Francesco Schettini1, Tomás Pascual2, Benedetta Conte3, Nuria Chic4, Fara Brasó-Maristany5, Patricia Galván6, Olga Martínez5, Barbara Adamo2, Maria Vidal2, Montserrat Muñoz2, Aranzazu Fernández-Martinez7, Carla Rognoni8, Gaia Griguolo9, Valentina Guarneri9, Pier Franco Conte9, Mariavittoria Locci10, Jan C Brase11, Blanca Gonzalez-Farre12, Patricia Villagrasa13, Sabino De Placido14, Rachel Schiff15, Jamunarani Veeraraghavan16, Mothaffar F Rimawi17, C Kent Osborne15, Sonia Pernas18, Charles M Perou7, Lisa A Carey19, Aleix Prat20. 1. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain. 2. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. 3. Department of Medical Oncology, Ospedale Policlinico San Martino, University of Genova, Genova, Italy. 4. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. 5. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. 6. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain. 7. Department of Genetics, University of North Carolina, Chapel Hill, USA. 8. Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Milan, Italy. 9. Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy; Division of Medical Oncology 2, Istituto Oncologico Veneto - IRCCSS, Padova, Italy. 10. Department of Neuroscience, Reproductive Medicine, Odontostomatology, University of Naples Federico II, Naples, Italy. 11. Novartis Pharma AG, Basel, Switzerland. 12. Department of Pathology, Hospital Clinic, Barcelona, Spain. 13. SOLTI Breast Cancer Research Group, Barcelona, Spain. 14. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. 15. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. 16. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. 17. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 18. SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medical Oncology, Institut Català d'Oncologia-H. U. Bellvitge-IDIBELL, Barcelona, Spain. 19. Department of Medicine, University of North Carolina, Chapel Hill, USA. 20. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. Electronic address: alprat@clinic.cat.
Abstract
BACKGROUND: HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-Enriched (HER2-E) appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT). METHODS: A systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins' I2 was used to quantify heterogeneity. RESULTS: Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR] = 3.50, p < 0.001, I2 = 33%), in HR+ (OR = 3.61, p < 0.001, I2 = 1%) and HR-negative tumors (OR = 2.28, p = 0.01, I2 = 47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR = 5.52, p < 0.001, I2 = 0%) and in HR + disease (OR = 4.08, p = 0.001, I2 = 0%). HR-negative status was significantly associated with pCR compared to HR + status in all patients (OR = 2.41, p < 0.001, I2 = 30%) and within the HER2-E subtype (OR = 1.76, p < 0.001, I2 = 0%). CONCLUSIONS: The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.
BACKGROUND:HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-Enriched (HER2-E) appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT). METHODS: A systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins' I2 was used to quantify heterogeneity. RESULTS: Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR] = 3.50, p < 0.001, I2 = 33%), in HR+ (OR = 3.61, p < 0.001, I2 = 1%) and HR-negative tumors (OR = 2.28, p = 0.01, I2 = 47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR = 5.52, p < 0.001, I2 = 0%) and in HR + disease (OR = 4.08, p = 0.001, I2 = 0%). HR-negative status was significantly associated with pCR compared to HR + status in all patients (OR = 2.41, p < 0.001, I2 = 30%) and within the HER2-E subtype (OR = 1.76, p < 0.001, I2 = 0%). CONCLUSIONS: The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.
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