EGFR acquired resistance due to histologic transformation - 1254695

Jazz
Posts:279

We saw it with Laya's Mom - going from adenocarcinoma to small cell, but here the transformation is to "high grade" neuroendocrine carcinoma as the mechanism of acquired resistance. Very intriguing. I wish I could get the entire article for free. Docs, if you can read the whole thing, maybe one of you could summarize?

http://www.lungcancerjournal.info/article/S0169-5002(12)00712-X/abstract

Thanks,
Jazz

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Reply # - March 13, 2013, 02:15 AM

laya d.
Posts: 714

Hi Jazz - -

Just a small clarification that the biopsy of one lung nodule that was progressing about 2 years into treatment showed a suprising mutation from adeno to "squamous" (according to my Mom's doc, the first ever documented case, and they were able to trace it back to adeno - - so it was not a new primary) - - NOT "small cell" (which, I guess is a mutation seen a little bit more often upon a rebiopsy, but still a very small segment of the lung cancer population). But, it may have just been that one nodule, because a later biopsy of a supraclavical lymph node that suddenly appeared on a CT scan and signified progression was adeno with an EGFR activating mutation and a T790m resistance mutation. Just crazy. . .

I'm interested to see what this article you posted is all about as well. . .

xoxo,
Laya

Reply # - March 13, 2013, 11:03 AM

Jazz
Posts: 279

Oh right, thanks for clarifying, Laya. I got your Mom's rebiopsy mixed up with something we probably heard on a webinar. But to find that these transformations are happening and are another mechanism of acquired resistance is, while not surprising, mind-boggling. I'm hoping to find more on the topic -

Jazz

Reply # - March 13, 2013, 04:21 PM

Dr West
Posts: 4735

It's all the same principle, and the publication just describes the case report of a very similar situation. Here, it's essentially the exact same situation Dr. Lecia Sequist described of a neuroendocrine carcinoma that has an EGFR mutation, so it presumably mutated from the same cancer that was previously biopsied, except that the more well-described situation (still 10-15% at most, and I and many others think that's probably an overestimate) is to find a small cell lung cancer (which is a neuroendocrine carcinoma). In this case report, it's just small cell's less common cousin, large cell neuroendocrine carcinoma (LCNEC), but otherwise the same story.

-Dr. West

Reply # - March 15, 2013, 12:53 AM

Jazz
Posts: 279

Thanks, Dr. West. What I'm trying to understand is the resistance aspect. Even if the transformation is from adeno to mixed SCLC/Adeno and then to Large cell (and as you point out both small cell and large cell ARE neuroendocrine arcinomas), even if EGFR activating mutation is retained, the histological type makes it resistant to TKI's? In other words, TKI's are only effective on nonsquamous/squamous adenocarcinomas with EGFR mutations, and not the other histologies? Makes sense but I thought the EGFR mutation was the trump and other mutations like T790m overrode EGFR.

So in a situation like this, the idea would be to treat with chemo designed for LCNEC?

Jazz

Reply # - March 15, 2013, 12:52 PM

Dr West
Posts: 4735

No, if someone has a tumor with an EGFR mutation, even in a less common histology for it, they can still respond well, and presumably there are other mutations that have made the cancer resistant if it's progressing on an EGFR inhibitor. It's not that they have a different histology alone that they would progress, if they still have an activating mutation, but rather that there must be something else that confers resistance.

If the cancer is progressing and it shows neuroendocrine differentiation, it would be very appropriate to prioritize a chemo regimen that is typically effective for neuroendocrine carcinomas, specifically something like a platinum with etoposide, or irinotecan, perhaps.

-Dr. West

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