Adjuvant aromatase inhibitors

Hormonal therapy is the single most important and effective therapy we have for breast cancer, so any advance in that area will improve patient outcome. The current aromatase inhibitor trials in postmenopausal women demonstrate approximately a 25 to 50 percent relative reduction in the risk of recurrence compared to tamoxifen, which translates into a two to five percent absolute difference in overall events, including local and distant recurrences and new contralateral cancers.

In postmenopausal patients, when using an aromatase inhibitor, I base my selection on the current clinical research data. For example, in a patient presenting for initial adjuvant hormone therapy, I use anastrozole based on the ATAC trial, but if the patient has completed five years of adjuvant tamoxifen, I select letrozole based on the data from Goss and colleagues’ MA17 trial. In patients who have completed only two or three years of tamoxifen, I choose exemestane based on the Intergroup exemestane study, but one could also use anastrozole based on Boccardo’s data.

It’s ideal to have several choices for tolerability, but I believe in time we’ll find the aromatase inhibitors are interchangeable. I’ve definitely seen cases in which patients with musculoskeletal complaints have noted improvement when switched to a different agent. I also believe it’s reasonable to use an aromatase inhibitor in patients who have been off adjuvant tamoxifen for a couple of years. We don’t have data on this, but we have to extrapolate from what we know, and the bottom line is that these patients are still at risk for recurrent breast cancer.

Tolerability of aromatase inhibitors versus tamoxifen in the adjuvant setting

All of the studies comparing adjuvant aromatase inhibitors to tamoxifen are reporting compositely better tolerability with the aromatase inhibitors. The side effects of vaginal discharge, vaginal bleeding, hot flashes and uterine cancer are more common with tamoxifen, while arthralgias and myalgias are more common with aromatase inhibitors. As women become older — late sixties, seventies, and eighties — the risk of deep-vein thrombosis and stroke in women on tamoxifen becomes significant, and this is clearly not observed with aromatase inhibitors.

Osteoporosis and fractures are a concern with aromatase inhibitors, and I recommend using bisphosphonates, as we would in patients not taking these agents. I believe it’s important to obtain a baseline bone mineral density, more for long-term management rather than to make an initial decision. I counsel patients with very low bone mineral density differently based on their age, but by the early seventies the cardiovascular risk with tamoxifen is significant, and some risk of osteoporosis might be acceptable.

None of the current trials are giving patients calcium supplementation. I believe we can reduce the bone density concern by recommending calcium and vitamin E for all patients, and using bisphosphonates a little earlier than we might in patients not on aromatase inhibitors.

Clinical trials of adjuvant trastuzumab

Approximately 20 percent of women with breast cancer have HER-positive tumors by gene amplification. Trastuzumab is a proven, active agent in this population. In metastatic disease, trastuzumab has clearly shown a benefit in survival and response rates in patients with HER2-positive tumors. Adding trastuzumab to chemotherapy — particularly the taxanes although probably other agents as well — improves outcome. The adjuvant studies are the next logical step, and I predict we will see a five to seven percent reduction in recurrence at five years and an impact on disease-free survival in the adjuvant setting.

The ongoing adjuvant trastuzumab trials are limited to patients with node-positive or high-risk, node-negative disease because the expected benefit must outweigh the known three to five percent short-term risk of cardiotoxicity associated with trastuzumab. The most common design is doxorubicin combined with cyclophosphamide followed by a taxane with or without trastuzumab.

One study also includes a carboplatin in combination with docetaxel arm because of the synergy seen in vitro and the possibility that omitting the anthracycline may mitigate cardiotoxicity. These studies have approximately 3,000 to 5,000 patients and are designed to detect small variations in outcome — approximately a five percent difference in recurrence and possibly a two percent survival benefit.

The adjuvant trials are evaluating one year of trastuzumab therapy, except for the European HERA study that randomly assigns patients to observation, one year or two years of trastuzumab. The natural history of breast cancer suggests that longer-term biological therapy is more beneficial, so I believe more than one year of trastuzumab will be necessary for optimal effect.

Adjuvant trastuzumab off protocol

I don’t believe adjuvant trastuzumab should be used off protocol because we don’t know that the benefit will outweigh short- and long-term toxicities; however, in some situations, a well-informed patient could be offered trastuzumab after extensive discussion.

On the other hand, off-protocol neoadjuvant trastuzumab may be appropriate in patients with locally advanced disease or borderline resectable disease. The FDA indicates it’s reasonable to use trastuzumab in unresectable disease that is unresponsive to other therapies, so it then becomes a matter of judgment. Is this tumor resectable? Is it localized? Can I achieve negative margins? If the disease is extensive enough that the margins might be a problem and the patient is not responding to AC/paclitaxel, using trastuzumab with paclitaxel might be reasonable. We know the odds of recurrence are higher in such a patient, so the potential benefit is greater.

Response from neoadjuvant trastuzumab

Neoadjuvant studies are attractive because we can look at both clinical and tissue markers of response. In a study conducted at Baylor, patients received weekly trastuzumab for three weeks, followed by trastuzumab and docetaxel for 12 weeks prior to surgery. Interestingly, every patient experienced a reduction in tumor size after just three weeks of trastuzumab alone, and biopsies performed before and after single-agent trastuzumab showed apoptosis, which seemed to be a marker of clinical response.

We have always known patients respond better in the neoadjuvant setting than in the metastatic setting. Neoadjuvant chemotherapy response rates of 80 percent are common, whereas response rates of only 30 to 40 percent are seen in the metastatic setting, so it’s no surprise to see clinical responses to preoperative, single-agent trastuzumab. Still, it’s a little surprising to see the responses occur so quickly.

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Dr Tripathy is a Professor of Medicine and Director of the Komen UT Southwestern Breast Cancer Research Program at the University of Texas Southwestern Medical Center in Dallas, Texas.

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