DR RAPPAPORT: This is a 41-year-old, premenopausal woman with infiltrating ductal carcinoma of the breast, metastatic to six lymph nodes. She had a modified radical mastectomy and has been treated with four cycles of AC at this point. The tumor is ER- and PR-positive and HER2-positive by FISH.

DR LOVE: Aman, how would you treat this patient?

DR BUZDAR: For this young lady, who has a very high risk of recurrence, we have an effective therapy that has been shown to reduce the risk of recurrence. I would discuss with her the potential benefits of trastuzumab and that convincing evidence exists that we can reduce her risk of recurrence by more than 50 percent. In spite of chemotherapy and the positive hormone receptor status, she still has a very high risk of recurrence and I, personally, would be very much in favor of using trastuzumab as an addition to her therapy.

DR LOVE: What specific chemotherapy and when would you add the trastuzumab?

DR BUZDAR: If she just was finishing the last of four cycles of AC, I would give trastuzumab with a taxane, and most of the data we have are with paclitaxel (Perez 2005, Romond 2005). I personally would use trastuzumab concomitantly with the taxane-based therapy because of the positive impact when given concurrently and the lack of benefit when it was given sequentially that we saw in the Intergroup trial. That is one area of discordance between the US trial, in which I have more faith, and the European HERA trial, which shows a very similar degree of benefit to the combined analysis (Piccart-Gebhart 2005). In the HERA trial, the choice of chemotherapy was up to the physician.

DR LOVE: When would you start hormonal therapy in this patient, and what agent would you use?

DR BUZDAR: My understanding is that in these trials, hormonal therapies were started after the completion of chemotherapy concomitantly with trastuzumab. We have utilized that approach in the neoadjuvant and adjuvant settings.

DR LOVE: If this patient continues to menstruate through the chemotherapy, what hormonal therapy would you use?

DR BUZDAR: In a patient who continues to menstruate, I still believe that tamoxifen is the standard of care. Of course, there are a number of ongoing randomized adjuvant trials in which pharmacological intervention and the substitution of tamoxifen with an aromatase inhibitor and an LHRH agonist is being evaluated; we should have some preliminary data from these in the next year or so.

DR LOVE: I assume you would use trastuzumab for a total of one year, as was used in the adjuvant trials.

DR BUZDAR: Yes, because we need to use the therapy as it was used in the study where the data were collected.

DR LOVE: Bill, how do you approach patients who have been treated in the past for HER2-positive disease and have not received trastuzumab?

DR GRADISHAR: This harkens back to the release of the MA17 data and then seeing patients who completed adjuvant tamoxifen six months or a year ago. Do you institute another endocrine maneuver? I think that’s one of the big questions we are going to be facing with delayed trastuzumab. The data we have from trials long ago, tracking the recurrence of breast cancer over time, are instructive because we know that even after five years — be they node-negative or node-positive, but particularly if they are node-positive — there’s a fraction of patients who are going to continue to be at risk for recurrence, even though the peak recurrence may be within the first few years.

So with that as the background, I think for a patient who has completed chemotherapy, it is reasonable to consider trastuzumab. The big question is, How long since the completion of chemotherapy? Six months? A year? Two years? If a patient had six or 10 positive nodes and were out six months or a year, I would still have the discussion about the data and consider adding trastuzumab, even though it doesn’t directly duplicate the trial design.

DR LOVE: In terms of hormonal therapy, do you agree with Aman that in this patient you would use tamoxifen alone? I’m not certain whether this patient would be eligible for the TEXT or SOFT trials, but would you consider ovarian suppression and an aromatase inhibitor in this patient off protocol?

DR GRADISHAR: I believe tamoxifen remains the standard for this type of patient. The data we have available on ovarian suppression with tamoxifen or an aromatase inhibitor are still relatively limited, so I would still view tamoxifen as the optimal therapy.

DR LOVE: Kent, there were a fair number of patients in the HERA study who had node-negative disease but not too many in the combined NSABP/ NCCTG analysis. Do you think that the concept of relative risk should be applied when considering trastuzumab in patients with node-negative disease who have received chemotherapy and hormonal therapy?

DR OSBORNE: First of all, we should stop stratifying patients for treatment by node-negative versus node-positive disease. That’s only one of many factors. A patient with a high-grade, large tumor that is node-negative may have a much worse prognosis than a patient with node-positive disease and two positive receptors. I would look at the patient’s risk of recurrence and base my decision on the risk of recurrence, and even though she’s node-negative, I’d treat her.

DR LOVE: Dr Rappaport, would you follow up with what happened to this patient?

DR RAPPAPORT: I plan to talk to her about starting a taxane and trastuzumab concomitantly. I am wondering whether we should give her an LHRH agonist, or should we use tamoxifen? Also, if she is on an LHRH agonist, do we start either tamoxifen or an aromatase inhibitor?

DR LOVE: Peter, what about the issue of patients who cease menstruating with chemotherapy? How do we determine whether they’re postmenopausal and whether to consider an AI?

DR RAVDIN: One of the things that’s been frustrating is to use serum estradiol and gonadotrophin levels to define the menopausal status of women who have become postmenopausal on chemotherapy. This patient is relatively young, so if she stops menstruating, there’s a reasonable chance that she’s going to start menstruating again.

In this type of patient, I still prefer tamoxifen rather than an aromatase inhibitor. If she receives tamoxifen, and at the end of two years she hasn’t menstruated and her estradiol levels are low, then you can switch her. Incidentally, tamoxifen usually pushes up the estradiol levels and makes it more obvious that a patient is premenopausal, so that if you drew an estradiol level after two years and it was in the postmenopausal range, and you wanted to start her on an aromatase inhibitor, I think there’s very little chance that she would start menstruating at that point (2.1).

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