Improved Survival of Ovarian Cancer Patients Receiving Treatment Guided by Comprehensive Tumor Profiling

A preliminary report from the Caris Registry™ demonstrated significantly longer post-profiling survival in patients with ovarian, Fallopian tube or primary peritoneal cancer who were given treatments that their tumor profile showed were likely to benefit.

Data from an ovarian cancer registry presented at the 2014 European Society for Gynaecological Oncology (ESGO) annual meeting reinforce comprehensive tumor profiling as a “game changer” for oncologists.

The preliminary report from the Caris Registry™ demonstrated significantly longer post-profiling survival in patients with ovarian, Fallopian tube, or primary peritoneal cancer who were given treatments that their tumor profile showed were likely to benefit them, as compared with patients who were treated with drugs that profiling suggested would be less effective. Data[1] revealed that patients whose treatment was guided by tumor profiling had a 46% lower risk of death (Hazard Ratio = 0.54, p value = 0.0018).

The comprehensive tumor profiling service used in the study measures a broad range of cancer “biomarkers” (proteins, genes or other molecules that affect how cancer cells grow, multiply and respond to therapies) and interprets the results to identify treatments most likely to be of benefit and help eliminate those that are less likely to benefit the patient. The results allow oncologists to better determine appropriate treatments for each patient, based on the individual makeup of their cancer rather than the site of the tumor.

Data from earlier studies show that comprehensive tumor profiling consistently identifies biomarkers linked to specific treatments in over 90% of patients[2], and that clinicians change their intended treatment decision based on profiling results in over 80% of cases[3].  Across a range of cancer types, tumor profiling-guided treatment has been shown to benefit patients[4] and improve outcomes when compared to unguided treatment[5].  The ESGO data demonstrate that for many ovarian cancer patients who have run out of options, comprehensive tumor profiling consistently offers oncologists actionable insights to help choose a patient’s next treatment and can improve patient outcomes.

Professor Hani Gabra

Professor Hani Gabra

Professor Hani Gabra, author of the ESGO publication and Director, Ovarian Cancer Action Research Centre at Imperial College London, said:

“The data presented at ESGO this year further support the use of comprehensive tumor profiling. It offers new options to patients whose cancers are difficult to treat or rare, or who have exhausted standard treatment options. I’m extremely excited to see this breadth of research on a global platform and I am hopeful that profiling will be rapidly adopted in clinical practice in Europe.”

Gilda Witte, CEO of Ovarian Cancer Action

Gilda Witte, CEO of Ovarian Cancer Action

Gilda Witte, Chief Executive of Ovarian Cancer Action, stated:

“In order to improve the outlook for women with ovarian cancer, we need to know much more about types of tumors, and tumor profiling is becoming paramount in this area. We are hugely impressed that Caris is investing in research to provide information on ovarian tumors and we hope that this potentially leads to a breakthrough in treatment which may subsequently impact survivorship.”

Andreas Voss

Andreas Voss, VP of Medical & Clinical Affairs, Caris Life Sciences

Andreas Voss, Vice President, Medical and Clinical Affairs, Caris Life Sciences said:

“Comprehensive tumor profiling is a hot topic this year. It is becoming increasingly clear that the best approach to tumor profiling is to use a variety of methods to test for mutations, gene expression levels, and protein biomarkers. These combined analyses provide a comprehensive report and actionable treatment options for oncologists. Caris Molecular Intelligence™ remains the world’s most advanced commercial tumor profiling service – we are proud to be working with leading oncologists worldwide to bring the benefits of tumor profiling to cancer patients.”

Caris Molecular Intelligence™ is not yet formally reimbursed across Europe but it is available to purchase in all European markets. Individual insurance companies, clinics and organizations in some countries have agreed to reimburse the service on application. Caris Life Sciences is dedicated to working to ensure the service is reimbursed across Europe.

References:

1. Poster by Oliver KE et al. Tumour molecular profile-directed treatment is associated with improved survival in recurrent epithelial ovarian cancer. ESGO 2014. See also Oliver KE et al. The impact of tumor molecular profile-directed treatment on survival in recurrent ovarian cancer. J Clin Oncol 32:5s, 2014 (suppl; abstr 5591).

2. Astsaturov IA et al. Profiling of 1,250 neuroendocrine tumors identifies multiple potential drug targets. J Clin Oncol 32, 2014 (Suppl 3; Abstr 214).

3. Epelbaum R et al. Molecular Profiling (MP)-Selected Therapy for the Treatment of Patients with Advanced Pancreaticobiliary Cancer (PBC), 2013 ASCO GI Symposium. Jan 2013. (Abstract Number 195).

4. Von Hoff D et al., Pilot Study Using Molecular Profiling of Patients’ Tumors to Find Potential Targets and Select Treatments for Their Refractory Cancers, J Clin Oncol. Nov 20;28(33)2010:4877-83. Compare Doroshow JH. Selecting systemic cancer therapy one patient at a time: is there a role for molecular profiling of individual patients with advanced solid tumors? J Clin Oncol. 2010 Nov 20;28(33):4869-71. doi: 10.1200/JCO.2010.31.1472. Epub 2010 Oct 4. [PMID: 20921466].

5. Tsimberidou AM et al., Personalized Medicine in a Phase I Clinical Trials Program: The MD Anderson Cancer Center Initiative. Clin Cancer Res 18:6373-6383.

About Caris Life Sciences and Caris Molecular Intelligence™

Caris Life Sciences is a leading biosciences company focused on fulfilling the promise of precision medicine. Caris Molecular Intelligence™, the industry’s first and largest tumor profiling service, provides oncologists with the most potentially clinically actionable treatment options available to personalize care today. Using a variety of advanced and clinically validated technologies, which assess relevant biological changes in each patient’s tumor, Caris Molecular Intelligence correlates biomarker data generated from a tumor with biomarker/drug associations derived from the cancer clinical literature. The company is also developing a series of blood tests based on its proprietary Carisome® TOP™ platform, a revolutionary blood-based testing technology for diagnosis, prognosis, and theranosis of cancer and other complex diseases. Headquartered in Irving, Texas, Caris Life Sciences offers services throughout Europe, the U.S., Australia, and other international markets. To learn more, please visit http://www.carislifesciences.eu.

Source:  Improved Survival of Ovarian Cancer Patients Receiving Treatment Guided by Comprehensive Tumor Profiling, Caris Life Sciences Press Release, dated September 11, 2014 (with editorial changes)

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Glutamine Ratio is Key Ovarian Cancer Indicator

Glutamine plays an important role in cellular growth in several cancers. A Rice University-led study shows how ovarian cancer metabolism changes between early and late stages. In this study, a further link between glutamine dependency and tumor invasiveness is established in ovarian cancer.

