A 7-Gene Biosignature for Ductal Carcinoma in situ of the Breast Identifies Subpopulations of HER2-positive Patients With Distinct Recurrence Rates After Breast-Conserving Surgery and Radiation Therapy.

Purpose: A subpopulation of women with ductal carcinoma in situ (DCIS) remains at risk for in-breast recurrence (IBR) following breast-conserving surgery (BCS) and radiation therapy (RT). The NSABP B-43 trial evaluated the role of concurrent RT and trastuzumab in patients with HER2-positive DCIS but did not reach the prespecified endpoint. We hypothesized that a 7-gene biosignature (DCISionRT) with its Residual Risk subtype (RRt) could identify 2 groups of HER2(3+) patients with significantly different IBR risks after BCS plus RT.
Patients and Methods: All patients with HER2(3+) DCIS (n = 178) treated with BCS plus RT were selected from a combined multinational patient cohort. Treatment decisions were neither randomized nor strictly rules-based. Biosignature testing was performed on all patients and stratified with previously defined groups: (1) Combined Low Risk group (DS ≤ 2.8) and Elevated Risk group (DS > 2.8) without RRt or (2) Residual Risk subtype. Kaplan-Meier analysis was used to compute IBR curves.
Results: Sixty-three percent of HER2(3+) patients (113/178) were classified into the Residual Risk subtype. These patients had significantly higher 10-year rates of IBR compared to the nonresidual risk group (16.2% vs. 1.6%, P = .01). The Residual Risk subtype had more nuclear grade 3 disease (87% vs. 63%, P < .001), but age, size, and grade were not associated with IBR rate (P = NS) on univariate and multivariable analysis. Only the Residual Risk group was associated with IBR (P = .05) in multivariate analysis.
Conclusion: The 7-gene biosignature with RRt identified a subset of HER2(3+) patients with greater IBR rates following BCS and RT beyond traditional clinical and pathologic features. Consideration of therapies to reduce these elevated IBR rates should be evaluated, including the incorporation of HER2-targeted therapy.
Competing Interests: Disclosure FV is a research advisor for PreludeDx and PreludeDx supported his institution for the conduct and management of a separate clinical trial. FV is also a consultant for ImpediMed, unrelated to this research. CS is a consultant for and has received research funding from PreludeDx for separate research projects. CS is also a consultant for ImpediMed, Videra Surgical and Evicore and has received grant funding from Varian Medical Systems, and VisionRT unrelated to this research. KM and SS are employees of PreludeDx and have stock options for PreludeDx. SW and ML have received grant support from PreludeDx for a previously published validation study. RR has received research funding from PreludeDx for a separate clinical study. Unrelated to this study, RR has stock and other ownership interests in Abbott Laboratories, Bristol-Myers Squibb, Intuitive Surgical, IDEXX Laboratories. FW is a consultant for PreludeDx and was supported by PreludeDx for the conduct and management of previous studies. PW is on an advisory board and has received research funding from PreludeDx. Unrelated to this study, PW has stock and other ownership interests in Reverse Medical, Rebound Medical, Lazarus, Cerebrotech, Targeted Medical Education and Medtronic, is on advisory boards for Medtronic, Lumicell, ImpediMed, and Cianna Medical, and has received research funding from Invitae, Intact Medical, Agendia and ImpediMed. BC has intellectual property rights for ImmunoRestoration and receives consulting fees from Merit Medical unrelated to this research. TB is an employee of PreludeDx, holds intellectual property rights for the DCISionRT test, and has an ownership interest in PreludeDx. JA and MK have no competing interests (Figure 1, Supplemental Figures 1 and 2, Table 1, Table 2, Table 3, Table 4).
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)