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Sawyers C.L.,Sloan Kettering Cancer Center | Abate-Shen C.,Columbia University | Anderson K.C.,Dana-Farber Cancer Institute | Barker A.,Arizona State University | And 12 more authors.
Clinical Cancer Research | Year: 2013

Background Amazing progress has been made against cancer because of the dedicated work of researchers throughout the biomedical research enterprise. Their efforts have spurred, and continue to spur, the translation of scientific discoveries into new and better ways to prevent, detect, diagnose, and treat cancer. These remarkable advances are contributing to the rise in the number of people who are surviving longer and living life to the fullest after their cancer diagnosis. In fact, the number of cancer survivors living today in the United States is estimated to be more than 13.7 million. The improvements in health care that have significantly reduced the burden of cancer were made possible by the scientific foundation provided through the many decades of investments in basic, translational, and clinical research. These investments come from the federal government, philanthropic individuals and organizations, and the private sector. The federal investments in biomedical research, made primarily through the National Institutes of Health (NIH) and the National Cancer Institute (NCI), have been particularly instrumental in building our current scientific foundation. Although extraordinary advances in cancer research have deepened our understanding of how cancer develops, grows, and threatens the lives of millions, it is projected that 580,350 Americans will die from one of the more than 200 types of cancer in 2013. Moreover, because more than 75 percent of cancer diagnoses occur in those aged 55 and older and this segment of the population is increasing in size, we face a future where the number of cancer-related deaths will increase dramatically. As a result, cancer is predicted to soon become the number one disease-related killer of Americans. This trend is being mirrored globally, and it is estimated that in 2030, more than 13 million people worldwide will lose their lives to cancer. As the number of cancer deaths increases, the economic burden of cancer will mushroom. Given that the global economic toll of cancer already is 20 percent higher than that from any other major disease, it is imperative that all sectors of the biomedical research enterprise work together to deliver future breakthroughs to help reduce the incidence of cancer. Fortunately, we have never been better positioned to capitalize on our hard-won understanding of cancer - what causes it, what drives it. We now know that changes in an individual's genes alter certain protein components of the cell, driving cancer initiation, development, and spread (metastasis). We also know that therapies that specifically target these defects are often beneficial to patients while being less toxic than older therapies. However, continued progress is in jeopardy. This is because investments in the NIH by the federal government have been steadily declining for the past decade. On top of this, on March 1, 2013, sequestration slashed the NIH budget by $1.6 billion, or 5.1 percent. This third AACR Cancer Progress Report to Congress and the American public seeks again to serve as a comprehensive educational tool that illustrates the astounding return on investment in cancer research and biomedical science, while also celebrating the many ways that we have continued to make research count for patients in the past year. Scientific momentum has brought the arrival of a new era in which we will be able to develop even more effective interventions and save more lives from cancer, but to do so will require an unwavering, bipartisan commitment from Congress and the administration to invest in our country's remarkably productive biomedical research enterprise. © 2013 American Association for Cancer Research. © The Ecological Society of America.


Wolff A.C.,Johns Hopkins Kimmel Comprehensive Cancer Center | Hammond M.E.H.,University of Utah | Hicks D.G.,University of Rochester | Dowsett M.,Royal Marsden Hospital | And 15 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. Methods: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. Results: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. Recommendations: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. Copyright © 2013 American Society of Clinical Oncology and College of American Pathologists. All rights reserved.


Wolff A.C.,Johns Hopkins Kimmel Comprehensive Cancer Center | Lazar A.A.,University of California at San Francisco | Bondarenko I.,State Medical Academy | Garin A.M.,Russian Oncological Research Center | And 15 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose: Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. Patients and Methods: This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). Results: Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). Conclusion: Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation. © 2012 by American Society of Clinical Oncology.


Metzger-Filho O.,Dana-Farber Cancer Institute | Metzger-Filho O.,Free University of Colombia | Metzger-Filho O.,Breast European Adjuvant Study Team Data Center | de Azambuja E.,Free University of Colombia | And 24 more authors.
Oncologist | Year: 2013

Purpose. This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries. Methods. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. Results. South America had a significantly longer time to RA approval (median: 236 days, range: 21-257 days) than Europe (median: 52 days, range: 0 -151 days), North America (median: 26days, range:22-30days),and Asia-Pacific (median:62 days, range: 37-75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21-257 days) than high-income (median: 47 days, range: 0-112 days) and lower-middle income economies (median: 57 days, range: 37-62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0-174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26-412 days). Conclusion. This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. Thiswould enable faster access of patients to innovative therapies and enhance the efficiency of clinical research. © AlphaMed Press 2013.


Lichtman S.M.,Sloan Kettering Cancer Center | Cirrincione C.T.,Duke University | Hurria A.,City of Hope | Jatoi A.,Mayo Medical School | And 7 more authors.
Journal of Clinical Oncology | Year: 2016

Purpose: CALGB 49907 showed the superiority of standard therapy, which included either cyclophosphamide/doxorubicin (AC) or cyclophosphamide/methotrexate/fluorouracil over single-agent capecitabine in the treatment of patients age $ 65 with early-stage breast cancer. The treatment allowed dosing adjustments of methotrexate and capecitabine for pretreatment renal function. The purpose of the current analysis was to assess the relationship between pretreatment renal function and five end points: toxicity, dose modification, therapy completion, relapse-free survival, and overall survival. Methods: Pretreatment renal function was defined as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Multivariable logistic and proportional hazards regression were used to model separately for each regimen the relationship between CrCl and the first three binary end points and the last two time-to-event end points, respectively, after adjusting for variables of prognostic importance. Results: Six hundred nineteen assessable patients were analyzed. The incidence of stage III (moderate) or stage IV (severe) renal dysfunction was 72%, 64%, and 75% for treatment with cyclophosphamide/methotrexate/fluorouracil, AC, and capecitabine, respectively. There was no relationship for any regimen between pretreatment renal function and the five end points. For AC, as CrCl increased, the odds of nonhematologic toxicity decreased (P=.008), whereas for capecitabine, as CrCl increased, the odds of experiencing toxicity of any type also increased (P=.035). Patients with renal insufficiency who received dose modifications were not at increased risk for complications compared with those who did not have renal insufficiency and received a full dose. Conclusion: Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients. © 2016 American Society of Clinical Oncology. All rights reserved.

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