Breast Cancer: Receptor-Guided Therapy & High-Risk Care
Receptors pick the drugs; risk picks the screening and surgery
Receptor status sets the plan
Testing. Every invasive breast cancer is tested for estrogen and progesterone receptors by immunohistochemistry and for HER2. HER2 IHC 3+ is positive and 0–1+ negative; 2+ is equivocal and reflexes to in situ hybridization (FISH) for gene amplification. Only amplified or IHC 3+ tumors receive anti-HER2 therapy.
| Subtype | Share | Typical patient and behavior | Backbone of systemic therapy |
|---|---|---|---|
| HR+/HER2− | ~70% | Older women; slower growth, late recurrences possible | Endocrine therapy 5–10 years ± CDK4/6 inhibitor or chemotherapy |
| HER2+ | ~15–20% | Aggressive without targeted therapy | Trastuzumab ± pertuzumab with chemotherapy |
| Triple-negative | ~10–15% | Younger, premenopausal, Black women, BRCA1 carriers; early visceral and brain relapse | Chemotherapy ± pembrolizumab; olaparib if germline BRCA |
Hormone receptor–positive disease
Choosing the endocrine drug. Tamoxifen, a selective estrogen receptor modulator, is the standard for premenopausal women; aromatase inhibitors outperform it after menopause. Endocrine therapy lasts 5–10 years, with longer courses for higher-risk disease.
| Feature | Tamoxifen | Aromatase inhibitor |
|---|---|---|
| Mechanism | Blocks the estrogen receptor in breast; agonist in bone and endometrium | Blocks peripheral androgen-to-estrogen conversion (anastrozole, letrozole, exemestane) |
| Who | Pre- or postmenopausal | Postmenopausal, or premenopausal with ovarian suppression |
| Adverse effects | Hot flashes, VTE, endometrial hyperplasia and cancer, cataracts | Arthralgias, myalgias, vaginal dryness, bone loss and fractures |
| Monitoring | Evaluate any postmenopausal bleeding | Baseline and periodic DEXA |
Tamoxifen details. Because tamoxifen stimulates the endometrium, postmenopausal bleeding requires transvaginal ultrasound or endometrial biopsy, but asymptomatic women are not screened. Its agonist effect on bone preserves density after menopause. Tamoxifen is a prodrug converted by CYP2D6 to endoxifen, so strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion) are avoided; venlafaxine, citalopram or escitalopram, and gabapentin are preferred for hot flashes or depression.
Aromatase inhibitor details. These drugs fail on their own when the ovaries still function. Bone loss is managed with calcium, vitamin D, and a bisphosphonate or denosumab for low bone density. They carry no excess VTE or endometrial cancer risk.
Escalating therapy. High-risk premenopausal women add ovarian function suppression (a GnRH agonist or oophorectomy) to an aromatase inhibitor or tamoxifen. Node-positive high-risk disease adds an adjuvant CDK4/6 inhibitor (abemaciclib or ribociclib), and metastatic HR+ disease is treated with endocrine therapy plus a CDK4/6 inhibitor (including palbociclib). Neutropenia is the class toxicity; abemaciclib mainly causes diarrhea, and ribociclib causes QT prolongation and hepatotoxicity.
21-gene recurrence score. For HR+/HER2− early cancer that is node-negative, or has 1–3 positive nodes after menopause, the score predicts chemotherapy benefit. A score of 26 or more adds chemotherapy to endocrine therapy. A score of 25 or less in postmenopausal women or women over 50 means endocrine therapy alone, whereas younger premenopausal women with intermediate scores may still benefit from chemotherapy.
HER2-positive and triple-negative disease
HER2-positive. Trastuzumab (1 year in total), with or without pertuzumab, is combined with taxane-based chemotherapy and is usually started before surgery for tumors larger than 2 cm or node-positive disease. Residual invasive cancer after neoadjuvant therapy prompts a switch to T-DM1 (ado-trastuzumab emtansine), which lowers recurrence. Trastuzumab lowers LVEF reversibly, so an echocardiogram is obtained at baseline and every 3 months.
