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You are here: Home: Meet The Professors Vol. 4 Issue 1: Case 2
Edited excerpts from the discussion: DR SIMON: This 78-year-old woman noted a painless lump in her right breast and quickly sought medical attention. On exam, there was a five-centimeter mass in the right breast and a two-centimeter palpable right axillary lymph node. A core biopsy revealed invasive lobular carcinoma. Estrogen and progesterone receptors were both strongly positive, and HER2 was 1+ by IHC. She underwent a right modified radical mastectomy. Pathology showed a 4.5-centimeter tumor and two of 30 positive lymph nodes. She received postoperative radiation therapy. She was otherwise completely healthy, married and living with her husband. She was totally opposed to chemotherapy. DR LOVE: We have another 78-year-old woman who doesn’t like the idea of adjuvant chemotherapy. Maybe we want to explain the potential benefits and risks to consider. One of the most pressing questions is defining the optimal chemotherapy regimen for the patient at higher risk, particularly one with node-positive disease. Cliff, if this woman, with two positive nodes and an ER-positive, HER2-negative tumor, instead of being very reluctant about chemotherapy, said, “I want you to do everything you can to reduce my risk of relapse,” how would you respond?
DR HUDIS: If she wants chemotherapy, we would treat her with dose-dense AC
DR LOVE: What if she says, “I’ve been on the internet and see all this controversy about dose-dense AC DR HUDIS: Without question, the Oxford overview and virtually every study across the board ever done, including the TAC/FAC trial (Martin 2005a), shows clear evidence of a greater magnitude of benefit for patients with ER-negative disease who receive chemotherapy than those in the ER-positive subset (2.1). In the TAC to FAC comparison, the benefit in the ER-positive subset is statistically significant. In some of the other trials, it is not. That trial had the advantage of centralized ER testing and control over the hormone therapy. When we conducted our studies in the CALGB, we recommended but didn’t stipulate hormone therapy. We didn’t do centralized ER testing. So our results are hypothesis generating. Our hypothesis is that chemotherapy is, on average, less effective in ER-positive than in ER-negative breast cancer. I don’t think that’s a big stretch. DR LOVE: Do you set an age limit above which you just won’t administer chemotherapy? DR HUDIS: I would be tempted to treat this patient without chemotherapy anyway. What you presented to me was a patient who walks in and demands it. I won’t put an age number there, because I can’t. But certainly, above age 80, it’s exceedingly rare for us to give adjuvant chemotherapy to any patient. We do it, but it’s very rare. Those patients usually have ER-positive disease.
DR LOVE: The San Antonio meeting revealed a lot of controversy about this issue. Dr Piccart-Gebhart gave the opening presentation addressing this question of chemotherapy for patients with ER-positive disease. You’re saying, in general, for a 78year-old patient with an ER-positive tumor and two positive nodes, you would not administer chemotherapy? DR HUDIS: Yes. DR LOVE: What if she were 58 years old? DR HUDIS: I’d be much less comfortable not administering chemotherapy if the patient were 58. The reason is that whatever small benefit chemotherapy may offer patients with ER-positive disease is likely to play out over many, many years, and you need to have a long life expectancy to see that difference. ER-positive breast cancer has a long, chronic relapse track. Interestingly — and not many people appreciate this — by 30 years after diagnosis, it doesn’t matter whether you had ER-positive or ER-negative disease, untreated. The overall risk of relapse and the overall survival is the same. So the notion that ER-positive disease is overall a better disease is undermined. What’s different is the timing of