Important for Her2+ on Tamoxifen

orange1

Many of you may have seen references indicating that women with Her2+ BC don't do as well on tamoxifen as women with Her2- BC.  In fact, there have been studies that demonstrated that tamoxifen can actually fuel Her2+ cancer growth in cell cultures.  I asked my Mayo onc, given this, why shouldn't I have ovarian suppression (Lupron or ooph) and take an AI instead of tamoxifen?  He explained to me that tamoxifen is not the active form of the drug.  Tamoxifen is what is known as a pro-drug, it must be metabolized by the body into its active form called endoxifen.  Unmetabolized tamoxifen can indeed fuel breast cancer growth. However, the metabolized form of the drug (endoxifen) is an extremely potent blocker of the estrogen receptor (recent research from Mayo has shown that endoxifen actually degrades estrogen receptors in cancer cells, slowing their growth).  My onc went on to say that endoxifen is so potent, it blocks any stimulating effect tamoxifen has on breast cancer.

The potential problem is when tamoxifen is not effectively metabolized to endoxifen. An enzyme in the liver called CYP2D6 is responsible for the metabolism of tamoxifen into endoxifen.  About 7% of Caucasians and African Americans are "poor metabolizers". They inherited a genetic form of the CYP2D6 gene that does not allow tamoxifen to be converted into endoxifen.  In hormone receptor positive BC (the population including both Her2- and Her2+) poor metabolizers have significantly higher rates of breast cancer recurrence than good or "extensive metabolizers".  There have been a few studies published that demonstrated this effect. 

He went on to tell me that Her2+ poor metabolizers do exceptionally poorly on tamoxifen, much worse than even Her2- poor metabolizers.

There is a simple blood test that will tell you your metabilizer status.  It costs only a few hundred dollars and some insurance will pay for it.  I think its a good idea for all patients that are considering taking tamoxifen to be tested.  But in light of what my onc told me about Her2+ BC having a much poorer prognosis if you are a poor metabolizer on tamoxifen, I think it is critical for Her2+ women.

Why not just go on an AI?  My onc was very much in favor of tamoxifen for EMs due to quality of life issues and he was confident that Her2+ EMs do very well on tamoxifen. With trepidation, I went along with it; I have been on tamoxifen for a little over a year.  Later, I found evidence that Her2+ EMs do, in fact, do very well on tamoxifen.  (I'll explain in a later post as this one is getting very long).

In addition to "extensive metabolizers" (EMs) and "poor metabolizers" (PMs), there is also a group of people that inherited one of each gene.  These people are termed "intermediate metabolizers (IMs) and in the Mayo study including all hormone receptor positive BCs (Her2- and Her2+) IMs fared slightly less well than EMs, but significantly better than PMs.  We did not discuss the impact of IM status on Her2+ women.

Bottom line: If taking tamoxifen, please consider getting tested for metabolizer status.  Also, stay away from drugs that interfere with the metabolism of tamoxifen.

lexislove

THANK YOU!

I will be asking about that test in a few months.The CYPD test is not routinely done in Canada, and I will have to pay for it out of pocket, about $600.00. I finally did find a hospital that will do the test for me.

I do like the figure 7% of individuals DO NOT metabolize Tamoxifen well, so the majority of woman do. that said, its still a good idea to be tested because someone has to fall in that 7% right? Who says it can't be me?

My onc did not want me to pull my ovaries and do the AI thing as well. I'm glad...I am terrified of AI's and their se's. I tolerate Tamox + Lupron pretty well...I hope to stay on the Tamox for longer than the 5 years.

Orange..since I am Canadian but about a 2.5 hour drive from Seattle Washington, would I be able to find a hospital/clinic there and do the test myself? I wonder about costs ect. It would probably take less time to get the results as well...

orange1

Lexislove -

I am not sure of the best way to get the test, especially since you are in Canada.  I think most oncs still are not doing it here either.  Hopefully that will change soon.

