A New Laser-based Diagnostic to Detect Malignant Breast Cancer Tumors

It has been some time since I last addressed a medical laser application not connected with ophthalmology on this site. As many of you who visit this Journal regularly know, the vast majority of my consulting time was spent in ophthalmology, including applications involving ophthalmic lasers. I did, however, do a considerable amount of consulting work (and writing) about medical and surgical lasers.

So, when I read this story about a new hand-held device for detecting breast cancers using laser diagnostics, I decided to look further into the invention, and discovered that it is was an important story that should be brought to your attention.

The original story appeared on the University of California-Irvine (UCI) website, and the version I read appeared in the Spring 2010 issue of the Beckman Laser Institute Newsletter (BLI), LASER I have incorporated portions of both writeups in my version below, along with a synopsis of the journal article, based on this technology, that appeared in the January 2010 issue of Radiology, all presented with the permission of the Director of the BLI, Dr. Bruce Tromberg and Tom Vasich of UCI.

Using Lasers to Improve Cancer Care

In 2003, UC-Irvine Beckman Laser Institute (BLI) researchers received a $7 million grant from the National Cancer Institute (NCI) to standardize the use of a laser imaging device they had created for better breast cancer detection and treatment. This effort is beginning to bear positive results.

In January 2010, the researchers reported in the journal Radiology (Radiology 254: 277-284, 2010) that this hand-held laser breast scanner (LBS) can accurately distinguish between malignant and benign tumors, potentially providing an easy-to-use, non-invasive technique to see whether breast tumors warrant further aggressive treatment. The study involved 60 subjects and will be replicated with a larger test group.

The team’s approach is based on a sophisticated new analysis method developed by UCI Biomedical Engineering Professor Enrico Gratton and M.D./Ph.D. student Shwayta Kukreti, that produces a spectral “fingerprint” or signature for each patient. Their technique was developed specifically for the hand-held laser breast scanner (LBS) developed by Beckman Laser Institute (BLI) Director and grant Principal Investigator, Professor Bruce Tromberg, and BLI Professor Albert Cerussi.

Bruce Tromberg (right), director of the Beckman Laser Institute, and UCI oncologists John Butler, David Hsiang and Rita Mehta (from left) are evaluating a breast imaging device that produces metabolic "fingerprints."

The scanner works by measuring metabolism in breast tumors and normal breast tissue. Unlike mammography, the LBS provides detailed functional information by measuring hemoglobin, fat and water content, as well as tumor oxygen consumption and tissue density. In the study, the researchers found that potentially dangerous malignant tumors have a different metabolic fingerprint compared to benign tumors.

“The LBS spectral signature method has the potential to help improve detection and diagnosis in women with dense breast tissue who don’t do well with mammography,” according to co-author and UCI surgical oncologist Dr. David Hsiang.

“Unlike with other technologies, the laser breast scanner provides a metabolic fingerprint of tumors without the use of added contrast agents,” says Tromberg, who worked with a multidisciplinary team of biomedical engineers and oncologists on this effort. “This can help make diagnosis more exact and treatment more focused.”

Younger women typically have dense breast tissue, and since breast cancer in that demographic is often more deadly, early detection is critical.

In a second area, the UCI laser breast scanner is being used to evaluate the effectiveness of chemotherapy treatments. The scanner is proving beneficial for providing detailed information on changes in breast tumor metabolism during chemotherapy. This information, which can be accessed quickly at the bedside, allows oncologists to target chemotherapy treatments more effectively and safely, tailoring them to how the patient responds.

“The use of chemotherapy for tumor reduction prior to surgery is an important approach for certain types of breast cancer,” says surgical oncologist Dr. John Butler, who works with medical oncologist Dr. Rita Mehta and the BLI team. “The metabolic fingerprint the laser breast scanner provides gives detailed clues on how the chemotherapy is working and allows doctors to adjust treatments as needed.”

Currently, the BLI/UCI researchers are also working with colleagues at the University of Pennsylvania, Dartmouth College, UC San Francisco and Massachusetts General Hospital in Boston to start a five-center clinical study, coordinated by the NCI and the American College of Radiology Imaging Networks (ACRIN), for monitoring and predicting the effectiveness of chemotherapy treatments in breast cancer patients. In addition, the San Francisco Bay Area biotechnology company FirstScan has licensed the technology for commercial applications.

“This is an important opportunity to standardize our approach and determine, in a national multi-center trial, how this new technology can help improve the treatment and quality of life for breast cancer patients,” Tromberg added.

