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EGFR Mutations Demystified

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It has become a common topic of conversation on this site (and in the lung cancer community at large) to discuss mutations in the epidermal growth factor receptor (EGFR). However, since we frequently throw out the terms “deletion 19 mutation”, “L858R”, and “T790M”, I thought would be worthwhile to explain a little bit about the different EGFR mutations and what we know about their clinical significance.

The history and significance of EGFR mutations has been covered quite well in previous posts here, but I’ll provide my own quick synopsis, from the perspective of someone working in Boston during the time this work was being done. In the early 2000s the EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) were tested in large numbers of patients with non-small cell lung cancer. It was known the EGFR was an important target in lung cancer, since most NSCLC tumors express it and high levels of expression were associated with a worse prognosis, and the results of numerous trials testing these drugs in unselected patients were modestly positive. In a phase III trial, Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC patients (leading to the death of this drug in the USA), but the similar BR.21 trial (testing Tarceva rather than Iressa) did show a modest (~2 month) improvement in overall survival in previously treated NSCLC patients. This led to the approval of Tarceva in all NSCLC patients who had failed one or two prior chemotherapy regimens.

However, what was immediately evident from these and earlier trials, was that about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. When they looked at who these people were, they found that most were women, all had adenocarcinoma (or BAC, a type of adenocarcinoma), many were Asian ethnicity, and most had either never smoked or smoked very little compared to average NSCLC patients. In 2004, investigators at the Dana Farber Cancer Institute and at Massachusetts General Hospital in Boston, and also at Memorial Sloan Kettering Cancer Center in NYC, simultaneously published results showing that most of these “dramatic responders” had specific mutations in the tyrosine kinase (TK) domain of the EGFR gene. The EGFR protein sits in the cell membrane and straddles the inside and outside of the cell.

Sequist EGFR mutation figure JCO 2007

(Click to enlarge)

The TK is the part of the protein, located inside the cell, which “switches on” when a growth factor (or ligand) from outside the cell binds to the outside portion of the EGFR. This switch, when flipped on, allows the EGFR to signal the cell to grow and survive. In the NSCLC patients who have mutations in the TK domain of the EGFR, very little growth factor is needed to flip on the switch, and once turned on the cancer cell is driven to grow and divide essentially through this one signal. This makes the cancer cell exquisitely sensitive to dying when the switch is turned off by a drug like Iressa or Tarceva and explains why some patients can do so well on these drugs.

However, there was controversy for many years about the true significance of these mutations, which have only recently been resolved. Investigators from the BR.21 trial looked at the tumor samples from the patients on the trial (there were relatively few available) and tested them for EGFR mutations to see if the patients with mutations lived longer when treated with Tarceva than placebo. When they published that they were unable to detect any survival benefit in the mutant patients, this threw a wrench in the concept of the importance of mutations that only recently has been corrected. The problem with their analysis, not completely understood at that time, was that all EGFR mutations are not the same and most of the ones they found were not important ones. The EGFR gene has 28 exons (parts of the DNA that serve as the blueprint for the EGFR protein), and exons 18 through 21 code for the TK part of the receptor. There can be mutations anywhere in the TK domain, but only some of them confer sensitivity to the TKIs!

Sharma EGFR mutations Nat Rev Cancer 2007

About 45% of sensitizing mutations are what are called in frame deletions in exon 19, making them the most common EGFR mutations. Deletion mutations result when short segments of the DNA are removed (deleted) from the DNA, but without interrupting the blueprint. To use an analogy: in this house, the light switch was deleted from the blueprint, so that the completed house always has the lights on with no way to switch them off.

About 40-45% of the sensitizing mutations are point mutations in exon 21, the most common being L858R (At the “point” in the 858th position, the normal amino acid leucine (L) is switched out for an arginine (R), which changes the protein function). In THIS house, the light switch looks like it is there but has actually been traded for a switch that can’t be turned off. When we talk about “EGFR mutant patients” in other posts, we are by and large talking about the patients with deletion 19 and L858R mutations.

