Study finds BRAF mutations in colorectal cancer cause resistance to anti-EGFR therapy

October 23, 2008

European researchers have found that metastatic colorectal cancer patients with a mutation in the BRAF gene do not respond to anti-EGFR therapy with cetuximab and panitumumab. The finding could help doctors better identify which patients are likely to benefit from such treatment, which is commonly used as last-effort therapy but only works in a fraction of patients. The research was presented at the 20th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Geneva today (Thursday 23 October).

Colorectal cancer is one of the most common cancers worldwide and a leading cause of cancer death. Once the disease has spread, the five-year survival rate is less than 10%. The targeted drugs cetuximab (Erbitux) and panitumumab (Vectibix) - monoclonal antibodies that inhibit EGFR - are used to treat patients with chemotherapy-resistant metastatic colorectal cancer. However, they are effective in only 10-20% of such patients. Mutations in the KRAS gene explain about 30-40% of the non-responsive cases, but the reason for the rest of the failures is unknown.

The results of a study presented by Dr Federica Di Nicolantonio of the Institute for Cancer Research and Treatment at the University of Turin School of Medicine in Italy suggest that BRAF mutations may account for another 12% of resistant cases.

In the study, Dr Di Nicolantonio and colleagues conducted a genetic analysis of 113 tumours taken from patients with advanced colorectal cancer who had been treated with cetuximab or panitumumab at Ospedale Niguarda Ca' Granda (Milan, Italy) or at the Oncology Institute of Southern Switzerland (Bellinzona, Switzerland). They found that KRAS mutations were present in 30% of the patients, and that this mutation was associated with resistance to the drugs. A BRAF V600E mutation was detected in 11 of the remaining 79 patients who did not have KRAS mutations, representing 10% of the total number of patients. Mutations in the two genes are mutually exclusive.

"None of the patients with tumours containing BRAF mutations had responded to the treatment, and in cases where the treatment did work, none of those patients had BRAF mutations. This shows that for anti-EGFR therapy to work, the BRAF gene must be the wild type and suggests that BRAF status could be a useful biomarker for selecting patients suitable for anti-EGFR treatment," Dr Di Nicolantonio said, adding that progression-free survival and overall survival was significantly shorter in patients who had the BRAF mutation than in patients without the mutation.

The researchers also tested the influence of BRAF mutation on the success of anti-EGFR treatment prospectively by conducting a laboratory study that involved adding the drugs to colorectal cells altered to contain the mutated version of the BRAF gene. They found that introducing the mutated gene dramatically impaired the ability of cetuximab and panitumumab to work. They then added the BRAF inhibitor sorafenib. That restored the sensitivity of the cells to the anti-EGFR treatment, with the combination of the cetuximab and sorafenib resulting in massive cell death in the cells carrying the mutated BRAF gene.

"These findings suggest that combination therapy that simultaneously blocks EGFR and BRAF in patients with BRAF-mutated tumours may be a useful approach to increase the number of patients who could benefit from anti-EGFR therapy, but that remains to be assessed in a clinical trial," Dr Di Nicolantonio said.

"This research does not complete the picture of resistance to EGFR inhibitors. In spite of the predictive value of both KRAS and BRAF mutations, in our cohort 52 per cent of non-responsive patients did not have mutations in either gene. This means further molecular markers are needed to better define patients who are unlikely to benefit from EGFR-targeted treatment," she added.

