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Cortazar P.,U.S. Food and Drug Administration | Zhang L.,U.S. Food and Drug Administration | Untch M.,HELIOS Klinikum | Mehta K.,German Breast Group | And 33 more authors.
The Lancet | Year: 2014

Background Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. Methods We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response-ypT0 ypN0, ypT0/is ypN0, and ypT0/is-for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. Findings We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone- receptornegative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R2=0·03, 95% CI 0·00-0·25) and OS (R2=0·24, 0·00-0·70). Interpretation Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.

Sinicrope F.A.,Mayo Medical School | Foster N.R.,Mayo Medical School | Marsoni S.,SENDO Foundation | Monges G.,Institute Paoli Calmettes | And 5 more authors.
Journal of the National Cancer Institute | Year: 2011

Background Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables.MethodsWe included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using χ2 or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided.ResultsIn this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P <. 001), delayed TTR (P <. 001), and fewer distant recurrences (22% vs 12%; P <. 001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P =. 005) and improved DFS (P =. 035) and OS (P =. 031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P =. 011) and reduced recurrence to all sites for pMMR tumors (P <. 001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P =. 006). ConclusionsPatients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors. © 2011 The Author.

News Article | December 16, 2016
Site: www.eurekalert.org

Philadelphia, PA -- NRG Oncology clinical trial NRG-LU001 successfully reached its accrual goal of 168 patients. NRG-LU001: Randomized Phase II Trial of Concurrent Chemoradiotherapy with or without Metformin Hydrochloride (HCL) in Locally Advanced Non-Small Cell Lung Cancer (NSCLC) is the first clinical trial that seeks to determine whether metformin added to standard, concurrent chemoradiotherapy can improve progression-free survival (PFS) for patients with locally advanced NSCLC. NRG-LU001 initially opened for patient enrollment on August 25, 2014 and over the past 15 months enrolled patients from 80 institutions in the United States, Canada, and Israel. Metformin is commonly used in the treatment of diabetic patients; however, pre-clinical and retrospective clinical studies have suggested that it may be able to improve the response of epithelial tumors to chemoradiotherapy. "Metformin modifies carbohydrate and lipid metabolism and mediates in cells a state of mild energy stress. This is shown to lead to inhibition of oncogenes and activation of molecular tumor suppressors," stated Theodoros Tsakiridis, MD, PhD, FRCPC, a radiation oncologist at the Juravinski Cancer Center in Ontario, Canada and co-principal investigator for NRG-LU001. "We hope that the results of this prospective randomized study will confirm the pre-clinical and retrospective trial results and help us design future trials with metformin." NRG-LU001 aims to examine if the connection between metformin and the modification of metabolism can improve chemoradiotherapy responses for patients with stage IIIA or IIIB NSCLC. "If the addition of a commonly used agent like metformin can improve outcomes following a diagnosis of locally advanced NSCLC, this could potentially open the gates to re-purposing drugs currently used for other diseases," said Heath Skinner, MD, PhD, assistant professor of radiation oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas and co-principal investigator for NRG-LU001. "Additionally, based on pre-clinical data, metformin sensitizes other tumor types to radiation and chemotherapy as well, thus a positive clinical trial in lung cancer could lead to trials in other types of cancer." "Thank you and congratulations to the research sites in the United States, Israel, and Canada that enrolled patients on the NRG-LU001 trial. We eagerly await the results of this NRG Oncology trial and the impact it could have for NSCLC patients," says Walter J. Curran, Jr, M.D., the report's senior author, NRG Oncology Group Co-Chair, and Executive Director of the Winship Cancer Institute of Emory University in Atlanta. For more information on this trial, please visit NRG-LU001. NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group. The research organization seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology's extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI's National Clinical Trials Network.

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 16 more authors.
Archives of Pathology and Laboratory Medicine | Year: 2014

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 patientswith 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 © 2014 College of American Pathologists.

