Intra-tumor heterogeneity drives neoplastic progression by supplying the fuel for natural selection among neoplastic cells. It also complicates screening and treatment of neoplasms. We hypothesize that the degree of intra-tumor heterogeneity in DCIS should predict which tumors are likely to become invasive and metastatic. We initiated a pilot project to test this hypothesis by comparing 9 cases of pure DCIS to 9 cases of DCIS with adjacent invasive disease. For each case, we sequenced the exome from two spatially distinct regions of DCIS as well as normal tissue taken from a lymph node with no tumor involvement. This required the development of new methods to extract high quality sequencing data from small amounts of DNA extracted from FFPE samples. We calculated the genetic divergence between the two tumor regions, defined as percent of the sequenced regions of the genome showing differences between the two samples that had sufficient sequencing coverage and quality scores for confident scoring. We also employed automated imaging analysis to score microenvironmental differences between the two tumor regions. These microenvironmental measures are based on ecological methods for measuring organismal interactions and habitats. We will present initial data on differences in phenotypic and genotypic intra-tumor heterogeneity comparing pure DCIS to DCIS associated with invasive breast cancer. Our methods can be readily translated to large tissue banks of FFPE samples from DCIS.

Citation Format: Fortunato A, King L, Mallo D, Kovacheva V, Yuan Y, Boddy A, Graham T, Aktipis A, Mardis ER, Hall A, Marks JR, Hwang S, Maley CC. Genomic and microenvironmental intra-tumor heterogeneity in DCIS [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-30.