Systemic Progestogen Therapy After Breast Cancer: Contraindicated
Systemic progestogen therapy (oral, injectable, or transdermal) is contraindicated in patients with a prior history of breast carcinoma, regardless of hormone receptor status. 1, 2
Guideline-Based Contraindications
The evidence against systemic progestogen use in breast cancer survivors is clear and consistent:
The NCCN explicitly states that menopausal hormone therapy (which includes progestins) is contraindicated in survivors with a history of hormonally mediated cancers, including breast cancer, due to increased risk of recurrence. 1
The ESO-ESMO international consensus guidelines clearly state that exogenous hormonal therapy is generally contraindicated in young cancer survivors, irrespective of disease subtype. 1
The FDA drug label for progesterone warns that the WHI estrogen plus progestin substudy demonstrated a statistically significant increased risk of invasive breast cancer (relative risk 1.24) compared to placebo, with 41 versus 33 cases per 10,000 women-years. 2
Evidence of Harm
The data demonstrating increased recurrence risk is compelling:
The HABITS trial demonstrated a significantly increased risk of breast cancer recurrence with hormonal therapy use in breast cancer survivors, with a cumulative incidence at 5 years of 22.2% in the hormone therapy arm versus 8.0% in the control arm. 1
Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, with 46 versus 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. 2
Invasive breast cancers diagnosed in women using combined estrogen-progestin therapy were larger, more likely to be node positive, and diagnosed at a more advanced stage compared with placebo. 2
Mechanism of Harm
The biological rationale supports the clinical findings:
Progesterone stimulates proliferation and promotes cytoplasmic localization of the cell cycle inhibitor p27 in steroid receptor positive breast cancers, leading to increased tumor cell proliferation. 3
Progestins are reported to increase the risk of more aggressive ER+ PR+ breast cancers in postmenopausal women through activation of Src and PI3K pathways. 3
Clinical Pitfalls to Avoid
Several common misconceptions must be addressed:
Do not assume that hormone receptor-negative breast cancers are safe for progestogen therapy—guidelines contraindicate use irrespective of disease subtype. 1
Do not confuse local progestogen therapy (such as levonorgestrel IUD for specific endometrial indications) with systemic progestogen therapy—the question specifically addresses systemic routes (oral, injectable, transdermal). 1
Do not rely on older observational studies suggesting safety—the highest quality randomized trial data (HABITS, WHI) demonstrate clear harm. 1, 2
Alternative Management Strategies
For menopausal symptoms in breast cancer survivors:
Non-hormonal alternatives should be used, including selective serotonin reuptake inhibitors (venlafaxine), clonidine, vitamin E, and gabapentin for vasomotor symptoms. 4
For osteoporosis prevention, bisphosphonates, diet, and exercise should be used instead of hormone therapy. 4
For cardiovascular disease prevention, statins, diet, and exercise are appropriate alternatives. 4
Special Consideration: Premature Ovarian Insufficiency
Even in the specific scenario of premature ovarian insufficiency after breast cancer treatment:
The ESHRE guideline explicitly states that HRT (including progestogens) is generally contraindicated in breast cancer survivors, despite the significant cardiovascular and bone health risks of untreated premature ovarian insufficiency. 5
The American College of Obstetricians and Gynecologists recommends avoiding hormone replacement therapy in women with a personal history of breast cancer as an absolute contraindication. 6