A Rice University-led analysis of the metabolic profiles of hundreds of ovarian tumors has revealed a new test to determine whether ovarian cancer cells have the potential to metastasize, or spread to other parts of the body. The study also suggests how ovarian cancer treatments can be tailored based on the metabolic profile of a particular tumor.

The research, which appears online this week in Molecular Systems Biology, was conducted at the Texas Medical Center in Houston by researchers from Rice University, the University of Texas M.D. Anderson Cancer Center, and the Baylor College of Medicine.

Deepak Nagrath

Deepak Nagrath, Assistant Professor of Chemical and Biomolecular Engineering at Rice University

“We found a striking difference between the metabolic profiles of poorly aggressive and highly aggressive ovarian tumor cells, particularly with respect to their production and use of the amino acid glutamine,” said lead researcher Deepak Nagrath Ph.D. of Rice University. “For example, we found that highly aggressive ovarian cancer cells are glutamine-dependent, and in our laboratory studies, we showed that depriving such cells of external sources of glutamine — as some experimental drugs do — was an effective way to kill late-stage cells.

“The story for poorly aggressive cells was quite different,” said Nagrath, Assistant Professor of Chemical and Biomolecular Engineering at Rice. “These cells use an internal metabolic pathway to produce a significant portion of the glutamine that they consume, so a different type of treatment — one aimed toward internal glutamine sources — will be needed to target cells of this type.”

The research is part of a growing effort among cancer researchers worldwide to create treatments that target the altered metabolism of cancer cells. It has long been known that cancer cells adjust their metabolism in subtle ways that allow them to proliferate faster and survive better. In 1924, Otto Warburg showed that cancer cells produced far more energy from glycolysis than did normal cells. The Nobel Prize-winning discovery became known as the “Warburg effect,” and researchers long believed that all cancers behaved in this way. Intense research in recent decades has revealed a more nuanced picture.

“Each type of cancer appears to have its own metabolic signature,” Nagrath said. “For instance, kidney cancer does not rely on glutamine, and though breast cancer gets some of its energy from glutamine, it gets even more from glycolysis. For other cancers, including glioblastoma and pancreatic cancer, glutamine appears to be the primary energy source.”

Rice University Researchers

Researchers at Rice University’s Laboratory for Systems Biology of Human Diseases analyzed the metabolic profiles of hundreds of ovarian tumors and discovered a new test to determine whether ovarian cancer cells have the potential to metastasize. Study co-authors include, from left, Julia Win, Stephen Wahlig, Deepak Nagrath, Hongyun Zhao, Lifeng Yang and Abhinav Achreja.

Nagrath, director of Rice University’s Laboratory for Systems Biology of Human Diseases, said the new metabolic analysis indicates that ovarian cancer may be susceptible to multidrug cocktails, particularly if the amounts of the drugs can be tailored to match the metabolic profile of a patient’s tumor.

The research also revealed a specific biochemical test that pathologists could use to guide such treatments. The test involves measuring the ratio between the amount of glutamine that a cell takes up from outside and the amount of glutamine it makes internally.

“This ratio proved to be a robust marker for prognosis,” said University of Texas M.D. Anderson Cancer Center co-author Anil Sood, M.D., Professor of Gynecologic Oncology and Reproductive Medicine and co-director of the Center for RNA Interference and Non-Coding RNA. “A high ratio was directly correlated to tumor aggression and metastatic capability. Patients with this profile had the worst prognosis for survival.”

The three-year study included cell culture studies at Rice as well as a detailed analysis of gene-expression profiles of more than 500 patients from the Cancer Genome Atlas and protein-expression profiles from about 200 M.D. Anderson patients.

“The enzyme glutaminase is key to glutamine uptake from outside the cell, and glutaminase is the primary target that everybody is thinking about right now in developing drugs,” Nagrath said. “We found that targeting only glutaminase will miss the less aggressive ovarian cancer cells because they are at a metabolic stage where they are not yet glutamine-dependent.”

Lifeng

Lifeng Yang, Study Lead Author & Graduate Student, Systems Biology of Human Diseases, Rice University

Rice University graduate student Lifeng Yang, lead author of the study, designed a preclinical experiment to test the feasibility of a multidrug approach, involving the use of a JAK inhibitor and a glutaminase inhibitor. This “drug cocktail” approach inhibited the early stage production of internal glutamine, while also limiting the uptake of external glutamine.

“That depleted all sources of glutamine for the cells, and we found that cell proliferation decreased significantly,” Yang said.

Nagrath said the study also revealed another key finding — a direct relationship between glutamine and an ovarian cancer biomarker called “STAT3” (Signal Transducer And Activator Of Transcription 3).

“A systems-level understanding of the interactions between metabolism and signaling is vital to developing novel strategies to tackle cancer,” said M.D. Anderson co-author Prahlad Ram Ph.D., Associate Professor of Systems Biology and co-director of the M.D. Anderson Cancer Center’s Systems Biology Program. “STAT3 is the primary marker that is used today to ascertain malignancy, tumor aggression and metastasis in ovarian cancer.”

Nagrath said, “The higher STAT3 is, the more aggressive the cancer. For the first time, we were able to show how glutamine regulates STAT3 expression through a well-known metabolic pathway called the TCA cycle, which is also known as the ‘Krebs cycle.’”

Nagrath said the research is ongoing. Ultimately, Dr. Nagrath hopes the investigations will lead to new treatment regimens for cancer as well as a better understanding of the role of cancer-cell metabolism in metastasis and drug resistance.

Co-authors include Hongyun Zhao, Stephen Wahlig, Abhinav Achreja and Julia Win (all affiliated with Rice University); Tyler Moss, Lingegowda Mangala, Guillermo Armaiz-Pena, Dahai Jiang, Rajesha Roopaimoole, Cristian Rodriguez-Aguayo, Imelda Mercado-Uribe, Gabriel Lopez-Berestein and Jinsong Liu (all affiliated with M.D. Anderson Cancer Center); Juan Marini of Baylor College of Medicine; and Takashi Tsukamoto of Johns Hopkins University.

The research was supported by seed funding from (i) the Collaborative Advances in Biomedical Computing Program at Rice Univesity’s Ken Kennedy Institute for Information Technology, (ii) Rice University’s John and Ann Doerr Fund for Computational Biomedicine, (iii) the Odyssey Fellowship Program at the MD Anderson Cancer Center, (iv) the estate of C.G. Johnson Jr., (v) the National Institutes of Health, (vi) the Cancer Prevention and Research Institute of Texas, (v) the Ovarian Cancer Research Fund, (vi) the Blanton-Davis Ovarian Cancer Research Program, (vii) the Gilder Foundation, and (viii) the MD Anderson Cancer Center.

