News Reports: April 2007

BREAST CANCER SPOTLIGHT

%u25BA New Clues to Herceptin Resistance

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esearchers at Harvard and Yale Universities discovered markers in breast cancer tumors associated with resistance to Herceptin® (trastuzumab, Genentech). “Herceptin has revolutionized the care of HER2-positive breast cancer for many patients, but unfortunately, not for some,” noted Lyndsay Harris, MD, the study’s lead author and associate professor and director of the Breast Cancer Disease Unit at Yale University Medical Center. “This research is important in that it has generated a hypothesis of certain markers that are associated with resistance. A second study is required to validate these markers to tell us which ones are truly causative.”

Most importantly, Dr. Harris said, “We were the first to discover that HER2 tumors have a basal subgroup.” The non-responding tumors were observed to be more likely to express genes associated with basal-like breast cancer. This is surprising because most basal-like tumors are HER2-negative, she explained. Such cancers are often more aggressive and have unique features, making them resistant to therapy.

About a quarter of patients newly diagnosed with breast cancer annually have the HER2 class of tumor. Response rates for Herceptin, although hard to accurately determine, seem to be only about 30%, noted Dr. Harris. Along with chemotherapy, however, the response rates double, she added. The Herceptin plus chemotherapy regimen, though, can cause heart damage, according to Dr. Harris. “Hence, one reason we decided to do this study was to find a less toxic regimen than Herceptin and chemotherapy. Another focus was to try and define molecular markers associated with Herceptin resistance.”

Navelbine®(vinorelbine, Glaxo Wellcome), approved for lung cancer, has been shown to be very effective and less toxic in breast cancer than standard chemotherapy. “Thus, we decided to study the Herceptin/Navelbine combination and use that to assess markers for resistance,” she explained.

In the February 15 issue of Clinical Cancer Research, the researchers report that the combination was well tolerated. The non-responsive tumors showed a continued overexpression of HER2. “That tells us that the cancer cells are still creating HER2 surface proteins even as Herceptin is being used, and that means HER2 loss does not appear to be a mechanism of resistance in earlystage breast cancer,” Dr. Harris remarked.

The researchers derived about 50 to 60 markers that were either up-regulated or down-regulated in the Herceptin-resistant tumors, including certain basal markers, growth factors and growth factor receptors. Insulin-growth factor receptor 1 (IGF-1R) was associated with a Herceptin response rate that was half that of tumors that did not express IGF-1R. Similar association of IGF-1R to Herceptin resistance has been reported in three previous studies, noted Dr. Harris. Herceptin-resistant tumors were

also more likely to express a variety of growth factors, suggesting that “activation of parallel pathways may release tumors from dependence on HER2 proliferation and survival.”

If additional studies validate these findings, it may be possible to select those patients that will be resistant to Herceptin and treat them with additional drugs to restore sensitivity. “Our goal is to see what the tumor tells us before any treatment starts and tailor therapy accordingly.”

Dr. Harris plans to conduct a bigger study to compare the Navelbine/Herceptin regimen and standard paclitaxel/carboplatin/ Herceptin regimen for tolerance. She will also test the profile of markers found in the current study in its ability to predict outcome in the second study. Additionally, she plans to study IGF-R1 and inhibitors of IGF-R1.

—Querida Anderson

BREAST CANCER SPOTLIGHT

%u25BA First Genetic-Based Breast Cancer Risk Test Introduced

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fter seven years of research, Oklahoma City, OK-based InterGenetics, a predictive medicine company, has announced the release of the first genetic-based breast cancer risk test in the United States and abroad. The test, OncoVue, combines personal history with genetic information to determine a woman’s future breast cancer risk. Genetic health service provider Opaldia will release OncoVue in the United Kingdom and Ireland, while the test has been released in the US at certain centers under an FDA-approved Investigational Device Exemption study conducted by InterGenetics.

The test is easy to take: women have to first answer a medical history questionnaire, and then they have to swirl a mouthwash and deposit it in a tube. This fluid sample contains DNA from the women’s cheek cells, which is tested at InterGenetics’ laboratories. Based on specimens from 8,000 women with and without breast cancer in five different geographic regions of the US, the company has identified multiple single nucleotide polymorphisms, or SNPs—variations in a single nucleotide between two DNA sequences—that are believed to be associated with breast cancer. Research has shown that the combination of multiple SNPs and personal history play a significant role in a woman’s risk of developing sporadic breast cancer, which affects 90-95% of women.

InterGenetics now has a database of over a million different genotypes along with the personal histories of women with and without the disease. By weighing an individual’s DNA sample and personal history against the database, the OncoVue test produces a report that assesses a woman’s risk for developing breast cancer in three stages of life: pre-menopause, peri-menopause, and postmenopause.

Currently, there aren’t any tests available that effectively identify women most at-risk for developing breast cancer. According to InterGenetics, the OncoVue test can potentially predict the risk of cancer many years before diagnosis, improving the chances of long-term patient survival. Moreover, the test reputedly covers the 80—90% of women who develop breast cancer but have no strong family history of the disease.

