How should a patient presenting with a breast mass be evaluated, staged, and treated for breast cancer?

Evaluation and Management of Breast Cancer

A patient presenting with a breast mass should undergo immediate diagnostic imaging—bilateral mammography plus ultrasound for women ≥30 years, or ultrasound alone for women <30 years—followed by core needle biopsy of any suspicious findings, with treatment decisions based on molecular subtype (hormone receptor status, HER2 status, and triple-negative classification) and anatomic stage. 1, 2

Initial Evaluation and Diagnosis

Clinical Assessment

• Obtain a complete personal and family medical history, including evaluation of menopausal status, risk factors for breast cancer (BRCA mutations, prior chest radiation), and any symptoms such as pain, skin changes, or nipple discharge. 1, 2
• Perform a thorough physical examination with the patient both upright and supine, systematically palpating the entire breast and all regional nodal basins (axillary, supraclavicular, infraclavicular). 1, 2
• Document tumor size in centimeters, precise location, consistency (firm vs. hard), margin characteristics (well-defined vs. poorly circumscribed), any skin changes (peau d'orange, erythema, dimpling), nipple abnormalities, and axillary lymph node status. 1, 2

Imaging Strategy

• For women ≥30 years: Begin with bilateral diagnostic mammography (with a radio-opaque marker placed over the palpable mass) followed immediately by targeted breast ultrasound of the mass and regional lymph nodes. 1, 2
• For women <30 years: Proceed directly to targeted breast ultrasound as the initial study, reserving mammography only for suspicious ultrasound findings or highly concerning clinical examination. 1, 2
• Breast MRI is not routinely recommended for initial evaluation but should be considered in specific scenarios: familial breast cancer with BRCA mutations, breast implants, lobular cancers, suspected multifocality/multicentricity, or large discrepancies between conventional imaging and clinical examination. 1

Tissue Diagnosis

• Core needle biopsy is mandatory for any suspicious mass (BI-RADS 4 or 5), preferably obtained by ultrasound or stereotactic guidance. 1, 2
• Core biopsy is superior to fine needle aspiration because it provides higher sensitivity (97-99%), correct histological grading, and allows assessment of biomarkers. 1, 2
• Place a marker (surgical clip or carbon) into the tumor at the time of biopsy to ensure accurate surgical resection if needed. 1
• Complete all imaging before performing biopsy to avoid biopsy-related changes (hematoma, architectural distortion) that can obscure subsequent image interpretation. 2

Pathological Assessment Requirements

The pathology report must include: 1

• Histological type and grade
• Estrogen receptor (ER) status
• Progesterone receptor (PgR) status for invasive cancer
• HER2 status (by immunohistochemistry or in situ hybridization)
• Proliferation measure such as Ki67
• If ER/PgR and HER2 are negative in the biopsy specimen, retest them in the surgical specimen to account for tumor heterogeneity. 1

Staging and Risk Assessment

Lymph Node Evaluation

• Assess lymph nodes by clinical examination and ultrasound, supplemented by ultrasound-guided fine needle aspiration or core biopsy of suspicious lymph nodes. 1
• Sentinel lymph node biopsy is the standard approach for most breast cancers with clinically negative axillary nodes. 3, 4

Baseline Laboratory Studies

• Obtain complete blood count, liver and renal function tests, alkaline phosphatase, and calcium levels. 1
• Do not routinely order tumor markers (CA 15-3, CA 27.29, CEA) for staging asymptomatic early breast cancer, as they do not benefit patients. 1

Metastatic Work-Up

• For early-stage disease (stage I-II) with no symptoms: Routine comprehensive staging (chest CT, abdominal imaging, bone scan) is not indicated, as asymptomatic distant metastases are very rare and patients do not benefit from this approach. 1
• Consider additional staging studies (chest CT, abdominal ultrasound or CT, bone scan) for patients with: 1
  • Clinically positive axillary nodes
  • Large tumors (≥5 cm)
  • Aggressive biology (triple-negative, high-grade)
  • Clinical signs, symptoms, or laboratory values suggesting metastases
• For locally advanced or inflammatory breast cancer: PET/CT scanning can replace traditional imaging due to the high risk of metastatic disease. 1

Cardiac Assessment

• In patients planned for anthracycline-based chemotherapy and/or trastuzumab (for HER2-positive disease), evaluation of cardiac function with echocardiogram or MUGA scan is essential before treatment initiation. 1

Treatment Strategy by Stage and Subtype

Molecular Subtype Classification

Breast cancers are categorized into three major subtypes that determine treatment: 5, 6

1. Hormone receptor-positive/HER2-negative (70% of cases): ER and/or PgR positive, HER2 negative
2. HER2-positive (15-20% of cases): HER2 amplified or overexpressed, regardless of hormone receptor status
3. Triple-negative (15% of cases): ER, PgR, and HER2 all negative

Stage 0: Ductal Carcinoma In Situ (DCIS)

• DCIS is noninvasive but progresses to invasive cancer in up to 40% of untreated patients. 4
• Treatment: Breast-conserving surgery (lumpectomy) plus radiation therapy, or mastectomy. 3, 4
• No lymph node exploration or systemic chemotherapy is required for pure DCIS. 3
• If DCIS is ER-positive, add endocrine therapy (tamoxifen or aromatase inhibitor) for 5 years to reduce recurrence risk. 4

