BBI Contributing Editor
CHICAGO, Illinois Cancer is the second-leading cause of death in the U.S., and is a growing health problem not only in the developed regions of the world but also in many developing countries due to aging of the population, environmental factors, and continued high rates of smoking in many countries. As shown in Table 1, the estimated number of new cases of cancer exceeds 10 million per year worldwide, while prevalence is approaching 22.5 million (Table 1). While a cure has proven elusive for most cancer types, considerable progress continues in developing technologies that provide incremental improvements in length of survival and quality of life for patients with cancer, and in early detection. A number of new advances in cancer diagnosis and treatment were discussed at the annual meeting of the American Society of Clinical Oncology (ASCO, Alexandria, Virginia), held here in early June.
Chemotherapy remains an integral part of the treatment of most cancer patients, as a first-line treatment for some cancer types (e.g., hematologic cancers) and as an adjuvant therapy following surgical resection. While there have not been significant advances in conventional chemotherapy agents recently, there has been progress in the development of agents that can improve a patient's ability to tolerate the side effects of chemotherapy, including drugs to boost cell counts as well as anti-emetic drugs. More importantly, a number of targeted drugs have been introduced or are in late stages of development that exhibit improved efficacy with significantly reduced side effects, including Herceptin, from Genentech (South San Francisco, California), for an aggressive form of breast cancer; Rituxan, another Genentech agent used in the treatment of non-Hodgkin's lymphoma; and Gleevec, a compound developed by Novartis (Basel, Switzerland), used in the treatment of both chronic myeloid leukemia and gastrointestinal stromal tumors. Such drugs rely on the presence of specific molecular targets that play a key role in the proliferation of a cancer and that can thus be inhibited to shut down the specific pathway underlying tumor growth. In the case of Herceptin, for example, the target is the her-2/neu oncogene, which is amplified in about one-fourth of breast cancers. Patients whose tumors test positive for her2 oncogene amplification are candidates for Herceptin treatment and typically exhibit a significant positive response while experiencing a much lower level of adverse side effects as compared to chemotherapy. A new approach to targeted therapy involves genetic profiling, using microarrays or other molecular diagnostic techniques, to determine the drugs that will be the most effective in an individual patient. Molecular testing also can be used to identify patients who are likely to have a serious adverse response to a particular drug, helping to avoid a potentially life-threatening event and allowing use of an alternative therapy and preserving the patient's ability to undergo treatment. Progress also is being made in the development of cancer vaccines, which activate a patient's own immune system to specifically target and eradicate cancer cells.
New developments in cancer screening and prevention already have provided important reductions in mortality, and a number of new technologies are under development that may further improve the ability to detect more cancers at an early stage when they are most curable. At the ASCO meeting, an important new study described the ability of magnetic resonance imaging to improve the detection of breast cancer in high-risk women, addressing the second-largest cancer type worldwide next to lung cancer, with an incidence of more than 1 million new cases annually. Another in vivo testing modality, LIFE bronchoscopy, is proving increasingly useful in screening for lung cancer, a cancer type responsible for more than 1.2 million new cases annually worldwide. Other new developments described at the meeting that are expected to have a positive impact on cancer diagnosis and therapy include combined PET/CT imaging, advanced approaches in radiotherapy and new, less-invasive surgical techniques for cancer.
Targeted therapy's growing impact
The era of targeted cancer therapy began in earnest about five years ago with the approval of Herceptin, a drug with reported sales of $385 million worldwide in 2002, up 11% vs. 2001. Rituxan, another target-specific, monoclonal antibody-based drug, was introduced about a year earlier than Herceptin and had reported sales of $1.163 billion in 2002, an increase of 42%, primarily because of increased use for B-cell non-Hodgkin's lymphoma. Now, pharmaceutical companies are investigating drugs aimed at a wide range of other molecular targets, including epidermal growth factor receptor (EGFR); PKC 412, a growth regulator of acute myelogenous leukemia; CD20 and CD22 in non-Hodgkin's lymphoma; vascular endothelial growth factor (VEGF); and 2C4 in solid tumors.
