Friday, October 24th, 2008
In a recent blog, I noted that the CEO of ImClone said KRAS testing has grown substantially since the announcements earlier this summer linking mutations in KRAS with resistance to Erbitux and Vectibix therapies. We may now have to add mutations in BRAF as well, in order to get a more comprehensive view of whether a patient will benefit from these therapies.
A study presented this week at the annual EORTC meeting in Geneva showed that patients with a mutation in the BRAF gene also do not benefit Erbitux or Vectibix. So far, these clinical observations fit perfectly with what we know about the biology of the EGFR pathway. Because KRAS lies downstream of the EGFR, activating mutations in KRAS would be expected to override any inhibition of the EGFR that occurs upstream. Similarly, BRAF lies downstream of KRAS, so activating mutations in BRAF would also be expected to override any inhibition of the EGFR that occurs upstream as well. The study (of 113 patients) found that KRAS and BRAF mutations were mutually exclusive, suggesting that a BRAF mutation is as sufficient as a KRAS mutation in mediating resistance to these therapies, although larger studies would be needed to truly determine this. If these observations fit so well with the biology of EGFR – KRAS – BRAF signaling, you might wonder why it took so long to figure it out (given that we’ve understood these pathways for a quite a long time). To be sure, hindsight is always 20/20, but studies on patient specimens are immensely more challenging than pre-clinical studies, and only in the last several years have more sensitive methods of sequencing and mutation detection come about that can really pinpoint mutations in clinical specimens, where the DNA is generally of poor quality and also may be limiting if only small amounts of tumor are present in a specimen.
So it looks like we may need to test colon cancer patients for both KRAS and BRAF together. While the exact frequency of BRAF mutations in colorectal cancer is not yet known, it is probably at least 10% and perhaps as high as 25%. So even being conservative, we can probably say that almost half (and possibly more) of colon cancer patients will have either a KRAS or BRAF mutation. This is another step forward for personalized medicine since more patients can be put on therapies sooner that will have a real chance of helping them.
At TMD, we’ve been ahead of the curve, by providing the KRAS Mutation test since earlier this year, and also validating the BRAF Mutation test, as we expected that it was only a matter of time before BRAF was found to be important as well. The BRAF Mutation test we use employs the same highly sensitive technology as the KRAS Mutation test. Please contact us to find out how we can provide both KRAS and BRAF testing.
Posted in Biomarkers, Companion Diagnostics, General, Targeted Therapy Development | No Comments »
Monday, September 29th, 2008
New data presented at the Molecular Diagnostics in Cancer Therapeutic Development meeting from investigators at Wyeth shows that the Src pathway may play a role in resistance to some breast cancer therapies. Src is an enigmatic player in cancer. Despite being one of the oldest known oncogenes and having potent transforming capabilities in chicken cells, Src’s exact role in human cancer has remained somewhat elusive. The new research indicates that high activation of the Src pathway is often seen in tumors that are estrogen receptor, progesterone receptor and HER2 negative (so called “triple negative breast cancer”). Patients with high levels of Src pathway biomarkers were generally correlated with lower overall survival.
Because there are now Src inhibitors in clinical trials, this finding raises the intriguing possibility that current breast cancer therapies could be combined with Src inhibitors to augment the action of breast cancer therapy or perhaps decrease the chance of a patient developing resistance. At TMD, we’ve been involved with the clinical development of Src inhibitors and have many bioamarkers to interrogate the activation state of the Src pathway such as phospho-Src, phospho-FAK and phospho-paxillin, to name just a few. These biomarkers can be performed in real time and used to guide patient therapy or can be part of larger biomarker strategy for a retrospective study analysis. Please see the biomarker section of website for a complete list of our validated biomarkers. We also offer a full range of clinical development services.
Posted in Biomarkers, General, Targeted Therapy Development | No Comments »
Thursday, September 18th, 2008
A recent study published in Molecular Cancer Research found an association between the expression of a histone deacetylase, SIRT1, and resistance to cisplatin. Cells that were initially sensitive to cisplatin were made resistant to the drug by continuous exposure. The researchers found high levels of SIRT1 in the resistant lines. Reducing the levels of SIRT1 made the cells more sensitive to cisplatin again. This study was conducted at the NCI. Although this is an early study performed in cell lines in the laboratory, it is important because while a great deal of effort goes into discovering biomarkers for targeted therapies, there has not been a lot of focus on finding biomarkers for traditional chemotherapies, like cisplatin-based drugs.
