Dr Mintzer: This 55-year-old woman was treated three years ago for a T1N1M0, ER/PR-negative, HER2-negative left-breast cancer. She elected to undergo a mastectomy, which was followed by AC for four cycles and paclitaxel times four. She presented three years later, with symptomatic pericardial effusion, which was histologically confirmed to be recurrence.

She was managed with a peri-cardiectomy and is now asymptomatic and working full-time, but she still has evidence of disease in the contralateral right axillary nodes and small pleural effusions on CT scan.

Dr Winer: You're comfortable with the HER2 testing?

Dr Mintzer: Yes. She actually did have FISH, and it was negative, as was the IHC.

Dr Winer: I would use single-agent therapy, and I'm not convinced that there's an optimal sequence in which it should be given (Figure 4.1). Any of the active single agents are fine. I realize that the traditional choices are anthracyclines and taxanes. In this patient, given the fact that she's had four cycles of AC, most oncologists would probably use a taxane rather than an anthracycline. I probably wouldn't use a taxane, and would likely use something that is better tolerated. In these kinds of situations, these days, I actually often use capecitabine.

Dr Love: She received paclitaxel three years ago. What about docetaxel?

Dr Winer: Clearly, there are responses to docetaxel in patients who have been on paclitaxel, but there aren't a huge number. The response rate to docetaxel in the study that was reported a few years ago in patients who received paclitaxel was about 20 percent (Figure 4.2).

So there is some activity. In this situation, I would not view her disease as being either anthracycline-or taxane-resistant, and in practice, I consider going back to an anthracycline at some point. Going back to a taxane is also a possibility.

Dr Love: Dr. Mintzer, what was this woman's perspective on her situation?

Dr Mintzer: She basically left it up to me. The quandary here is that -although she had a pericardial effusion that could have been fatal -that is now relieved, and she's really asymptomatic. Do we approach this like an aggressive symptomatic person or, now that she's asymptomatic, in a more indolent fashion? Because of the pericardiectomy, I think it's unlikely for her to have recurrent symptomatic pericardial disease. Most patients have prolonged relief after an adequate window, although some patients do fail that therapy. I'm a big believer that you can only make asymptomatic patients feel worse, not better.

Dr Love: Hy, how would you have thought through this case?

Dr Muss: I would actually use capecitabine in a patient like this outside of a clinical trial. We just did a trial evaluating oral chemotherapy, which was relatively nontoxic, but I think all of our therapy is palliative in these patients. That's the bottom line.

And I agree, you can't improve on being asymptomatic. So, I think capecitabine is a good choice. She won't lose her hair again, she won't become myelosuppressed, and you can monitor her closely for hand-foot syndrome. I think capecitabine offers a good quality of life for a lot of these women. You can go back to the other agents later and, as Eric said, you can pick anything.

This patient had a three-year interval since her adjuvant chemotherapy. It's not great, but it's better than a one-year, disease-free interval, and I think the patient is likely to have a better quality of life with capecitabine than with IV taxanes or coming back for anthracyclines and having to buy another wig in two to three weeks. I would lean toward capecitabine.

Figure 4.1

Figure 4.2

From the floor: Did she have a mammogram to show that she doesn't have new onset disease on the right side?

Dr Mintzer: There was nothing clinically palpable in the right breast at that time. I did not do a mammogram because she had proven metastatic disease, so it would seem to have been relatively irrelevant. However, I will tell you that six months later she developed a mass in that right breast.

Dr Love: Did you have some kind of premonition about this? What made you ask the question and actually predict what happened?

From the floor: She had a three-year disease-free interval, and women certainly do develop bilateral breast cancer. She had a contralateral node. Maybe her metastatic disease is not the same as her primary disease. I think you have to figure out the options, so I would retest HER2 and I would probably do an MRI on the right breast.

Dr Love: The other issue would be whether her disease was resistant, or potentially resistant, to her prior adjuvant therapy. What happened with this woman?

