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. Author manuscript; available in PMC: 2024 Sep 15.

Published in final edited form as: Cancer. 2023 Jun 22;129(18):2773–2788. doi: 10.1002/cncr.34904

Figure 2: — The proposed sequencing algorithm in (a) HR-negative HER2-low BC and (b) HR+ HER2-low BC

a: Sequencing Algorithm in HR-negative HER2-low BC. *Based on the keynote-355 clinical trial, in HR-negative HER2-low BC, chemotherapy + pembrolizumab can be considered as first-line treatment if CPS ≥ 10. Paclitaxel, nab-paclitaxel (if disease free survival>=12 months), and gemcitabine-carboplatin (disease free survival <=12 months) are the chemotherapy options that can be used based on the trial. **DESTINYBreast04 trial enrolled patients in the T-DXd arm after one line of chemotherapy (63 patients with HR-negative HER2-low breast cancer) and ***the ASCENT trial is a large phase III trial which enrolled patients to SG after chemotherapy. Therefore, we propose the use of either of T-DXd or SG as next-line treatment option. ****Given the significant OS benefit of PARP inhibitors if used in the first line setting based on the OlympiAD trial, we propose to use PARP inhibitors as first-line in HR-negative HER2-low patients with germline BRCA mutation. HER2= Human epidermal growth factor receptor 2, TNBC= Triple-negative breast cancer, CPS= Combined positive scoring, T-DXd= Trastuzumab deruxtecan, SG= Sacituzumab govitecan, OS= Overall survival.

b: Sequencing Algorithm in HR+ HER2-low BC. In HR-positive HER2-low BC the first-line treatment is CDK4/6 inhibitors + endocrine therapy followed by other lines of endocrine therapy. *Elacestrant is preferred when ESR1 mutation is identified through guardant 360/liquid biopsy (preferred based on FDA approval) or next generation sequencing and if the progression-free survival on CDK4/6 inhibitors is more than 12 months. When the disease is endocrine-resistant, the next line of treatment is chemotherapy (**Physician’s choice of chemotherapy based on patient’s clinical condition and preference). ***As the DESTINY-Breast04 trial enrolled patients in the T-DXd arm after one line of chemotherapy, we propose using T-DXd as the next line of treatment. ****As the TROPiCS-02 trial enrolled patients in the SG arm after two lines of chemotherapy, we propose to consider SG after T-DXd. HR+HER2= Hormone receptor-positive human epidermal growth factor receptor 2, CDK4/6 i= Cyclin-dependent kinase 4 and 6 inhibitors, ET= Endocrine therapy, T-DXd= Transtuzumab Deruxtecan, SG= Sacituzumab govitecan.

Figure 2: — The proposed sequencing algorithm in (a) HR-negative HER2-low BC and (b) HR+ HER2-low BC

a: Sequencing Algorithm in HR-negative HER2-low BC. *Based on the keynote-355 clinical trial, in HR-negative HER2-low BC, chemotherapy + pembrolizumab can be considered as first-line treatment if CPS ≥ 10. Paclitaxel, nab-paclitaxel (if disease free survival>=12 months), and gemcitabine-carboplatin (disease free survival <=12 months) are the chemotherapy options that can be used based on the trial. **DESTINYBreast04 trial enrolled patients in the T-DXd arm after one line of chemotherapy (63 patients with HR-negative HER2-low breast cancer) and ***the ASCENT trial is a large phase III trial which enrolled patients to SG after chemotherapy. Therefore, we propose the use of either of T-DXd or SG as next-line treatment option. ****Given the significant OS benefit of PARP inhibitors if used in the first line setting based on the OlympiAD trial, we propose to use PARP inhibitors as first-line in HR-negative HER2-low patients with germline BRCA mutation. HER2= Human epidermal growth factor receptor 2, TNBC= Triple-negative breast cancer, CPS= Combined positive scoring, T-DXd= Trastuzumab deruxtecan, SG= Sacituzumab govitecan, OS= Overall survival.

b: Sequencing Algorithm in HR+ HER2-low BC. In HR-positive HER2-low BC the first-line treatment is CDK4/6 inhibitors + endocrine therapy followed by other lines of endocrine therapy. *Elacestrant is preferred when ESR1 mutation is identified through guardant 360/liquid biopsy (preferred based on FDA approval) or next generation sequencing and if the progression-free survival on CDK4/6 inhibitors is more than 12 months. When the disease is endocrine-resistant, the next line of treatment is chemotherapy (**Physician’s choice of chemotherapy based on patient’s clinical condition and preference). ***As the DESTINY-Breast04 trial enrolled patients in the T-DXd arm after one line of chemotherapy, we propose using T-DXd as the next line of treatment. ****As the TROPiCS-02 trial enrolled patients in the SG arm after two lines of chemotherapy, we propose to consider SG after T-DXd. HR+HER2= Hormone receptor-positive human epidermal growth factor receptor 2, CDK4/6 i= Cyclin-dependent kinase 4 and 6 inhibitors, ET= Endocrine therapy, T-DXd= Transtuzumab Deruxtecan, SG= Sacituzumab govitecan.