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      Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer

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          Novel anticancer targets: revisiting ERBB2 and discovering ERBB3.

          Aberrant receptor expression or functioning of the epidermal growth factor receptor (Erbb) family plays a crucial part in the development and evolution of cancer. Inhibiting the signalling activity of individual receptors in this family has advanced the treatment of a range of human cancers. In this Review we re-evaluate the role of two important family members, ERBB2 (also known as HER2) and ERBB3 (also known as HER3), and explore the mechanisms of action and preclinical and clinical data for new therapies that target signalling through these pivotal receptors. These new therapies include tyrosine kinase inhibitors, antibody-chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2-ERBB3 dimers.
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            Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study.

            We report cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC). Left ventricular ejection fraction (LVEF) ≥ 50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m(2) q3w. The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and pertuzumab arm). Declines in LVEF by ≥ 10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (pertuzumab arm) of those patients recovered to a value ≥ 50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff. The combination of pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.
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              Translating neoadjuvant therapy into survival benefits: one size does not fit all

              Neoadjuvant therapy has been established as an effective therapeutic approach for patients with locally advanced breast cancer. Similar outcomes between neoadjuvant and adjuvant chemotherapy have been demonstrated in several trials. Nevertheless, neoadjuvant therapy has some advantages over adjuvant therapy, including tumour downstaging, in vivo assessment of therapeutic efficacy, reduced treatment durations, and the need to enrol fewer patients for clinical trials to reach their preplanned objectives. The number of neoadjuvant trials in patients with breast cancer has increased substantially in the past 5 years, particularly in the context of HER2-positive disease. Substantial improvements in the pathological complete response rate to anti-HER2 therapy, a proposed surrogate end point for long-term clinical benefit, have been observed with neoadjuvant dual-agent HER2 blockade. Thus, it was hypothesized that this approach would provide additional survival benefits over standard-of-care therapy with the anti-HER2 antibody trastuzumab in the adjuvant setting. Emerging data, however, are calling this notion into question. We discuss potential reasons why results of neoadjuvant trials of targeted therapies have not been mirrored in the adjuvant setting, and other than inherent differences in clinical-trial designs and statistical power, we consider how the biology of the disease, patient characteristics, and drug administration and schedule might influence the results.
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                New England Journal of Medicine (NEJM/MMS)
                0028-4793
                1533-4406
                July 13 2017
                July 13 2017
                : 377
                : 2
                : 122-131
                Article
                10.1056/NEJMoa1703643
                5538020
                28581356
                1dfd9d7d-731a-48b2-ad99-acd4eac0f7c7
                © 2017
                History

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