Non-Invasive Optical Characterization of Breast Physiology

Institution: University of California, Irvine
Investigator(s): Bruce Tromberg, Ph.D. - John Butler, M.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6EB-0123 Award: $499,915
Award Type: TRC Full Research Award
Research Priorities
Detection, Prognosis and Treatment>Imaging, Biomarkers, and Molecular Pathology: improving detection and diagnosis

Initial Award Abstract (2000)
As more women undergo regular mammographic screening, new problems have emerged for physicians trying to distinguish between breast cancer and non-cancerous (benign) breast abnormalities. Because breast is a complex, dynamic tissue, benign changes are much more prevalent than cancer. As a result, a large number of surgical procedures are now performed to examine suspicious breast tissue for the presence of disease. This can add considerable cost and anxiety to each attempted breast cancer diagnosis. If new information could be provided by a rapid, low-cost, non-invasive technique, some of the difficulties associated with mammography, particularly for pre- and peri-menopausal women, could be minimized. This idea has lead to the development of "breast diaphanography", a simple, low-cost, near-infrared (NIR) light imaging method. Unfortunately, the initial promise of NIR diaphanography has not been realized, primarily due to the effect of intense light scattering by structures in the breast. Scattering blurs our ability to find small, light-absorbing tumors much in the same way that a cloud obscures our view of an airplane passing overhead. But, research by our group and many others in the biomedical optics community has lead to new strategies for understanding light scattering, rejuvenating interest in NIR optical methods for breast cancer detection.

We plan to use BCRP funding to explore recent developments in a new NIR optical technique, "Frequency Domain Photon Migration" (FDPM), for breast tumor diagnosis. FDPM is unique because it is sensitive to subtle breast tissue physiological changes that occur throughout life, such as aging, hormonal fluctuations, and menopause. This information could be used to provide clinicians with immediate insight into the nature and severity of a problem and the efficacy of various treatment options.

Our aims are first to demonstrate whether normal and malignant breast tissues can be distinguished optically by FDPM using human patients. A specially designed, portable, hand-held probe will be used as a bedside device. Unlike mammography, FDPM does not employ ionizing radiation or breast compression. Tissue functional properties that are measured include hemoglobin concentration (both oxy- and deoxy- forms), blood volume fraction, water content, fat content, and details of cellular structure. We know that these physiological parameters can change significantly in tumors. In the proposed work we plan to investigate whether we can use these data in a clinical setting to characterize tumor progression, therapeutic response, and the efficacy of chemoprevention strategies.

In summary, advances in optical technologies and computational power have helped stimulate new, non-invasive, bedside approaches for breast cancer management. Potential impact areas include detection in younger women, treatment monitoring, and screening high-risk subjects. We anticipate this research will have important near-term benefits for patients undergoing cancer therapies. Expected long-term benefits include enhancing our understanding of normal breast physiology, identifying specific changes associated with tumor formation and characterizing functional alterations that can be used to predict disease risk.

Final Report (2004)
Note: This grant was extended one year to complete the funding and aims.

Introduction: We have used CBCRP support to develop a non-invasive optical technique, Diffuse Optical Spectroscopy (DOS, to improve breast cancer clinical management. The unique ability of DOS to measure breast tissue physiology makes it suitable for: (1) monitoring patients with locally advanced-breast cancer undergoing neoadjuvant chemotherapy (chemotherapy prior to surgery), (2) studying women with benign and malignant breast cancer to increase imaging specificity and reduce the number of biopsies, and (3) studying normal and high-risk women. Through CBCRP funding we have been able to establish and maintain a two-center trial with the University of California, San Francisco, Magnetic Resonance Imaging Center to combine novel optical methods with established clinical techniques such as MRI (Magnetic Resonance Imaging).

Topic Addressed: Our mission is to non-invasively characterize breast physiology to enhance current clinical methods in breast health, namely breast cancer screening, diagnosis and therapeutic monitoring. We have used near-infrared light in a prototype device to characterize tissue function by quantifying the concentrations of various biochemical constituents namely hemoglobin (oxy- and deoxy- forms), water, lipids and tissue scattering. Major research questions addressed are: (1) Is it possible to detect malignant lesions using DOS, (2) Can DOS determine early response to neoadjuvant chemotherapy using optical methods, and (3) Can combining optical techniques with standard clinical methods such as MRI enhance the specificity and sensitivity of present techniques?

