“Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence.”
Collaborative Group on Hormonal Factors in Breast Cancer. The Lancet 29th August’2019


The following is a review of the three major studies on menopausal hormone therapy (MHT) use and breast cancer risk.

Significant findings from the Collaborative Group on Hormonal Factors in Breast Cancer. The Lancet 2019 study:

This meta-analysis includes 58 epidemiological studies over the period January 1992 - January 2018 pooling data of 108,647 postmenopausal women who developed breast cancer of which 55,575 (51%) had used MHT. This review suggests an increase in the risk of breast cancer with MHT intake, except for vaginal estrogens. Risks were greater for estrogen-progestogen than for estrogenonly preparations, but was also increased, although to a lesser extent, with oestrogen only systemic MHT.
Risk of breast cancer depends on type of progesterone used in MHT. It suggests that all MHTs are not the same. Supplementary data on subgroup analysis suggests, for the oestrogen-progestagen preparations, risks did not generally differ between different progestagenic constituents, including micronised [natural] progesterone, but appeared to be somewhat lower for combinations containing dydrogesterone . After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following a mean of 3 years of MHT use. Starting MHT between the age of 40 and 50 was also associated with an increased risk of breast cancer, but the number of women in this sub-group was relatively small.

Significant findings from the Collaborative Group on Hormonal Factors in Breast Cancer. The Lancet 1997 study:

This epidemiological study included individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries .The study suggested a causal relationship between menopausal hormone therapy (MHT) and breast cancer. Short-term use of combined estrogen-progestin  therapy less than four years appears not to increase the risk of breast cancer significantly, although it may make mammographic detection more difficult.The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1–3), 6 (3–9), and 12 (5–20). Whether HRT affects mortality from breast cancer is not known.

What does the 2019 study add to the information on MHT and breast cancer ?

For the oestrogen-progestagen preparations, risks did not generally differ between different progestagenic constituents, including micronised [natural] progesterone, but appeared to be somewhat lower for combinations containing dydrogesterone 1 For a given preparation, the relative risks during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years. Risk were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese).Hence, the absolute and relative excess risks associated with MHT use were greater for lean women than for obese women. Whether MHT affects mortality from breast cancer is not known. Risk increased with increasing BMI among never users an association that did not weaken with age, but not among current users.

Significant findings from the Woman’s Health Initiative (WHI)

WHI a randomized controlled clinical trial of hormone replacement therapy (HRT) was initiated to address cardiovascular disease, cancer, and osteoporosis, the most common causes of death, disability, and impaired quality of life in postmenopausalwomen. Initiated in 1993, the WHI enrolled 161,808 women aged 50-79. In the combined estrogen-progestin WHI trial, there were eight excess cases per 10,000 person- years at an average of 5.2 years the estimated additional risk of breast cancer based upon WHI data was three additional cases per 1000 women for five
years of combined conjugated estrogen-MPA use between the ages of 50-59 yrs.This falls in the rare adverse event category by the definition for adverse events by The Council for International Organizations of Medical Sciences (CIOMS) During the active intervention phase (median duration 5.9 years), there was a nonsignificant lower risk of breast cancer (104 versus 135 cases in the estrogen and placebo groups, respectively (HR 0.79, 95% CI 0.61-1.02) [6]. With median followup of 13 years, there were 168 versus 216 cases of breast cancer, respectively (HR 0.79, 95% CI 0.65-0.97).
For unopposed conjugated estrogen, they estimated there would be 2.5 fewer cases of breast cancer per 1000 women (in their 50s) taking hormones for five years There is evidence of a significant reduction in coronary heart disease among young women at menopause using MHT, and the fracture risk reduction associated with the use of MHT is well described.

Placing “risk” into perspective

Common lifestyle factors such as reduced physical activity, obesity and alcohol consumption (>2 drinks a day) are associated with similar or greater risk of breast cancer compared with MHT. The most important modifiable risk factor for postmenopausal breast cancer weight gain during adult life; Public health messages highlighting the importance of minimising weight gain is important for prevention of breast cancer.2

IMS response-Does the 2019 study effect the prescription pattern of MHT ?

Prescription of menopausal hormone therapy (MHT) appears to be a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years ,who do not have contraindications to MHT and are at low risk for breast cancer.
Like all medicines, HT needs to be used appropriately and judiciously. Women considering MHT should have their underlying risks for disease routinely assessed before making a therapeutic decision. Presently ,we do not have a validated risk assessment model for breast cancer. Online questionnaire based risk assessment tools like the modified Gail model ,includes race as one off the factors and may be used.The result is a Gail score, which estimates the risk of developing invasive breast cancer in the next 5 years.Gail model is 1% at five years (10/1000 women) and the relative risk is 1.29, then the excess risk is 2.9/1000. With a Gail model score of 5% (50/1000) the excess risk is 16/1000. This reasoning supports the recommendation to calculate risk of breast cancer in all women considering the use of MHT. For safety in the use of MHT, indivulisation of treatment is important ,which includes understanding the indication, the age of the woman ,type of oestrogen and progesterone , dose and route of therapy.
Intensive cost-effective methods like awareness of the modifiable risk factors, risk assessment, monthly self breast examination, yearly breast examination by a professional to downstage the disease and improve survival are needed to be popularised. The government and the medical societies need to establish country specific diagnostic screening protocols.

Trends in Breast cancer in India: In Indian perspective is MHT is a major risk
factor?

In India, MHT uses are not common, yet over the 26-year period, the agestandardised incidence rate of breast cancer in females increased by 39·1% (95% UI 5·1–85·5) from 1990 to 2016. 3 For breast cancer, a substantial increase in age-standardised incidence rate is consistent with changes in some risk factors over time in India, such as later age at first birth, lower parity, and increase in overweight and obesity. More younger women are getting diagnosed with breast cancer. 25 years back, 69% of the patients were above 50 years of age. Presently, almost 48% patients are below 50 years age 4. Breast cancers in the young are hormone positive in 48%, rest are negative and tend to be more aggressive. Many of these cancers are HER2 positive and ER/PR negative, or HER2/ER/PR all three negative (31% triple negative).5 In the United States , 89 women out of 100 are likely to survive for 5 yrs after breast cancer. In India a rough estimate is not even 60 % and present at in stages 3 and 4.

References:

  • Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–111
  • Rulla M. Tamimi; Donna Spiegelman; Stephanie A. Population Attributable Risk of Modifiable and Nonmodifiable Breast Cancer Risk Factors in Postmenopausal Breast Cancer, Am J Epidemiol. 2016;184(12):884893
  • National Cancer Registry Programme- India (Three Year Report of the Population Based Cancer Registries 2012 – 2014 & Consolidated Report of the Hospital Based Cancer Registries 2012 – 2014). http://www.breastcancerindia.net/statistics/trends.html
  • Gurprataap S. Sandhu, Sebhat Erqou, Heidi Patterson, Aju Mathew. Prevalence of TripleNegative Breast Cancer in India: Systematic Review and Meta-Analysis. Journal of Global Oncology. Volume 2, Issue 6, December 2016. (412-21).
  • Boardman HMP, et al. Hormone therapy for preventing cardiovascular disease in postmenopausal women. Cochrane Database Syst Rev. 2015, Issue 3.R
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