Is Preventive Molecular Imaging Possible for Cancer?
Molecular imaging has advanced in leaps and bounds in recent years and clinicians can now offer patients truly personalized medicine by using cancer biomarkers for precise surgical mapping and experimental therapy monitoring. The most advanced cancer biomarker research may very well be moving beyond the realm of diagnostic imaging, surgical planning and monitoring of drug therapies to include a whole new arena of predictive medicine. This development is being ushered in thanks to greater understanding of tumor biology and therapeutic and diagnostic targets.
In-depth tumor characterization and the ability to image biological processes such as angiogenesis, hypermetabolism and the expression of growth factors in certain tumors can be imaged with advanced molecular imaging systems and used to predict the potential effectiveness of a range of anti-cancer therapies. The next natural step is to examine whether cancer biomarkers have not just predictive, but preventive, potential. Can biomarker evidence provide a means of very early cancer prevention? We asked experts in radiology, molecular imaging and pathology to weigh in on the discussion. The collective prognosis was that preventive molecular imaging is well on its way in other imaging disciplines, but it is still an ambitious concept and not quite yet on the horizon for cancer imaging. However, the limitations are based on current research, which could change in the near to distant future depending on how fast scientists' understanding of cancer biology continues to grow.
Molecular imaging biomarkers are already being used to determine progression of disease. Their ability to offer clinicians important information about the likelihood of metastases and how aggressive treatment should be is now being expanded to offer predictive information about potential therapy response and survival during the planning stage of the patient care cycle. Cancer biomarkers can give clinicians insight about patients' potential resistance to therapies and help determine which therapies would be most effective by revealing the presence or absence of tumor characteristics and genetic factors, but is there a turning point where predictive biomarker evidence can be applied for cancer prevention?
"Although several monoclonal antibodies are being used for therapy, some in combination with other [chemo]therapies, in mostly hematological malignancies, their use in molecular imaging for detection of cancer is in its infancy," says Aram van Brussel, MD, a researcher for the department of pathology at Utrecht University Medical Center in The Netherlands. "Preventing cancer with molecular imaging would imply detection of benign lesions or precursor lesions, like ductal carcinoma in situ (DCIS) in breast cancer. Tracers targeting the proteins HER2, EGFR, CAIX, VEGF to detect DCIS are under development, although no tracers exist that are specific for the pre-invasive stage only."
The major hurdle for researchers is that there simply haven't been enough molecular imaging studies to drive predictive molecular imaging all the way into the fast lane, let alone imaging studies that explore biomarkers for precursors in precancerous growths. Scientists just aren't versed enough in this emerging field to be able to develop the right biomarkers for those as yet unknown cancer precursors.
"In the places where molecular imaging and biomarker imaging have been applied, I actually think you see the areas where the latest and greatest research might actually have some preventive application is in cardiovascular disease and some of the neurologic diseases, but I struggle with the idea for cancer prevention," says David A. Mankoff, MD, PhD, a professor of radiology, medicine, and bioengineering at the University of Washington in Seattle.
The real promise of preventive molecular imaging is currently cropping up in the detection of vascular inflammation and the use of biomarkers for the very early detection and prevention of atherosclerotic disease and amyloid deposition imaging for Alzheimer's disease. These are highlighted because the underlying disease processes are already known and developing in the patient prior to the point of clinical significance and diagnosis. (The ability to diagnose Alzheimer's via PET/CT imaging with the help of a unique biomarker could hit the U.S. market this year.) What it takes for preventive molecular imaging of cancer to really take off is the ability to catch precancerous processes early enough to prevent them before they become clinically overt. How do you catch cancer-progressing abnormalities soon enough? Researchers don't quite know how to do this yet.
"I think it is possible that there could be some applications of molecular imaging for breast cancer detection," says Mankoff. "They are just starting these studies, but none of them have really hit the mainstream yet in the cancer world."
Steven M. Larson, MD, is a nuclear medicine specialist at Memorial Sloan-Kettering Cancer Center in New York City. He agrees that preventive molecular imaging has made strides in cardiovascular imaging and in the case of amyloid neuroimaging, but there needs to be a lot more in the way of predictive studies before researchers can really focus on prevention.
