Breast cancer overview

Breast Cancer Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2] Ammu Susheela, M.D. [3] Nehal Eid, M.D.[4]

Breast Cancer

Breast cancer is a heterogeneous group of malignant tumors arising from the terminal duct-lobular unit of the breast. It includes biologically distinct diseases defined by histology, estrogen receptor (ER), progesterone receptor (PR), HER2/ERBB2 status, grade, and stage. These features determine prognosis and guide systemic and local treatment.

Breast cancer is the most common non-skin cancer in women and remains a major cause of cancer mortality worldwide. Clinical care progresses from risk-based screening and diagnostic imaging to tissue diagnosis, biomarker testing, staging, subtype-directed multimodal treatment, and survivorship care.

Clinical framework

• Histology: Most invasive tumors are invasive carcinoma of no special type (NST, formerly invasive ductal carcinoma). Invasive lobular carcinoma is a distinct entity with different growth patterns and patterns of recurrence.
• Receptor-based clinical subtype: Hormone receptor (HR) status refers primarily to ER and PR. Tumors are categorized clinically as HR-positive/HER2-negative, HR-positive/HER2-positive, HR-negative/HER2-positive, or triple-negative breast cancer (TNBC).
• Intrinsic molecular subtype: PAM50-based classification includes luminal A, luminal B, HER2-enriched, basal-like, and normal-like subtypes. Molecular and immunohistochemical classifications are related but not completely concordant.
• Genomic classification: Validated genomic assays, including the 21-gene recurrence score, can provide prognostic information and help determine the value of adjuvant chemotherapy in selected HR-positive/HER2-negative cancers.

Headline treatment logic by clinical subtype

Clinical subtype	Overview of treatment logic
HR-positive/HER2-negative	Endocrine therapy is the systemic-treatment backbone. Genomic assays may refine chemotherapy decisions, and adjuvant CDK4/6 inhibitor therapy may be added in selected high-risk early-stage disease.
HR-positive/HER2-positive	Endocrine therapy is combined with HER2-directed treatment, usually within a trastuzumab-based regimen and with treatment intensity determined by stage and risk.
HR-negative/HER2-positive	HER2-directed therapy, commonly trastuzumab-based, is integrated with chemotherapy according to stage, tumor burden, and treatment response.
Triple-negative breast cancer	For stage II–III disease, neoadjuvant chemotherapy plus pembrolizumab followed by adjuvant pembrolizumab is an established treatment paradigm. Residual disease and germline findings may influence additional therapy.

HER2-low and HER2-ultralow describe treatment-relevant levels of HER2 expression rather than separate traditional receptor subtypes. These categories may affect eligibility for antibody-drug conjugates in selected advanced or metastatic settings.

Screening orientation

• For average-risk women, the USPSTF recommends biennial screening mammography from age 40 through 74 years (Grade B).
• Screening recommendations differ among organizations. The ACR/SBI and NCCN generally recommend annual mammography beginning at age 40, while the ACS and ACP use different age and interval frameworks.
• Women with an estimated lifetime breast cancer risk of at least 20%, including many BRCA1/2 carriers, generally require annual mammography plus annual contrast-enhanced breast MRI according to high-risk screening frameworks.

Diagnosis and staging orientation

• A suspicious breast lesion requires diagnostic evaluation with appropriate breast imaging and tissue diagnosis. Core needle biopsy is the definitive diagnostic test for most suspicious lesions.
• Every invasive breast cancer should be characterized by ER, PR, and HER2 status because these biomarkers directly affect systemic treatment selection.
• The AJCC 8th edition retains anatomic TNM staging but incorporates grade and ER, PR, and HER2 status into prognostic staging. Thus, anatomic stage and tumor biology are interpreted together.
• A normal mammogram does not exclude cancer, particularly in dense breasts or with invasive lobular carcinoma. A clinically suspicious palpable lesion requires appropriate diagnostic assessment even when screening imaging is unrevealing.

Treatment paradigm

Treatment is multidisciplinary and depends on stage, receptor status, histology, patient factors, and response to neoadjuvant therapy.

• Local therapy: In appropriately selected early-stage disease, breast-conserving surgery followed by radiation provides outcomes comparable to mastectomy. Sentinel lymph node biopsy has replaced routine axillary dissection for many clinically node-negative patients, with further axillary de-escalation in selected settings.
• HR-positive/HER2-negative disease: Endocrine therapy is generally given for 5–10 years. Genomic assays can help identify patients who may safely avoid or require adjuvant chemotherapy in appropriate clinical settings.
• HER2-positive disease: Trastuzumab-based therapy, with or without pertuzumab and other HER2-directed agents, is selected according to stage and risk. Post-neoadjuvant treatment may be escalated when residual invasive disease is present.
• TNBC: Neoadjuvant chemoimmunotherapy is central for many stage II–III tumors. Treatment after surgery is influenced by pathologic response, residual disease, and germline findings.
• Germline BRCA1/2-associated disease: Patients with high-risk, HER2-negative early breast cancer and a pathogenic germline BRCA1/2 variant may be candidates for adjuvant olaparib.
• Advanced/metastatic disease: Stage IV or unresectable disease is managed primarily with subtype-directed systemic therapy. Detailed treatment sequencing belongs in the dedicated medical-therapy microchapter.

Prognosis and clinical pearls

Prognosis is stage- and biology-dependent. Prognostic staging refines anatomic TNM with tumor grade and biomarker status, while treatment response and residual disease provide additional prognostic information.

• Classify every invasive tumor by ER, PR, and HER2 status at diagnosis.
• Do not confuse biennial screening with twice-yearly screening; biennial means once every 2 years.
• Do not treat HER2-low or HER2-ultralow expression as clinically irrelevant in advanced disease.
• Do not assume that mastectomy is oncologically safer than breast-conserving surgery when breast-conserving surgery and appropriate radiation are suitable.
• Apply high-risk screening pathways to patients with a lifetime risk of at least 20%, pathogenic hereditary variants, or prior chest radiation rather than using average-risk screening recommendations.
• Male breast cancer is uncommon and is usually hormone-receptor positive; evaluation for hereditary risk is important when clinically indicated.