Breast cancer is the most common cancer in South Africa with an incidence of 21.8% of all female cancers, as reported by the National Cancer Registry for 2014.(1) This is in line with the global burden of the disease where breast cancer is again the most common cancer in females and second most common cancer overall after lung cancer.(2)
There is, however, a disproportionate mortality to incidence ratio between low-middle income countries (LMIC) and high income countries (HIC), with the most concerning difference seen in the mortality from breast cancer in low income countries. For South Africa, an upper middle income country, the mortality to incidence ratio is 46.9 versus 18.8 for a HIC such as the USA.(3)
Various factors have been identified as contributing to this difference. In South Africa, these include urban versus rural residence, socio-economic status, educational level, limited understanding of the disease process, barriers to diagnostic and treatment access and difficulty with referrals for treatment.(4)
Any tools available to reduce the incidence of breast cancer would have an impact on disease incidence and outcomes, yet the implementation of any such intervention requires a clear understanding of its risks and benefits.
One such tool is the prophylactic use of oestrogen receptor blockers or aromatase inhibitors in individuals considered to have a higher risk of breast cancer. Such patients include those who have a diagnosis of atypical (ductal or lobular) hyperplasia or lobular carcinoma in-situ, an estimated 5-year risk National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool score of at least 3%, a 10-year risk International Breast Intervention Study [IBIS] Risk Calculator score of at least 5%, or a relative risk of at least four times the population risk for their age group if they are age 40 to 44 years or twice the population risk for their age group if they are 45 to 69 years of age.(5)
The recently published US Preventative Task Force (USPSTF) recommendation on medication to reduce the risk of breast cancer outlines the potential to reduce risk.(6) There are various online risk calculation models available to calculate breast cancer risk. Amongst the most widely used models is the NCI Breast Cancer Risk Assessment Tool,(7) the Gail model (8,9) (incorporated into the NCI risk tool) and the Breast Cancer Surveillance Consortium Risk Calculator.(10) These models, in different combinations of factors, include age, age at menarche, age at first childbirth, family history of breast cancer in first-degree relatives, number of prior breast biopsies, history of atypical hyperplasia, race/ethnicity, prior false-positive mammography results or benign breast disease, body mass index (BMI) or height, oestrogen and progestin use, breastfeeding history, menopausal status or age, smoking, alcohol use, physical activity, education, breast density and diet. These risk tools have been validated in the USA population; however, the ability to predict risk is modest in the general population and somewhat less so in an individual.(11) The best estimation of risk is in models incorporating breast density, postmenopausal hormone use and a more extensive family history. None of the risk models assessed patients with a previous invasive breast cancer or ductal carcinoma in-situ and have not been fully validated for women with pathogenic BRCA1/2 gene mutations or in patients receiving chest radiation in childhood or adolescence. Importantly, the risk models reviewed by the USPSTF were conducted in numerous HIC sites across the USA, UK and Europe, which enrolled predominantly white patients (84–97%) (5) and thus its applicability in LMIC is largely unknown.
The trials reviewed by the USPSTF assessed tamoxifen, raloxifene and aromatase inhibitors to reduce the risk of breast cancer. Tamoxifen was evaluated in premenopausal and postmenopausal women at risk of breast cancer, while raloxifene and aromatase inhibitors were only evaluated in high risk postmenopausal women.(5) All 3 medications reduced invasive oestrogen (ER)-positive breast cancer but not ER-negative breast cancer.(5) In the pooled results of placebo-controlled trials projecting benefits over 5 years, the use of tamoxifen would result in 8 fewer cases (per 1000 women over 5 years of treatment use) of ER-positive breast cancer (risk ratio (RR), 0.58 [95% CI, 0.42–0.81]).(5) Raloxifene would yield 9 fewer cases of invasive breast cancer (RR, 0.44 [95% CI, 0.24–0.80]) and 8 fewer cases of ER-positive breast cancer (RR, 0.33 [95% CI, 0.15–0.73]).(5) Aromatase inhibitors would result in 16 fewer cases of invasive breast cancer (RR, 0.45 [95% CI, 0.26–0.70]) and 15 fewer cases of ER-positive breast cancer (RR, 0.37 [95% CI, 0.19–0.63]).(5) The risk reduction was essentially similar between the three treatment groups even though there were few studies where head to head comparisons were undertaken. In one study however, tamoxifen did have a greater risk reduction than raloxifene after long-term follow-up (5), while in 2 studies with tamoxifen alone, the risk reduction of both invasive and ER-positive breast cancer persisted up to 8 years after the discontinuation of tamoxifen.(12,13)
The decision to initiate these risk reductions therapies is not simply one of identifying those patients over the age of 35 years of age at higher risk of developing breast cancer and prescribing these agents. It requires careful deliberation regarding the benefits and risks of adverse effects to ascertain which agent, if any, would be best suited to an individual. The final decision to initiate these therapies will differ from one patient to another depending on what is acceptable to the individual and her life style.