Stage I-II: Early Invasive Breast Cancer

Surgical Options

• Breast-conserving surgery (lumpectomy) plus radiation therapy is the preferred approach when the tumor can be excised completely with good cosmetic results. 3, 4
• Mastectomy is an alternative with similar survival rates. 3, 4
• Radiation therapy following breast-conserving surgery decreases both mortality and recurrence. 3
• Perform sentinel lymph node biopsy for staging when there is no clinically evident nodal disease. 3, 4

Systemic Therapy by Subtype

Hormone receptor-positive/HER2-negative: 5, 4

• Endocrine therapy for 5-10 years is essential (tamoxifen for premenopausal women; aromatase inhibitors for postmenopausal women). 5, 4
• Add chemotherapy only for patients with high-risk features (node-positive disease, large tumor size, high-grade histology, or high genomic risk scores). 5, 4

HER2-positive: 5, 4

• Combination chemotherapy (anthracycline and taxane-based regimens) plus HER2-targeted therapy (trastuzumab with or without pertuzumab) is standard. 5, 3, 4
• Continue trastuzumab for one year total. 5
• If hormone receptors are also positive, add endocrine therapy after completing chemotherapy. 5

Triple-negative: 5, 4

• Chemotherapy alone is the standard systemic treatment, as these tumors do not respond to endocrine or HER2-targeted therapies. 5, 4
• Triple-negative breast cancer has a higher recurrence risk, with 85% 5-year breast cancer-specific survival for stage I disease compared to 94-99% for hormone receptor-positive and HER2-positive subtypes. 5

Timing of Systemic Therapy

• Systemic therapy may be delivered before surgery (neoadjuvant) or after surgery (adjuvant). 5, 4
• Neoadjuvant therapy is now standard for most early-stage HER2-positive and triple-negative breast cancer, allowing tumor downstaging and assessment of treatment response. 6, 4
• If preoperative systemic therapy is planned, core needle biopsy is mandatory to ensure diagnosis of invasive disease and assess biomarkers. 1

Stage III: Locally Advanced Breast Cancer

• Induction (neoadjuvant) chemotherapy is required to downsize the tumor and facilitate breast-conserving surgery. 3
• After chemotherapy, perform surgery (lumpectomy plus radiation or mastectomy) and axillary lymph node evaluation. 3
• Inflammatory breast cancer (a particularly aggressive form of stage III disease) requires: 3
  • Induction chemotherapy
  • Mastectomy (not breast-conserving surgery)
  • Axillary lymph node dissection
  • Chest wall radiation
• Continue systemic therapy postoperatively based on molecular subtype (endocrine therapy for hormone receptor-positive, HER2-targeted therapy for HER2-positive). 3

Stage IV: Metastatic Breast Cancer

• Metastatic breast cancer is treatable but not curable; treatment goals are prolonging life and palliating symptoms. 1, 5, 4
• Median overall survival is approximately 1 year for metastatic triple-negative breast cancer versus approximately 5 years for hormone receptor-positive and HER2-positive subtypes. 5

Treatment by Subtype

Hormone receptor-positive/HER2-negative: 1, 6

• Endocrine therapy combined with targeted agents (CDK4/6 inhibitors such as palbociclib, ribociclib, or abemaciclib; or PI3K inhibitors for PIK3CA-mutated tumors) is the preferred first-line approach unless rapid response is warranted or endocrine resistance is suspected. 1, 6
• Reserve chemotherapy for patients with visceral crisis, rapid clinical progression, or endocrine-resistant disease. 1

HER2-positive: 1, 6

• HER2-directed therapy should be offered early, either as a single agent, combined with chemotherapy, or combined with endocrine therapy (if hormone receptors are also positive). 1, 6
• Patients progressing on one anti-HER2 therapy should be offered a second line of anti-HER2 therapy (e.g., trastuzumab emtansine [T-DM1], trastuzumab deruxtecan, or lapatinib plus capecitabine). 1

Triple-negative: 6

• Chemotherapy is the primary treatment. 6
• For BRCA1/2 mutation carriers, add PARP inhibitors (olaparib or talazoparib). 6
• For tumors expressing PD-L1, consider adding immune checkpoint inhibitors (pembrolizumab or atezolizumab) to chemotherapy. 6

Sequencing and Monitoring

• Sequential monochemotherapy is preferred over combination chemotherapy in the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom control. 1
• See patients every 2-4 months if on endocrine therapy and before every one or two cycles of chemotherapy (with toxicity and blood count checks before each cycle). 1
• If progression is suspected (due to new or worsening symptoms and/or significant increase in tumor marker levels), perform response evaluation immediately. 1

Follow-Up After Curative Treatment

• For patients treated for non-metastatic breast cancer, follow-up should include regular clinical examinations and annual mammography. 1
• Do not routinely order CT scans, bone scans, PET scans, or tumor markers for surveillance in asymptomatic patients, as these do not improve outcomes. 1
• Patients need a care plan outlining all aspects of treatment, potential side effects, and impact on functional, emotional, and social well-being. 1

Critical Pitfalls to Avoid

• Never delay biopsy of a clinically suspicious mass while awaiting imaging or based on negative imaging alone—clinical suspicion takes precedence. 2
• Never accept discordance between pathology results, imaging findings, and clinical examination; this requires repeat sampling or surgical excision. 1, 2
• Do not order PET, MRI, or molecular breast imaging as part of the initial evaluation of a palpable mass; these have no role in routine work-up. 1, 2
• Do not perform biopsy before completing imaging, as biopsy-related changes will obscure subsequent image interpretation. 2
• Do not deny breast-conservation therapy based on MRI findings alone in the absence of tissue sampling. 1