Breast Cancer Endocrine Therapy

Endocrine therapy should be offered to patients with invasive hormone receptor positive (HR+) breast cancer.  Patients with low HR positivity (Allred 3-5) should be considered for endocrine therapy but clinicians should discuss the likelihood of lower clinical benefit which may not outweigh the side-effects of treatment.  Endocrine therapy may be given concurrently with radiotherapy but is usually given sequentially after chemotherapy to limit cumulative adverse effects.

The choice of initial therapy is indicated by menopausal status at diagnosis and the risk of disease recurrence.  Shared decision discussion with patients should include the risk of recurrence and toxicity of treatment and take into consideration a patient’s age and co-morbidities.  Up to 50% of patients will discontinue treatment before completing the scheduled duration due to the impact of adverse effects on their quality of life. 

Non-adherence is associated with a reduction in overall survival, therefore the foremost factor dictating choice of therapy is that best tolerated by the patient.

Women can be considered post-menopausal if one of the following definitions are met:

• Bilateral surgical oophorectomy
• Age >49 and natural amenorrhoea > 2 years
• Age <55 natural amenorrhoea of more than 1 year but less than 2 years duration and FSH >25 IU/L and oestradiol within locally defined postmenopausal range*
• Age ≥55 and natural amenorrhoea of at least 1 year duration
• Patients with an intrauterine device may be considered postmenopausal if FSH >25 IU/L and oestradiol within locally defined postmenopausal range.

*Local laboratory defined post-menopausal range will vary. An acceptable alternative, less conservative, cut-off is <110pmol/l.

The definition of high-risk features may include one or more of the following:

• Grade 3
• T3
• Node positive (including micrometastases)
• HER2 positive.

Individual patients should be assessed to determine whether they are considered high risk. The above features serve as a guide but are not a definitive list. Where patients are considered borderline for high risk, the benefits, risks and uncertainties should be discussed fully with the patient to inform shared decision making.

Risk of recurrence and treatment choice

Either tamoxifen or Aromatase Inhibitors (AI) are both standard treatments for initial treatment of post-menopausal women.  

Tamoxifen may be considered in the absence of high-risk features, if AI’s are not tolerated or contraindicated or for patient preference. 

Offer an AI as the preferred initial therapy in the presence of one or more high-risk features. 

At least 5 years of treatment should be recommended. All patients should be offered a specialist review appointment after 5 years to discuss extended therapy. 

Low-risk disease

For patients without high risk features the benefits of extended therapy are unlikely to outweigh the risks of side effects and treatment should be discontinued after 5 years.

High-risk disease

Patients who have been taking tamoxifen or an AI for 5 years review should be recommended for an additional 2 years of AI to make 7 years of endocrine therapy in total.

For patients who opt for tamoxifen in preference to an AI on grounds of contraindications or side effects, a further 5 years of tamoxifen should be recommended to complete 10-years of adjuvant endocrine therapy in total.

Risk of recurrence and initial treatment choice

In the absence of high-risk features, single agent of tamoxifen is the standard of care for pre-menopausal women.  If tamoxifen is contraindicated, ovarian function suppression (OFS) alone can be considered, but the risk of adverse effects must be discussed.

Offer tamoxifen in combination with OFS in patients with one or more high-risk features.  

Tamoxifen and OFS may be initiated in a stepwise approach.

Consider AI + OFS in younger patients (<35) or with multiple features suggesting very high risk of recurrence.

At least 5 years of treatment should be recommended. All patients should be offered a specialist review appointment after 5 years to discuss extended therapy. Choice of extended therapy longer than 5 years depends on menopausal status and previous treatment.  Shared decision making with the patient should include the risk/benefit of extended therapy with the impact of treatment on quality of life. 

Pre-menopausal at 5-year review

OFS should stop at 5-years. 

For patients with at least one high risk feature, who remain within the pre-menopausal age range after 5 years of endocrine therapy, a further 5 years (10 years in total) of tamoxifen should be offered. 

For patients who are post-menopausal (e.g. >55yrs) after 5 years of therapy, refer to the post-menopausal strategy above. As neither amenorrhoea nor FSH/oestradiol measurements can be used here, this is based solely on age.

Therapeutic options for medical OFS

Gonadotrophin-releasing hormone agonists (GnRHa) should be initiated by a specialist, after which they may be prescribed and administered in primary care.  Various formulations of GnRHa are available for subcutaneous (SC) or intramuscular (IM) injection and licensed for the treatment of early breast cancer.  Choice of GnRHa may be based on cost-effectiveness, availability, local formulary and patient preference. 

Monitoring of ovarian function during OFS

For patients treated with tamoxifen and OFS, monitoring of ovarian function is not necessary.

For patients treated with OFS and AI, check oestradiol after 3, 6 and 12 months to confirm undetectable; if three consecutive results are below threshold further monitoring is not required.

Endocrine treatment can be teratogenic and thus should be avoided during pregnancy. However, for many younger patients who wish to start a family, waiting 5-10 years to complete endocrine therapy may not be possible or practical due to diminishing fertility with age.

Whilst the long-term impact remains uncertain, a recent prospective study has demonstrated that among select women with previous hormone receptor–positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort.

The following points from the study should be considered when discussing potentially pausing treatment with patients:

• Patients had received a minimum of 18 months of endocrine therapy
• A 3 month wash-out period was required
• Patients had a maximum of two years treatment break before resuming endocrine therapy.

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