Breast Cancer Systemic Therapy
On this page
Direct answer
Breast cancer systemic therapy is chosen mainly by the receptor status of the tumour, namely oestrogen receptor, progesterone receptor and HER2. Oestrogen-receptor-positive disease is treated with endocrine drugs such as tamoxifen or an aromatase inhibitor, HER2-positive disease adds trastuzumab, and triple-negative disease relies on chemotherapy.
What you must remember
- ER and PR: Oestrogen and progesterone receptor positivity predicts benefit from endocrine therapy.
- HER2: Overexpression or gene amplification predicts benefit from trastuzumab and other HER2-directed agents.
- Premenopausal endocrine therapy: Tamoxifen is used, or an aromatase inhibitor combined with ovarian function suppression.
- Postmenopausal endocrine therapy: An aromatase inhibitor such as letrozole, anastrozole or exemestane is commonly preferred.
- Duration: Endocrine therapy is commonly continued for about five years, with extension considered in selected patients.
- Trastuzumab toxicity: Cardiotoxicity is the key concern, and it is worsened by prior or concurrent anthracyclines.
- Triple-negative disease: Chemotherapy is the mainstay, since neither endocrine nor HER2-directed drugs have a target.
- Tamoxifen toxicities: Endometrial cancer, venous thromboembolism and hot flushes are the important adverse effects.
Choosing therapy from receptor status
A 48-year-old postmenopausal woman has an ER-positive, PR-positive, HER2-negative invasive carcinoma after surgery. The receptor profile and menopausal status together decide the endocrine drug and whether chemotherapy is needed.
- Confirm the receptors: Check ER, PR and HER2 status on the tumour using validated immunohistochemistry, with in-situ testing for HER2 where the result is equivocal.
- Assess menopausal status: Menopausal status decides whether an aromatase inhibitor can be used alone or needs ovarian function suppression.
- Select endocrine therapy: Use tamoxifen in premenopausal women, or an aromatase inhibitor in postmenopausal women, for a commonly used duration of about five years.
- Add HER2-directed therapy: For HER2-positive disease, add trastuzumab, usually with chemotherapy and often with pertuzumab, under current protocols.
- Plan chemotherapy by subtype: Triple-negative and high-risk disease commonly receive anthracycline and taxane-based chemotherapy, whereas low-risk endocrine-sensitive disease may avoid it.
- Monitor toxicity: Check left ventricular ejection fraction before and during trastuzumab, and monitor bone density and the endometrium according to the drug used.
Where the exam tries to catch you
Most traps involve drug choice by menopausal status, drug interactions and cardiac monitoring.
- Trap: Using an aromatase inhibitor alone in a premenopausal woman. Correct: Aromatase inhibitors need ovarian suppression before menopause, because the ovaries otherwise keep producing oestrogen.
- Trap: Prescribing tamoxifen with fluoxetine or paroxetine. Correct: These CYP2D6 inhibitors reduce conversion of tamoxifen to its active metabolite, so the combination is avoided.
- Trap: Treating HER2 testing as optional before trastuzumab. Correct: Trastuzumab acts only in HER2-positive disease, so HER2 status decides eligibility.
- Trap: Ignoring cardiac function during trastuzumab. Correct: Trastuzumab causes cardiotoxicity, which is worsened by anthracyclines, so LVEF is monitored throughout.
Frequently asked questions
Which endocrine drug is preferred for postmenopausal ER-positive breast cancer?
An aromatase inhibitor such as letrozole, anastrozole or exemestane is commonly preferred for postmenopausal women with ER-positive breast cancer. These agents block peripheral oestrogen synthesis and avoid the endometrial risk associated with tamoxifen.
Why is trastuzumab given only to HER2-positive breast cancer?
Trastuzumab is a monoclonal antibody against the HER2 receptor, so it acts only when HER2 is overexpressed or amplified on the tumour. HER2 testing by immunohistochemistry or in-situ hybridisation therefore decides whether trastuzumab is given.
What is the major toxicity of trastuzumab in breast cancer?
Cardiotoxicity is the major toxicity of trastuzumab, appearing as a fall in left ventricular ejection fraction. The risk rises when trastuzumab is combined with anthracyclines, so cardiac function is checked before and during treatment.
Why does fluoxetine reduce the benefit of tamoxifen?
Fluoxetine and paroxetine inhibit CYP2D6, the enzyme that converts tamoxifen into its active metabolite endoxifen. This lowers the active drug level, so these antidepressants are avoided with tamoxifen where possible.
Which breast cancer subtype usually needs chemotherapy as the mainstay?
Triple-negative breast cancer, which lacks ER, PR and HER2 expression, usually relies on chemotherapy as the mainstay of systemic therapy. Endocrine and HER2-directed drugs have no target in this subtype, so they are not useful.