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MEDICAL FRONTIERS San Antonio Breast Cancer Symposium

San Antonio, Texas / December 10-14, 2008

The potential practice-changing results of the Intergroup Exemestane Study (IES) emerged during patient accrual for the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial, a randomized, phase III clinical trial comparing exemestane (aromatase inhibitor or AI) and tamoxifen (selective estrogen receptor modulator or SERM) as adjuvant therapy for postmenopausal early stage breast cancer. The reduction in the risk of recurrence demonstrated with exemestane in IES necessitated a reassessment and amendment of the TEAM original trial design, indicated Dr. Stephen E. Jones, US Oncology Research, Houston, Texas.

As originally designed in 2001, TEAM compared five years of adjuvant hormonal therapy with tamoxifen or exemestane. The primary end point was disease-free survival (DFS) at five years. After IES demonstrated significant improvement in DFS in patients switched from tamoxifen to exemestane, TEAM investigators amended the protocol to make the trial a comparison of sequential therapy with 2.5 to three years of tamoxifen followed by exemestane for a total of five years vs. upfront exemestane continued for five years. Co-primary end points were DFS at 2.75 and five years.

TEAM involved 9,775 postmenopausal women with hormone receptor-positive breast cancer. All patients underwent curative surgery, followed by radiotherapy and/or chemotherapy, according to local clinical practice in the nine participating countries. Adjuvant hormonal therapy began within 10 weeks of surgery and/or chemotherapy. An intention-to-treat (ITT) analysis of DFS revealed a hazard ratio (HR) of 0.89; 95% CI, 0.77-1.03 in favour of upfront exemestane, although the difference did not quite achieve statistical significance (P=0.118). Analysis of relapse-free survival demonstrated a statistically significant 15% improvement in favour of upfront exemestane (HR 0.85; 95% CI, 0.72-1.00; P=0.05). Patients randomized to upfront exemestane also had significant prolongation of time to distance metastasis (HR 0.81, 95% CI, 0.67-0.98; P<0.03) (Figure 1).

Figure 1.

Investigators performed a per-protocol analysis using the on-study drug data prior to switch and excluding never-treated patients which showed a 17% improvement in DFS at 2.75 years significantly favouring exemestane over tamoxifen (HR=0.83; 95% CI, 0.71-
re 2).

Figure 2.

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“Overall, the event rate in both groups is quite low at this point in time, and I think that is good news for patients,” declared Dr. Jones. “Only 570 breast cancer events have occurred. Exemestane was associated with improvement in DFS, on-study drug DFS, relapse-free survival, and time to distant metastases.”

“No unexpected adverse events occurred with either treatment,” Dr. Jones told the audience. Patients treated with tamoxifen had significantly higher rates of gynecologic events, hot flushes and thromboembolic events. Patients in the AI group had more arthralgia, arthritis, reported osteoporosis and blood pressure elevations.

TEAM Substudies: Bone Health, Quality of Life, Neuropsychological Outcomes

Three substudies of the TEAM trial examined various lifestyle and quality-of-life issues in breast cancer patients. TEAM included an extensive evaluation of lifestyle factors and behaviours.

Dutch investigators presented findings from an assessment of physical activity with 543 TEAM participants. They found that physical activity decreased markedly in the first year after diagnosis of breast cancer, regardless of baseline activity level. The prediagnosis activity level averaged 51 metabolic equivalents (METs), decreasing to 43 METs during the first year after diagnosis. During the second year, physical activity partly recovered toward prediagnosis levels (mean METs 48).

Patients who managed to maintain relatively high prediagnosis activity levels had markedly better quality of life compared with women whose physical activity level declined, noted Dr. Janine van Nes, Netherlands Cancer Institute, Amsterdam. Patients who remained active scored higher on functional scales of physical, emotional, social, and global health, which correlated with a reduction in symptoms such as fatigue, dyspnea, and constipation.

Participants in the TEAM trial completed a substudy on a neuropsychological assessment at baseline and after one year of adjuvant endocrine therapy without chemotherapy. Results were compared with those of a matched healthy control group, according to Dr. Christien Schilder, Netherlands Cancer Institute.

Patients treated with tamoxifen performed significantly worse than controls on tests of verbal memory (P=0.006) and executive functioning (P=0.004). They also performed worse than exemestane users on a test of information processing speed (P=0.02). The treatment groups did not differ significantly from each other or the control group with respect to visual memory, working memory, verbal fluency, reaction speed, or motor speed.

Analysis of results by age showed that tamoxifen users <u><</u>65 performed significantly worse than health controls on executive functioning (P=0.014). Among patients older than 65, tamoxifen users performed significantly worse than health controls on verbal memory (P=0.003) and information processing speed (P=0.03). Moreover, older tamoxifen users also performed significantly worse than exemestane users with respect to information processing speed (P=0.005).

Separate analyses of TEAM and IES data focused on the relative bone effects of tamoxifen and exemestane. TEAM investigators assessed changes in bone mineral density (BMD) from baseline to 12 months. BMD and markers of bone turnover were assessed in a subgroup of 200 patients at baseline and after six and 12 months of adjuvant endocrine therapy; 161 patients were available for final analysis.

BMD decreased from baseline to 12 months in the exemestane patients, but the magnitude of the decrease was much smaller during months six to 12, reported Dr. Peyman Hadji, University of Marburg, Germany. Biomarkers of bone turnover increased in patients treated with exemestane and decreased in those treated with tamoxifen. The investigators concluded that 24-month data on BMD and bone turnover and data on fracture rate are needed to arrive at a definitive conclusion about the bone effects of the two endocrine therapies.

