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Spatiotemporal strategies to identify aggressive biology in precancerous breast biopsies

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Abstract Over 90% of breast cancer is cured; yet there remain highly aggressive breast cancers that develop rapidly and are extremely difficult to treat, much less prevent. Breast cancers that rapidly develop between breast image screening are called “interval cancers.” The efforts of our team focus on identifying multiscale integrated strategies to identify biologically aggressive precancerous breast lesions. Our goal is to identify spatiotemporal changes that occur prior to development of interval breast cancers. To accomplish this requires integration of new technology. Our team has the ability to perform single cell in situ transcriptional profiling, noncontrast biological imaging, mathematical analysis, and nanoscale evaluation of receptor organization and signaling. These technological innovations allow us to start to identify multidimensional spatial and temporal relationships that drive the transition from biologically aggressive precancer to biologically aggressive interval breast cancer. This article is categorized under: Cancer > Computational Models Cancer > Molecular and Cellular Physiology Cancer > Genetics/Genomics/Epigenetics
Schema depicting the use of seqFISH for evaluating transcript expression in biopsy tissue. (a) Biopsy tissue is obtained and preserved. (b) Tissue undergoes successive rounds of mRNA hybridization and probe stripping. (c) Transcripts are identified by specific bar code identification (BRCA1 and BRCA2 are used as illustrations. (d) Transcript expression is analyzed for each transcript in each cell using unsupervised hierarchical clustering. (e) Cells are classified based on expression pattern, a color assigned for each cell type, and the tissue architecture is reconstructed. (f) Keynode proteins are validated by IHC
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Matched MRI guided biopsy and MRI imaging demonstrates Wnt10B, HMGA2, and EZH2 expression in both morphologically normal biopsy at 0 months and follow up MRI imaging at 6 months. (a) 36‐Year‐old high‐risk premenopausal woman and (b) 61‐year‐old high‐risk woman had an abnormal screening MRI at 0 months and 6 months MRI follow‐up. For both women, biopsy at 0 months demonstrated morphologically normal tissue that had high expression of Wnt10B/HMGA2/EZH2; 6 month follow‐up biopsy demonstrated TNBC that also expressed high levels of Wnt10B/HMGA2/EZH2, both women had multiple lymph nodes that contained invasive TNBC but no metastatic disease. After greater than 5 years follow‐up both women are alive and disease free
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Screening breast MRI imaging of slowly progressing (a) versus rapidly progressing interval (b) breast cancer. (a) Slowly progressing ER/PR+ HER2‐wild‐type breast cancer; arrow at 36 months indicates when breast cancer was first observed, however at that time, it was too small for our clinical team to biopsy; arrow at 48 months demonstrates slow growth of the tumor over the 12 month interval; the breast cancer was biopsied at that point, staging revealed a T1N0M0 indolent breast cancer (b) Rapidly progressing ER/PR− HER2‐wild‐type triple negative breast cancer (TNBC), 0 months is a normal MRI, at 6 months a change in MRI patterning was observed, this was one of our first bilateral screening MRI and our team did not recognize the importance of this change and recommended a 6 month follow‐up, biopsy at 12 months (see arrows) demonstrated a T2N0M0 TNBC, the woman underwent bilateral mastectomy and chemotherapy, she is currently alive and disease free
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Current multi‐modality schema for evaluating aggressive biology in precancerous and cancerous breast tissue. qSMLM, quantitative‐single molecule localization microscopy; SBHPACT, single breath‐holding photoacoustic computed tomography; seqFISH, sequential fluorescence in situ hybridization
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Example of SBHPACT imaging of a cancerous breast. (a) Mammogram of the affected breasts; white circle identified the breast cancer (RCC right cranial‐caudal, RML right medio‐lateral). (b) Depth‐encoded vascular breast imaging acquired by SBHPACT. (c) Maximum amplitude projection (MAP) images of thick slices in sagittal planes marked by white dashed lines in (b). (d) Automatic tumor detection on vessel density map. Background images in gray scale are the MAP of vessels deeper than the nipple. Maps of the relative area change during breathing in the regions outlined by blue dashed boxes in the angiographic images (e) Elastographic study of the affected breast
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Touch prep‐qSMLM for imaging of HER2 in breast cancer tissues. (a) Scheme of HER2 receptor detected using fluorescently labeled trastuzumab. Alexa Fluor 647 was the fluorophore used in this case. (b) Image of HER2 positive breast cancer patient cell. Top, red signal represents localizations of Alexa Fluor 647 labeled trastuzumab detected with dSTORM. Bottom, gray signal represents signal from anti‐cytokeratin 7 antibody detected with diffraction limited microscopy. Scale bar, 5 μm. (c) Average detected HER2 density obtained with touch prep‐qSMLM versus HER2 copy number obtained from FISH. For six patients, the correlation coefficient was 0.979 with 95% CI [0.813, 0.998] with a p‐value of .0007. Image adapted from Tobin et al. (2018)
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