study evaluated the safety and maximally tolerated dose of tivantinib plus CETIRI. The phase 2, randomized, double‐blinded, placebo‐controlled study of biweekly CETIRI plus tivantinib or placebo was restricted to patients who had received only one prior line of chemotherapy. The phase 2 primary endpoint was progression‐free survival (PFS). The recommended phase 2 dose was tivantinib (360 mg/m2 twice daily) with biweekly cetuximab (500 mg/m2) and irinotecan (180 mg/m2). Among 117 patients evaluable for phase 2 analysis, no statistically significant PFS difference was observed: 8.3 months on tivantinib vs. 7.3 months on placebo (HR, 0.85; 95% confidence interval, 0.55–1.33; P = 0.38). Subgroup analyses trended in favor of tivantinib in patients with MET‐High tumors by immunohistochemistry, PTEN‐Low tumors, or those pretreated with oxaliplatin, but subgroups were too small to draw conclusions. Neutropenia, diarrhea, nausea and rash were the most frequent severe adverse events in tivantinib‐treated patients. The combination of tivantinib and CETIRI was well tolerated but did not significantly improve PFS in previously treated KRAS WT mCRC. Tivantinib may be more active in specific subgroups.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

Eng

Bessudo

Hart

et al. 2016

Intl Journal of Cancer

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“…KRAS mutations are observed in 35% to 40% of CRCs and arise more often in codons 12 (80%) and 13 (15%) of exon 2 [ 7 , 8 , 9 ] and to a lesser extent in codons 61, 117, and 146 [ 7 , 8 , 9 ]. Unsual KRAS mutations affecting more than 1 codon and insertions have also been reported [ 10 , 11 ]. Recent studies have shown that CRC patients with tumors that harbor NRAS gene mutations also have poorer response rates to EGFR inhibitors compared with those with wild-type NRAS [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

RAS mutations vary between lesions in synchronous primary Colorectal Cancer: Testing only one lesion is not sufficient to guide anti-EGFR treatment decisions.

et al. 2015

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IntroductionMutations in KRAS and NRAS genes are negative predictors of anti-EGFR therapies response in metastatic colorectal cancer. There are few reports on RAS testing in synchronous primary colorectal cancer (SP-CRC) and a lack of recommendations on which tissue should be tested for the mutation in this disease. This study analyzed the RAS status of both lesions in SP-CRC patients and in their metastasis.Materials and methodsDNA was obtained from formalin-fixed-paraffin-embedded tissue, and mutations were analyzed by pyrosequencing.ResultsRAS status was heterogeneous in 6 (75%) of 8 SP-CRC patients between primary lesions. Five showed heterogeneity regarding RAS mutational status, and from these, four presented with metastasis: 3 cases (75%) had WT metastatic tissue, and 1 case (25%) had mutated metastatic tissue. One patient showed divergence regarding RAS mutation type.DiscussionRAS mutations vary significantly between SP-CRC lesions, and the status of the metastasis is unpredictable. Testing for RAS mutations in only 1 of the primary lesions can misguide clinical decisions and hind the predictive potential of anti-EGFR treatment. A more appropriate approach in metastatic SP-CRC is to test the metastatic tissue or both primary lesions for providing more accurate mutation scenery and support more assertive clinical decisions.

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“…Multiple studies have shown that alterations across KRAS exons 2, 3, and 4 similarly predict cetuximab and panitumumab resistance, and the National Comprehensive Cancer Network (NCCN) and American Society for Clinical Oncology (ASCO) guidelines have expanded to recommend extended KRAS testing, as well as testing for NRAS and BRAF mutations [6,9,15,16,52]. Additionally, KRAS insertions within or adjacent to hotspot regions have been reported; these mutations have been characterized as activating and oncogenic, and may similarly predict resistance, although this has not yet been established [53][54][55][56].…”

Section: Discussionmentioning

confidence: 99%

Broad detection of alterations predicted to confer lack of benefit from EGFR antibodies or sensitivity to targeted therapy in advanced colorectal cancer

Klempner

Rankin²,

Erlich³

et al. 2016

Annals of Oncology

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KRAS insertions in colorectal cancer: What do we know about unusual KRAS mutations?

Cited by 11 publications

References 24 publications

A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

A randomized, placebo‐controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild‐type KRAS who have received first‐line systemic therapy

RAS mutations vary between lesions in synchronous primary Colorectal Cancer: Testing only one lesion is not sufficient to guide anti-EGFR treatment decisions.

Broad detection of alterations predicted to confer lack of benefit from EGFR antibodies or sensitivity to targeted therapy in advanced colorectal cancer

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