Evolution of HER2-low expression from primary to recurrent breast cancer

Miglietta, Federica; Griguolo, Gaia; Bottosso, Michele; Giarratano, Tommaso; Mele, Marcello; Fassan, Matteo; Cacciatore, Matilde; Genovesi, Elisa; Bartolo, Debora De; Vernaci, Grazia Maria; Amato, Ottavia; Conté, Pierfranco; Guarneri, Valentina; Dieci, Maria Vittoria

doi:10.1038/s41523-021-00343-4

Cited by 140 publications

(126 citation statements)

References 41 publications

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Section: Insights From the Biological Landscape Of Her2 Low Expressionsupporting

confidence: 70%

“…In terms of HR status, a significant difference was observed between the two groups since HER2-low breast cancer was enriched with HR+ tumors, while the HER2-zero cohort was enriched with HR- cases. Such correlation between HR signaling and HER2-low expression has also been reported in a retrospective, large-cohort, gene expression profiling study, where PAM50-based-subtypes accounted for approximately 80% of HER2-low-positive cases ( Miglietta et al, 2021 ). Concerning the pathological complete response (pCR) data, in the HR+ cohort, the authors observed a lower pCR in patients with HER2-low breast cancer compared to those with HER2-zero disease with no effect on long-term survival ( Denkert et al, 2021 ).…”

Section: Rebooting Her2 Testing In Breast Cancersupporting

confidence: 65%

“…These observations, along with the pooling of HER2 scores 0 and 1+ under the broader definition of HER2-negative breast cancer, may explain to a certain extent some of the discrepancies that have been observed in HER2 testing. In this context, several studies that assessed the reproducibility of HER2 testing between local and central laboratories revealed a remarkable inter-observer, intratumoral, and temporal heterogeneity of HER2 low status ( Miglietta et al, 2021 ). Therefore, a precise assessment of HER2-low cases demands the harmonization of all methodologies coupled with straightforward and well-defined guidelines ( Angerilli et al, 2021 ).…”

Section: Rebooting Her2 Testing In Breast Cancermentioning

confidence: 99%

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HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer

Venetis

Crimini

Sajjadi

et al. 2022

Front. Mol. Biosci.

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HER2 status in breast cancer is assessed to select patients eligible for targeted therapy with anti-HER2 therapies. According to the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), the HER2 test positivity is defined by protein overexpression (score 3+) at immunohistochemistry (IHC) and/or gene amplification at in situ hybridization (ISH). The introduction of novel anti-HER2 compounds, however, is changing this paradigm because some breast cancers with lower levels of protein expression (i.e. score 1+/2+ with no gene amplification) benefited from HER2 antibody-drug conjugates (ADC). Recently, a potential for HER2 targeting in HER2 “ultra-low” (i.e. score 0 with incomplete and faint staining in ≤10% of tumor cells) and MutL-deficient estrogen receptor (estrogen receptor)-positive/HER2-negative breast cancers has been highlighted. All these novel findings are transforming the traditional dichotomy of HER2 status and have dramatically raised the expectations in this field. Still, a more aware HER2 status assessment coupled with the comprehensive characterization of the clinical and molecular features of these tumors is required. Here, we seek to provide an overview of the current state of HER2 targeting in breast cancers beyond the canonical HER2 positivity and to discuss the practical implications for pathologists and oncologists.

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Section: Insights From the Biological Landscape Of Her2 Low Expressionsupporting

confidence: 70%

Section: Rebooting Her2 Testing In Breast Cancersupporting

confidence: 65%

Section: Rebooting Her2 Testing In Breast Cancermentioning

confidence: 99%

See 1 more Smart Citation

HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer

Venetis

Crimini

Sajjadi

et al. 2022

Front. Mol. Biosci.

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“…While more studies are required, this finding has important implications for future diagnostic algorithms given the inherent challenge for pathologists to distinguish HER2-zero and HER2-low tumours by IHC in clinical practice. It also warrants further study for a general understanding of HER2-low disease biology given that HER2 status can drift with treatment [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis

Tan

Ong

Lee

et al. 2022

BMC Med

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Background HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC). Methods Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH−) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH− status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS. Results ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82–0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76–0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85–0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79–0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83–0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78–0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH− and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59–0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found. Conclusions HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.

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“…Although glandular autograft is known to be the most effective technique, in place of alternative therapies, autologous transplantation is not always possible. Allografts are a good way to treat patients who are unable to receive autograft treatment, but this has limited success due to the side effects associated with tissue rejection [ 4 ]; therefore, MSC therapy as a treatment for hypoparathyroidism is expected to be used clinically in the future.…”

Section: Introductionmentioning

confidence: 99%

Density-Dependent Differentiation of Tonsil-Derived Mesenchymal Stem Cells into Parathyroid-Hormone-Releasing Cells

Kim

Park

et al. 2022

IJMS

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Mesenchymal stem cells (MSCs) can differentiate into endoderm lineages, especially parathyroid-hormone (PTH)-releasing cells. We have previously reported that tonsil-derived MSC (T-MSC) can differentiate into PTH-releasing cells (T-MSC-PTHCs), which restored the parathyroid functions in parathyroidectomy (PTX) rats. In this study, we demonstrate quality optimization by standardizing the differentiation rate for a better clinical application of T-MSC-PTHCs to overcome donor-dependent variation of T-MSCs. Quantitation results of PTH mRNA copy number in the differentiated cells and the PTH concentration in the conditioned medium confirmed that the differentiation efficiency largely varied depending on the cells from each donor. In addition, the differentiation rate of the cells from all the donors greatly improved when differentiation was started at a high cell density (100% confluence). The large-scale expression profiling of T-MSC-PTHCs by RNA sequencing indicated that those genes involved in exiting the differentiation and the cell cycle were the major pathways for the differentiation of T-MSC-PTHCs. Furthermore, the implantation of the T-MSC-PTHCs, which were differentiated at a high cell density embedded in hyaluronic acid, resulted in a higher serum PTH in the PTX model. This standardized efficiency of differentiation into PTHC was achieved by initiating differentiation at a high cell density. Our findings provide a potential solution to overcome the limitations due to donor-dependent variation by establishing a standardized differentiation protocol for the clinical application of T-MSC therapy in treating hypoparathyroidism.

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Evolution of HER2-low expression from primary to recurrent breast cancer

Cited by 140 publications

References 41 publications

HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer

HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer

HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis

Density-Dependent Differentiation of Tonsil-Derived Mesenchymal Stem Cells into Parathyroid-Hormone-Releasing Cells

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