Breast Cancer

Risk factors

• Female sex, age
• Family history; BRCA1/BRCA2, TP53 (Li-Fraumeni), PTEN (Cowden), CDH1, PALB2, ATM, CHEK2
• Increased estrogen exposure: early menarche, late menopause, nulliparity, late first pregnancy, no breastfeeding, postmenopausal obesity, combined HRT
• Personal history: previous breast cancer, atypical hyperplasia, LCIS
• Prior chest wall radiation (especially for childhood Hodgkin)
• Dense breast tissue
• Alcohol intake

Pathophysiology

Stepwise genetic and epigenetic changes drive normal ductal/lobular epithelium through hyperplasia → atypia → in situ carcinoma → invasive cancer. ER-positive tumors are driven by estrogen signaling; HER2-positive by amplification of ERBB2; triple-negative often basal-like with BRCA association. Invasive lobular carcinoma loses E-cadherin (CDH1), so small cells infiltrate in single-file cords; it is often multifocal or bilateral and subtle on mammography. DCIS is a localized precursor usually found as mammographic microcalcifications, whereas LCIS is an incidental marker of increased cancer risk in both breasts.

Clinical presentation

Differential diagnosis

• Fibroadenoma — Young women, mobile rubbery mass; ultrasound: well-circumscribed solid
• Fibrocystic changes — Cyclic tenderness, lumpiness, bilateral; resolve with menses
• Simple breast cyst — Anechoic on ultrasound; can aspirate
• Mastitis or breast abscess — Tender, warm, erythematous; lactating or postpartum
• Fat necrosis — History of trauma or surgery; can mimic cancer on imaging
• Phyllodes tumor — Rapidly enlarging firm mass; spectrum benign to malignant
• Inflammatory breast cancer (vs mastitis) — Erythema, peau d'orange, no fever, no improvement with antibiotics — biopsy mandatory
• Paget disease of nipple — Unilateral eczematous nipple lesion spreading to the areola that fails topical steroids; needs full-thickness biopsy; underlying DCIS or invasive cancer in most cases

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Breast mass or<br/>abnormal mammogram] --> B[Diagnostic mammography<br/>± ultrasound]
  B --> C{BI-RADS}
  C -->|0| N["Incomplete: additional<br/>views or ultrasound"]
  C -->|1-3| D[Routine or short-interval<br/>follow-up imaging]
  D -.->|Palpable mass still clinically suspicious| E
  C -->|4-5| E[Core needle biopsy]
  E --> F{Pathology}
  F -->|Benign| G[Concordance review;<br/>routine surveillance]
  F -->|DCIS| H[Lumpectomy + RT or<br/>mastectomy; tamoxifen if ER+]
  F -->|Invasive cancer| I[Determine ER, PR, HER2,<br/>genomic risk]
  I --> J{Subtype}
  J -->|HR+ HER2−| K[Surgery + endocrine therapy<br/>± chemo by Oncotype]
  J -->|HER2+| L[Surgery + chemo +<br/>trastuzumab ± pertuzumab]
  J -->|Triple-negative| M[Neoadjuvant chemo +<br/>immunotherapy ± PARP]

Treatment

Complications

• Lymphedema (especially after axillary dissection + radiation)
• Cardiotoxicity from anthracyclines, trastuzumab
• Endometrial cancer (tamoxifen, ~2-3x risk)
• Aromatase inhibitor effects: osteoporosis, arthralgia (up to half of users; the leading reason for stopping), hot flashes, vaginal dryness; continue the AI and treat symptoms (exercise, NSAIDs, duloxetine; SNRI or gabapentin for hot flashes; vaginal moisturizers), switching agents only if intolerable
• VTE with tamoxifen
• Cognitive effects ('chemo brain')
• Recurrence (local, regional, distant) — bone, lung, liver, brain most common

PANCE pearls

• Triple assessment (clinical exam + imaging + biopsy) is required for any breast mass — concordance reduces missed cancers.
• Inflammatory breast cancer mimics mastitis but does NOT improve with antibiotics within 1-2 weeks; mandatory biopsy in any non-resolving 'mastitis.'
• Offer germline BRCA1/2 testing to all patients with breast cancer diagnosed at ≤65, and after 65 if triple-negative, male, a PARP-inhibitor candidate, of Ashkenazi Jewish ancestry, or with a suggestive personal/family history (ASCO-SSO 2024). Unaffected women with a suggestive family history: brief familial risk assessment tool, then genetic counseling before any testing (USPSTF 2019).
• Tamoxifen and raloxifene both raise VTE and stroke risk and should be avoided with prior VTE or stroke; in a postmenopausal woman an aromatase inhibitor is the alternative (raloxifene is used only for risk reduction, never to treat breast cancer).
• Aromatase inhibitors alone are ineffective in premenopausal women because they cannot block ovarian estrogen production; use them after menopause or together with ovarian function suppression, so confirm menopausal status before starting.
• Male breast cancer is rare (~1% of breast cancer) but warrants BRCA testing in all cases.
• Biennial mammography ages 40-74 (USPSTF 2024, Grade B) — high-risk women add MRI.

References

• USPSTF 2024 — Screening for Breast Cancer: USPSTF Recommendation Statement, 2024
• NCCN Breast 2024 — NCCN Clinical Practice Guidelines in Oncology: Breast Cancer
• ACS 2015 — Breast Cancer Screening for Women at Average Risk: ACS Guideline Update (Oeffinger et al., JAMA 2015)
• ASCO 2019 — Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update (Burstein HJ et al., J Clin Oncol 2019;37:423-438)
• ASCO-SSO 2024 — Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline (Bedrosian I et al., J Clin Oncol 2024;42:584-604)
• USPSTF 2019 — Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: USPSTF Recommendation Statement (JAMA 2019;322:652-665)