Edited excerpt from the discussion:

DR ZELKOWITZ: This 36-year-old lady came to my office from a far-away community, and I had the sense that she had been to a lot of different places for opinions.

She had a positive family history of breast carcinoma — her sister had breast cancer at age 40. The patient had a 1.8-centimeter, poorly differentiated tumor that was ER/PRpositive and HER2 FISH positive with three negative sentinel lymph nodes. She recently was married, and this turned out to be a huge issue in her decision. She was very nice and receptive and seemed very intelligent. She previously opted to have a unilateral mastectomy.

DR LOVE: Had anyone at that point brought up the issue of genetic testing, or did you discuss it with her?

DR ZELKOWITZ: We discussed it, and we certainly recommended it simply based on her age at diagnosis and her family history, but it wasn’t the primary focus of her initial visit. She had been given prior recommendations regarding adjuvant therapy, and discussing adjuvant therapy was the real focus of our discussion.

DR LOVE: What were her thoughts regarding chemotherapy and systemic therapy in general?

DR ZELKOWITZ: I use Ravdin’s model Adjuvant! (Ravdin 2001) a lot, and when we looked at the numbers regarding risk of relapse, they were very impressive with a poorly differentiated tumor.

The focus for this young woman was the issue of pregnancy and we discussed that, in all likelihood, at the age of 36, she would still be able to maintain fertility. She had no children, was married recently and wished to have children.

DR LOVE: Certainly every patient in this situation has concerns about recurrence of the tumor. What did she verbalize to you? Was that her primary concern or was it more about future childbearing?

DR ZELKOWITZ: Her main focus was the issue of pregnancy and maintaining fertility.

DR LOVE: Nancy, I know your practice is very heavily weighted towards younger women, so this is a very common situation that you deal with. How would you have thought through all the numbers you might present to her with various systemic options, and then how would you integrate this issue of fertility?

DR DAVIDSON: I would be thinking about her as having a moderate risk of recurrence over 10 years — I would guess approximately 25 to 30 percent, so I believe that’s a pretty substantial risk of recurrence. I would remind her that I think of hormone therapy as sort of her first line of defense, since she has receptor-positive breast cancer.

Traditionally, the therapy would be five years of tamoxifen, which for her is going to be a “show stopper” if having a family is important, because she’s going to be well into her forties.

You could also make a case with a poorly differentiated, HER2-positive, moderate- sized tumor to integrate some kind of chemotherapy. I believe that any of the standard anthracycline-containing regimens would be quite rational.

I would not be a great enthusiast about taxanes for her, but plenty of other people would be and I don’t know if there’s a right or a wrong answer to that. From an optimal breast cancer point of view, I would be considering chemo/hormonal therapy for this patient, and I would guesstimate that those two therapies together would decrease her risk of recurrence in absolute terms by 10 or 15 percent.

DR LOVE: Kathy?

DR MILLER: How long has it been since she’s had her surgery?

DR ZELKOWITZ: Her surgery was within the last four weeks.

DR MILLER: My sense is that she has seen at least a couple of other oncologists, and I suspect they’ve all suggested that she would optimally be treated with some sort of chemotherapy and then hormone therapy. I get the sense that she’s not coming to you as much to see what she ought to do, but rather seeking permission not to have chemotherapy and not to have the things that she doesn’t want to have.

DR ZELKOWITZ: I think that’s exactly correct. She had heard on two prior occasions that she needed chemotherapy and hormone therapy and, frankly, I couldn’t say I disagreed.

However, as the third person she was seeing, I think she was looking for at least something that could be an alternative to that.

DR MILLER: I’ve seen many of these women, and I’m often the one they come to for permission to not do things other folks have suggested to them. I’m a big fan of choosing my battles, and my sense is that if I tell this lady exactly the same thing that everybody else has told her, she’ll go to a fourth person looking for permission.

I would think about actually posing it to her in that way. If I try to work within the boundaries she gives us, I might be able to convince her to have some therapy — perhaps not everything, but some would be better than no therapy, which she may end up with.

