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PRIORITY PRESS - 12th Milan Breast Cancer Conference

Milan, Italy / June 16-18, 2010

According to Dr. Jack Cuzick, Head, Centre of Epidemiology, Mathematics and Statistics, Cancer Research UK, London, “This new 10-year update of the ATAC [Arimidex, Tamoxifen Alone or in Combination] trial confirms that the safety and efficacy benefits of anastrozole over tamoxifen are maintained beyond five years of treatment.”

Dr. Cuzick noted that the ATAC trial compared the aromatase inhibitor (AI) anastrozole 1 mg/day and tamoxifen 20 mg/day alone or in combination as primary adjuvant endocrine therapy for women with localized invasive breast cancer. Previous analysis after five years of treatment showed significantly prolonged disease-free survival (DFS), time to recurrence, significantly reduced distant metastases and fewer contralateral breast cancers with the AI compared with tamoxifen in hormone receptor-positive (HR+) women, he commented. The primary end point, DFS, and secondary end points of time to recurrence and overall survival were assessed in both the total (anastrozole n=3125, tamoxifen n=3116) and clinically important HR+ subpopulations (84% of total). After treatment completion, data on fractures and serious adverse events continued to be collected. The combination treatment arm was discontinued after an initial analysis showed no efficacy or tolerability benefits over tamoxifen.

10-year Efficacy

“At the median follow-up of 120 months in this new trial update, significant improvements were still seen for anastrozole compared with tamoxifen for DFS and time to recurrence in the HR+ population,” Dr. Cuzick reported. “For DFS, a primary end point in the 10-year analysis, the significant benefit for anastrozole patients was maintained after treatment completion at five years, with a DFS hazard ratio of 0.86 [P=0.003]” (Figure 1).

He added that the absolute difference in time to recurrence for the AI over tamoxifen in HR+ patients increased with time, to 4.3% at 10 years from 2.7% at year 5. That carryover effect in favour of the AI compared with tamoxifen was statistically significant after treatment completion (P=0.0002). “The benefits over tamoxifen are clearly apparent in the first five years and still significant out to eight years, after which they seem to diminish,” he told delegates, “so it may be that anastrozole’s improvement over tamoxifen is strongest in the first eight years, but is still evident after 10 years. Deaths after recurrence were non-significantly lower in the anastrozole group than among tamoxifen-treated women, 345 [11.2%] vs. 400 [12.9%] [P=0.09].”

The curves for distant recurrence also widened progressively over time, showing the AI effect to be two times greater than tamoxifen at 10 years than it was at five years. Its benefit clearly seen at five years continued out to 10 years by and large, Dr. Cuzick added. The reduction in time to distant recurrence in HR+ patients was 15% compared to tamoxifen (P=0.02).

Fewer Contralateral Tumours

Dr. Cuzick reported a significant reduction in contralateral tumours among patients treated with the third-generation AI compared to tamoxifen. Moreover, he reported that the absolute reduction with the AI was twice as great at year 10 (1.7%) than at year 5 (0.8%) (P=0.003) and about a 40% reduction of contralateral tumours occurring in both the first and second five-year periods and still quite apparent at year 10.

Noting, too, that overall survival was similar in both treatment groups (P=0.35), he said that a total of 1149 women died in the clinically important HR+ population, 563 (21.5%) in the AI and 586 (22.6%) in the tamoxifen groups. Deaths following recurrence were fewer, but not significantly Milan - Studies have now established the efficacy of adjuvant third-generation aromatase inhibition over the antiestrogen tamoxifen in reducing the risk of breast cancer recurrence among postmenopausal women with hormone receptor-positive tumours. The efficacy of anastrozole after five years compared to tamoxifen, for example, has also been shown to improve disease-free survival (DFS) and reduce early distant metastasis, which may ultimately translate into improved overall survival. As aromatase inhibitors (AIs) offer prolonged DFS, long-term safety becomes an important issue. AIs can cut the risk of major side effects in half, whereas the effectiveness of tamoxifen decreases over time, even increasing the risk of endometrial cancer after five years of treatment. Nevertheless, some clinicians continue to express doubt about the duration of safety and efficacy of AIs vs. tamoxifen because of the absence of long-term studies. To that end, results from the 10-year analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial comparing the efficacy and safety of anastrozole vs. tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer were presented here for the first time. PRIORITY PRESS so, among AI-treated patients than those on tamoxifen at 284 (10.8%) vs. 320 (12.3%) (P=0.09). On that basis, anastrozole 1 mg meets the criteria for non-inferiority compared with tamoxifen 20 mg.

Summarizing the efficacy data from the ATAC 10-year update, Dr. Cuzick stated the significant advantage for the AI over tamoxifen for DFS and time to recurrence at five years was maintained at a median follow-up of 120 months. Five years of therapy with anastrozole 1 mg is more effective than five years of tamoxifen 20 mg, the previous standard of care for early breast cancer patients requiring endocrine treatment, and the AI benefits continue after completion of treatment.

Fracture Risk

Turning to the key safety end points in the 10-year ATAC analysis, Dr. Cuzick characterized the effect on fractures as “striking.” “We saw an increase of about 50% in the incidence of first fractures during active treatment with anastrozole, but it immediately disappeared following completion of treatment, and the annual first event fracture rates were similar in both treatment groups thereafter [P=0.5]. We found no evidence whatsoever of any differences in fracture rates between anastrozole and tamoxifen after stopping treatment,” he told delegates.

“This was also seen in the new IBIS-II [International Breast Cancer Intervention Study II],” he continued, “in which there was a loss of bone density associated with anastrozole of about 2%, which is clearly significant but not enough to lead to osteoporosis. Women who start off osteoporotic and are given a bisphosphonate achieve an increase in bone density within one year, regardless of whether they are taking an AI. If they are not taking one, they gain an increase in bone density of around 3%. If they are taking an AI, the gain is just under 2%, so you can actually give AIs to women with osteoporosis by adding a bisphosphonate and get an overall benefit in bone density because the beneficial effects of a bisphosphonate outweigh the detrimental effects of the AI. It is reassuring that the bone loss problem is manageable with bisphosphonates,” Dr. Cuzick remarked.

The 10-year update also confirmed the overall incidence of new primary cancers to be similar in the two treatment groups (13.7% AI vs. 13.9% tamoxifen). While differences in the rates of some new primary cancers were observed, including endometrial, contralateral breast, ovarian, melanoma, lung, colorectal and head and neck cancer, the differences were not statistically significant, with the exception of endometrial cancer, which showed a fourfold increase on tamoxifen (P=0.014). Dr. Cuzick suggested this interesting new data on the AI’s effect on new tumours is likely to be sustained for a long period, at least in the adjuvant setting, which has proved to be a good model for tamoxifen.

The ATAC 10-year analysis reported that cardiovascular events were consistent with the known safety profiles of the two treatments, with no excess of ischemic cardiovascular or cerebrovascular events in AI-treated patients and no increased risk of myocardial ischemia. Patients treated with tamoxifen are generally known to experience more frequent and higher-grade thromboembolic events as well as endometrial pathology, hot flushes, night sweats and vaginal bleeding.

Summary

Dr. Cuzick concluded that the data from the extended ATAC study confirm the long-term improved efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with HR+ early breast cancer. The results demonstrate an enhanced balance of known benefits vs. potential risks for the AI relative to tamoxifen, confirming that it represents a significant advance in breast cancer treatment.