HR+/HER2- Advanced Breast Cancer

Authored by Ilana Schlam, published on 2026-08-21 21:45:12.0

The algorithm is broadly aligned with contemporary HR+/HER2- metastatic breast cancer practice: endocrine-based therapy with a CDK4/6 inhibitor in the first-line setting, followed by biomarker-directed options (PIK3CA/AKT/PTEN, ESR1, gBRCA) and later-line ADCs and chemotherapy. It appropriately highlights that optimal sequencing among pathway-targeted therapies and ADCs remains uncertain. A key caveat is that the inavolisib triplet is emerging and may be jurisdiction-/approval-dependent, and some later-line choices (e.g., Dato-DXd positioning) are evolving with recent and ongoing data.

  1. HR+/HER2- advanced disease
    Broad disease-level management (endocrine-first in the absence of visceral crisis, routine biomarker testing, and sequencing concepts) is primarily established in major guidelines for metastatic HR+/HER2- breast cancer.
    • PD on adjuv ET or within 12 months of ET*
      *patients who never received ET in early breast cancer stage, or relapsing ≥12 months after completing adjuvant ET, or diagnosed with de novo stage IV breast cancer.
      • NGS
        • PIK3CA mut.
          • Palbo + fulvestrant + Inavolisib (INAVO120)
            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown. This node reflects an emerging PI3K-alpha–pathway triplet strategy in PIK3CA-mutant HR+/HER2- advanced disease. Evidence is primarily from the INAVO120 phase 3 trial program; guideline incorporation and approval may be region- and timing-dependent.
            • PIK3CA, PTEN, AKT alteration
              Efficacy of sequential targeting of PIK3CA pathway is unknown (adj ET…)
              • Capivasertib + ET CAPItello-291
                • None of the above or after progression in 1L lines of therapy from prior
                  Patients who never received ET in early breast cancer stage, or…
                  • Everolimus, AI or Fulvestrant
                    BOLERO
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                  • Gedatolisib + fulvestrant ± palbociclib
                    VIKTORIA-1
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
            • ESR1 mut.
              • Elacestrant - EMERALD / Imlunestrant - EMBER-3
                • None of the above or after progression in 1L lines of therapy from prior
                  Patients who never received ET in early breast cancer stage, or…
                  • Everolimus, AI or Fulvestrant
                    BOLERO
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                  • Gedatolisib + fulvestrant ± palbociclib
                    VIKTORIA-1
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
            • gBRCA 1/2 mut.
              • PARPi (Ola, Tal) OLYMPIAD, EMBRACA
                • None of the above or after progression in 1L lines of therapy from prior
                  Patients who never received ET in early breast cancer stage, or…
                  • Everolimus, AI or Fulvestrant
                    BOLERO
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                  • Gedatolisib + fulvestrant ± palbociclib
                    VIKTORIA-1
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
            • PIK3CA mut.
              • Alpelisib + ET SOLAR-1, BYLieve
                • None of the above or after progression in 1L lines of therapy from prior
                  Patients who never received ET in early breast cancer stage, or…
                  • Everolimus, AI or Fulvestrant
                    BOLERO
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                  • Gedatolisib + fulvestrant ± palbociclib
                    VIKTORIA-1
                    • Assess HER2 expression
                      • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                      • HER2 low (IHC 1+ or IHC 2+/ISH−)
                        • T-DXd*** DESTINY-Breast06
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo (cape)
                          • Chemo
                          • T-DXd*** DESTINY-Breast 04
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • HER2 null (IHC 0 with no staining)
                        • Chemo (cape)
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo
        • PIK3CA wt
          • CDK4/6 inhibitor + endocrine therapy
            Ribo - Monaleesa 2, 3, 7; Abema - Monarch 2, 3; Palbo - Paloma 2, 3… ** Ribociclib showed a statistically significant OS benefit
            • NGS and germline testing
              • PIK3CA, PTEN, AKT alteration
                Efficacy of sequential targeting of PIK3CA pathway is unknown (adj ET…)
                • Capivasertib + ET CAPItello-291
                  • None of the above or after progression in 1L lines of therapy from prior
                    Patients who never received ET in early breast cancer stage, or…
                    • Everolimus, AI or Fulvestrant
                      BOLERO
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                    • Gedatolisib + fulvestrant ± palbociclib
                      VIKTORIA-1
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
              • ESR1 mut.
                • Elacestrant - EMERALD / Imlunestrant - EMBER-3
                  • None of the above or after progression in 1L lines of therapy from prior
                    Patients who never received ET in early breast cancer stage, or…
                    • Everolimus, AI or Fulvestrant
                      BOLERO
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                    • Gedatolisib + fulvestrant ± palbociclib
                      VIKTORIA-1
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
              • gBRCA 1/2 mut.
                • PARPi (Ola, Tal) OLYMPIAD, EMBRACA
                  • None of the above or after progression in 1L lines of therapy from prior
                    Patients who never received ET in early breast cancer stage, or…
                    • Everolimus, AI or Fulvestrant
                      BOLERO
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                    • Gedatolisib + fulvestrant ± palbociclib
                      VIKTORIA-1
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
              • PIK3CA mut.
                • Alpelisib + ET SOLAR-1, BYLieve
                  • None of the above or after progression in 1L lines of therapy from prior
                    Patients who never received ET in early breast cancer stage, or…
                    • Everolimus, AI or Fulvestrant
