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PRIORITY PRESS - 15th European Cancer Conference (ECCO) and 34th ESMO Multidisciplinary Congress

Berlin, Germany / September 20-24, 2009

Eighty per cent of all postmenopausal breast cancer is hormone receptor-positive (HR+). Thus, in the adjuvant setting, tamoxifen therapy is virtually always recommended as it is associated with significantly lower rates of recurrence and mortality than control arms. In recent years, aromatase inhibitors (AIs) have been shown to be more effective than standard anti-estrogen therapy and they are now considered a viable alternative in the setting of HR+ breast cancer.

Results from the longest follow-up of endocrine therapy in the adjuvant breast cancer setting have shown that switching to the aromatase inhibitor (AI) exemestane after two to three years of tamoxifen significantly reduced disease-free survival (DFS) events as well as the relative risk of death in postmenopausal women with early breast cancer.

The Intergroup Exemestane Study (IES) was a landmark trial in which 4724 patients were either switched to an AI after being on tamoxifen for two to three years or who were randomized to remain on tamoxifen. Virtually identical numbers of patients were randomized to either arm, and treatment was continued for an additional two to three years. Over 85% of women in the IES were estrogen receptor-positive (ER+), while approximately 11% were of unknown receptor status and 2.6% of women were ER-negative (ER-). It is well established that ER- patients derive no benefit from hormonal therapy.

Slightly over half of patients in IES were node-negative, while one-third of patients received adjuvant chemotherapy. The primary end point was DFS, defined as time from randomization to recurrence of breast cancer at any site, second primary breast cancer or death from any cause.

After a total treatment interval of five years, switching the intent-to-treat (ITT) population to the AI led to a 16% reduction in DFS events at a median follow-up of 91 months compared with staying on tamoxifen (P=0.002). Among ER+ patients and in patients whose receptor status was unknown, there was an 18% reduction in the risk of DFS events in favour of the switch arm (P=0.0009) for an absolute difference of 3% in DFS event rates between the two arms, reported Prof. Charles Coombes, Head of Oncology, Imperial College, London, UK, and principal investigator of the IES. There were 373 deaths in the AI arm vs. 420 deaths in the tamoxifen arm after more than eight years of follow-up; the majority of the reductions in deaths seen were due to breast cancer, he observed.

For the secondary end point of overall survival, there was an 11% relative risk reduction in death in favour of the AI switch arm. This increased to a statistically significant 14% reduction in the risk of death in the ER+/unknown population (P=0.04).

“There was no subset of patients who did not benefit from AI therapy,” Prof. Coombes stated, “and these findings are important to patients and physicians alike as they reaffirm their confidence in switching to exemestane after two to three years of tamoxifen.”

Safety Profile

At a median follow-up of 91 months, the safety profile of exemestane in IES was similar to that previously reported at 55.7 months of follow-up. Importantly, Prof. Coombes observed that rates of cardiac death and death from vascular causes were not different between the two arms, although patients switched to the AI tended to develop more hypertension than patients who remained on tamoxifen.

As previously observed, thromboembolic events were more common in the tamoxifen arm but rates of musculoskeletal pain, arthralgia, osteoporosis and fracture were higher in the AI arm, although once off therapy, the incidence of all musculoskeletal symptoms tended to return to normal, Prof. Coombes noted. The risk of muscle cramps was higher among women who remained on tamoxifen. Carpel tunnel syndrome was more common when women were switched to the AI but this, too, was likely to return to normal once women were off treatment.

As Prof. Coombes suggested, women should be informed that treatment with exemestane can cause carpel tunnel syndrome as they often do not attribute the syndrome to treatment. They can then weigh for themselves the risks and benefits of undergoing surgery while remaining on the AI.

Gynecological symptoms were all less frequent in switch patients. “The AIs have been extensively tested in postmenopausal HR+ breast cancer and there is clear evidence that they are more effective than tamoxifen,” commented Dr. Robert Coleman, Professor of Medical Oncology, University of Sheffield, UK. Compared to many other treatments used to treat cancer, “both of these agents were extremely well tolerated and there was no difference in discontinuation rates between the two arms.”

He added that patients should be counselled to take calcium and vitamin D during treatment with an AI and bisphosphonates should be prescribed if low BMD scores warrant their initiation.

Hormone Therapy Options

According to Prof. Christos Markopoulos, Associate Professor of Surgery, Athens University Medical School, Greece, “Clearly now, we have four options for hormonal therapy.” Patients with ER+ disease can be started on either tamoxifen or an AI and remain on the same therapy for five years, or they can be switched to an AI after having received tamoxifen for two to three years, as was the protocol in the IES. They may also be treated with tamoxifen for five years, and then an AI for another four to five years.

Over the past 10 years, evidence has emerged in favour of each of these options, he noted. “The only way to decide how we are going to treat our patients depends on the time we come across them.”

In contrast to AI therapy, an initial two years on tamoxifen can also have a favourable effect on BMD as well as lipids, both desirable effects in an older female population. The rationale for switching patients to an AI after two to three years of tamoxifen can be justified based on good evidence that this strategy is scientifically sound, as results from IES showed.

In addition, after about two years of tamoxifen, “we know that we have little [remaining] benefit in terms of disease outcome and we might increase side effects,” Prof. Markopoulos told delegates.

He concluded, “Patients are very well informed nowadays and I believe we have to explain the results of the IES to our patients and make the final decision together.”

Summary

There is now sound evidence that switching postmenopausal women with ER+ early breast cancer to exemestane after two to three years on tamoxifen continues to exert a protective effect over tamoxifen some 91 months after initiation of treatment. Serious side effects are rare with both agents, and the switch strategy appears to minimize the risk of adverse events as well. Physicians therefore have an obligation to discuss the IES results with women who are candidates for hormonal therapy.

<a href="http://cmwebcast.covr.be/presentations/ECCO15/5339/default.aspx" target="_blank">To view the webcast of Prof. Charles Coombes’ IES six-year results presentation from the 2009 ECCO-ESMO congress, please click here </a>