Abstract
SummaryBackgroundBoth clinical and genomic data independently predict survival and treatment response in early-stage HER2-positive breast cancer. Here we present the development and validation of a new HER2DX risk score, and a new HER2DX pathological complete response (pCR) score, both based on a 27-gene expression plus clinical feature-based classifier.MethodsHER2DX is a supervised learning algorithm incorporating tumour size, nodal staging, and 4 gene expression signatures tracking immune infiltration, tumour cell proliferation, luminal differentiation, and the expression of the HER2 amplicon, into a single score. 434 HER2-positive tumours from the Short-HER trial were used to train a prognostic risk model; 268 cases from an independent cohort were used to verify the accuracy of the HER2DX risk score. In addition, 116 cases treated with neoadjuvant anti-HER2-based chemotherapy were used to train a predictive model of pathological complete response (pCR); two independent cohorts of 91 and 67 cases were used to verify the accuracy of the HER2DX pCR likelihood score. Five publicly available independent datasets with >1,000 patients with early-stage HER2-positive disease were also analysed.FindingsIn Short-HER, HER2DX variables were associated with good risk outcomes (i.e., immune, and luminal) and poor risk outcomes (i.e., proliferation, and tumour and nodal staging). In an independent cohort, continuous HER2DX risk score was significantly associated with disease-free survival (DFS) (p=0·002); the 5-year DFS in the low-risk group was 97·4% (94·4-100·0%). For the neoadjuvant pCR predictor training cohort, HER2DX variables were associated with pCR (i.e., immune, proliferation and HER2 amplicon) and non-pCR (i.e., luminal, and tumour and nodal staging). In both independent test set cohorts, continuous HER2DX pCR likelihood score was significantly associated with pCR (p<0·0001). A weak negative correlation was found between the HER2DX risk score versus the pCR score (correlation coefficient -0·19).InterpretationThe two HER2DX tests provide accurate estimates of the risk of recurrence, and the likelihood to achieve a pCR, in early-stage HER2-positive breast cancer.FundingThis study received funding from Reveal Genomics, IDIBAPS and the University of Padova.
Highlights
HER2-positive breast cancer causes a substantial proportion of deaths.[1]
Decisions nowadays about escalation or de-escalation of systemic therapies are still based on traditional parameters, i.e., tumour size, nodal status, expression of the hormone receptors, and response to neoadjuvant therapy
Our previous study[19] showed that the best prognostic models integrated tumour size, nodal status, tumour-infiltrating lymphocytes (TILs), and the main biology associated with the 4 intrinsic subtypes
Summary
HER2-positive breast cancer causes a substantial proportion of deaths.[1]. In the early stages, (neo)adjuvant chemotherapy plus trastuzumab (plus endocrine therapy in hormone receptor-positive disease) have consistently shown significant increases in survival.[2]substantial clinical and biological heterogeneity exists in HER2-positive disease, which affects patients' prognosis and treatment benefit.2À5Strategies to either escalate or de-escalate systemic therapy in early-stage HER2-positive breast cancer to improve survival outcomes and quality of life have been explored,[6] such as decreasing the number of cycles of chemotherapy and/or the duration of trastuzumab,7À10 increasing HER2 blockade with pertuzumab[11] or neratinib,[12] or switching anti-HER2 therapy to trastuzumab emtansine in patients who do not achieve a pathological complete response (pCR) following neoadjuvant therapy.[13]. HER2-positive breast cancer causes a substantial proportion of deaths.[1] In the early stages, (neo)adjuvant chemotherapy plus trastuzumab (plus endocrine therapy in hormone receptor-positive disease) have consistently shown significant increases in survival.[2]. Several variables beyond tumour burden have been associated with patients prognosis and/or treatment response in early-stage, HER2-positive breast cancer. A tool that objectively integrates these multiple variables together will likely show better performance that any single feature, which would be a useful tool to help guide therapy in early-stage HER2- positive breast cancer. In 2020, we reported HER2DX,[19] a first attempt to build a multi-feature prognostic score in early-stage
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