NCCN Breast Cancer Guidelines: V1.2026 → V2.2026 Key Changes

1. Metastatic Triple-Negative Breast Cancer (mTNBC) - 1st Line

• The upgrade of sacituzumab govitecan (Trodelvy) + pembrolizumab (Keytruda) to Category 1 for PD-L1-positive (CPS ≥10) mTNBC was the primary change driving V2.2026, updated on February 27, 2026.
• Based on data from the ASCENT-04 trial.
• The combination remains under FDA/EMA regulatory review at the time of the update.

2. HR+/HER2- Early Breast Cancer - Adjuvant Chemotherapy Selection (New in V2.2026)

• V2.2026 adds reference to emerging data from the 2025 San Antonio Breast Cancer Symposium (SABCS) supporting the use of MammaPrint + BluePrint genomic stratification to guide chemotherapy regimen selection.
• Specifically: patients classified as MammaPrint High Risk 2 (HR+/HER2-, early-stage) may benefit from anthracycline-containing regimens (e.g., AC-T) over non-anthracycline regimens (e.g., TC).
• Patients classified as MammaPrint High Risk 1 do not appear to derive the same differential benefit.
• This was observational/registry data, not an RCT, so it does not mandate decisions - it supports individualized shared decision-making.

Changes Already Present in V1.2026 (Context for Comparison)

Surgery / Local Therapy (de-escalation)

• SLNB omission now supported for postmenopausal patients >50 years, cT1N0, HR+/HER2-, Grade 1-2, negative axillary ultrasound, planning whole-breast RT + endocrine therapy (based on SOUND and INSEMA trials). Caution in lobular histology.
• Old age-based SLNB omission (≥70 years) removed; replaced by biology- and imaging-driven selection.
• Routine imaging of reconstructed breast not recommended after mastectomy (imaging only if clinically indicated).
• Pre-operative MRI downgraded to Category 2B (selective use) - evidence shows MRI does not improve re-excision rates, local control, or survival in BCS candidates.
• Low-risk DCIS patients may be exempted from radiotherapy.

Adjuvant Systemic Therapy

• Adjuvant ribociclib (CDK4/6 inhibitor) for high-risk HR+/HER2- early breast cancer - Category 1 standard option.
• Adjuvant T-DXd (trastuzumab deruxtecan) for HER2+ patients with residual disease after neoadjuvant therapy - Category 1 (based on DESTINY-Breast05/long-term data).
• APHINITY trial long-term follow-up (median 11.3 years) confirms pertuzumab + trastuzumab + chemo benefit maintained.

Metastatic HR+/HER2- Disease (V1.2026 forward)

• Fulvestrant/inavolisib/palbociclib combination added for PIK3CA-mutated HER2- advanced breast cancer.
• Imlunestrant + abemaciclib added as a subsequent-line option.
• T-DXd added as a first-line option for HR+/HER2-low/HER2-ultralow advanced disease.

HER2+ Metastatic Disease

• Endocrine + anti-HER2 combinations acknowledged (fulvestrant or tamoxifen + trastuzumab) for indolent/asymptomatic HR+/HER2+ disease after prior chemotherapy.

Molecular Testing

• Comprehensive germline + somatic profiling emphasized as standard for metastatic disease - multigene testing to guide targeted therapy and ADC sequencing.

Summary Table: V1.2026 → V2.2026 Specific Changes