You are here: Home: BCU 7|2002: Debu Tripathy, MD

	Debu Tripathy, MD
Professor of Medicine and Director, Komen Alliance Breast Cancer Research Center, University of Texas Southwestern Medical Center

Edited comments by Dr Tripathy

Choice of adjuvant chemotherapy

Currently, I am using four cycles of doxorubicin/cyclophosphamide mostly for patients with negative lymph nodes. If a patient with ER-negative, node-positive disease presented today, I would use adjuvant doxorubicin/ cyclophosphamide, followed by paclitaxel.

In patients with ER-positive disease, I think it is reasonable to use paclitaxel. I am, however, concerned about the subanalysis showing a lack of benefit in patients with ER-positive disease. Although the statisticians tell us not to look at that subset, CALGB 9344 had 2,000 ER-positive and 1,000 ER-negative cases. Early data from NSABP B-28 seems to show a trend in the same direction.

Even though I think taxanes are reasonable, and, in fact, they are the control arm of many of the Intergroup studies, for my patients with node-positive, ER-positive disease, I also think it is reasonable to use six cycles of an anthracycline-containing regimen, like FAC or FEC. That is typically what I am using.

Choice of adjuvant hormonal therapy in premenopausal patients

In patients with ER-positive disease and positive lymph nodes, I would use tamoxifen following the adjuvant chemotherapy. In women who are still menstruating, I think the LHRH agonists are reasonable as well, but the value of adding an LHRH agonist to tamoxifen is still questioned. In the large European study, the Zoladex® in Premenopausal Patients (ZIPP) trial, there was a clear advantage with goserelin, but in the subgroup of women on tamoxifen, it was not statistically significant.

A proposed Intergroup study will evaluate chemotherapy followed by tamoxifen, with or without an LHRH agonist, in women who are still menstruating after chemotherapy. Now that the ATAC trial results are available, they are also thinking about evaluating an LHRH agonist plus anastrozole in those women. I would support a trial where the control arm would be tamoxifen and the experimental arms would be an LHRH agonist plus tamoxifen, and an LHRH agonist plus an aromatase inhibitor.

Postmastectomy radiation therapy

Unless a patient has a primary tumor that is more than five centimeters, or with skin involvement or more than four positive lymph nodes, I do not routinely use radiation therapy postmastectomy. It is still unclear whether a positive HER2 status alone would be enough of a risk factor for local recurrence to warrant the use of radiation therapy.

The use of postmastectomy radiation therapy in patients with one to three positive lymph nodes is an area that is under investigation. Patients with one to three positive lymph nodes, and a primary tumor that is less than five centimeters, are the subjects of a randomized trial comparing postmastectomy radiation therapy to observation.

Responses to second-, third- and fourth-line chemotherapy

I have seen maybe two or three patients with a dramatic response to second-, third- or fourth-line chemotherapy. For example, we start them on capecitabine, and they have a great response — independent of trastuzumab.

I have seen HER2-negative patients progress on doxorubicin and then on paclitaxel, and then have a great response to capecitabine. Even though these patients are not common, we do occasionally encounter patients who respond to their third- or fourth-line chemotherapy much more dramatically than prior agents. We need to develop markers of resistance and sensitivity to therapy, so we can know ahead of time what drugs to use.

Choice of systemic therapy for patients with HER2-positive metastatic disease

In patients with HER2-positive metastatic disease, it is a given that those patients will receive trastuzumab. Whether to add chemotherapy is the question. In the absence of cardiac disease, I would use trastuzumab monotherapy in a patient who is asymptomatic or whose disease was not immediately life-threatening.

An asymptomatic patient with bone-only or soft-tissue disease would be — in my mind — an ideal candidate for trastuzumab monotherapy. In a patient with multiple liver lesions who might get into trouble with a little progression — even though they were asymptomatic — I might consider combination therapy with chemotherapy plus trastuzumab.

For combination therapy, I use a taxane with trastuzumab. Since the data is based on paclitaxel, I tend to use that. There are early trial results from combinations with docetaxel showing response rates from 35% to 60%. Certainly, I think docetaxel is active in combination with trastuzumab.

The group at UCLA strongly believes that the synergy with docetaxel — at least in the laboratory — is greater than with paclitaxel. Therefore, they have designed their trials, both in advanced and early-stage disease, with docetaxel.

