Risk of Recurrent Disease in HER2-Positive Patients

Barbara2 · 03-10-2010, 10:34 PM

http://www.clinicaloptions.com/Oncol...Page%2012.aspx

Hopeful · 03-11-2010, 07:44 AM

Robert S. Mocharnuk, MD:
Mansell and colleagues^[33] presented data from a study that evaluates the influence of HER2 on recurrence patterns in estrogen receptor–positive early breast cancer (Capsule Summary).

William J. Gradishar, MD, FACP:
Mansell and colleagues^[33] analyzed prognostic factors in a dataset of 402 ER-positive patients with early-stage breast cancer and found that HER2-positive patients (12.7%) were at significantly increased risk of developing recurrent disease within 2.5 years after diagnosis compared to HER2-negative patients. In addition, at 2.5 years, DFS was 74.5% (95% CI: 68.4-80.6) in HER2-positive patients compared with 90.1% (95% CI: 88.5-91.7) in HER2-negative patients. Aromatase inhibitors were also found to reduce the risk of recurrence in HER2-positive patients.

This study demonstrated that HER2-positive patients developed recurrent disease at a peak of about 2.0-2.5 years, which is different than what we see with HER2-negative patients who had more of a consistent annual risk of recurrence during the study period. HER2-positive, ER-positive patients were at much higher risk of recurrence, which is supported by results of trials in similar patients with metastatic disease. Progression-free survival is much shorter in patients receiving hormonal therapy alone. These study findings support the idea of targeting both pathways and indicate that hormonal therapy will not suffice.

Paul E. Goss, MD, PhD, FRCPC, FRCP:
Only a small subset of ER-positive patients had HER2-positive tumors, but this is an important subset of patients. It is possible that HER2 positivity confers a degree of tamoxifen resistance; preclinical and other data suggest that the HER2 positivity may cause tamoxifen to behave like an estrogen, and actually drive breast cancer growth or at least be less effective. Blocking HER2 activity is important on ER-positive disease.

The findings in this study suggest that early use of an AI is strongly superior to tamoxifen, because it helps prevent the early recurrences to which HER2-positive patients are susceptible. However, neither of these treatments may be the optimal endocrine therapy because HER2 positivity confers ligand-independent signaling to the ER response element machinery. Consequently, fulvestrant, rather than tamoxifen or AIs, may be particularly useful in preventing the HER2 pathway from stimulating the ER pathway.

In general, ER-positive patients, if they are also HER2 positive, receive short-term anti-HER2 therapy and long-term antiendocrine therapy, and this may not be the optimal approach. Concurrent ongoing blockade of the HER2 pathway may be more fruitful. That may be in contrast to the situation with ER-negative patients, in whom short-term anti-HER2 therapy may be sufficient. I think these issues have yet to be confirmed in clinical trials.

Daniel F. Hayes, MD:
What I find interesting about this study is that with ER-positive cancer there is an ongoing risk of recurrence for a long period of time. It looks as though there is a secondary spike between 8 and 12 years. Dr. Goss did not necessarily agree with that, but there have been some reports of this, whereas in ER-negative patients, the tumor recurs within the first 5-7 years or it does not recur. But it seems as though the risk of recurrence after a long period of time diminishes, and in this way, HER2-positivity may make the tumor behave more like an ER-negative rather than an ER-positive tumor. I agree with the point Dr. Goss made that this study includes only 4 years of follow-up, and only very small numbers are included in the longer-term follow-up. Ultimately, this study may not help clarify what happens over the long term.

Paul E. Goss, MD, PhD, FRCPC, FRCP:
Dr. Hayes raises a very interesting point. The peak at 2.5 years in HER2-positive patients is valid, and there is unquestionably a sharp spike of recurrences early in ER-positive, HER2-positive breast cancer. That is the issue addressed in this paper. But what Dr. Hayes is suggesting is very interesting. HER2 positivity drives the risk of recurrence, even many years later during follow-up. However, I am not sure how dependent this result is on ER expression and how early anti-HER2 therapy may influence long-term recurrence risk.

William J. Gradishar, MD, FACP:
This paper may encourage long-term study of different durations of anti-HER2 therapy

Rich66 · 03-11-2010, 12:30 PM

More support for the Her2/ER crosstalk concept.
The really interesting aspect (missing from the discussion) of this is that there is more than a suggestion that the actual ER and Her2 status can essentially change after extended therapy. So..someone with a Her2+/ER- biopsy may get benefit from ER therapies after the Herceptin and/or Tykerb therapies "upregulate" the ER side.

The other more obvious bit here is that Fulvestrant needs to be made available in adjuvant.

