RAS testing

[ConnieSPK]

Just something I came across today
http://www.medscape.com/viewarticle/831 ... c=207977EG

Connie K.

[CRguy]

Connie this link just goes to your own login page
( Medscape still requires a free login for someone else to actually access the article themselves )

Could you post the actual title of the article and maybe we could copy the abstract at least, then folks can decide if they want to register to see the full article.
I think it could be of interest to a lotta folks here.

Cheers
CRguy

[Laurettas]

And I hope they don't forget BRAF along the way since it shows the same lack of benefit from Erbitux-type therapy. Sounds like that type of therapy is being limited to a smaller and smaller group of people.

[Maia]

Mandatory Extended RAS Testing for mCRC

Alok A. Khorana, MD
September 19, 2014
Extended RAS Mutations and Anti-EGFR Monoclonal Antibody Survival Benefit in Metastatic Colorectal Cancer: a Meta-analysis of Randomized Controlled Trials

Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS

Ann Oncol. 2014 Aug 12. [Epub ahead of print]
Study Summary

Multiple subgroup analyses of randomized trials[1-5] have suggested that patients who have "extended RAS" mutations (in exons 3 and 4 of KRAS and exons 2, 3, and 4 of NRAS) not only may not benefit from anti-epidermal growth factor receptor (EGFR) therapy but may potentially be harmed. Sorich and colleagues conducted a systematic review and meta-analysis of such reported trials. Overall, nine trials of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria.

Approximately 20% of KRAS exon 2 wild-type tumors were found to have one of the extended RAS mutations. "True" wild-type RAS mutations (either KRAS exon 2 or new RAS mutations) had significantly superior progression-free survival (PFS) (P < .001) and overall survival (OS) (P = .008) with use of anti-EGFR monoclonal antibodies (mAbs). Benefits were consistent across anti-EGFR agents, variations in chemotherapy backbone, and lines of therapy. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > .05).
Viewpoint

This study confirms emerging data from a variety of subgroup analyses of previously conducted randomized controlled trials that extended RAS mutations should properly be classified alongside KRAS and be considered a contraindication to treatment with anti-EGFR therapy. Altogether, approximately 55% of all metastatic colorectal patients are now considered to be RAS-mutant. Continuing to treat these patients with anti-EGFR therapy exposes them to significant additional toxicity without likelihood of benefit; in addition, this approach also costs the health system significant financial resources.

Although there was significant treatment-effect heterogeneity across studies in the mutant population, it is worthwhile to note that some subgroup analyses suggested worsened median survival in RAS-mutant patients. At the time of treatment decision, extended RAS testing (as opposed to only KRAS) should therefore be mandatory. Pathology departments and treating clinicians will need to ensure that testing on clinical specimens can be coordinated in a timely fashion to prevent patients from receiving potentially harm-inducing regimens.

[Maia]

J Clin Pathol. 2014 Jul 4. pii: jclinpath-2014-202467. doi: 10.1136/jclinpath-2014-202467. [Epub ahead of print]
RAS testing of colorectal carcinoma-a guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group.
Wong NA1, Gonzalez D2, Salto-Tellez M3, Butler R4, Diaz-Cano SJ5, Ilyas M6, Newman W7, Shaw E8, Taniere P9, Walsh SV10.
Author information
Abstract

Analysis of colorectal carcinoma (CRC) tissue for KRAS codon 12 or 13 mutations to guide use of anti-epidermal growth factor receptor (EGFR) therapy is now considered mandatory in the UK. The scope of this practice has been recently extended because of data indicating that NRAS mutations and additional KRAS mutations also predict for poor response to anti-EGFR therapy. The following document provides guidance on RAS (i.e., KRAS and NRAS) testing of CRC tissue in the setting of personalised medicine within the UK and particularly within the NHS. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such RAS testing.http://www.ncbi.nlm.nih.gov/pubmed/24996433

[Maia]

Laurettas... 2008, and we're still waiting for mandatory testing, so people don't get hit with Erbitux or Vectibix 'just in case'.

BRAF Mutations Predict Resistance to Treatment for Advanced Colorectal Cancer; New Gene-Expression Assay Predicts Response to Chemotherapy Combination

October 28, 2008 — Mutations in the BRAF gene limit the response to anti-epidermal growth-factor receptor (anti-EGFR) therapy in patients with metastatic colorectal cancer, researchers reported at the 20th Annual European Organization for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics, in Geneva, Switzerland. BRAF-mutation status can therefore help identify patients who are most likely to benefit from treatment with the monoclonal antibodies cetuximab (Erbitux; ImClone, Merck) and panitumumab (Vectibix, Amgen).

"Our data clearly point out BRAF mutations as another determinant of resistance to EGFR-targeted monoclonal antibodies," said lead author Federica Di Nicolantonio, PharmD, PhD, from the Institute for Cancer Research and Treatment at the University of Turin School of Medicine, in Italy.

She pointed out that none of the patients in their study who had tumors containing BRAF mutations responded to anti-EGFR treatment. Conversely, none of the patients who responded to treatment had BRAF mutations. http://www.medscape.com/viewarticle/582705

Same date, 2008: "n another study presented at the EORTC–NCI–AACR symposium, researchers report identifying an 11-gene signature that could be used to separate patients who will respond to the FOLFIRI chemotherapy regimen (leucovorin, fluorouracil, and irinotecan) from those who will not. Currently, FOLFIRI is a commonly used first-line therapy for metastatic colorectal cancer. Still waiting, too.

[Laurettas]

I know, Maia, I know. Our insurance company paid $150,000 for a drug that was not going to help Jake, not to mention the lovely side effects that he had to endure from it and the fact that his cancer grew like wildfire while on it. And, early in his reception of Erbitux, I found the article you quoted about BRAF mutations, did the research to discover that one third of SRC cancer has a BRAF mutation, brought all of that to the attention of the onc and he REFUSED to do the test for BRAF. One of the many pleasant experiences with our current cancer treatment procedures.

[rp1954]

The CA19-9 + CSLEX1 stains for a definitive determination of long term cimetidine benefit would cost about $300 and benefit ca 2/3rds of the stage III and IV cases a lot more, both on average stats and in the usual + + mCRC cases specifically. We've been stuck at the preliminary recognition level for 12+ years now, dying to know asap. It's just criminal, insane and ruinously expensive.