You are here: Home: BCU 7|2002: Clifford A Hudis, MD

	Clifford A Hudis, MD
Associate Professor of Medicine, Weil College of Medicine, Cornell University Chief, Breast Cancer Medicine Service; Associate Attending Physician; Co-leader, Breast Disease Management Team; Memorial Sloan-Kettering Cancer Center

Edited comments by Dr Hudis

2002 ASCO technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptorpositive breast cancer

Winer EP et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: Status report 2002. J Clin Oncol 2002;20:3317-27.

In developing these guidelines, our group struggled with issues related to the role the aromatase inhibitors would play. Eric Winer highlighted that in the short run, maybe the most important outcome of the ATAC trial, is that now we have a proven alternative.

In the past, we had some data for toremifene versus tamoxifen, but the ATAC trial shows us that there’s a drug that could be better and that certainly appears in many ways to be safer — and specifically safer in terms of toxicities that bother patients.

I have a very informed patient population. My patients come in asking questions, and I like those patients in terms of my own style of practice. It’s the one that works for me.

So, I share this information with them, not only for the purpose of education, but also because even if I don’t talk about it with them and even if they don’t bring it up, it’s very likely that after they leave my office in the weeks or months that follow, they’re going to hear about this. I’d rather talk about it with them at the beginning.

Adjuvant hormonal therapy in women previously taking tamoxifen or raloxifene

This comes at exactly the right time, because we may now have patients who have already taken tamoxifen and/or raloxifene, either for prevention of breast cancer or osteoporosis. A burning question has been: What to do with the breast cancers that develop in those patients, if they are ER-positive? Now we know that those patients can be offered an aromatase inhibitor as adjuvant therapy.

Another issue is the woman who develops a second primary ER-positive breast cancer while on tamoxifen, many physicians would have immediately used an aromatase inhibitor in the past. ATAC provides a little more solid evidence to support that decision.

Adjuvant hormonal therapy in women with contraindications to or intolerable toxicities from tamoxifen

In a patient who has a history of a hypercoagulable state or unacceptable toxicities with tamoxifen, one might consider switching to an aromatase inhibitor. Although, I am not convinced that switching to an aromatase inhibitor will alleviate patients’ hot flashes.

In women complaining of weight gain with adjuvant tamoxifen, the first thing we do is counsel them. There is no guarantee that some of those complaints will not continue when the patient switches to an aromatase inhibitor. If, after a long discussion, the patient says they are going to stop taking tamoxifen, I certainly would encourage an aromatase inhibitor.

Adjuvant hormonal therapy in women with HER2-positive breast cancer

I agree with the findings of the ASCO technology assessment guidelines that at present time, HER2 status should not be used to determine adjuvant therapy in early stage breast cancer.

Adjuvant therapy in an elderly patient with a 2-cm tumor (ERpositive, HER2-positive) and two positive lymph nodes

I would treat this type of patient with adjuvant combination chemotherapy and five years of tamoxifen. The age cut-off at which I would not recommend adjuvant chemotherapy depends on what the patient looks like. That is obviously not true in the extreme; I cannot imagine a situation in which I would give adjuvant chemotherapy to a 98-year-old woman.

This decision more involves the physiologic age than the chronoloic age. It also requires a very informed discussion with the patient about the risks and benefits of therapy. I can imagine treating patients into their eighties with adjuvant chemotherapy, but I would certainly be less likely to do so as they get older.

Outside of a clinical trial, I would use adjuvant doxorubicin/cyclophospha-mide followed by paclitaxel (ACT), backing off only if there was a specific toxicity in a particular patient. I am not convinced that ACT is much more toxic than AC. Elderly patients would also be eligible for Hy Muss’ trial, comparing single-agent capecitabine to either CMF or AC.

Adjuvant systemic therapy of patients with HER2-positive breast cancer

In patients who also have HER2-positive breast cancer, unless there is a specific contraindication, I would be biased in favor of using an anthracycline. Although many experts believe that HER2 status is not a proven predictive factor for response to chemotherapy, I think there is more than a little evidence to suggest that patients with HER2-positive disease may derive marginal benefit from anthracyclines.

TAC compared to FAC

As demonstrated in Jean Marc Nabholtz’s abstract comparing TAC (docetaxel/doxorubicin/cyclophosphamide) to FAC (5-fluorouracil/ doxorubicin/ cyclophosphamide). Overall, there was a statistically significant improvement in disease-free survival associated with TAC.

Interestingly, it was most striking in the group with one to three positive lymph nodes, and a preplanned subset analysis showed no benefit in the group with four or more positive lymph nodes. The TAC versus FAC trial is another brick in the foundation indicating that there is a small and clinically important advantage to the taxanes. Patients with HER2-positive disease seem to get a marginal benefit from taxanes also.

First-line therapy for recurrent ER-positive, HER2-positive breast cancer

In a patient relapsing two years after adjuvant ACT and while on tamoxifen, with bone-only disease that is easily managed, I would certainly be inclined to try an aromatase inhibitor as my first maneuver. I would use either anastrozole or letrozole.

I would watch the patient closely in that situation. If there were signs of early disease progression, it would not take much to convince me to change direction and think about using trastuzumab.

Atwo-year time period is the threshold at which point one would be biased in favor of using more hormone therapy. We know that an early relapse on adjuvant tamoxifen does not speak well for subsequent responses to hormone therapy. In some studies, two years has been the cut-off for the likelihood of response to subsequent hormonal treatments.

Second-line therapy for recurrent ER-positive, HER2-positive breast cancer

In a patient not responding to first-line therapy with an aromatase inhibitor, the algorithm is a little different from what it was in the past. There are now three options.