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Ovarian Cancer Tumors Can Grow For Ten Years Or More Before Being Detected By Today’s Blood Tests

A new mathematical model developed by Stanford University School of Medicine scientists finds that ovarian cancer tumors can grow for 10 years or longer before currently available blood tests will detect them.

A new mathematical model developed by Stanford University School of Medicine scientists indicates that tumors can grow for 10 years or longer before currently available blood tests will detect them. The analysis, which was restricted to ovarian cancer tumors but is broadly applicable across all solid tumor types, was published online November 16 in Science Translational Medicine.

“The study’s results can be viewed as both bad and good news,” said Sanjiv “Sam” Gambhir, M.D., Ph.D., professor and chair of radiology and the study’s senior author. Sharon Hori, Ph.D., a postdoctoral scholar in Dr. Gambhir’s laboratory, is the lead study author.

The mathematical model developed by Dr. Sam Gambhir’s lab shows that it would be possible to detect tumors years before they grow big enough to metastasize if researchers can develop the right biomarkers.

The bad news, as explained by Dr. Gambhir, is that by time a tumor reaches a detectable size using today’s available blood tests, it is likely to have metastasized to other areas of the body, making it much more deadly than if it had been caught earlier. “The good news is that we have, potentially, 10 or even 20 years to find the tumor before it reaches this size, if only we can improve our blood-based methods of detecting tumors,” said Dr. Gambhir. “We think our mathematical model will help guide attempts to do that.”

The study advances previous research about the limits of current detection methods. For instance, it is strikingly consistent with a finding reported two years ago by Stanford biochemistry professor Patrick Brown, M.D., Ph.D., that current ovarian cancer tests could not detect tumors early enough to make a significant dent in the mortality rate. There is a push to develop more-sensitive diagnostic tests and find better biomarkers, and Dr. Gambhir’s new model could be an essential tool in this effort. For the first time, the new model connects the size of a tumor with blood biomarker levels being shed by that tumor.

To create their model, Drs. Gambhir and Hori used mathematical models originally developed to predict the concentration of drugs injected into the blood. The investigators linked these to additional models of tumor cell growth.

Tumors do not secrete drugs, but they can shed telltale molecules into surrounding tissue, from which those substances, known as “biomarkers,” diffuse into the blood. Some biomarkers may be made predominantly by tumor cells.  These substances can be measured in the blood as proxies for a tumor.

Some biomarkers are in wide use today. One is the well-known PSA (prostate specific antigen) for prostate cancer. Another example of a biomarker is CA-125 (cancer antigen 125) for ovarian cancer. But these and other currently used blood tests for cancer biomarkers were not specifically developed for early detection, and are generally more effective for relatively noninvasive monitoring of the progress of a late-stage tumor or tumor response to treatment. That is, rising blood levels of the substance may indicate that the tumor is growing, while declining levels may indicate possible tumor shrinkage.

Both CA-125 and PSA are also produced, albeit in smaller amounts, by healthy tissue, complicating efforts to detect cancer at an early stage when the tumor’s output of the biomarker is relatively low.

The new mathematical model employs separate equations, each governing the movement of a biomarker from one compartment into the next. Into these equations, one can plug known values — such as how fast a particular type of tumor grows, how much of the biomarker a tumor cell of this type sheds per hour, and the minimum levels of the biomarker that must be present in the blood for a currently available assay to detect it.

As a test case, Drs. Gambhir and Hori chose CA-125, a well-studied biomarker which is shed into the blood by ovarian cancer tumors. Ovarian cancer is a notorious example of a condition for which early detection would make a significant difference in survival outcomes.

CA-125 is a protein made almost exclusively by ovarian tumor cells. The well-known pharmacokinetics, metabolic fates (typical amounts secreted by an ovarian cell), typical ovarian tumor growth rates, and other properties of CA-125 make the biomarker an excellent candidate for “road testing” with Gambhir and Hori’s model. CA-125 is by no means the ideal biomarker, said Dr. Gambhir, while noting that it can still be used to better understand the ideal properties of biomarkers for early ovarian cancer detection.

Applying their equations to CA-125, Drs. Gambhir and Hori determined that an ovarian cancer tumor would need to reach a size of approximately 1.7 billion cells, or the volume of a cube with a 2-centimeter edge, before the currently available CA-125 blood test could reliably detect it. At typical tumor-growth rates, it would take a single cancer cell approximately 10.1 to 12.6 years of development to become a tumor containing 1.7 billion cells.

The model further calculated that a biomarker otherwise equivalent to CA125 — but shed only by ovarian tumor cells — would allow reliable detection within 7.7 years, while the tumor’s size would be that of a tiny cube about one-sixth of an inch high.

In the last decade, many potential new biomarkers for different forms of cancers have been identified. There’s no shortage of promising candidates — six for lung cancer alone, for example. But validating a biomarker in large clinical trials is a long, expensive process. So it is imperative to determine as efficiently as possible which, among many potential tumor biomarkers, is the best prospective candidate.

“This [mathematical] model could take some of the guesswork out of it,” Gambhir said. He also stated:

“It [the mathematical model] can be applied to all kinds of solid cancers and prospective biomarkers as long as we have enough data on, for instance, how much of it a tumor cell secretes per hour, how long the biomarker can circulate before it’s degraded and how quickly tumor cells divide. We can tweak one or another variable — for instance, whether a biomarker is also made in healthy tissues or just the tumor, or assume we could manage to boost the sensitivity of our blood tests by 10-fold or 100-fold — and see how much it advances our ability to detect the tumor earlier on.”

There are new detection technologies capable of detecting biomarkers at concentrations as low as a few hundred molecules per milliliter (1-cubic centimeter) of blood. In 2009, Dr. Gambhir and his colleagues reported on one such developing technology: “magneto-nanosensors” that can detect biomarkers with a 100-fold greater sensitivity than current methods.

Better biomarker detection alone might allow ovarian cancer tumor detection at the 9-year point, said Gambhir.

A second priority is to come up with new and better biomarkers. “It’s really important for us to find biomarkers that are made exclusively by tumor cells,” Dr. Gambhir said.

Under the right conditions (a highly sensitive assay measuring levels of a biomarker that is shed only by cancer cells), Gambhir stated, the model predicts that a tiny tumor with a volume equivalent to a cube less than one-fifteenth of an inch (or 1.7 millimeters) on a side could be detected.

