The three aromatase inhibitors manufactured by Pfizer, Novartis and AstraZeneca were prominent at this year’s San Antonio Breast Cancer Symposium, as the case was made for their use as adjuvant therapy in post-menopausal women with hormone receptor-positive early breast cancer in preference to, or following, the gold standard tamoxifen, now patent-expired.

The disease represents a sizeable market with over 240,000 women developing breast cancer each year in the USA alone. Of these, about 70% have hormone-sensitive cancers and potentially require years of adjuvant therapy. American Cancer Society statistics suggest 2.5 million breast cancer survivors are currently alive. In the UK an estimated 90,000 women were prescribed tamoxifen in the past year.

TEAM results promising at 2.75 years survival
The largest randomised study, involving almost 10,000 women, was presented by Pfizer, manufacturer of Aromasin (exemestane). The company’s TEAM trial is comparing upfront exemestane for five years against tamoxifen for two to three years followed by a switch to exemestane for the remainder of the five-year-period. The trial originally compared the two drugs upfront as monotherapies but had to be modified when Pfizer’s previous IES study showed that women who switched from tamoxifen to exemestane lived longer.

Data from TEAM presented by Dr Steve Jones showed an 11% relative risk reduction in the intention to treat (ITT) analysis of the trial’s first co-primary endpoint - disease-free survival at 2.75 years (p=0.12). The second co-primary endpoint is the five-year DFS data to be presented next year. “The result was effectively sabotaged by large numbers of women in the tamoxifen arm switching over to exemestane before 2.75 years,” he said. When these were excluded, the DFS showed a significant 17% relative risk reduction (p=0.02).

Secondary endpoint data showed relapse-free survival, measuring only breast cancer events, showed a significant 15% risk reduction favouring exemestane (p=0.05). Time to distant metastases – usually in bone, lung and liver - showed a significant 19% difference favouring exemestane (p=0.03). This endpoint suggests the drug could influence overall survival outcomes, Dr Jones intimated.

Median survival after development of distant metastases is in the region of only 1.5 to 2 years. Side-effect data were in line with the other aromatase inhibitors showing more arthralgia and increased bone resorption. However a TEAM substudy showed only insomnia effects impacted quality of life at the 2.75 year timepoint.

Novartis’ Femara; six-year data from BIG 1-98
Latest results from the International Breast Cancer Study Group on the BIG 1-98 trial of 8,000 women featuring Novartis’ AI Femara (letrozole) came from the ITT analysis of median follow-up at 76 months of upfront letrozole head-to-head versus tamoxifen as adjuvant therapy. Results showed a 13% survival benefit that did not reach significance (p=0.08).

Lead investigator Henning Mouridsen of Copenhagen University Hospital said the data were scuppered by 25% of women crossing over from tamoxifen to letrozole. A censored analysis comparing outcomes for the two drugs after cross over showed a 19% difference favouring letrozole. But this result could also be biased, he said, because patients crossing over from one arm to the other may have been non-responders to the first drug they received. The monotherapy part of the trial also showed a significant 12% relative risk reduction in DFS events (p=0.03) and a 15% risk reduction in distant metastases (p=0.05) favouring letrozole.

In the Sequential Treatment Analysis (STA) of BIG 1-98 comparing tamoxifen for two years followed by three of letrozole against letrozole for two years followed by three of tamoxifen in 6182 patients, both arms were also compared against the two agents as monotherapies; the primary endpoint was DFS. Results showed no significant differences between letrozole alone versus either sequence. Comparing letrozole alone versus the tamoxifen-letrozole sequence there was a trend favouring letrozole alone in DFS, overall survival and time to distant recurrences. Investigators concluded that patients at high risk should start on letrozole alone but switch to tamoxifen after two years if necessary.

Updated data on AstraZeneca’s Arimidex vs tamoxifen
Updated data on relapse-free and overall survival for 2,922 subjects from the Austrian Breast cancer Study Group’s (ABCSG) Trial 8, were presented by Dr Raimund Jakesz of Vienna Medical School, Austria

The trial was a sequencing study comparing two years treatment with tamoxifen followed by three years’ Arimidex (anastrazole) in 1,865 newly-diagnosed women against five years’ tamoxifen treatment in 1,849 women. The trial differs from others by excluding prior chemotherapy, women over 80 and including only ductal and lobular breast cancers.

Results showed a 21% relative risk reduction in RFS favouring the sequence over tamoxifen alone (p=0.03) and a 23% relative risk reduction for death (p=0.02). When patients who crossed over from the tamoxifen arm to the sequence arm were excluded the RFS risk reduction was 27% (p=0.001) but risk reduction for death was 22% (p=0.03). “There is a clear survival benefit shown for patients switching from tamoxifen to anastrazole after two years” commented Dr Jakesz. “Further research is continuing to find the optimal adjuvant therapy strategy.” By Olwen Glynn Owen in San Antonio