                      BOLERO
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                    • Gedatolisib + fulvestrant ± palbociclib
                      VIKTORIA-1
                      • Assess HER2 expression
                        • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                        • HER2 low (IHC 1+ or IHC 2+/ISH−)
                          • T-DXd*** DESTINY-Breast06
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                          • Chemo (cape)
                            • Chemo
                            • T-DXd*** DESTINY-Breast 04
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Sacituzumab govitecan TROPiCS***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Dato-DXd Tropion Breast 01***
                              ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • HER2 null (IHC 0 with no staining)
                          • Chemo (cape)
                          • Dato-DXd Tropion Breast 01***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
                          • Sacituzumab govitecan TROPiCS***
                            ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                            • Chemo
    • De novo PD, 1L on adjuv or after adjuv ET*
      *patients who never received ET in early breast cancer stage, or relapsing ≥12 months after completing adjuvant ET, or diagnosed with de novo stage IV breast cancer.
      • CDK4/6 inhibitor + endocrine therapy
        Ribo - Monaleesa 2, 3, 7; Abema - Monarch 2, 3; Palbo - Paloma 2, 3… ** Ribociclib showed a statistically significant OS benefit
        • NGS and germline testing
          • PIK3CA, PTEN, AKT alteration
            Efficacy of sequential targeting of PIK3CA pathway is unknown (adj ET…)
            • Capivasertib + ET CAPItello-291
              • None of the above or after progression in 1L lines of therapy from prior
                Patients who never received ET in early breast cancer stage, or…
                • Everolimus, AI or Fulvestrant
                  BOLERO
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                • Gedatolisib + fulvestrant ± palbociclib
                  VIKTORIA-1
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
          • ESR1 mut.
            • Elacestrant - EMERALD / Imlunestrant - EMBER-3
              • None of the above or after progression in 1L lines of therapy from prior
                Patients who never received ET in early breast cancer stage, or…
                • Everolimus, AI or Fulvestrant
                  BOLERO
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                • Gedatolisib + fulvestrant ± palbociclib
                  VIKTORIA-1
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
          • gBRCA 1/2 mut.
            • PARPi (Ola, Tal) OLYMPIAD, EMBRACA
              • None of the above or after progression in 1L lines of therapy from prior
                Patients who never received ET in early breast cancer stage, or…
                • Everolimus, AI or Fulvestrant
                  BOLERO
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                • Gedatolisib + fulvestrant ± palbociclib
                  VIKTORIA-1
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
          • PIK3CA mut.
            • Alpelisib + ET SOLAR-1, BYLieve
              • None of the above or after progression in 1L lines of therapy from prior
                Patients who never received ET in early breast cancer stage, or…
                • Everolimus, AI or Fulvestrant
                  BOLERO
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                • Gedatolisib + fulvestrant ± palbociclib
                  VIKTORIA-1
                  • Assess HER2 expression
                    • HER2 ultralow (IHC 0 with faint, incomplete membrane staining)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                    • HER2 low (IHC 1+ or IHC 2+/ISH−)
                      • T-DXd*** DESTINY-Breast06
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                      • Chemo (cape)
                        • Chemo
                        • T-DXd*** DESTINY-Breast 04
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Sacituzumab govitecan TROPiCS***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Dato-DXd Tropion Breast 01***
                          ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                    • HER2 null (IHC 0 with no staining)
                      • Chemo (cape)
                      • Dato-DXd Tropion Breast 01***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
                      • Sacituzumab govitecan TROPiCS***
                        ***Optimal sequencing of therapies for endocrine sensitive disease and ADCs remains unknown
                        • Chemo
tosprivacyA Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Participants With PIK3CA-Mutant, Hormone Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120)Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer (MONALEESA-2)Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer. (MONALEESA-3)Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer (MONALEESA-7)A Study of Abemaciclib (LY2835219) Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer (MONARCH 2)A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer (MONARCH 3)A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/​HER2- Advanced Breast Cancer (PALOMA-2)Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3)Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/​HER2- Breast Cancer (CAPItello-291)Phase 3 Trial of Elacestrant Versus Standard of Care for the Treatment of ER+/​HER2- Advanced Breast Cancer (EMERALD)A Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3)Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/​2 Mutations. (OlympiAD)A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/​or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study) (EMBRACA)Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. (SOLAR-1)Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer Who Have Progressed on or After Prior Treatments (BYLieve)Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer (DB-06)A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator's Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01)Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician's Choice in Participants With HR+/​HER2- Metastatic Breast Cancer (TROPiCS-02)Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]