I would try calling Mayo directly, and if you can make it through I am sure what will be hours to days worth of dead ends on the phone, perhaps they can recommend a route to get tested.  Since they did much of the research on this topic, I am guessing they are starting to get many calls.  Since they do the test there, perhaps they can suggest a way to have a sample sent to them.  (Their prices are very reasonable for US healthcare - I have been pleasantly shocked when I receive my bills from them.)  Perhaps by having a local lab send a sample to them - but I am sure a doctor will have to order the test.

Another route is to check out Genelex.  They are a company that offers DNA tests over the internet. They offer a test (cheek swab) for $295.  I have no reason to believe there is anything wrong with their test.  Its just unusual to order your own lab test over the internet.  Check out genelex.com and tamoxitest.com.

Other approach - post on another board, and ask for the name of an onc in Washington State that has ordered the test for a patient, then go see that doctor. 

Good Luck

Estepp

I am ONLY her2+... so I suppose I am not in this..

orange1

This is only relevant for those on tamoxifen, so no need to worry if you are hormone receptor negative.

helena67

Another source of information might be large universities that teach life sciences (such as pharmacy schools or medical schools). They typically have a department of (clinical) pharmacology. For example University of Washington or Georgetown University. They have known for years that tamoxifen is subject to the poor and extensive metabolizer issue but clinicians are typically very slow to pick up on these things and incorporate them into their routine. I don't know why. Perhaps because they don't understand pharmacology all that well. In any case, any scientist should be able to give you the names of high-quality laboratories that can do this and then you can discuss this with your Onc.

Lastly, as orange1 already pointed out so wisely, avoid drugs that are also metabolized by the same enzyme (CYP2D6) OR that inhibit CYP2D6. Ask your pharmacist - go over the list of drugs you take and check every time you start something new.

Best, Helena.

mmm5

Orange and LexisL

Hi how are you both doing on Tamox, any SE's to speak of? How do you monitor for uterine problems?

Just had visit with my ONC and they are starting to think I am coming out of Menopause hence I am coming off Femara and we are regrouping in 60 days to decide what to do.

I am 43 and my estrogen has been all over the place it was at 10 and came up to 43 after I tried Estring, now back to 18 after getting rid of the cream.

lexislove

mmm5,

I tolerate the Tamox very well. I still get the hotflash here and there, but it does not interupt my quality of life. Thats why my onc wants me to STAY on the Tamox. He says that yanking my ovaries now and switching to an AI might not be as pleasant. I am terriefied of the AI se's. I hope to be on the Tamox for more than the 5 years recommended.

How do I monitor potentil Uterine problems? I did a transvaginal ultra sound a couple of months ago to have a "base" line to compare to future ultrasounds. I think all woman should do the same.

This Estring stuff, I don't know much about. I haven't visited that area in a while...lmao.

lexislove

Oh and I found that online sute about ordering the test for $300.00. I think I should post on the Seattle ladies threads and ask some q's.

orange1

I posted the same item on the hormonal therapy board.  Tender responded on that forum with some information that may help.

From Tender's post: Most hospitals carry accounts with large reference labs, including Mayo Laboratories which does the CYP2D6 test (not affiliated with them). You just bring your prescription from your oncologist to out pt laboratory and then the hospital sends in the blood under their account.

You just need to convince your onc to order the test.  I am guessing polite persistence, with the emphasis on persistence, will pay off here.  If you bug your doctor enough, eventually he may order the test just to get you off his back.

orange1

mmm5 -

Its hard to sort out which side effects are caused by tamoxifen, and which by chemopause for me.  The major side effect I have now is hot flashes, although they have subsided a lot after the first 6 months or so.  Also, at first I had a lot of vaginal itching/discharge/irritation.  Now the itching and irritation are gone - I still have discharge.

As far as monitoring, I only have a yearly pap smear, and my docs ask me about spotting, etc. (I don't have any.)

lexislove

Hmmm..convincing my onc to recommend the test. I remember bringing up the test about 8 months ago and he told me to save my money, that the chances of me NOT being a IM are slim. He is usually good though about doing things that I want..I'll just start crying that works for ALL men don't it?..lol

KarenW

great info! thank you!  I just posted a question on Hormone therapy and this is new information for me... so I will ask my doc here in Italy to do the test to see how I metabolize....

