What is the breast‑cancer risk associated with Myfembree (relugolix + estradiol + norethindrone acetate), particularly in women with a personal or family history of estrogen‑receptor‑positive breast cancer?

Breast Cancer Risk with Myfembree

Myfembree (relugolix/estradiol/norethindrone acetate) carries an increased risk of estrogen-receptor-positive breast cancer and should be avoided in women with a personal or family history of breast cancer, particularly estrogen-receptor-positive disease.

Mechanism of Breast Cancer Risk

The breast cancer risk with Myfembree stems from its hormonal add-back therapy component (estradiol plus norethindrone acetate), which is included to mitigate hypoestrogenic side effects of the GnRH antagonist relugolix 1, 2. This combination therapy maintains systemic estradiol concentrations in a therapeutic range 1, but this estrogen exposure creates oncologic risk.

Evidence from Hormone Therapy Studies

The combination of estrogen plus progestin (similar to Myfembree's estradiol/norethindrone component) significantly increases breast cancer risk:

• Combined estrogen-progestin therapy increases breast cancer incidence by 26% (HR 1.26; 95% CI, 1.00-1.59) according to the Women's Health Initiative 3
• The HERS study demonstrated similar increases with HR 1.27 (95% CI, 0.84-1.94) over 6.8 years 3
• Cancers diagnosed in hormone therapy users were more advanced stage than in placebo groups 3

Estrogen-Receptor Status Matters Critically

The risk is specifically for estrogen-receptor-positive breast cancer, which is the predominant type in most women:

• Selective estrogen-receptor modulators (like tamoxifen and raloxifene) reduce estrogen-receptor-positive invasive breast cancer by 7-9 fewer events per 1000 women over 5 years 4
• These agents do not reduce risk for estrogen-receptor-negative breast cancer 4
• In BRCA1 mutation carriers, 69% of breast cancers are estrogen-receptor-negative, while only 16% of BRCA2-associated cancers are estrogen-receptor-negative 4

Contraindications in High-Risk Women

Personal History of Breast Cancer

Women with a personal history of breast cancer should not receive Myfembree, as the estradiol component will stimulate any residual estrogen-receptor-positive disease. The evidence shows that:

• Estrogen-progestin therapy increases breast cancer recurrence risk 3
• The Million Women Study showed RR 1.30 (95% CI, 1.21-1.40; P < 0.0001) even with estrogen alone 3

Family History and BRCA Mutations

Women with strong family history or known BRCA mutations face complex risk:

• BRCA1 carriers have predominantly estrogen-receptor-negative cancers (69%), so estrogen exposure may pose lower relative risk for this specific mutation 4
• BRCA2 carriers have predominantly estrogen-receptor-positive cancers (84%), making estrogen exposure particularly hazardous 4
• Risk-reducing medications like tamoxifen reduce estrogen-receptor-positive breast cancer in high-risk women 4, but adding exogenous estrogen (as in Myfembree) would counteract this protective effect

Quantifying the Excess Risk

The cumulative excess breast cancer cases per 1000 women starting hormone therapy at age 50 is 2 additional cases (95% CI, 1-3) with just 5 years of use 3. For women already at elevated baseline risk due to family history or genetic predisposition, this relative increase becomes clinically significant.

Alternative Management Strategies

For women with contraindications to Myfembree who need fibroid or endometriosis management:

• Relugolix monotherapy (without estrogen add-back) eliminates the breast cancer risk but requires monitoring for bone mineral density loss and vasomotor symptoms 5, 1
• Surgical options (myomectomy, hysterectomy) avoid hormonal exposure entirely 6
• GnRH agonists with short-term use can manage severe symptoms before surgery 1
• Non-hormonal approaches including NSAIDs, tranexamic acid, or uterine artery embolization 7

Clinical Decision Algorithm

1. Screen for breast cancer history: Personal history of breast cancer = absolute contraindication to Myfembree
2. Assess family history: First-degree relatives with breast cancer, especially if premenopausal or bilateral = high caution
3. Consider genetic testing: Known BRCA2 mutation = avoid Myfembree; BRCA1 mutation = individualized discussion but generally avoid
4. Evaluate alternative therapies: Prioritize non-hormonal or surgical options in high-risk women
5. If Myfembree is considered despite moderate risk: Implement intensified breast surveillance with annual mammography and consider breast MRI 8

The fundamental principle is that exogenous estrogen exposure increases estrogen-receptor-positive breast cancer risk, and this risk is magnified in women with pre-existing elevated baseline risk from personal or family history 4, 3.