What are the treatment guidelines for invasive breast carcinoma, specifically for luminal A, luminal B, HER2 (Human Epidermal growth factor Receptor 2) enriched, and TNBC (Triple Negative Breast Cancer) subtypes, by stage?

Treatment Guidelines for Invasive Breast Carcinoma by Molecular Subtype and Stage

Treatment of invasive breast carcinoma must be stratified by molecular subtype (Luminal A, Luminal B HER2-negative, Luminal B HER2-positive, HER2-enriched, and TNBC) with distinct systemic therapy approaches for each, combined with appropriate locoregional management based on anatomic stage. 1

Molecular Subtype Definitions

The surrogate intrinsic subtypes are defined by immunohistochemistry as follows 1:

• Luminal A-like: ER-positive, HER2-negative, Ki67 low (<20%), PgR high (≥20%)
• Luminal B-like (HER2-negative): ER-positive, HER2-negative, and either Ki67 high (≥20%) or PgR low (<20%)
• Luminal B-like (HER2-positive): ER-positive, HER2-positive, any Ki67, any PgR
• HER2-enriched (non-luminal): HER2-positive, ER and PgR absent
• Triple-negative (TNBC): ER, PgR, and HER2 all negative

Stage-Specific Locoregional Management

Early Stage Disease (Stage I, IIA, IIB, T3N1M0)

Surgical Options 1:

• Breast-conserving surgery (BCS) with sentinel lymph node biopsy (SLNB) followed by whole breast radiation therapy
• Mastectomy with SLNB, with consideration of immediate or delayed reconstruction
• For clinically node-positive disease: axillary lymph node dissection if sentinel nodes are positive on frozen section or final pathology 2

Radiation Therapy 1:

• Mandatory after BCS to achieve local recurrence rates <0.5% per year
• Post-mastectomy radiation indicated if ≥4 positive nodes or T3/T4 disease 3, 4

Locally Advanced Disease (Stage IIIA, IIIB, IIIC)

Neoadjuvant systemic therapy is preferred 1:

• Allows for assessment of treatment response
• May enable breast conservation in initially inoperable disease
• Should start within 2-4 weeks of diagnosis completion 1

Systemic Therapy by Molecular Subtype

Luminal A-Like Tumors

Endocrine therapy (ET) alone is recommended for the majority of cases 1:

• Chemotherapy should be considered ONLY if high tumor burden (≥4 lymph nodes, T3 or higher) 1
• Most luminal A-like tumors do not require chemotherapy, as the absolute benefit is extremely small when balanced against toxicity 1
• Special histologic types (tubular, mucinous, cribriform) may be treated with locoregional therapy and ET alone, as prognosis is excellent 1, 2

Endocrine Therapy Regimens 1, 4:

• Postmenopausal women: Aromatase inhibitors preferred over tamoxifen
• Premenopausal women: Tamoxifen ± ovarian function suppression
• Duration: Minimum 5 years 4

Luminal B-Like HER2-Negative Tumors

Chemotherapy followed by endocrine therapy for the majority of cases 1:

• Decision depends on individual risk of recurrence, presumed ET responsiveness, and patient preferences
• Genomic assays (Oncotype DX, MammaPrint, Prosigna, Endopredict) may be used in cases of uncertainty regarding chemotherapy benefit 1

Chemotherapy Regimens 1:

• Sequential anthracycline/taxane-based regimen is standard (e.g., AC or EC followed by paclitaxel) 1
• Duration: 12-24 weeks (4-8 cycles) 1
• Dose-dense schedules with G-CSF support should be considered for highly proliferative tumors 1
• Alternative for lower-risk patients: 4 cycles of anthracycline-based or taxane-based chemotherapy 1

Luminal B-Like HER2-Positive Tumors

Chemotherapy + anti-HER2 therapy followed by endocrine therapy for all patients 1:

• In selected very low-risk patients (T1abN0), ET + anti-HER2 therapy alone can be considered, though no randomized data exist 1

Anti-HER2 Therapy 1:

• Trastuzumab combined with chemotherapy approximately halves recurrence and mortality risk 1
• Dual HER2 blockade with trastuzumab + pertuzumab is standard for higher-risk disease 1
• Continue trastuzumab for 1 year total duration 1

Chemotherapy Regimens 1:

• Sequential anthracycline followed by taxane + trastuzumab
• Non-anthracycline regimens (e.g., docetaxel-carboplatin-trastuzumab) may be used in patients at risk of cardiac complications 1

