The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment (original) (raw)
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The genomic profile of HER2 -amplified breast cancers: the influence of ER status
Journal of Pathology, 2008
Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
2021
BackgroundHuman epidermal growth factor receptor 2 (HER2) low expressed breast cancer was considered as a distinct subtype different from HER2 negative tumors. We investigated the clinicopathological features and recurrence score (RS) of HER2-low and HER2- patients and their prognostic value in hormone receptor (HR) positive breast cancer.MethodsA total of 2,099 HR-positive primary female breast cancer patients between Jan 2009 and Jan 2019 were collected and tumors with immunohistochemistry 1 + or 2 + with negative in situ hybridization results was defined as HER2 low. We retrospectively compared the clinical and genetical features of HER2-low (n = 1,732) and HER2- (n = 367) breast cancer and theirs impacts on disease-free survival (DFS).ResultsThe HER2 low tumors had a higher ratio of concurrent estrogen receptor (ER) high expression than HER2- patients both at protein level (ER > 90%: 78.2% vs 58.6%, p
Evolving concepts in HER2 evaluation in breast cancer: Heterogeneity, HER2-low carcinomas and beyond
Seminars in Cancer Biology, 2020
The human epidermal growth factor receptor 2 (HER2) is a well-known negative prognostic factor in breast cancer and a target of the monoclonal antibody trastuzumab as well as of other anti-HER2 compounds. Pioneering works on HER2-positive breast cancer in the 90s' launched a new era in clinical research and oncology practice that has reshaped the natural history of this disease. In diagnostic pathology the HER2 status is routinely assessed by using a combination of immunohistochemistry (IHC, to evaluate HER2 protein expression levels) and in situ hybridization (ISH, to assess HER2 gene status). For this purpose, international recommendations have been developed by a consensus of experts in the field, which have changed over the years according to new experimental and clinical data. In this review article we will document the changes that have contributed to a better evaluation of the HER2 status in clinical practice, furthermore we will discuss HER2 heterogeneity defined by IHC and ISH as well as by transcriptomic analysis and we will critically describe the complexity of HER2 equivocal results. Finally, we will introduce the clinical impact of HER2 mutations and we will define the upcoming category of HER2-low breast cancer with respect to emerging clinical data on the efficacy of specific anti-HER2 agents in subgroups of breast carcinomas lacking the classical oncogene addition dictated by HER2 amplification.
2014
The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status. A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA. HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual-signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number ≥6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio ≥2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas. The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction-based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH.
Breast Cancer Research and Treatment, 2020
In stage IV breast cancer, the efficacy of human epidermal growth factor receptor 2 (HER2) targeted therapies in cases with discordance in HER2 expression between primary and metastatic site is not well known. We studied progression free (PFS) and overall survival (OS) by HER2 concordance when treating women with taxanetrastuzumab (+/-pertuzumab) in first or second line and trastuzumab-emtansine (T-DM1) or capecitabine-lapatinib in later lines. Patients and Methods: Retrospective monocentric study including all breast cancer patients receiving trastuzumab between January 2002 and September 2017 at the University Hospital in Leuven; we selected metastatic patients with an available HER2 status in primary and metastatic site. The Kaplan-Meier method was used for estimating PFS/OS and log-rank test for analyzing between group differences. A Cox model is used for testing difference between groups while correcting for Pertuzumab. Multivariable Cox regression is used to model overall survival as a function group, correcting for possible confounders. Results: We included 74 patients; 46 had an unchanged HER2 status (positive/positive), 9 lost HER2 (positive/negative), while 19 acquired HER2 amplification (negative/positive). 25 out of 28 cases with a discordant HER2 status were positive for ER and/or PgR in the primary site. HER2 positive/negative cases had a significantly lower PFS for taxane-trastuzumab-(pertuzumab) (PFS = 5.5 months), compared to HER2 positive/positive (PFS 9 months, p = 0.01) and HER2 negative/positive (PFS 14 months, p = 0.01) patients. PFS for later line T-DM1 (n= 30) was significantly higher for the HER2 positive/positive group (PFS 6.0 months) than for the discordant groups HER2 negative/positive (PFS 1.0 month, p=0.04) and HER2 positive/negative (PFS 1.5 month, p = 0.01). After correcting for possible confounders, the HER2 positive/negative group had a significantly worse OS compared to HER2 positive/positive (HR 0.19, 95% CI 0.08-0.44) and negative/positive (HR 0.15, 95% 0.06-0.38). Conclusion: Conversion of HER2 status was seen in 28 out of 74 cases and was mostly observed in hormone receptorpositive tumors. In contrast to patients with HER2 loss, patients with a positive conversion of HER2 status derived substantial benefit from first line treatment with taxane-trastuzumab-(pertuzumab). This study highlights the importance of re-biopsying the metastatic lesion and changing treatment according to the last HER2 result.
Clinical Medicine & Research, 2009
To compare the clinicopathologic features and survival in the four breast cancer subtypes defined by immunohistochemistry (IHC) expression of estrogen receptor (ER) or progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2): ER/PR+,Her2+; ER/PR+, Her2-; ER/PR-,Her2+; and ER/PR-,Her2-. Methods: A 7-year retrospective study of 1134 invasive breast cancer subjects. Clinical and pathologic features and survival of the four subtypes were compared. Results: Using ER/PR+ and Her2-as a reference, ER/PR-,Her2-had the worst overall survival (hazard ratio, 1.8; 95% confidence interval [CI], 1.06-3.2) and the worst disease-free survival (hazard ratio, 1.5; 95% CI, 0.8-3.0). In ER/PR+,Her2-, chemotherapy conferred significant overall and disease-free survival advantages. Subtype comparison revealed statistically significant differences in outcomes. Conclusion: The triple negative subtype has the worst overall and disease free survival. Efforts should be directed at standardization of current testing methods and development of more reliable and reproducible testing.
Histopathology, 2009
Aims: Histological grade is one of the most important prognostic factors in breast carcinomas, but poorly differentiated neoplasms still have quite heterogeneous biological behaviour, since they can be genetically classified as basal-like, HER2+ or even luminal. The aim was to analyse the frequency of oestrogen receptor (ER), progesterone receptor (PR) and HER2 expression profiles among breast carcinomas with <10% tubular formation, and their correlation with classic prognostic factors.Methods and results: One hundred and thirty-four samples of paraffin-embedded tumours were studied retrospectively. The tumours were classified in to four groups by their ER/PR/HER2 profile: (i) ER+ and/or PR+ but HER2−; (ii) ER+ and/or PR+ and HER2+; (iii) ER− and/or PR− but HER2+; and (iv) ER−, PR− and HER2− (triple-negative). The histological features of triple-negative and HER2+ carcinomas overlap. The only difference was the expression of basal cytokeratins (basal CK), which was more frequent among triple-negative carcinomas. Basal-CK expression defined a more aggressive group of tumours, according to the pathological features, regardless of the immunohistochemical profile.Conclusions: Group 1 and 2 tumours (ER+ and/or PR+ tumours with or without HER2 expression) were not statistically different, suggesting that poorly differentiated carcinomas with hormone receptors correspond to the luminal B type of tumour. Among poorly differentiated breast carcinomas, the classic profile associated with basal-CK identifies distinct subtypes equivalent to those seen by genetic classification.