Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jan 4;7(1):1.
doi: 10.1038/s41523-020-00208-2.

Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer

Francesco Schettini  1   2   3 , Nuria Chic  2   3   4 , Fara Brasó-Maristany  2   4 , Laia Paré  3 , Tomás Pascual  2   3   4   5 , Benedetta Conte  2   6 , Olga Martínez-Sáez  2   4 , Barbara Adamo  2   3   4 , Maria Vidal  2   3   4 , Esther Barnadas  2 , Aranzazu Fernández-Martinez  5 , Blanca González-Farre  2   3   7 , Esther Sanfeliu  2   3   7 , Juan Miguel Cejalvo  8 , Giuseppe Perrone  9 , Giovanna Sabarese  9 , Francesca Zalfa  9 , Vicente Peg  10   11 , Roberta Fasani  12 , Patricia Villagrasa  3 , Joaquín Gavilá  3   13 , Carlos H Barrios  14   15 , Ana Lluch  11   16   17 , Miguel Martín  11   18 , Mariavittoria Locci  19 , Sabino De Placido  1 , Aleix Prat  20   21   22
Affiliations

Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer

Francesco Schettini et al. NPJ Breast Cancer. .

Erratum in

  • Author Correction: Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer.
    Schettini F, Chic N, Brasó-Maristany F, Paré L, Pascual T, Conte B, Martínez-Sáez O, Adamo B, Vidal M, Barnadas E, Fernández-Martinez A, González-Farre B, Sanfeliu E, Cejalvo JM, Perrone G, Sabarese G, Zalfa F, Peg V, Fasani R, Villagrasa P, Gavilá J, Barrios CH, Lluch A, Martín M, Locci M, De Placido S, Prat A. Schettini F, et al. NPJ Breast Cancer. 2023 Apr 29;9(1):32. doi: 10.1038/s41523-023-00538-x. NPJ Breast Cancer. 2023. PMID: 37120452 Free PMC article. No abstract available.

Abstract

Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.

PubMed Disclaimer

Conflict of interest statement

A.P. has declared an immediate family member being employed by Novartis, personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo, travel, accommodations and expenses paid by Daiichi Sankyo, research funding from Roche and Novartis, consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb, and patent PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY. C.B. declares research funding, consulting and honoraria form Astra Zeneca, Novartis, Roche, GSK, Pfizer, Libbs, Daiichi Sankyo, and MSD. A.L. declares clinical research fundings from Amgen, Astra Zeneca, Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Celgene, Pierre Fabre and advisory boards and consulting for Novartis, Pfizer, Roche/Genentech, Eisai, Celgene. M.M. declares research grants from Roche, PUMA and Novartis, consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, Daiichi Sankyo and Pfizer and speakers’ honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis and Pfizer. J.G. has declared speakers’ honoraria and participation in advisory boards from Pfizer, Roche, and Novartis. S.D.P. has declared honoraria from Roche, Pfizer, Astra-Zeneca, Novartis, Celgene, Eli Lilly, Amgen, and Eisai. The other authors have nothing to declare.

Figures

Fig. 1
Fig. 1. STROBE flow-chart.
Flow-chart resuming the patient selection process, showing causes for exclusion and the number of patients with available data for the main analyses presented in the study. GEICAM Grupo Español de Investigación en Cáncer de Mama, CIBOMA Coalición Iberoamericana de Investigación en Oncología Mamaria, VHIO Vall d’Hebron Institute of Oncology, SOLTI Solid Tumor Intensification Group, IHC immunohistochemistry, ISH in-situ hybridization, HR hormone receptors.
Fig. 2
Fig. 2. Hormone receptor status, HER2-low status, and IHC scores distributions within the HER2-negative population.
HR hormone receptors, IHC immunohistochemistry, ISH in situ hybridization (including either FISH, SISH, and CISH).
Fig. 3
Fig. 3. Intrinsic subtype distribution according to HER2 status and HR status.
HR hormone receptors, TNBC triple-negative breast cancer, IHC immunohistochemistry, ISH in situ hybridization (including either FISH, SISH, and CISH). Number of patients in A (n = 1576), B (n = 1137); C (n = 437); D (n = 673); E (n = 701); F (n = 325).
Fig. 4
Fig. 4. Gene expression profiles of HER2-negative breast cancer according to HER2 expression and HR status.
Supervised clustering of 55 genes across four tumor classes defined according to HER2 IHC expression and HR status. All samples and gene expression data in each category have been combined into a single group. For each gene in a group, we calculated the standardized mean difference between the gene’s expression in that class vs. its overall mean expression in the dataset using a 4-class Significance Analyses of Microarrays. The red color represents relative high gene score, green represents relative low gene score, and black represents median gene score. HR-positive hormone receptor positive, TNBC triple-negative breast cancer.
Fig. 5
Fig. 5. ERBB2 mRNA levels within the overall, HR-positive and TNBC populations according to HER2-low expression.
Relative transcript abundance of ERBB2 (HER2 gene) within the overall population (n = 871) and within HR-positive disease (n = 494) and TNBC (n = 377) according to HER2 IHC-based expression. The boxes represent the interquartile range (25th and 75th percentiles), and the horizontal line in the box represents the median value. The whiskers show the range of largest and smallest values. HR-positive hormone receptor positive, TNBC triple-negative breast cancer.
Fig. 6
Fig. 6. Overall survival in patients with advanced HER2-negative breast cancer according to HER2 expression.
The figure shows Kaplan–Meier curves of overall survival for HER2-low vs HER2 0 tumors in the HR-positive (A) and TNBC (C) populations, as well as OS curves for HER2 2+ vs. HER2 1+ vs. HER2 0 tumors for the HR-positive (B) and TNBC (D) populations with number at risk shown at the bottom of each box. p-values for log-rank tests are also reported; HR-positive hormone receptor positive, TNBC triple-negative.
See this image and copyright information in PMC

References

    1. Wolff AC, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2018;36:2105–2122. doi: 10.1200/JCO.2018.77.8738. - DOI - PubMed
    1. Wolff AC, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2013;31:3997–4013. doi: 10.1200/JCO.2013.50.9984. - DOI - PubMed
    1. Cronin KA, Harlan LC, Dodd KW, Abrams JS, Ballard-Barbash R. Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US. Cancer Invest. 2010;28:963–968. doi: 10.3109/07357907.2010.496759. - DOI - PMC - PubMed
    1. Slamon DJ, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182. doi: 10.1126/science.3798106. - DOI - PubMed
    1. Schalper KA, Kumar S, Hui P, Rimm DL, Gershkovich P. A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: impact of 2007 American Society of Clinical Oncology/College of American Pathologists criteria. Arch. Pathol. Lab. Med. 2014;138:213–219. doi: 10.5858/arpa.2012-0617-OA. - DOI - PubMed