the recurrences. With ER-positive disease, you see the impact of therapy over the long haul. With ER-negative disease, you see it right up front. So for a young patient with a long life expectancy, I wouldn’t be so quick to forgo that potential benefit. But the older you get, the longer you have to live to see the potential benefit, and the more likely you are not to get there. DR LOVE: John? DR MACKEY: For the most part, I agree with Cliff’s comments. But I just want to point out that we’ve struggled over the last five or six years with HER2 testing and what is the right way to do it. And I think we finally agreed that you need a good, reproducible assay and a good centralized laboratory. The estrogen receptor is, in many cases, a much more important signal that we need to make our treatment decisions, yet we tend to rely on uncontrolled, nonquantitative, nonreproducible assessments for our patient care. If I could make just one recommendation to any practitioner, it would be to quiz your laboratory staff and find out what they have actually done to validate their hormone receptor status results. To make the mistake of not offering a woman with ER-positive disease hormonal therapy is probably the biggest sin you can commit in adjuvant treatment. Make sure that your lab knows what it’s doing. We had the benefit of a central review for our estrogen receptor data on the BCIRG 001 trial (Martin 2005a), and I agree with Cliff. This may be part of the reason we’re clearly defining a benefit in that population, while the contamination of the ER-negative groups in other studies may obviate that. DR LOVE: John, getting back to Dr Simon’s case: 78-year-old woman, ER-positive tumor, two positive nodes. What if she wants to do everything she can to reduce the risk of relapse? DR MACKEY: I’d still try to talk her out of chemotherapy. I think the advantage is probably trivial. It’s untested and if you want to demonstrate that, you can go to www.AdjuvantOnline.com and enter this patient’s age and comorbidities. To be blunt, she’s likely to die of something else (Arriagada 2006). Chemotherapy probably isn’t going to change that much, and sometimes you have to resort to hard numbers, even though they’re estimates, to drive your point home. Using Adjuvant! Online, I’ve been impressed by our trainees’ surprise at the marginal benefits of chemotherapy in the older ER-positive population. DR LOVE: I will ask you to respond to the same scenario I asked Cliff about. What if she were a 58-year-old woman? DR MACKEY: I would very much want to treat her with chemotherapy. Although I admit that we don’t have cross-trial comparisons, my bias is to use TAC in the ER-positive population. We know that it works, clearly, in ER-positive disease. Paclitaxel probably does also, but again, I’m just not comfortable enough with the data sets that have been derived to accept that there is a major difference. I don’t feel as strongly about that today as I did one month ago because the ECOG1199 study showed that no clear signal distinguishes the taxanes (Sparano 2005; [2.2]). I’m less inclined to believe a taxane/ER-specific interaction might have been indicated. I think it’s probably largely differences in the trial design and conduct. DR LOVE: I’m going to guess that even if the tumor were ER-negative you’d prefer TAC?
DR MACKEY: I think not as strongly, because we know, clearly, that dose-dense AC If you consider most other malignancies, combination therapy with curative intent is not as likely to be sequential. It tends to be combination regimens. You can’t use combination anthracycline/paclitaxel adjuvant therapy, in general, because of cardiotoxicity. You can do it with docetaxel. If a big advantage truly exists, it’ll come from that, I think. DR LOVE: Dr Simon, would you follow up with what happened with this woman? DR SIMON: She was prescribed anastrozole and alendronate because she had some osteopenia. She’s been doing well, and it’s over a year since her surgery.