Characterization of Metabolic Differences between Benign and Malignant Tumors: High-Spectral-Resolution Diffuse Optical Spectroscopy

To provide further insight, the following information was taken from the article describing the new technology, published in the January 2010 issue of Radiology.

Program Objective/Purpose: The objective of the study was to develop a near-infrared spectroscopic method to identify breast cancer biomarkers and to retrospectively determine if benign and malignant breast lesions could be distinguished by using this method.

Through the application of a spectral analysis method that accounts for interpatient variability, it was discovered that metabolic differences occur between malignant and normal tissues that result from subtle changes in molecular disposition. The purpose was to demonstrate how absorption signatures, likely resulting from changes in lipid, hemoglobin, and water metabolism, rather than the abundance of molecules, help distinguish between benign and malignant breast tumors.

Materials and Methods: By using self-referencing differential spectroscopy (SRDS) analysis, the existence of specific spectroscopic signatures of breast lesions on images acquired by using diffuse optical spectroscopy imaging in the wavelength range (650–1000 nm) was established. The SRDS method was tested in 60 subjects (mean age, 38 years; age range, 22–74 years). There were 17 patients with benign breast tumors and 22 patients with malignant breast tumors. There were 21 control subjects .

Patients Studied: From a search of patient records dating from August 2004 to January 2007, DOS imaging data for 60 subjects were selected; there were 22 malignant tumors, 18 benign tumors (17 patients), and 21 control subjects. Selection criteria from the protocol were as follows: female, older than 21 years, not pregnant, not taking light sensitive medications, and had given written informed consent. In addition, for patients with lesions, the subject must have had a suspicious finding on a mammogram or sonogram prior to enrollment in the study. All subjects had palpable lesions. Patients were generally referrals from a physician.

Tumor disease was confirmed by using standard of care biopsy results, and control subjects had normal mammographic findings. All subjects were women (age range, 22–74 years). Within each group, mean age and range were as follows: malignant group (mean age, 39 years; range, 32–65 years), benign group (mean age, 33 years; range, 22–57 years), and normal group (mean age, 42; range, 22–74 years).

Instrumentation: The diffuse optical spectroscopy (DOS) instrument used a combined frequency-domain and continuous-wave tissue. The combined system was necessary to provide absorption and scattering spectra from 650 to 1000 nm (approximately 1000 wavelengths with 8-nm spectral resolution). The frequency-domain light sources are six independent laser diodes (660, 690, 780, 808, 830, and 850 nm), while the continuous-wave light source is a tungsten-halogen lamp. Frequency-modulated light was detected by using an avalanche photodiode detector, and continuous-wave light was detected by using a back-illuminated spectrometer.

The handheld probe, (as shown in use in Fig 1), incorporated source (i.e, optical fibers) and detector (i.e, avalanche photodiode detector and a spectrometer detector fiber) channels. Less than 20 mW of optical power was launched into the tissue at any time by using reflection geometry (28-mm source detector separation). Frequency domain measurements were calibrated with a tissue-simulating phantom with known absorption and scattering properties. Spectral response was calibrated by using a commercial reflectance standard (Spectralon, Labsphere, North Sutton, NH).

Figure 1. Photo of Device in Use

DOS imaging measurements were acquired by moving the handheld probe over the tumor in lines of discrete measurement points spaced 10 mm apart ( Fig 1 ). Tumor locations were known a priori from mammographic findings, ultrasonographic (US) findings, and/or palpation. Patients were measured in the supine position. Probe contact was similar to that as used with ultrasonography, by using gentle contact on the breast without compression. Full broadband absorption and reduced scattering spectra were measured at each spatial location, requiring less than 10 seconds per spatial location. Similar measurements were taken on the mirrored location of the contra lateral breast.

Results: Figure 2 shows the specific tumor components (STC) spectra acquired from 22 malignant breast tumors and the spatially equivalent normal tissue from the same patients, as well as normal regions from 21 control subjects. Despite the wide range in patient age and tumor size, the STC spectrum was present in all 22 tumors and was not found in the normal tissues of any subjects in this study. STC spectra were found in all malignant cases and displayed notable features in the following five wavelength regions: 650– 665, 730–800, 875–930, 930–960, and 980–1000 nm. We noted that the specific choice of normal region had little effect on the overall shape of the STC spectrum. The STC spectral shapes were similar to the original, and the tumors were classified as benign or malignant.

