Reports

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30th Annual San Antonio Breast Cancer Symposium

San Antonio, Texas / December 13-16, 2007

The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial (ATAC Trialists’ Group. Lancet 2005; 365:60-2) represented a challenge to the long-time standard of care—five years of tamoxifen—for hormone receptor-positive localized breast cancer.

The trial involved over nine thousand (N=9366) postmenopausal women who were randomized to the aromatase inhibitor (AI) anastrozole, tamoxifen or the combination of the two hormonal therapies for five years of treatment. The primary end point was disease-free survival. After an interim analysis showed the combination to be no more effective than either agent alone, the combination arm was discontinued.

At a median follow-up of 68 months of the hormone receptor-positive cohort (84% of the study population), the data showed that compared to tamoxifen, the AI improved disease-free survival (hazard ratio [HR] 0.83, P=0.005); prolonged time to recurrence (HR 0.74, P=0.0002); and reduced the risk of distant metastases (HR 0.84, P=0.022) and of contralateral breast cancer (26 vs. 53, P=0.004).

Fewer patients withdrew from the AI arm, which was associated with significantly fewer serious adverse events, including venous thromboembolisms (VTEs), ischemic cerebrovascular events and endometrial cancer. The findings led the ATAC investigators to conclude, “Anastrozole should be the preferred initial treatment for postmenopausal women with localized hormone receptor-positive breast cancer.”

Long-term Benefits

Although the five-year results demonstrated a clear advantage for the AI, several questions remained unanswered, including the issue of how long treatment effects and side effects persist after therapy ends. The 100-month follow-up data from ATAC answered that question by showing that anastrozole’s advantages over tamoxifen were still in evidence and, in some instances, had increased over time.

At a median of 40 months after discontinuation of therapy, AI-treated patients had a HR of 0.85 for disease-free survival compared with tamoxifen patients (P=0.003), reported Dr. John Forbes, University of Newcastle, Australia. The difference represented further improvement with anastrozole since the end of randomized therapy.

“The absolute difference between the two arms in the proportion of women who relapsed almost doubled in the four years after treatment ended, from 2.8% to 4.8%,” Dr. Forbes told delegates. “This is the first demonstration of a carryover effect [with an AI].”

Focusing on years 5 through 9 of the ATAC trial, after discontinuation of therapy, the AI reduced the risk of recurrence by 25%, reflected in a HR of 0.75 vs. tamoxifen (P=0.01) (Figure 1).

Figure 1. Time to Recurrence (HR+ Patients)

Other statistically significant differences favouring anastrozole included time to recurrence (HR 0.76, P=0.0001); time to distant recurrence (HR 0.84, P=0.022); and contralateral breast cancer (HR 0.60, P=0.004).

The improvement in time to distant recurrence occurred only after discontinuation of therapy, providing further evidence of a carryover effect of anastrozole treatment, Dr. Forbes confirmed.

The 68-month follow-up data showed a significantly higher fracture risk in anastrozole-treated patients. That difference disappeared in the 100-month analysis (146 events with anastrozole vs. 143 with tamoxifen; HR 1.03, P=0.79).

“These data show long-term safety and establish clearly the long-term efficacy of anastrozole compared with tamoxifen as initial adjuvant treatment for postmenopausal women with hormone-sensitive, early breast cancer,” Dr. Forbes concluded. “The data provide statistically significant evidence of a larger carryover effect after five years of adjuvant treatment with anastrozole compared with tamoxifen.”

Other data presented at the San Antonio meeting provided additional evidence of the AI’s safety and efficacy as adjuvant therapy for women with hormone-sensitive breast cancer.

Aromatase Inhibition and Bone Loss: SABRE 12-month Data

Aromatase inhibitors have a class-wide accelerated effect on loss of bone mineral density (BMD) compared with tamoxifen. Whether concomitant treatment with a bisphosphonate would slow or prevent AI-associated loss in bone mineral had not been examined closely. Twelve-month follow-up data from the Study of Anastrozole with the Bisphosphonate Risedronate (SABRE) provided reassurance in that respect.

