Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer

Abstract

RAS family proteins (including KRAS and NRAS) play important roles in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in RAS genes (occurring at loci in exons 2, 3, and 4) often result in constitutive activation of RAS proteins and persistent downstream signaling. Mutations in KRAS exon 2 (codon 12/13) are an established predictor of lack of response to the anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer (mCRC), and have been used routinely in clinical practice to identify patients unlikely to derive benefit from these therapies. However, a meaningful proportion of patients with mCRC have tumors bearing other mutations in RAS genes. Recent studies have demonstrated that evaluation of an extended panel of RAS mutations—including mutations in KRAS exon 2, 3, and 4 and NRAS exons 2, 3, and 4—can better define the patient population that is unlikely to benefit from anti-EGFR therapy, with concomitant improvements in outcomes in the more highly selected RAS wild-type group. This discovery has changed the practice of oncology and has the potential to spare patients from exposure to ineffective therapy. In the near future, it is important for the oncology community to validate extended RAS analysis assays and make certain that patients who are candidates for anti-EGFR therapy undergo appropriate testing and treatment.

Current biologics for treatment of biliary tract cancers

“…In fact, none has used EGFR genomic alterations as a biomarker. Additionally, lessons from the colorectal cancer world have informed us that KRAS mutations negate response to anti-EGFR therapy (42)(43)(44). However, only a few of the BTC trials have used KRAS status to stratify patients.…”

A genetic variant in Rassf1a predicts outcome in mCRC patients treated with cetuximab plus chemotherapy: results from FIRE-3 and JACCRO 05 and 06 trials

“…Rassf1a is involved not only in Ras signaling, but also it is a recognized upstream regulator of Hippo signaling interacting with MST through its SARAH domain 5 . The critical importance of Ras signaling in mCRC is widely known 20 . Regarding Hippo signaling, several recent works are highlighting influence of Hippo not only in the prognosis of CRC patients 21, 22 , but also in the lack of response to chemotherapy by favoring stemness and quiescence status of tumor cells 23, 24 .…”

Current applications of molecular pathology in colorectal carcinoma

“…Clinical trials have provided evidence that these mutations are negative predictors of response to anti-EGFR therapy [83][84][85][86][87][88]. BRAF is an immediate downstream molecule of RAS.…”