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Dimercaprol

Visualize and quantify the allelic expression status of imprinted genes by in situ hybridization using probes targeting the nascent RNAs

Quantitative Chromogenic Imprinted Gene in situ Hybridization (QCIGISH)

Encheng Li, MD

Ming Ding, MD

Jian Zhou, PhD

Qi Wang, MD

The goal of this multicenter observational study is to evaluate the lung cancer diagnostic value of epigenetic imprinting detection in bronchoalveolar lavage. This study will mainly focus on varifing the previously identified epigenetic imprinting biomarkers for lung cancer and upgrading and validating a lung cancer imprinting diagnostic model specifically for bronchoalveolar lavage. The lavage sample will be collected from each eligible paticipants under bronchialscopy and undergo QCIGISH detection to analyze the allelic expression status of imprinted genes. The QCIGISH detection results will be compared with the final surgical histopathology. No interventions will be taken according to the QCIGISH detection results.

Bronchial biopsy and bursh are widely used in lung cancer diagnosis but not bronchoalveolar lavage because of its low sensitivity. As the molecular alterations usually occur before the morphological changes, genetic and epigenetic biomarkers will be helpful for early diagnosis of cancers. As an important epigenetic regulation in mammalian embryo development, genomic imprinting plays important roles in cancers. In normal post-natal somatic cells, imprinted genes are "silenced", that is mono-allelically expressed either from the maternal or paternal allele, while in cancers, some silenced imprinting genes' copies could be reactivated, leading to expressions from both alleles. The loss of monoallelic gene regulation is named loss of imprinting (LOI), and has been previously found in various human cancers. Our previous studies has identified several imprinted genes with elevated aberrant allelic expressions in lung cancer. A diagnostic model based on the epigenetic imprinting biomarkers achieved 99.1% sensitivity and 92.1% specificity. In this study, we will first verify the epigenetic imprinting biomarkers in bronchoalveolar lavage, and refine the previously developed diagnostic model specifically for lavage samples. The diagnostic model will be independently validated in a group of prospectively enrolled cases. This study will help to distinguish benign and malignant pulmonary nodules presurgically, and improve the early diagnosis of lung cancer.

Lung Cancer Diagnosis by Detecting Epigenetic Imprinting Alterations in Bronchoalveolar Lavage

A Multicenter Study for Evaluating the Benign and Malignant Pulmonary Noldules by Detecting the Epigenetic Imprinting Alterations in Bronchoalveolar Lavage

Cancer risk scores calculated by combining the biallelic expressions, multiallelic expressions and total expressions of several imprinted genes

Fudan University

Zongda Hospital affiliated to Southeast University

West China Hospital

Henan Provincial People's Hospital

First Hospital of China Medical University

Shengjing Hospital

The First Affiliated Hospital of Guangzhou Medical University

Lisen Imprinting Diagnostics, Inc.

The Second Affiliated Hospital of Dalian Medical University

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Estrogens

Mitogens

Progesterone

MammaTyper™ will be used to assess tumor material of patients treated with neo-adjuvant therapy.

MammaTyper™ is an in vitro molecular diagnostic test for the quantitative detection of the biomarkers estrogen receptor (ESR1), progesterone receptor ( PgR), Human epidermal growth factor receptor 2 (HER2) and proliferation antigen Ki-67 on the basis of the values of the messenger ribonucleic acid (mRNA).

MammaTyper™

This is a prospective examination of ribonucleic acid (RNA) extracted from tumor material of breast cancer patients treated with a neo-adjuvant therapy. The RNA will be analysed for expression of estrogen receptor (ER 1), progesterone receptor (PgR), HER2 and Ki-67 with MammaTyper™.

According to the determined values for the individual parameters at least 4 subtypes can be distinguished to date

* Luminal A-type
* Luminal B-type
* HER2-type
* Triple-negative-type As non-clinical endpoint, the agreement of new subtyping with Immunohistochemical methods will be evaluated.

As clinical objective, the 5 year Distant metastasis free survival (DMFS) and Overall survival (OS) will be reevaluated according to the new subtyping.

Tumor material collected from patients who received neoadjuvant therapy either with four cycles of doxorubicin 60 mg/m² plus pemetrexed 500 mg/m² on day 1 every 21 days followed by four cycles of docetaxel 100 mg/m² on day 1 every 21 days or four cycles of doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² on day 1 every 21 days followed by four cycles of docetaxel 100 mg/m² on day 1 every 21 days will be re-analyzed with the MammaTyper Kit. The Kit is an in-vitro molecular diagnostic test for molecular subtyping of breast cancers into Luminal A \& B, HER2 and Triple negative. It allows quantitative detection of the RNA expression status of the genes for estrogen receptor (ESR1), PgR, HER2 and Ki-67 on the basis of their mRNA present in the samples. This prospective diagnostic study will investigate the subtyping-results of the MammaTyper™ analysis and will compare them to the subtyping of the former immunohistochemical analysis performed. Based on the MammaTyper™-subtypes the efficiency of the therapy regimen and the outcome will be re-evaluated from the patient data.

Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy

Evaluation of the MammaTyper Kit, Ref 90020/90021 Performed on Clinical Material Obtained From Patients With Early Breast Cancer: Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy

For each MammaTyper and immunohistochemical based subtype categorization, percent agreement, positive and negative percent agreement as well as kappa-statistics are calculated.

Assessed as rate of patients in subgroup Luminal A with 5 year OS vs. rate of patients in combined subgroups with 5 year OS based on MammaTyper subtyping

Assessed as rate of patients with complete response and Ki-67 determination according to MammaTyper and visual scoring assessment

Assessed as rate of patients with 5 year OS and high or low expression of ESR1 mRNA

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lung Cancer Diagnosis by Detecting Epigenetic Imprinting Alterations in Bronchoalveolar Lavage	NCT05707585	Lung Cancer	Quantitative Ch...	18 Years - 75 Years	The Second Affiliated Hospital of Dalian Medical University
Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy	NCT02449993	Breast Cancer	MammaTyper™	18 Years - 70 Years	BioNTech Diagnostics GmbH
Lung Cancer Diagnosis by Detecting Epigenetic Imprinting Alterations in Bronchoalveolar Lavage	NCT05707585	Lung Cancer	Quantitative Ch...	18 Years - 75 Years	The Second Affiliated Hospital of Dalian Medical University
Re-Examination of Tumor Material and Re-Evaluation of Patient Data From Patients Treated With Neo-adjuvant Therapy	NCT02449993	Breast Cancer	MammaTyper™	18 Years - 70 Years	BioNTech Diagnostics GmbH

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