Most of the remaining mutations don’t cause the EGFR to be sensitive to EGFR TKIs, but more importantly some of them do turn on the EGFR and drive the cancer cell to grow, but actually prevent the TKIs from working, a phenomenon known as resistance. The most important of these is the T790M, a point mutation in exon 20 resulting in the substitution of methionine (M) for threonine (T). This mutation seems to allow the EGFR TK to work much better than normal, so that the TKI no longer has an advantage in binding over the normal ligand, something called ATP.

Mutations (usually in this case called insertion mutations) in exon 20 have also been associated with resistance. The significance of these goes further. We now have evidence that the exon 19 deletion mutations tend to be associated with a higher chance of responding to the TKIs, and that patients with these mutations may live significantly longer than patients with the L858R mutations. This is probably due to differences in how well the TKIs are able to inhibit EGFR signaling in the two types of mutant EGFR proteins.

In conclusion, EGFR mutations are not all created equal and do not all have the same significance. The ones we care about as indicators for using drugs like Tarceva are the deletion 19 mutations and exon 21 point mutations (i.e. L858R), and the one that is most frequently associated with resistance to TKIs is the T790M in exon 20. This is a lot to throw into a short post, so please ask questions in comments if this isn’t clear!


28 Responses to EGFR Mutations Demystified

  • dfourer says:

    A very informative article.
    A rash is predictive of a response, but my sense was that the rash reflects a difference in body metabolism and not tumor genetics. Is this true? Are there two requirements for TKI success–tumor genetics and drug metabolism?
    What are the chances of a patient getting tested for EGFR mutation? Are patients getting tumor samples specifically for genetic testing?

  • Dr Pennell
    Dr Pennell says:

    Generally I think that the rash predicts for benefit, but not necessarily response. In the patients I have treated with EGFR mutations, I have seen dramatic responses with no rash at all, and I am not sure how important rash is in this population. In my mind, rash may be more predictive for the patient without a mutation who still is getting stabilization of disease and perhaps living longer because of Tarceva, but not necessarily having a big response.

    As for EGFR mutation testing, I am sending this on patients but it takes about 3-4 weeks to come back. There are faster tests, but we are not yet running them here in Cleveland (this is a major goal of mine in the coming year).

  • dfourer says:

    What is the procedure for getting a sample for EGFR mutation testing? Do the tumor samples come from previous surgery to remove a tumor, or is there a procedure specifically for getting a sample for testing?

  • Dr West
    Dr. West says:

    You can use tissue from a prior surgery or “core” biopsy, which collects more tissue than a fine needle aspirate (FNA), which typically only collects enough cells to make a diagnosis but not enough to do much more.

    While there is some growing recognition of situations in which testing prospectively for an EGFR mutation may be especially helpful, particularly if you’re considering using an EGFR inhibitor as first line therapy, most oncologists would only be inclined to order the test if it has implications for how you’d manage the patient. As a general rule in medicine, it only makes sense to order tests that can change how you would intervene. If tarceva is approved as second and third line therapy for advanced NSCLC (as it is) and a patient is already on or past first line therapy, it doesn’t make much sense to me to send the test, because giving tarceva is an appropriate course of action either way. Having an EGFR mutation is associated with a very high probability of a good response and prolonged survival, but there’s still an overall anticipated survival benefit for patients who don’t necessarily have an EGFR mutation.

    An exception would be if there’s an investigational agent that is available on a trial only for patients with an EGFR mutation. In that setting, it would make sense to send for the mutation even if that patient had previously received an EGFR inhibitor.

    -Dr. West

  • JimC Forum Moderator
    JimC says:

    Last year my wife was diagnosed with NSCLC through a thoracentesis in which a liter of fluid was drained. Our oncologist told us that the pathologist spun the cancer cells into a block, which was sent for EGFR testing. Apparently it was enough to determine that she was indeed EGFR-positive.