(Psst! Green tea is thought to inhibit both Her2 and ER)

Hopeful · 03-11-2010, 12:34 PM

I think an important part of the discussion is the recognition that ER+ Her2+ patients need continual dual blockade, i.e., the system of one year of Herceptin and 5 years of endocrine therapy is not optimal. I was very uncomfortable continuing endocrine therapy w/o some corresponding anti-Her2 therapy.

Hopeful

bejuce · 03-11-2010, 01:17 PM

Very interesting, thank you for posting. I intend to bring this up with my oncologist at my next appt. I had thought about asking her for 6 more months of Herceptin beyond the standard year and this will just help me do that.

As for Fulvestrant, does it require the patient to be post-menopausal? I'm pre-menopausal, taking Tamoxifen (intermediate metabolizer) and have not (and do not intend to unless someone shows me convincing evidence) done an oomph. Should I be taking Fulvestrant instead? My tumor is only 30 % ER+ and PR-. Does the PR negativity or positivity play any role in how the HER-2 interacts with the ER receptors?

Thanks!

1rarebird · 03-12-2010, 08:31 AM

The opinions of the doctors reported here are indeed disturbing--particularly Dr. Goss's statement that certain data suggest that Tamoxifen may behave like an estrogen and promote breast cancer growth, or render it less effective. I am just about to begin Tamoxifen rather than an AI for reasons based on my gender and hormonal environment. Luckily I am on Herceptin at present, but like bejuice, I'm thinking that longer term Her2 receptor blockade may be the correct thing to do after my year of Herceptin ends this July. Perhaps getting in the NeratinibTrial would achieve the same thing if (and that's a big if) one receives the drug and not the placebo. More to worry about now, it seems--

bird

Hopeful · 03-12-2010, 10:30 AM

Please refer to the article I posted in this link http://her2support.org/vbulletin/sho...eferrerid=1173

wherein the designers of the trial considered tamoxifen to be such a potent up regulator of Her2, that they suggest all future trials of tamoxifen should include a Her2 inhibitor, regardless of the Her2 status of the subject.

The seminal discussion on this issue began in the 20 year retrospective of the Naples GUN trial in 2003: http://clincancerres.aacrjournals.or.../9/3/1039.full, with the discovery that Her2 positive women who received only tamoxifen fared more poorly than Her2 positive women who recieved no further treatment. The authors found the use of chemotherapy to be confounding to reaching a clear conclusion on the matter. As more research is conducted, it is becoming more apparent that there is an exposure (as yet unquantified) to using tamoxifen treatment in some Her2 positive patients.

On a side note, it is my personal belief that Oncotype Dx, which calculates a recurrence score based on the assumption that the patient receives no treatment other than adjuvant tamoxifen, artifically inflates the scores of Her2+ patients based on the GUN results described above. Think about it - if you are doing a test for the purpose of calculating likelihood of recurrence by comparing the outcome of the subject based on that subject receiving a specific treatment, in relation to other subjects who had been given the same treatment which has been shown to induce recurrence, rather than prevent it, well - what kind of score would you expect to see? I would like to see this issue addressed by Genomic Health, the inventor of the Oncotype test.

Hopeful

Becky · 03-12-2010, 01:44 PM

Due to extensive research, it is why I got an oophorectomy to take an AI - Tamoxifen was just a bad actor especially if low to moderate positivity or just being ER+ but PR neg.

I also took Herceptin longer although still only on an AI now. That begs the question for me as in a couple of months, I will hit my 5 years on the AI (of which about 4 years were alone without Herceptin). I am wondering if I should stay on the AI if offered to me or not due to the possible stronger awaking of Her2???

Who knows. I am 5 1/2 years from surgery and still ok!?

1rarebird · 03-13-2010, 09:18 AM

This GUN study is a real eye-opener for me. I will have to take it up with my doctor soon. One thing I believe I am seeing in figure 5. of the report is that for at least the first year to year and a half there does not appear to be any significance in the OS of the Her2+/ER+ with TAM group versus those not taking TAM. Hopefully, that should allow me enough time to work out the pros and cons of switching to an AI or finding a way to continue the Her2 blockade once my Herceptin year ends in July.

This hormonal therapy is so complicated. Out of all the therapies I have had to deal with since diagnosis last year, it has been the hardest by far for me to deal with.

bird

Jean · 03-13-2010, 01:55 PM

Becky,
First of all LOVE your new photo - Glamour Girl...

Do you remember 2yrs. ago when I talked to you about a tune up approach with herceptin. I really believe that after 5 yrs. on AI and surgery behind us, etc.
we may need a booster of Herceptin. Are there any trials of herceptin going on like this? I only know of one
trial of herceptin for DCIS at this time.

