Breast Cancer Functional Imaging with Optics and MRI

Institution: University of California, Irvine
Investigator(s): Bruce  Tromberg , Ph.D. - John  Butler , M.D. - Nola  Hylton , Ph.D. -
Award Cycle: 2004 (Cycle 10) Grant #: 10EB-0208 Award: $500,000
Award Type: TRC Full Research Award
Research Priorities
Imaging, Biomarkers, & Molecular Pathology>Developing and Improving imaging technologies: better and easier detection



Initial Award Abstract (2004)
Drawbacks associated with the widespread use of screening x-ray mammography include high false-negative rates and low sensitivity for pre- and peri- menopausal women. Thus, researchers are actively developing alternative methods for earlier detection in this challenging population. What is needed are new methods that can provide more clinically useful information related to tissue functional changes associated with the appearance, progression, and treatment of breast cancer.

This CBCRP-funded collaborative grant seeks to expand the advantages of previous work by Dr. Tromberg (partially supported by the CBCRP) to develop an optical detection-based Laser Breast Scanner (LBS) with the research of Dr. Hylton on magnetic resonance imaging (MRI). Dr. Tromberg's group at the University of California, Irvine is developing the optical technology of broadband Diffuse Optical Spectroscopy (DOS) as a non-invasive technique for breast tissue characterization. In previous work, it was demonstrated that the hand-held laser breast scanner (LBS), based on DOS technology, displayed sensitivity to tumors (malignant and benign) as well as hormonal status, HRT use, and chemotherapy.

The LBS utilizes intensity-modulated, near-infrared (NIR) light to quantitatively measure optical properties in thick tissues. Optical properties (i.e. absorption and scattering parameters) derived from LBS measurements are used to construct low-resolution (0.5 - 1 cm) functional maps of tissue hemoglobin (total, oxy-, and deoxy- forms), oxygen saturation, blood volume fraction, water content, fat content and cellular structure. Our interest in the current research is to find ways to make the "functional parameters" from optical imaging complementary to "high anatomic resolution images" derived from MRI.

In preliminary translational studies supported by the CBCRP, it was possible to combine the LBS with the UCSF MRI and demonstrate optical/MRI tumor co-registration. Our hypothesis for the current project is that further development of a combined optical and MRI approach can dramatically improve detection, clinical management, and quality of life for breast cancer patients. Our specific aims are to: 1) Develop standardized instrumentation and techniques for co-registering optical and MRI scans and quantitatively characterizing breast tissue in human subjects; 2) Study the impact of menopausal status, hormone replacement therapy (HRT), and neoadjuvant chemotherapy on physiological properties in normal and high risk subjects; and 3) Develop "Tissue Optical Indices" (TOI) that report on functional parameters related to metabolism, angiogenesis, and cell/matrix density.

Measurements are performed using a non-invasive LBS optimized for clinical studies. Up to 120 patients per year will be enrolled at UCI and UCSF with a total of approximately 150 normal subjects and 210 subjects with tumors. LBS studies are conducted prior to and following MRI scans. Data are acquired using a hand-held scanning probe placed in multiple locations mapping the breast surface. Both normal and tumor-containing breasts are studied. Each tissue location is characterized in terms of wavelength-dependent absorption and scattering parameters which, in turn, are used to calculate physiological properties. All data are correlated with structural information derived from conventional sources, such as clinical exam, mammography, ultrasound and histopathology. New methods for co-registering, visualizing, and analyzing LBS and MRI data will be developed and advanced. Dr. John Butler is a co-PI for this project, and serves as the clinical coordinator.

The long-term goal of this research is to advance our understanding of the functional origin of optical and MRI signals in breast tissue imaging. We expect the proposed study results will play a critical role in determining whether optical devices should become much more widely available to patients as a screening/diagnostic tool.


Final Report (2007)

Diffuse optical spectroscopy (DOS) combines experimental measurements and model-based data analysis to measure the bulk absorption and reduced scattering properties of cm-thick tissues. DOS uses near-infrared (NIR) light, (650nm to 1000 nm), where light propagation in tissue is dominated by scattering, and the absorption of light is mostly dye to hemoglobin (oxy- and deoxy- forms), water, and bulk lipids. The DOS method differs substantially from conventional NIR methods, such as diaphanography (or transillumination) because most NIR measurements do not distinguish between absorption and scattering. The information content recovered by DOS is all available with endogenous contrast, although exogenous contrast agents can certainly increase information content.

