ASCO GUIDELINESS FOR ADJUVANT HORMONAL THERAPY IN BREAST CANCER UPDATED

July 16, 2010 — An update to the clinical practice guidelines on the use of endocrine therapy for women with hormone-receptor-positive breast cancer from the American Cancer of Clinical Oncology (ASCO) was published online July 12 in the Journal of Clinical Oncology.

Postmenopausal women with hormone-receptor-positive breast cancer should "consider incorporating aromatase inhibitor (AI) therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen," the latest update recommends.

The conclusion is similar to what was recommended when the guidelines were last updated, in 2004, but that document was based essentially on expert opinion, whereas the new update is evidence-based, lead author Harold Burstein, MD, PhD, from the Dana-Farber Cancer institute, in Boston, Massachusetts, told Medscape Medical News.

The methodology for compiling guidelines has evolved and is now radically different, he explained. In the intervening years, several major clinical trials have been published, and "we conducted an exhaustive methodological review of the data."

"So now we can say with some certainty" that the 2 approaches — of using an AI up-front or sequentially after tamoxifen — are equally efficacious, both in improving disease-free survival and overall survival," he said. "This is new, and patients should feel very comfortable that this is supported by evidence," he added.

Also new are the detailed data on adverse effects associated with AIs, because "we have learned so much more about this," he said. This includes new data on osteoporosis and osteoporotic fracture, on the newly recognized syndrome of bone and joint stiffness, which is unique to AIs, and on hypertension and hypercholesterolemia, which occur to a greater extent than was previously recognized. "These are new and important observations," he added.

The third new point in the update is that all 3 of the commercially available AIs — anastrozole, exemestane, and letrozole — are clinically the same, he said.

"To a first-order approximation, all of these aromatase inhibitors are interchangeable," Dr. Burstein said.

"This may be very relevant," he added, because one of these drug — anastrozole — has just become available as a generic in the United States, as reported by Medscape Medical News.

There is also an increasing appreciation, from the data now accumulated, that the actual benefits of AIs on long term-outcomes, compared with tamoxifen, "are small at best." Most of the clinical trial data have not shown a major survival advantage for AIs over tamoxifen, and "I think that this context is also important as doctors and patients make their decisions on which drug strategy to pursue."

Many Different Options

Endocrine adjuvant therapy is used in hormone-receptor-positive breast cancer after other treatments to reduce the risk for relapse, and the drug options include tamoxifen and AIs. However, AIs are effective only in postmenopausal women, so the guidelines recommend that women who are premenopausal or perimenopausal at diagnosis should be treated with tamoxifen for 5 years; they also note that tamoxifen remains the standard option for men with breast cancer.

For postmenopausal women, the guidelines state that AIs should be used, but how they are used is left open, and several different approaches are outlined:

* AIs can be used as primary therapy or after 2 or 3 years of tamoxifen; both of these strategies yield equivalent outcomes.
* Treatment with an AI should not exceed 5 years.
* Sequential therapy can comprise 2 to 3 years of tamoxifen followed by an AI for a total of 5 years, or an initial AI followed by tamoxifen for a total of 5 years.
* The best time for switching from one to another is not known, but switching at 2 to 3 years is recommended.
* There is also an option for extended therapy with tamoxifen for 5 years followed by an AI; switching at 5 years is also supported by available data.

However, the guidelines note that "the optimal timing and duration of endocrine treatment remain unresolved."

There are no specific markers or clinical subsets to indicate which women will benefit most from an AI or tamoxifen alone, or from a sequential therapy with both drugs. Testing for the CYP2D6 genotype to choose therapy is not recommended (although this is being done at some centers, including the Mayo Clinic). However, caution is recommended with the concurrent use of drugs than inhibit CYP2D6 (such as paroxetine and fluoxetine) in women taking tamoxifen because of drug–drug interactions (a list of drugs to avoid was published recently).

As Dr. Burstein highlighted, the new guidelines state that there are no meaningful clinical differences between the 3 commercially available AIs. They add that there is no evidence that AIs are less toxic or better tolerated than tamoxifen, and no obvious clinical advantages of any one AI over another.

Adverse effects and patient preferences should be taken into consideration in deciding whether and when to incorporate AI therapy, the document states.

Problems With Compliance

Patient compliance is a huge problem with endocrine adjuvant therapy for breast cancer — a recent study found that only half of women complete the therapy. Discontinuation on tamoxifen has been widely reported, but new data suggest that "persistence is no better with AIs," the panel of experts note.

"Physicians may underestimate the rate of nonadherence and nonpersistence," they add. One of the main reasons for discontinuation is adverse effects, so "information support for patients about anticipated adverse effects and management of those adverse effects may increase persistence," they explain.

Another reason could be financial constraints. "While physicians are generally reluctant to discuss costs of cancer therapies, inquiring about patients' cost concerns may help direct patients to assistance programs and create opportunities to stress the benefits of persistence with adjuvant endocrine therapy," the panel points out.

A PDF of the guideline update and a set of slides summarizing the main points are available on the ASCO Web site.

Several of the authors report relevant financial relationships, as follows: Jennifer Malin reports acting as a consultant to Pfizer; Eleftherios Mamounas reports acting as a consultant for and receiving honoraria from Novartis and Pfizer; Karen Gelmon reports receiving honoraria from Novartis, AstraZeneca, and Pfizer; and Vered Stearns reports receiving honoraria from AstraZeneca and research funding from Novartis and Pfizer.

J Clin Oncol. Published online July 12, 2010. Abstract