The high response rates with the combination of vinorelbine/trastuzumab are encouraging. Soon, we may have reason to use it as first-line therapy. There are proposed trials comparing a taxane to vinorelbine, in combination with trastuzumab, as front-line therapy. Vinorelbine/trastuzumab and paclitaxel/trastuzumab are both very tolerable. Bone marrow toxicity may occur a little earlier with vinorelbine.

Trastuzumab pivotal trial

The primary outcome initially chosen was time to disease progression. Survival, even though it was captured, was not expected to be different. In fact, that is why the crossover was allowed. When the survival difference emerged, despite the fact that close to 70% of the patients crossed over, it was indeed remarkable.

In retrospect, it would have been interesting to have trastuzumab monotherapy as the third arm of that trial. In fact, such a trial is now being proposed. For example, trastuzumab alone will be compared to trastuzumab plus a taxane. Then, upon progression on trastuzumab alone, there will be a second randomization to either a taxane alone, or a taxane plus trastuzumab. I think that that will be an excellent trial.

Trastuzumab in combination with other agents

Another area of interest is the combination of trastuzumab with other drugs. Some of these combinations are driven by in vitro data. The combinations with gemcitabine and the platinums look interesting.

Much of the original preclinical work was done with cisplatin. In fact, an early Phase II study by Mark Pegram demonstrated activity for trastuzumab in combination with cisplatin in very refractory patients. The BCIRG and the group at UCLA are capitalizing on this in their adjuvant trial.

There is also data from a trial in metastatic disease looking at trastuzumab in combination with either carboplatin, or cisplatin along with docetaxel, which found very high response rates.

Trastuzumab/vinorelbine

Probably the most exciting data is the high degree of activity demonstrated with the trastuzumab/vinorelbine combination. This has been confirmed in a separate trial, but I think it still needs to be confirmed in the large ongoing multicenter trial. Furthermore, I believe there is a trial comparing paclitaxel or docetaxel to vinorelbine in combination with trastuzumab.

Neoadjuvant trastuzumab

The neoadjuvant data for trastazumab exemplify a totally different set of circumstances. With chemotherapy alone, clinical response rates are in the 70% to 90% range. It is not surprising then that the trastuzumab combinations show those same response rates. Since the pathologic complete response rate is a surrogate for survival, we are very interested in that.

I support these trials. I do not treat patients outside of a trial with neoadjuvant trastuzumab, but we are certainly going to participate in the CALGB trial with neoadjuvant trastuzumab. That trial is designed to determine the efficacy of dexrazoxane (Zinecard®), trastuzumab in combination with paclitaxel, and one year of trastuzumab following surgery.

First, the patients are randomized to receive doxorubicin/cyclophosphamide, with or without dexrazoxane. This part of the trial will determine whether the introduction of a cardioprotectant can have a long-term effect on controlling cardiotoxicity. In the second phase of the study, the patients will receive paclitaxel/trastuzumab. Then, the patients will have surgery, and they will receive trastuzumab for one year.

Algorithm for HER2 testing

We assume that the tumors with a 3+ score on immunohistochemistry (IHC) are truly HER2-positive, and we do not test them further. If a tumor has a 2+ score on IHC, we test with fluorescence in situ hybridization (FISH). Even in patients with an IHC score of 0 or 1+ and other features of excessively aggressive disease, we may also do a FISH test.

An IHC score of 3+ is pretty reliable, as long as it is done at a laboratory that performs a lot of assays. Both the Intergroup and the NSABP study discovered that smaller community hospitals were overscoring tumors as 3+. Close to 30% of the 3+ scores were downstaged when they were reviewed centrally. These protocols have now been amended to require that the patients wait for final randomization until there is a central review of their HER2 status.

I think the same things apply to FISH testing. Since FISH testing already tends to be done at more centralized laboratories, we have not yet explored the quality control issues. I suspect there will be a proliferation of FISH testing, and the reagents will go out to all the community hospitals. Even though there is probably less room for interobserver variability, the same issues will apply. I hope as the FISH technology disseminates, people will do these quality control-type studies.

At some point, it may be possible that the only test that will be done is FISH. Personally, I believe it to be more accurate and less subject to interobserver variability. I think the cost should be downplayed if it is only a difference of $100 or $200. However, when trastuzumab is given incorrectly for several months, that involves many thousands of dollars. It behooves us all — even from a cost standpoint — to get the most accurate test up and running.