EGFR is a particularly popular target. Development-stage drugs targeting EGFR include ABX-EGF, a monoclonal antibody agent from Amgen (Thousand Oaks, California) and Abgenix (Fremont, California); Tarceva (erlotinib) from Genentech and OSI Pharmaceuticals (Melville, New York); and Erbitux (cetuximab) from ImClone Systems and Bristol-Myers Squibb (both New York). Applications of EGFR inhibitors are being explored in the treatment of colorectal cancer, non-small-cell lung cancer (NSCLC), colorectal cancer, and head and neck cancer. In principle, the use of agents that target specific molecular entities such as EGFR, VEGF or cell surface markers such as CD20 is guided by diagnostic tests to verify that the target is present in a patient's tumor. So far, the only agent that has a requirement for testing and target verification prior to prescribing its use is Herceptin. However, many oncologists discussing future cancer treatments at the ASCO sessions believe that treatment will become increasingly personalized, using new testing modalities to characterize the genetic makeup of the tumor as well as of the patient to allow selection of the most effective drug having the fewest adverse effects.
A number of companies are actively developing profiling technologies such as DNA microarrays to help guide targeted therapy, as shown in Table 2 below. One example is a microarray developed by Millennium Pharmaceuticals (Cambridge, Massachusetts) for genomic profiling to identify breast cancer patients who are likely to respond to particular chemotherapy regimens. The microarray test does not identify a specific therapeutic target but instead allows classification of patients into responders and non-responders, based on their individual expression profile for the 75 genes selected by Millennium. In an initial study described by Lajos Pusztai, MD, PhD, of M.D. Anderson Cancer Center (Houston, Texas) involving 21 patients, four of whom had a pattern predicting responsiveness, three or 75% of the four candidate patients experienced complete tumor shrinkage after receiving chemotherapy, compared to a typical response rate of 25% to 30% in the general population. One advantage of using a microarray is that, in addition to providing gene profile data, other commonly required tests, such as estrogen receptor, progesterone receptor and her-2/neu, can be performed simultaneously on the same chip, improving efficiency and lowering the cost of testing. Another important finding of Pusztai's study was that results generated with the Millennium microarray showed excellent agreement with results obtained using the Affymetrix (Santa Clara, California) microarray platform. That finding indicates that microarray technology is able to provide consistent and reproducible results, as will be required for clinical use.
Another example, described at the ASCO meeting by Sarada Gurubhagavatula, MD, of Massachusetts General Hospital (Boston, Massachusetts), involves the use of PCR-RFLP genotype analysis of patient blood samples to detect variations in DNA repair pathways that allow prediction of survival in non-small cell lung cancer. A study involving 103 patients with late stage (Stage III or IV) NSCLC treated with cisplatin or carboplatin found that variations in the XPD and XRCC1 genes were associated with shortened survival. There was a direct correlation between survival time and the number of variant alleles, ranging from 6.8 months for those with three variations to 20.4 months for those with no variations. A high number of variations is believed to result in a reduced ability to repair DNA defects, leading to a more aggressive tumor type with a higher propensity for metastasis.
Many researchers are using the LightCycler system and PCR analyzer from Roche Diagnostics (Indianapolis, Indiana), the leading supplier of clinical molecular diagnostic systems, in the development of genotyping tests. As described by Richie Soong of the University of Alabama at Birmingham (Birmingham, Alabama) at the ASCO sessions, one application involves testing for sequence variants of the thymidylate synthase (TS) enhancer region as well as protein expression levels via immunohistochemistry in colorectal tumors. Using a 45-minute LightCycler/PCR assay, Soong has demonstrated that variations in the TS gene influence TS levels that may be related to tumor-specific events.
David Sidransky, MD, of Johns Hopkins University (Baltimore, Maryland), described the use of another molecular testing technology now in widespread clinical use, the ligase chain reaction (LCR) technology, to guide cancer therapy. Sidransky has used LCR to perform a real-time test for mutations in the p53 oncogene during surgical resection of head and neck squamous cell cancers, enabling determination of molecular margins. The technique potentially can allow a more sensitive assessment of tumor extent than typical histopathology analysis.
Advances in diagnostic technologies for use in the guidance of cancer therapy are not limited to the molecular testing arena. Cell imaging technologies for improving the analysis of tumor specimens are gaining increased acceptance, although so far most sales are for research use. Chromavision Medical Systems (San Juan Capistrano, California) markets the Automated Cellular Imaging System (ACIS), an automated image analysis system with applications in scoring of colon, breast and prostate tumor specimens using specific markers supplied by the company. The ACIS also can analyze tissue microarrays, which are finding increasing use in drug discovery and preclinical trials to rapidly determine the effect of a drug on various tissues. Chromavision reported 2002 sales of $9.3 million, up almost 90% over 2001. Another key supplier in the market, Applied Imaging (Santa Clara, California), markets the OncoPath series of systems for automated genetic image analysis. A key application is objective scoring of her-2/neu expression in breast tumor tissue sections. The system has the capability to analyze multiple slides stained for different markers, and to then electronically display the images to allow comparison of the expression of multiple markers, such as ER, PR and HER2, in the same region of the tissue. Applied Imaging has installed more han 3,000 systems in over 1,000 laboratories and clinics worldwide and reported 2002 product sales of $16.5 million, up 20% vs. the prior year.
