Near-infrared (NIR) diffuse optical spectroscopy (DOS) and diffuse optical imaging (DOI) show promise as noninvasive clinical techniques for breast cancer screening and diagnosis. Since NIR methods are based on optical contrast between healthy and diseased tissue, it is essential to characterize the sources of endogenous contrast in normal subjects. We report intra- and inter-subject variation and bilateral asymmetry of the optical and physiological parameters of 31 women using a seven-wavelength NIR frequency-domain photon migration (FDPM) instrument. Wavelength-dependent absorption and reduced scattering parameters (micro(a) and micro(s'), respectively) were measured in four major quadrants and the areolar regions of left and right breasts. These values were used to determine tissue concentrations of oxy-(HbO(2)) and deoxy-(Hb-R) hemoglobin, lipid content, water concentration, and tissue "scatter power." Mean total hemoglobin for premenopausal (PRE) women (20 to 30 microM) is approximately two-fold higher than for postmenopausal (POST) subjects at all positions. POST women have approximately 50% higher lipid content (50 to 60%) than PRE at all positions. Water concentration on average is 1.8-fold higher for PRE subjects (30 to 40%) than POST. These differences are most pronounced when comparing the areolar complex to the other regions of the breast. In premenopausal women, the areolar regions have 40 to 45% increased total hemoglobin concentration (THC), 20 to 25% lower lipid content, and 30 to 60% higher scatter power versus the quadrants. Small-scale (3 cm) changes in optical properties are negligible compared to large-scale variations over all quadrants, where the intrinsic spatial heterogeneity of healthy breast tissue is 20 to 40% for micro(a) and 5 to 12% for micro(s'). Although no consistent right-left differences are observed in the study population, relative differences between symmetric positions ranged from 18 to 30% for THC, 10 to 40% for adipose, 10 to 25% for water, and 4 to 9% for scattering (674 nm) within an individual.

Diffuse optical spectroscopy (DOS) of breast tissue provides quantitative, functional information based on optical absorption and scattering properties that cannot be obtained with other radiographic methods. DOS-measured absorption spectra are used to determine the tissue concentrations of deoxyhemoglobin (Hb-R), oxyhemoglobin (Hb-O₂), lipid, and water (H₂O), as well as to provide an index of tissue hemoglobin oxygen saturation (S_tO₂). Tissue-scattering spectra provide insight into epithelial, collagen, and lipid contributions to breast density. Clinical studies of women with malignant tumors show that DOS is sensitive to processes such as increased tissue vascularization, hypoxia, and edema. In studies of healthy women, DOS detects variations in breast physiology associated with menopausal status, menstrual cycle changes, and hormone replacement. Current research involves using DOS to monitor tumor response to therapy and the co-registration of DOS with magnetic resonance imaging. By correlating DOS-derived parameters with lesion pathology and specific molecular markers, we anticipate that composite “tissue optical indices” can be developed that non-invasively characterize both tumor and normal breast-tissue function.

Rationale and objectives

Near-infrared (NIR) diffuse optical spectroscopy and imaging may enhance existing technologies for breast cancer screening, diagnosis, and treatment. NIR techniques are based on sensitive, quantitative measurements of functional contrast between healthy and diseased tissue. In this study, the authors quantified the origins of this contrast in healthy breasts.

Materials and methods

A seven-wavelength frequency-domain photon migration probe was used to perform noninvasive NIR measurements in the breasts of 28 healthy women, both pre- and postmenopausal, aged 18-64 years. A diffusive model of light transport quantified oxygenated and deoxygenated hemoglobin, water, and lipid by their absorption signatures. Changes in the measured light-scattering spectra were quantified by means of a "scatter power" parameter.

Results

Substantial quantitative differences were observed in both absorption and scattering spectra of breast as a function of subject age. These physiologic changes were consistent with long-term hormone-dependent transformations that occur in breast. Instrument response was not adversely affected by subject age or menopausal status.

Conclusion

These measurements provide new insight into endogenous optical absorption and scattering contrast mechanisms and have important implications for the development of optical mammography. NIR spectroscopy yields quantitative functional information that cannot be obtained with other noninvasive radiologic techniques.

