Progress in Cancer Genomic Medicine: A Year in Review, 2012
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SummaryDuring the past year, the oncology community has been witness to a number of major reports regarding molecular-based therapeutics, as well as prognostic and predictive approaches based on genomic data, which challenge or simply change the standard paradigms for the management of malignant disease. In this brief commentary, several provocative reports are highlighted.
New Insights Into the Genetic Underpinnings of CancerTwo reports shed some light on the genetic causes of certain cancers, both of which give new insight into how we might approach these diseases in the clinic.
It is well established that germline BRCA mutations are associated with the development of cancers of the breast and ovary. The question that investigators sought to answer was whether BRCA mutations were susceptible to so-called genetic anticipation, leading to the development of cancer at earlier ages because of increasing DNA instability. In a cohort of 132 "second-generation" patients, median age for the development of a BRCA-associated breast cancer was 42 (range, 28-55 years) vs a considerably older median age of 48 (range, 30-72) in the preceding generation in these same families.  For the entire group, it was estimated that the second generation developed cancer 7.9 years earlier than did the preceding generation, and significant differences were noted when looking at subgroups such as BRCA1 or BRCA2 mutations only and maternal or paternal inheritance only. These data, if confirmed by other investigators, have important implications for cancer screening schedules and for optimal timing of possible risk-reducing surgery with mastectomy and oophorectomy.
It has long been recognized that nodular sclerosing Hodgkin lymphoma has a strong heritable component. In an effort to discover particular genetic polymorphisms that may increase the risk for the development of this disease, investigators conducted genome-wide analysis of 393 patients with nodular sclerosing Hodgkin lymphoma and 3315 controls and found that several polymorphisms on chromosome 6p21.32 were highly associated with this uncommon cancer, with P values ranging from 10 -8 to 10 -10.  Of note, these impressive results were confirmed in an independent dataset and provide strong support for the importance of specific germline polymorphisms in the development of this malignancy.
Using Genetics to Maximize Cancer Treatment BenefitThree investigations focused on ways to better identify which patients might benefit most from different cancer treatments, and all have clear implications for the way that cytotoxic and targeted therapies might be evaluated and used in the clinic.
Investigators at the MD Anderson Cancer Center reported their experience with treating patients on phase 1 trials upon matching a molecular abnormality in an individual tumor to an investigative agent that is suggested to favorably affect that target.  A total of 460 patients (40% of those tested) had at least 1 well-defined molecular abnormality. A group of 175 patients with a single aberration treated with an investigational antineoplastic agent that was "matched" to the abnormality was compared with 116 patients in the program who were treated without the benefit of matching. The objective response rate of 27% vs 5% ( P < .0001) as well as the median overall survival of 13.4 months vs 9.0 months ( P = .017) were both superior in the matched population. In a multivariate analysis, treatment that matched a drug to a particular molecular abnormality was an independent factor that predicted response and time to treatment failure. These data provide very strong support for employing such strategies in the phase 1 trials arena.
An intriguing report suggested a possible explanation for dramatic responses seen in a small handful of patients with metastatic bladder cancer treated with the mTOR inhibitor everolimus in a phase 2 clinical trial.  Whole genome sequencing of a tumor from a patient managed on this trial who had achieved a complete response and had maintained the response for more than 2 years revealed loss-of-function mutations in TSC1 and NF2. In preclinical models, mutations in these genes have been shown to inhibit mTOR signaling, [5,6] suggesting that tumors with these mutations might be exquisitely sensitive to treatment with mTOR-inhibiting agents. Analysis of sequencing of tumors from 13 additional patients treated on this trial showed that the presence of these mutations was associated with both a longer time to disease recurrence (median, 4.1 months vs 1.8 months; P = .001) and an ability to stay on therapy for a longer period of time (median, 7.7 months vs 2.0 months; P = .004). Although the number of patients examined is very small, the data clearly suggest that identifying mutated TSC1 and NF2 may be a highly relevant method for the selection of patients with bladder cancer (and perhaps other tumor types) who might benefit from an mTOR inhibitor.
Chemotherapy resistance is a major problem in many tumor types, and it has been suggested that epigenetic alterations in DNA that result in changes to methylation status may affect the benefits of anticancer therapy. To study this issue in colon cancer, investigators examined the relationship between sensitivity to chemotherapy and the methylation status of TFAP2E, a gene that encodes proteins known to be important to the development of colon cancer.  A striking increase of almost 6-fold in tumor response was seen in patients whose tumors exhibited hypomethylation of TFAP2E vs the entire treated population, while a significantly lower objective response rates was seen where hypermethylation was observed ( P < .001). These data, if confirmed by others, suggest that obtaining a pretreatment analysis of the methylation status of TFAP2E could be quite useful in determining an optimal management strategy for individual patients with colon cancer.
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