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6th European Breast Cancer Conference

Berlin, Germany / April 15-19, 2008

Dr. Michael Gnant, Professor of Surgery, Medical University of Vienna, and President, Austrian Breast and Colorectal Cancer Study Group, considers that in general, “Optimal endocrine treatment of patients with endocrine-responsive disease should include an aromatase inhibitor (AI) as initial treatment or after treatment with tamoxifen.”

Case Study

In a series of interactive clinical case reports, he presented that of a 60-year-old postmenopausal woman who had undergone sentinel node mapping and breast-conserving surgery. She had grade II infiltrating ductal carcinoma, no vascular or lymphatic channel invasion and a 1.6-cm tumour with clear surgical margins. Histology was T1c. Her status was 70% estrogen receptor (ER)-positive, 40% progesterone receptor (PR)-positive, Ki-67 staining index of 12, HER2 fluorescence in situ hybridization (FISH)-negative and one out of 12 axillary nodes were found to be positive following dissection. The woman’s medical history included hormone replacement therapy for four years following menopause. She was submitted to radiation therapy, six cycles of epirubicin and cyclophosphamide followed by tamoxifen.

Although 52% of the audience suggested that risk of recurrence was 15%, Dr. Gnant noted it was actually 34%. “We should not underestimate the risk of recurrence at 10 years for this woman with surgery and local radiotherapy alone,” he remarked. “While we are happy that the prognosis of breast cancer has improved recently, we tend to underestimate the long-term risk of our endocrine-responsive patients.” Treatment consisted of adjuvant tamoxifen for a proposed period of five years.

Dr. Gnant asked delegates: after two years of uninterrupted tamoxifen, what would be the optimal policy for continuing her adjuvant endocrine therapy? To continue tamoxifen for a total of five years, switch to an AI and continue for three years, or to complete the five years of tamoxifen and recommend continuing with an AI for an additional five years? The audience voted 81% in favour of switching to an AI and continuing for three years. Agreeing with those opinions, Dr. Gnant noted that only 4% of the voters were in favour of giving the full five years of tamoxifen to this patient. While it is well known that tamoxifen’s effectiveness decreases over time, the patient is still at risk of recurrence after two years and when it does, it would most likely be distant disease.

Towards a Consensus: An Evidence-based View

At its consensus meeting in March, the St. Gallen oncology group had expressed a clear preference for switching from tamoxifen to an AI after two to three years, with a substantial minority also supporting an initial use of an AI. Very few were in favour of a prospective policy of five years of tamoxifen followed by an AI. For patients completing five years of tamoxifen, the majority of the panel supported the addition of an AI only for patients with node-positive disease. Initial AI was more acceptable in patients at higher risk or with HER2-positive breast cancer.

Intergroup Exemestane Study Findings

There are switching trials which show benefits from replacing tamoxifen with an AI, the largest and most robust of which is the Intergroup Exemestane Study (IES), Dr. Gnant noted. In that multicentre trial, breast cancer patients were randomized, following two to three years of tamoxifen treatment, to either switching to exemestane (n=2362) or completing their five-year tamoxifen regimen (n=2380). The primary end point was disease-free survival (DFS).

After a median follow-up of 4.8 years, women who switched to exemestane had a 15% lower risk of dying than those who continued to take tamoxifen. They also had a 24% lower risk of breast cancer recurrence or of dying from an illness other than breast cancer. In addition, the AI-treated group had a 44% lower risk of developing cancer in the contralateral breast and their risk of metastases fell by 17%. Of the 449 first events reported (local or metastatic recurrence, contralateral breast cancer, or death), 183 occurred in the AI-treated group and 266 in the tamoxifen group. All these findings were statistically significant in favour of the AI. Regarding the primary end point of the study, exemestane achieved an absolute benefit in DFS of 4.7%, although overall survival did not significantly differ between the groups. A substudy of 582 women in the IES found no significant difference in quality-of-life measures between the treatment populations, indicating that the clinical benefits of exemestane over tamoxifen are achieved without significant detrimental effect on daily living.