Over and above the benefit of the cancer risk reduction with tamoxifen and raloxifene, these two agents also help improve bone mineral density and reduce the risk of vertebral and non-vertebral fractures,(5) unlike aromatase inhibitors which not only do not reduce fracture risk but actually increase its likelihood. Other patient co-morbidities need to be weighed up against the benefits of these agents with cardiovascular risk factors in particular a concern for patients where aromatase inhibitors are being considered, as this class of drugs has shown a trend towards a higher risk of transient ischaemic attacks, cerebrovascular and cardiovascular events.(14) Musculoskeletal symptoms with worsening of arthritic symptoms, gastrointestinal side effects and an exacerbation of menopausal vasomotor symptoms are also frequent with aromatase inhibitors.(15)
For women who have not had a hysterectomy, the risk of developing endometrial cancer is increased with the use of tamoxifen. The National Surgical Adjuvant Breast and Bowel Project Prevention Trial (P-1), which studied prophylactic tamoxifen in high risk patients, showed an RR of 2.5 for developing endometrial cancer in women using tamoxifen compared to women receiving placebo.(16) In addition, the ability of tamoxifen to induce endometrial malignancy as well as other histopathologic conditions appears to differ between premenopausal and postmenopausal women in that women over the age of 50 years had a four-fold higher risk of endometrial malignancy when treated with tamoxifen.(16) The risk of vascular thromboembolic events (VTEs) also increases with the use of tamoxifen and raloxifene even in patients with a conventional risk of atherosclerosis,(17) as does the risk for cataracts.(18) It is important to note that while the benefits of tamoxifen persist up to 8 years beyond discontinuation, the risk for VTEs and endometrial cancer return to baseline after discontinuation of tamoxifen.(19)
In the South African context, to reduce breast cancer incidence in high risk individuals, medical therapy must be considered with careful discussion of costs, risks and benefits. There are no local guidelines on how to reduce risk of breast cancer. Risk models allow us to have a discussion with each patient about her estimated potential risk if she falls into a group that was studied in a research clinical trial. As these trials mostly under-represented the vast majority of our patients, we then need to open up a dialogue, with an outline of the various drug benefits and a frank discussion of the drug adverse effects, their expectations, co-morbidities and fears before embarking on any form of adjuvant therapy. It is imperative that in addition to considering endocrine therapy we do not neglect to encourage lifestyle modification with a reduction of alcohol intake, limiting saturated fats and refined sugars, increasing physical activity and reducing BMI, a reconsideration of the oral contraceptive pill after 35 years of age and a limitation of hormone replacement therapy. Furthermore, patients at higher risk should also be included in regular breast cancer screening programs.
However, we should be cognizant that in the South African health sector environment, much still needs to be implemented to improve awareness about breast cancer in all communities. These include screening at primary health care level, adequate roll out of awareness campaigns, educational programs and improving access to screening for breast cancer. Ultimately the mortality to incidence ratio in South Africa can only improve if we address the factors which lead to delayed presentation and remove obstacles to appropriate care. These changes, along with improved local data and the validation of risk models for our population, are urgently required.