Breast cancer can be prevented in healthy women with medication. Studies prove the effectiveness. In some countries, endocrine therapy is approved for this indication. However, acceptance of chemoprevention is generally low. News on this topic was presented at the St. Gallen Breast Cancer Conference.
Preventive drug treatment of healthy women who have a high risk of breast tumors, e.g., due to a family history, is generally not well accepted – despite approval in some countries and although it might be an alternative to the highly invasive procedures of bilateral mastectomy or oophorectomy in certain women. The substances in question are effective and comparatively safe. However, the willingness of many high-risk patients to tolerate the side effects of chemoprophylaxis is low in the long term. This may be due in no small part to the fact that clear evidence of a survival benefit has yet to be provided. However, the exact reasons for the rejection remain unclear.
Dr. Jack Cuzick recapped the advances and findings of the past few years and pointed out where the optimal areas of prevention use are.
The beginnings
It is now more than thirty years ago, in 1985, when the first evidence was published that tamoxifen adjuvant plays a crucial role not only in the treatment of breast cancer but also in its prevention [1]. This observation is not least due to a specific condition of breast cancer: If one breast already has cancer and is being treated, it is possible to observe whether the second breast, which is still healthy, also benefits from the therapy or is less likely to develop a tumor later on. Tamoxifen significantly reduced the cumulative incidence of contralateral breast cancer from 10 to 3 cases. This observation was confirmed in further studies, which led, among other things, to the proposal as early as 1986 by a group led by Dr. Cuzick that breast cancer should be addressed not only therapeutically but also preventively with drugs (similar to cardiovascular diseases).
Tamoxifen was thus the first agent to be studied in this context. Shortly after the aforementioned publication came the Royal Marsden, the NSABP-P1, an Italian, and finally the IBIS-I trial (in which Dr. Cuzick was instrumental) – all testing tamoxifen at the 20 mg/d dose in populations at increased risk. In addition, there was broad evidence from trials that continued to study tamoxifen in the adjuvant setting and provided data on the contralateral breast.
Preventive effect over at least 20 years
The speaker specifically singled out the IBIS-I study. Over 7000 premenopausal and postmenopausal high-risk patients participated. They received either tamoxifen or placebo over a therapy duration of five years. Meanwhile, the median follow-up time is an impressive 16 years (in many women even 20 years) – blinding on the part of the investigators and patients has been maintained for the most part over this period [2]. The results are impressive: 20 mg/d of tamoxifen for five years reduced the risk of breast cancer by 28% after only ten years. The Number Needed to Treat (NNT) at that time was 59, meaning that it took 59 high-risk women five years of treatment to protect one of them from breast cancer within the first ten years. When the group was followed for another ten years – without the patients having to take tamoxifen again – the preventive benefit from endocrine therapy was even more pronounced. Taken together, a reduction in breast cancer incidence was found from 12.3% to 7.8%, corresponding to an NNT of 22. Thus, primary preventive therapy for five years protects one from breast cancer in a group of 22 women over the next 20 years. The risk reduction was 29% after the prolonged follow-up. It was even more pronounced in invasive estrogen receptor-positive breast cancer at 34% (long-term rates of 8.3% vs. 4.9%, NNT=29). This is the main focus of prevention. Invasive estrogen receptor-negative cases could not be prevented by tamoxifen.
Moreover, the curves diverge further, so it is possible that the preventive effect is not limited to 20 years. A further extension of the study will provide information on this.
In contrast to other studies, IBIS-I allowed concomitant hormone replacement therapy (HRT), if needed, which proved to be disadvantageous. Women on HRT experienced a significantly smaller effect of tamoxifen administration than those without HRT.
Do the patients also live longer?
What has not yet been shown in IBIS-I is a prolongation of breast cancer-specific survival or a significant impact of tamoxifen on breast cancer-specific mortality rates. It may simply be too early to observe such an effect, as Dr. Cuzick suggested. At present, the statistical power is still insufficient; fortunately, most of the women with the disease are still alive. Therefore, one would have to wait at least ten more years of follow-up to be able to prove – or not prove – a statistically relevant effect. After the first ten years, a slight increase in mortality was initially found with tamoxifen, although this did not increase further during the course of the observation, but rather decreased again. Of course, they are aware of the potential impact on the development of endometrial cancer, he said. However, the mortality increase was not significant in this area so far (5 vs. 0 deaths). There was no increase in all-cause mortality.