Dr. Gambhir is also the Virginia and D.K. Ludwig Professor in Cancer Research and director of the Molecular Imaging Program at Stanford, the director of the Canary Center at Stanford for Cancer Early Detection, and a member of the Stanford Cancer Institute.

The study was funded by the Canary Foundation and the National Cancer Institute.

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Mesothelin Antibodies Occur In Some Women With An Epidemiologic Risk For Ovarian Cancer.

Researchers at Rush University Medical Center discover mesothelin antibodies in the bloodstream of infertile women, who possess a higher risk of ovarian cancer.

Using a new approach to developing biomarkers for the very early detection of ovarian cancer, researchers at Rush University Medical Center have identified a molecule in the bloodstream of infertile women, who possess a higher risk of ovarian cancer. This finding may be relevant in the future for screening women at high risk for the disease — or even those with early-stage ovarian cancer.

The molecule — an antibody that the human body manufactures — is an autoimmune response to mesothelin. Mesothelin a well-characterized ovarian cancer antigen and protein which is found in abundance on the surface of ovarian cancer cells, but present only in limited amounts in normal human tissue.

The study is published in the August 16 online version issue of Cancer Epidemiology, Biomarkers & Prevention, published by the American Association for Cancer Research (AACR).

Judith Luborsky, Ph.D., Lead Study Author; Professor, Pharmacology, Obstetrics & Gynecology and Preventive Medicine, Rush Medical College

“The finding is extremely important because at present medical tests are unable to detect ovarian cancer in its early stages, which is why death rates from this disease are so high,” said Judith Luborsky, Ph.D., professor of pharmacology, obstetrics and gynecology and preventive medicine at Rush and the lead author of the study.

“Our approach to discovering cancer biomarkers was unique in this study. Instead of investigating molecules specific to ovarian cancer alone, we asked what molecules women with a risk of ovarian cancer and those with ovarian cancer had in common,” Luborsky said.

The study may have enabled the researchers to explain, in part, the link between infertility and ovarian cancer that has been established in numerous epidemiological surveys.

“More important, with the discovery of the mesothelin antibody, we now have what appears to be a biomarker that can potentially be used in screening tests to help us conquer ovarian cancer,” Luborsky said.

According to the American Cancer Society’s most recent estimates, it is anticipated that 21,900 new cases of ovarian cancer will be diagnosed in the U.S. in 2011, and approximately 15,460 deaths will occur in connection with the disease. Ovarian cancer is the ninth most common cancer in women (not counting skin cancer) and ranks as the fifth highest cause of cancer death in women. It is the most lethal gynecologic cancer. The poor prognosis for women with ovarian cancer is due to the lack of both clinical symptoms when the cancer first develops and the absence of laboratory tests specific to the disease.

In the study at Rush, researchers tested for mesothelin antibodies in the bloodstream of 109 women who were infertile; 28 women diagnosed with ovarian cancer, 24 women with benign ovarian tumors or cysts, and 152 healthy women. Causes of infertility included endometriosis, ovulatory dysfunction, and premature ovarian failure. Some causes of infertility were unexplained.

Significant levels of mesothelin antibodies were found in women with premature ovarian failure, ovulatory dysfunction and unexplained infertility, as well as in women with ovarian cancer. The same results were not found in women with endometriosis, good health, or benign disease. Endometriosis is generally associated with the clear cell and endometrioid subtypes of epithelial ovarian cancer, as compared to other forms of the disease associated with infertility, which may explain why mesothelin antibodies were not found in the endometriosis cases.

It is important to emphasize that the explanation as to why the presence of mesothelin antibodies in the bloodstream should be linked with ovarian cancer is not clear.

“It has been hypothesized that an autoimmune response precedes or somehow contributes to the development and progression of malignant tumors,” Luborsky said. “We think that antibodies may arise in response to very early abnormal changes in ovarian tissue that may or may not progress to malignancy, depending on additional triggering events. Or, alternatively, antibodies may bind to normal cells in the ovary, causing dysfunction and leading to infertility — and, in a subpopulation of women, to the development of ovarian cancer.”

Other researchers involved in the study were Yi Yu, MS, and Seby Edassery, MS, both from Rush, as well as a group led by Ingegerd Hellstrom, M.D., Ph.D., and Karl Eric Hellstrom, M.D., Ph.D., which included Yuan Yee Yip, BS, Jade Jaffar, BS, and Pu Liu, Ph.D. from Harborview Medical Center at the University of Washington.

The study was supported by funding from the National Institutes of Health and Fujirebio Diagnostics, Inc.

About Rush

Rush is a not-for-profit academic medical center comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health.

Rush’s mission is to provide the best possible care for its patients. Educating tomorrow’s health care professional, researching new and more advanced treatment options, transforming its facilities and investing in new technologies—all are undertaken with the drive to improve patient care now, and for the future.

Sources:

  • Luborsky JL, et al. Autoantibodies to Mesothelin in Infertility. Cancer Epidemiol Biomarkers Prev. 2011 Aug 16. PubMed PMID: 21846819 [Epub ahead of print]
  • Researchers at Rush University Medical Center Discover Antibody That May Help Detect Ovarian Cancer in its Earliest Stages, News Release, Rush University Medical Center, August 16, 2010.

ASCO 2011: Genetic Biomarker Predicts Taxane Drug-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

New study results involving a genetic marker which can predict taxane drug-induced neuropathy were highlighted today in the ASCO press briefing, as summarized below.

Genetic Biomarker Predicts Taxane-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane drug-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment. The finding may eventually lead to a simple blood test to determine whether a patient is at high risk for neuropathy.

Bryan P. Schneider, M.D., Physician & Researcher, Indiana University Melvin & Bren Simon Cancer Center; Associate Director, Indiana Institute for Personalized Medicine

“If these findings can be replicated, this may allow physicians to know prior to recommending therapy whether the patient is at an inordinate risk for developing taxane-induced neuropathy,” said Bryan P. Schneider, M.D., lead author and a physician/researcher at the Indiana University Melvin and Bren Simon Cancer Center and Associate Director for the Indiana Institute for Personalized Medicine. “This may allow for better counseling, use of alternative drugs or schedules, or omission of taxanes in the appropriate settings. These genetic findings might also provide insight into the mechanism of this side effect and help develop drugs to prevent this toxicity altogether.”

Such damage to the nerves can cause pain and numbness and limit the dose of chemotherapy a patient can receive. While only a few factors seem to predict which patients are likely to get peripheral neuropathy, including a history of diabetes and advanced age, genetic variations may explain why some patients are more sensitive to taxane drugs.

