HER2 low expression breast cancer subtyping and their correlation with prognosis and immune landscape based on the histone modification related genes
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC10709565 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description: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. 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)). 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. 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.
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Project description:Little is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2- breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2- early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.
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Project description:HER2-low breast cancer (BC) is a newly defined subset of HER2-negative BC that has HER2 immunohistochemical (IHC) score of 1+ or score of 2+/in situ hybridization (ISH) negative phenotype. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating this group of tumors. Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC was recently approved by the U.S. Food and Drug Administration as the first targeted therapy to treat HER2-low BC. However, HER2-low BC is still not well characterized clinically and pathologically. This review aims to update the current biological, pathological and clinical landscape of HER2-low BC based on the English literature published in the past two years and to propose the future directions on clinical management, pathology practice, and translational research in this subset of BC. We hope it would help better understand the tumor biology of HER2-low BC and the current efforts for identifying and treating this newly recognized targetable group of BC.
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Project description:The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance. In this study, we retrospectively analyzed 1071 metastatic breast cancer (MBC) patients and the circulating tumor DNA (ctDNA) to investigate clinicopathological and genetic alterations of HER2-low MBC patients. The effect of HER2-low status on different treatment modalities was explored in two prospective clinical trials (NCT03412383, NCT01917279) and a retrospective study. Our findings suggest TP53, PIK3CA, and ESR1 are frequently mutated genes in HER2-low MBC. Compared to the HER2-0 group, mutations observed in the HER2-low group are more closely associated with metabolic pathway alterations. Additionally, among patients with ERBB2 mutations and treated with pyrotinib, the HER2-low group may experience superior prognosis when compared to the HER2-0 group. Notably, we did not find any statistically significant disparity in the response to chemotherapy, endocrine therapy, or CDK4/6 inhibitor therapy between HER2-0 and HER2-low breast cancer patients. Interestingly, within the subgroup of individuals with metabolic pathway-related gene mutations, we found that HER2-low group exhibited a more favorable response to these treatments compared to HER2-0 group. Additionally, dynamic analysis showed the HER2-low MBC patients whose molecular tumor burden index decreased or achieved early clearance of ctDNA after the initial two treatment cycles, exhibited prolonged survival. Moreover, we classified HER2-low MBC into three clusters, providing a reference for subsequent treatment with enhanced precision. Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.
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Project description:Currently, the human epidermal growth factor receptor 2 (HER2) status of breast cancer is classified dichotomously as negative or positive to select patients for HER2-targeted therapy. However, with the introduction of novel treatment options, it is important to get more insight in the biology of cancers with low HER2 expression. Therefore, we studied several clinicopathologic characteristics in relation to the level of HER2 expression (HER2- versus HER2low). We used a well-documented cohort of breast cancer patients (n = 529), with available tissue microarrays and Affymetrix mRNA expression data. HER2 status was scored as negative (immunohistochemistry 0) or low (immunohistochemistry 1 + or 2 + without amplification). We associated HER2 status with several clinicopathologic characteristics, gene-expression data and survival, stratified for estrogen receptor (ER) status. Overall, breast cancers were scored as HER2- (n = 429) or HER2low (n = 100). Within the ER+ cohort (n = 305), no significant associations were found between the HER2 groups and clinicopathologic features. However, HER2low tumors showed several differentially expressed genes compared to HER2- cases, including genes that are associated with worse outcome and depletion of immunity. In ER- cases (n = 224), HER2low status was significantly associated with increased regional nodal positivity, lower density of tumor infiltrating lymphocyte and a lower protein expression of Ki-67 and EGFR compared to HER2- cases. After multivariate analysis, only density of tumor infiltrating lymphocytes remained significantly associated with HER2low status (P = 0.035). No difference in survival was observed between HER2low and HER2- patients, neither in the ER+ nor ER- cohort. In conclusion, our data suggests that HER2low breast cancer is associated with a lower immune response compared to HER2- breast cancer.
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Project description:BackgroundHER2-low cancers are heterogeneous with different degrees of HER2 expression and hormone receptor (HR) status. Currently, its analysis is mostly focused on the standard clinic-pathologic features or common biomarkers expression, without considering the heterogeneity within the category. A further characterization and understanding of this cancer subgroup will facilitate its management.MethodsA large cohort of HER2-negative cancers (N = 1464) was included. The HER2-low (N = 412) and HER2-zero cancers (N = 1052) were compared and correlated with a comprehensive panel of clinico-pathologic features and biomarker expression according to different HER2 expressions and HR statuses. The prognostic values of these features in HER2-low cancers were also evaluated.FindingsThe characteristics of HER2-low breast cancers, as compared to HER2-zero, varied with the HR status. HER2-low luminal cancers were associated with younger age, larger tumor, high pAKT and high HLA expression. Among TNBCs, opposite trends in age and tumor size were found. Additionally, HER2-low TNBC showed less necrosis, higher pN, lower c-kit and CK14 than HER2-zero cancers. Nonetheless, regardless of HR status, HER2-low status was associated with increased COX2 and AR expression, implicated in the biology of HER2-low cancers. HER2-low cancers showed high expression of HLAs in tumors and PD-L1 in immune cells. In particular, the co-expression of HLAs was found to be associated with better survival in HER2-low cancers.InterpretationThis study revealed further characteristic of HER2-low breast cancers as compared to HER2-zero cancers, provided further insights into its prognostication and therapeutic strategies.FundingHealth and Medical Research Fund (08190586), Cheng Yue Pui Charity Foundation and CUHK direct grant.
