Evaluating Ductal Carcinoma in Situ Progression via Tissue Oxygenation and Perfusion Using Photoacoustic and Contrast-Enhanced Ultrasound
Authors:   , Margolis Ryan , Eisenbrey John Robert , Lewin Peter A. 
Published: July 2021

Breast cancer accounts for 30% of all cancer in women with an estimated 266,000 new cases and over 40,000 deaths in 2018. In the U.S., breast cancer treatments exceed $16.5 billion per year. The gold standard for treatment commonly involves a combination of breast conserving surgery and radiation. Treatments are only successful if the cancers are accurately detected. Breast cancers detection is commonly done through mammography or manual palpation. While mammography has reduced the death rate and allowed for earlier treatments, it is limited by dense breast tissue. Furthermore, about 50% of women experience false-positives. It is reported that approximately 30% of early stage breast cancer, also referred to as ductal carcinoma in situ (DCIS), is over diagnosed and overtreated, causing physical and emotional distress. This thesis aims to address the clinical need for predictive precursors for the aggressiveness and development of DCIS to invasive breast cancer by measuring tissue oxygenation and perfusion using photoacoustic and contrast-enhanced ultrasound imaging. Furthermore, exercise has been proposed as a mechanism to not only reduce the risk of breast cancer, but its progression as well. Therefore, the effects of voluntary physical exercise will be evaluated through the aforementioned parameters above. Mouse models consisting of FVB/NJ mice (n=20) and Tg(C3-1-TAg)cJeg mice (n=10) were evenly divided into exercise and control subgroups, where the exercise groups had access to an exercise wheel. The Tg(C3-1-TAg)cJeg (SV40 Tag) mouseline is genetically predisposed to develop DCIS. Mice were weighed biweekly. Tissue perfusion was measured using the combination of ultrasound contrast agents and high frequency nonlinear imaging. Time intensity curves were generated from perfusion flow within tumor ROIs to extract wash-in rate and area under the curve values. Average SO2 values were compared for tissue oxygenation from photoacoustic images. There was a significant difference between the exercise and control subgroups for the FVB/NJ and SV40 Tag mice. For the FVB/NJ mice, the exercise group exhibited lower weight changes than the control group (0.43 ± 0.70 g vs. 0.99 ± 2.31 g, respectively, p = 0.002). The SV40 Tag mice demonstrated similar differences in weight gain (2.67 ± 1.38 g vs. 3.36 ± 1.36 g, respectively, p = 0.006). There were no differences between the exercise and control subgroups of the FVB/NJ mice with regards to tissue oxygenation (5.16 ± 23.68 % vs. 10.93 ± 27.67 %, respectively, p=0.947). However, for the SV40 Tag mice, the animals with access to voluntary exercise showed mammary tissue more indicative of a hypoxic environment than the control group (-15.64 ± 30.95 % vs. 21.73 ± 27.10 %, respectively, p=0.061). Neither the FVB/NJ or SV40 Tag mice displayed any differences between the exercise or control subgroups when measuring perfusion using contrast-enhanced ultrasound. The WIR was greater for the FVB/NJ (p = 0.685) and SV40 Tag (p = 0.659) exercise groups than the control groups. Likewise, the AUC held a similar relationship between the two subgroups for the FVB/NJ (p = 0.073) and SV40 Tag (p = 0.523) mice. The higher WIR suggest higher vascularization in the exercise groups. Lastly, preliminary results did not support any significant differences between tumor sizes, although the control group did exhibit higher weekly tumor growth (p = 0.902). DCIS-like tumors were visibly seen in all mice at 12 weeks of age, while invasive cancer was indicative of the increasing weekly tumor size at weeks 15. Preliminary results show the potential for tissue oxygenation to be predictive precursor of DCIS progression. By predicting DCIS growth, the proper treatments can be determined to avoid the unnecessary physical, psychological, and financial costs caused by over diagnosis and overtreatments of DCIS.