The authors conducted a genome wide association study on 2,204 patients enrolled in an Eastern Cooperative Oncology Group breast cancer clinical trial (E5103) in which all patients received taxane-based chemotherapy, namely paclitaxel (Taxol). The study looked for variations in DNA (deoxyribonucleic acid) called single nucleotide polymorphisms, or SNPs (pronounced “snips”), by evaluating more than 1.2 million SNPs in each patient.  A SNP is a DNA sequence variation which occurs when a single nucleotide — A (adenine), T (thymine), C (cytosine), or G (guanine) — in the genome (or other shared sequence) differs between two individuals, or between paired chromosomes located within the nucleus of an individual’s cells.

With a median follow-up of 15 months, the study identified genetic subgroups that were markedly more likely to develop peripheral neuropathy.

Those who carried two normal nucleotides in the RWDD3 gene had a 27 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 40 percent risk; and those who carried two SNPs had a 60 percent risk.

In contrast, those who carried two normal nucleotides in the TECTA gene had a 29 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 32 percent risk; and those who carried two SNPs had a 57 percent risk.

The study also found that older patients and African Americans were much more likely to have peripheral neuropathy, and further analysis of SNPs in these groups is underway.

The authors plan to continue their work in additional trials to validate these findings and to determine whether a different type or schedule of taxane therapy would result in less neuropathy in the more susceptible genetic groups. The authors also are collaborating with neurobiologists to understand why these genetic variations might make the nerves more sensitive to these drugs.

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2011 NCCN Conference: New Treatment Options Lead to Steady Progress Against Ovarian Cancer

Recommendations stemming from recent clinical trials highlight notable updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Ovarian Cancer at the National Comprehensive Cancer Network® (NCCN®) 16th Annual Conference.

Robert J. Morgan, Jr., M.D., Professor of Medical Oncology, City of Hope Comprehensive Cancer Center; Chair, NCCN Guidelines Panel for Ovarian Cancer

Although finding effective screening tools remains a priority, new treatment options for women with ovarian cancer, such as the ones outlined in the updated NCCN Guidelines for Ovarian Cancer,[1] are vital to making steady progress against the disease according to Robert J. Morgan, Jr., M.D., of City of Hope Comprehensive Cancer Center and chair of the NCCN Guidelines Panel for Ovarian Cancer. Dr. Morgan outlined significant updates to the NCCN Guidelines during a recent presentation at the NCCN 16th Annual Conference.

The NCCN Guidelines address epithelial ovarian cancer (including borderline or low malignant potential) and less common histopathologies, including malignant germ neoplasms, carcinosarcomas, and sex cord-stromal tumors. They also discuss fallopian tube cancer and primary peritoneal cancer, which are less common neoplasms that are managed in a similar manner to epithelial ovarian cancer.

“Regardless of the type of cancer, the NCCN Guidelines for Ovarian Cancer reflect the importance of stage and grade of disease on prognosis and treatment recommendations,” said Dr. Morgan.

The NCCN Guidelines continue to recommend that women with borderline epithelial ovarian cancer of low malignant potential be primarily surgically managed. In contrast to patients with frankly invasive ovarian carcinoma, women with borderline disease tend to be younger and are often diagnosed with stage I disease.

“The benefits of postoperative chemotherapy has not been demonstrated for patients who have no microscopically demonstrable invasive implants, said Dr. Morgan. “Even patients with advanced stage disease at presentation have an excellent prognosis and chemotherapy should be avoided.”

The NCCN Guidelines recommend surgery limited to a unilateral salpingo-oophorectomy (USO) (preserving the uterus and contralateral ovary) for women who wish to maintain their fertility, and standard ovarian cancer debulking surgery is recommended for those not concerned about fertility preservation.

On the contrary, in women diagnosed with stage II, III, or IV epithelial ovarian cancer, the NCCN Guidelines recommend intraperitoneal chemotherapy for first-line therapy and have been updated to include dose-dense paclitaxel (Taxol®:, Bristol-Myers Squibb) as a possible treatment option.

Dr. Morgan noted that in a recent clinical trial, dose-dense weekly paclitaxel with carboplatin (Paraplatin®:, Bristol-Myers Squibb) showed an increase in both progression-free survival and overall survival when compared with conventional intraperitoneal chemotherapy of weekly carboplatin/paclitaxel.[2]

“However, the dose-dense regimen is more toxic, and patients discontinued dose-dense paclitaxel therapy more often than those receiving standard therapy,” stated Dr. Morgan. “As with all treatment decisions, the patient needs to weigh the potential benefits and risks and discuss them thoroughly with their physician.”

Dr. Morgan discussed two additional phase 3 trials assessing bevacizumab (Avastin®:, Genentech/Roche) combined with carboplatin/paclitaxel in the upfront setting compared to carboplatin/paclitaxel alone.[3-4] Although data regarding overall survival and quality of life have not been reported yet, the studies did indicate that the median progression-free survival increased in patients receiving bevacizumab as a first line and maintenance therapy.

“Only modest improvements in progression-free survival were observed in both of these trials. The NCCN Guidelines Panel prefers to await mature results of these trials prior to recommending the routine addition of bevacizumab to carboplatin/paclitaxel,” said Dr. Morgan.

As such, the updated NCCN Guidelines includes new language detailing the Panel’s view on bevacizumab encouraging participation in ongoing clinical trials that are further investigating the role of anti-angiogenesis agents in the treatment of ovarian cancer, both in the upfront and recurrence settings.

Biomarkers continue to emerge as an area of interest in predicting future patterns of the disease. In patients with ovarian cancer, Dr. Morgan discussed the value of monitoring CA-125 levels in regards to a recent study[5] comparing early versus delayed treatment of relapsed ovarian cancer.

“Often, levels of CA-125 have been shown to rise prior to a clinical or symptomatic relapse in women with ovarian cancer. This trial looked at whether there was a benefit of early treatment on the basis of increased CA-125 concentrations compared with delayed treatment on the basis of clinical recurrence,” said Dr. Morgan.

The study, which was published in The Lancet, found that there was no survival benefit to early institution of treatment based on increased CA-125 levels and that the quality of life was superior in patients in the late treatment arm.

“The results of the trial suggest that the utility of the routine monitoring of CA-125 levels in limited,” said Dr. Morgan. “The NCCN Guidelines Panel encourages patients and their physicians to actively discuss the pros and cons of CA-125 monitoring based upon these findings and have updated the NCCN Guidelines to include language supporting this recommendation.”

Virtually all drugs used in oncology have the potential to cause adverse drug reactions while being infused, which can be classified as either infusion or allergic reactions. Recently, hypersensitivity to platinum compounds has been recognized as a potential issue for patients being administered these compounds.

