Rare EGFR: p.E709_T710>D - 1258084

bolu
Posts:11

Hi,

First of all, thank you for this wonderful support forum.

My mom-in-law has NSCLC/adenocarcinoma with a very rare EGFR mutation, in exon 18 of the EGFR gene: p.E709_T710>D (a.k.a. delE709_T710insD, p.Glu709_Thr710delinsAsp, 2127_2129delAAC).

In this mutation, three nucleotides near the beginning of exon 18 (around the start of the tyrosine kinase domain) were removed: AAC. As a result, two amino acids in the EGFR protein, glutamic acid and threonine, were replaced with one, aspartic acid (on position 709).

Typical mutations in EGFR are L858R (exon 21) and exon 19 deletions. Afatinib (Gilotrif) was recently approved for those. For exon 20 it is known that Erlotinib (Tarceva) won't work. But what about exon 18 and its rare mutations??

Now, of course, I am wondering: can Erlotinib (Tarceva) work for our rare EGFR case? Would Afatinib (Gilotrif) work? Mom is currently on chemo and it would be great to switch to something else because the side effects are pretty bad (e.g. neuropathy in fingers).

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Reply # - July 20, 2013, 09:33 AM

bolu
Posts: 11

Thank you very much for your reply, JimC.

Thank you for the link. I have seen that article before I wrote my question. I dismissed it because I didn't see my mom-in-law's mutation in the article.

But, I did not realize one thing until you wrote to me: all mutations listed in that article that are in exon 18 are associated with sensitivity. So intuitively, we could guess that our mutation would also be good. There is one mutation in the picture in the article that looks similar to ours: E709K/Q. It has the same location (709), but T710 is not deleted as in our case, and the replacement amino acid is different (K or Q, not D).

I hope that the oncologists will decide to try Tarceva and that it will work...

Does my intuitive reasoning above make sense? Does anyone have more thoughts about it?

I also have a separate question - about afatinib and the p.E709_T710>D mutation. If I understand correctly the science behind afatinib, it was designed to only interfere with mutated EGFR. The designers of the afatinib molecule have shaped it such that it will bind to an EGFR protein produced from an EGFR gene that has a p.L858R mutation or deletions in exon 19. Now, the shape of the EGFR protein produced from an EGFR gene with p.E709_T710>D will be different. From a theoretical standpoint of the design of afatinib, would it still bind to such mutated EGFR protein? This may be a difficult question... should I maybe send it directly to Boehringer Ingelheim, the maker of afatinib?

Reply # - July 20, 2013, 01:48 PM

catdander
Posts:

bolu, I'll ask one of our doctor's with the most probability of being able to answer such a specific question to answer. It may take a couple of days since it's the weekend.

All best,
Janine
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Reply # - July 20, 2013, 07:03 PM

Dr West
Posts: 4735

bolu,

I think the only other place I could suggest checking is the mycancergenome.org website for a catalog of rare mutations.

As for predicting what might happen and the exact science of afatinib, I would be very wary about trying to extrapolate results with EGFR TKIs to very rare mutations. Beyond the most common mutations on exons 19 and 21, I think the best answer is that we just don't know what to expect. Bear in mind that even for patients with an exon 19 or exon 21 mutation, the response rate is 60-70%, not 100%. In general, though, there's an enormous gulf between the concepts of what an agent does in a lab and what actually happens in the real world.

My perspective is that if someone has a rare mutation, it absolutely makes sense to try an EGFR tyrosine kinase inhibitor in a timely way, especially if they are progressing on chemotherapy or not tolerating it especially well. Tarceva is an approved and very appropriate agent for maintenance therapy or second line treatment, after all, so trying it even if you can't predict a high probability of benefit with confidence. It's still a reasonable enough possibility that it's a good option to pursue in a timely way.

Good luck.

-Dr. West

Reply # - October 25, 2013, 06:33 AM

bolu
Posts: 11

Dear Dr West,

Thank you very much for your response. I apologize for replying to you 100 times slower than you did - it took you one day and now here I am with more questions, a quarter later :-)

Mom has finished first line cisplatin+alimta two months ago, after four cycles. Her disease has stabilized (SD) (primary tumor shrunk marginally, lymph node mets shrunk, but there is some uncertainty with respect to bone mets - she most likely does have some osteosclerotic spine and bone mets, but it is not completely clear). She is now not receiving any treatment. She is under observation and her next chest and neck CT is scheduled for end of November.

Mom is feeling relatively well, she is experiencing some pain in the bones, coughs only occasionally, and this month we went with her for sighseeing in Paris and in Prague (~4 days each time), and she was able to walk around the cities and enjoy them for whole day.

1) Dear Dr West, in this situation, would you put mom on maintenance Tarceva, or would you wait until disease progression, as the doctors in Poland decided to do?

2) If you do think that maintenance Tarceva would be a better option for mom than observation now, would you be so kind and estimate how bad it is that she is not getting Tarceva now? What is the danger of waiting until disease progression? I fear that if we wait and do nothing, the cancer may spread so much that it will be too late for Tarceva.

I am asking these questions because we did try to get Tarceva maintenance for mom and we did talk with the doctors here about Tarceva, they did try to get it using some "non-standard chemotherapy form", but failed. Access to targeted therapies is a very complex issue here in Poland - with insurance, doctors' fears of lawsuits, possibility of loss of future insurance, and so on... every conversation with the doctors here is polluted with these issues and it's very difficult to get a clear medical answer.

Reply # - October 25, 2013, 12:21 PM

catdander
Posts:

bolu,

Don't worry about not responding until you had more questions. We like to hear back from our members but understand all too well the time constraints cancer adds to a family's life. That includes the wonderful vacations you've taken. How absolutely wonderful. Dr. West will reply in a bit. I would like to comment as well, as a wife of a man with nsclc whose body has been devastated by cancer, surgery, treatment, and the awful sorrow of losing so much. Please don't worry about your mom not getting treatment when she is feeling so well. If she were to have moved right into tarceva she may not have been able to enjoy her vacations. The doctors here take enjoying life very seriously when planning treatments.

I hope she moves smoothly through the next month and hope she is able to access her doctor and a CT if symptoms or pain arise. What a lucky mother in law she is to have a son in law who cares so much.

Janine

this will help as a starter read, http://cancergrace.org/lung/2009/06/06/saturn-np/ and https://www.google.com/url?q=http://cancergrace.org/lung/2009/06/15/atl…

Reply # - October 25, 2013, 10:55 PM

Dr West
Posts: 4735

I hate to provide no clear answer, but there is no clear answer here. I personally tend to favor maintenance Alimta (pemetrexed) after doublet chemo in patients who are doing well, though I don't hesitate to give a break to patients who want or need it and are not progressing.

I don't feel at all confident predicting that rare EGFR mutations will respond well, so in such patients, I always want them to get an EGFR inhibitor at some point, preferably in the first couple of lines of therapy, but I don't feel compelled to rush it as a first line or switch maintenance therapy.

As for the harm from not doing maintenance therapy, I have always felt that patients would do every bit as well getting the same treatments after a break...specifically, there is nothing magical and critical about keeping patients on maintenance therapy, except that in some trials, people who don't get maintenance therapy never get the active drug at all. So I think maintenance therapy is important only to the extent that it gives access to a drug that a person might not receive later. To the extent that a patient can be ensured to get the same treatment after a break vs. before or instead of it, I am completely comfortable offering and even recommending a break. There is no data to say that a break is harmful if a patient can receive the same treatments after the treatment break.

-Dr. West

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