title: Impact of neoadjuvant single or dual HER2 inhibition and chemotherapy backbone upon pathological complete response in operable and locally advanced breast cancer: Sensitivity analysis of randomized trials.
abstract: The role of the dual HER2 inhibition, and the best chemotherapy backbone for neoadjuvant chemotherapy still represent an issue for clinical practice. A literature-based meta-analysis exploring single versus dual HER2 inhibition in terms of pathological complete response (pCR, breast plus axilla) rate and testing the interaction according to the chemotherapy (anthracyclines-taxanes or taxanes) was conducted. In addition, an event-based pooled analysis by extracting activity and safety events and deriving 95% confidence intervals (CI) was accomplished. Fourteen trials (4149 patients) were identified, with 6 trials (1820 patients) included in the meta-analysis and 31 arms (14 trials, 3580 patients) in the event-based pooled analysis. The dual HER2 inhibition significantly improves pCR rate, in the range of 16-19%, regardless of the chemotherapy backbone (relative risk 1.37, 95% CI 1.23-1.53, p<0.0001); pCR was significantly higher in the hormonal receptor negative population, regardless of the HER2 inhibition and type of chemotherapy. pCR and the rate of breast conserving surgery was higher when anthracyclines were added to taxanes, regardless of the HER2 inhibition. Severe neutropenia was higher with the addition of anthracyclines to taxanes, with an absolute difference of 19.7%, despite no differences in febrile neutropenia. While no significant differences according to the HER2 inhibition were found in terms of cardiotoxicity, a slightly difference for grade 3-4 (1.2%) against the addition of anthracyclines was calculated. The dual HER2 inhibition for the neoadjuvant treatment of HER2-positive breast cancer significantly increases pCR; the combination of anthracyclines, taxanes and anti-Her2 agents should be currently considered the standard of care.
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: emiliobria@yahoo.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: luisa.carbognin@gmail.com.
authors.forename: Luisa
authors.initials: L
authors.lastname: Carbognin
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: jenny.furlanetto@hotmail.it.
authors.forename: Jenny
authors.initials: J
authors.lastname: Furlanetto
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: sara.pilotto.85@alice.it.
authors.forename: Sara
authors.initials: S
authors.lastname: Pilotto
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: mari.bonomi0429@gmail.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Bonomi
authors.affiliation: Medical Oncology, Istituto Oncologico Veneto IRCCS, University of Padova, Padova, Italy. Electronic address: valentina.guarneri@unipd.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarneri
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: cecivice@gmail.com.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Vicentini
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: matteo.brunelli@univr.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: rolando.nortilli@ospedaleuniverona.it.
authors.forename: Rolando
authors.initials: R
authors.lastname: Nortilli
authors.affiliation: Chirurgia 'A', Department of Surgery and Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: francesca.pellini@ospedaleuniverona.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellini
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Roma, Italy. Electronic address: isperduti@yahoo.it.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Roma, Italy. Electronic address: giannarelli@ifo.it.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Chirurgia 'A', Department of Surgery and Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: giovanni.pollini@ospedaleuniverona.it.
authors.forename: Giovanni Paolo
authors.initials: GP
authors.lastname: Pollini
authors.affiliation: Medical Oncology, Istituto Oncologico Veneto IRCCS, University of Padova, Padova, Italy. Electronic address: pierfranco.conte@unipd.it.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy. Electronic address: giampaolo.tortora@univr.it.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D018943:Anthracyclines; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; C508053:ERBB2 protein, human
keywords: Breast cancer; HER2-positive; Meta-analysis; Neoadjuvant; Trastuzumab