Edited excerpts from the discussion:

DR SMITH: My patient is a 46-year-old intramenopausal woman with irregular periods. She developed a 1.4-centimeter, Grade II infiltrating ductal carcinoma, which was ER-positive, PR-negative and HER2-positive — IHC 3+ and amplification by FISH. She had three positive lymph nodes and was accepted into the Intergroup adjuvant trastuzumab trial, but when randomly assigned to the nontrastuzumab arm, she insisted on receiving trastuzumab and dropped out of the trial.

DR LOVE: Were you surprised that this patient dropped out of the clinical trial?

DR SMITH: I was surprised and a little annoyed, since it confounds the trial results. Initially, I persuaded her to stay on study, but then she sought other opinions until she found someone who would put her on trastuzumab and then returned to me. This actually occurred about a month before the adjuvant trastuzumab data were released last April.

I administered four cycles of AC followed by weekly paclitaxel with concomitant trastuzumab and, upon conclusion of the paclitaxel, continued trastuzumab every three weeks. I also have her on tamoxifen.

DR LOVE: Interesting. Can you tell us a bit more about this woman and her situation?

DR SMITH: The patient is married and has two children. She is a psychiatrist and her sister is a radiologist. As many of these patients do, she went on the internet, made the rounds, and carefully read the study consent.

DR LOVE: Gersh, what are your thoughts regarding this patient enrolling and then dropping out of the clinical trial in order to receive adjuvant trastuzumab?

DR LOCKER: I wish I could say that this was an isolated phenomenon, but this is a common problem. In every consent form it states that patients can withdraw consent at any time, and a lot of patients do avail themselves of that right. I do think you were dealing with a patient who was perhaps a little more educated or did a little more homework than most.

DR LOVE: This case raises the question, “When do we use a therapy that has not been proven?” We know from our Patterns of Care studies that in clinical practice, physicians had not been using adjuvant trastuzumab prior to the data becoming available, and every time I interview a breast cancer researcher they strongly discourage it. Maybe this patient read Aman’s paper on neoadjuvant trastuzumab and got excited about the idea of adjuvant therapy (Buzdar 2005; [2.1]).

DR SMITH: She actually did read Aman’s paper.

DR LOVE: Aman, why do you think physicians were so hesitant to use adjuvant trastuzumab off protocol?

DR BUZDAR: I think one of the major concerns was that trastuzumab has a known risk of cardiotoxicity and we didn’t know the degree of benefit, so we didn’t know whether the risk-benefit ratio would favor treatment.

However, the results from our neoadjuvant study showed substantial improvement in pathological complete response, and I think that, provided indirect evidence, the adjuvant trials would be positive.

DR LOVE: It’s interesting that this educated woman who was very aggressive about wanting trastuzumab is content with tamoxifen, which in a patient with three positive nodes and HER2-positive disease, is not aggressive hormone therapy. Has the issue of ovarian suppression been raised in this case?

DR SMITH: Yes, it’s been raised and she is struggling with the thought of using leuprolide or goserelin. I think what she’ll probably do is have an oophorectomy.

If this patient opted not to do that, I’d like to query what one would do with this patient who is intramenopausal. She stopped menstruating after the second or third cycle of AC, but I don’t think she can be considered permanently postmenopausal.

DR LOVE: This is a vexing and common question. Aman, how do you approach endocrine intervention in perimenopausal patients who stop menstruating during chemotherapy, particularly in the high-risk, HER2-positive populations?

DR BUZDAR: There is no good way to define these patients. The best thing we can do is serial evaluations of the patient’s LH, FSH and serum estradiol levels. If her LH and FSH levels remain high and the serum estradiol levels remain very low in the postmenopausal range, chances are she will not resume her cycles. Still, I think that if she does not want ovarian suppression, then it is reasonable to start with tamoxifen.

DR LOCKER: I think we need to put this all in context. We are discussing this issue because women with ER-positive, PR-negative disease and with HER overexpressed tumors are two subsets of patients who, based on several studies, don’t do as well as the average patient on tamoxifen. Data from ATAC and other trials and, in the case of HER2-positive disease, data in the neoadjuvant setting, demonstrate that these patients do better on an aromatase inhibitor (AI). So we’d like to see this patient on an AI, but she can’t be on it unless she’s clearly postmenopausal.

