American Society of Clinical Oncology educational book
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Am Soc Clin Oncol Educ Book · Jan 2014
ReviewNational Cancer Institute's Precision Medicine Initiatives for the new National Clinical Trials Network.
The promise of precision medicine will only be fully realized if the research community can adapt its clinical trials methodology to study molecularly characterized tumors instead of the traditional histologic classification. Such trials will depend on adequate tissue collection, availability of quality controlled, high throughput molecular assays, and the ability to screen large numbers of tumors to find those with the desired molecular alterations. ⋯ The NCTN has the ability to seamlessly perform ethics review, register patients, manage data, and deliver investigational drugs across its many sites including both in cities and rural communities, academic centers, and private practices. The initial set of trials will focus on different questions: (1) Exceptional Responders Initiative-why do a minority of patients with solid tumors or lymphoma respond very well to some drugs even if the majority do not?; (2) NCI MATCH trial-can molecular markers predict response to targeted therapies in patients with advanced cancer resistant to standard treatment?; (3) ALCHEMIST trial-will targeted epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting?; and (4) Lung Cancer Master Protocol trial for advanced squamous cell lung cancer-is there an advantage to developing drugs for small subsets of molecularly characterized tumors in a single, multiarm trial design? These studies will hopefully spawn a new era of treatment trials that will carefully select the tumors that may respond best to investigational therapy.
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Am Soc Clin Oncol Educ Book · Jan 2014
ReviewPrecision cancer medicine: the future is now, only better.
The promise of precision medicine for cancer is already being realized with the recent introduction of many targeted therapies, some with companion diagnostic tests that identify patients most likely to benefit from treatment. The utility of molecular profiling of cancer to identify actionable aberrations has been suggested by several small clinical trials conducted in patients with advanced cancer and by many anecdotes but is yet to be proven in well-designed, prospective, randomized trials. ⋯ Looking to the future, advanced omics technologies and computational techniques will enable assessment of not only genomic variants, as performed today, but also of pathway and network aberrations that will greatly facilitate selection of drug combinations likely to benefit specific patients. As our deepening understanding of tumor biology converges with rapid advances in measurement science and technology and computational analysis, we have an enormous opportunity to create a future for precision medicine in oncology that provides for highly specific, minimally toxic, and dramatically effective treatment for each patient.
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Risk for breast cancer can be easily and rapidly assessed using validated, quantitative models. Multiple randomized studies show that the selective estrogen response modifiers (SERMs) tamoxifen and raloxifene can safely reduce the risk of invasive breast cancer in both pre- and postmenopausal women. Treatment resulted in a 38% reduction in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. ⋯ The MAP3 trial showed a 65% reduction in the annual incidence of invasive breast cancer in postmenopausal women who were at moderately increased risk for breast cancer who took the aromatase inhibitor exemestane. The IBIS-II trial showed a 53% reduction in the risk of invasive breast cancer in postmenopausal women aged 40 to 70 who took the aromatase inhibitor anastrozole. Of the 50 million white women in the United States aged 35 to 79, 2.4 million would have a positive benefit/risk index for chemoprevention.
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Am Soc Clin Oncol Educ Book · Jan 2014
ReviewManagement and future directions in non-small cell lung cancer with known activating mutations.
Lung cancer accounts for a quarter of all cancer deaths. Non-small cell lung cancer (NSCLC) is currently segregated by the presence of actionable driver oncogenes. This review will provide an overview of molecular subsets of lung cancer, including descriptions of the defining oncogenes (EGFR, ALK, KRAS, ROS1, RET, BRAF, ERBB2, NTRK1, FGFR, among others) and how these predict for response to small molecule tyrosine kinase inhibitors (TKIs) that are either clinically available or in clinical trial development for advanced NSCLC. ⋯ Similar to EGFR mutations, ALK rearrangements exemplify an oncogene-driven NSCLC that can be effectively palliated with a precision TKI therapy (the multitargeted ALK/MET/ROS1 TKI crizotinib). When resistance to first-line crizotinib therapy occurs, multiple second generation ALK TKIs have demonstrated impressive rates of disease control in clinical trials, and these may modify long-term outcomes for patients with ALK-positive NSCLC. The development of TKIs for other oncogene-driven NSCLCs may expand the portfolio of precision therapies for this recalcitrant cancer.
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We have entered the genomic sequencing era in the treatment of acute myeloid leukemia (AML); our patients increasingly and justifiably demand personalized treatment based on aberrations of their own leukemia. Except in rare cases we are not yet able to provide truly personalized therapy, so the question of "hope or hype?" posed by the American Society for Clinical Oncology (ASCO) for this educational topic is quite timely. The answer based solely on advances in genomic sequencing is "both". ⋯ However, there is no question that ultimate success lies in understanding the genetic underpinnings of disease. When decades of research in molecular biology and immunology are combined with transformative advances in cancer genetics, the answer is undeniably that our patients finally have reason for hope. Here, we review selected novel therapies for AML in areas such as immunotherapeutics, epigenetics, kinase inhibition/pathway inhibition, and the marrow microenvironment.