News Article | October 28, 2016
Site: www.prweb.com

New Allegheny Health Network research, presented this week at the American Society for Radiation Oncology (ASTRO) meeting in Boston, has found that early stage breast cancer patients with cardiac pacemakers – who are typically advised to choose mastectomy, or complete breast removal – can be successfully treated with lumpectomies in combination with whole breast radiotherapy (WBRT). A breast-conserving lumpectomy followed by radiation therapy is the preferred treatment for most early stage breast cancer patients, but radiation can damage cardiac pacemakers. Some are advised to have the implanted device relocated prior to surgery, which can be an unsafe procedure for some patients. “We want to raise awareness that radiation following lumpectomy can be safely used to treat these women, without damaging the pacemaker or sacrificing efficacy,” said Mark Trombetta, MD, System Director of Clinical Programs, AHN Cancer Institute, Division of Radiation Oncology. “With careful planning of radiation treatment, these women can feel confident in choosing to preserve their breast. For most patients, mastectomy can be avoided.” The AHN researchers studied 20 women with early stage breast cancer and cardiac pacing devices, all of whom had been advised to consider mastectomy. They underwent lumpectomies, then radiation treatment with a variety of modalities chosen and calibrated in order to avoid exposing the pacemaker to excessive radiation. Pre-treatment planning estimated the dose of radiation to the device, and a dosimeter measured exposure during treatment. The pacemaker’s function was monitored prior to, during and after treatment. None of the patients experienced device failure, and all are disease-free at a mean follow-up time of three years. One woman’s pacemaker recalibrated during treatment and was immediately reset to specifications. “Mastectomies, although therapeutic, cause disfigurement and have lasting side effects such as lymphedema and limited arm movement,” said Thomas B. Julian, MD, Director of Breast Surgical Oncology at AHN. “We are happy to be able to offer women with pacemakers a less invasive surgical option that effectively treats their cancer and retains their dignity and quality of life.” “Allegheny Health Network has long been known for research that reduces the treatment burden for women with cancer,” said David Parda, MD, Chair, Allegheny Cancer Institute. “Our patients know that we will provide them with effective, evidence-based treatment that addresses their individual needs.” About Allegheny Health Network Cancer Institute The Allegheny Health Network Cancer Institute is home to a comprehensive cancer prevention, diagnosis, treatment, education, and research program that provides the complete spectrum of oncology care. The Network is comprised of more than 50 oncology clinics across the western Pennsylvania region, including hospital-based programs at Allegheny General Hospital, Allegheny Valley Hospital, Forbes Hospital, Jefferson Hospital, West Penn Hospital and other collaborative hospital partners. The Network is home to more than 200 medical, surgical and radiation oncology physicians, one of the state’s largest bone marrow transplant and cellular therapy programs, and the nation’s largest radiation oncology network accredited by both the American Society for Radiation Oncology and American College of Radiology. Allegheny Health Network’s cancer research program offers patients access to more than 200 clinical trials and the Network’s physicians hold leadership roles at the National Cancer Institute, the NCI-funded National Surgical Adjuvant Breast and Bowel Project, (the world’s foremost breast and bowel cancer research group based at Allegheny General Hospital), and many national and international organizations that advance cancer care. The AHN Cancer Institute also has a formal collaboration with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center to share knowledge and expertise to advance patient care, education, and research for cancer patients and oncology professionals.

