Discovery of diagnostic biomarkers and targeted therapy for ductal carcinoma in situ (DCIS)

Abstract

Breast cancer remains a significant public health problem affecting a remarkable proportion of women globally. Ductal carcinoma in situ (DCIS) is the most common non-invasive neoplasm found in mammography screenings and has an excellent prognosis in general. Nevertheless, approximately 10% of patient with high grade DCIS have a form of breast cancer known as neoductgenesis where cancerous duct-like structures of invasive nature are forming. Currently, neoductgenesis has no specific diagnosis and it is underdiagnosed as DCIS. Therefore, the aim of this thesis was to provide increased knowledge and histopathological markers for neoductgenesis. This thesis also aimed to test the efficacy of novel disulfide bridge-stabilized scFv antibody fragments of trastuzumab to improve the current treatment options of HER2-positive breast cancer. Imaging mass cytometry and immunofluorescence imaging were utilized to distinguish the spatial molecular features of selected breast cancer tissue samples that a pathologist had evaluated as high grade DCIS with or without neoductgenesis. The capacity of the ds-scFv-Fc antibody fragments to inhibit the proliferation of HER2-positive breast cancer cells was analyzed to evaluate whether the ds-scFv-Fc antibody fragments with potentially improved pharmacological properties have equal or even better efficacy compared to trastuzumab. This study identified several molecular features that appear specific to neoductgenesis and that help to explain its distinct and invasive nature. In the future, these findings have the potential to help the identification of the patients with neoductgenesis from DCIS in clinical histopathology. In addition, the ds-scFv-Fc antibody fragments demonstrated superior efficacy to inhibit the proliferation of trastuzumab-resistant HER2-positive breast cancer cells compared to trastuzumab, hence providing an alternative solution to overcome trastuzumab resistance. Further research is needed to validate the potential biomarkers for neoductgenesis in a larger sample cohort and to investigate the molecular action of the ds-scFv-Fc antibody fragments in trastuzumab-resistant cells.