Breast Cancer Risk Reduction

by Dr Natalie Shenker, BM BCh (Oxon), MSc, PhD Epigenetics and Breast Cancer (Imperial)

Breastfeeding and Breast Cancer Risk: What Are the Facts?

  • Breastfeeding can significantly reduce the risk of triple negative breast cancer (TNBC, the most aggressive breast cancers), probably in pre-menopausal women
  • Breastfeeding may not affect the incidence or risk of hormone receptor positive disease (oestrogen and/or progesterone receptors) or HER2 disease.

My PhD was in breast cancer risk- was it possible to find epigenetic biomarkers of risk in healthy women that could predict their chance of getting cancer in the future? Most of the work in our lab at Imperial looked at cells from blood samples, cell lines or tissue biopsies, none of which told us exactly what was going on in the cells in the breast.

Most breast cancers will arise from cells in the ductal system – a single layer of epithelium with stem cells in amongst them. As an aside, these stem cells normally cycle up 2-fold during the period of ovulation, preparing to launch off into rapid growth (10-fold cell turnover rates) if a pregnancy occurs. However, we needed a source of epithelial cells to examine for epigenetic and genetic mutations. So I spent the last 18 months of my PhD working out if we could use cells derived from breast milk to confirm the changes we were seeing in blood cells from women at high risk of breast cancer. If this was possible, then it could pave the way for a new tool to enhance high risk breast cancer screening.

I rapidly became fascinated with the papers I was reading about the possibility of reducing the risk of cancer by breastfeeding, as it just didn’t match up with my medical training. When I was at medical school, we were taught about breast cancer by breast surgeons, who would get us to write up a list of risk factors– high risks were age and strong family history (BRCA mutations had only just been discovered). Moderate risk factors included mainly hormonal factors (early menarche, late menstruation, parity, age at first child). Breastfeeding was classed as a low risk modifier– the published estimates back then were a reduction in risk of only about 4-5% for every year a woman breastfeeds over a lifetime1, which is a relatively small effect in the grand scheme of things.

Since 2002, molecular medicine has been able to look at cancers from thousands of different women. These studies have shown that ductal breast carcinomas, the most common form of breast cancer (>95%), cluster into five main biological types: luminal A, luminal B, HER2 positive, basal and the claudin-low/normal type2, 3.

dendrogram
Dendrogram showing clustering of breast cancer subtypes

Many, many more subtypes are and will be discovered as genetic and pathological checks get even better, but these five subtypes are important, as they likely indicate tumours that originate from different cells of origin within the breast ducts4 (see figure below by Visvader et al).

breastcancer-cells
Breast cancer cell subtypes

It became apparent last year that these subtypes were also important for the impact of breastfeeding. A meta-analysis of case-control and cohort studies that divided studies of risk according to breast cancer subtype showed no effect of breastfeeding on the hormone receptor subtypes (luminal A, B and HER2), which make up 70-75% of breast cancers5.

However, it did show a 16-24% risk reduction for triple negative breast cancers (TNBC, tumour cells do not express oestrogen and progesterone receptors or HER2/ERBB2 receptors)5.

forestplot
Forest Plot showing risk reduction due to breastfeeding for triple negative breast cancers

This systematic review looked at ‘ever breastfeeding’, rather than the duration of breastfeeding, as there were not enough studies that had recorded that to be analysed. Given that most studies have shown breastfeeding to have a dosage effect (the longer a woman breastfeeds, the lower their breast cancer risk), future studies that look specifically at these tumours may show a greater effect with prolonged breastfeeding duration.

Triple Negative Breast Cancers

TNBCs are one of the most aggressive forms of breast cancer. These tumours tend to occur in younger women and those with genetic mutations. Pregnancy-associated breast cancers also tend to be TNBCs. These are cancers that are diagnosed during pregnancy and, although the cut off is unclear, for up to 5 years after birth.  The mechanism, or mechanisms, that explain how breastfeeding reduces TNBC risk are not clear, but are the subject for a great deal of future research, some of which we are hoping to facilitate in the future at the Hearts Milk Bank.

TNBCs also tend to occur in younger women, those with inherited genetic mutations (BRCA1 in particular), and in certain ethnic groups. Around eight out of ten women with a BRCA1 mutation will develop breast cancer at some point in their life. If a woman with this mutation breastfeeds over a lifetime for 1 year, they reduce this risk by 35-40%, and by 55-60% if they breastfeed for 2 years6-8. A similar effect has been reported for ovarian cancer9. This dramatic reduction is of particular interest, as it appears to have a higher risk reduction than prophylaxis with tamoxifen. These findings are not well known in the clinical genetics community though, who generally advise that women do not breastfeed for long, in order that they can have a screening MRI at 3 months after birth.

However, a small number of women (approximately 100-120 each year in the UK) who breastfeed will still develop aggressive breast cancers. As with everything in medicine and public health, breastfeeding protects some, but in others:

  1. The mechanisms will be inadequate and the cancer would develop anyway or
  2. The molecular and cellular mechanisms that occur in preparing for and performing lactation may trigger some women with a specific genetic make up to develop a cancer.

So, does breastfeeding protect women from breast cancer? For the majority of tumours, perhaps not, but more research is needed to look at the effect of long-term breastfeeding on the other subtypes of breast cancer. At the Hearts Milk Bank, we will be working with scientists across a range of fields to facilitate research that can determine how this effect happens.

For the 20-30% of TNBCs with the worst prognosis, which affect premenopausal women, breastfeeding is probably a very powerful way to reduce risk.

With thanks to Dr Shenker for her contribution to this website. She is a co-founder of the Hearts Milk Bank, the UK’s newest milk bank, which will provide donor milk across London and the South East and support a new programme of breast cancer research.

References

  1. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet. 2002;360(9328):187-195
  2. Perou C, Sørlie T, Eisen M, van de Rijn M, Jeffrey S, Rees C et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747-752.
  3. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron J, Nobel A et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proceedings of the National Academy of Sciences. 2003;100(14):8418-8423.
  4. Visvader J, Stingl J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes & Development. 2014;28(11):1143-1158.
  5. Islami F, Liu Y, Jemal A, Zhou J, Weiderpass E, Colditz G et al. Breastfeeding and breast cancer risk by receptor status—a systematic review and meta-analysis. Annals of Oncology. 2015;379.
  6. Kotsopoulos J, Lubinski J, Salmena L, Lynch H, Kim-Sing C, Foulkes W et al. Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Research. 2012;14(2).
  7. Jernstrom H, Lubinski J, Lynch H, Ghadirian P, Neuhausen S, Isaacs C et al. Breast-feeding and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers. JNCI Journal of the National Cancer Institute. 2004;96(14):1094-1098.
  8. Pan H, He Z, Ling L, Ding Q, Chen L, Zha X et al. Reproductive factors and breast cancer risk among BRCA1 or BRCA2 mutation carriers: Results from ten studies. Cancer Epidemiology. 2014;38(1):1-8.
  9. Kotsopoulos J, Lubinski J, Gronwald J, Cybulski C, Demsky R, Neuhausen S et al. Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. International Journal of Cancer. 2014;137(5):1136-1146.
Published April 2017