“Platinum compounds remain very important in the treatment of ovarian cancer in both the upfront and recurrence settings, so it was important to design strategies to allow for the safe desensitization of these agents in patients who develop allergies,” said Dr. Morgan.

Standard desensitization regimens include slowly increasing infusion concentrations over several hours. However, Dr. Morgan noted that these procedures must be done in a specific manner in order to be safely administered and pointed to the recommendations within the updated NCCN Guidelines discussing the management of drug reactions.

In conclusion, Dr. Morgan emphasized that although steady progress is being made in the treatment of ovarian cancer, further trials are necessary to investigate the role of targeted agents alone and in combination in newly diagnosed and recurrent ovarian cancer. In addition, enrollment of patients with ovarian cancer must be encouraged.

The NCCN Guidelines are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of expert physicians from NCCN Member Institutions. The most recent version of this and all NCCN Guidelines are available free of charge at NCCN.org. The NCCN Guidelines for Patients™: Ovarian Cancer is available at NCCN.com.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit NCCN.org.

The NCCN Member Institutions are:

  • City of Hope Comprehensive Cancer Center
  • Dana-Farber/Brigham and Women’s Cancer Center
  • Massachusetts General Hospital Cancer Center
  • Duke Cancer Institute
  • Fox Chase Cancer Center
  • Huntsman Cancer Institute at the University of Utah
  • Fred Hutchinson Cancer Research Center / Seattle Cancer Care Alliance
  • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Robert H. Lurie Comprehensive Cancer Center of Northwestern University
  • Memorial Sloan-Kettering Cancer Center
  • H. Lee Moffitt Cancer Center & Research Institute
  • The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute
  • Roswell Park Cancer Institute
  • Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
  • St. Jude Children’s Research Hospital / University of Tennessee Cancer Institute
  • Stanford Comprehensive Cancer Center
  • University of Alabama at Birmingham Comprehensive Cancer Center
  • UCSF Helen Diller Family Comprehensive Cancer Center
  • University of Michigan Comprehensive Cancer Center
  • UNMC Eppley Cancer Center at The Nebraska Medical Center
  • The University of Texas MD Anderson Cancer Center
  • Vanderbilt-Ingram Cancer Center

References:

1/ Ovarian Cancer Including Fallopian Tube Cancer & Primary Peritoneal Cancer, Version 2.2011, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™), National Comprehensive Cancer Network. [PDF Adobe Reader Document – requires free registration and log-in at NCCN.org]

2/ Katsumata N, Yasuda M, Takahashi F, et. alJapanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trialLancet. 2009 Oct 17;374(9698):1331-8. Epub 2009 Sep 18. PubMed PMID: 19767092.

3/ Burger RA, Brady MF, Bookman MA, et. al.  Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC):  a Gynecologic Oncology Group study.  J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1).

4/ Perren T, Swart AM, Pfisterer J, et. alICON7: A phase III randomized gynecologic cancer intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC).Ann Oncol 21;viii2, 2010 (suppl 8; abstr LBA4).

5/Rustin G, van der Burg M, Griffin C, et. al. Early versus delayed treatment of relapsed ovarian cancer. Lancet. 2011 Jan 29;377(9763):380-1. PubMed PMID: 21277438.

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Additional 2011 NCCN Annual Meeting Information

Caris Life Sciences Launches Molecular Profiling Service For Ovarian Cancer Patients

Caris Life Sciences announces the launch of a new molecular profiling service for ovarian cancer patients

Caris Life Sciences, Inc. (Caris), a leading biosciences company focused on enabling precise and personalized healthcare through the highest quality anatomic pathology, molecular profiling, and blood-based diagnostic services, announced the launch of a new, Caris Target Now™ molecular profile for ovarian cancer patients. This expansion of the Caris Target Now™ offering provides individualized molecular information to treating physicians, relevant to the selection of therapies to treat this highly-lethal cancer. Ovarian cancer affects more than 20,000 women annually and produces some of the highest five-year mortality rates found among the 200+ types of cancer.

Caris Target Now™ molecular profiling examines the unique genetic and molecular make-up of each patient’s tumor so that treatment options may be matched to each patient individually.  Caris Target Now™ helps patients and their treating physicians create a cancer treatment plan based on the tumor tested. By comparing the tumor’s information with data from published clinical studies by thousands of the world’s leading cancer researchers, Caris can help determine which treatments are likely to be most effective and, just as important, which treatments are likely to be ineffective.

The Caris Target Now™ test is performed after a cancer diagnosis has been established and the patient has exhausted standard of care therapies or if questions in therapeutic management exist. Using tumor samples obtained from a biopsy, the tumor is examined to identify biomarkers that may have an influence on therapy. Using this information, Caris Target Now™ provides valuable information on the drugs that will be more likely to produce a positive response. Caris Target Now™ can be used with any solid cancer such as lung cancer, breast cancer, prostate cancer, and now, ovarian cancer.

Evidence Behind Caris Target Now™

Daniel D. Von Hoff, M.D., F.A.C.P., is the Executive Director of Caris Life Sciences' Clinical Research

A multi-center, prospective, pilot study first published in The Journal of Clinical Oncology (JCO) in October 2010 [1] — along with an accompanying editorial [2] —  determined that personalized cancer treatment tailored to a tumor’s unique genetic make-up identified therapies that increased progression free survival (PFS) over previous therapies in 27% of patients with advanced disease.

The purpose of the study was to compare PFS using a treatment regimen based on the molecular profiling (MP) of a patient’s tumor with the PFS determined for the most recent regimen on which the patient had experienced progression after taking that regimen for 6 weeks.  Unlike a typical control study, each patient was his or her own study control.  Tissue samples from patients with refractory metastatic cancer were submitted for MP in two formats including:

In many of these refractory tumors, targets for conventional therapies were identified, which was “a surprise finding,” according to Dr. Daniel Von Hoff, the Executive Director of Caris’ Clinical Research.  But the profiling also suggested therapies in cases where the treating physician was unsure regarding the next line of treatment. The MP approach was found to have clinical benefit for the individual patient who had a PFS ratio (PFS on MP selected therapy/PFS on prior therapy) of ≥ 1.3.  Among the 86 patient tumors that were profiled with Caris Target Now™:

  • 84 (98%) had a detected molecular target;
  • 66 of the 84 patients were treated with therapies that were linked to their MP results; and
  • 18 (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38% range; one-sided, one-sample P = .007).

The study investigators concluded that it is possible to identify molecular targets in patients’ tumors. In 27% of the patients, the MP approach resulted in a longer PFS on a MP-based regimen than on the regimen that was based on physician’s choice.  “It was also encouraging to see that the overall survival in these 18 patients was better than that for the whole group of 66 patients (9.7 vs. 5 months),” said Von Hoff.

