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Socinski M.A.,University of Pittsburgh | Goldman J.,Premiere Oncology | El-Hariry I.,Synta Pharmaceuticals | Koczywas M.,City of Hope | And 19 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC). Experimental Design: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies. Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.©2013 AACR. Source


Prasad V.,Knight Cancer Institute | Fojo T.,Columbia University | Brada M.,University of Liverpool
The Lancet Oncology | Year: 2016

Imatinib, the first and arguably the best targeted therapy, became the springboard for developing drugs aimed at molecular targets deemed crucial to tumours. As this development unfolded, a revolution in the speed and cost of genetic sequencing occurred. The result-an armamentarium of drugs and an array of molecular targets-set the stage for precision oncology, a hypothesis that cancer treatment could be markedly improved if therapies were guided by a tumour's genomic alterations. Drawing lessons from the biological basis of cancer and recent empirical investigations, we take a more measured view of precision oncology's promise. Ultimately, the promise is not our concern, but the threshold at which we declare success. We review reports of precision oncology alongside those of precision diagnostics and novel radiotherapy approaches. Although confirmatory evidence is scarce, these interventions have been widely endorsed. We conclude that the current path will probably not be successful or, at a minimum, will have to undergo substantive adjustments before it can be successful. For the sake of patients with cancer, we hope one form of precision oncology will deliver on its promise. However, until confirmatory studies are completed, precision oncology remains unproven, and as such, a hypothesis in need of rigorous testing. © 2016 Elsevier Ltd. Source


News Article
Site: http://www.scientificamerican.com

Yet another major study has challenged the efficacy of mammograms. The study examined the claim that mammography has helped reduce breast-cancer mortality in North America and Europe by 15 percent or more over the past two decades. Carried out by Archie Bleyer of the Knight Cancer Institute in Oregon and two colleagues and published in the International Journal of Cancer, the study found little correlation between screening and the decline in breast-cancer deaths. “In the United States,” the authors state, “the magnitude of the mortality decline is greater in the unscreened, younger women than in the screened population and regional variation in the rate of breast cancer mortality reduction is not correlated with screening penetrance, either as self-reported or by the magnitude of screening-induced increase in early-stage disease.” An examination of data from other countries points to the same conclusion. “Countries without a nationally-established screening program at the time of onset of their breast cancer mortality reduction (Norway, Belgium, Canada, Republic of Ireland, Northern Ireland) had rate reductions (mean 2.25% per year) equivalent to or greater than countries with implemented national programs (United States, Sweden, Netherlands) (mean 1.79% per year). The country with the highest participation rate in screening mammography had the slowest reduction (Sweden).” The authors attribute the decline in breast-cancer mortality to advances in treatment, with screening playing a “minor role.” But they cite other studies that raise doubts about even a “minor” benefit; when all causes of mortality are considered rather than just breast-cancer mortality, women who are screened do not live longer than unscreened women. At the end of their paper, Bleyer and his colleagues imply that not all analyses of mammography are carried out in good faith. Quoting another health-care analyst, they note that some researchers “torture the data to make it confess to what one knows to be the real truth!” This quote came to mind when I read “Early Detection of Breast Cancer Backed by U.K. Study” by Melinda Beck of The Wall Street Journal. Beck reports on a study, published in Lancet, on screened British women diagnosed with abnormal milk duct cells, also called ductal carcinoma in situ, or DCIS. “Some experts argue that DCIS shouldn’t be labeled cancer at all, since it’s unclear whether it will spread outside the milk ducts,” Beck states. But the British study found that “in 90% of the local screening areas, for every three cases of DCIS detected and treated, one fewer case of invasive cancer was diagnosed in the following three years than would have been without early intervention.” The study provided no evidence that early diagnosis of DCIS extended women’s lives, and it implied that some women diagnosed with DCIS might have been treated unnecessarily. Stephen Duffy, the study’s lead author, nonetheless tells Beck that the findings “suggest that a substantial proportion of DCIS will become invasive if untreated, and it is therefore worth detecting and treating early.” That sounds like torturing the data, especially in light of Bleyer’s study; or this 2013 analysis by the Cochrane Group, which is renowned for its impartial assessments of health-care practices; or other studies on which I have reported (see Further Reading). See also this recent article in the online journal FiveThirtyEight by science journalist Christie Aschwanden, who has reported brilliantly and courageously on the mammography debate. She writes: “Underneath the debate about at which age and at what frequency we should urge women to get mammograms, another important question looms: Is it reasonable to recommend a test that will produce false positives for something like half of the people who take it? Is it OK to risk harming hundreds of women in hopes of helping a handful avert a breast cancer death? The [American Cancer Society and U.S. Preventive Services Task Force] have concluded yes, but that’s a value judgment, not a scientific one.” Do Mammograms Kill More Women Than They Save? Consumers Must Stop Insisting on Mammograms and Other Ineffective Cancer Tests. Celebrities Should Inform Women about Risks as Well as Benefits of Mammograms.


Zamah A.M.,University of California at San Francisco | Mauro M.J.,Knight Cancer Institute | Druker B.J.,Knight Cancer Institute | Oktay K.,New York Medical College | And 3 more authors.
Oncologist | Year: 2011

Imatinib mesylate is the first in a family of highly effective, minimally toxic, targeted agents used widely to treat Philadelphia-positive leukemias and selected other cancers, leading to a steady rise in the prevalence of patients using such therapy. Because failure of therapy would require conventional gonadotoxic chemotherapeutics, many female patients using imatinib may choose to preserve fertility. Herein, we provide evidence of a potential negative effect of imatinib on ovarian function by reporting the first case of a woman who showed a severely compromised ovarian response to gonadotropin stimulation while on imatinib, with a normal ovarian response after stopping this medication. © AlphaMed Press. Source


Dao K.-H.T.,Knight Cancer Institute | Tyner J.W.,Oregon Health And Science University | Tyner J.W.,Knight Cancer Institute
Clinical Cancer Research | Year: 2013

Disease relapse remains a major cause of death in patients with BCR-ABL-positive leukemia despite advances in treatment with kinase inhibitors. Significant efforts are underway to target pathways that maintain leukemia stem cells. Targeting these pathways holds promise for definitive leukemia eradication or improvement of the effectiveness of currently available therapies. © 2013 AACR. Source

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