Breast cancer (BC) guidelines subdivide the disease into three main groups, namely hormone receptor (HR)-positive HER2-negative, HER2-positive, and triple-negative BC (TNBC). The natural history of the HER2-positive subtype has changed since the introduction of HER-targeted therapies, which demonstrated benefit only in case of HER2 overexpression (IHC, score 3+) or gene amplification. Such observation may depend on direct drug inhibition of HER2 downstream signaling, which is needed for survival and proliferation in HER2-addicted BC. Clinically focused categories cannot comprehensively describe biology, as almost half of the currently defined HER2-negative BCs show some degree of IHC expression and have been recently renamed as HER2-low. Why? As technological breakthroughs enable the synthesis of antibody-drug conjugates (ADCs), target antigens may be viewed not only as a biological switch to be turned on-off by targeted drugs but also as an anchor for ADC docking and tethering. As trastuzumab deruxtecan (T-DXd) has already proven in the clinical trial DESTINY-Breast04, even fewer HER2 available receptors on cancer cells may be sufficient for a clinical benefit. So, for HR-negative HER2-low subtype (similar to 40% of TNBCs), though only 58 patients had been enrolled in DESTINY-Breast04, the observed benefit, together with the dismal prognosis of TNBC, warrants the use of T-DXd. Notably, another topoisomerase-based ADC, sacituzumab govitecan, has already been granted approval for pretreated TNBC (ASCENT). As no head-to-head comparison has been performed, the choice relies on regulatory approvals at the time of patient assessment, critical appraisal of available evidence, and careful evaluation of possible cross-resistance with sequential use of ADCs. As for HR-positive HER2-low disease (similar to 60% of HR-positive tumors), DESTINY-Breast04 provides solid evidence for T-DXd prioritization in either second or third treatment lines. Although the remarkable activity observed in this setting favorably compares with outcomes observed in treatment-naive patients, the ongoing DESTINY-Breast06 will clarify the role of T-DXd in this population.

HER2-Low Breast Cancer: a New Subtype? / C. Corti, F. Giugliano, E. Nicolò, P. Tarantino, C. Criscitiello, G. Curigliano. - In: CURRENT TREATMENT OPTIONS IN ONCOLOGY. - ISSN 1534-6277. - 24:5(2023 May), pp. 468-478. [10.1007/s11864-023-01068-1]

HER2-Low Breast Cancer: a New Subtype?

C. Corti
Primo
;
F. Giugliano
Secondo
;
P. Tarantino;C. Criscitiello
Penultimo
;
G. Curigliano
Ultimo
2023

Abstract

Breast cancer (BC) guidelines subdivide the disease into three main groups, namely hormone receptor (HR)-positive HER2-negative, HER2-positive, and triple-negative BC (TNBC). The natural history of the HER2-positive subtype has changed since the introduction of HER-targeted therapies, which demonstrated benefit only in case of HER2 overexpression (IHC, score 3+) or gene amplification. Such observation may depend on direct drug inhibition of HER2 downstream signaling, which is needed for survival and proliferation in HER2-addicted BC. Clinically focused categories cannot comprehensively describe biology, as almost half of the currently defined HER2-negative BCs show some degree of IHC expression and have been recently renamed as HER2-low. Why? As technological breakthroughs enable the synthesis of antibody-drug conjugates (ADCs), target antigens may be viewed not only as a biological switch to be turned on-off by targeted drugs but also as an anchor for ADC docking and tethering. As trastuzumab deruxtecan (T-DXd) has already proven in the clinical trial DESTINY-Breast04, even fewer HER2 available receptors on cancer cells may be sufficient for a clinical benefit. So, for HR-negative HER2-low subtype (similar to 40% of TNBCs), though only 58 patients had been enrolled in DESTINY-Breast04, the observed benefit, together with the dismal prognosis of TNBC, warrants the use of T-DXd. Notably, another topoisomerase-based ADC, sacituzumab govitecan, has already been granted approval for pretreated TNBC (ASCENT). As no head-to-head comparison has been performed, the choice relies on regulatory approvals at the time of patient assessment, critical appraisal of available evidence, and careful evaluation of possible cross-resistance with sequential use of ADCs. As for HR-positive HER2-low disease (similar to 60% of HR-positive tumors), DESTINY-Breast04 provides solid evidence for T-DXd prioritization in either second or third treatment lines. Although the remarkable activity observed in this setting favorably compares with outcomes observed in treatment-naive patients, the ongoing DESTINY-Breast06 will clarify the role of T-DXd in this population.
Antibody-drug conjugates; Breast cancer; HER2-low; Human epidermal growth factor receptor 2; Immunohistochemistry; Trastuzumab deruxtecan
Settore MED/06 - Oncologia Medica
mag-2023
27-mar-2023
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/985532
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