Understanding the Limited Impact of Hormonal Contraception and Menopausal Hormone Therapy on Breast Cancer Risk
I recently listened to Prof JA Eden's presentation at the World Menopause Congress on the topic “Why do hormonal contraception and menopausal hormonal treatment have such a small effect on breast cancer risk?”. This is a summary and my interpretation of his talk.
Breast Cancer Basics:
Breast cancer is a common malignancy in women, with most tumours being oestrogen receptor-positive (ER+) and often progesterone receptor-positive (PR+).
Interestingly, contrary to what many might expect, long-term use of hormonal contraception or menopausal hormonal therapy (MHT) doesn't significantly increase the risk of ER+ breast cancer or worsen prognosis.
In fact, the Women's Health Initiative (WHI) study showed that oestrogen-only treatment in women who had undergone hysterectomy actually led to a lower risk of developing breast cancer and dying from the disease.
Risk Factors:
It's important to understand the various risk factors associated with breast cancer. These can be categorised into high-risk, moderate-risk, and minimal-risk factors:
High-risk factors (RR > 4) include being female, increasing age, Caucasian ethnicity, specific genes (e.g., BRCA1/2 mutations), previous breast cancer, atypical hyperplasia/DCIS, high-density mammograms, age at first pregnancy, and Western diet.
Moderate-risk factors (RR > 2) include height, obesity, young age at menarche, late age at menopause, and alcohol intake.
Minimal-risk factors (RR < 2) include recent hormonal contraceptive usage, recent/prolonged MHT, high birth weight, late first pregnancy, low physical activity, ionizing radiation, and working on an aeroplane.
The Role of Breast Stem Cells:
Recent evidence suggests that a small population of breast stem cells drives the breast cancer process. These stem cells are unspecialised cells capable of self-renewal and differentiation into all breast cell types. They represent between 1/200 and 1/1000 cells within the breast and are located in niches along the breast duct. Most breast cancers are believed to be initiated in these long-lived breast stem cells.
Hormonal Therapy and Breast Cancer:
Hormone Replacement Therapy (HRT) demonstrates a relatively minor influence on breast cancer risk (RR < 2) when compared to other factors such as regular alcohol consumption (RR > 2), advancing age (RR > 4), and increased height or body mass index.
Current research suggests that breast cancer originates from cumulative genetic and epigenetic alterations in long-lived breast stem cells. Once a stem cell becomes malignant, it escapes its regulatory environment and generates abnormal progeny. These descendant cells subsequently develop oestrogen and progesterone receptors, constituting most of the tumour mass. Oestrogen serves as the primary growth stimulant for ER+ breast cancer cells, with locally synthesised oestrogens from adipose and breast tissue playing a crucial role in tumour progression.
The Women's Health Initiative (WHI) study's combined oestrogen-progestin arm, which administered menopausal hormone therapy to women with a mean age of 64 (older than typical HRT users), revealed a modest increase in breast cancer risk. This effect was likely attributable to a minor promotional impact on pre-existing tumours, which may have been detected slightly later without HRT. Conversely, the oestrogen-only arm of the WHI study demonstrated a reduced breast cancer risk, potentially due to the apoptotic effect of oestrogen administration in older postmenopausal women. Notably, women undergoing HRT at the time of breast cancer diagnosis have shown improved survival rates, also providing reassurance regarding HRT use.