  • Dr West
    Dr. West says:

    Jim,

    It’s important to make the distinction between being EGFR positive by “immunohistochemitry” (IHC), which measures the protein on tumor cells, being positive for EGFR by fluorescence in situ hybridization (FISH), which measures the number of copies of the EGFR gene, and having an EGFR mutation. Being EGFR positive by IHC and FISH have been generally correlated with more favorable outcomes with EGFR inhibitors, but the results are considerably less consistent and dramatic than the generally very good results seen in patients with EGFR mutations who receive an oral EGFR inhibitor like iressa (gefitinib) or tarceva (erlotinib).

    Therefore, it’s helpful to be clear about what test is being referred to when someone is said to be “EGFR positive”.

    -Dr. West

  • JimC Forum Moderator
    JimC says:

    Dr. West,

    Dr. West,

    I see; always more to learn! My recollection is that the oncologist said “you have the EGFR mutation” (although I don’t know which one since at that time I didn’t know to ask), but I’ll have to ask about that at our next meeting. Not that it will change the current treatment with Tarceva, which seems to be working.

    I posted this info because at the time it seemed that the oncologist viewed the submission of a sample from pleural fluid to be a novel way of testing for the mutation. In your experience, is this common?

    JimC

  • Dr Pennell
    Dr Pennell says:

    Oh sure, a cell block from a malignant effusion is perfectly fine for mutation testing if that is all you have. All they need is sufficient cancer cells to get DNA for testing, and a clump from the effusion would work just fine.

  • JimC Forum Moderator
    JimC says:

    Yesterday we were able to verify with our oncologist that the EGFR status was determined by gene sequencing, and that it is the exon 19 deletion. Good news, and one more example of how uniquely helpful this site is. I would never have known which questions to ask, nor the significance of the responses without the help of Dr. Pennell and Dr. West.

    Jim

  • Dr West
    Dr West says:

    Great to hear that she has the mutation, and it’s also very nice to know that we’ve been able to help!

  • Dr Pennell
    Dr Pennell says:

    Great news, and thanks for the feedback!

  • henryfarkas says:

    My daughter wants to know if she has an increased chance of lung cancer. I have a mutation at exon 19. Is this a dominant or a recessive gene mutation?

  • Dr Pennell
    Dr Pennell says:

    Dominant and recessive mutations are what we call “germ line” mutations, which means they are present in all of a person’s cells and DNA, and can be passed on to children. EGFR mutations, such as the exon 19 deletion, are what are called “somatic” mutations, which means they occur only in the cancer cells but not in your normal cells. So as far as we know, there is no need to worry about passing this on to your children and I would not suggest they be tested.

  • Dr West
    Dr West says:

    Sorry I missed this one. I had seen it and got distracted before I responded but would have said the exact same thing: it’s a random mutation that developed over time, but it isn’t passed from one generation to the next.

    Thanks, Dr. Pennell, for not letting this good question go unanswered for too long.

  • almas says:

    Is there statistics about patients with both exon 19 and 21 mutation?
    If yes, how significant it is?

  • Dr West
    Dr West says:

    I am not aware of any information about patients with both mutations. This would be an extremely unusual event.

  • almas says:

    Found 2 articles online with abstract only, they seem to have double mutation study:

    Clinical Oncology — Volume 19, Issue 7, September 2007, Pages 499-506

    Epidermal Growth Factor Receptor Double Activating Mutations
    Involving Both Exons 19 and 21 Exist in
    Chinese Non-small Cell Lung Cancer Patients

    Cancer Letters– Volume 265, Issue 2, 8 July 2008, Pages 307-317

    Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated
    non-small cell lung cancer patients is due to
    differential inhibition of downstream signals

  • Charlie58 says:

    In early December my oncologist gave me the long overdue results of my EGFR testing: I have an exon 19 mutation which is of benefit – and an exon 20 mutation with intrinsic resistance. He told he did not know what to do. I suggested we not worry about it since the 11/30/09 CT chest report concluded no evidence of recurrence. Although my next scan is not until 2/26/10, I would appreciate your thoughts regarding potential benefit of Tarceva in this scenario. As an aside, I was recently notified by my health insurance company that Tarceva is now subject to quantity/duration limits.