— Prachi Patel-Predd

BREAST CANCER SPOTLIGHT

%u25BA Good News More Likely from Industry-Supported Breast Cancer

Clinical

Trials

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n recent years, breast cancer clinical trials supported by the pharmaceutical industry have reported more positive results than non-industry supported research, according to a study published online in the journal Cancer. The study brings up the important question of conflicts of interest and the potential impact of industry funding on the quality of research. Since 1992, the pharmaceutical industry has provided more funds for clinical trials than the National Institutes of Health, the study’s authors

point out.

Jeffrey Peppercorn, an assistant professor of medicine at the University of North Carolina at Chapel Hill, and his colleagues analyzed 140 clinical trials of breast cancer treatments published in 1993, 1998, and 2003 in 10 English-language medical journals. Close to half of the studies had reported some sort of pharmaceutical industry involvement—they either received funding or drugs from a drug company, or at least one of the authors worked for the industry.

The researchers found that drug company involvement went up from 44% in 1993 to 57% a decade later. Of the 32 studies that involved the drug industry in 2003, 84% showed positive results, while only 54% of the other studies were positive. The researchers also found that there was a correlation between industry involvement and a study’s features. About twothirds of industry-supported trials in 2003 used single-arm designs—pilot studies or phase II trials where a drug’s efficacy is not

compared with a control group. Moreover, they found that a significant 72% of industry-associated trials evaluated metastatic disease stages, where new drugs are frequently tested first.

“These are appropriate studies for drug development, but these types of studies may not address many other important clinical questions facing our patients such as how long should we use the drug, how can we best select patients who may benefit, should a drug be continued until progression of disease, or are breaks in therapy OK, and similar questions,” Peppercorn told Oncology & Biotechnology News.

The results of Peppercorn’s work imply that pharmaceutical research may be focused on certain important questions, such as which new agents are safe and effective in metastatic disease. “But as industry becomes the dominant source of funding, we want to make sure that other important questions are addressed,” he said.

According to Peppercorn, there are multiple possible explanations for the association between industry involvement and positive results. The association does not warranty the assumption that drug companies are hiding negative results of breast cancer clinical trials. Instead, it could imply a positive spin in single-arm trials, or biased trial design or presentation of results. It is also possible, Peppercorn says, “that this association could reflect superior choice of experimental therapy to test in human subjects, superior selection of target population, or more conservative choices regarding which drugs to push forward in later phase trials.”

— Prachi Patel-Predd

%u25BA Expert Cancer Centers Cost-Effective for Managing Ovarian Cancer

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xpert medical centers that have extensive experience in managing cancer may have higher overall costs, but their approach is more cost-effective over time than referring patients to less experienced medical centers, according to a study led by researchers at the Johns Hopkins Medical Institutions in Baltimore. The study, published online on March 12 in the journal Cancer, showed that expert centers can provide significantly longer quality of lifeand survival compared to less experienced centers, which means a lower cost for each quality-adjusted lifeyear that patients gain.

The reason behind these results could be a difference with respect to adherence to recommended standards at expert versus less-experienced centers. “Adherence to standards is generally more likely to occur at larger institutions that have a multidisciplinary care team capable of performing the often-complicated surgical procedures and managing the toxicity of chemotherapy,” the study’s lead researcher Robert E. Bristow of the Kelly Gynecologic Oncology Service at Johns Hopkins told Oncology & Biotechnology News. “These results suggest that increased efforts to concentrate the care of ovarian cancer patients within institutions that are in accordance with recommended treatment standards are warranted.”

Bristow and his colleagues compared the treatment efficacy, costs, and cost-effectiveness of referring patients to an expert center versus a less experienced center. They analyzed a hypothetical group of patients with advanced ovarian cancer using decision-analysis modeling. They found that the overall cost of managing the disease at an expert center was about $50,000, compared to about $40,000 at a less experienced center.

At the same time, the quality of life and survival of patients was also significantly better at expert facilities, making them a more cost-effective option for managing ovarian cancer. They measured the cost-effectiveness of the centers in terms of the cost per quality-adjusted lifeyear of managing the disease, which turned out to be $9,893 at expert centers, an amount at least $7,000 less than the cost per quality-adjusted lifeyear at a less experienced center.

“The results indicate that when recommended treatment standards for ovarian cancer care are adhered to—in terms of a proactive surgical approach and utilization of contemporary chemotherapy treatment regimens—there is a great potential for significantly improved clinical outcomes at an economically affordable cost,” Bristow said.

Studies in the past have shown that gynecologic oncologists have better outcomes than other surgeons in managing ovarian cancer patients. Studies have also shown that ovarian cancer patients managed at high-volume, multidisciplinary medical centers fared better than those managed at lowvolume medical centers. Still, said Bristow, less than half of ovarian cancer patients in the US have access to surgery by a gynecologic oncologist.