Of the 66 participants, 27% had breast cancer, 17% had colorectal cancer, and 8% had ovarian cancer; the remainder were classified as miscellaneous.  The improvement in PFS among the various types of cancer patients was as follows: 44% in patients with breast cancer, 36% in those with colorectal cancer, 20% in those with ovarian cancer, and 16% in the miscellaneous group.

The investigators in the study utilized Caris Target Now™ molecular profiling, which is currently available to oncologists and their patients.

“Oncologists commonly expect a 1-in-20 chance of patient response in 3rd- and 4th-line therapies.  This recent study suggests those odds can be improved to 1-in-4 when using therapeutic guidance provided by Caris Target Now™.”

Dr. Jeff Edenfield, a practicing oncologist with US Oncology, and routine user of Caris Target Now™

Since 2008, more than 15,000 cancer patients have received a Caris Target Now™ molecular profile. Caris Target Now™ has been designed to provide treating physicians with therapeutic options, often identifying anti-tumor agents that may not have been considered before. The Caris Target Now™ report is based on the genetic make-up of an individual patient’s tumor cross-referenced with a vast and growing proprietary database of clinical literature, correlating genetic tumor information to therapeutic response. Using biomarker-based therapies has been linked to the likelihood of a positive patient response.

James H. Doroshow, M.D., Director, Division of Cancer Treatment & Diagnosis, National Cancer Institute

In the accompanying JCO editorial, James H. Doroshow, M.D., the Director of the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis, commented that the study by Von Hoff et. al. possessed several limitations. [2] The stated limitations of the study include (i) uncertainty surrounding the achievement of the study’s primary end point based upon use of the time-to-disease progression (TTP) index; (ii) limited prior experience with patients as their own controls, and (iii) lack of study randomization.  Despite these limitations, Dr. Doroshow noted that important lessons can be learned from the study conducted by Von Hoff et. al.

“First and foremost, this study vividly reminds us that the need for therapeutic intervention arises one patient at a time. When we sit with an individual who is trying to live with an advanced solid tumor after having already received several different chemotherapy regimens, it is unlikely that any published prognostic index or gene signature, as currently implemented, will be of much help in decision making—for physicians or for patients. [citation omitted]. Thus, a truly urgent need exists to move past the empiric therapeutic paradigm that launched the first half century of systemic oncologic treatment. [citation omitted]. Von Hoff et al have taken a noteworthy, albeit somewhat flawed, first step in this direction in their attempt to imagine a novel paradigm for cancer therapy, using the techniques of molecular tumor characterization on an individual patient basis. Future investigators of new cancer therapies should learn from this initial effort and focus on how these rapidly evolving molecular tools can be used in the development of an entirely new investigative model for the systemic treatment of cancer.”

Caris is currently conducting and initiating additional studies of Caris Target Now™ molecular tumor profiling through collaboration with leading institutions and cancer centers. 

With 300% growth in utilization in 2010, medical oncologists are recognizing the utility and value of this novel approach in providing improved care to patients. Physician adoption is rapidly accelerating, as Caris recently reached the threshold of providing Caris Target Now™ services to more than 1,000 patients per month. This new introduction for ovarian cancer is most relevant for physicians treating women who have progressed on platinum-based therapy and/or who need guidance for third-line treatment options. Caris Target Now™ for ovarian cancer offers the opportunity for these women to benefit from personalized and targeted therapy guidance based upon molecular profiling.

“Ovarian cancer is a highly-lethal cancer that presents distinct diagnostic and therapeutic challenges, often presenting no major symptoms until the cancer has metastasized,” said Dr. Les Paul, Caris’ Senior Vice President for Medical Affairs. “Choosing the optimal therapeutic intervention at the earliest possible stage is critical to extending progression free survival in ovarian cancer patients. With the introduction of the Caris Target Now™ ovarian profile, we are able to support physicians with as much information as possible, including the latest relevant clinical literature citations to aid them in making the best therapeutic decision possible for each patient.”

Examples of the potential use of an existing clinical trial drug to target a specific molecular characteristic possessed by an ovarian cancer include:

Use of Molecular Profiling By Leading Medical Institutions; Sponsorship By A Charitable Foundation

It should be noted that molecular profiling is already being used in clinical practice at several leading cancer institutions.  At Massachusetts General Hospital, (MGH), The MGH Cancer Centre uses a PCR-based mutation-detection assay and state-of-the-art robotic technology, called “SNaPshot,” to look for 130 known gene mutations in tumor tissue. “We are already using molecular profiling for all our lung cancer patients,” said Jeffrey Settleman, Ph.D., scientific director at the MGH Cancer Center, to Medscape Oncology in 2009. [12] “This has already had an impact on treatment decisions, and it appears to be improving treatment. We have seen better response rates and we hope that this will translate into better survival.”  In fact, MGH is engaged currently in the largest study aimed at matching tumor genomes to potential anticancer treatments. [13] It is our understanding that MGH performs molecular profiling currently on melanoma, leukemia, brain and metastatic breast cancer, and metastatic adenocarcinoma that start in the lung, colon or rectum.

Several other institutions are in the process of developing or have developed their own systems, including the University of Texas M.D. Anderson Cancer Center [14], and the Dana-Farber Cancer Institute [15].  All are striving to profile individual tumors so that therapy can be personalized, which means that it has a better chance of working because it targets specific mutations found in a patient’s tumor. The MP approach also prevents patients from being exposed to drugs that have a limited chance of success, eliminating toxicity and improving quality of life.

We should also note the Clearity Foundation sponsors molecular profiling services on behalf of ovarian cancer patients at no cost. The Clearity Foundation is a 501(c)(3) not-for-profit, founded by Laura Shawver, Ph.D., who is an ovarian cancer survivor and research scientist.  The Clearity Foundation seeks to improve treatment outcomes in recurrent and progressive ovarian cancer patients by providing diagnostic services that determine the molecular profile of the individual patient with the belief that a molecular “blueprint” is crucial to finding appropriate treatments.

About Caris Target Now™

Caris Target Now™ is a comprehensive tumor analysis coupled with an exhaustive clinical literature search, which matches appropriate therapies to patient-specific biomarker information to generate an evidence-based treatment approach. Caris Target Now™ testing provides information that may help when considering potential treatment options.

Caris Target Now™ begins with an immunohistochemistry (IHC) analysis. An IHC test measures the level of important proteins in cancer cells providing clues about which therapies are likely to have clinical benefit and then what additional tests should be run.