  • Peter says:

    My pathology report:

    Diagnosis:
    Lung, tumour, for EGFR mutation analysis
    -Mutation positive with L858R in exon 21 and T790M in exon 20 identified.

    What type of drugs can be used effectively in such case ?

  • Dr West
    Dr West says:

    I’m afraid at this time we haven’t identified any agents that are effective in patients with the T790M mutation associated with resistance to EGFR inhibitors. Some centers, such as Memorial Sloan Kettering in NYC and Dana Farber in Boston, are trying to identify agents for clinical trials that may be useful, but there is certainly nothing available for clinical use now that can identify as being active.

  • Laya D. says:

    Are we any closer in finding out why resistance to drugs like Tarceva occur over time, including for those with the Exon 19 mutation?

  • JimC Forum Moderator
    JimC says:

    Laya,

    If you haven’t seen it yet, Dr. Dubey wrote a post on that subject last year: http://cancergrace.org/lung/2009/03/09/sd-egfr-mechs-of-resistance/

    Jim

  • Laya D. says:

    Thank you, Jim. I just read Dr. Dubey’s post in the link you provided, and found it very encouraging.

  • carewarrior says:

    Thank you for the informative post Dr. Pennell. My loved one was recently diagnosed with stage iv nsclc (adenocarcinoma of the lung) and she has BOTH the exon 20 and the exon 21 mutations. Have you seen that before? Which one tends to dominate in this case? Has Tarceva shown to be effective for these types of patients? Any help would be greatly appreciated.

    Thank you so much!

  • Dr West
    Dr West says:

    Carewarrior,

    I apologize for the delay in getting your question answered: your comment was stuck in our over-protective spam filter for comments until I released it from purgatory.

    This isn’t an extremely rare situation: I have a patient who I very recently tested who shows the same pattern. This is consistent with there being a de novo resistance mutation along with the activating mutation, so I would anticipate that a robust or long lasting response would be unlikely. However, there is still some variability in this, and I would be inclined to pursue EGFR TKI therapy after first line treatment. I would just say that the presence of a resistance mutation helps explain why the response rate of EGFR TKIs among patients with an activating EGFR mutation isn’t 100%, but rather typically around 60-75%. Some of the minority who aren’t showing a significant response have a resistance mutation along with an activating EGFR mutation.

  • FaithAndHope79 says:

    Thank you, Dr. Pennell, for using “switch on/switch off” to explain how drugs like Iressa and Tarceva work. It made me recall how you use “a pretty girl in a bar” to explain the difference between reversible inhibitors and irreversible inhibitors (I couldn’t find it because it is somewhere in a long thread of questions/answers).

  • Isac Estwani says:

    The EGFR results of my wife are as follows (adenocarcenoma stage 4):

    Exon 18 : Wild Type
    Exon 19 : Mutation p.K745_760, c. 2236_2249;2260 G>A
    Exon 20 : Wild Type
    Exon 21 : Silent mutation p. L858L (p.=) ; c 2572C>T

    Does that mean that she may have a good response according to Dr. Pennell’s article?. She is on 100 mg Tarceva since April 2011 and so far Scans are excellent. If I make I ask the diference between L858L and L858R that Dr. Pennells mentioned above?

  • pdjones says:

    Thanks alot for your explanation. That greatly demystifies things for me. My fiance was diagnosed with stage 4 NSCLC egfr exon 19 nearly three years ago and the tumors were held at bay for most of that time while she was taking Iressa. Now she is on Afatinib. Hopefully that will give her some more breathing space while other drugs in the same family are developed. There is one becoming available here in Australia shortly I believe. Whatever, it is a nerve wracking thing having a loved one with such a disease. So much hope but progression and death always looming large. The secondaries are the main problem in her case and we do all we can to try to halt the advance of these little buggers. Her oncologist seems to believe that there are other mutations lingering amonst the exon 19 cells and they are the ones causing the trouble.

    Thanks again for the time you and your colleagues spend contributing to this blog. It is fantastic and most informative. Wonderful.

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