Several recent key advances highlight the unique features of DOS and our clinical instrument, the Laser Breast Scanner (LBS). We first developed standard instrumentation and techniques for co-registering breast data between the LBS and MRI. These new tools facilitated quantitative comparisons between the two techniques, and may also be generalized for use with DOS and any other imaging modality. Using this technique, we demonstrated that the breast density as measured by MRI correlates well with breast density as measured by the parenchyma components of the breast.

In the largest published work to date of malignant tumor NIR spectra, we demonstrated that optical contrast functions are effective in detecting lesions in breast tissues in both pre-menopausal and post-menopausal patients. We have generated low-resolution maps of tumor biochemistry using these optical indices. We have also developed new spectral analysis tools that have revealed the existence of specific NIR absorption signatures that are unique to malignant lesions and are not found in normal tissues. Similar spectral biomarkers also exist in fibroadenomas, and are spectrally distinct from malignant spectral signatures. Using an index derived from these spectra called the malignancy index, we were able to reliably stratify malignant from benign lesions with 100% sensitivity and 92% specificity in a 40 patient sample.

We also demonstrated that DOS measurements of tumors convey important information about tumor pathological response to neoadjuvant chemotherapy. Pre-treatment measurements of tumors in an 11 patient study demonstrated that lesions with high oxygenated hemoglobin concentrations relative to normal tissues exhibited better pathological responses to neoadjuvant chemotherapy. Measurements taken within 1 week after neoadjuvant chemotherapy in the same population revealed that changes in tumor deoxy-hemoglobin and water could predict final pathological response months later. In a separate 13 patient study, we also demonstrated that changes in DOS parameters measured prior to treatment relative to those measured just prior to surgery could reveal the pathological extent of residual disease. In 12/13 patients we correctly identified pathological response (i.e., no response, partial response, and complete pathological response).

Because this is a new technology, the overall patient experience, anticipated benefit and perceived risks are important in development of the LBS. We analyzed the patient experience with the LBS exam to determine patient interest and expected compliance for this potential clinical technology. Critical issues to explore are motivation for involvement, anxiety related to laser technologies, comfort during the procedure, perceived benefits, and overall expectations regarding the future role of this technology in breast care. From a patient perspective the surveys revealed that in patients approved of the technique and were not anxious from the use of lasers.




Symposium Abstract (2005)
The Laser Breast Scanner (LBS) is a novel non-invasive laser based technique for breast cancer diagnosis and clinical management. The LBS is a relatively inexpensive and bedside-capable approach that requires no compression and ionizing radiation. The LBS does not provide anatomical information but rather quantitative physiological data on tissue function. This unique information cannot be provided by current radiological techniques such as mammography, ultrasound or MRI. Because the effectiveness of the LBS is not impeded by breast density, it is potentially valuable for screening young women with dense breasts, frequent screening for women who are high-risk, and for therapeutic monitoring.

Because this is a new technology, the overall patient experience, anticipated benefit and perceived risks are important in development of the LBS. In this paper we analyze the patient experience with the LBS exam to determine patient interest and expected compliance for this potential clinical technology. We have studied more than 250 patients over the course of eight years using the laser breast scanner. Critical issues that will be explored are motivation for involvement, anxiety related to laser technologies, comfort during the procedure, perceived benefits, and overall expectations regarding the future role of this technology in breast care. Quantitative measures of the patient experience were conducted by phone interviews. The outcome of these ongoing studies will be used to optimize the technical performance and design features of the LBS from a patient perspective.


Symposium Abstract (2005)
Background: Diffuse Optical Spectroscopy (DOS) is a non-invasive, non-ionizing technique that uses near infrared-light (600-1000nm) to quantify concentrations of biological tissue components namely deoxy-hemoglobin, oxy-hemoglobin, lipid and water that relate to disease processes such as increased vasculature, angiogenesis, necrosis and metabolism. Because of DOS sensitivity to tissue physiology the technique has shown promise for monitoring tumor response to neoadjuvant chemotherapy. Materials and Methods: A DOS instrument, the Laser Breast Scanner, was used to determine a full NIR scattering and absorption spectra in the breast tissue of 5 women undergoing neoadjuvant chemotherapy. Daily DOS monitoring was performed during the first week of treatment and bi-weekly thereafter. Changes in DOS parameters and optical indices throughout the treatment were correlated to quantitative dynamic contrast-enhanced (DCE) MRI kinetic and anatomic parameters for validation. Early changes (~1st week) in DOS and MRI parameters were compared to establish sensitivity of DOS compared to MRI and determine MRI and DOS correlates. Early DOS response was correlated to surgical pathology to assess the predictive value of DOS results to pathological outcome. Results: An invasive ductal carcinoma undergoing a regimen of bi-weekly doxorubicin/cyclophosphamide followed by weekly Carboplatin /Paclitaxel therapy shows a 24% reduction in water and 30% decrease in deoxy-hemoglobin after the first week of therapy and a return to normal values (compared to the contralateral breast) by completion of treatment. DCE-MRI co-localization shows corresponding decreases in contrast-enhancement and lesion size within the first treatment cycle complete pathological response at surgery. Analysis of response of 5 women within the first week of therapy show significant changes in DOS-derived parameters which precede changes in MRI enhancement kinetics.