Reporting on behalf of the IES Study Group, Dr. Robert E. Coleman, Imperial College, London, UK, presented data from an analysis of bone effects from baseline, through two years of adjuvant hormonal treatment and two years of post-trial follow-up. The data showed that BMD decreased during treatment with exemestane but remained stable in tamoxifen-treated patients. At 24 months from the end of endocrine therapy, BMD had increased in the exemestane group but decreased in the tamoxifen patients.

Similar differences were observed for markers of bone turnover, which increased in the exemestane group during treatment and decreased after withdrawal of therapy. The opposite effects were observed in tamoxifen-treated patients. Additionally, fracture rates increased during treatment with exemestane but decreased substantially after withdrawal of therapy and returned to levels similar to those of the tamoxifen group.

With respect to BMD, Dr. Coleman and colleagues concluded, “In estrogen receptor-positive, postmenopausal early breast cancer, the overall risk-benefit clearly favours a tamoxifen-exemestane switch strategy over five years of tamoxifen.”

More Evidence of AI’s Role in Early Breast Cancer Treatment

A meta-analysis encompassing almost 20,000 patients with early breast cancer shed additional light on the relative benefits of AIs vs. tamoxifen as adjuvant hormonal therapy. Dr. James N. Ingle, Mayo Clinic, Rochester, Minnesota, presented results of two analyses: (1) trial comparisons of AIs and tamoxifen for five years upfront (cohort 1) and (2) trials evaluating two to three years of adjuvant tamoxifen followed by randomization to tamoxifen or to an AI for an additional two to three years (cohort 2).

The first analysis involved a total of 9,856 patients. Treatment with an AI upfront significantly reduced the risk of recurrence at five and eight years. At five years, tamoxifen- treated patients had a recurrence rate of 12.6% vs. 9.6% with AIs. By eight years, the between-group difference had increased: 19.2% with tamoxifen and 15.3% with AIs. The advantage in recurrence-free survival for AIs was highly significant (P<0.00001). Analysis of first recurrence by site demonstrated a consistent benefit for treatment with an AI.

Analysis of recurrence by treatment duration also favoured AIs, although the magnitude difference grew smaller over time, beginning with a HR of 0.67 for year 0 to 1 a
0.83 for five or more years of treatment (Table 1).

Table 1.

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The second analysis, comparing a switch from tamoxifen to an AI vs. continuation of tamoxifen, involved 9,015 patients. Similar to the head-to-head comparisons, the switch studies demonstrated a consistent advantage for AIs.

Cumulatively, patients switched to AIs had a recurrence rate of 5.0% at three years and 12.6% at six years, compared with 8.1% and 16.1% with tamoxifen (P<0.00001). Analysis by site of recurrence and duration of therapy also significantly favoured the AI switch strategy for every comparison.

“We analyzed the data by progesterone receptor status, age, nodal status, and tumour grade and found no significant heterogeneity, either globally or within any subset,” indicated Dr. Ingle. Life-table analysis of breast cancer mortality, death without recurrence, and death from any cause all demonstrated differences in favour of switching to an AI. For breast cancer mortality, switching to an AI was associated with a three-year gain of 0.7% and a six-year gain of 1.6% (P=0.02). The benefit for death without recurrence was 0.4% at three years and 0.7% at six years (P=0.08). The gain in overall survival (OS) also increased over time, from 1.1% at three years to 2.2% at six years (P=0.004) (Table 2). In conclusion, switching from tamoxifen to an AI offers a significant reduction in breast cancer mortality when compar
No survival advantage was observed in the AI upfront vs tamoxifen alone arm in this meta-analysis.

Table 2.

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CYP2D6 and Tamoxifen Metabolism

A report based on data from the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG-8) provided new insight into the phenomenon of tamoxifen resistance and the role of AIs in the treatment of breast cancer that has become resistant to tamoxifen.

Study lead investigator Dr. Matthew Goetz, Assistant Professor of Oncology and Pharmacology, Mayo Clinic, Rochester, presented findings from a retrospective analysis of pharmacogenetic and gene expression profiles of patients in ABCSG-8 and the profiles’ correlation with clinical outcomes.

Rationale for the analysis came from research showing that the CYP2D6 genotype strongly influences tamoxifen metabolism. Tamoxifen is metabolically converted to endoxifen, its active form, by cytochrome p450 2D6 (CYP2D6). In a separate report at the symposium, Dr. Goetz and colleagues showed that impaired CYP2D6 activity (conferred by CYP2D6 genotype *3, *4, and *6) increases the risk of breast cancer recurrence.

Analysis of the ABCSG-8 data showed that poor metabolizers accounted for 16% of recurrences in ABCSG-8, which involved almost 3,000 patients. However, switching such patients to an AI after two years of tamoxifen was not associated with an increased risk of recurrence.

On the basis of the findings, Dr. Goetz and colleagues recommended testing for CYP2D6 status in postmenopausal women being considered for adjuvant tamoxifen. Tamoxifen should be avoided in patients who have a poor-metabolizer genotype, they indicated. Moreover, the findings suggested that women already taking tamoxifen also should be tested for CYP2D6 status, and those with a poor-metabolizer genotype should be switched to an AI.

Summary

Now data from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial have shown that initiating adjuvant hormonal therapy with exemestane significantly improves on-study drug DFS when compared to tamoxifen alone. The role of AIs as adjuvant therapy for early breast cancer continues to evolve. They have demonstrated clinical benefit in comparison with tamoxifen. Also, switching from tamoxifen to an AI leads to improved DFS, and possibly to better survival that occurs early in the course of treatment. Studies that seek to explain the development of tamoxifen resistance may lead to new therapeutic options for women with early-stage breast cancer.