ECCO-the European CanCer Organisation

---

---

	Latest melanoma research sparks new tx options. (Selectively Targeting BRAF Mutations).: An article from: Family Practice News by Bruce Jancin (Author) This digital document is an article from Family Practice News, published by International Medical News Group on May 1, 2003. The length of the article is 2787 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Latest melanoma research sparks new tx options. (Selectively Targeting BRAF Mutations). Author: Bruce Jancin Publication: Family Practice News (Magazine/Journal) Date: May 1, 2003 Publisher: International Medical News Group Volume: 33 Issue: 9 Page: 41(1) Distributed by Thomson...
	BRAF mutation flags aggressive thyroid cancer.(Metabolic Disorders): An article from: Family Practice News by Bruce Jancin (Author) This digital document is an article from Family Practice News, published by Thomson Gale on October 1, 2007. The length of the article is 734 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: BRAF mutation flags aggressive thyroid cancer.(Metabolic Disorders) Author: Bruce Jancin Publication: Family Practice News (Magazine/Journal) Date: October 1, 2007 Publisher: Thomson Gale Volume: 37 Issue: 19 Page: 17(1) Distributed by Thomson...
	BRAF mutation signals thyroid ca risk.(Endocrinology): An article from: Internal Medicine News by Bruce Jancin (Author) This digital document is an article from Internal Medicine News, published by Thomson Gale on August 15, 2007. The length of the article is 647 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: BRAF mutation signals thyroid ca risk.(Endocrinology) Author: Bruce Jancin Publication: Internal Medicine News (Magazine/Journal) Date: August 15, 2007 Publisher: Thomson Gale Volume: 40 Issue: 16 Page: 7(1) Distributed by Thomson...
	BRAF, KIT--mutation targeters offer hope.(CUTANEOUS ONCOLOGY): An article from: Skin & Allergy News by Patrice Wendling (Author) This digital document is an article from Skin & Allergy News, published by International Medical News Group on August 1, 2009. The length of the article is 586 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available immediately after purchase. You can view it with any web browser. Citation Details Title: BRAF, KIT--mutation targeters offer hope.(CUTANEOUS ONCOLOGY) Author: Patrice Wendling Publication: Skin & Allergy News (Magazine/Journal) Date: August 1, 2009 Publisher: International Medical News Group Volume: 40 Issue: 8 Page: 20(1) Distributed by Gale, a part of Cengage...
	Agent targeting BRAF mutations shows promise.(CUTANEOUS ONCOLOGY): An article from: Skin & Allergy News by Patrice Wendling (Author) This digital document is an article from Skin & Allergy News, published by International Medical News Group on November 1, 2009. The length of the article is 987 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available immediately after purchase. You can view it with any web browser. Citation Details Title: Agent targeting BRAF mutations shows promise.(CUTANEOUS ONCOLOGY) Author: Patrice Wendling Publication: Skin & Allergy News (Magazine/Journal) Date: November 1, 2009 Publisher: International Medical News Group Volume: 40 Issue: 11 Page: 18(1) Distributed by Gale, a part of Cengage...
	BRAF mutation predicts thyroid ca recurrence.(CANCER): An article from: Family Practice News by Kerri Wachter (Author) This digital document is an article from Family Practice News, published by International Medical News Group on June 15, 2010. The length of the article is 674 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available immediately after purchase. You can view it with any web browser. Citation Details Title: BRAF mutation predicts thyroid ca recurrence.(CANCER) Author: Kerri Wachter Publication: Family Practice News (Magazine/Journal) Date: June 15, 2010 Publisher: International Medical News Group Volume: 40 Issue: 11 Page: 40(1) Distributed by Gale, a part of Cengage...
	Glucose deprivation selects for KRAS and BRAF mutations in colorectal cancer. by Jihye Yun (Author) Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Mutations in KRAS and BRAF provide excellent examples of this central issue in cancer research. Activating KRAS and BRAF mutations are mutually exclusive during human tumorigenesis, implying their common origin and effect. Despite advances in the molecular delineation of KRAS and BRAF mutations, the specific microenvironmental pressures that drive these mutations and how these mutations alleviate these pressures are unknown. To explore this issue, we performed global gene expression analyses using paired isogenic colorectal cancer cell lines that differ only in the mutational status of their KRAS or BRAF genes, using both microarray and serial analysis...
	The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care by Eric Topol M.D. (Author) What if your cell phone could detect cancer cells circulating in your blood or warn you of an imminent heart attack? Mobile wireless digital devices, including smartphones and tablets with seemingly limitless functionality, have brought about radical changes in our lives, providing hyper-connectivity to social networks and cloud computing. But the digital world has hardly pierced the medical cocoon.  Until now. Beyond reading email and surfing the Web, we will soon be checking our vital signs on our phone. We can already continuously monitor our heart rhythm, blood glucose levels, and brain waves while we sleep. Miniature ultrasound imaging devices are replacing the icon of medicine—the stethoscope. DNA sequencing, Facebook, and the Watson supercomputer have already saved lives. For...
	The BRAF gene is frequently mutated in malignant melanoma.(SKIN CANCER FOUNDATION UPDATE): An article from: Journal of Drugs in Dermatology by Michael R. Stratton (Author), Richard W. Wooster (Author), P. Andrew Futreal (Author) This digital document is an article from Journal of Drugs in Dermatology, published by Journal of Drugs in Dermatology, Inc. on September 1, 2004. The length of the article is 1557 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: The BRAF gene is frequently mutated in malignant melanoma.(SKIN CANCER FOUNDATION UPDATE) Author: Michael R. Stratton Publication: Journal of Drugs in Dermatology (Refereed) Date: September 1, 2004 Publisher: Journal of Drugs in Dermatology, Inc. Volume: 3 Issue: 5 Page: 573(3) Distributed by Thomson...
	Genes, Chromosomes, and Disease: From Simple Traits, to Complex Traits, to Personalized Medicine (FT Press Science) by Nicholas Wright Gillham (Author) This very readable overview of the rise and transformations of medical genetics and of the eugenic impulses that have been inspired by the emerging understanding of the genetic basis of many diseases and disabilities is based on a popular nonmajors course, "Social Implications of Genetics," that Gillham gave for many years at Duke University. The book is suitable for use as a text in similar overview courses about genes and social issues or genes and disease. It gives a good overview of the developments and status of this field for a wide range of biomedical researchers, physicians, and students, especially those interested in the prospects for the new, genetics-based personalized medicine.