News Article | January 22, 2016
Site: www.biosciencetechnology.com

Some stage-2 colon cancer patients may benefit from the use of chemotherapy after surgery, according to a retrospective study by researchers at the Stanford University School of Medicine. Previous studies have suggested that chemotherapy given to such patients had limited benefit. The study was published Jan. 21 in The New England Journal of Medicine along with two editorials describing its significance. The researchers first categorized colon cancer patients based on the presence or absence of a protein called CDX2, which is found in mature colon cells. In these cells, CDX2 helps to control the expression of other genes that drive colon cell specialization. The researchers found that about 4 percent of people with colon cancer have tumors that don’t express CDX2. In an initial study of 466 patients with any stage of colon cancer, only about 41 percent of those with cells lacking CDX2 lived disease-free for five years after treatment, compared to 74 percent of those with CDX2 in their cancer cells.   CDX2-negative cancers respond well to chemo But the researchers identified another important distinction between the two groups, particularly in those with stage-2 disease: Patients whose tumor cells didn’t express CDX2 were much more likely to benefit from chemotherapy in addition to surgery than were people with CDX2-positive tumors. About 91 percent of patients with CDX2-negative cancers treated with chemotherapy in addition to surgery lived disease-free for five years versus about 56 percent of those who did not receive chemotherapy. Previous studies that did not distinguish between CDX2-positive and CDX2-negative cancers suggested that chemotherapy provided little additional benefit to stage-2 colon cancer patients. “We’ve learned that a patient group that formerly was not known to need adjuvant chemotherapy may, in fact, benefit from this treatment. Conversely, it may be possible to identify those patients who could avoid the toxic side effects of chemotherapy,” said Michael Clarke, M.D., professor of medicine and the Karel H. and Avice Beekhuis Professor in Cancer Biology. The retrospective study looked at gene expression in cancer cells and tissues from over 2,000 patients whose treatment courses and outcomes were known. The researchers emphasize that a randomized, prospective clinical trial is necessary to further confirm the results before clinical changes are codified. Clarke, who is also a member of the Stanford Cancer Institute and the associate director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, is the senior author of the study. Former instructors and Siebel fellows Piero Dalerba, M.D., and Debashis Sahoo, Ph.D., share lead authorship of the study. Dalerba is now an assistant professor of pathology and cell biology and of medicine (Division of Digestive and Liver Diseases) at Columbia University, and Sahoo is an assistant professor of pediatrics and of computer science at the University of California-San Diego. Stem cell, cancer connection Clarke and his colleagues have been studying the connection between stem cells and cancer for several years. For this study, Dalerba and Sahoo sought to devise a way to identify colon cancers that were more stem-cell-like, and thus likely to be more aggressive. They looked for a gene that was expressed in more mature cells but not in stem or progenitor cells. They did this by using a novel bioinformatics approach that drew on their knowledge of stem cell biology to identify developmentally regulated genes important in colon tissue maturation. Because they knew from previous research by Dalerba in the Clarke laboratory that stem and immature colon cells express a protein called ALCAM, Dalerba and Sahoo looked for genes whose protein product was negatively correlated with ALCAM expression. “We reasoned that those proteins would likely be involved in the maturation of colon tissue and might not be found in more aggressive, immature cancers,” Sahoo said. Finally, to ensure their results would be useful to doctors, the researchers added another criterion: The gene had to make a protein that was easily detectable by an existing, clinical-grade test. The screening technique identified a promising candidate: the CDX2 protein. “We chose CDX2 because it was the only candidate that was already used as a diagnostic biomarker in the clinic,” Dalerba said. “However, we were also intrigued by the fact that CDX2 is a master transcription factor controlling the expression of many differentiation genes in colon epithelial cells.” When they separated colon cancer cases into those with cells that either did or did not express CDX2, they found a marked difference in both five-year, disease-free survival rates and in response to chemotherapy. Data sharing and collaboration “The CDX2 protein plays a role in the differentiation of the intestinal epithelium,” said Clarke, who is also deputy director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. “The novel bioinformatics analyses used in this paper links its expression to more differentiated cells in colon cancers. We found that patients whose cancers lacked CDX2 expression, which suggests that their tumors have a high proportion of cancer stem and progenitor cells, had a much worse prognosis. However, their outcomes improved significantly if they had received chemotherapy as part of their treatment.” The study is hailed in an accompanying editorial in the journal as an endorsement of data sharing and collaboration among many different research groups. The Stanford researchers used information stored in the National Center for Biotechnology Information’s Gene Expression Omnibus database to identify CDX2. Tissue samples were provided by the Cancer Diagnosis Program of the National Cancer Institute, the National Surgical Adjuvant Breast and Bowel Project and the Stanford Tissue Microarray Database. “A major question in the cancer field is whether the study of cancer stem cells can lead to increases in survival for cancer patients. This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes,” Clarke said.