TMD has validated immunohistochemistry (IHC) assays for the detection and measurement of SIRT1 and SIRT2 in tissue. They can be used for pre-clinical development work such as xenograft studies or for clinical development in human tissue. Please contact us for more information about our SIRT1 or SIRT2 assays.
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Thursday, August 28th, 2008
A recent article on personalized testing in CAP Today discussed many of the issues surrounding KRAS testing. There are many benefits of KRAS testing for patients, not only health related but economic as well. Nearly 4 out of 10 patients with colorectal cancer (CRC) will harbor a KRAS mutation (the actual percentage seems to be approximately 38%). Of the remaining 6 patients (62% to be exact) with normal KRAS, typically 3 of the 6 will experience some benefit from EGFR targeted therapy (the reason why all 6 do not respond is probably because we need additional biomarkers, but this will be the subject of a future blog). So with KRAS testing, 3 of 6 instead of 3 of 10 patients will derive benefit, thus sparing 4 patients from a therapy that they will not benefit from and therefore any adverse effects from these drugs as well. In addition, the one thing that most cancer patients lack is time. The longer someone has to wait, the further their tumor can spread, so they can not afford the time it takes to be treated with an ineffective therapy.
The article goes on to state that there is an obvious economic impact to KRAS testing as well. Erbitux treatment can cost nearly $10,000 per month per person. The cost for 10 patients would be nearly $100,000 per month. If 4 out of 10 people would not benefit from Erbitux treatment, this would amount to a savings of almost $40,000 per month (which easily eclipses the cost of 10 KRAS mutation tests). One reason these costs matter to patients is because ultimately the decision by payors to reimburse for a test has a large impact on how widespread adoption of the test becomes. In this scenario, the cost of a KRAS test to a payor is in the hundreds of dollars (and a 1 time expense) compared with a savings of thousands of dollars every month in treatment costs.
At TMD we are actively speaking with payors about the benefits of KRAS testing, including the different methods of KRAS testing. We are always open to discussion on this topic.
Posted in Targeted Therapy Development | No Comments »
Monday, December 17th, 2007
TMD announced the commercial availability of a new laboratory test to help identify colorectal cancer (CRC) patients who are resistant to EGFR targeted monoclonal antibody therapies. K-ras mutations have also been associated with resistance to EGFR tyrosine kinase inhibitors especially in non-small cell lung cancer (NSCLC). Mutated K-ras genes have been detected in about 40% of metastatic colorectal cancer and 15% of NSCLC patients. TMD’s K-ras Mutation Assay may help identify patients who harbor specific K-ras mutations and therefore may not respond to EGFR inhibitors.
The TMD K-ras Mutation Assay utilizes SNP-based Real-Time PCR technology to identify 7 of the most common K-ras mutations in DNA from frozen or formalin fixed paraffin embedded (FFPE) tumor specimens. Because the K-Ras assay does not rely on sequencing, it has much greater sensitivity. Clinical specimens are often in the form of formalin fixed paraffin embedded slides which can contain large amounts of normal tissue and stroma and small amounts of tumor cells. SNP-based assays, because of their reliance on TaqMan chemistry, have higher sensitivity and K-Ras mutations can be detected even when mutant DNA comprises only 1% of the total DNA present in the sample.
In one study, TMD identified mutations in 43% of CRC patients using this technology. The results of the assay are available within 4 – 5 days from receipt of the specimen at TMD. The TMD K-ras Mutation Assay is designed for use in clinical development of EGFR-based targeted therapies and to guide treatment options for patients with these mutations. TMD can provide specimen collection kits to collect patient blocks or slides that are compatible with this assay. We look forward to hearing your comments or questions. To review the full press release, visit TMD at www.tmdlab.com.
Posted in General, Targeted Therapy Development | No Comments »