More evidence suggesting that aromatase inhibitors (AIs) have slightly better efficacy than tamoxifen (Tam) as adjuvant therapy for postmenopausal women with estrogen-receptor-positive (ER+) breast cancer was at the 31st Annual San Antonio Breast Cancer Symposium (SABCS) on December 17.
Both drug approaches reduce estrogen, but in different ways. Tamoxifen is a selective estrogen-receptor modulator (also called a SERM) that prevents estrogen from interacting with its receptor, whereas AIs act by inhibiting an enzyme involved in the synthesis of estrogen from androgen after the menopause, and hence reduce the level of the hormone interacting with its receptor.
Three AIs are currently marketed in Australia— letrozole (Femara, Novartis), anastrozole (Arimidex, AstraZeneca) and exemestane (Aromasin, Pfizer).
So far, various combinations of trials (giving an AI versus Tam for 5 years), giving Tam for 2-3 years and then “switching” to an AI or giving 5-years of an AI after 5 years of Tam have all shown that AI’s are slightly better in reducing relapse but survival gains have been relatively small.
Relapse free survival time is the measure of time between diagnosis and an “event”. These events include a new cancer in the opposite breast, disease coming back in the same breast (if breast conservation was undertaken) or the chest-wall (if a mastectomy was undertaken) or disease coming back elsewhere in the body. Many trials also include the appearance of a totally different cancer or dying from something unrelated to breast cancer as an “event”. A more robust end-point for assessing the benefit of anticancer drugs is overall survival (the time from diagnosis to death from any cause) or breast cancer mortality (the time from diagnosis until death from breast cancer).
Apart from relapse or survival, quality of life is also very important. Although the survival data are very similar between Tam and AI’s, the toxicity profiles are quite distinct, with great sexual morbidity for some women with the AIs and more joint pain and osteoporosis. This has to be balanced with a slightly higher risk of a blood clot (or “DVT”) or cancer of the womb (endometrial cancer) with Tam.
The meta-analysis that Dr. Ingle presented at the meeting was split into two cohorts:
Cohort 1 consisted of data from “monotherapy” clinical trials that directly compared an AI to tamoxifen (9586 patients with a median follow-up of 5.9 years).
Cohort 2 consisted of data from "switching" trials in which the patients on tamoxifen were switched to an AI after 2 or 3 years (9015 patients with a median follow-up of 3.9 years). Here’s the fine print from the abstracts:
Cohort 1: 9,856 pts with 50,000 woman-years of follow-up. At 5 yrs, AI therapy was associated with an absolute 2.7% (standard error [SE] 0.7) decrease in BC recurrence (10.7% vs 13.4%, relative decrease 20% [SE 5], p=0.00004). There appeared to be greater proportional decreases in isolated local recurrence (30% [SE 10], p=0.003) and in contralateral disease (38% [SE 12], p=0.003) than in distant recurrence (12% [SE 6], p= 0.04). AIs yielded an absolute 1.0% (SE 0.5) decrease in BC mortality (5.5% vs 6.5%, relative decrease 7% [SE 7], p=0.28. The difference was even less and about 0.5% at 8 years.
Cohort 2: 9,015 pts with 33,000 woman-years of follow-up. At 6 yrs from treatment divergence (i.e., 8-9 yrs from diagnosis), AI therapy was associated with an absolute 3.5% (SE 1.1) decrease in BC recurrence (12.6% vs 16.1%, relative decrease 29% [SE 6], p<0.00001). There appeared to be greater proportional reductions in isolated local recurrence (40% [SE 13], p=0.002) and in contralateral disease (35% [SE 16], p=0.03) than in distant recurrence (24% [SE 7], p= 0.001). AIs yielded an absolute 1.6% (SE 0.8) decrease in BC mortality (6.3% vs 8.0%, relative decrease 22% [SE 9], p=0.02). Subset analyses with respect to PgR status, age, tumor grade and nodal status revealed no apparent heterogeneity between the proportional reductions in recurrence and no indication of an increase or decrease in non-breast deaths with AIs in either cohort 1 or 2.
Very importantly non breast cancer mortality and overall mortality were not higher with the AIs in either cohort was reassuring regarding their overall safety.
My view is that any efficacy gain had to be balanced not only against tolerability for each patient but also the risk of recurrence and presence of other risk factors such as osteoporosis or a family history of thrombosis. If the risks of recurrence are low (e.g a strongly ER positive grade 2 tumour measuring under 15mm) then the benefit of an AI over Tam is miniscule at most. If the risk of recurrence is higher then I would tend to favour an AI. On the other hand if a woman is perimenopausal and I am not really sure if she has stopped ovulating it is safer to start off with Tamoxifen as AI’s can stimulate ovulation and cause an unwanted pregnancy. If a woman has a strong family history of blood clots or more rarely endometrial cancer then Ais are a better approach.
Tamoxifen is now available as a generic, so is much cheaper than the branded AIs. In Australia the the difference may be between $20 and $300, for Tam versus an AI. Of course there needs to be a return on the multiple millions of dollars invested by pharmaceutical companies testing and discovering new drugs but in many situations, such as poorer Pacific islands or countries without pharmaceutical reimbursement, Tam may be a much better option.
Although AIs carry the risk for osteoporosis, this can be monitored and countered with bisphosphonates. I usually recommend baseline blood levels of calcium, vitamin D and parathyroid hormone and organise a baseline bone density measure before we start AI’s. Many women are Vit D deficient and this can make matters worse for bone strength.
A good middle ground approach supported by this new metaanalysis is to start patients with Tam for 2-3 years which can maintain or indeed increase bone strength particularly in the younger perimenopausal woman where we may not be certain that ovulation has ceased. The switching data also show that there may be a small survival advantage.
A major question than remains, however, is how long such treatment should be continued. Studies are currently in progress, comparing 5 years of therapy with 10, and 10 years of therapy with 15. Certainly, for women at higher risk of relapse (say with positive nodes) it makes sense to continue treatment for at least 10-years for the moment based at least on the MA-17 trial which shows a survival advantage of 5-years of Femara after 5-years of Tam (2). Ultimately, each patient needs to be assessed almost on an individual basis based on her prognosis, psychology and side-effect questions.
References:
1. http://sabcs.org/
2. http://www.ncbi.nlm.nih.gov/pubmed/16730271
This is the breast cancer site of Prof John Boyages, author of Breast Cancer: Taking Control