Schedules of trastuzumab plus weekly taxanes

It was expected that weekly taxanes would be effective with trastuzumab, and, in fact, it was found to be the case. This paves the way for using weekly taxane regimens in the adjuvant setting and also for metastatic disease.

Trastuzumab administered every three weeks

Trastuzumab administered at longer intervals (every three weeks) and at three times the dose is being investigated. Brian Leyland-Jones presented data on paclitaxel with trastuzumab given every three weeks that demonstrated the trough did not go below the desirable level. In fact, the overall area under the curve and the peak concentration are higher without any additional toxicity. This may allow for the convenience of every-three-week administration.

I still, however, use weekly trastuzumab. I want a little more toxicity data. For many drugs, it is the peak level that actually mediates toxicity. That may not be the case with trastuzumab, but I would like a little longer follow-up, especially for cardiotoxicity.

Adjuvant trastuzumab

Whether it makes sense to use adjuvant trastuzumab in a woman whose odds of dying from breast cancer are less than the odds of dying from atherosclerotic heart disease is a big question. We do not know the answer yet. Therefore, adjuvant trastuzumab is being evaluated in high-risk women with node-positive disease, where the potential benefits might be at least proportionally larger.

It may be reasonable to use adjuvant trastuzumab off-protocol for a young woman with multiple (i.e., 15) positive nodes and HER2-positive disease, or for a young woman with HER2-positive, inflammatory breast cancer. Although I personally have not done that, I think it is sound medical judgment as long as the patient is informed of the potential toxicities.

Clinical implications of the ATAC trial results

The biggest change in breast cancer has been the advances in hormonal therapy. I was surprised, when the early results from the ATAC trial were reported, that the benefits with anastrozole were evident so early.

I think the data from the ATAC trial is very convincing. It is a huge trial with more than 9,000 patients, and it is very unlikely that the curves will change over time. However, I am not sure what the long-term toxicities will be. The data already suggests that there may be a higher risk of fracture in women on aromatase inhibitors.

Currently, my approach is to use tamoxifen for low-risk patients with nodenegative disease. In higher-risk patients (i.e., multiple positive nodes), I could probably make a case that, even with a small risk of osteoporosis, there is more to gain from an aromatase inhibitor. The benefits are proportional to the risks.

The final issue is the risk of tamoxifen. Tamoxifen is generally a safe drug, but in women over the age of 70, there is an excess risk of stroke. I think in women over the age of 70, I am also compelled to consider an aromatase inhibitor. Even in lower-risk women, my threshold for risk goes a little lower in those over the age of 70, mostly because of the risk of stroke.

In premenopausal women with multiple positive nodes, I would consider medical oophorectomy. In those types of patients, it might be reasonable to use an aromatase inhibitor. In premenopausal women with multiple positive nodes who stop menstruating after chemotherapy and have low estradiol levels, I would also consider an aromatase inhibitor.

Interchangeability of the aromatase inhibitors

In the adjuvant setting, I am currently using anastrozole, but I think the aromatase inhibitors are generally equivalent. At least, we have data on anastrozole. Soon, we will have data with some of the other aromatase inhibitors in the adjuvant setting.

Fulvestrant: Sequencing of hormones therapy in metastatic disease

Fulvestrant (Faslodex®) creates a dilemma, in that the pivotal trials were conducted in tamoxifen-refractory patients. Fulvestrant will be used in patients after an aromatase inhibitor, and there is no data on the efficacy of fulvestrant given after an aromatase inhibitor. How effective fulvestrant will be in women who have progressed on an aromatase inhibitor is the key question that needs to be answered.

Biologically speaking, fulvestrant removes the estrogen receptor. It is an estrogen-receptor downregulator. Once fulvestrant complexes with the estrogen receptor, the receptor is actually degraded. In contrast, the estrogen receptor and tamoxifen complex is translocated to the nucleus. The aromatase inhibitors basically remove estrogen, and fulvestrant removes the estrogen receptor. Therefore, nothing goes to the nucleus with either an aromatase inhibitor or fulvestrant.

In a woman who has relapsed on adjuvant tamoxifen and has never received an aromatase inhibitor, I would generally use an aromatase inhibitor. In this type of situation, fulvestrant was found to be roughly equivalent to an aromatase inhibitor, and the American trial suggested that the time to disease progression might actually be a little bit longer for fulvestrant. Since that was not the primary end point, I think we have to look at that information cautiously. Fulvestrant and the aromatase inhibitors, in my mind, really represent equivalent therapeutic choices.

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