The Lancet
Oncology : ARTICLES| VOLUME
21, ISSUE 11, P1455-1464, NOVEMBER 01, 2020
Background
In early-stage HER2-positive breast cancer, escalation or
de-escalation of systemic therapy is a controversial topic. As an aid to
treatment decisions, we aimed to develop a prognostic assay that integrates
multiple data types for predicting survival outcome in patients with newly
diagnosed HER2-positive breast cancer.
Methods
We derived a combined prognostic model using retrospective
clinical–pathological data on stromal tumour-infiltrating lymphocytes, PAM50
subtypes, and expression of 55 genes obtained from patients who participated in
the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed,
node-positive, HER2-positive breast cancer or, if node negative, with at least
one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular
invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and
randomly assigned them to adjuvant anthracycline plus taxane-based combinations
with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered
intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg
thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and
2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane
dose. Median follow-up was 91·4 months (IQR 75·1–105·6). The primary objective
of our study was to derive and evaluate a combined prognostic score associated
with distant metastasis-free survival (the time between randomisation and
distant recurrence or death before recurrence), an exploratory endpoint in
Short-HER. Patient samples in the training dataset were split into a training
set (n=290) and a testing set (n=145), balancing for event and treatment group.
The training set was further stratified into 100 iterations of Monte-Carlo
cross validation (MCCV). Cox proportional hazard models were fit to MCCV
training samples using Elastic-Net. A maximum of 92 features were assessed. The
final prognostic model was evaluated in an independent combined dataset of 267
patients with early-stage HER2-positive breast cancer treated with different
neoadjuvant and adjuvant anti-HER2-based combinations and from four other
studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free
survival outcome data.
Findings
From Short-HER, data from 435 (35%) of 1254 patients for
tumour size (T1 vs rest), nodal status (N0 vs rest), number
of tumour-infiltrating lymphocytes (continuous variable), subtype
(HER2-enriched and basal-like vs rest), and 13 genes composed the
final model (named HER2DX). HER2DX was significantly associated with distant
metastasis-free survival as a continuous variable (p<0·0001). HER2DX median
score for quartiles 1–2 was identified as the cutoff to identify low-risk
patients; and the score that distinguished quartile 3 from quartile 4 was the
cutoff to distinguish medium-risk and high-risk populations. The 5-year distant
metastasis-free survival of the low-risk, medium-risk, and high-risk
populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0), and 73·9%
(66·0–82·7), respectively (low-risk vs high-risk hazard ratio [HR]
0·04, 95% CI 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was
significantly associated with disease-free survival as a continuous variable
(HR 2·77, 95% CI 1·4–5·6, p=0·0040) and as group categories (low-risk vs high-risk
HR 0·27, 0·1–0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk
group was 93·5% (89·0–98·3%) and in the high-risk group was 81·1% (71·5–92·1).
Interpretation
The HER2DX combined prognostic score identifies patients
with early-stage, HER2-positive breast cancer who might be candidates for
escalated or de-escalated systemic treatment. Future clinical validation of
HER2DX seems warranted to establish its use in different scenarios, especially
in the neoadjuvant setting.