Triple-negative. These tumors relapse early, mostly within 3–5 years, often in viscera and brain. Stage II–III disease receives neoadjuvant chemotherapy plus pembrolizumab; residual disease after surgery is treated with capecitabine. Germline BRCA1/2 carriers with high-risk HER2− disease receive 1 year of adjuvant olaparib, a PARP inhibitor. Every patient with triple-negative cancer is offered germline genetic testing.
BRCA1 predisposes to triple-negative breast cancer and ovarian cancer; BRCA2 also raises the risk of male breast, prostate, and pancreatic cancer.
Presentations that need a biopsy now
Inflammatory breast cancer. Erythema, warmth, and edema with peau d'orange develop over weeks and involve at least one-third of the breast, usually without a discrete mass, because tumor emboli block dermal lymphatics. "Mastitis" in a nonlactating woman that fails antibiotics requires diagnostic mammography and ultrasound plus core biopsy of the breast and a skin punch biopsy. The diagnosis is clinical with confirmed invasive carcinoma; dermal lymphatic invasion supports it but is not required. It is at least stage III (T4d).
- Neoadjuvant systemic therapyChemotherapy, plus anti-HER2 therapy when HER2-positive.
- Modified radical mastectomyNo breast conservation and no sentinel-node biopsy; axillary dissection is performed.
- Postmastectomy radiationChest wall and regional lymph nodes.
Paget disease of the nipple. A unilateral scaly, crusting, sometimes ulcerated or bleeding lesion begins on the nipple and spreads to the areola, whereas eczema is usually bilateral, begins on the areola, and spares the nipple. Paget disease usually overlies DCIS or invasive cancer, so a persistent nipple lesion needs diagnostic mammography and a full-thickness nipple biopsy rather than repeated steroid creams.
Survivorship and high-risk women
Follow-up. Survivors have a history and physical every 3–6 months for the first years and then annually, plus annual mammography of remaining breast tissue. Tumor markers (CA 15-3, CEA), bone scans, CT, and PET are not used in asymptomatic survivors because they do not improve survival; new symptoms are investigated. Aromatase-inhibitor users need DEXA, and bleeding on tamoxifen needs endometrial evaluation.
BRCA carriers. Clinical breast exams every 6–12 months and annual breast MRI begin at 25, and annual mammography is added at 30, often alternating with MRI every 6 months. No ovarian cancer screening works (CA-125 and transvaginal ultrasound do not reduce mortality), so risk-reducing salpingo-oophorectomy after childbearing is recommended at 35–40 for BRCA1 and 40–45 for BRCA2. It lowers ovarian and fallopian tube cancer risk by about 80% and reduces all-cause mortality; the tubes are removed because many "ovarian" cancers begin there. Bilateral risk-reducing mastectomy lowers breast cancer risk by about 90% and is an alternative to intensive screening.
| Drug | Menopausal status | Key cautions |
|---|---|---|
| Tamoxifen | Pre- or postmenopausal | VTE, stroke, endometrial cancer |
| Raloxifene | Postmenopausal only | VTE; no endometrial cancer risk |
| Exemestane, anastrozole | Postmenopausal only | Bone loss, arthralgias |
Breast cancer in pregnancy
Diagnosis. A persistent breast mass in a pregnant or lactating woman is never attributed to pregnancy without workup: ultrasound first, mammography with abdominal shielding, and core biopsy.
Treatment. Surgery is safe in any trimester; sentinel node mapping uses radiocolloid alone because blue dyes are avoided. Anthracycline-based chemotherapy can be given in the second and third trimesters. Tamoxifen (teratogenic), trastuzumab (oligohydramnios), and radiation are deferred until after delivery. Terminating the pregnancy does not improve survival.