Figure 2. Spectra of Cancerous vs. Normal Tissue

In Figure 3, a comparison of STC spectra that have been normalized to the amplitude (thereby providing a ratio) to retrieve the differences in spectral shape, as opposed to magnitude, from both benign (fibroadenoma) (n = 18) and malignant (n = 22) tumors. Distinctive spectral differences exist between the STC spectra of these populations.

Figure 3. Spectra of Cancerous vs. Benign Tumors

As noted in the results, three of the 40 tumors analyzed were misclassified. One benign tumor was misclassified as cancer, and two cancers were misclassified as benign, showing that more work on this method is needed.

Conclusions: On the basis of the wavelength dependence of the STC spectrum, it was hypothesized that the signature is due to changes in lipid metabolism. Recent studies have shown that cancers can alter the lipid metabolism. Benign lesions such as fibroadenomas display hemodynamic signatures similar to those of malignant lesions.

There were limitations to the study. Fibroadenomas were the only type of benign tumors measured. Furthermore, the lesions were not corrected for depth.

In conclusion, the SRDS method relies on the presence or absence of a spectral fingerprint that reports on molecular disposition and not molecular abundance. These changes in molecular disposition are on the order of parts per thousand and are possibly due to alterations in the lipid state. The SRDS technique subtracts for the unique metabolism of each individual patient and facilitates comparisons across patient populations. The observed molecular dispositions were converted into a simple index that stratified benign and malignant tumors in a population of 40 subjects with lesions. The observation of pathologic state-specific spectral signatures provided a potentially significant method for differential diagnosis and monitoring response to therapy.

Editors Note: For some perspective, I asked a noted breast cancer oncologist from the Dana Farber Cancer Institute in Boston for his thoughts on the technology and the paper in Radiology.

Basically, he said that “The technology will have to improve, since missing 2 out of 22 tumors is simply not good enough. That said, it is an interesting technology and has the ability to push the field forward. Since the researchers are evaluating whether a breast abnormality is benign or malignant, the technology can probably be evaluated in several hundred patients. If it is a useful test in that setting, there is potential to launch a large screening study, though such a study would have to be several orders of magnitude larger.”

Next Steps:

The 60 patient study reported in the Radiology article was completed in 2008. Currently, the BLI/UCI teams are working with colleagues at four other institutions, to undertake a five-center clinical study, being coordinated by the National Cancer Institute and the American College of Radiology Imaging Networks (ACRIN), for monitoring and predicting the effectiveness of chemotherapy treatments in breast cancer patients.

The four other institutions are: the University of Pennsylvania, Dartmouth College, UC-San Francisco, and the Massachusetts General Hospital in Boston.

I asked Bruce Tromberg about the follow-on study and learned that the ACRIN 6691 is a protocol recently approved by the NCI to assess how well the Diffuse Optical Spectroscopic Imaging (DOSI) technology works in monitoring and predicting patient response to pre-surgical neoadjuvant chemotherapy. BLI, which has published extensively on this topic, has been working on the protocol for about 3 years, and the NCI committee, CTEP, has just approved it as a national protocol for the five sites. DOSI instruments have been located at all sites and the teams hope to officially kick off the study this fall. It should take about 2-3 years to complete. The clinical endpoint is pathological complete response (pCR), and the teams will be looking at how its tissue optical index (TOI) correlates with and predicts pCR.

He also said, “Outside of neoadjuvant chemotherapy monitoring, our near term goal with this technology, in terms of detection/diagnosis, is to focus on younger and mammographically dense subjects. This population has no good alternatives, with sensitivity/specificity ranging from ~50% to "unable to determine"...so the standard of care "bar" we need to beat is quite a bit lower.”

In addition, a Bay area company called FirstScan has licensed the technology for commercial applications. In checking their website, I discovered it had not been updated since 2005 – so I asked the Dr. Tromberg how this company is involved and what are they doing with the technology?

His response: “FirstScan has licensed our technology, broadband DOS, from UCI, for breast cancer applications. This technology allows us to get full absorption and scattering spectra from thick tissues. They are developing a handheld breast scanner using optical imaging. They are a spinoff of Spectros which makes tissue oximeters.”

Further, as stated in the Radiology article, several of the authors hold patents related to the technology, are board members, and have licensed these patents to a company called Volighten, about which I could find very little information. I asked Dr. Tromberg how Volighten is involved and what were they were doing with the technology?

Again, he was kind enough to provide the answer. “This company has licensed the broadband DOS for applications, other than breast cancer. It was started by one of my former postdocs. Their goal is to develop portable prototypes and components for DOS, such as the scanning handpiece. It is a very early-stage company. I am one of the co-founders with less than a 5% interest.”