Risk factors

The clearest risks for invasive breast cancer are:

• female sex
• the presence of preinvasive cancer:
  • lobular carcinoma in situ
  • ductal carcinoma in situ
• previous breast cancer

Other risk factors (classified as increased risk above normal) include:

• family history of breast cancer - the risk of breast cancer in a woman has been quantified with respect to the number of affected first degree relatives and by the age of affected first degree relative (1)

Table 1: Relative risk for breast cancer by number of affected first degree female relatives

Table 2: Relative risk for breast cancer by age of affected first degree relative

• age - peak incidence 45-75 years but any age postmenarche >> 4x
• country of residence - high in West > 4x e.g. UK, low in East e.g. Japan
• previous breast cancer > 4x
• irradiation of chest - shows a linear dose-response relationship 2-4x
• social class (I vs. V) 2-4x
• race - more common in Caucasians < 2x
• previous ovarian or endometrial cancer < 2x
• early menarche or late menopause < 2x
• nulliparity or older than 30 years before first child < 2x
• obesity - oestrogen synthesis in adipose tissue
• alcohol consumption

In the male, Klinefelter's syndrome is a risk factor for breast cancer.

Notes:

• smoking and breast cancer risk
  • most studies on active cigarette smoking show no association with breast cancer (2)
    • some investigators, however, have argued that most of these studies have failed to consider that both nonsmokers and smokers are exposed to environmental tobacco smoke (ETS), which has potentially masked any effects of active smoking on breast cancer
  • a US observational study concluded that regular ETS exposure is causally related to breast cancer diagnosed in younger, primarily premenopausal women and that the association is not likely explained by bias or confounding (3)
    
    
• review of the evidence for breast cancer risk and HRT (4,5,6,7,8):
  • the British Menopause Society (BMS), International Menopause Society (IMS), European Menopause and Andropause Society (EMAS), Royal College of Obstetricians and Gynaecologists (RCOG) and Australasian Menopause Society (AMS) have issued clarification of the evidence on the risk of breast cancer with menopausal hormone therapy (MHT) in response to the recommendations of the European Medicines Agency (EMA) - the central European drug regulatory body - Pharmacovigilance Risk Assessment Committee on 11-14 May 2020 that followed on from a meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) published in the Lancet on 30 August 2019.

This advice is summarised below (4):

• interpretation of the evidence on the risk of breast cancer with MHT
  • the findings from the CGHFBC meta-analysis are in keeping with the NICE guidance 2015 analysis of the observational data on the risk of breast cancer and MHT
  • the findings from the CGHFBC meta-analysis should be explained to women when discussing the benefits and risks of MHT. However, discussions on the risk of breast cancer with MHT should also include the findings from the WHI placebo-controlled randomized trials and the large E3N observational studies, which reported on the risk of breast cancer risk in users of micronized progesterone and dydrogesterone compared with other progestogens. Neither of the latter two studies was included in the CGHFBC meta-analysis
  • the recently published WHI data showed a significant decrease in the risk of diagnosis of breast cancer with estrogen-only MHT and a significant reduction in breast cancer mortality compared with placebo
    • women who took combined estrogen and progestogen MHT had an increased risk of breast cancer compared to placebo, in keeping with NICE guidance conclusions, but showed no significant difference in breast cancer mortality compared with placebo
  • the E3N observational studies suggested a lower breast cancer risk in users of micronized progesterone and dydrogesterone compared to users of other progestogens
  • the joint statement highlights that
    • " Recommendations on the risk of breast cancer with MHT should take into consideration the findings from the WHI randomized trials and the observational data on micronized progesterone and dydrogesterone from the E3N study as well as those from the CGHFBC meta-analysis

Reference:

1. Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 without the disease. Lancet 2001;358:1389-99.
2. Gammon MD et al. Environmental tobacco smoke and breast cancer incidence. Environmental Research 2004; 96 (2):76-185
3. Miller MD et al. The association between exposure to environmental tobacco smoke and breast cancer: a review by the California Environmental Protection Agency. Prev Med. 2007 Feb;44(2):93-106
4. BMS, IMS, EMAS, RCOG and AMS Joint Statement on menopausal hormone therapy (MHT) and breast cancer risk in response to EMA Pharmacovigilance Risk Assessment Committee recommendations in May 2020
5. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394:1159-68. doi: 10.1016/S0140-6736(19)31709-X 31474332.
6. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA. 2020;324(4):369–80. doi: 10.1001/jama.2020.9482
7. Fournier A, Mesrine S, Dossus L, et al. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Research and Treatment 2014;145(2):535-43
8. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ 2020;371:m3873.