Publication: American Journal of Clinical Pathology, 2025, Vol. 163, No. 6

Authors: Natasha Hunter, MD; Lisa Han, MD; Haley Corbin, MD; Eric Q. Konnick, MD, MS, ; William R. Gwin III, MD; Shaveta Vinayak, MD; Hannah Linden, MD; William Audeh, MD; Lavanya Samraj, MD, MS; Andrea R. Menicucci, PhD; FLEX Investigators Group; T. Rinda Soong, MD, PhD

Title: Clinicopathologic and molecular characterization of low-grade, early-stage, and HER2-positive invasive breast carcinoma

Abstract

Objectives:

Breast carcinomas overexpressing human epidermal growth factor receptor 2 (HER2) are typically associated with higher tumor grade and faster progression. HER2 positivity is rare in low-grade breast carcinomas with unclear biological implications. We aimed to characterize their clinicopathologic and molecular profiles in this study.

Methods:

There were 2 cohorts of Nottingham grade 1, HER2-positive invasive breast carcinomas examined: (1) an institutional series (n = 14) and (2) tumors from patients (n = 59) enrolled in the FLEX multicenter clinical registry with MammaPrint and BluePrint profiling.

Results:

Most (79%) in the case series were both estrogen receptor (ER) and proges terone receptor (PR)-positive. Over half were pathologic or clinical T1N0 tumors. In the 9 cases with adequate material for next-generation sequencing, the majority (66%) dem onstrated ERBB2 copy number variations. Most (66%) received HER2-targeted therapy. No recurrences were observed, with a median follow-up time of 43 months. In the FLEX cohort, most tumors were ER-positive (86%) and PR-positive (68%), and over half were clinical T1. Most (70%) were of the luminal phenotype, and over half (54%) were low-risk on MammaPrint.

Conclusions:

Low-grade HER2-positive breast carcinomas constitute mostly low stage, luminal-type, and apparently low-risk tumors, warranting investigation into whether therapy de-escalation could achieve favorable outcomes with less toxicity in this population.