NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?-Case series and review of the literature.

Upfront KRAS and NRAS gene testing ('RAS') is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent 'NeoRAS wild-type' phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies.

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Déclaration de conflit d'intérêts

Conflicts of interest statement L.V. received research funding from Pierre Fabre, participant in the Charité-BIH Clinician Scientist Program funded by the Charité Universitätsmedizin Berlin and Berlin Institute of Health. L.V. spouse is an employee and shareholder of Bayer AG. U.K. received honoraria from AstraZeneca, Bayer Schering Pharma, Bristol-Myers Squibb, Glycotope GmbH, Merck KGaA, MSD Oncology, Novartis, Pfizer, Roche/Genentech; consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, Merck Serono, MSD Oncology, Pfizer; speakers' bureau for AstraZeneca, Bayer Schering Pharma, Bristol-Myers Squibb, Merck Serono, MSD Oncology, Novartis; and received research funding from AstraZeneca/MedImmune (Inst), Pfizer (Inst), Travel, Accommodations, Expenses: AstraZeneca, Bayer Schering Pharma, Ipsen, Merck Serono, MSD Oncology, Pierre Fabre. A.H.S.A. consulting or advisory role for Roche and received travel, accommodations, expenses from Pfizer, Roche, Eli Lilly, Novartis, PharmaMar. J.C.v.E. received honoraria from Merck, Roche, Amgen, Sanofi, Pierre Fabre, Servier, Taiho, BMS, Eisai, Novartis; consulting or advisory role for Amgen, Pierre Fabre, BMS, Servier; travel, accommodations, expenses: AstraZeneca, Apceth. A.S. received honoraria from Roche, Servier; travel, accommodations, expenses from Roche, Merck KgA, MSD Sharp & Dohme, Pfizer, Amgen. A.K. received honoraria from Taiho Pharmaceutical, Servier; travel, accommodations, expenses: Roche, Medac. D.P.M. received honoraria from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Pfizer, Roche, Servier, Taiho Pharmaceutical; consulting or advisory role: Amgen, Merck Serono, Merck Sharp & Dohme, Roche, Servier; received research funding from Amgen (Inst), Merck Serono (Inst), Roche (Inst); travel, accommodations, expenses: Amgen, Bayer, Bristol-Myers Squibb, Merck Serono, Roche, Servier. S.S. received honoraria Amgen, Bayer, Lilly, Merck KGaA, Pierre Fabre, Roche, Sanofi, Servier, Sirtex Medical, Taiho Pharmaceutical, Takeda; consulting or advisory role: Amgen, Bayer, Boehringer Ingelheim, Lilly, Merck KGaA, MSD, Pierre Fabre, Roche; Sanofi, Servier, Takeda; research funding: Merck Serono (Inst), Pierre Fabre (Inst), Roche Molecular Diagnostics (Inst); travel, accommodations, expenses: Amgen, Bayer, Lilly, Merck KGaA, Pierre Fabre, Roche, Sanofi, Sirtex Medical, Takeda. I.J. received honoraria from Bristol-Myers Squibb, Roche. All remaining authors have declared no conflicts of interest.