I don’t think that she’s going to find anybody who tells her that medically it’s okay for her not to have any chemotherapy or hormonal therapy.

DR ZELKOWITZ: I think that was the challenge. I felt it was my obligation to still reiterate the need for chemotherapy and then she said to me, “I’ve been through this and I’ve heard this, and I’m not going there.”

DR DAVIDSON: Was it your sense that she has a reasonable understanding of the risks and benefits as best we can estimate them for the individual patient?

DR ZELKOWITZ: Yes. And I actually had the opportunity later to read through the previous consultations. These were well written out, well lined up for her, so she understood that completely.

DR LOVE: What about less commonly utilized regimens like MF in terms of effects on fertility and other chemotherapeutic agents?

DR DAVIDSON: MF is a forgotten regimen, but it’s not a bad chemotherapy at all. That was one of the seminal papers in the New England Journal of Medicine on the treatment of node-negative breast cancer years ago (Fisher 1989).

It is very ovary sparing, and it is chemotherapy. It is six months of therapy, but I think that’s a rational treatment that we’ve put off of our radar, because we’re very interested in anthracyclines and taxanes and so forth.

The other issue is whether some kind of combined hormone therapy would be in her best interest — some sort of ovarian suppression strategy with tamoxifen, which would likely be an ovary-sparing type of therapy and may be more acceptable to her.

DR ZELKOWITZ: I was comfortable at that point that she understood the decision she was making.

I didn’t think about MF, and we went on to the issue of hormone therapy.

DR LOVE: Could I also ask about the Oncotype DX™ assay in this situation (Paik 2004)? We know from unpublished data from Soon Paik and the NSABP that, at least initially, there weren’t any HER2-positive cases in their low-risk subset.

This patient has a HER2-positive, poorly differentiated tumor. Kathy, do you think any additional information would be useful? If she were in the high-risk subset, do you think that would be helpful in this type of situation?

DR MILLER: Potentially. I would present this to her and see if that would sway her thinking. She is very unlikely to be in the low-risk group, but she certainly could be in the intermediate-risk group, and that would trigger us to adjust our estimates of the risks and benefits of chemotherapy. She might find that quite pleasing, because if that’s the case, it would support her decision not to have chemotherapy.

On the other hand, if she’s really in the very high-risk group, would that alter her thinking about chemotherapy? If she’s already clear that it’s not going to change her decisions, then I don’t think there’s anything to be gained from the test.

However, if she says, “I want to be alive, and I’ll take the chemotherapy if I’m at high risk,” then I think it would be very helpful.

DR LOVE: The Ravdin numbers utilize the concept of relative risk reduction, but now for the first time with Oncotype DX, we’re seeing that this doesn’t always apply.

The patients at high risk had a 75 percent relative risk reduction from chemotherapy, whereas the “good-risk” patients had virtually none. If the patient was open to all possibilities, would you be more inclined to ask for the assay to be done?

DR DAVIDSON: I would order the assay only if she and I thought it would affect her decision-making. If she is one of the many people we see who wants chemotherapy no matter what, why bother? Similarly, if she is, as you might be describing her, somebody who is adverse to chemotherapy no matter what you tell her, again, why do it?

DR HART: If she would accept chemotherapy, would there be a role for starting an LHRH agonist prior to it as a potential means of sparing her ovaries?

DR DAVIDSON: That question has a lot of different answers. One possibility would be that you, in fact, are starting it with therapeutic intent. For example, the TEXT trial (2.1) looks at ovarian suppression from a therapeutic point of view and assumes that women need or should have ovarian suppression as part of their treatment protocol. The randomization is then between tamoxifen and an aromatase inhibitor.

If this young woman entered that trial, for example, and you knew you wanted to give her chemotherapy, she would receive it and an LHRH agonist simultaneously. The goal here is more of changing her breast cancer recurrence than it is to try and preserve her fertility.

The second half of your question is do these things protect fertility? In a nonprotocol setting, I personally wouldn’t start an LHRH agonist and suggest to somebody that I was going to protect her fertility. I think that we’re really out on a limb with that.