"Biomarkers have been a part of medicine for a very long time," says Larson. "Recently there have been some examples of studies using PET imaging for the monitoring of treatment response and obviously there are suggestions that this would be good, but these have been based on small studies. What you really need to do first is have significantly larger studies. One of the things that has greatly raised the bar for biomarkers is that the FDA has now made a formal proposal for the guidance documents on how to work up a biomarker and they are saying that you must first do studies that show there is reasonable reproducibility. You have to then qualify it with multi-center clinical trials, which should up the ante for biomarker studies."
Whether cancer biomarkers will move into preventive medicine really depends on the success of continued research. The more scientists learn about how drugs target tumor processes, the more they will know how these processes develop in earlier stages. Larson says some of the most advanced research in predictive molecular imaging involves monitoring androgen receptor expression and genetic testing to understand a given tumor's potential response to therapy.
"Recently, there have been some reports of tyrosine kinase inhibitors binding to mutant signal transduction molecules in patients with lung cancer," says Larson. "There will be more examples like this as time goes by."
There also are technological limitations. Preventive cancer imaging would be dependent on the continued advancement of scanning technology. "In theory, lesions smaller than one millimeter could be detected, but in daily practice, the threshold is rather 0.5-1 cm for the best radiotracers," says van Brussels.
Still, there appears to be some hope that this will be the eventual direction of biomarker research. "Molecular imaging could increase the detection of cancer at an earlier time point, before metastases form, which would most likely increase the chances of curative radical excision, and consequently of tumor specific survival," he says. "When probes now in development and in clinical trials are shown to accumulate specifically in tumors, these have then to be validated as tools for screening or preventive set-up. For such studies, the selection of patients can be a limiting factor."
Only time will tell just how far cancer biomarkers can go. It could take several more years of hard-earned imaging research yet before clinicians can switch their focus from cancer cure to cancer prevention.
In-depth tumor characterization and the ability to image biological processes such as angiogenesis, hypermetabolism and the expression of growth factors in certain tumors can be imaged with advanced molecular imaging systems and used to predict the potential effectiveness of a range of anti-cancer therapies. The next natural step is to examine whether cancer biomarkers have not just predictive, but preventive, potential. Can biomarker evidence provide a means of very early cancer prevention? We asked experts in radiology, molecular imaging and pathology to weigh in on the discussion. The collective prognosis was that preventive molecular imaging is well on its way in other imaging disciplines, but it is still an ambitious concept and not quite yet on the horizon for cancer imaging. However, the limitations are based on current research, which could change in the near to distant future depending on how fast scientists' understanding of cancer biology continues to grow.
Molecular imaging biomarkers are already being used to determine progression of disease. Their ability to offer clinicians important information about the likelihood of metastases and how aggressive treatment should be is now being expanded to offer predictive information about potential therapy response and survival during the planning stage of the patient care cycle. Cancer biomarkers can give clinicians insight about patients' potential resistance to therapies and help determine which therapies would be most effective by revealing the presence or absence of tumor characteristics and genetic factors, but is there a turning point where predictive biomarker evidence can be applied for cancer prevention?
"Although several monoclonal antibodies are being used for therapy, some in combination with other [chemo]therapies, in mostly hematological malignancies, their use in molecular imaging for detection of cancer is in its infancy," says Aram van Brussel, MD, a researcher for the department of pathology at Utrecht University Medical Center in The Netherlands. "Preventing cancer with molecular imaging would imply detection of benign lesions or precursor lesions, like ductal carcinoma in situ (DCIS) in breast cancer. Tracers targeting the proteins HER2, EGFR, CAIX, VEGF to detect DCIS are under development, although no tracers exist that are specific for the pre-invasive stage only."
The major hurdle for researchers is that there simply haven't been enough molecular imaging studies to drive predictive molecular imaging all the way into the fast lane, let alone imaging studies that explore biomarkers for precursors in precancerous growths. Scientists just aren't versed enough in this emerging field to be able to develop the right biomarkers for those as yet unknown cancer precursors.
"In the places where molecular imaging and biomarker imaging have been applied, I actually think you see the areas where the latest and greatest research might actually have some preventive application is in cardiovascular disease and some of the neurologic diseases, but I struggle with the idea for cancer prevention," says David A. Mankoff, MD, PhD, a professor of radiology, medicine, and bioengineering at the University of Washington in Seattle.