— Prachi Patel-Predd

%u25BA New Breathalyzer "Smells" Lung Cancer in Early Stages

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esearchers at the Cleveland Clinic in Ohio have developed a compact, disposable device that can detect the signature pattern of chemicals present in the breath of lung cancer patients. In results presented in the online edition of the journal Thorax, they showed that the breath test correctly identified 73% of patients with lung cancer.

According to the Lung Cancer Alliance, more than half of new lung cancer cases will be diagnosed at a very late stage. The new nickel-sized breath analyzer, while not completely accurate, could be a step towards an inexpensive, easy-touse test to detect the early stages of lung cancer.

Researchers have known for at least two decades that the metabolic changes related to lung cancer leads to a unique pattern of volatile organic compounds in a patient’s breath. The device consists of an array of 36 tiny dots, each made of a different chemical-sensing compound, which change colors in response to the chemicals they come in contact with. So a pattern of chemicals in a person’s breath corresponds to a pattern of color changes on the array.

Peter Mazzone and his colleagues at the Cleveland Clinic tested the sensor on 143 people, including 49 lung cancer patients, 73 people with other lung diseases, and 21 healthy controls. The participants breathed into the device for 12 minutes. The researchers used the sensor changes from 70% of the volunteers to develop a prediction model—a color pattern corresponding to the breath of lung cancer patients. Then they tested the accuracy of the sensor system on the remaining 30% of the participants. The researchers emphasize that the study is a “proof of principle” to show that lung cancer could, indeed, be detected by breath analysis. “It is likely to take another 5 to 10 years of research before it can be used clinically,” Mazzone told Oncology & Biotechnology News.

Up until now, canines have been the most accurate at recognizing the lung cancer-related volatile compounds in patients’ breath. In a study released in March 2006 in the journal Integrated Cancer Therapies, dogs that were trained to recognize the breath of lung cancer patients accurately detected the disease between 99% of the time. With more research, the Cleveland Clinic researchers’ work could lead to a simple, disposable sensor that does the same. “We need to learn more about the chemical differences in the breath of lung cancer patients,” Mazzone said. “We can then apply that knowledge to improving current sensors or developing new ones.”

— Prachi Patel-Predd

%u25BA PSA Adjusted for Prostate Size is Possible Identifier of

Men at Risk for Developing Life-Threatening Cancer

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new mathematical method has been discovered to assess which men are at a risk of developing aggressive prostate cancer even after their first biopsy came back clean.

“Studies have shown that biopsies can miss the cancer up to 26% of the time,” stated Mark Garzotto, MD, director of urologic oncology at the Portland Veterans Affairs Medical Center, assistant professor of surgery (urology) in the OHSU School of Medicine, and member of the OHSU Cancer Institute. “Until now, we’ve really had no clear and consistent method to recommend further follow-up or diagnostic procedures for men who have a negative biopsy. We have derived a simple

marker so urologists can identify who is at risk for high-grade prostate cancer.”

Dr. Garzotto followed 511 men at the Portland Veterans Affairs Medical Center from 1992 to 2006. All had been referred to urology clinics for suspicion of prostate cancer in spite of one prior negative biopsy. The study included 1,319 biopsies, and the average follow-up time was four years. He observed that 10% of the participants were found to have high-grade cancer in the repeat biopsy.

“We found a high prostate-specific antigen (PSA) adjusted for prostate size was the best way to determine risk for developing high-grade cancer,” Dr. Garzotto said. “Using this PSA conversion, doctors can tell a patient that they won’t develop life-threatening prostate cancer with 96% assurance.”

PSA was particularly adjusted for volume and size, or density, called PSAD. Higher PSA relative to size of prostate increased risk. However, higher PSA along with larger prostate size lowered the risk. Dr. Garzotto concluded that a person with a higher PSAD is about six times more likely to develop high-grade cancer. A PSAD value less than or equal to 0.304 ng/ml/cc carried two-year aggressive cancer detection rate of 4% and was 9% at five years. A PSAD value greater that 0.304 ng/ml/cc carried detection rates of 23% and 36% at two and five years, respectively.

Such information could help urologists determine which men are most appropriate for a repeat biopsy. “The ability to detect high grade prostate cancer at low stage of development could make all the difference,” Dr. Garzotto commented. “The risk of dying from high-grade cancer can be up to 40 times greater than that from dying from low-grade cancer. It thus behooves us as researchers to find ways to detect prostate cancer in time so that it can be treated effectively.”

Dr. Garzotto concluded, “This is a simple test. No extra equipment is needed and a urologist can use it right now. All they have to do is calculate the corrected PSA to a get a ratio of PSA and PSA size. Once detected, doctors can request for more frequent biopsies. Instead of doing routine biopsies of 8 to 12 times, they can do saturation biopsies of 20 to 24 times.”

—Querida Anderson