Another cell-based test for cancer therapy guidance that is achieving increased acceptance is the Extreme Drug Resistance (EDR) assay from Oncotech (Tustin, California). The Oncotech assay, which is provided as a testing service to cancer clinicians, is used to identify chemotherapy drugs to which an individual patient's tumor will not respond, thereby avoiding the unnecessary toxicity, time and cost of using an ineffective drug. The EDR assay uses a sample of the patient's tumor derived by disaggregating a biopsy specimen. The cells from the specimen are then cultured in soft agar and exposed to a panel of tumor type-specific chemotherapy agents for five days. A high level of drug exposure is used, ranging from five to 80 times that occurring in vivo. A cell proliferation assay is then performed, and treated cells are compared to untreated controls to determine their resistance characteristics. The test has been reimbursed under the Medicare program since 2000, as well as by private insurers, and about 100,000 cancer patients from more than 1,000 hospitals worldwide have been tested. The EDR assay has greater than 99% accuracy in identifying ineffective agents. In part, the increased acceptance of the assay is due to the development of effective new drugs. Oncotech is developing proteomic and genomic tests to complement the EDR assay, which will allow patient-specific assessment of the efficacy of targeted agents as well as conventional chemotherapy drugs.
New developments in early detection
New technologies for performing cell-based tests also have had a significant impact on cancer screening. Improved screening methods to provide early detection of cancer arguably offer the best means to achieve significant gains in survival, since cancer therapy is typically most effective when applied to early-stage disease. Use of the pap test, for example, to screen for cervical cancer, has been a major success, helping to drive a significant reduction in mortality from the disease in those countries where screening has been widely implemented. A major advance in screening for cervical cancer is the addition of human papilloma virus (HPV) analysis to the test protocol, since it is now known that HPV is the primary cause of virtually all cervical cancer. An FDA-approved HPV test employing nucleic acid probe technology, the Hybrid Capture II test from Digene (Gaithersburg, Maryland), is widely available and is now performed by over 200 major clinical laboratories in the U.S. that collectively represent 45% of the U.S. pap smear testing market. Digene has established a partnership with Cytyc (Boxborough, Massachusetts) to jointly market its Hybrid Capture II test along with Cytyc's ThinPrep Pap test, which provides improved quality for pap smears, allowing more accurate and efficient testing.
Recently, a new alternative emerged when Ventana Medical Systems (Tucson, Arizona) reported the availability of its Inform HPV as an analyte-specific reagent designed for use with samples prepared using the SurePath test pack from TriPath Imaging (Burlington, North Carolina). That will allow labs to perform automated HPV analysis using Ventana's Benchmark automated slide staining system, priced at $95,000 in the U.S., combined with pap analysis using slides prepared using either TriPath's SurePath technology or the Cytyc ThinPrep technology. A recent study published in Modern Pathology reported a sensitivity of 97% for Ventana's Inform HPV vs. 87% for the Digene Hybrid Capture II test, and positive predictive values of 52% vs. 21%, respectively. For the quarter ended March 31, Ventana reported sales of $29.3 million, a 32% increase over 1Q02.
Screening also has been widely implemented, at least in the U.S. and Europe, for prostate cancer, using a combination of the prostate-specific antigen (PSA) test and the digital rectal exam. As shown in Table 3, PSA accounted for more than half of the worldwide market for serum tumor marker products in 2002, and most PSA tests are performed for screening purposes. A new molecular testing technology using PCR techniques to detect hypermethylation of the glutathione-S-transferase gene, described by Johns Hopkins' Sidransky for applications in the diagnosis of head and neck cancers, may also prove useful in addressing the shortcomings of prostate cancer screening with PSA. In a study conducted by Sidransky, a real-time PCR test for DNA methylation of the glutathione S-transferase gene provided a 19% improvement in detection of tissues containing cancer cells, whereas standard pathology analysis or PSA testing failed to detect the positive tissue. The test could prove useful for the 30% to 40% of individuals who have indeterminate PSA levels on their screening test. A prospective study described by Sidransky found that the GSTP test showed a 90% positivity rate for cancer in individuals with indeterminate PSA levels. There is considerable controversy, however, regarding the use of PSA screening, due to the high rate of detection of non-significant disease. According to data presented by Fritz Schroeder, MD, PhD, of Erasmus University (Rotterdam, the Netherlands), 84 of every 100 prostate cancers detected by screening may not result in death by age 85, and it requires 17 radical prostatectomies to prevent one prostate cancer death. Nevertheless, the introduction of PSA screening has resulted in a significant drop in prostate cancer deaths in those countries where it has been widely implemented, whereas in other countries such as Mexico where PSA screening has not been widely adopted, prostate cancer mortality has continued to increase.
