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. 2021 Jun 5;13(11):2824.
doi: 10.3390/cancers13112824.

HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

Elisa Agostinetto  1   2   3 , Mattia Rediti  4 , Danai Fimereli  4 , Véronique Debien  1 , Martine Piccart  5 , Philippe Aftimos  6 , Christos Sotiriou  4 , Evandro de Azambuja  1
Affiliations

HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

Elisa Agostinetto et al. Cancers (Basel). .

Abstract

Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes.

Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas dataset. We described the distribution of PAM50 intrinsic subtypes within HER2-low BC subtype according to hormonal receptor status (positive (HR+) and negative (HR-)). Secondly, we assessed the impact of HER2-low on survival outcomes (progression-free interval (PFI), disease-free interval (DFI), and overall survival (OS)).

Results: We analyzed 804 primary BCs, including 410 (51%) HER2-low BCs (336 HR+ and 74 HR-). The proportion of HER2-enriched tumors was higher in the HER2-low/HR- group compared to HER2-low/HR+ (13.7% versus 1.2%, respectively). HER2-enriched tumors were more frequent in HER2-low/HR- and HER2-low/HR+ subtypes, compared to HER2-negative/HR- and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in PFI, DFI, and OS between HER2-low subtypes and each non-HER2-low subtype paired by HR status.

Conclusions: Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer may explain the different clinical behaviors and responses to treatment, and ultimately support further investigation of new treatment strategies in the HER2-low category. Moreover, it highlights the importance of considering HR status in the HER2-low category.

Keywords: HER2-low; PAM50; TCGA; breast cancer; prognosis.

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Conflict of interest statement

Elisa Agostinetto, Mattia Rediti, Danai Fimereli and Véronique Debien have no conflicts of interests. Martine Piccart: Board Member (Scientific Board): Oncolytics; Consultant (honoraria): AstraZeneca, Camel-IDS, Crescendo Biologics, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche, Seattle Genetics, Immutep, NBE Therapeutics, SeaGen; Research grants to her Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon (outside the submitted work). Philippe Aftimos: Consulting: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte; Honoraria: Synthon, Amgen, Novartis, Gilead; Travel grants: Amgen, MSD, Pfizer, Roche; Research funding to my institution: Roche (outside the submitted work). Christos Sotiriou: advisory board (receipt of honoraria or consultations fees): Astellas, Cepheid, Vertex, Seattle genetics, Puma, Amgen. Participation in company sponsored speaker’s bureau: Eisai, Prime Oncology, Teva, Foundation Medicine. Other support (travel, accommodation expenses): Roche, Genentech, Pfizer (outside the submitted work) Evandro de Azambuja: honoraria and advisory board: Roche/GNE, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre and Lilly; travel grants: Roche/GNE, GSK/Novartis. Research grant for his institute: Roche/GNE, AstraZeneca, Novartis, and Servier (outside the submitted work).

Figures

Figure 1
Figure 1
The distribution of PAM50 intrinsic subtypes in the entire cohort and among each breast cancer subtype (n = 789). Abbreviations: HR: hormone receptor, HER2-E: HER2-enriched, LumA: Luminal A, LumB: Luminal B.
Figure 2
Figure 2
The distribution of breast cancer subtypes (HER2+/HR+, HER2-low/HR+, HER2−/HR+, HER2+/HR−, HER2-low/HR−, HER2−/HR−) according to PAM50 intrinsic subtypes (n = 789). Abbreviations: HR: hormone receptor.
Figure 3
Figure 3
ERBB2 and ESR1 gene expression according to breast cancer subtypes (n = 799). In the boxplots, the boxes are defined by the 25th to 75th percentiles; the median is shown as a bold colored horizontal line. Statistical differences were assessed using a two-sided Mann–Whitney U-test followed by Benjamin and Hochberg correction for multiple testing. FDRs < 0.05 are shown. Abbreviations: * 0.05 > adjusted p-value ≥ 0.01, ** 0.01 > adjusted p-value ≥ 0.001, *** adjusted p-value < 0.001, HR: hormone receptor.
Figure 4
Figure 4
Disease-free interval in HER2-low/HR+ versus HER2−/HR+ (A), in HER2-low/HR− versus HER2−/HR− (B), in HER2-low/HR+ versus HER2+/HR+ (C) and in HER2-low/HR− versus HER2+/HR− (D) tumors. Abbreviations: HR: hormone receptor.
Figure 5
Figure 5
Progression-free interval in HER2-low/HR+ versus HER2−/HR+ (A), in HER2-low/HR− versus HER2−/HR− (B), in HER2-low/HR+ versus HER2+/HR+ (C) and in HER2-low/HR− versus HER2+/HR− (D) tumors. Abbreviations: HR: hormone receptor.
Figure 6
Figure 6
Overall survival in HER2-low/HR+ versus HER2−/HR+ (A), in HER2-low/HR− versus HER2−/HR− (B), in HER2-low/HR+ versus HER2+/HR+ (C) and in HER2-low/HR− versus HER2+/HR− (D) tumors. Abbreviations: HR: hormone receptor.
Figure 7
Figure 7
(A–F). Disease-free interval (DFI), progression-free interval (PFI), and overall survival (OS) according to breast cancer subtypes (A–C), and in HER2-low/HR+ versus HER2-low/HR− breast tumors (D–F). Abbreviations: HR: hormone receptor.
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