HER2+ Breast Cancer

Authored by Ilana Schlam, published on 2026-08-20 19:14:13.0

The algorithm is broadly aligned with current HER2-positive breast cancer practice across early-stage and metastatic settings, including de-escalated adjuvant TH for small node-negative tumors, standard HP-based neoadjuvant/adjuvant strategies for higher-risk disease, and post-neoadjuvant escalation for residual disease. It incorporates key 2025–2026 landmark updates (DESTINY-Breast05, DESTINY-Breast09, DESTINY-Breast11, PATINA) and appropriately flags major sequencing evidence gaps created by earlier-stage T-DXd adoption. The main caveat is that several novel FDA-labeled strategies (not yet fully embedded in all society guidelines) have evolving real-world positioning, especially around prior perioperative T-DXd exposure and post–first-line T-DXd sequencing.

  1. Early Stage HER2+
    • <2 Cm and Node Negative
      • Surgery
        • pT1pN0
          • Weekly TH x12
            Tolaney, NEJM 2015. *Can consider a year of TDM1 per ATEMPT
            • Complete 1 Year Of Trastuzumab
        • pT2 Or pN1+
          • Adjuvant Chemotherapy With Trastuzumab +/- Pertuzumab
            Aphinity
            • Complete 1 Year Of Trastuzumab +/- Pertuzumab
              Aphinity Add endocrine therapy and/or radiation as indicated.
              • Consider 1 Year Of Neratinib (HR and N+)
                *Control trial for diarrhea management ExteNET study revealed a greater benefit in patients with hormone receptor positive and HER2 positive breast cancer. Patients in that study did not receive pertuzumab or TDM1.
    • >=2 Cm or Node Positive
      • Low Risk
        • THP For 12-18 W
          NeoCARHP, HELEN-006, COMPASS - pCR
          • Surgery
            • pCR
              • Complete 1 Year Of Trastuzumab +/- Pertuzumab
                Aphinity Add endocrine therapy and/or radiation as indicated.
                • Consider 1 Year Of Neratinib (HR and N+)
                  *Control trial for diarrhea management ExteNET study revealed a greater benefit in patients with hormone receptor positive and HER2 positive breast cancer. Patients in that study did not receive pertuzumab or TDM1.
            • RD
              • Complete 1 Year Of TDM1 Vs TDXd
                Katherine, DESTINY-Breast 05 Add endocrine therapy and/or radiation as indicated.
                • Consider 1 Year Of Neratinib (HR and N+)
                  *Control trial for diarrhea management ExteNET study revealed a greater benefit in patients with hormone receptor positive and HER2 positive breast cancer. Patients in that study did not receive pertuzumab or TDM1.
      • High Risk
        • THP => TDXd
          Order can be inverted DESTINY-Breast 11 Consider MRI to guide therapy in HR- (consider TCHP)
          • Surgery
            • pCR
              • Complete 1 Year Of Trastuzumab +/- Pertuzumab
                Aphinity Add endocrine therapy and/or radiation as indicated.
                • Consider 1 Year Of Neratinib (HR and N+)
                  *Control trial for diarrhea management ExteNET study revealed a greater benefit in patients with hormone receptor positive and HER2 positive breast cancer. Patients in that study did not receive pertuzumab or TDM1.
            • RD
              • Complete 1 Year Of TDM1 Vs TDXd
                Katherine, DESTINY-Breast 05 Add endocrine therapy and/or radiation as indicated.
                • Consider 1 Year Of Neratinib (HR and N+)
                  *Control trial for diarrhea management ExteNET study revealed a greater benefit in patients with hormone receptor positive and HER2 positive breast cancer. Patients in that study did not receive pertuzumab or TDM1.
  2. Advanced HER2+ Disease
    • THP=> HP
      Cleopatra
      • T-DXd
        DESTINY-Breast 12
      • *Palbo + ET 1L maintenance after THP (Consider for HR+)
        Adding palbociclib to maintenance anti-HER2 therapy plus endocrine therapy after induction HP-taxane is supported by PATINA and is an emerging standard pending breadth of guideline adoption and local availability. The node appropriately restricts this approach to HR+ disease and the maintenance setting post-induction.
    • TDXd + P
      DESTINY-Breast 09 (induction not studied)
      • Tucatinib, Trastuzumab, Capecitabine
        HER2CLIMB No data continuing a tucatinib-containing regimen after progression on tucatinib.
        • Trastuzumab + Chemotherapy
        • Neratinib + Capecitabine
          NALA
        • Lapatinib + Capecitabine
          NALA
        • Margetuximab + Chemotherapy
          SOPHIA
      • TDM1
        EMILIA There are limited data about the role of TDM1 after T-DXd in the metastatic setting.
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