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May 06, 2014

Cancer Omics—How Much Information is Enough?

Knowledge is power, but is that knowledge always worth the cost?

Cancer Omics—How Much Information is Enough?

The 21-gene expression Oncotype DX assay was developed to estimate the benefit of adjuvant chemotherapy for hormone receptor–positive breast cancer. [©Tyler Olson/Fotolia]

  • All genomic evidence points to increasing complexity in analyzing cancers for molecular characterization to indicate an appropriate treatment course and determine prognosis. But while we wait for interpretable results to emerge from mountains of data, can a few gene signatures, other types of omics tests, and even animal-based testing, provide enough actionable information to clinicians?

    Multiple tests now being either supplied or under development though small companies, big pharma, and supported by new investment, all aim at helping physicians and patients make better and more humane decisions about potential cancer treatments.

    Scientists and physicians, particularly breast cancer oncologists and healthcare economists, have raised concerns about genomics-based tests, their scientific validity, true clinical utility, and ultimate cost-benefit ratios. And experts in the fields of both oncology and biostatistics continue to ask whether the independently published significant statistical contributions of these new assays will hold up over time as more patients are tested. Moreover, experts comment that test results can easily be misused, e.g., using the test in the wrong clinical setting, which can lead to misplaced reassurance about test-driven decisions.

    But some tests have been around long enough to have a track record and clinicians have come to rely on them. Writing in the British Medical Journal, Daniel F. Hayes, M.D., co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, and his colleagues comment that while few assays that have emerged from the genomics revolution in the last 12 years, Oncotype DX has proven one of the most reliable. This assay was developed to estimate the benefit of adjuvant chemotherapy for hormone receptor–positive breast cancer (HR-positive BC).

    According to a study published in 2012 in the Journal of Clinical Oncology, use of this gene expression profile (GEP) has been associated with a shift in the characteristics of and overall reduction in the proportion of women with HR-positive BC receiving adjuvant chemotherapy. This test looks at 21 different genes within the cells of a tumor sample. Certain patterns suggest a more aggressive cancer that is more likely to come back after treatment. 

  • Good Evidence

    Dr. Hayes and his colleagues wrote that “there is really good evidence to show that if an estrogen receptor-positive node-negative patient has a low recurrence score, her odds of the cancer recurring over the next 10 years—assuming she will get endocrine therapy—are so low that even if chemotherapy works, it will not help enough people to outweigh the potentially life-threatening side effects of chemotherapy.” They further note that due to the wide use of the test in the U.S. a 20% reduction in chemotherapy therapy for that group of patients over the last 10 years has occurred. “In my opinion,” he said, “this is exactly what we are trying to do with patient-tailored therapy.”

    Many companies, including big pharma, are betting that commercialized tests will prove increasingly useful to clinicians. Pfizer thinks so, as it inked an early-April deal with IntegraGen, a developer and marketer of molecular diagnostic testing in oncology. IntegraGen will provide Pfizer with access its molecular signature for hepatocellular carcinoma. The 56-gene molecular signature covered by the agreement is intended to predict the clinical prognosis of patients with hepatocellular carcinoma and subcategorize patients into six separate classifications based on the molecular characteristics of their liver tumors.

    Results of a study reported in 2013 demonstrated that a five-gene molecular signature accurately predicted the clinical prognosis of patients with primary liver hepatocellular carcinoma and in whom surgical resection of the affected part of the liver was being considered. The signature allowed for the determination of which patients will likely benefit the most from the surgery.

  • Better Definition

    The investigators anticipate that the signature will be of particular interest to clinicians since it may allow for a better definition of transplant indications in this patient population and an improved understanding of an individual’s risk of cancer recurrence or death.

    IntegraGen is also developing a second series of biomarkers that have been shown to be prognostic for outcomes in patients with hepatocelluar carcinoma. This effort is a result of original research by Jessica Zucman-Rossi, M.D., Ph.D., Professor of Medicine, Oncology, University Paris Descartes, Hopital Européen Georges Pompidou and Head of the INSERM unit on Functional Genomics of Solid Tumors in Paris. By studying the expression of genes, IntegraGen aims to better predict survival outcomes and the potential for cancer recurrence in patients with liver cancer and to identify differing subgroups of patients where surgery and targeted therapies are more effective.

