Development and application of novel spectroscopic tools for breast cancer diagnosis

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1 Development and application of novel spectroscopic tools for breast cancer diagnosis LBRC researchers: Ramachandra Dasari, Jeon Woong Kang, Niyom Lue, Rishikesh Pandey, Nicolas Spegazzini External technology collaborators: Dr. Maryann Fitzmaurice (Case Western Reserve University, Cleveland, OH) Technology Overview The focal point of this project is the development of optical modalities for the real time characterization of breast cancer lesions at the patient bedside. We have developed a Raman spectroscopy technique to simultaneously identify microcalcification status and diagnose the underlying breast lesion, in real- time, during stereotactic core needle biopsy procedures. Further, we have introduced an approach based on diffuse reflectance spectroscopy for detection of microcalcifications that focuses on variations in optical absorption stemming from the calcified clusters and the associated cross- linking molecules. By correlating the diffuse reflectance spectra with the corresponding radiographic and histologic assessment, we have developed a support vector machine- derived decision algorithm, which shows high diagnostic power. Biomedical Application Potential We have demonstrated the potential of Raman spectroscopy to concomitantly detect microcalcifications and diagnose associated lesions, including ductal carcinoma in situ (DCIS), and thus provide real- time feedback to radiologists during such biopsy procedures, reducing nondiagnostic and false- negative biopsies. The clinical translation of such integrative photonics approaches will offer new diagnostic methods, due to their ability to provide high- throughput and high- content information in real- time and with minimal system perturbation. Ongoing Projects a. Raman spectroscopic study to identify microcalcifications and underlying breast lesions at stereotactic core needle biopsy b. Classification algorithms for lesion discrimination in stereotactic breast biopsies with microcalcifications c. Diffuse reflectance spectroscopy and microcalcifications

2 Histopathology and Raman spectrum (blue) with model fit (red) and residual (black) for a typical breast lesion (FCC) with type II microcalcifications. The microcalcifications are visible as dark blue concretions (arrow) in the photomicrograph in A (H&E; X 10). Note the yellow ink on the breast tissue surface at the top in A, marking the site for spectral correlation. The corresponding Raman spectrum in B shows a prominent band at 960 cm - 1 due to CHA (arrow), which is a major constituent of type II microcalcifications.

3 Representative diffuse reflectance spectra acquired from breast tissue

4 Illustration of principal components for diffuse reflectance measurements. The first three principal components in order of net variance corresponding to the diffuse reflectance spectra acquired from the freshly excised breast tissue cores. PC1 and PC2 both demonstrate oxy- hemoglobin absorption features, namely the Soret band at 414 nm, and the Q bands at ca. 547 and 580 nm, with a shallow absorption trough at 563 nm. PC3 shows a wider trough in the nm region, which contains β- carotene absorption features (typically at 450 and 480 nm). ROC curve for SVM- derived diffuse reflectance algorithm for the diagnosis of breast lesions with microcalcifications. The ROC curve in red plots sensitivity versus (1- specificity) for the SVM decision algorithm as the discrimination threshold is varied. For comparison, the ROC curve of two indistinguishable classes (represented by the solid black line) is also shown. The area under the curve is 0.88 compared with an AUC of 1.00 for a perfect algorithm (TP = true positive; FP = false positive).

5 Background Publications 1. Shen, L., et al., Application of shape- analysis to mammographic calcifications. IEEE T Med. Imaging 1994 ;13: p Haka AS, Fitzmaurice M. Raman spectroscopy diagnosis of breast cancer and atherosclerosis: a primer. In: Tunnel JW, editor. Biophotonics: in vivo clinical imaging and diagnosis. New York, NY: McGrawHill; p Haka AS., et al., Diagnosing breast cancer by using Raman spectroscopy. Proc Nat Acad Sci 2005;102: Richards- Kortum, R., et al., Quantitative optical spectroscopy for tissue diagnosis. Annu. Rev. Phys. Chem., : Representative Center Publications 1. Soares, J.S., et al., Diagnostic power of diffuse reflectance spectroscopy for targeted detection of breast lesions with microcalcifications. Proceedings of the National Academy of Sciences, (2): Dingari, N.C., et al., Development and comparative assessment of Raman spectroscopic classification algorithms for lesion discrimination in stereotactic breast biopsies with microcalcifications. Journal of biophotonics, (4): Barman, I., et al., Application of Raman spectroscopy to identify microcalcifications and underlying breast lesions at stereotactic core needle biopsy. Cancer research, (11):