Methylation Markers that Provide Molecular Diagnosis by Distinguishing Between Benign from Malignant Breast Cancer and Predict Risk

Unmet Need

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in low and middle income countries (LMICs), and is expected to increase in incidence due to longer life expectancies, decreased burden of infectious diseases, and changes in reproductive risk factors. In LMICs, breast cancer mortality rates are as high as 25.5% due to a lack of organized screening programs and late diagnosis stages. After patients receive a breast biopsy, there may be delays of up to 10 months for diagnosis due to a critical shortage of clinical pathologists, preventing timely treatment. Non-histopathological techniques, such as palpation, have low accuracy at assessing whether a tumor is benign or malignant. Current attempts to automate screening for breast tumor classification have used methylated genes found in patients with benign breast disease, but these tests lack high levels of sensitivity and specificity. Hence, there is a need for an accessible method with high sensitivity and specificity that can rapidly and accurately provide breast cancer diagnosis, enabling health care providers in LMICs to distinguish between benign and malignant tumors.

Technology Description

Methylation is the process through which methyl groups are attached to DNA, altering expression of certain genes. During breast cancer development, hypermethylation of DNA in specific regions known as CpG islands located in tumor suppressor genes occurs, so DNA methylation increases in select tumor specific genes may be associated with malignant progression. After screening for methylation markers that were present in low or undetectable levels in benign breast disease, but were present at easily detectable levels in malignant breast cancer, the inventors identified 6 genes that could reliably distinguish between benign and malignant tumors in various types of breast diseases (usual ductal hyperplasia, papilloma, fibroadenoma) and cancer. While previous work on applying methylated marker panels has primarily concentrated on classifying tumors as in situ or lobular, this panel is the first methylated marker panel specifically selected to distinguish between malignant and benign lesions for diagnostic purposes. By using such a molecular diagnostic test, patients can receive a rapid diagnosis that subtypes their tumor within 5 hours, allowing treatment plans to be made without delay. Consequently, this panel overcomes the long delays associated with histopathological analysis and may help drive down the mortality rate of breast cancers in LMICs. An automated cartridge for breast cancer detection was also developed alongside the panel. Because the panel is automated, it is not skill- or specialist-dependent, enabling more efficient processing of caseloads and expedited diagnosis.

Stage of Development

The inventors have selected a panel of 6 methylated gene markers that can distinguish between benign and malignant tumors. Tests of the panel with fine needle aspiration samples from breast lesions demonstrated a sensitivity of >95% and specificity of 100%, verifying the reliability of the panel as a diagnostic tool to differentiate between benign and malignant tumors.

Publications:

Clin Cancer Res. 2019 Nov 1;25(21):6357-6367