A new test for the early detection of colorectal cancer was described at the ASCO conference by Targeted Diagnostics and Therapeutics (TDT; West Chester, Pennsylvania). The GCC-B1 test from TDT uses RT-PCR technology to detect the presence of guanylyl cyclase C, a receptor that is uniquely expressed by intestinal and colorectal cancer cells, but not by extraintestinal tissues or tumors. The test can detect one colorectal cancer cell among as many as 10 million normal blood cells, and only 500 to 5,000 circulating tumor cells in the body are required for detection, according to the company. The test is currently used to detect colorectal cancer recurrence, which occurs in more than 40% of patients. It presently is offered as a reference lab test priced at $495, but the company also is interested in licensing the technology for use in a commercial kit.
An important advance in breast cancer screening was reported at the ASCO meeting by researchers from the University of Bonn (Bonn, Germany). As discussed by Christiane Kuhl, MD, there is a need for improved methods to detect early-stage breast cancers in high-risk women. While the average lifetime risk for breast cancer in the female population is 12%, certain high-risk groups, namely those who are positive for BRCA gene mutations, have a risk of 80% to 90%. Half of BRCA-positive women develop a first breast cancer prior to age 50. Kuhl's team evaluated the use of contrast-enhanced MRI compared to mammography, clinical breast exams and ultrasound exams for early detection in BRCA-positive women, and reported a major improvement in positive predictive value in a five-year study involving 462 women. MRI gave a positive predictive value of 54% and sensitivity of 96.1%, vs. a PPV of 26% and a sensitivity of 42.8% for mammography. In no case did MRI miss a cancer that was detected by mammography or ultrasound. Other researchers performing similar evaluations have also found MRI to be the most sensitive method for early detection of breast cancer in high-risk groups. A study described by Jan Klijn, MD, PhD, of Erasmus Medical Center, reported 71% sensitivity for MRI vs. 36% for mammography, although the specificity of MRI of 88% was lower than for mammography (95%). Other researchers, such as Mark Robson, MD, of Memorial Sloan Kettering Cancer Center (New York), have not found as significant an improvement with MRI, but have been able to detect early-stage cancers in high-risk women that were not detected by a prior mammography. Less than 5% of women are positive for BRCA mutations, thus limiting the target population for MRI screening to a small subset of the total number undergoing routine screening.
The impetus for using MRI on high-risk populations may be intensified, though, because of the possibility, suggested by Kuhl, that high-risk women may be more likely to develop breast cancer as a result of exposure to ionizing radiation from mammography exams. Theoretically, the heightened risk is due to the fact that such women already are highly predisposed to develop breast cancer and have a higher than average risk to develop disease if additional mutations are induced by radiation. Furthermore, because high-risk women are advised to begin undergoing mammography screens earlier in life (as early as age 30), their cumulative radiation exposure is greater. While an increased risk from mammography is only theoretical at this point, and may never be verifiable in a randomized trial, it provides an added incentive for the use of MRI in the BRCA-positive population. MRI already has been shown in numerous other studies to have some advantages over other breast cancer screening techniques for certain populations of women, particularly those with dense breasts and certain types of breast cancer.
Limiters of the use of MRI for breast cancer screening include its high cost (about $1,500 for a scan in the U.S., not including professional fees, vs. $300 to $400 for mammography), the need for specialized equipment to biopsy a lesion visible only via MRI, the requirement for an intravenous injection in the case of contrast-enhanced MRI, and the high level of expertise needed on the part of the radiologist to accurately interpret MR images. The latter factor may explain why the results of the study conducted in Germany showed considerably better predictive value than for centers in the U.S. that are also experimenting with MRI screening, since the German radiologists were part of an expert team with considerable experience in using MRI for breast cancer diagnosis. Key suppliers of MRI systems include GE Medical Systems (Milwaukee, Wisconsin), Philips Medical Systems (Best, the Netherlands), Toshiba Medical (Tokyo) and Siemens Medical Systems (Munich, Germany). The technology for identifying women with BRCA mutations is already in wide use via a reference testing service offered by Myriad Genetics (Salt Lake City, Utah). Myriad is performing about 300 BRCA tests a week at a price for a full test panel of $2,760. The test is covered by private insurers in about 80% of cases.