Dr Mintzer: The right breast was biopsied and showed infiltrating ductal carcinoma that was ER/PR-negative and HER2-negative, just as the original contralateral primary tumor had been.

Dr Love: How did you manage her new contralateral primary cancer?

Dr Mintzer: After the pericardiectomy, I gave her capecitabine and she had stable disease for about three months. By four months, the new breast lesion had appeared and she had rising tumor markers. Then we put her on docetaxel and the new breast lesion shrank down. We debated whether or not she should have a mastectomy on the other side.

Dr Love: So, your conclusion was that she was progressing in the other breast while on capecitabine?

Dr Mintzer: She clearly was progressing. Whether she was progressing from her metastatic initial primary or whether she was progressing from a second primary was unclear.

Dr Winer: I'd like to go back to one of the prior points. The fact that she could have another primary illustrates the importance of retesting ER, PR and HER2 status, if there's any question. Knowing whether there's anything in that breast once you've retested ER, PR and HER2 may or may not make a difference in your treatment at this point. The issue of resistance to AC and paclitaxel doesn't exist because it's a new primary, and chances are that primary was there when she received the AC and paclitaxel three years ago. So, I don't know that this would change my thinking either.

Dr Love: What is your plan in terms of this second primary?

Dr Mintzer: She had a contralateral mastectomy at her insistence two days ago.

Dr Love: And axillary dissection? Dr Mintzer: No axillary dissection. Dr Love: What went into her decision?

Dr Mintzer: She was actually very well-informed. I told her that the systemic disease might be more of a problem before she had local progression in that breast. I generally do not recommend mastectomy in the setting of metastatic disease, but I felt this was an unusual case (Figure 4.3).

Dr Love: Did she have reconstruction?

Dr Mintzer: No. She did not request it,

and I did not recommend it.

Dr Love: What about the question of retesting metastatic disease for HER2 in a patient who has a HER2-negative primary?

Dr Muss: I don't routinely do it, but it's not an unreasonable thing to do. HER2 is usually consistent in the primary lesion and metastases. If you look at ER/PR status, it's vastly different. Studies show that you can divide a breast cancer into 12 sections and one part will be strongly ER-positive and another part will be stone-cold negative. I think HER2 is usually more consistent. We are trying to give every patient every break, so, depending on the clinical situation and how sick the patient is, it's not unreasonable to retest for HER2 (Figure 4.4).

A patient was recently referred to me whose HER2 was retested and was positive, and it really gave this patient another option for therapy. So, in selected patients, I think it's a reasonable thing to do.

Dr Winer: Ann Thor evaluated the concordance rate between the primary and the metastatic lesion. Her lab did the testing side by side on both of them, thereby eliminating the potential for false positives in some other lab. The concordance rate was 80 to 90 percent. It wasn't 100 percent, so they are different once in a while. I actually just treated a patient last week with recurrent disease that was progressing on trastuzumab. Her oncologist wanted to continue trastuzumab with something else. There had been some issues with the past testing, and I thought it was very likely not a HER2-positive tumor. We did a punch biopsy just to prove that it was HER2-negative, which one of the biopsies had shown before, and lo and behold, it was 3+ HER2-positive. I think we're still early enough in all of this testing that, if there's any question, it makes sense to obtain new tissue and retest.

Figure 4.3

Figure 4.4

From the floor: Would you routinely do FISH on any HER2 lesion that was zero on IHC?

Dr Winer: Very few patients whose biopsies are zero on IHC in a group lab have FISH-positive disease. With 1+, you start getting into the single digits, and I think that's where you really have to take into account their clinical situation. In patients with 2+ or 3+ disease, it makes sense to do FISH.

From the floor: What clinical setting would make you think that this disease was HER2-positive, despite a negative result?

Dr Winer: Nothing is absolute. A mix of different features - more common in this setting of ER- and PR-negative disease (although probably 50 percent of HER2-positive disease is ER-positive), visceral disease, a patient presenting initially with DCIS with necrosis, and a short disease-free interval. You just have to use your judgment. And, if you're not sure, it's probably reasonable to re-test.

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