The first option is to consider yet another hormonal therapy. Since the response to one hormonal therapy, on average, predicts the response to subsequent hormonal therapies, I think that is the option least likely to be successful. The other options include chemotherapy, conventionally, and single-agent trastuzumab, less conventionally.

Choice of therapy for women with indolent disease

Until a few years ago, the only other option would have been chemotherapy. For a patient with what appears to be indolent disease but that is nevertheless progressing, the toxicities of many chemotherapy agents would make me less enthusiastic about this approach. The availability of single-agent trastuzumab changes the playing field. In this type of patient, I would feel most justified in using single-agent trastuzumab.

Randomized trial data clearly shows a time-to-progression and survival advantage for chemotherapy plus trastuzumab, compared to chemotherapy alone, and no data demonstrates that trastuzumab alone is equivalent to trastuzumab plus chemotherapy. There is indirect data, however, suggesting that trastuzumab can be initiated, and if there is disease progression, chemotherapy can subsequently be started while continuing the trastuzumab, without any real loss of apparent benefit.

From Chuck Vogel’s data there is good evidence that in patients with HER2- positive (FISH-positive or IHC 3+) metastatic disease, single-agent trastuzumab before chemotherapy is comparable to conventional chemotherapy. That data provides me with the basis for using single-agent trastuzumab.

Choice of therapy for women with visceral crisis

In patients with approaching visceral crisis (i.e., ascites, a pleural effusion, multiple new pulmonary nodules and multiple new liver metastases), I would start chemotherapy plus trastuzumab. If the patient had received adjuvant AC and paclitaxel, in my practice, the patient would be treated with trastuzumab in combination with vinorelbine, gemcitabine or often capecitabine.

These are combinations for which there are no randomized trial data. But the patient is, most likely, refractory to paclitaxel, which would have normally been my first choice. So, I must base my decision on Phase II evidence, and for all those drugs, there is Phase II evidence of safety.

Third-line therapy for recurrent ER-positive, HER2-positive breast cancer

In patients progressing after one year of trastuzumab, I would next turn to chemotherapy. One situation where I would almost always continue trastuzumab would be when I did not think the trial was adequate. For example, in a patient treated with trastuzumab who had progression at week eight, I would be concerned that we did not establish adequate serum levels.

If the patient had not received paclitaxel in the adjuvant setting, I would use paclitaxel. If the patient had received paclitaxel in the adjuvant setting, I would use capecitabine next. The quality-of-life aspects of capecitabine make it a natural choice.

I am biased towards capecitabine because of its oral route, flexible scheduling/dosing and its decidedly different toxicity profile. It does not cause profound neutropenia or alopecia. Commonly, patients who have had adjuvant AC/paclitaxel and develop metastatic disease are disheartened when they are told that they will get alopecia once again. In terms of quality of life, being able to offer a regimen that does not cause alopecia is appealing.

I do not use the package insert dose of capecitabine for any patients initially. For compliance reasons, I think it is easier to recommend a single pill size — 500 milligrams. Typically, I calculate the dose based on a 25% reduction from the package insert dose — about 1,000 mg/m2 twice a day for 14 days. Going into the second cycle, I often escalate the dose a bit, maybe by one pill a day, for patients without any toxicity.

I think that with this adjusted-dose approach, most patients get away with minimal diarrhea and nominal hand-foot syndrome. When we first started using capecitabine, we encountered serious diarrhea. Now that we have made this adjustment, I do not believe we see the same incidence. Certainly, we do not have the same trouble having patients continue on the drug that we did at the very beginning with the full doses. In terms of the hand-foot syndrome, we tend to dose capecitabine to the point where the hands are a little bit red.

HER2-positive, hormone receptor-negative inflammatory breast cancer in an 82-year-old woman

If the patient were healthy enough to have surgery, my inclination would be to use combination chemotherapy (doxorubicin/cyclophosphamide), and if she responds, then treat her with surgery followed by paclitaxel and radiation therapy.

This patient would be also eligible for the CALGB trial evaluating neoadjuvant trastuzumab. That trial involves four cycles of AC, with or without dexrazoxane, and 12 weeks of paclitaxel/trastuzumab followed by surgery and trastuzumab to complete a year. If she were not healthy enough to have surgery, that changes the equation a little for me. Then, I would actually be thinking about trastuzumab for its palliative benefit. I would think of her as a patient with metastatic disease.

Controversy regarding sentinel node examination

Two abstracts presented at ASCO 2002 highlighted this controversy. One, a retrospective analysis of a large data-set suggests that the discovery of any cancer cells (either by IHC or H&E) — regardless of the number — connotes a poor prognosis compared to no cells.

Interestingly, the curves do not appear to diverge until many years — maybe eight or more. If this were the case, it warns us not to be so quick to accept the lack of significance seen with short-term follow-up studies. The limitation to this study is that it was not a sentinel node trial. The patients all had axillary dissections, which were retrospectively analyzed. Since the vast majority of patients on this trial had a single positive node, we think it could correlate to the sentinel node.

On the other hand, the abstract presented immediately afterwards suggested no link between survival and the discovery of epithelial-staining cells in the bone marrow or the sentinel node. The discrepancy highlights that this is still an unanswered question.

In patients with an IHC-positive sentinel node that is H&E negative, it is a tough call. Patients with larger tumors with poor prognostic features will receive treatment anyway. The situations that are the most difficult are the older patient who will be treated with hormonal therapy alone, or the patient with a very small primary tumor for whom presence of nodal involvement would dramatically change the approach.

Based on the retrospective data-set from our center — presented at ASCO — I am inclined to think about systemic therapy for those patients. However, I would prefer that those patients enroll on a clinical trial.

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