All this information is so hard to really grasp and figure out what is really best for me personally --- so I'm still trying to get my head around it!  :-)  And .... then if/when I get my head around this... how do I explain it in Italian to my doc!?  :-)  Hee hee!  They are really patient with me - but most of the docs here think I am the "pazza american!" - crazy american! 

THX!  Karen

KarenW

I'm from the Seattle area - but now live in Italy - but I know that when I was back a year ago and we were doing some tests on my fiance...  most doctors give a "cash" discount --- if you are not putting it through your insurance company (American gig) but.... I would think you could call around the hospitals and clinics in Seattle and price out this test for the best rate.  If you need any help - I have lots of close friends there and also they could probably give you some ideas of "which" hospitals to call --- so ping me again and I can hook you up if you need an over night safe house!  :-)

 Karen Wheel

karen_mppseattle@hotmail.com

Sardegna, Italy

44 years old.  6mm tumor - removed 1/4 - or partial mastectomy Feb 2009  3 nodes taken for biopsy and were not involved.

Her-2 3+ , Est 80% + ,  Prog 10% +

orange1

Lexislove-

Tears.  I love it!  Your are right - its probably the most effective strategy.

orange1

Does hormone receptor (HR) positivity affect the prognosis in breast cancers with human epidermal growth factor receptor 2 (HER2) overexpression?

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Sub-category:

Prognostic Factors

Category:

Tumor Biology and Human Genetics

Meeting:

2009 ASCO Annual Meeting

Abstract No:

e22091

Citation:

J Clin Oncol 27, 2009 (suppl; abstr e22091)

Author(s):

Y. Lee, J. Sohn, B. Park, H. Chung, C. Suh, S. Kim, J. Koo, J. Kim, H. Choi, Y. Kim; Yonsei University College of Medicine, Seoul, Republic of Korea; National Health Insurance Co. Ilsan Hospital, Goyang, Republic of Korea

Abstract:

Background: Biologically, there is an unclear issue about the role of HR positivity in HER2 positive breast cancer. These HER2(+)/ HR(+) pts were grouped into luminal B type apart from HER2(+)/ HR(-) pts in molecular profiling. However, from the clinical point of view, these pts have been categorized and been treated as either the only HER2(+) disease regardless of HR status or vice versa. Thus, we investigated the impact of HR status on clinical outcomes in HER2-overexpressed breast cancers. Methods: We retrospectively reviewed medical charts of HER2-positive breast cancer pts who underwent curative surgical resection from 1996 to 2001 in the Severance hospital, Korea. Demographic comparisons were performed by Chi-square tests. Tumor size, nodal stage, TNM stage, HR status, and adjuvant tamoxifen use were included in the Cox proportional hazards model. Results: Among the total 174 HER2-positive pts, HR (n=93) was positive in 53.5% (n = 93) and HR-positive tumors were more likely to be premenopausal (73% v 52%; P=0.01) and well- differentiated (grade 1or 2; 77% v 62%; P=0.04). There were no significant differences according to HR status in terms of tumor size, nodal stage, TNM stage, operation methods, and chemotherapy regimen. In these HER2-positive pts, the 5-year disease free survival (DFS) was longer in HR(+) pts than in HR(-) pts (DFS; 82.9% v 61.5%; P= 0.01). In a subset analysis, the 5-year DFS of HER2(+)/ER(+) pts without adjuvant tamoxifen (n=26) was not different from that of HER2(+)/ ER(-) pts (DFS; 57.7% v 61.5%; P= 0.32). However, the 5-year DFS of HER2(+)/ ER(+) pts with adjuvant tamoxifen was significantly prolonged compared with that of HER2(+)/ ER(-) pts (DFS; 91.5% v 61.5%; P< 0.001). In a multivariate analysis of DFS, tumor size and adjuvant tamoxifen use significantly affected DFS with an adjusted hazard ratio of 2.56 (95% CI, 1.2-4.9; P= 0.01) and 6.58 (95% CI, 2.8-20.3; P< 0.001), respectively. Conclusions: In an analysis of HER2-overexpressed breast cancer, the presence of HR itself did not affect the prognosis. However, most of the survival benefit seems to be driven from adjuvant tamoxifen therapy not the HR status itself.

