Background: Mammographic screening for breast cancer offers the possibility of reducing morbidity and mortality from the disease but has economic and safety implications. Thromboembolism is a well-recognized, potentially life-threatening complication of cancer. Detection and characterization of tumour emboli comprising Circulating Ensembles of Tumor Associated Cells (C-ETACs) has however remained largely unstudied, essentially due to the difficulties in their isolation. Here we present for the first time an observational study describing the prevalence of C-ETACs in breast cancer patients and in asymptomatic individuals using a novel, label and hypothesis free process.
Methods:15 ml of peripheral blood was collected from 7075 female volunteers including 1582 previously diagnosed cases of breast cancer with definite radiological and histopathological evidence of disease of which 361 were non-metastatic, 792 were metastatic, 425 cases were recently diagnosed and treatment naïve and 1006 patients had received prior treatments. The control population comprised 5493 asymptomatic individuals with age-related increased risk of breast cancer. The control patients underwent mammography and had a BI-RADS category score of 1, consistent with absence of malignancy in the breast. Peripheral blood mononuclear cells from the study population were grown in an epigenetically active cell culture medium with paradoxical cytotoxicity that selectively kills normal cells and confers survival and growth advantage on apoptosis-resistant cells of tumorigenic origin and their emboli, viz., C-ETACs. C-ETACs are defined as clusters comprising Epcam+ and CK+ cells irrespective of CD45 expression. In a subset of 100 samples from breast cancer patients we confirmed that the isolated C-ETACs contained cells that were positive for GCDFP.
Results: C-ETACs were detected in 1413 / 1582 cases of breast cancer giving a sensitivity of 89.3%. There were no statistically significant differences between metastatic vs non-metastatic status of the disease or prior treatment. Among the 5493 individuals with unremarkable mammography, C-ETACs were detected in 104 (1.89 %) individuals. These individuals are being followed up prospectively for manifestation of clinical or radiological signs of malignancy of the breast as well as in other organs.
Conclusions: Our study shows that heterotypic C-ETACs are a common feature of breast cancer irrespective of type, stage and grade and are almost entirely absent in asymptomatic, mammographically normal individuals. Our results therefore identify a potential biomarker for breast cancer which is specific and sensitive and which satisfies the requirements for the non-invasive, radiation-free detection of breast cancer. As such, it is a candidate for development as a modality for population screening.
Citation Format: Timothy Crook, Dadasaheb Akolkar, Pradip Fulmali, Revati Patil, Cynthe Sims, Pooja Fulmali, Vineet Datta, Sachin Apurwa, Ajay Srinivasan, Rajan Datar. Circulating ensembles of tumor associated cells for detection of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-05.