The 2017 Hormone Therapy Position Statement of The North American Menopause Society

The North American Menopause Society 2017 Hormone Therapy Position Statement Advisory Panel

Disclosures

The North American Menopause Society (NAMS). 2018;24(7):728-753. 

In This Article

Breast Cancer

Potential differences may exist in breast cancer risk with ET, EPT, and CEE combined with bazedoxifene therapies. Different types of estrogen or progestogen, as well as different formulations, doses, timing of initiation, durations of therapy, and patient characteristics, may play a role in HT's effect on the breast.

Estrogen-alone Therapy

Compared with women who received placebo, women who received CEE alone in the WHI showed a nonsignificant reduction in breast cancer risk after an average of 7.2 years of randomization, with 7 fewer cases of invasive breast cancer per 10,000 person-years of CEE (HR, 0.79; 95% CI, 0.61–1.02; Figure 1).[14] The nonsignificant pattern of reduction in breast cancer remained evident for up to a median 13 years' cumulative follow-up (HR, 0.80; 95% CI, 0.58–1.11). A statistically significant reduction of breast cancer risk resulting from CEE in the WHI was observed overall in women who were at least 80% compliant with therapy (HR, 0.67; 95% CI, 0.47–0.97) and in women with no prior HT use (HR, 0.65; 95% CI, 0.46–0.92; Pfor interaction, 0.09) versus prior use of HT.[192] Smaller trials have shown similar nonsignificant reductions in breast cancer with ET;[182,193] however, many but not all observational studies have shown an increased risk.[194]

Longer duration of estrogen-alone therapy use. There are no RCTs designed or powered for breast cancer to inform our understanding of long durations of ET and the risk of breast cancer. One small, randomized, nonblinded trial found no increased risk of breast cancer for up to 10 years' HT use and 16 years' follow-up, but this was not a primary outcome.[182] Observational studies on long duration are mixed, with some observational studies and meta-analyses reporting an elevated risk of breast cancer with estrogen-alone use for more than 5 years,[195,196] whereas others have not.[197–204]

Estrogen-progestogen Therapy

In the WHI, daily continuous-combined CEE + MPA resulted in increased risk of breast cancer (a rare absolute risk of breast cancer), with 9 additional breast cancer cases per 10,000 person-years of therapy (Figure 1).[14] The increase in breast cancer risk in the WHI for CEE + MPA was found after 5.6 years, significant in nominal statistics (HR, 1.24; 95% CI, 1.01–1.53) but not significant in multiadjusted statistics[14,205] or when adjustments were made for multiple risk factors.[206] The increase appears to begin at 3 years,[207] and the HR remained elevated at 13 years in the postintervention, unblinded follow-up (HR, 1.32; nominal 95% CI, 1.08–1.61).[14] In post hoc subgroup analysis, the increased incidence of breast cancer was limited to women who had prior exposure to HT (HR, 1.85; 95% CI, 1.25–2.80), whereas in women without prior exposure to HT, breast cancer incidence was not significantly affected byCEE + MPA (HR, 1.16; 95% CI, 0.98–1.37) over 11 years' follow-up (including mean intervention time of 5.6 y; Pfor interaction, 0.03).[205,206] These results should be treated with caution until confirmed elsewhere.

Attributable Risk of Breast Cancer

The attributable risk of breast cancer in women (mean age, 63 y) randomized to CEE + MPA in the WHI is less than 1 additional case of breast cancer diagnosed per 1,000 users annually,[14] a risk slightly greater than that observed with one daily glass of wine, less than with two daily glasses, and similar to the risk reported with obesity, low physical activity, and other medications.[202,208]

Early Hormone Therapyin Women at Genetic Risk for Breast Cancer

One study provides some reassurance about estrogen given to younger women at higher risk.[209] The Two Sister Study of 1,419 sister-matched cases of breast cancer in women aged younger than 50 years and 1,665 controls showed no increased risk of young-onset breast cancer with use of EPT (OR, 0.80; 95% CI, 0.41–1.59), whereas unopposed estrogen use was associated with a reduced diagnosis of young-onset breast cancer (OR, 0.58; 95% CI, 0.34–0.99)

Role of Progestogens

Some but not all observational data suggest that MP may have less effect on breast cancer risk, whereas more potent progestogens such as MPA may have a more adverse effect,[15,204] but randomized trials are needed.

Mammographic Breast Density and Estrogen

Different HT regimens may be associated with increased breast density, which may obscure mammographic interpretation.[210] More mammograms and breast biopsies were required in women receiving CEE + MPA in the WHI.[211] In trials up to 2-years' duration, breast tenderness, breast density, and breast cancers were not increased with oral CEE plus bazedoxifene compared with placebo.[212–214]

Use of Hormone Therapy in Women With Genetic Risk Factors for Breast Cancer

Limited observational evidence suggests that HT use does not further increase risk of breast cancer in women with a family history of breast cancer or in women after oophorectomy for BRCA 1 or 2 gene mutation.[215–220]

Hormone Therapy After Breast Cancer

The use of systemic HT in survivors of breast cancer is generally not advised. Observational studies and randomized trials report both neutral effects[221–230] and increased risk of breast cancer recurrence.[221,228,231] However, low-dose vaginal ET remains an effective treatment option for GSM, with minimal systemic absorption, and treatment may be considered after an initial trial of nonhormone therapies and in consultation with an oncologist, with more concern for women on AIs.[69]

Area of Scientific Uncertainty

Breast tissue recently exposed to endogenous estrogen and progesterone may react differently to exogenous hormones than if more distantly exposed, but this theory of estrogen-induced apoptosis of occult tumors remains unproven.[232,233] Different types of estrogen may have different effects on the breast, thus limiting the generalizability of the findings of reduced breast cancer cases with CEE in the WHI.

Key Points

• The effect of HT on breast cancer risk may depend on the type of HT, dose, duration of use, regimen, route of administration, prior exposure, and individual character istics.

   - Women's Health Initiative results suggest a nonsignificant reduced risk of breast cancer with CEE alone in women with a hysterectomy. Similar nonsignificant reductions for estradiol were observed in two smaller randomized trials (approximately 1,000 perimeno-pausal and postmenopausal participants), although not in all large observational studies.

   - A rare absolute risk of breast cancer (< 1 additional case/1,000 person-years of use) was seen with daily continuous-combined CEE + MPA in the WHI but not seen in all trials or all subanalyses of the WHI, such as in women without prior HT exposure, but it is consistent with many observational trial results.

   - The potential risk of breast cancer should be included in discussions about benefits and risks of HT.

• Duration of HT use may be an important factor in breast cancer risk, because in some studies, risk increased with longer durations of use.

• Different HT regimens may be associated with increased breast density, which may obscure mammographic interpretation, leading to more mammograms or more breast biopsies.

• In trials up to 2-years' duration, breast tenderness, breast density, and breast cancers were not increased with oral CEE plus bazedoxifene compared with placebo.

• Limited observational evidence suggests that HT use does not further increase risk of breast cancer in women with a family history of breast cancer or in women after oophorectomy for BRCA 1 or 2 gene mutation.

• Systemic HT is not recommended for survivors of breast cancer, although selected cases with compelling reasons may be discussed in conjunction with an oncologist after nonhormone options have been unsuccessful.

• For survivors of breast cancer with bothersome GSM symptoms, low-dose vaginal ET, with minimal systemic absorption, may be considered after a failed trial of non-hormone therapies and in consultation with an oncologist. There is a concern even with low-dose vaginal ET for women on AIs because of suppressed estradiol levels.

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