SABRE is an ongoing international phase III/IV trial evaluating the effects of the AI with and without concomitant risedronate on bone health in postmenopausal women with early-stage, hormone-responsive breast cancer. The trial involves 234 patients who are being treated with open-label anastrozole, some of whom have also been randomized to risedronate or placebo. The patient population comprises 38 women who are at high risk for fragility fracture, 42 at low risk and 154 at moderate risk, explained Dr. Catherine Van Poznak, University of Michigan, Ann Arbor.

High-risk patients received anastrozole plus risedronate, and low-risk patients received AI monotherapy. Women in the moderate-risk stratum were randomized to receive risedronate or placebo in addition to anastrozole.

The primary end point of SABRE is BMD of the lumbar spine. The 12-month results showed a statistically significant increase in lumbar spine BMD (P<0.001) in high-risk patients and in moderate-risk patients treated concomitantly with the AI and the bisphosphonate (P<0.001). Low-risk patients had a nonsignificant change in lumbar BMD at 12 months. Changes in total hip BMD (the secondary end point) mirrored those of the lumbar spine, reported Dr. Van Poznak.

Analysis of bone-turnover markers showed that AI plus risedronate significantly decreased levels of the markers compared with anastrozole alone in moderate-risk patients (P<0.0001). High-risk patients also had a significant decrease in markers (P=0.004 to P<0.0001), whereas low-risk patients had increased levels of bone-turnover markers.

Another objective of SABRE is to examine the effect of aromatase inhibition on lipid levels. The 12-month analysis showed a small decrease in LDL-C from baseline in patients treated with anastrozole alone or in combination with risedronate. The difference was statistically significant in patients treated with AI monotherapy (-5.4%, P=0.0007). HDL-C increased significantly in the intent-to-treat analysis (6.75%, P<0.0001) and in patients who had a normal lipid profile at baseline (6.85%, P=0.0016). Triglycerides and total cholesterol did not change significantly.

“In postmenopausal women with breast cancer receiving adjuvant anastrozole and who are already at moderate or high risk of fragility fracture, BMD can be managed with risedronate and bone health can be managed according to established guidelines without any detrimental effects on lipid profiles,” Dr. Van Poznak concluded.

Preserving Bone Health

Two additional reports provided information about the effects of AIs on bone health and management of those effects. A large randomized clinical trial examined the effects of combined hormonal therapy and compared the relative effects of anastrozole and tamoxifen on bone health (J Clin Oncol 2007;25:3194-7). The Austrian Breast and Colorectal Cancer Study Group-12 investigation included 1801 premenopausal patients with endocrine-responsive early-stage breast cancer. Following surgery, all patients received goserelin and were randomized to anastrozole or tamoxifen with or without zoledronic acid (four groups total). Treatment continued for three years, reported Prof. Michael Gnant, Department of Surgery, University of Vienna, Austria.

He presented findings from a bone substudy involving 404 patients who had a total of 1533 BMD assessments during follow-up. The BMD results showed that patients randomized to endocrine therapy without zoledronic acid lost an average of 11.3% of BMD over three years. After discontinuation of hormonal therapy, fewer than half the patients regained baseline BMD, and at five years BMD loss averaged 6.3%. In contrast, patients who received zoledronic acid every six months throughout endocrine therapy maintained baseline BMD and had a 4% improvement at five years.

“Prevention of treatment-induced bone loss should be considered for premenopausal breast cancer patients receiving estrogen-reducing adjuvant therapies,” Prof. Gnant stated.

Similar findings emerged from the second International Breast Cancer Intervention (IBIS-II) study. The ongoing trial ultimately will involve 6000 postmenopausal women at high risk for breast cancer. They are being randomized to anastrozole or placebo for five years. A bone substudy will involve 1000 patients who have bone scans at baseline and at one, three, five, and seven years, Dr. Shalini Singh, Queen Mary’s School of Medicine and Dentistry, London, UK, informed delegates.

Patients in the bone substudy are separated into three risk strata at baseline: normal (T-score ³-1), osteopenic (T-score -1 to -2.5), and osteoporotic (T-score -2.5 to >-4.0). Patients in the normal stratum receive no bone-focused therapy, and those in the high-risk stratum all receive risedronate. Osteopenic patients are randomized to risedronate or placebo.