In conclusion, tamoxifen clearly had a preventive effect on incidence, but uncertainties remained regarding its effect on survival prognosis.
Other prevention approaches
After tamoxifen, we tested whether a preventive effect could also be achieved with another selective estrogen receptor modulator (SERM), namely raloxifene. Two further large studies with lasofoxifene and arzoxifene followed. In the adjuvant setting, aromatase inhibitors (letrozole, anastrozole, exemestane) were approved, also yielding promising results in prevention – and finally, agents such as NSAIDs, bisphophonates, metformin, and statins were investigated with (at least so far) less convincing results in the preventive setting.
SERM: The MORE trial and its extension called CORE are waiting with dramatic risk reductions of 60% (raloxifene). In addition, there is the RUTH and finally the STAR study. The speaker went into more detail on the latter. With almost 20,000 participants, the study was set to be very extensive. It directly compared raloxifene 60 mg/d with tamoxifen 20 mg/d – this in high-risk postmenopausal patients over five years of therapy. While the initial evaluation [3] suggested equivalence of the two approaches, prolonged follow-up of 81 months [4] showed tamoxifen to be 24% more effective than raloxifene in terms of prevention (p=0.01). Due to the better tolerance (especially with regard to endometrium), raloxifene remains an option, said the speaker. The results were nevertheless rather disappointing, given the hopes that MORE/CORE had raised. With lasofoxifene, a significant effect was again found in the PEARL study at higher doses, but development in the corresponding indication is not currently being pursued. Taking into account the heterogeneity of the studies (targets) mentioned, one can roughly assume a risk reduction in the range of 30-40% after ten years. A slightly higher risk reduction is expected for invasive estrogen receptor-positive breast tumors.
Aromatase inhibitors: again, the initial evidence came from the adjuvant setting. Two studies have also investigated the drug class in postmenopausal women without breast cancer but at high risk. One of them called MAP3 [5] observed a pronounced risk reduction with exemestane compared to placebo of 65% (p=0.002). The observation period was rather short, with a median of just over 30 months. It turned out that after this period (the follow-up was then limited, of course) even significantly more happened.
The second study from this area is called IBIS-II [6]. Here, anastrozole (1 mg/d) served as the investigational agent. It was administered to 3864 postmenopausal women aged 40 to 70 years at high risk of breast cancer (including family history, atypia, lobular carcinoma in situ [LCIS], high breast density) over five years. HRT was not allowed this time. The results were comparable to MAP3. In the primary endpoint, overall breast cancer incidence, the aromatase inhibitor was found to reduce risk by 53% after a median of five years of follow-up (p<0.0001) – strong evidence that anastrozole is a good preventive agent, according to Dr. Cuzick. When invasive estrogen receptor-positive breast tumors were considered separately, the reduction was also greater, 58%, as in the primary endpoint of MAP3 (again, no significant effect was found in invasive estrogen receptor-negative cases).
Compared with previous adjuvant trials, the fracture rate was lower and non-significantly increased compared with placebo (8.5% vs. 7.7%). This was also due to the fact that osteoporotic women were taking bisphosphonates and those with osteopenia were undergoing regular DXA scans. Musculoskeletal events, a known problem with aromatase inhibitor therapy, were indeed very common, occurring in 64% in the study group but also in 57.8% in the control group (p=0.0001). In non-controlled situations, they are often attributed entirely to aromatase inhibitors, with much of it simply related to uninfluenceable factors such as age, the expert said. Of course, if aromatase inhibitors were to be used broadly in prevention, one would have to think about concomitant exercise therapy to prevent such events.
Overview 1 summarizes the main findings from breast cancer prevention via endocrine therapy.
Source:15th St. Gallen International Breast Cancer Conference, March 15-18, 2017, Vienna.
Literature:
- Cuzick J, Baum M: Tamoxifen and contralateral breast cancer. Lancet 1985 Aug 3; 2(8449): 282.
- Cuzick J, et al: Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 2015 Jan; 16(1): 67-75.
- Vogel VG, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006 Jun 21; 295(23): 2727-2741.
- Vogel VG, et al: Update of the National Surgical Adjvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer. Cancer Prev Res (Phila) 2010 Jun; 3(6): 696-706.
- Goss PE, et al: Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011 Jun 23; 364(25): 2381-2391.
- Cuzick J, et al: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 2014 Mar 22; 383(9922): 1041-1048.
InFo ONCOLOGY & HEMATOLOGY 2017; 5(2): 23-26.
