Article and Video CATEGORIES

Cancer Journey

Search By

Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

Ras Mutations and EGFR Resistance

Please Note: New Treatments Have Emerged Since this Original Post
Author
Howard (Jack) West, MD

Most of the focus on predicting response to EGFR inhibitors has been on identifing molecular markers that are associated with major response to this kind of treatment. But we know that there is a group of patients who get no benefit from these expensive drugs, and in these patients, EGFR inhibitors would just lead to side effects and keep them from a potentially more effective therapy for them. As you can see, the overall survival and progression-free survival curves from the BR.21 trial (abstract here) show that there are a group of patients clustered on the right side of the curve who do no better than the placebo group. In addition to detecting which patients are going to be the greatest beneficiaries, we need to identify which patients will get no benefit at all from EGFR tyrosine inhibitors like Tarceva.

Ras (rhymes with mass) is a gene and protein product that are involved in molecular signalling and very important in many cancers. There are several related genes in the family, and most of the focus is on k-ras. Mutations are seen in a significant minority of lung cancers and are far more likely to be seen in smokers than in non-smokers (abstract here). As you can see from the tables below, ras mutations are consistently more common in smokers than in non-smokers in multiple case series, and they are essentially mutually exclusive with EGFR mutations that have been associated with a high response rate to EGFR tyrosine kinase inhibitors like Iressa and Tarceva.

ras mutations smokers vs. nonsmokers (click to enlarge) ras and EGFR mutations

The available evidence also suggests that patients with ras mutations don't respond to EGFR inhibitors. Looking at the BR.21 trial of tarceva vs. placebo, the patients with an identified k-ras mutation had a worsening of survival if they received tarceva (abstract here), compared to recipients of placebo (remember, with a hazard ratio, numbers lower than 1 mean a benefit, and numbers above 1 translate to a harmful effect of the treatment, in this case a 67% worse survival):

k-ras on BR.21

Similarly, Dr. Miller looked at EGFR and k-ras mutations from tumors in a trial of Tarceva in bronchioloalveolar carcinoma (BAC)(abstract here) and found that there were no responders among the patients with k-ras mutations, vs. a 30% response rate for patients who don't have this mutation:

k-ras and erlotinib in BAC

Some other analyses that have looked at ras mutations and EGFR inhibitors have also supported this finding.

Testing for ras mutations isn't commonly done yet, but it is commercially available in some labs. Perhaps it's because we're reluctant to find a reason not to treat a patient with a certain therapy when the options are limited, or maybe we really should be doing this test routinely in order to help us clarify the patients in whom this approach is just a waste of time and money. I'd be interested to know whether patients would want to know before trying tarceva whether they shouldn't bother with it, or whether the hope of a new therapy would lead people to prefer a "don't ask, don't tell" policy, even if it means eliminating a treatment from a short list of agents that has a demonstrated survival benefit for patients with advanced NSCLC who have progressed through at least one line of chemo.

Next Previous link

Previous PostNext Post

Related Content

Article
Advance directives are a powerful way to take control of healthcare choices. These documents allow you to outline preferences for medical care and specify end-of-life wishes. These documents can also be a way to appoint loved ones who you would like to help with these decisions, such as a healthcare proxy (someone to make decisions on your behalf, if you cannot). As cancer treatments can involve aggressive treatments and/or complex medical management, having advance directives ensures that your desires regarding treatment options and end-of-life care are clearly communicated. 
Image
2024-25 patient perspectives header
Article
Tell your story and help us help others! Apply online now for this paid opportunity. This program gives a voice to those who have experience in participating in a clinical trial for a cancer diagnosis. Your voice helps to educate and advocate for others who are in or who may be considering a clinical trial.  We want to hear from you!
Image
Foro de Pacientes de Terapias Dirigidas de Cáncer de Pulmón
Video
¡El vídeo completo bajo demanda está disponible para verlo!

Forum Discussions

Hello Linda, my name is Alexandra Beneke, I'm the Outreach Manager for GRACE. Your willingness to share your experiences and knowledge with the cancer community is truly inspiring. Your dedication to...

Hi Bluebird,  Welcome to GRACE.  I'm sorry you're going through this scare and hope it's just inflammation or from an infection you didn't know you had. 

 

A CT would be...

Radiation + Brain Operation has just been discarded due to high risk. They will double Tagrisso dosis and then wait to see if it works, then try traditional Chemo. I would...

Hi and welcome to GRACE.  I'm sorry to know you are entering a new stage.  I'm not about to comment just now but wanted to let you know I see your...

Edit to say, we can't give advice but we can comment with views and facts.  :)

 

My first thought is to ask if she has been seen at a large...

Hi Barbro, Welcome to GRACE. I'm sorry you're worrying about this. We aren't able to give feedback on scan reports. Interpreting scan reports in this setting is not only unethical but...

Recent Comments

JOIN THE CONVERSATION
Tagrix FDA Approval
By mariachristian on
Hi Judy! It is so good to…
By JanineT GRACE … on
Tagrix vs Tagrisso
By Dipakchavan on
Hello Linda, my name is…
By AlexandraGBeneke on