Reduction of Global H3K27me3 Enhances HER2/ErbB2 Targeted Therapy

Publication date: 8 October 2019Source: Cell Reports, Volume 29, Issue 2Author(s): Alison Hirukawa, Salendra Singh, Jarey Wang, Jonathan P. Rennhack, Matthew Swiatnicki, Virginie Sanguin-Gendreau, Dongmei Zuo, Kamilia Daldoul, Cynthia Lavoie, Morag Park, Eran R. Andrechek, Thomas F. Westbrook, Lyndsay N. Harris, Vinay Varadan, Harvey W. Smith, William J. MullerSummaryMonoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me3 in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me3 depletion in Trastuzumab-resistant dis...
Source: Cell Reports - Category: Cytology Source Type: research

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AbstractBackgroundCharacterization of breast cancer phenotypes has improved our ability to predict breast cancer behavior. Triple-negative (TN) breast cancers have higher and earlier rates of distant events. It has been suggested that this behavior necessitates treating TNs faster than others, including use of neoadjuvant chemotherapy (NACT) if time to surgery is not rapid.MethodsA review of women diagnosed with non-inflammatory, invasive breast cancer was conducted using the National Cancer Database for patients not having NACT, diagnosed between 2010 and 2014. Changes in overall survival due to delay were measured by phe...
Source: Annals of Surgical Oncology - Category: Cancer & Oncology Source Type: research
CONCLUSIONS: We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2 targeted therapies resistance in breast cancer which can be reversed by FGFR inhibitors. PMID: 31699826 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
CONCLUSION: Most mastectomies are advised for large tumour to breast size ratio, but there is an inconsistency in the use of NST to downsize tumours in patients with large ER+ or HER2+ cancers. The application of standardized recommendations for NST could reduce the number of mastectomies advised by MDTs. PMID: 31691270 [PubMed - as supplied by publisher]
Source: The British Journal of Surgery - Category: Surgery Authors: Tags: Br J Surg Source Type: research
Conclusions: With data obtained from patients treated in clinical practice, it has been possible to verify that the addition of pertuzumab to trastuzumab and neoadjuvant chemotherapy substantially increases the rate of pCR, especially in the HER2-enriched subtype but also in luminal subtypes, with no apparent benefit in basal-like tumors.
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Authors: Neola B, Puppio B, Marino G, La Torre G Abstract BACKGROUND: Some Trials have demonstrated that the rate of false negative results of a sentinel lymph node biopsy in patients undergoing neoadjuvant chemotherapy is>10%. The aim of this study is to identify the predictive factors of a pathologic complete response in the axilla in order to make a better choice between the performance of an axillary lymphadenectomy or the performance of a sentinel lymph node biopsy. METHODS: All patients diagnosed with positive axillary lymph nodes and achieving a clinical complete response after a neoadjuvant therapy w...
Source: Annali Italiani di Chirurgia - Category: Surgery Tags: Ann Ital Chir Source Type: research
Authors: Schütz F, Fasching PA, Welslau M, Hartkopf AD, Wöckel A, Lux MP, Janni W, Ettl J, Lüftner D, Belleville E, Kolberg HC, Overkamp F, Taran FA, Brucker SY, Wallwiener M, Tesch H, Fehm TN, Schneeweiss A, Müller V Abstract The further development of therapies for women with early breast cancer is progressing far more slowly than in the case of patients with advanced breast cancer and is additionally delayed compared to developments in metastatic breast cancer. Nonetheless, significant advancements have been able to be recorded recently. This review summarises the latest developments in view ...
Source: Geburtshilfe und Frauenheilkunde - Category: OBGYN Tags: Geburtshilfe Frauenheilkd Source Type: research
CONCLUSIONS: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from de-escalation of therapy. PMID: 31662331 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
AbstractBiomarkers of breast cancer such as hormone receptors (HR) and human epidermal growth factor 2 (HER2) can be altered after neoadjuvant chemotherapy (NAC). However, whether the conversion of these receptors affects the prognosis of patients remains to be determined. We sought to evaluate the prognostic value of HR and HER2 receptors before and after NAC and to analyze their clinical implications. Relevant studies were used to calculate the pooled hazard ratios, 95% confidence interval (95% CI). This meta-analysis included eight studies with 2847 patients. Compared to patients with HR+  → +, patien...
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
CONCLUSIONS: LPBC was marginally associated with higher pCR rate than non-LPBC in LT treated HER2+ BC patients. Quantitative assessment of the immune infiltrate by m-IF is feasible and may help correlate individual immune cell subpopulations and immune cell profiles with treatment response. PMID: 31653641 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Conclusion: Breast MRI showed good accuracy in the prediction of a pathological complete response after NAC. The sensitivity and positive predictive value were highest for the HER2 and triple-negative subtypes.Resumo Objetivo: Avaliar a acur ácia da ressonância magnética (RM) das mamas na identificação de resposta patológica completa em pacientes com câncer de mama submetidas a quimioterapia neoadjuvante (QTN). Materiais e Métodos: Teste de validação diagnóstica, realizado por meio de estudo observacional, unicêntrico e ret rospectivo. As vari...
Source: Radiologia Brasileira - Category: Radiology Source Type: research
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