Policy Issues in the Development of Personalized Medicine in Oncology Workshop Summary (2010) / Chapter Skim
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Personalized Cancer Medicine Technology
Personalized Cancer Medicine Technology
Pages 3-24
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• Gene expression variations in tumors that predict breast cancer recurrence (Oncotype DX, MammaPrint)
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to predict patients' response to panitumumab and cetuximab therapy in colorectal cancer.1 Phase III clinical trials have recently confirmed the predictive value of EGFR mutations for response to gefitinib (Iressa) and erlotinib (Tarveva)
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R01618 vector editable designed clinical trials, that a predictive test truly predicts response to treatment, rather than indicating a prognosis independent of treatment. A potential benefit of predictive tests is that they limit the number of individuals who will have an adverse or ineffective response to a therapeutic treatment.
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DECIPHERING THE CLINICAL IMPLICATIONS Dr. Donald Small of the Sidney Kimmel Comprehensive Cancer Center illustrated some of the difficulties of making treatment decisions based on the results of predictive tests.
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Shak noted that personalized medicine requires the integration of other prognostic factors, such as tumor size and grade, with genetic factors. "These factors all need to be taken into account.
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; Meshinchied uneditable image originally published in Blood. Meshinchi, S., T
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The use of KRAS genotyping results in a near doubling of response rate and progression-free survival of patients with colorectal cancer treated with these medicines, compared to an unselected patient population, Dr. Amado said (Jonker et al., 2007)
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Dr. Friend described several predictive tests that examine large sets of genetic markers that use this technology, including an FDA-cleared, 70-gene expression test called MammaPrint, which predicts women likely to experience a recurrence of their breast cancer, and the Oncotype DX test (Paik et al., 2004; van't Veer et al., 2002)
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Ratain concurred, stating that "our current strategy in pharmacogenomics is to collect DNA samples in conjunction with large clinical trials and to perform genome-wide typing to identify candidates associated with both toxicity and efficacy. Then we can conduct replication studies using samples from other similar studies, and perform mechanistic studies to confirm function." A recent study used such a strategy to show a genomic basis for an adverse reaction to statin treatment (statin myopathy)
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2009. Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks.
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Mass said. Adding to the complexity of developing personalized cancer medicine is individual variability in how much of a given drug reaches its target, Dr.
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. "Shouldn't we be individualizing drug dosing to attain sufficient inhibition in all patients?
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. Predictive tests also should be useful in clinical decision making and in improving patient outcomes (clinical utility)
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Although prospective clinical trials are viewed as the gold standard for determining clinical utility, such retrospective/prospective trials suffice, as long as they are done in a rigorous manner (i.e., a different dataset is used for clinical utility than was used for validation, and the analyses are prespecified, robust, and show a large treatment effect)
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Dr. Shak said the clinical validation study done on the Oncotype DX test would have been impossible if the National Surgical Adjuvant Breast and Bowel Project, a clinical trials cooperative group, had not preserved tissue samples it collected in the 1990s to establish the benefit of chemotherapy in women with breast cancer (Paik et al., 2004)
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She suggested using a strategy similar to that used by Dr. Susan Love, who used the Internet to create a "million-person army" of women with breast cancer; participating women are notified of clinical studies on breast cancer, including clinical trials on breast cancer drugs (Love/Avon Army of Women, 2009)
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TEST RELIAbILITy Even if all the obstacles above are overcome, and tests and clinical trials do reveal the analytical validity, clinical validity, and clinical utility of a predictive test, the reliability of test results can still be problematic due to 2 The Clinical Laboratory Improvement Amendments of . Public Law 100-578.
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The breast cancer drug Herceptin is only effective in women with tumors that have excess copies of the HER2 gene. When Herceptin was ready for clinical testing, a technique used to detect gene amplification called fluorescent in situ hybridization (FISH)
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TRANSLATION CHALLENGES An additional technological hurdle to personalized medicine in oncology is implementing predictive tests into clinical practice. For example, an analysis by United Healthcare revealed that patients who are eligible for Herceptin often do not receive it, and those who are unlikely to respond to Herceptin are often treated with the drug (Phillips, 2008)
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. Clinical decision support tools, such as electronic medical records, might be able to fill in some of the gaps in that education, said SACGHS Chair Dr.
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Dr. Johnson noted that there may also be limited availability of patient tumor tissue for such testing, especially for inaccessible tumors, such as lung cancers.
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He suggested that the FDA should stipulate that no registry trial be accepted without a prospective codevelopment plan, or at least a prospective plan for a specimen bank, and a transparent system to access specimens that provides adequate protection for intellectual property rights. "The sin is that the large pharmaceutical companies have not collected and bagged and stored specimens so that we could ask questions from the trials that they've run," he said.
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