The real promise of preventive molecular imaging is currently cropping up in the detection of vascular inflammation and the use of biomarkers for the very early detection and prevention of atherosclerotic disease and amyloid deposition imaging for Alzheimer's disease. These are highlighted because the underlying disease processes are already known and developing in the patient prior to the point of clinical significance and diagnosis. (The ability to diagnose Alzheimer's via PET/CT imaging with the help of a unique biomarker could hit the U.S. market this year.) What it takes for preventive molecular imaging of cancer to really take off is the ability to catch precancerous processes early enough to prevent them before they become clinically overt. How do you catch cancer-progressing abnormalities soon enough? Researchers don't quite know how to do this yet.
"I think it is possible that there could be some applications of molecular imaging for breast cancer detection," says Mankoff. "They are just starting these studies, but none of them have really hit the mainstream yet in the cancer world."
Steven M. Larson, MD, is a nuclear medicine specialist at Memorial Sloan-Kettering Cancer Center in New York City. He agrees that preventive molecular imaging has made strides in cardiovascular imaging and in the case of amyloid neuroimaging, but there needs to be a lot more in the way of predictive studies before researchers can really focus on prevention.
"Biomarkers have been a part of medicine for a very long time," says Larson. "Recently there have been some examples of studies using PET imaging for the monitoring of treatment response and obviously there are suggestions that this would be good, but these have been based on small studies. What you really need to do first is have significantly larger studies. One of the things that has greatly raised the bar for biomarkers is that the FDA has now made a formal proposal for the guidance documents on how to work up a biomarker and they are saying that you must first do studies that show there is reasonable reproducibility. You have to then qualify it with multi-center clinical trials, which should up the ante for biomarker studies."
Whether cancer biomarkers will move into preventive medicine really depends on the success of continued research. The more scientists learn about how drugs target tumor processes, the more they will know how these processes develop in earlier stages. Larson says some of the most advanced research in predictive molecular imaging involves monitoring androgen receptor expression and genetic testing to understand a given tumor's potential response to therapy.
"Recently, there have been some reports of tyrosine kinase inhibitors binding to mutant signal transduction molecules in patients with lung cancer," says Larson. "There will be more examples like this as time goes by."
There also are technological limitations. Preventive cancer imaging would be dependent on the continued advancement of scanning technology. "In theory, lesions smaller than one millimeter could be detected, but in daily practice, the threshold is rather 0.5-1 cm for the best radiotracers," says van Brussels.
Still, there appears to be some hope that this will be the eventual direction of biomarker research. "Molecular imaging could increase the detection of cancer at an earlier time point, before metastases form, which would most likely increase the chances of curative radical excision, and consequently of tumor specific survival," he says. "When probes now in development and in clinical trials are shown to accumulate specifically in tumors, these have then to be validated as tools for screening or preventive set-up. For such studies, the selection of patients can be a limiting factor."
Only time will tell just how far cancer biomarkers can go. It could take several more years of hard-earned imaging research yet before clinicians can switch their focus from cancer cure to cancer prevention.
| I SPY II Infiltrates & Predicts Breast Cancer Treatment Outcomes Using MRI Biomarkers |
| The Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis is a long-standing cooperation of studies, beginning in 2000, that originally involved 60 to 70 patients with breast cancer scheduled to receive chemotherapy preoperatively. They underwent serial MRI exams throughout their treatment course and before surgery to follow changes in the status of their tumors and to determine how they were responding to therapy. Pilot data for the first set of I SPY studies was revealing and scientists found that they could extract MRI measurements as biomarkers to study the ways tumors behave and then use those data to predict response in patients presenting with similar tumor characteristics. The new I SPY II trial is expected to eventually include about 800 women and is backed by the FDA, the National Institutes of Health and pharmaceutical companies involved with the Foundation for the National Institutes of Health. Nola Hylton, PhD, director of the breast MRI program at University of California San Francisco and one of the front-running scientists for I SPY, says it is all about improving breast cancer treatment effectiveness and overall outcomes by building upon a body of MRI biomarker evidence to make increasingly better predictions about breast cancer patients and their prospective treatments. If researchers can refine those biomarkers, they may eventually be able to confidently say, for example, that a given patient has a 90 percent chance of failing a particular drug treatment. These predictive determinations go on to affect the rate of randomization and the prospective use of specific treatment arms, but more studies need to be conducted for I SPY data to actually be used to prescribe treatments. “We are at an age where our tools are giving us remarkable information, but we have to get our biomarker information in a uniform, standardized way, which can be really difficult,” says Hylton. “This offers amazing potential to give us biology in a completely noninvasive way, but for us to do this for every patient is still a ways off.” |