Expert Point of View: Michael Gnant, MD

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Clearly, decisions about extended treatment will now be individualized.
— Michael Gnant, MD

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Michael Gnant, MD, Professor of Surgery at the Medical University of Vienna in Austria and President of the Austrian Breast & Colorectal Cancer Study Group, was the invited discussant of the three studies of extended endocrine therapy. “The trials did not reach the necessary statistical levels to demonstrate a clear benefit for aromatase inhibition extension,” he commented. “Extending aromatase inhibitor therapy may be a good idea for many patients after 2 to 5 years of tamoxifen, but after initial treatment with an aromatase inhibitor, the benefits and risks must be carefully balanced on an individual basis. We are going to need the ‘art of medicine’ here.”

Dr. Gnant began his discussion by emphasizing the need to evaluate the benefit of extended endocrine therapy. “At least 50% of relapses with hormone receptor–positive breast cancer occur after the first 5 years of treatment. Since the risk persists long term, extending adjuvant therapy is obviously a compelling concept,” he said.

B-42 and MA.17R Trials

All first-generation adjuvant extended therapy trials investigated the use of aromatase inhibitors after 5 years of tamoxifen, and all showed benefits, but those trials did not answer this question: “Should we also use extended aromatase inhibitors after an aromatase inhibitor was already used as initial adjuvant therapy?” he said. “That’s why B-42 is so important.”

B-42 was similar to MA.17R in structure, except that patients were randomized after 5 years of an aromatase inhibitor, rather than after tamoxifen, as was done in MA.17R, he pointed out.

“The hazard ratio of 0.85 for the primary endpoint reflects what is technically a nonsignificant relative improvement, and this was based on a difference of just 47 events in a 4,000-patient trial. Eventually, this modest difference translated into a 3.4% absolute progression-free survival difference at 7 years, without any difference in overall survival. Surely there will be debate as to whether this is clinically relevant,” Dr. Gnant said.

The “more optimistic” perspective, he added, is that extended treatment reduced contralateral disease in MA.17R and distant relapses in B-42, with curves diverging after 4 years.

IDEAL and DATA Trials

He also suggested that, based on the IDEAL and DATA findings, there may be some benefit to extended endocrine therapy when tamoxifen is the initial treatment. In DATA, the initial therapy was tamoxifen, whereas in IDEAL, patients received tamoxifen, an aromatase inhibitor, or tamoxifen followed by an aromatase inhibitor.

“Both are technically negative in their primary endpoint analysis,” he said, although extended treatment after initial tamoxifen produced a 21% nonsignificant relative progression-free survival benefit. “Since these trials are otherwise comparable, this adds to the notion that longer duration of an aromatase inhibitor may mainly benefit patients who started on tamoxifen.”

IDEAL and DATA exploratory subgroup analyses also suggest that patients with high-risk features may benefit the most and that tumors expressing both hormone receptors may drive the benefits. Genomic classifiers could eventually prove helpful in selecting patients, he said.

Any benefit from extended aromatase inhibitor therapy, however, comes at a price, Dr. Gnant emphasized. “There was striking similarity in the three trials—the constant decline in treatment adherence,” he pointed out. “Just 55% to 65% of patients were still on their medications after 5 years. We all know that arthralgias, myalgias, bone pain, and hot flashes are frequent with aromatase inhibitors, and compliance is likely to be even poorer outside of clinical trials…. There is also likely to be a positive selection of patients in the trials who are already tolerating the drugs reasonably well.”

Treatment Approach

Based on these findings, he called for “careful assessment of the potential risks and benefits before recommending extended treatment…. Clearly, decisions about extended treatment will now be individualized.”

To Dr. Gnant, this means that patients initially treated with tamoxifen could receive an aromatase inhibitor, unless there are contraindications, such as poor bone health. The more complex scenario is for the patient who receives initial or sequential aromatase inhibitor therapy. “There are factors favoring extension and others that speak against it,” he said.

When considering extended treatment, he starts with patient characteristics. “In reality, the main trigger for this decision is how the individual patient tolerated treatment in the first years,” he said. “Given the real risk for fractures, bone health is important and should be prominently considered. Younger age (long life expectancy) is a factor. And classical risk factors as well as tumor luminality have been proposed as factors favoring extension. Whether we use genomic assays is undecided at this point.”

Weighing against extension is the treatment burden the patient has already experienced. “Some patients actually count down the weeks and days until they can stop. It is unlikely we can convince them to go on extended treatment, except in cases of exceptional risk,” he said. Patients deemed at low risk for recurrence, according to clinical and genomic assessments, are probably also not candidates for extended treatment.

In conclusion, Dr. Gnant called for a better understanding of “the mystery of chronic residual risk.” He suggested, “We simply need new concepts, such as directly targeting stem cells to eliminate the source of late metastases for good, to attack the chronic part of luminal breast cancer recurrence risk. Attacking the enemy with our ordinary drugs apparently will not cure all patients.” ■

Disclosure: Dr. Gnant has received honoraria from Roche, Novartis, AstraZeneca, Celgene, and GSK; research funding from AstraZeneca, Novartis, Roche, and Pfizer; and travel/accommodation expenses from Celgene, AstraZeneca, Novartis, Pfizer, and Eisai. He has had a consulting/advisory role with Accelsiors, and a member of his immediate family is employed by Sandoz.

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