Note that this study was done on tumors before herceptin was used as adjuvant therapy. 

Some evidence that our tamoxifen is not killing us.  More to come on this.

orange1

The above abstract provides evidence that overall, tamoxifen improves outcomes in Her2+/Hormone Receptor (HR) positive patients.  When I say overall, I mean for a group of patients with Her2+/HR+ BC. 

Based on what my onc told me, I still strongly believe that each of us as individuals  should have our CYP status checked because in the case of poor metabolizers, outcomes are very poor on tamoxifen.  This result for individuals will not show up in the study analysis unless the investigators are specifically looking for it.  Also, even Her2- poor metabolizers do less well than extensive metabolizers.  Women with either type of tumor (her2+ and her2-) should be tested so if found to be a poor metabolizer, can take an AI instead.

The above is a small study, but the results were statistically significant, meaning the results must have been very consistent (low variability), thus I think we can rely on the information.

I think the best evidence that overall, tamoxifen improves outcomes in Her2+/ER+ women are the results from the large HERA study.  I have to dig up specific results at work and will post.

AlaskaAngel

Hi.

At the time I was diagnosed HER2+++, trastuzumab was not available for me, and I have never had it. At the time, CAF or CMF or CEF was a common therapy and that is what I had. I was 51 at the time and was prescribed tamoxifen. At about 1 3/4 years out, information from ASCO indicated that tamoxifen might fuel the cancer for a subgroup of patients based on AIB1. Is AIB1 a different issue than being a nonmetabolizer, or is it part of that issue? In other words, are there actually 2 separate rationales for being cautious about tamoxifen, or just one? (Google AIB1 and tamoxifen.)

orange1

Hi AlaskaAngel,

I did google A1B1.  From what I understand, the A1B1 issue does not involve the CYP issue (or the other way around).  Based on some publications, I can understand why many Her2+ are afraid of tamoxifen.  Based on 2 factors, I am no longer afraid of tamoxifen:

1. The discussion with my Mayo onc (see above posts) - his experience is that Her2+, hormone receptor positive (HR+) do very well on tamoxifen IF they are extensive metabolizers and stay away from drugs that interfere with tamoxifen metabolism

2. Hard numbers from the HERA trial.  3 year disease free survival (DFS) was 95% for node negative HR + patients.  Patients with positive lymph nodes also showed relatively high 3 year DFS.  Since the major risk for Her2+ is in the first 3 years and 4th year follow up from HERA showed virtually no change from 3 year follow up (for entire study population - subgroup analysis has not been published), these are very good stats, especially considering that there were a couple issues with treatment in the HERA trial (sequential to chemo vs simultaneous with chemo herceptin treatment and non-optimal chemo regimens.) 

In the 2 studies I have seen where hormone receptor results were broken down, HR+ did a little better in both cases.  This would not be true if Her2+, HR+ women were being killed by tamoxifen in large numbers.  (Based on the years these trials took place and the menopausal status of the women, most HR+ took tamoxifen, not AI.) 

jap

Hi Orange,

Could you please give me the statistics for women with positive lymph nodes?   What is "relatively high 3 year DFS?"  Is this figure for HER2 positive, HR positive stage II with positive nodes?

Thanks

Jo Anne

orange1

jap - I'll PM you

pmellon

Orange1 - Thanks for all of the great information on tamoxifen in relation to her2.  My onc. told me I will be starting soon and I have been worried about this issue.  I will make sure before I go on it to discuss the blood test. 

orange1

Bump for Njanja