    In a completely different approach to providing actionable information to oncologists, Champions Oncology’s use of patient-derived xenografts, or mouse avatars, accurately predicted treatment efficacy in all evaluated patients with advanced sarcoma. In this process, a slice of the patient’s living tumor is removed during surgery for biopsy and is implanted in mice. By implanting the tumor together with its microenvironment, TumorGrafts® continue to very closely resemble the patient’s tumor, with 94% genetic correlation to the tumor in the patient. Approximately 70% of implanted tumors grow successfully in mice.

    The results support, says the company, the predictive capabilities of Champions TumorGrafts in providing actionable direction to oncologists to optimize cancer treatment. The article, titled “Patient-derived xenografts for individualized care in advanced sarcoma,” was published online in April in Cancer.

    In the study, 16 patients with heavily pretreated advanced sarcoma had their tumors successfully engrafted into mice as avatars to test different drug treatments. Thirteen of the 16 patients commenced treatment with the avatar-directed therapy and all showed a correlation between the results in their mice and their clinical outcome. Mouse avatar drug sensitivity data was used more than once for three patients to accurately predict responses to several lines of therapy without requiring fresh tissue grafting.

    “When treating patients with advanced disease, we frequently have a number of treatment options at our disposal but no predictive methods for determining which one will have the best outcome for the individual patient,” said Justin Stebbing, M.D., Professor of Cancer Medicine and Oncology of Imperial College London and principal investigator of the study. “In this study, the technology has shown the potential to provide a predictive approach to finding the right treatment for the individual patient.”

    Every TumorGraft is preserved as a living sample for future patient use and can be re-grown and tested in the event of cancer progression or recurrence.

  • Better Informed Treatment Decisions

    The Clearity Foundation, launched in 2008 in San Diego to help ovarian cancer patients across the U.S. and their physicians make better-informed treatment decisions, provides molecular profiling information about individual ovarian tumors. The foundation’s reports, according to founder Laura K. Shawver, Ph.D., uses protein profiling for chemosensitivity and resistance markers in addition to determining DNA sequences to examine genomic alterations such as mutations, deletions, and amplifications to prioritize treatment options for ovarian cancer patients.

    Clearity works with CLIA-certified labs to perform the testing. Dr. Shawver, herself an ovarian cancer survivor, told GEN: “We don’t want to give toxicity without benefit. As patients, we can tolerate it if we think it will give a benefit but toxicity without benefit is unacceptable.”

    This is one potential benefit of profiling, i.e., to weed out drugs that have a lower probability of working. This can be important when physicians have multiple drugs to choose from or multiple clinical trials for which their patient is eligible. Dr. Shawver notes that ovarian cancer is typically treated with the same chemotherapy at initial diagnosis but, at recurrence, there are multiple choices of both FDA approved therapies and clinical trials. 

    In a paper published in Gynecological Oncology last year Dr. Shawver and colleague used targeted next-generation sequencing (NGS) to evaluate its ability to identify unanticipated targetable genomic alterations for patients with relapsed ovarian epithelial carcinoma.

    The scientists sequenced 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries. DNA was isolated from FFPE sections from 48 histologically verified relapsed ovarian cancer specimens. The original primary tumor was sequenced in 26 (54%) of the cases and recurrent/metastatic tumor site biopsies were sequenced in 22 (46%) of the cases.

    Actionability was defined as genomic alterations that predict sensitivity or resistance to approved or standard therapies or are inclusion or exclusion criteria for specific experimental therapies in NCI registered clinical trials.

    NGS’ assessment of therapy-resistant ovarian cancer the authors concluded, identifies an unexpectedly high frequency of genomic alterations that could influence targeted therapy selection for the disease.

    Dr. Shawver’s day job is as CEO of Cleave Biosciences, a cancer drug discovery company. The company expects to begin clinical trials this summer on a novel p97 inhibitor, measuring predictive enrichment markers in their studies.

    The next few years will prove a critical phase of the development of molecular diagnostics tests, where we will learn whether patient outcomes can be improved and whether the benefits will outweigh the costs of these emerging molecular diagnostics tests.

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