If there is access to a frozen sample of patient tissue available, Caris may also run a gene expression analysis by microarray. The microarray test looks for genes in the tumor that are associated with specific treatment options.

As deemed appropriate based on each patient, Caris will run additional tests. Fluorescent In-Situ Hybridization (FISH) is used to examine gene copy number variation (i.e., gene amplification) in the tumor. Polymerase Chain Reaction (PCR) or DNA sequencing is used to determine gene mutations in the tumor DNA.

Caris takes the results from each test and applies the published findings from thousands of the world’s leading cancer researchers. Based on this analysis, Caris Target Now™ identifies potential therapies for patients and their treating physicians to discuss.

Caris Target Now™ was developed and its performance characteristics were determined by Caris, a CLIA-certified medical laboratory in compliance with the U.S. Clinical Laboratory Amendment Act of 1988 and all relevant U.S. state regulations. It has not been approved by the United States Food and Drug Administration.

About Caris Life Sciences

Caris Life Sciences, a leading biosciences company, specializes in the development and commercialization of the highest quality anatomic pathology, molecular profiling, and blood-based diagnostic technologies, in the fields of oncology, dermatopathology, hematopathology, gastrointestinal pathology and urologic pathology. The company provides academic-caliber consultations for patients every day, through its industry-leading team of expert, subspecialty pathologists. Caris also offers advanced molecular analyses of patient samples through prognostic testing services and genomic, transcriptomic, and proteomic profiling to assist physicians in their treatment of cancer. Currently, Caris is developing the Carisome™ platform, a proprietary, blood-based technology for diagnosis, prognosis, and theranosis of cancer and other complex diseases. The company is headquartered in the Dallas metroplex, and operates laboratories at the headquarters, as well as in the Phoenix and Boston metro areas.

About Daniel Von Hoff, M.D., FACP, Executive Director, Caris Life Sciences Clinical Research

Daniel D. Von Hoff, M.D., is currently physician-in-chief and director of translational research at Translational Genomics Research Institute (TGen) in Phoenix, Arizona. He is also chief scientific officer for US Oncology and the Scottsdale Healthcare’s Clinical Research Institute.  He holds an appointment as clinical professor of medicine at the University of Arizona College of Medicine.

Dr. Von Hoff’s major interest is in the development of new anticancer agents, both in the clinic and in the laboratory. He and his colleagues were involved in the beginning of the development of many of the agents now in routine use, including: mitoxantrone, fludarabine, paclitaxel, docetaxel, gemcitabine, irinotecan, nelarabine, capecitabine, lapatinib and others.

At present, Von Hoff and his colleagues are concentrating on the development of molecularly targeted therapies particularly for patients with advanced pancreatic cancer. Dr. Von Hoff’s laboratory interests and contributions have been in the area of in vitro drug sensitivity testing to individualize treatment for the patient, mechanisms of gene amplification, particularly of extrachromosomal DNA, and understanding of and targeting telomere maintenance mechanisms. His laboratory work now concentrates on the discovery of new targets in pancreatic cancer.

Dr. Von Hoff has published more than 543 papers, 133 book chapters, and more than 956 abstracts. Dr. Von Hoff  also served on President Bush’s National Cancer Advisory Board from June 2004 through March 2010.

Dr. Von Hoff is the past president of the American Association for Cancer Research(AACR) (the world’s largest cancer research organization), a fellow of the American College of Physicians, and a member and past board member of the American Society of Clinical Oncology (ASCO). He is a founder of ILEX™ Oncology, Inc. (acquired by Genzyme after Ilex had 2 agents, alemtuzumab and clofarabine approved for patients with leukemia). He is founder and the editor emeritus of Investigational New Drugs – The Journal of New Anticancer Agents; and, editor-in-chief of Molecular Cancer Therapeutics. He is also proud to have been a mentor and teacher for multiple medical students, medical oncology fellows, graduate students, and post-doctoral fellows. He is a co-founder of the AACR/ASCO Methods in Clinical Cancer Research Workshop.

References:

1/ Von Hoff DD, Stephenson JJ Jr, Rosen P, et. al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010 Nov 20;28(33):4877-83. Epub 2010 Oct 4. PubMed PMID: 20921468.

2/ Doroshow JH. Selecting systemic cancer therapy one patient at a time: Is there a role for molecular profiling of individual patients with advanced solid tumors? J Clin Oncol. 2010 Nov 20; 28(33):4869-71. Epub 2010 Oct 4. PMID: 20921466.

3/Addition of Dasatinib (Sprycel) to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancers, by Paul Cacciatore, Libby’s H*O*P*E*™, April 19, 2009.

4/UCLA Researchers Significantly Inhibit Growth of Ovarian Cancer Cell Lines With FDA-Approved Leukemia Drug Dasatinib (Sprycel®), by Paul Cacciatore, Libby’s H*O*P*E*™, November 11, 2009.

5/BMS-345541 + Dasatinib Resensitizes Carboplatin-Resistant, Recurrent Ovarian Cancer Cells, by Paul Cacciatore, Libby’s H*O*P*E*™, July 1, 2010.

6/PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity, by Paul Cacciatore, Libby’s H*O*P*E*™, April 23, 2010.

7/ Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriersN Engl J Med. 2009 Jul 9;361(2):123-34. Epub 2009 Jun 24. PMID: 19553641.

8/Audeh MW, Penson RT, Friedlander M, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 2009;27(supplement):p. 15S.

9/PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study, by Paul Cacciatore, Libby’s H*O*P*E*™,  November 17, 2010.

10/PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target?, by Paul Cacciatore, Libby’s H*O*P*E*™,  November 20, 2009.

11/Endocyte’s EC145 Produces Significant Anti-Tumor Activity In Advanced Stage Chemoresistant Ovarian Cancer Patients, by Paul Cacciatore, Libby’s H*O*P*E*™, October 21, 2009.

12/Massachusetts General Hospital Cancer Center To Genetically Profile All Patient Tumors, by Paul Cacciatore, Libby’s H*O*P*E*™, March 14, 2009.

13/Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results, by Paul Cacciatore, Libby’s H*O*P*E*™, August 3, 2010.

14/An Initiative for Molecular Profiling in Advanced Cancer Therapy (IMPACT) Trial. A Molecular Profile-Based Study in Patients With Advanced Cancer Treated in the Investigational Cancer Therapeutics Program, University of Texas M.D. Anderson Cancer Center, ClinicalTrials.gov Identifier: NCT00851032.

15/Dana-Farber Researchers “OncoMap” The Way To Personalized Treatment For Ovarian Cancer, by Paul Cacciatore, Libby’s H*O*P*E*™, November 16, 2010.

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Additional Information: