Question regarding Mutually Exclusive Oncogenic Alterations - 1270638

Tue, 07/28/2015 - 13:47


I have read several papers that seem to say they have found that treatment naive patients with EGFR (L858R) mutation concomitant with EERB2 amplification are mutually exclusive of patients harboring (L858R)T790M.

My question is what does this mean?

Does this mean that the patient with the EERB2 amplification cannot acquire TKI resistance through activation of T790M and must acquire TKI resistance by activating another pathway such as MET?

I really need to understand this more fully.

Thank you

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I believe that's what it means when it happens in a lab but it hasn't been shown to work that way in real life. Let me have a faculty field this question.


Dr Pennell

Hi Tjv, I am not aware of any clinical evidence in lung cancer patients suggesting that having both EGFR mutations and Erbb2 (HER2) amplification prior to starting treatment has any effect on the eventual cause of acquired resistance after treatment. T790M is common (~50%) in patients with EGFR mutations (like L858R) who have developed resistance to drugs like Tarceva and afatinib, but T790M is very rare in treatment naive patients. Having Erbb2 amplification should not affect whether the tumor develops a secondary T790M mutation at some point after treatment, again at least as far as I am aware this hasn't been shown in patients.

If you have seen studies suggesting otherwise please feel free to post the references, I am happy to take a look!


Thanks Dr. Pennell! I'm afraid I was wrong in my statement, alluding to other research that doesn't apply here, and didn't check my understanding since we were waiting on your reply.

tjv87, very sorry for my confusion. So glad for our ability to check with our great faculty.



Hi Janine & Dr. Pennell,

Thank you very much for your response. It is wonderful to have this resource available to lung cancer patients as information about lung cancer and how to treat it seems to be increasing exponentially. The complexity of the information is daunting for patients and their caregivers especially when trying to absorb the enormity of the diagnosis and what it will mean to the individual and their family.

There are 2 publications that seemed (to a layperson) to suggest that HER2 amplification is rare in treatment naive patients, that it is more commonly a factor in acquired resistance and that it does not overlap in acquired resistance or treatment naive patients.,-2013/simultaneous-egfr-mutation…

Am I understanding this correctly?

If HER2 amplification and T790M do not show overlap in either of these groups does it follow that the treatment naive group of HER2 amplified that are treated with TKI will not acquire T790M and the treatment naive group of T790M will not acquire HER2 amplification? If they did, wouldn't the acquired resistance group show some overlap?

Thank you again for your consideration of this question.

Dr Pennell

Thank you for posting the papers! Indeed HER2 amplification is probably one of the mechanisms for developing acquired resistance to EGFR inhibitors, and yes it would likely be mutually exclusive of T790M, but I do not think HER2 amplification in treatment naive patients would necessarily mean you would not develop T790M at some point.

HER2 amplifications in conjunction with EGFR mutations at diagnosis appear to be rare, but when the cancer becomes resistant to the EGFR inhibitor there are many ways the cancer can "get around" the EGFR inhibition. The most common way is the secondary mutation T790M, and if this is the mechanism then there probably won't be another one present as well most of the time (i.e. mutually exclusive). If there is no T790M, though, then something else is going on to cause resistance. In some cases, HER2 amplification could be the way the cancer becomes resistant to the EGFR inhibitor. In this case, the HER2 amplification was not present at diagnosis, only when resistance developed.

However, none of that suggests that if you DID happen to have HER2 amplification at diagnosis that you would necessarily be resistant to an EGFR inhibitor or that if the cancer eventually acquired resistance that it would have to be because of the HER2 amplification and not some other mechanism like T790M.

Does that make sense?


Dr. Pennell,

Yes, it makes perfect sense. Just something I wanted to get straight.

If you happen to look at my profile at the bottom of my post you will see why I am so interested in the HER2 amplification. The HER2 amplification for my Father was found to exist simultaneously with EGFR (L858R) exon 21 PRIOR to any treatment. The sequencing report that came back from the lab actually noted that this was an uncommon event and that the HER2 amplification may indicate resistance to treatment with TKI.

That's what got my research started.

I became interested in studying if one TKI would be better than another for a longer PFS and what sort of (way around) the reversible EGFR TKI vs. the irreversible EGFR/HER2&4 blockers would be selecting for in this group assuming that HER2 amplification confers resistance. Since HER2 amplification with EGFR prior to treatment seems to be so uncommon, most of the research on efficacy of first, second and third generation TKI's does not address that small group of patients. The information I am able to find is mostly incidental and directed at patients who acquire HER2 amplification as resistance to TKI (as you noted).

Any information regarding this specific subset of patients you or the panel there at GRACE have or can find and post here for me would be greatly appreciated.

Thanks Again!

Dr Pennell

Yes I did see your tagline so your questions are very reasonable! I have had patients with both EGFR mutations and HER2 amplification at diagnosis who have responded to EGFR inhibitors, although for most of the time we have been using these drugs and testing for mutations we haven't routinely been looking for HER2 amplification so I think the outcomes for patients with this combination is not well known. I think you have a good grasp on the data for this situation, which is very little. I'm sorry there isn't more to convey!


Thank you Dr. Pennell for taking the time to answer these questions for me! I greatly appreciate your opinion on the matter.