DR LOVE: Any side effects or problems with the anastrozole? DR SIMON: None whatsoever. DR LOVE: Cliff, how would you treat this patient if she were osteopenic with an ER- positive, PR-negative tumor? What would you think about anastrozole or an aromatase inhibitor? DR HUDIS: I think it’s perfectly reasonable. The ER and PR subset analysis isn’t consistent across the aromatase inhibitor trials right now, and I would be biased in favor of the aromatase inhibitor. DR MACKEY: I agree, but I believe we also have to get these women on calcium, vitamin D and weight-bearing exercise. I routinely recommend that all women on aromatase inhibitors receive 1,500 milligrams of calcium and 800 units of vitamin D. I talk to them about exercise, in part because we’ve conducted randomized trials in our center showing that the quality-of-life benefits from exercise are far better than those of any of the other reported interventions. The aromatase inhibitor is an excuse for me to hammer home these life-style issues. DR SCHWARTZ: Cliff, does a group of node-negative patients exist whom you feel are at a high enough risk at this time to add a taxane? DR HUDIS: We have two axes of risk. One is geography: Are the nodes involved or not? That’s always been a surrogate for distant metastases. The other axis is biology, which is the receptor status. A patient with high-risk node-negative disease is, in all these trials that have included them, a patient with ER/PR-negative disease. For example, we are learning that patients who have node-negative, triple-negative disease are at high risk, and we would treat them as we treat patients with node-positive disease. That is, for sure, in many ways overstepping the limits of the currently available data, but I don’t think it’s unreasonable. Those patients’ early risk of recurrence is higher than the patients with ER-positive disease who, by nodal status, were eligible for the trials. DR LOVE: Dr Freedman? DR FREEDMAN: I appreciate Dr Mackey’s comments regarding the potential synergy of docetaxel with an anthracycline. We had the opportunity to participate in both BCIRG 001 (Martin 2005b) and the dose-dense study (Citron 2003; Hudis 2005), and I find that the difference in toxicity is substantial. The TAC regimen is extremely toxic, and we’ve been amazed at the ease of administration of the dose-dense regimen. So although they may be equally efficacious, I hope the NSABP trial shows us the answer. In our community practice, we have favored dose density just because of the more favorable side-effect profile. DR HUDIS: Can I ask a question before you go on? Did you use growth factors for the TAC regimen when you were administering it, because on the study they were not allowed, right? DR FREEDMAN: That’s correct DR HUDIS: That could skew your perspective. DR MACKEY: That’s exactly my point. I believe that TAC without growth factors is more toxic than dose-dense AC. We have data from a trial in which Miguel Martin, in Spain, treated node-negative patients with TAC or FAC. Early in the trial they thought, “Gee, for node-negative disease, this TAC is quite tough,” and they mandated G-CSF. At that point, they found that the tolerability increased dramatically. It’s not a randomized trial, and it’s an intervention halfway through, but they found that not only did the febrile neutropenia rate drop, but the mucositis, fatigue and diarrhea decreased as well. In addition, the quality-of-life decrements that come with chemotherapy were also less after G-CSF was initiated. At the end of the day, I completely agree with you that “naked” TAC without growth factors is probably tougher than dose-dense therapy with growth factor. However, I think that difference would be much less if you used primary prophylaxis with pegfilgrastim or filgrastim. I would suggest that if you were going to use it, use it with growth factor support, and that’s my preference in this case.
DR LOVE: John, I was talking to Gary Lyman, who does a lot of patterns of care studies. He agrees with what we found in our own CME group’s Patterns of Care studies, that without a doubt the most common regimen utilized for node-positive breast cancer is dose-dense AC One of the shifts that was interesting, though, is that in the last year we’ve seen a flip in the number two regimen, which has changed from AC But Gary told me something else that was shocking. I assumed that everybody knew that if you use TAC, based on what you just talked about, you use growth factors. Yet according to his fairly recent patterns of care studies, for which he goes into practices and actually sees what people receive, almost half of the TAC being administered in this country is not being used with growth factors. Cliff, is that your take? DR HUDIS: The only thing I can think of is that some people may be reading the drug approval in the adjuvant setting and literally following the label. Unfortunately, the label doesn’t explicitly talk about the use of G-CSF, but anybody who’s used the regimen or paid attention should know that G-CSF is required with TAC.
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Case 1: from the practice of Leon H Dragon, MD Case 2: from the practice of Sheryl R Simon, MD Case 3: from the
practice of Howard R Abel, MD Case 4: from the practice of Mary
Ann K Allison, MD Case 5: from the practice of Richard S
Zelkowitz, MD
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paclitaxel (Citron 2003; Hudis 2005). The clinical trial imposed no upper age limit, and approximately 12 percent of the patients were above age 60. Arti Hurria at our center has specifically studied octogenarians treated with chemotherapy and has identified relative safety for it. 
