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Addressing the Challenges in the Identification of HER2-Low and Ultralow Breast Cancer in Asia: A Delphi Consensus

Year: 2026

Type: article

Abstract: Human epidermal growth factor receptor type 2 (HER2) is overexpressed in 15–20% of primary invasive breast cancers, serving as a key predictive and prognostic factor. HER2-low is defined as immunohistochemistry (IHC) 1+ or 2+ with in situ hybridization (ISH) negative and HER2-ultralow is defined as membrane staining that is incomplete, faint/barely perceptible, and in at most 10% of tumor cells (0+/with membrane staining). Trastuzumab deruxtecan has shown improved outcomes in multiple clinical trials between these groups. A Delphi study was conducted to address challenges in testing, sampling, and reporting, and to identify unmet needs in Asia. The study comprised two online surveys and a participant meeting with 15 pathologists from nine countries in Asia and the Indo-Pacific region. Responses were recorded for 57 close-ended and 33 open-ended statements using a 1–9-point Likert scale ranging from agreement to disagreement with a consensus threshold of 75%. All participants completed both surveys and the meeting (100% response). Consensus was reached on 33/57 closed-ended statements (survey 1, 27/47; survey 2, 6/21), while 24/57 did not reach consensus. Ninety-three percent of participants agreed that biopsies of recurrent lesions should be performed, especially if the primary tumor was HER2-zero. Initially, participants did not reach consensus (73% agreement) on reassessing HER2 results for metastatic lesions scored as HER2-zero but later reached consensus (80% agreement). All testing-related questions reached consensus in survey 1. This Delphi study found strong consensus on key concepts for sampling, pathological testing, interpretation, and reporting of HER2-low and ultralow breast cancer. While the opinions expressed align with current guidelines, more evidence on the clinicopathological implications is needed. Human epidermal growth factor receptor type 2 (HER2) is a protein found in about 15–20% of invasive breast cancers and helps guide treatment decisions. HER2-low means the cancer shows low levels of HER2 (immunohistochemistry 1+ or 2+ with a negative in situ hybridization test), while HER2-ultralow refers to very minimal HER2 presence (immunohistochemistry 0 or slightly above). All participants completed both surveys and the meeting. This study found strong agreement on key concepts for sampling, pathological testing, interpretation, and reporting of HER2-low and ultralow breast cancer amongst experts. Agreement was reached on 33 of 57 statements, mostly in the first survey. A strong majority (93%) supported biopsying recurrent tumors, especially if the original was HER2-zero. Initially, there was no agreement on reassessing HER2 in metastatic HER2-zero cases (73% agreement), but this later improved to 80%. All testing-related questions reached agreement in the first round.

Source: Advances in Therapy

DOI: 10.1007/s12325-025-03426-x