Presurgical chemotherapy is widely used in the treatment of locally advanced breast cancer. Monitoring the response to therapy can improve survival and reduce morbidity. We employ a noninvasive, near-infrared method based on diffuse optical spectroscopy (DOS) to quantitatively monitor tumor response to neoadjuvant chemotherapy. DOS was used to monitor tumor response in one patient with locally advanced breast cancer throughout the course of her therapy. Measurements were performed prior to doxorubicin-cyclophosphamide therapy and at several time points over the course of three treatment cycles (68 days). Our results show strong tumor to normal (T/N) tissue contrast in total hemoglobin concentration (T/N=2.4), water fraction (T/N=6.9), tissue hemoglobin oxygen saturation, S(t)O(2) (T/N=0.9), and lipid fraction (T/N=0.7) prior to treatment. Over a 10-week period, the peak total hemoglobin and water dropped 56 and 67%, respectively. Lipid content nearly returned to baseline (T/N =0.9) while S(t)O(2) exceeded pretreatment levels (T/N =1.5). Approximately half of the hemoglobin and water changes occurred within 5 days of treatment (26 and 37%, respectively). These data suggest that noninvasive, quantitative optical methods that characterize tumor physiology may be useful in assessing and optimizing individual response to neoadjuvant chemotherapy.

Near infrared (NIR) diffuse optical spectroscopy and imaging may enhance existing technologies for breast cancer screening, diagnosis, and treatment. NIR spectroscopy yields quantitative functional information that cannot be obtained with other non-invasive radiological techniques. In this study we focused upon the origins of this contrast in healthy breast, especially from water and lipids. Non-invasive NIR measurements were performed on the breasts of 30 healthy women using a seven-wavelength frequency-domain photon migration probe. Subjects included pre- and post-menopausal women between the ages of 18 and 64. A diffusive model of light transport quantified oxygenated and deoxygenated hemoglobin, water, and lipid by their absorption signatures. Changes in the measured light-scattering spectra were quantified by a "scatter power" parameter. Substantial quantitative differences were observed in both absorption and scattering spectra of breast as a function of age. These physiological changes were consistent with long-term hormone-dependent transformations that occur in breast. Immanent response was not adversely affected by subject age or menopausal status. The impact of neglecting water and lipids upon optical measurements in the breast is to artificially ascribe extra absorption. The effect can be significant, causing 20-30% errors in hemoglobin concentration and 5% in hemoglobin saturation. These errors cold dull the inherent contrast between normal and tumor tissue and thus affect optical mammography.

A technique for measuring broadband near-infrared absoprtion spectra of turbid media is presented using a combination of frequency-domain (FD) and steady-state (SS) reflectance methods. Most of the wavelength coverage is provided by a white-light SS measurement, while the FD data are acquired at a few selected wavelengths. Coefficients of absorption (μa) and reduced scattering (μs') derived from the FD data are used to intensity-calibrate the SS measurements and to estimate μs'at all wavelengths in the spectral window of interest. After these steps are performed, μa can be determined by comparing the SS reflectance values to the predictions of diffusion theory, wavelength by wavelength. We present an application of this method to breast tumor characterization. A case study of a fibroadenoma is shown, where different absorption spectra were found between the normal and the tumor sides.

Local and superficial optical property characterization of biological tissues can be performed by measuring spatially-resolved diffuse reflectance at small source-detector separations. Monte Carlo simulations and experiments were performed to assess the performance of a spatially-resolved reflectance probe, employing multiple detector fibers (0.3 to 1.4 mm from the source). Under these conditions, the inverse problem, i.e. calculating the absorption and reduced scattering coefficients, is necessarily sensitive to the phase function. This effect must be taken into account by considering a new parameter of the phase function, which depends on the first and second moments of the phase function. Probe performance is compared to another technique for quantitatively measuring optical coefficients, based on the analysis of photon density waves (Frequency Domain Photon Migration). The two techniques are found to be in reasonable agreement. However, the spatially resolved probe shows optimum measurement sensitivity in the volume immediately beneath the probe, while FDPM typically samples much larger regions of tissues. Measurements on human brain in vivo are reported using both methods.