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Project description:BackgroundBreast cancer (BC), which is the most common malignant tumor in females, is associated with increasing morbidity and mortality. Effective treatments include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular-targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, an increasing amount of evidence has shown that the infiltration of immune cells into the tumor microenvironment, coupled with the immune phenotype of tumor cells, will significantly affect tumor development and malignancy. Consequently, immunotherapy has become a promising treatment for BC prevention and as a modality that can influence patient prognosis.MethodsIn this study, samples collected from The Cancer Genome Atlas (TCGA) and ImmPort databases were analyzed to investigate specific immune-related genes that affect the prognosis of BC patients. In all, 64 immune-related genes related to prognosis were screened, and the 17 most representative genes were finally selected to establish the prognostic prediction model of BC (the RiskScore model) using the Lasso and StepAIC methods. By establishing a training set and a test set, the efficiency, accuracy and stability of the model in predicting and classifying the prognosis of patients were evaluated. Finally, the 17 immune-related genes were functionally annotated, and GO and KEGG signal pathway enrichment analyses were performed.ResultsWe found that these 17 genes were enriched in numerous BC- and immune microenvironment-related pathways. The relationship between the RiskScore and the clinical characteristics of the sample and signaling pathways was also analyzed.ConclusionsOur findings indicate that the prognostic prediction model based on the expression profiles of 17 immune-related genes has demonstrated high predictive accuracy and stability in identifying immune features, which can guide clinicians in the diagnosis and prognostic prediction of BC patients with different immunophenotypes.
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Project description:Mounting evidence showed that HER2-Low breast cancer patients could benefit from the novel anti-HER2 antibody-drug conjugates (ADCs) treatment, which pointed the way towards better therapy for HER2-Low patients. The purpose of this study was to describe the clinicopathological features, along with chemotherapeutic effects and survival outcomes of HER2-Low and HER2-Zero in TNBC who received neoadjuvant chemotherapy (NACT). We retrospectively evaluated 638 triple-negative breast cancer patients who were treated with neoadjuvant chemotherapy between August 2014 and August 2022. Pathologic complete response (pCR) and survival outcomes were analyzed in HER2-Low cohort, HER2-Zero cohort and the overall patients, respectively. In the entire cohort, 342 (53.6%) patients were HER2-Low and 296 (46.4%) patients were HER2-Zero. No significant difference was found between HER2-Low and HER2-Zero patients based on all the clinical-pathological characteristics. 143 cases (22.4%) achieved pCR after NACT in the overall TNBC patients. The pCR rate of the HER2-Low patients and the HER2-Zero patients was 21.3% and 23.6%, respectively, exhibiting no statistical difference (p = 0.487). The survival of pCR group after NACT significantly improved compared to non-pCR group either in HER2-Low patients or in HER2-Zero patients. Although we found that patients with HER2-Low had longer DFS than patients with HER2-Zero, there was no considerable difference (p = 0.068). However, HER2-Low patients had a dramatically longer OS than HER2-Zero patients (p = 0.012). The data from present study confirmed the clinical importance of HER2-Low expression in TNBC. Further effort is needed to determine whether HER2-Low could be a more favorable prognostic marker for individual treatment.
| S-EPMC11266405 | biostudies-literature
Project description:Background: Human epidermal growth factor receptor 2 (HER2)-low tumor is a new entity defined as HER2 immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization (FISH)-negative. We aimed to evaluate whether HER2 mRNA levels tested by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) could better define HER2-low tumors. Patients and methods: Consecutive breast cancer patients with hormonal receptor-positive, HER2-negative diseases, and HER2 mRNA results were included. Clinicopathologic features, HER2 mRNA expression level, and prognosis were compared among HER2 0, 1+ and 2+/FISH− groups. Concordance of the HER2 category between qRT-PCR and IHC/FISH was analyzed for each group. Results: 2296 patients were included: 368 (16.0%) HER2 0, 911 (39.7%) 1+, and 1017 (44.3%) 2+/FISH− tumors. HER2 1+ cases shared similarities with HER2 0 tumors in terms of clinicopathologic features (all p > 0.05), whereas IHC 2+/FISH− cases were less often non-IDC (p = 0.045), node-negative (p = 0.044), and Ki-67 < 14% (p <0.001). The mRNA expression was similar between HER2 0 and 1+ cases (p = 0.063), and both were lower than 2+/FISH− cases (p < 0.001). A poor concordance rate was found between IHC/FISH and qRT-PCR for HER2 0 and HER2-low cases (Cohen’s kappa 0.126, p < 0.001). No survival difference was observed among these groups, whether stratified by HER2 IHC/FISH status or mRNA level (all p > 0.05). Conclusions: HER2 1+ cases had similar clinicopathological features to HER2 0 breast cancers, and both were different from HER2 2+/FISH− cases. HER2 mRNA levels were comparable between HER2 0 and 1+ tumors, and both were significantly lower than IHC 2+/FISH− tumors. Neither IHC nor qRT-PCR may be optimal to quantify HER2-low expression, especially for HER2 1+ patients.
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