Dr. Singh presented data on the first 350 patients followed for one year in the bone substudy: 227 at normal risk, 80 osteopenic, and 43 osteoporotic. In the randomized risk stratum II (osteopenic patients), treatment with anastrozole alone was associated with a loss of lumbar spine BMD that averaged 0.6% and a loss of total hip BMD of 1.3%. In contrast, patients who received risedronate in addition to the AI had a mean increase in BMD that averaged 1.1% in the lumbar spine and 2.07% in total hip.

At one year, 9% of the patients with normal baseline BMD had at least a 6% decline in BMD in the lumbar spine or total hip, but no patient had become osteoporotic. In stratum II, 6% of patients had BMD loss ³6% and one patient had become osteoporotic. In the high-risk stratum, 2% of patients had BMD loss ³6% but 20 (46%) experienced improvement in BMD so that they were no longer osteoporotic.

“For women initially osteopenic or osteoporotic, concomitant risedronate appeared to abrogate the BMD loss associated with anastrozole,” Dr. Singh concluded.

Joint Symptoms

In addition to bone loss, joint symptoms are a recognized effect of treatment with AIs. Tamoxifen does not appear to have an impact on joint symptoms, which are primarily related to low estrogen levels, noted Dr. Ivana Sestak, Queen Mary’s School of Medicine and Dentistry.

The ATAC trialists collected data on joint symptoms, affording an opportunity to examine the impact of endocrine therapy on symptoms and compare the relative impact of the AI and tamoxifen on joint symptoms. Significantly more patients treated with anastrozole reported joint symptoms compared to tamoxifen (36.5% vs. 30.9%, P<0.001). About 300 patients in each treatment arm had joint symptoms at baseline and were excluded from further analysis.

Most joint symptoms occurred early in the course of treatment and were generally mild in severity, said Dr. Sestak. Investigators evaluated the impact of a variety of risk factors on joint symptoms. Besides treatment assignment, they found joint symptoms were significantly associated with no prior hormone replacement therapy (P<0.001), no prior exposure to chemotherapy (P<0.01), estrogen receptor-positive tumours (P=0.05 to P=0.02 vs. unknown or negative status), North American geographic region (P<0.001) and body mass index >30 (P<0.001).

In an analysis that examined joint symptoms by risk factor and treatment group, Dr. Sestak found that treatment with anastrozole had a significant association only in women with a history of hormone replacement therapy (P=0.02 vs. tamoxifen).

“Most risk factors (for joint symptoms) are associated with a decrease in estrogen levels on treatment commencement,” remarked Dr. Sestak. “Risk factors for joint symptoms should be considered when counselling women to maximize compliance with endocrine treatment.”

Compliance with Endocrine Therapy

Compliance with long-term oral therapy frequently poses a clinical challenge. Noncompliance with tamoxifen has been reported as high as 23% at one year and 50% at four years. Clinical observation has suggested that compliance is even lower with anastrozole than with tamoxifen, but no real-world data exist to support that assumption, stressed Dr. Peyman Hadji, Philipps-University of Marburg, Germany.

To that end, investigators retrospectively examined patient records and supplemented that information with patients’ self-reported compliance with endocrine therapy and with prescription control data. The study involved 100 postmenopausal breast cancer patients, half treated with tamoxifen and half with anastrozole.

Patient charts revealed no association between compliance and baseline characteristics, including side effects. Patient self-reports indicated 100% compliance with both tamoxifen and anastrozole. In contrast, prescription-control data indicated that 40 of 50 patients (80%) were compliant with tamoxifen and 29 of 44 (66%) were compliant with anastrozole.

“An important goal of any therapeutic intervention is to achieve comparable efficacy in routine clinical practice to that demonstrated in randomized clinical trials,” stated Dr. Hadji. “Our results further support the suboptimal compliance of women with breast cancer on adjuvant tamoxifen treatment. Additionally, we, for the first time, evaluated an equivalent low compliance with anastrozole. More prospective studies are needed to increase our understanding of the underlying reasons for noncompliance in women with breast cancer.”