26 September, 2016: 

The management of women at high risk for breast cancer has evolved during the past years. This management includes the identification of these women and potentially offers them a preventive strategy. Chemical prevention by selective estrogen receptors modulators (SERMs) and aromatase inhibitors (AI) has been shown to decrease the risk of primary breast cancer, precancerous lesions, bilateral breast cancer and recurrence. Despite recommendations to use these treatments for prevention in some countries, a very low number of women use them. The main reason is fear of side-effects. The only alternative so far is surgical mastectomy.

A debate was organized at the Beth Israel Deaconess Medical Center to discuss the administration of these preventive medications and how to overcome women’s resistances [1]. A clinical case of Mrs Z, a premenopausal 51-year-old woman with a strong family history of breast cancer (mother at the age of 57, a sister at the age of 40, a maternal aunt at the age of 47 and a maternal grandmother who died of an unknown cancer at the age of 37) and no BRCA1/2 mutation, was the basis for the discussion. Three questions were addressed to two experts, Dr N. M. Tung (Associate Professor, Medicine, Harvard Medical School Director, Cancer Risk and Prevention Program) and Dr M. A. Schonberg (Assistant Professor, Medicine, Harvard Medical School, Instructor in Medicine, General Medicine and Primary Care). They recall that, 'In the US, 15% of women aged 35–76 years have more than a 1.7% chance of developing breast cancer in the 5 years and only 0.03% of these women report using tamoxifen and 0.21% of 50–79-year-olds report using raloxifene.'

The experts were asked the following questions: (1) What tools are there for assessing breast cancer risk? (2) How do you weigh the benefits/harms of the medications and how do you communicate these to Mrs Z? (3) What are the obstacles against implementing the chosen strategy?

The discussion was based on the recommendations of the US Preventive Task Force (USPTF) [2] and those of the American Society of Clinical Oncology (ASCO) [3] for preventive chemotherapy (tamoxifen, raloxifene and an aromatase inhibitor (AI), exemestane) for invasive breast cancer. These recommendations have evaluated the decrease in the risk of breast cancer, mortality and also side-effects (endometrial cancer for tamoxifen, thrombosis for both SERMs, cataracts, hot flushes, osteoporosis for AI) and bone protection (for tamoxifen and raloxifene). The recommendation of the USPTF was to discuss treatment of postmenopausal women with a 5-year risk of 3% and that of ASCO was to treat women > 35 years old with a1.66% 5-year absolute risk of breast cancer.

In response to question (1), both experts recalled that several scores are available to evaluate the risk of breast cancer. They discussed the limitation and advantage of each test and used either the modified Gail test (Breast cancer risk assessment tool, BRCAT) [4], the Claus risk tables which are mostly used for familial risk, or the International Breast Cancer Intervention (IBIS) studies [5]. These scores are freely available online. IBIS is more accurate than BCRAT when there exists a strong family history and includes clinical factors, which is not the case for the Claus risk tables; IBIS is known, however, to overestimate the risk compared to other scores. It is also known that none of the available scores can reach an accuracy better than 66%. None of these scores includes breast density. According to the various scores, Mrs Z is at increased risk and chemical prevention could be offered.

We also think that, in the case of a woman with this level of risk, in which it is not necessary systematically to perform a score (because it is clear she is at increased risk), the results of the score could nevertheless be used to convince her to implement a preventive strategy.

In response to questions (2) and (3), interestingly the second expert insisted that the patients should be presented with the absolute risk calculated from the results of the trials on prevention, using pictograms and avoiding medical jargon. The absolute risk should be expressed as the number of cancers/precancerous lesions diagnosed, the number of cancers to be prevented, and the number of deaths. None of the preventive trials had any reported benefit in terms of survival, but they were possibly not powered for this. There were no benefits for hormone receptor-negative cancers, which are the most aggressive. Both experts agreed on the benefit of tamoxifen, in the range of a 50% decrease in invasive breast cancer, raloxifene being 76% as effective and AI the most effective, with a 65% risk reduction. Then the risks of uterine cancer, venous thrombosis, stroke, cataracts, hot flushes and joint pain are presented in absolute numbers/1000 women for each medication. Interestingly, the first expert did not include in her evaluation the benefit/risk balance for climacteric symptoms! It was also pointed out that Mrs Z had to understand that using one of these treatments would decrease the risk of cancer but not suppress it and that her risk of dying would not be modified, with quite some side-effects. The conclusion was that, until the barriers were overcome, these patients should be referred to expert centers.

The main resistance from women to using a SERM or an AI for 5 years is the effect on quality of life, which might indeed be decreased severely in some women. In addition, the risk of potential morbidities induced by the treatments merits to be taken into consideration. This is why in France SERMs or AIs are not recommended. It could be proposed that tolerance testing could be offered to these patients in addition to complete information. But this information is complex for an average woman to understand; to integrate all the parameters of these treatments into the reality of harms/benefits is quite challenging!

Anne Gompel
Unité de Gynécologie-Endocrinienne, APHP, Port Royal Cochin Hospital and University Paris Descartes, France

References

1. Burns RB, Schonberg MA, Tung NM, Libman H.Should we offer medication to reduce breast cancer risk?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center. Ann Intern Med 2016;165:194-204
   http://www.ncbi.nlm.nih.gov/pubmed/27479221
2. Moyer VA; U.S. Preventive Services Task Force. Medications to decrease the risk for breast cancer in women: recommendations from the U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2013;159:698-708
   http://www.ncbi.nlm.nih.gov/pubmed/24061412
3. Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2013;31:2942-62 http://www.ncbi.nlm.nih.gov/pubmed/23835710
4. National Cancer Institute. Breast cancer risk assessment tool. http://www.cancer.gov/bcrisktool/
5. IBIS breast cancer risk assessment tool. http://www.ems-trials.org/riskevaluator/