What hormone replacement therapy (HRT) combination carries a lower breast cancer risk for postmenopausal women?

HRT Combinations and Breast Cancer Risk

Estrogen-only therapy carries a lower breast cancer risk compared to combined estrogen-progestin therapy for postmenopausal women, particularly when using natural progesterone instead of synthetic progestins if a progestogen is required. 1, 2, 3

Evidence on Breast Cancer Risk by HRT Type

Estrogen-Only vs. Combined Therapy

The Women's Health Initiative (WHI) study provides the strongest evidence regarding HRT and breast cancer risk:

• Estrogen-only therapy: After nearly 11 years of follow-up, women receiving estrogen-only therapy showed a statistically significant reduction in invasive breast cancer incidence compared to placebo (HR 0.77; 95% CI, 0.62 to 0.95), with an absolute risk reduction of 8 fewer cases per 10,000 person-years 1

• Combined estrogen-progestin therapy: Women receiving combined estrogen and progestin therapy had an increased risk of invasive breast cancer (HR 1.26; 95% CI, 1.00 to 1.59) 1

This difference in risk between the two regimens is striking and consistent across multiple studies. The WHI investigators reported that no increase in breast cancer was observed after 5 years of follow-up in the ongoing study of unopposed estrogen in women who had had a hysterectomy 1.

Natural Progesterone vs. Synthetic Progestins

For women who require a progestogen (those with an intact uterus), the type of progestogen matters:

• A meta-analysis of three studies involving 86,881 postmenopausal women found that natural progesterone was associated with a significantly lower risk of breast cancer compared to synthetic progestins 2

• Transdermal estradiol combined with natural progesterone may confer less or even no risk of breast cancer compared to estrogen with synthetic progestins 3

Clinical Decision Algorithm

1. For women without a uterus:

   • Estrogen-only therapy is preferred due to lower breast cancer risk
   • Use the lowest effective dose for the shortest duration needed 4

2. For women with an intact uterus (who require progestogen to prevent endometrial cancer):

   • Consider estrogen combined with natural progesterone rather than synthetic progestins 2, 3
   • Transdermal estradiol with natural progesterone may offer the best safety profile 3

3. Duration considerations:

   • Short-term use (<5 years) carries less risk than long-term use
   • Long-term users (>5 years) have a relative risk of 1.23 to 1.35 for breast cancer 1

Important Caveats and Considerations

• Women with prior breast cancer: HRT is generally contraindicated in women with a history of breast cancer 5

• Age factor: The risk of breast cancer with HRT appears to be greater in older women (60-64 years) with relative risk of 1.71 (95% CI, 1.34 to 2.18) for women using hormones for 5+ years 6

• Absolute risk perspective: While relative risks are important, the absolute increase in breast cancer cases with combined HRT is approximately 8 additional cases per 10,000 women-years 1

• Risk returns to baseline: The increased risk of breast cancer with HRT returns to normal shortly after treatment cessation 7

• Other health considerations: HRT decisions should also consider other risks including cardiovascular disease, venous thromboembolism, and stroke, which are increased with HRT use 1, 4, 8

Bottom Line

When HRT is indicated for management of menopausal symptoms, estrogen-only therapy carries the lowest breast cancer risk for women without a uterus. For women with an intact uterus who require progestogen, natural progesterone appears to be safer than synthetic progestins with respect to breast cancer risk. All HRT should use the lowest effective dose for the shortest duration needed.