Dr. Dirk G. Kieback, Head, Department of Obstetrics/Gynecology, Helios Klinikum, Aue, Germany, who studied endometrial safety of crossover treatment, reported that the steroidal AI exemestane does not induce endometrial hyperplasia thicker than 10 mm in up to two years of treatment. He followed 159 postmenopausal women with ER-positive breast cancer for that period after they were either switched to exemestane 25 mg/day after about two years or continued on tamoxifen 20 mg/day.

He reported that 65 patients were available for analysis in the tamoxifen arm and 78 in the AI-treated arm. In the median follow-up period, there were no findings of endometrial hyperplasia >10 mm in the exemestane patients (727 days) compared to 11 with tamoxifen (526 days) (P<0.0001). Hyperplasia >5 mm occurred in 11 AI-treated women vs. 34 tamoxifen-treated patients (P<0.006).

“In total, endometrial hyperplasia was observed 11 times in the exemestane patients and 45 times in the tamoxifen arm (P<0.0001),” Dr. Kieback reported. “Time to endometrial hyperplasia was significantly longer in the exemestane group (P<0.0001); the hazard ratio was 0.16, indicating an 84% risk reduction of hyperplasia among exemestane patients. Increase in endometrial thickness from baseline to six months was 2.94 mm [exemestane] vs. 5.41 mm [tamoxifen]; from baseline to 12 months, it was 2.64 mm vs. 6.0 mm, respectively (P<0.0006). Only one patient underwent histologic sampling in the exemestane group (no hyperplasia) vs. 18 in the tamoxifen subset.”

According to Dr. Kieback, exemestane leads to markedly fewer diagnostic surgical interventions, thereby increasing patient safety and comfort as well as saving health care costs.

Data from postmenopausal women with advanced disease indicate that steroidal and nonsteroidal AIs have similar tolerability profiles; however, emerging data suggest that there may be differences in their effects on end organs, which may become evident in longer-term use. Steroidal agents appear to have beneficial effects on lipid and bone metabolism, whereas nonsteroidal agents may have neutral or unfavourable effects. The differences may be attributable to the androgenic effects of steroidal agents. Some women who experience failure on one type of AI may subsequently derive benefits from the other type. The reason for this lack of cross-resistance is unknown.

Postmenopausal Status

One difficulty in optimizing the clinical outcome of a perimenopausal breast cancer patient with grade III infiltrating ductal carcinoma undergoing adjuvant endocrine therapy is to accurately determine her current menopausal status, stated Dr. Walter Jonat, Director, Gynecology and Maternity Unit, Kiel University Hospital, Germany.

In another interactive clinical case report, he described a 47-year-old woman with breast cancer diagnosed two years previously. Tumour size was 2.3 cm, 70% ER-positive, 40% PR-positive, HER2-negative, and two out of 12 nodes were positive for metastatic carcinoma. She became amenorrheic near the completion of chemotherapy and is now completing two years of tamoxifen.

In this case, the problem is determining if the patient was really postmenopausal. If amenorrheic after two years of tamoxifen, should one assume she is postmenopausal, without evaluation? Twelve per cent of the delegates were not sure how postmenopausal status should be determined in this clinical setting. The majority (78%) would check serial FSH and estradiol levels to be certain that they were within the postmenopausal range. Dr. Jonat confirmed that it would be the right course to follow.

For this woman who has completed two years with adjuvant tamoxifen, 16% of the audience recommended completion of the five-year course of tamoxifen, 59% thought it was best to switch from tamoxifen to an AI for three years, and 25% would choose to give tamoxifen for three additional years to be followed by an AI for five years. “So 41% said to continue tamoxifen,” Dr. Jonat remarked. “The other 59% must be very sure that the woman is postmenopausal.”

Summary

Five years of tamoxifen has been a longstanding strategy for postmenopausal women with primary ER-positive breast cancer. Recent advances in breast cancer therapy have increased the chances of survival and improved quality of life. The IES results indicate the AI exemestane significantly improves DFS after two to three years of tamoxifen compared to continuous tamoxifen administration for five years. Benefits of switching postmenopausal women with ER-positive breast cancer include fewer local or metastatic recurrences, less contralateral breast and endometrial cancer and improved overall survival, and no deleterious effects on quality of life.