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Review
. 2023 Dec;115(6):292-301.
doi: 10.32074/1591-951X-942.

Think "HER2" different: integrative diagnostic approaches for HER2-low breast cancer

Caterina Marchiò  1   2 , Carmen Criscitiello  3   4 , Cristian Scatena  5   6 , Alfredo Santinelli  7 , Paolo Graziano  8 , Umberto Malapelle  9 , Giulia Cursano  10 , Konstantinos Venetis  10 , Giuseppe Nicolò Fanelli  5   6 , Francesco Pepe  9 , Enrico Berrino  1   2 , Carmine De Angelis  11 , Giuseppe Perrone  12   13 , Giuseppe Curigliano  3   4 , Nicola Fusco  4   10
Affiliations
Review

Think "HER2" different: integrative diagnostic approaches for HER2-low breast cancer

Caterina Marchiò et al. Pathologica. 2023 Dec.

Abstract

This work explores the complex field of HER2 testing in the HER2-low breast cancer era, with a focus on methodological aspects. We aim to propose clear positions to scientific societies, institutions, pathologists, and oncologists to guide and shape the appropriate diagnostic strategies for HER2-low breast cancer. The fundamental question at hand is whether the necessary tools to effectively translate our knowledge about HER2 into practical diagnostic schemes for the lower spectrum of expression are available. Our investigation is centered on the significance of distinguishing between an immunohistochemistry (IHC) score 0 and score 1+ in light of the clinical implications now apparent, as patients with HER2-low breast cancer become eligible for trastuzumab-deruxtecan treatment. Furthermore, we discuss the definition of HER2-low beyond its conventional boundaries and assess the reliability of established diagnostic procedures designed at a time when therapeutic perspectives were non-existent for these cases. In this regard, we examine potential complementary technologies, such as gene expression analysis and liquid biopsy. Ultimately, we consider the potential role of artificial intelligence (AI) in the field of digital pathology and its integration into HER2 testing, with a particular emphasis on its application in the context of HER2-low breast cancer.

Keywords: Artificial Intelligence; HER2-low; breast cancer; liquid biopsy; pathology; testing methods.

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Conflict of interest statement

CM reports personal fees from Bayer, Roche, Daiichi Sankyo, AstraZeneca, Illumina, and Veracyte. CC reports personal fees for consulting, advisory role, and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead, Daiichi Sankyo, AstraZeneca, and Pfizer. CS reports personal fees for consulting, advisory role, and speakers’ bureau from Astra Zeneca, Bristol Myers Squibb, Daiichi-sankyo, Gilead, Novartis, and Veracyte. AS Roche-Ventana, Novartis, Astrazeneca, Amgen, Gilead PG Consulting/Honoraria from Eli-Lilly, Pfizer, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, MSD, Amgen. UM has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientific, Eli Lilly, Diaceutics, GSK, Merck and AstraZeneca, Janssen, Diatech, Novartis and Hedera unrelated to the current work. GNF reports personal fees for advisory role from Astra Zeneca. CDA reports advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Daicii-Sankyo, Gilead, and GSK and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, GSK, GILEAD, and Daiichi-Sankyo. Travel Grants from Gilead and research support (to the Institution) from Novartis, GILEAD, and Daiichi-Sankyo outside the submitted work. GP reports research funding (to Institution) from AstraZeneca, Exact Sciences, Diapath; personal honoraria as invited speaker from Amgen, AstraZeneca, Bio-Optica, Boehringer-Ingelheim; Diatech Pharmacogenetics, Exact Sciences, GlaxoSmithKline, Incyte, Janssen-Cilag; Lilly, Novartis, Roche, Merck Serono, Veracyte; participation in advisory board for Amgen, Astrazeneca, Novartis, Exact Sciences, Roche. GC reports funding from AstraZeneca, Daiichi Sankyo, and Merck; consulting fees from BMS, Roche, Pfizer, Novartis, Lilly, Astra Zeneca, Daiichi Sankyo, Merck, Seagen, and Ellipsis; honoraria from Pfizer, Lilly; support for attending meetings from Roche, Pfizer. NF has received honoraria for consulting, advisory role, speaker bureau, travel, and/or research grants from Merck Sharp & Dohme (MSD), Merck, Novartis, AstraZeneca, Roche, Menarini, Daiichi Sankyo, GlaxoSmithKline (GSK), Gilead, Adicet Bio, Sermonix, Reply, Veracyte Inc., Leica Biosystems, Lilly. These companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and/or in the decision to publish the results. All other authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Schematic depiction of HER2 expression range, according to ASCO/CAP guidelines.
Figure 2.
Figure 2.
Laboratory procedures for accurate assessment of low HER2 expression. Following excision (biopsy or surgery) the specimen should be transferred to the pathology lab using a temperature-controlled system. The cold ischemia time should not exceed 1 hour. Sample preservation during transport can be achieved either by vacuum sealing or submerging in 4% neutral buffered formalin. The time interval before sampling should fall within a range of 6 to 72 hours. Upon tissue processing, the pathologist should select the most representative sample, subjecting it to immunohistochemical analysis, with the possible option to employ validated digital pathology tools. The HER2 report must include details on the percentage of positive neoplastic cells, staining intensity, and pattern of membrane staining.
Figure 3.
Figure 3.
Overview of the existing barriers that may trouble HER2-low identification in breast cancer and practical solutions that could enhance the test.
See this image and copyright information in PMC

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