Dr Bernik: This 37-year-old woman was recently treated with a mastectomy for four invasive breast tumors, the largest of which was 1.5 centimeters. The tumor was ER-positive, HER2-positive and, on axillary dissection, there were seven positive nodes.

From the floor: Were these four separate tumors or was it intramammary spread? Were they exactly the same histologically?

Dr Bernik: They were histologically the same.

From the floor: Any information on her BRCA-1 and 2 status?

Dr Bernik: She did not undergo genetic testing.

From the floor: What about her family history?

Dr Bernik: She did not have a significant history.

Dr Love: Genny, would you do genetic testing in this situation?

Dr Grana: Absolutely, but I wouldn’t do genetic testing at the time of surgery. I think there are many issues that are difficult to address at that point. I would mainly spend the time and the energy addressing the systemic issues. The genetic issues will come into play
down the line.

Dr Love: Genny is one of the few oncologists who does both breast cancer treatment and prevention. This patient has no family history. What is making you think about genetic testing?

Dr Grana: The fact that she's 37. For breast cancer under age 40, the risk of genetic abnormalities is about 10 percent. The other thing that's very worrisome is the fact that she has multiple lesions.

From the floor: What about the metastatic work-up in this patient?

Dr Bernik: Her work-up showed no other evidence of disease.

Dr Love: What about the issue of reconstruction and timing of post-mastectomy radiation therapy? Pat?

Dr Borgen: This is something we struggle with all the time because it's largely a cosmetic issue, not an oncologic issue. In a very thin 37-year-old, an implant may be her only option for reconstruction. Very often, by not putting an implant in immediately, it's like saying, "You're not going to have a breast mound for the rest of your life."

The radiation oncologists tell us that the old fears of unpredictable scatter are probably overblown, and we'd probably get the same local control with an implant, as not.

This is something that our group struggles with all the time. I think the trend has been for us to put tissue expanders in these patients, exchange them for implants because there's metal in the expander, and radiate. There's no science behind that, but that's sort of the direction that I see us heading in.

Dr Love: Dr. Bernik, can you talk about your discussions with this woman in terms of her risk for future recurrence?

Dr Bernik: She was diagnosed almost a year ago, and she's undergone a lot of her treatment. She was very motivated. When I walked in and I told her she had seven positive nodes, she said, "You know what? It is what it is. I just have to do whatever I have to do." So, she wanted to be very

aggressive about her treatment. She has two children and she's very involved with their care. She's divorced and, as a single parent, she's raising these children pretty much on her own.

Dr Love: Kevin, in what kind of trials could she be enrolled?

Dr Fox: This woman would be eligible for what is, I think, in the minds of most of us, probably just about one of the most important clinical trials that we're doing, and that's basically a randomization of chemotherapy with or without trastuzumab. We would make a very, very strong case to have a woman like this participate. The study that we're doing is a clinical trial that evaluates AC followed by paclitaxel, with or without trastuzumab, and two-thirds of the patients are randomized to receive trastuzumab (Figure 1.1).

Figure 1.1

If she declines participation, the obvious question that follows is: Would we give a patient like this trastuzumab outside of a study? And I most certainly would not. This harkens back to the whole bone marrow transplant story and how we made a decade-long error in judgment by giving something that we thought was a good idea, which may not have been. So, I wouldn't give a patient like this trastuzumab outside of a study.

Dr Grana: I guess the other question is: If she does not enroll in one of the trastuzumab trials, what do you offer this patient? I think she would be a wonderful candidate for the dose-dense therapy regimens - either AC followed by paclitaxel at two-week intervals or A followed by T followed by C. I tend to use AC followed by paclitaxel, because it's four months of therapy as opposed to six. She would also be a good candidate for the TAC regimen.

The hormonal therapy issue is important. She's someone in whom I would not use an aromatase inhibitor unless I render her menopausal with oophorectomy, and even if she were to go into menopause with her chemotherapy, how comfortable are you that she's in a permanent menopause? I would give her tamoxifen. If she were to regain her menses, I might consider oophorectomy as a viable option in someone like this who is at such high risk.

Dr Love: Oophorectomy or LH-RH agonist?

Dr Grana: I find it hard to commit someone to five years of monthly injections, so I tend to be a proponent of oophorectomy. If she's interested in

childbearing, you're going to have a problem, because if you commit her to tamoxifen, you're saying that she's not going to bear children for five years, at which time she's likely to be infertile anyway. So, if that's an option, you really need to sit down with her at the beginning and plan.

I would recommend tamoxifen unless I chose to take out her ovaries, in which case the genetic testing might also push me a little bit. If you don't remove her ovaries, I think tamoxifen should be the standard of care for someone like this.

The other issue that comes up is whether ovarian ablation on top of other endocrine therapy is beneficial as a systemic approach. I think the data is very limited. The Intergroup trial showed some tendency toward benefit in patients less than 40 years of age. That study was problematic in many ways. I don't recommend oophorectomy in the majority of patients, but in someone like this, who is at such high-risk, I would offer whatever I could to ameliorate that. So, in node-positive patients, if they resume menses, I would absolutely offer oopherectomy (Figure 1.2).

Dr Love: And there are clinical trials of hormonal therapy in premenopausal women, particularly looking at the issue of ovarian suppression and an aromatase inhibitor.

Dr Mamounas: The IBCSG is doing three trials. The most important one is the SOFT trial, in which the randomization is between tamoxifen alone, tamoxifen plus an LH-RH agonist, or any form of ovarian ablation versus ovarian ablation and an aromatase inhibitor. It's a three-arm trial looking at whether ovarian ablation adds to tamoxifen and, after you ablate the ovaries, whether an aromatase inhibitor is better than tamoxifen (Figure 1.3).

Dr Love: The Austrians have looked at the strategy of an aromatase inhibitor and anastrozole, plus or minus a bisphosphonate, and they presented data on bone in these patients in San Antonio in 2002 (Figure 1.4). Kevin, any thoughts on that?

Dr Fox: That was my first exposure to that whole concept. The numbers were small, and the follow-up was short, but it was the first indication of what we all had hoped to see, which was that if we're going to prescribe aromatase inhibitors to women who were either in menopause naturally or women whom we chose to make menopausal, at least we had some reassurance that bisphosphonates could offset the side effect that we fear the most, which is premature bone loss.

Dr Love: What actually happened to this patient?

Dr Bernik: She chose to participate in the NSABP adjuvant trastuzumab trial and received chemotherapy plus trastuzumab. She is also receiving tamoxifen.

Figure 1.2

Figure 1.3

Figure 1.4

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