HER2-Enriched (Non-Luminal) Tumors

Chemotherapy + anti-HER2 therapy is mandatory 1:

• Exception: Selected cases with very low risk (T1abN0) where treatment decisions must weigh individual factors 1

Treatment Regimens 1:

• Sequential anthracycline/taxane + trastuzumab + pertuzumab
• Non-anthracycline alternatives if cardiac contraindications exist
• No endocrine therapy required (ER/PR negative) 1

Triple-Negative Breast Cancer (TNBC)

Chemotherapy is the primary systemic therapy 1, 3:

• No role for endocrine therapy or anti-HER2 therapy
• Special histologic types with low risk (adenoid cystic, secretory carcinoma, low-grade metaplastic) may not require chemotherapy 1

Chemotherapy Regimens 1, 3:

• Sequential anthracycline/taxane-based regimen is standard
• For node-negative disease ≤0.5 cm: Observation alone may be considered 3
• For node-negative disease 0.6-1.0 cm: Chemotherapy may be considered based on grade, lymphovascular invasion, age 3
• For node-negative disease >1.0 cm: Chemotherapy strongly recommended 3
• For node-positive disease: Chemotherapy mandatory regardless of tumor size 3
• Platinum compounds are NOT routinely recommended in the adjuvant setting, even for BRCA1/2 mutation carriers 1

Preferred Regimens 3:

• AC (doxorubicin/cyclophosphamide) followed by paclitaxel
• Dose-dense schedules for higher-risk presentations
• Docetaxel-cyclophosphamide (TC) if anthracyclines contraindicated

Special Considerations

Genomic Testing Indications 1

NOT recommended for:

• Clinicopathological low-risk tumors (pT1a, pT1b, G1, ER high, pN0)
• Patients with comorbidities who are not chemotherapy candidates
• Special luminal-like types (tubular, mucinous, cribriform carcinomas)

May be used for:

• Uncertainty regarding chemotherapy benefit in ER-positive, HER2-negative disease
• Particularly helpful in node-negative or 1-3 node-positive disease with other high-risk factors 1

Elderly Patients 3, 4

Treatment must be based on physiological age, not chronological age 4:

• For ER+/PR+/HER2- disease: Endocrine therapy is cornerstone, with aromatase inhibitors preferred over tamoxifen 4
• Absolute benefit of chemotherapy may be small and should be weighed against toxicity 4
• Factors favoring chemotherapy: Higher grade, larger size, lymph node involvement 4
• For small node-negative tumors in patients >70 years: Observation may be considered if chemotherapy would not be given 2

ER-Negative/PR-Positive Phenotype 3

This exceptionally rare phenotype (<1-3% of cases) should be treated as triple-negative disease 3:

• Repeat ER and PR testing mandatory before finalizing treatment, as most cases reclassify upon retesting 3
• Adjuvant chemotherapy is primary systemic therapy, NOT endocrine therapy 3
• May represent technical artifact or biologically aggressive tumor behaving like TNBC 3

Follow-Up Surveillance 3, 4

Clinical monitoring 3, 4:

• Every 3-4 months for years 1-2
• Every 6 months for years 3-5
• Annually thereafter

Imaging 4:

• Annual bilateral mammography and ultrasound
• No routine tumor markers, bone scans, or CT scans in asymptomatic patients 3

Endocrine therapy monitoring 4:

• Regular assessment of adherence and side effects
• Bone mineral density at baseline and periodically for patients on aromatase inhibitors
• Annual gynecologic assessment for patients on tamoxifen if uterus present

Critical Pitfalls to Avoid

Do not deny breast conservation based on MRI findings alone without tissue sampling 1:

• MRI has high false-positive rate and should be interpreted by experienced breast imaging teams capable of MRI-guided biopsy

Do not use high-dose chemotherapy with stem cell support 1:

• This approach is not recommended and should not be used

Do not use platinum compounds routinely in adjuvant setting for TNBC 1:

• No robust prospective randomized data exist, even for BRCA1/2 mutation carriers

Do not omit HER2 retesting on surgical specimen if positive on biopsy 1:

• Mandatory for invasive carcinoma NOS grade I, ER/PgR-positive, or special types (adenoid cystic, secretory)

Do not use TIL scoring to escalate or de-escalate treatment 1:

• While TILs have prognostic value in TNBC and HER2-positive disease, they should not guide treatment decisions