Discussion: DOS is sensitive to functional changes occurring with tumor response to therapy and may suitable as an adjunct to therapeutic monitoring. Because DOS can detect subtle changes in tissue biology it may detect physiological changes in tumor tissue due to chemotherapy that occurs prior to structural changes. Thus DOS may be a suitable for chemotherapy monitoring as an early predictor of long-term pathological response.

Spatial variations in optical and physiological properties of healthy breast tissue.
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Shah N, Cerussi AE, Jakubowski D, Hsiang D, Butler J, Tromberg BJ.
Yr: 2004 Vol: 9 Nbr: 3 Abs: Pg:534-40

Monitoring neoadjuvant chemotherapy in breast cancer using quantitative diffuse optical spectroscopy: a case study.
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Jakubowski DB, Cerussi AE, Bevilacqua F, Shah N, Hsiang D, Butler J, Tromberg BJ.
Yr: 2004 Vol: 9 Nbr: 1 Abs: Pg:230-8

The role of diffuse optical spectroscopy in the clinical management of breast cancer.
Periodical:Disease Markers
Index Medicus: Dis Markers
Authors: Shah N, Cerussi AE, Jakubowski D, Hsiang D, Butler J, Tromberg BJ.
Yr: 2004 Vol: 19 Nbr: 2-3 Abs: Pg:95-105

Combined diffuse optical spectroscopy and contrast-enhanced magnetic resonance imaging for monitoring breast cancer neoadjuvant chemotherapy: a case study.
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Shah N, Gibbs J, Wolverton D, Cerussi A, Hylton N, Tromberg BJ.
Yr: 2005 Vol: 10 Nbr: 5 Abs: Pg:051503

Coregistration of dynamic contrast enhanced MRI and broadband diffuse optical spectroscopy for characterizing breast cancer.
Periodical:Technology in Cancer Research and Treatment
Index Medicus:
Authors: Hsiang D, Shah N, et al, and,Tromberg B
Yr: 2005 Vol: 4 Nbr: 5 Abs: Pg:549-58

Diffuse optics in breast cancer: detecting tumors in pre-menopausal women and monitoring neoadjuvant chemotherapy.
Periodical:Breast Cancer Research
Index Medicus: Breast Cancer Res
Authors: Tromberg BJ, Cerussi A, Shah N, Compton M, Durkin A, Hsiang D, Butler J, Mehta R
Yr: 2005 Vol: 7 Nbr: 6 Abs: Pg:279-85

In vivo absorption, scattering, and physiologic properties of 58 malignant breast tumors determined by broadband diffuse optical spectroscopy.
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Cerussi A, Shah N, Hsiang D, Durkin A, Butler J, Tromberg BJ.
Yr: 2006 Vol: 11 Nbr: 4 Abs: Pg:044005

Intrinsic tumor biomarkers revealed by novel double-differential spectroscopic analysis of near-infrared spectra.
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Kukreti S, Cerussi A, Tromberg B, Gratton E.
Yr: 2007 Vol: 12 Nbr: 2 Abs: Pg:020509

Method for recovering quantitative broadband diffuse optical spectra from layered media.
Periodical:Applied Optics
Index Medicus:
Authors: Li A, Kwong R, Cerussi A, Merritt S, Hayakawa C, Tromberg B.
Yr: 2007 Vol: 46 Nbr: 21 Abs: Pg:4828-33

Diffuse optical monitoring of blood flow and oxygenation in human breast cancer during early stages of neoadjuvant chemotherapy.
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Zhou C, Choe R, Shah N, et al and Tromberg BJ
Yr: 2007 Vol: 12 Nbr: 5 Abs: Pg:051903