I will send this over to Dr. Slamon and see what he thinks.

Jean

Becky · 03-13-2010, 02:16 PM

It would be interesting to see what Dr. Slamon thinks on that because it is difficult to assess whether to stay on the AI longer than 5 yrs without it?! Thanks about the pix. I take horrible pictures so never really anything about putting up a current picture when I needed to retire the one from 5 years ago. I was at a company event last Monday and a photographer took my picture and showed it to me. It was a good one and I begged him to email it to me and he did. I wanted it just for this. Thanks - I miss you.

Rarebird - you should do some online research on Tamoxifen versus an AI in male bc patients. We only have had 2 other guys besides you on this board and I thought that men do not respond to an AI but they do respond to Tamoxifen. Another thing you could do is go on the main board and start a new Thread - the subject should be something like "Lani - Male Breast Cancer, Tamoxifen or AI". Lani really plummets the board with lots of research and data and she might just know (thus saving you the google time). I still have my memory but I think there was something to the Tamoxifen vs AI in men though.

1rarebird · 03-13-2010, 05:00 PM

Thank you Becky for the suggestion on a new thread. I'll think about how to start it so Lani will likely respond. As for only 2 other males apparently posting on this forum over the years---well that is one reason for the rarebird I.D. My surgeon called me that too.

bird

Hopeful · 03-14-2010, 11:26 AM

Jean,

I think the neratinib trial is sort of in the same niche as a "herceptin tune up." The concept is to give it to women who have had herceptin and are now NED, to see if it prevents recurrence. I think the feeling is that since Neratinib is an oral med rather than an infusion, it would be easier for the patients.

Becky,

I noticed your new photo too and think you look great!

Hopeful

Jean · 03-14-2010, 01:59 PM

Hi Hopeful,
I did a quick on neratinib trials, but only finding those that are using taxol combined for later stages.

Do you know of a trial with just neratinib?

Thanks.
Jean

Hopeful · 03-14-2010, 02:28 PM

Jean,

Yes, because I was solicited for it by my onc last year. It is giving the drug to early stage patients who completed adjuvant therapy within three years to see if it prevents recurrence. Turns out I didn't qualify for it. Terri had also posted about it a while ago: http://her2support.org/vbulletin/sho...eferrerid=1173

Hopeful

Jean · 03-14-2010, 11:52 PM

Hopeful,
There was a phase 111 Neratinib Trial, do you know if this will be the final trial?

I am past 2 yrs. since treatment and I believe you have to within 2 yrs from treatment. How long before the results will determine if early stage patients will be given
Neratinib as a tune up or to take a holiday from AI and
just have Neratinib. (I am thinking a few years)

jean

Jean · 03-19-2010, 05:44 AM

A follow up of my e mail to Dr. Slamon, he is out of the country and will be back at the end of March. But his NP
has contacted me and she is sending the emails to him.
I should receive answers but will take some more time.
Hang in.

jean

schoolteacher · 03-19-2010, 07:02 AM

Jean,

Thanks for contacting Dr. Slamon. Please let us know what the response is.

Amelia

Barbara2 · 03-19-2010, 09:46 AM

I agree with Jean's thoughts here:
Do you remember 2yrs. ago when I talked to you about a tune up approach with herceptin. I really believe that after 5 yrs. on AI and surgery behind us, etc. we may need a booster of Herceptin. Are there any trials of herceptin going on like this? I only know of one trial of herceptin for DCIS at this time.

In 2003 I posted a question (this board had a different name at that time) asking if anyone knew of a treatment or anything available to breast cancer patients that could be taken after adjuvent therapy, in an effort to keep the cancer from recurring. I received a reply from someone who said she did not know of anything of that sort and hadn't known of anyone who had even thought about such an approach; that most people are so glad when treatment is over, they are not wanting to ask for anything more; that once your treatment is over, that is it, and you hope and pray for a good outcome.

When I saw Dr. Pegram in 2007, I asked him if "Herceptin maintainance" had ever been considered, and he said no, and that in my case, I had a year of herceptin and that should be enough; that trials were underway using fewer doses of herceptin.

I am hopeful that in the near (?) future a "tune-up" approach to staying NED will be in the works. Because cancer sometimes has a way of returning, perhaps tune-ups of some kind could keep that from happening.

Janelle · 03-21-2010, 03:47 PM

I am also very interested in Dr. Slamon's opinion on this. I consulted with him a couple of years ago for a second opinion on whether to take tamoxifen which my primary onc strongly recommended. He seemed a bit on the fence but I would love to know if he has a more definitive opinion now.