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      HER2+ Early Breast Cancer: From Escalation via Targeted and Post-Neoadjuvant Treatment to De-Escalation

      review-article
      a , b , c , , a , b , d
      Breast Care
      S. Karger AG
      Breast neoplasms, HER2, ERBB2 protein, Human, Neoadjuvant therapy, Trastuzumab

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          Abstract

          Background

          Human epidermal growth factor receptor 2 positive (HER2+, also referred to as ERBB2+) breast cancer is a subtype, historically associated with a particularly poor prognosis. Research into biological and molecular pathomechanisms of breast cancer has resulted in the development and adoption of several therapies targeting HER2. In parallel, various escalation/de-escalation strategies have been examined to further optimize patient outcomes and care.

          Summary

          In this review, we highlighted the landmark trials in the evolution of treatment and management of HER2+ early breast cancer (eBC).

          Key Messages

          Continuous research over the last two decades has gradually prolonged survival in patients with early HER2+ eBC. Incorporation of post-neoadjuvant setting into clinical practice improved long-term outcomes in high-risk patients with residual disease after neoadjuvant therapy. In parallel, use of modern anti-HER2 agents may potentially allow omission of chemotherapy without compromising the survival in a significant number of selected patients. Current research focused on exploring the molecular heterogeneity of HER2+ breast cancer resulted in identification of new prognostic and predictive biomarkers which could pave the way toward the development of truly personalized therapy.

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          Most cited references59

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          Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

          Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
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            Adjuvant trastuzumab in HER2-positive breast cancer.

            Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).
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              Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.

              Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. F Hoffmann-La Roche. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Breast Care (Basel)
                Breast Care (Basel)
                BRC
                BRC
                Breast Care
                S. Karger AG (Basel, Switzerland )
                1661-3791
                1661-3805
                25 October 2023
                December 2023
                : 18
                : 6
                : 455-463
                Affiliations
                [a ]West German Study Group, Moenchengladbach, Germany
                [b ]Breast Center Niederrhein, Ev. Hospital Bethesda, Moenchengladbach, Germany
                [c ]Department of Gynecology, University Medical Center Hamburg, Hamburg, Germany
                [d ]University Clinics Cologne, Cologne, Germany
                Author notes
                Correspondence to: Monika Graeser, monika.graeser@ 123456wsg-online.com
                Article
                534670
                10.1159/000534670
                10730100
                38125917
                cff2f33c-4923-429f-b9fa-a2e5b576659c
                © 2023 The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) ( http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

                History
                : 1 September 2023
                : 17 October 2023
                : 2023
                Page count
                Figures: 1, Tables: 1, References: 59, Pages: 9
                Funding
                Not applicable.
                Categories
                Review Article

                breast neoplasms,her2,erbb2 protein,human,neoadjuvant therapy,trastuzumab

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