DR LOVE: Kevin Fox has done some work looking at the preservation of fertility (Fox 2003). Can you talk a little about what he did and what was seen?

DR DAVIDSON: Kevin was very interested in this approach because some of the lymphoma literature suggested that there might be utility to some of these type of approaches in young people who had been treated with common chemotherapeutic regimens.

He took a cadre of 24 premenopausal women in his practice. The median age was approximately 35, and the oldest women in that little series was approximately 40 or 42.

All of these women received one of the common chemotherapies that we deal with — AC, AC followed by T, etc. My memory is that 23 of the 24 women regained or retained their menstrual function. That was not too surprising to me because most of these patients were under the age of 40.

The thing that was sort of the kicker was that he tracked what happened over the next few years with their fertility. There were six pregnancies in five women. Only one has turned out to be a live birth.

There were some miscarriages, a case of Down’s Syndrome and a lot of complicated issues here. Looking at this little experience, I think the situation isn’t quite as promising as I would like it to be.

It doesn’t make me want to throw out the baby with the bath water though, which is why it’s a wonderful reason to do a trial to look at this in a prospective fashion in receptor-negative patients.

DR MILLER: Where are she and her husband in terms of timing, assuming she didn’t have breast cancer and it wasn’t an issue? Are they actively attempting to conceive or are they thinking about starting a couple of years from now because — besides the breast cancer therapies we may want to give her, fertility between 36 and 40 is not a certainty?

DR ZELKOWITZ: We factored that in when we got to the next step, which was what we would do for hormonal therapy.

My sense was that she wanted to become pregnant in a fairly short period of time. I tried to factor that in when we talked about what the hormonal options were.

DR LOVE: Nancy, how would you have thought through the hormone options for a patient in this kind of situation?

DR DAVIDSON: First, aromatase inhibitors as monotherapy are not a consideration because she is premenopausal. We tend to think of tamoxifen as the standard of care for these young women with breast cancer, and the big controversy we are all dealing with is whether or not there is a role for ovarian suppression or ovarian ablation.

There actually is a fair amount of information to suggest that there is a role. First, the Oxford overview with oophorectomy/ovarian irradiation suggests that, by itself, this is very good adjuvant therapy. If you go back to those old trials, there is approximately a 10 percent absolute change in mortality.

Second, we have a lot of information comparing ovarian suppression, with or without tamoxifen, to chemotherapeutic regimens in patients with receptor-positive tumors. In many European trials, those two approaches are basically equivalent, although they are imperfectly conducted trials.

Third, we have trials that have looked at whether or not you should use ovarian suppression after chemotherapy. The results are mixed right now. If you look at the trials in aggregate, they don’t show a clear-cut advantage for this approach. However, if you look at a couple of the trials from the point of view of retrospective subset analyses, there does emerge a feeling that perhaps the younger women who were premenopausal at the end of chemotherapy and then received ovarian suppression are the ones who might be helped the most.

The problem with all of these trials is that they started in the late ‘80s before we recognized that tamoxifen was a valid choice for young women with breast cancer.

All of these studies lacked five years of tamoxifen, which is now the standard of care. I think that is a fundamental flaw of these trials that we wish had been addressed.

HER2 status adds a little bit of a wrinkle in this case because there are small data sets of mostly preoperative studies for postmenopausal women who were taking tamoxifen versus aromatase inhibitors that suggest aromatase inhibitors are more effective than tamoxifen in this setting. You could say, “Well, I’m going to take that and extrapolate this to younger women.” Maybe that’s right and maybe it’s not right. I don’t know the answer to that.

The only information that I’m aware of about hormone therapy in young women that speaks to HER2 status is a trial that was performed by Dick Love in Southeast Asia (Love 2003). He did a very large trial with women from Vietnam who underwent mastectomy with or without immediate oophorectomy and tamoxifen. The only requirements were that the patient needed to be premenopausal and have early disease.

At the time, he didn’t have the wherewithal to check receptors or HER2 status in a proactive way, but he collected all the tissue and had Craig Allred study these later on. Not surprisingly, the patients with positive estrogen receptors were the ones who benefited from hormone therapy, and HER2 status didn’t matter. Regardless of whether the patient was HER2-positive or -negative in that trial, they did equally well with this combined hormone approach of oophorectomy plus tamoxifen.