Progress towards the Specific Aims: Over the past four years we have studied 212 women using DOS: 181 at UCI, including 60 cancer patients and 22 neoadjuvant chemotherapy patients, and 31 women under our collaboration with UCSF. Our progress towards the specific aims includes:

Aim 1: To develop and standardize our instrumentation and techniques we have developed an operations manual for the Laser Breast Scanner (LBS), and a graphical-user interface (GUI) for data-processing. We have developed three clinical instruments (1 at UCI Cancer Center, 1 at UCI Beckman Laser Clinic, and 1 at UCSF) and standardized data acquisition, patient measurement protocols and instrument operations. We have developed a training program for self-sufficient operation of DOS studies by non-optics personnel, which has been successfully implemented at the UCSF Magnetic Resonance Science Center. We have acquired data from 60 cancer patients (64 malignant tumors) and are in the process of analyzing optical and physiological signatures from this population.

Aim 2: DOS results in over 30 healthy women have shown marked differences in the physiology of pre and post-menopausal breast due to changes in glandular structure, exogenous hormones and menstrual cycle. We have established a long-term collaboration with Dr. Catherine Klifa of UCSF to use a combination of MRI and DOS to investigate breast density and cancer risk.

Aim 3: We have studied 24 subjects throughout the course of chemotherapy and our preliminary results show DOS can distinguish patient responders from non-responders from the first week of chemotherapy. We have also analyzed neoadjuvant chemotherapy with a combination of DOS and MRI at UCSF which served to validate DOS techniques.

Future Directions and Impact: The results from the UCI-UCSF collaboration have shown that the combination of MRI and DOS techniques provides validation of optical results as well as anatomic information vital for the development of our technique. Based on the success of our preliminary study, a long-term installment of the LBS in UCSF was initiated in February 2004 and another CBCRP grant was awarded starting July 2004. Our results in cancer patients demonstrate DOS maybe suitable for screening pre-menopausal women with dense breasts and high-risk women. Preliminary success using DOS to monitor neoadjuvant chemotherapy show that it may be a suitable technique for assessing regimen efficacy within 1-week of therapy. With continued technological development, diffuse optics methods could become available at low cost and in a compact design such that the instrumentation could be integrated into MRI magnets and mammography instruments, or as stand alone devices in physician's offices or clinics.

Spectroscopy enhances the information content of optical mammography
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Cerussi AE, Jakubowski D, Shah N, Bevilacqua F, Lanning R, Berger AJ, Hsiang D, Butler J
Yr: 2002 Vol: 7 Nbr: 1 Abs: Pg:60-71

Non-invasive functional optical spectroscopy of human breast tissue
Periodical:Proceedings of the National Academy of Sciences of the United States of America
Index Medicus: Proc Nat Acad Sci, U S A
Authors: Shah N, Cerussi A, Eker C, Espinoza J, Butler J, Fishkin J, Hornung R, Tromberg B
Yr: 2001 Vol: 98 Nbr: 8 Abs: Pg:4420-5

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

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

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

Comparison of water and lipid content measurements using diffuse optical spectroscopy and MRI in emulsion phantoms.
Periodical:Technology in Cancer Research and Treatment
Index Medicus:
Authors: Merritt S, Gulsen G, Chiou G, Chu Y, Deng C, Cerussi AE, Durkin AJ, Tromberg BJ, Nalcioglu
Yr: 2003 Vol: 2 Nbr: 6 Abs: Pg:563-9

Three-dimensional diffuse optical mammography with ultrasound localization in a human subject.
Periodical:Journal of Biomedical Optics
Index Medicus: J Biomed Optics
Authors: Holboke MJ, Tromberg BJ, Li X, Shah N, Fishkin J, Kidney D, Butler J, Chance B, Yodh AG.
Yr: 2000 Vol: 5 Nbr: 2 Abs: Pg:237-47

Non-invasive in vivo characterization of breast tumors using photon migration spectroscopy.
Index Medicus: Neoplasma
Authors: Tromberg BJ, Shah N, Lanning R, Cerussi A, Espinoza J, Pham T, Svaasand L, Butler J.
Yr: 2000 Vol: 2 Nbr: 1-2 Abs: Pg:26-40

Sources of absorption and scattering contrast for non-invasive optical mammography
Periodical:Academic Radiology
Index Medicus: Acad Radiol
Authors: Cerussi AE, Berger AJ, Bevilacqua F, Shah N, Jakubowski D, Butler J, Holcombe RF, et al.
Yr: 2001 Vol: 8 Nbr: 3 Abs: Pg:211-8