New, more effective technologies for lung cancer screening are also of significant interest within the oncology community. Lung cancer ranks No. 1 worldwide in incidence, and also has one of the highest mortality rates of any cancer type. Development of accurate screening methods has proven difficult, however, because essentially all smokers exhibit some degree of dysplasia in their lung tissue. Diagnostic techniques employed for lung cancer include positron emission tomography (PET) and X-ray computed tomography (CT) imaging as well as flexible fiberoptic bronchoscopy employing autofluorescence imaging. Autofluorescence bronchoscopy is one of the most powerful screening techniques, and devices are available from a number of suppliers including Xillix Technologies (Richmond, British Columbia). The Xillix LIFE (Light-Induced Fluorescence Endoscopy) system works in conjunction with white light endoscopy to provide a color-enhanced image that depicts lung tumor foci with high sensitivity. Xillix also manufactures the ONCO-Life system. When viewed via autofluorescence, foci of lung carcinoma appear as red areas in the LIFE image. Lesions identified by autofluorescence bronchoscopy can be ablated using endoscopic electrosurgical instruments. As discussed by Adi Gazdar, MD, of the University of Texas Southwestern Medical Center (Dallas, Texas), at the ASCO conference, the number of AFB lesions is correlated with the risk of progression to squamous cell carcinoma of the lung within five years. The technique has been shown to have better sensitivity than white light digital bronchoscopy. However, further improvements are in development, including confocal fiber optic devices with improved (1 micron to 3 micron) resolution. Ideally, physicians want techniques that could allow microscopic histopathological analysis to be performed in vivo, so that the progression of a suspect lesion can be monitored to determine when removal is necessary.
Due to the invasive nature of bronchoscopy, however, there still is demand for non-invasive imaging methods capable of providing early detection of lung cancer. For example, the utilization of PET imaging to diagnose lung and a wide variety of other cancers is expanding rapidly, in spite of its relatively high cost of $1,400 to $3,000 per exam. Studies have demonstrated improved diagnostic accuracy for PET for a variety of cancers including lung cancer, and advances in technology such as the combination of PET and CT imaging available from GE Medical Systems, as well as a reduction in scanning time to 25 minutes vs. 40 to 45 minutes previously, have made the technique more useful.
CTI (Knoxville, Tennessee), the leading manufacturer of PET imaging systems, estimates that about 30% of the PET systems now in use in the U.S. are mobile units, indicating the developing nature of the PET market, similar to the situation with MRI about a decade ago.
Interventional modalities also advance
While new targeted drug therapies for cancer attract the most publicity, there have also been significant advances in other cancer treatment modalities, such as radiotherapy and less-invasive surgical methods. An example is a radiotherapy device from Carl Zeiss Meditec (Oberkochen, Germany) exhibited at the ASCO meeting that promises to significantly improve the convenience of treating breast cancer patients post-surgery. Today, most breast cancer patients routinely receive a six-week course of daily radiotherapy treatments following surgical removal of a tumor in order to eradicate any residual cancer cells that may have been missed during resection. The Zeiss Intrabeam system uses low-energy focused radiation delivered intraoperatively to deliver a single dose that is the equivalent of one week of fractionated radiotherapy. The company is now performing a clinical trial, the TARGIT trial, to determine if the entire six-week treatment course can be replaced with a single dose delivered intraoperatively. The advantages include reduction in irradiation of normal breast tissues as occurs with conventional radiotherapy, lower equipment cost ($400,000) and a considerable improvement in convenience for the patient. The Zeiss Intrabeam system has already been approved for use in treating brain cancers and also has potential applications in the treatment of colorectal, skin and vaginal wall tumors.
Another interventional cancer treatment modality being used in an expanding number of applications is the RITA Wire from RITA Medical Systems (Mountain View, California). The RITA Radio Frequency Ablation system was approved by the FDA late last year for relieving the pain associated with metastatic bone disease, with about 95% of patients who previously failed conventional pain relief therapy reporting a significant reduction in pain. The technique also is used for the local control of metastatic liver tumors in patients whose cancer cannot be completely resected. The company is now performing research in the use of the RITA technology for the treatment of breast, lung, prostate and kidney cancer.