Putting this all together is very complicated, and I don’t think I know the answer to the question. That is actually one reason why I’m such a strong proponent of the SOFT trial, which evaluates tamoxifen versus ovarian suppression or ablation with tamoxifen versus ovarian suppression or ablation with an aromatase inhibitor. I think this trial would really help us to answer some of these questions that are a terrific struggle for us.

DR LOVE: Kathy, do you consider HER2 status in pre- or postmenopausal women when deciding about hormonal therapy?

DR MILLER: I don’t as an isolated factor, and I have the same problem interpreting the data that Nancy does. It is a bit all over the place. If you look at the trials that have tried to look at retrospective subsets of adjuvant trials, they have been very difficult to interpret, because there are generally a small number of samples available.

Those were studies that were often done quite early after the importance of HER2 was recognized and trastuzumab became available, and these studies often used very different ways of measuring HER2 than what we currently would consider standard. In particular, some of the studies that suggested there was a lesser benefit of tamoxifen in HER2 folks really didn’t define HER2 positivity in the way that we would now. I am not swayed by HER2 status as a single factor when making decisions for an individual woman.

DR LOVE: Rich, can you talk a little bit about your discussions with this woman?

DR ZELKOWITZ: We discussed tamoxifen as the standard of care for a premenopausal woman. We are participating in the SOFT trial (2.1), which we talked about at length but she declined to enroll.

Then I did a lot of extrapolating, because my sense was that there was no way she would complete five years of tamoxifen. I was convinced that in 18 months or two years, she would want to have a child. We talked about an LHRH agonist, to which she was agreeable.

The next question was: Do we do that in conjunction with tamoxifen or do we do that in conjunction with an aromatase inhibitor? I haven’t decided yet because we just started the LHRH agonist, but my inclination is to use an aromatase inhibitor for two reasons.

One, her disease is HER2-positive, for whatever that implies and two, I think I am only going to have a short period of time to actually treat this lady. Looking at some of the new hormone data, it appears that there is a percentage of patients who will relapse in the first two years and perhaps that number is less with an aromatase inhibitor. My inclination is to maintain her on leuprolide acetate monthly with an aromatase inhibitor.

DR LOVE: The reason we’re doing these trials is because we don’t have the definitive answer, but it is interesting that in our Patterns of Care surveys, a majority of oncologists in some way do consider HER2 status in their decision-making.

We also see that approximately a third have utilized an LHRH agonist plus an aromatase inhibitor. This is more commonly done in patients with multiple positive nodes and HER2-positive disease, but of course, there are extenuating circumstances as with this situation. Any thoughts, Nancy?

DR DAVIDSON: Keep an eye on her bones and good luck. I think it’s a good strategy. I would probably go with tamoxifen, but I wouldn’t fight you on this one. I agree that she presents a difficult challenge.

DR MILLER: I suspect that Nancy and I both see a fair number of these ladies coming in for second, third or fourth opinions.

In my experience, they are typically very appreciative when you are willing to acknowledge their concerns about fertility and work with them to try and find the best therapy within the boundaries that they have set for themselves and for our treat ments. Typically, they have not had that experience and have been told, “This is the therapy I want you to have, and it has these effects,” and that was the end of the story. They often come to see us after seeing several other oncologists down the line, as it sounds like this lady came to you, because they keep hearing the same story with no room for negotiation.

DR LOVE: It seemed like this woman wasn’t connecting with the doctors who had seen her before. I take it she has accepted your care at this point?

DR ZELKOWITZ: She travels across a bridge to see me, and it always impresses me that somebody would come over a bridge to see me. I think that if I said AC T or TAC, and that’s it, she would have just moved along. This was a matter of trying to find something that I could do with her, so we could feel like we were accomplishing something.

DR DAVIDSON: Our European colleagues would consider that combined therapy you are giving to be state of the art. A lot of them would not have thought very hard about chemotherapy.

Select publications