DR LOVE: Aman, what would you do if this patient came to you requesting an LHRH agonist and an aromatase inhibitor?

DR BUZDAR: The role of an LHRH agonist with an aromatase inhibitor in premenopausal women is under study, and a number of protocols are ongoing. We know the safety data. However, we don’t know the efficacy of this regimen, and until we see those data, I do not like to see it used in clinical practice.

DR LOVE: What if the same patient came to you requesting aromatase inhibitors after an oophorectomy?

DR BUZDAR: Then there is no question that I would put her on an aromatase inhibitor, because she would then be postmenopausal.

DR LOVE: Aman, about half of the patients in the adjuvant trastuzumab studies presented at ASCO 2005 had ER-positive tumors, although we don’t know the quantitative levels. Did trastuzumab impact these patients any differently?

DR BUZDAR: No. For these patients, appropriate endocrine therapy should be offered, because there is no question that endocrine therapy can substantially change the natural history of the disease in these patients, too.

DR LOVE: What do we know about combining hormonal therapy and trastuzumab, in terms of safety?

DR BUZDAR: In the NSABP study, patients who received endocrine therapy received trastuzumab concomitantly. No experimental data exist to suggest any adverse interactions, and none were reported.

DR LOVE: Gersh, it appears most physicians are waiting until the patient completes chemotherapy and then giving hormone therapy along with trastuzumab, as they did in the clinical trials.

DR LOCKER: Yes. In patients with HER2- positive disease, recurrences occur early. In the ATAC trial, an early blip was clear in time to recurrence, even with hormone receptorpositive disease. So you want to use your best guns early — meaning hormonal therapy and trastuzumab. I’d be very uncomfortable waiting a year until trastuzumab is completed.

DR LOVE: Let’s talk about chemotherapy in patients with HER2-negative tumors and positive nodes. How do you approach those patients?

DR LOCKER: If the tumor were ER/PR-positive and HER2-negative with multiple positive nodes and the patient understood the limited benefit of chemotherapy beyond the benefit she gains from hormonal therapy, I would use AC times four. I’m not even convinced that adding paclitaxel makes a difference. Now, if I were going to be more aggressive for whatever reason — say she has 20 nodes and wants to be as aggressive as possible — then perhaps I would use TAC, but that’s about as far as I’d go.

DR LOVE: What if the tumor were ER/PRnegative?

DR LOCKER: In a healthy patient with an ER/PR-negative tumor and multiple positive nodes, I would use TAC.

DR BUZDAR: TAC is a good combination, but when you combine either docetaxel or paclitaxel with other drugs, you increase the morbidity. I think patients tolerate sequential administration better, and you don’t have to use growth factors to overcome some of the side effects. My personal choice would be to administer anthracycline-based therapy followed by a taxane-based therapy in these patients.

DR LOVE: How does the relative efficacy of docetaxel compare with paclitaxel?

DR BUZDAR: In my judgment, the efficacy of docetaxel every three weeks is similar to weekly paclitaxel, whereas a study has shown paclitaxel every three weeks is inferior to docetaxel every three weeks in the metastatic setting (Jones 2005).

DR LOVE: Gersh, do you think at some point AC followed by nanoparticle albumin-bound (nab) paclitaxel will be used?

DR LOCKER: It’s possible. Nab paclitaxel has some advantages, but I’m not sure whether the difference in efficacy, if there is any, would warrant it. I think the bigger issue is whether we’re going to be doing stratification by receptors in terms of chemotherapy choices, the way we do stratification by receptors for hormonal therapy choices.

DR LOVE: Aman, if we find nab paclitaxel is equal to paclitaxel in efficacy, will the advantages of a shorter infusion time and the ability to administer it without premedication justify a shift in practice?

DR BUZDAR: Yes. I think the advantage of nab paclitaxel is that you don’t have to use steroids. When we use taxanes, one of the major complaints from patients, besides the neurotoxicity, is the weight gain and side effects related to steroids. If you can avoid that, you are actually enhancing the quality of life of these patients. Even if the antitumor activity of nab paclitaxel is identical to paclitaxel, I think it has a better safety profile.

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