Abstract ES1-2: Early HER2-positive breast cancer: Doing more and less
Authors: Carey L 
Published: May 2019

Abstract
The clinical impact of the HER2 oncogene, with more aggressive features and worse prognosis, was first described in 1989. The first HER2-targeted drug, trastuzumab, was FDA-approved less than 10 years later; since then multiple drugs have been successfully developed. The development of HER2-targeted drugs has entirely changed the prognostic landscape of early HER2-positive disease from one of the worst prognoses to one of the best.
The first, and most important, of these drugs is trastuzumab, which when combined with adjuvant chemotherapy and given for 1 year decreases relapse rates by 35-50% and improves overall survival rates by 40%. In neoadjuvant trials, adding a second anti-HER2 drug increases pathologic complete response (pCR) consistently but to a variable degree. pCR increase with pertuzumab added to trastuzumab plus chemotherapy in a large phase II neoadjuvant trial, NeoSPHERE, resulted in accelerated approval of pertuzumab in 2012. NeoSPHERE also highlighted the relative ineffectiveness of all-biologic therapy; the arm in which chemotherapy was omitted had the lowest pCR rate. Four neoadjuvant trials of a similar approach with lapatinib also demonstrated numerical pCR increases. However in the adjuvant setting, dual therapy has far more modest effects. Lapatinib added to trastuzumab plus chemotherapy in the phase III ALTTO trial demonstrated a numerical improvement in disease-free survival (DFS, hazard ratio [HR] = 0.84) that did not meet predefined criteria for significance. Pertuzumab added in a similar fashion in APHINITY had a DFS advantage (HR 0.81) that met criteria for significance and generated FDA approval for the adjuvant setting. The absolute 4-year iDFS advantage for adding pertuzumab was only 1.7%; 3.2% in node-positive disease and 2.3% in hormone receptor-negative (1.4% in hormone receptor-positive), hence the muted enthusiasm. In ExteNET, the irreversible HER1/2 inhibitor neratinib was tested against placebo for the year after completion of trastuzumab and chemotherapy, demonstrating a 27% improvement in iDFS, but an absolute difference of 2.5%. The patients with greatest benefit were those with ER-positive disease (surprisingly), and those with multiple involved lymph nodes (not surprisingly).
This escalation of adding ever more effective drugs comes at considerable physical, financial, and psychological costs. Neratinib without aggressive prophylaxis results in 40% with severe diarrhea, all of these regimens cost greater than $100,000 in the U.S., and few patients actually benefit. Shorter trastuzumab durations were tested in the Short-HER2, Phare, SOLD, and Persephone trials with mixed results but suggesting that 6 months is an acceptable option in those with toxicity or lower risk. Hope for more rational HER2-targeting came from a de-escalation trial, APT, in which patients with largely stage I (and mostly ER-positive) disease received only paclitaxel plus trastuzumab; the 4-year relapse-free survival was 98%. Extrapolation of these results is not possible to higher clinical stage disease, however several studies have now found that certain molecular subtypes such as the HER2-Enriched subtype or cancers with activated immune cells in the microenvironment have better prognosis and may be reasonable choices for de-escalation trials in the future.
Citation Format: Carey L. Early HER2-positive breast cancer: Doing more and less [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES1-2.