News Article | October 28, 2016
Site: www.prweb.com

SouthCoast Health is celebrating the one-year anniversary of its High Risk Breast Cancer Clinic during the month of October, which is Breast Cancer Awareness Month. Dr. Christa L. Jillard, who joined the practice on Sept. 1, 2015, leads the clinic, which became the first of its kind in Savannah. The clinic’s goals are early detection of women at high risk for breast cancer, to treat those at risk preventatively using a variety of measures and to use aggressive oncological treatments for those in need. Breast cancer is the most common cancer among women in the United States, other than skin cancer, according to the American Cancer Society (ACS), with 1-in-8 women (12 percent) developing invasive breast cancer during their lifetime. More than 7,000 new cases of breast cancer will be diagnosed in Georgia women in 2016, according to ACS estimates, and nearly 1,300 will die as a result of it. Dr. Jillard said that she wants to be an advocate for women in the Coastal Empire and Lowcountry. She recently became certified by medical technology company and surgical device manufacturer Invuity in its Hidden Scar surgical procedures, making her the only surgeon in Savannah with such a distinction. The cause of treating women with breast cancer – and women’s health, in general – is dear to Dr. Jillard, whose grandmother was diagnosed with the disease. “Being a female, I do have a strong interest in breast cancer,” Dr. Jillard said. “I also feel I have an obligation as a female surgeon not only to relate to patients who have this – I have friends and family who have been afflicted with this disease – but to use my skillset to really make a difference. Seeing that this is a specific kind of clinic that has not been established in Savannah, I see it as a great avenue and potential area for growth to make an impact on women here locally.” Women at high risk are those considered to have a five-year risk of developing breast cancer that is greater than 1.7 percent or those who have a lifetime risk of greater than 20 percent. To identify women at high risk, SouthCoast Health will use the Breast Cancer Risk Assessment Tool, also known as the “Gail model,” developed by scientists at the National Surgical Adjuvant Breast and Bowel Project (NSABP). The model has been tested and refined for more than 50 years to provide clinicians the highest possible degree of accuracy. Dr. Jillard cited ACS data that show a decrease in mortality of 34 percent between 1990 and 2010, largely because of improved surveillance and early detection — which, she said, are the hallmarks of work performed by high risk breast cancer clinics. SouthCoast Health brings a multi-disciplinary approach to its clinic, involving 15 to 20 clinicians across a range of specialties. Dr. Christa L. Jillard is board certified by the American Board of Surgery and practices at SouthCoast Health’s offices in Savannah, Hinesville and Bluffton. A graduate of Temple University School of Medicine in Philadelphia, she completed her residency in general surgery at the Medical University of South Carolina in Charleston. She completed a fellowship in endocrine surgery at Duke University Hospital in Durham, N.C., and is affiliated at St. Joseph’s/Candler Hospital and Memorial Health University Medical Center. SouthCoast Health is a multi-specialty, physician-owned medical group with 80 physicians and 18 locations. The organization has been providing quality healthcare solutions to the Coastal Empire and Lowcountry for more than 20 years and is dedicated to complete patient wellbeing. For more information, visit http://www.SouthCoast-Health.com and connect with SouthCoast Health on Facebook.

Chapman J.W.,Queen's University | O'Callaghan C.J.,Queen's University | Hu N.,Queen's University | Ding K.,Queen's University | And 6 more authors.
British Journal of Cancer | Year: 2013

Background:The ACCENT database, with individual patient data for 20 898 patients from 18 colon cancer clinical trials, was used to support Food and Drug Administration (FDA) approval of 3-year disease-free survival as a surrogate for 5-year overall survival. We hypothesised substantive differences in survival estimation with log-normal modelling rather than standard Kaplan-Meier or Cox approaches.Methods:Time to relapse, disease-free survival, and overall survival were estimated using Kaplan-Meier, Cox, and log-normal approaches for male subjects aged 60-65 years, with stage III colon cancer, treated with 5-fluorouracil-based chemotherapy regimens (with 5FU), or with surgery alone (without 5FU).Results:Absolute differences between Cox and log-normal estimates with (without) 5FU varied by end point. The log-normal model had 5.8 (6.3)% higher estimated 3-year time to relapse than the Cox model; 4.8 (5.1)% higher 3-year disease-free survival; and 3.2 (2.2)% higher 5-year overall survival. Model checking indicated greater data support for the log-normal than the Cox model, with Cox and Kaplan-Meier estimates being more similar. All three model types indicate consistent evidence of treatment benefit on both 3-year disease-free survival and 5-year overall survival; patients allocated to 5FU had 5.0-6.7% higher 3-year disease-free survival and 5.3-6.8% higher 5-year overall survival.Conclusion:Substantive absolute differences between estimates of 3-year disease-free survival and 5-year overall survival with log-normal and Cox models were large enough to be clinically relevant, and warrant further consideration. © 2013 Cancer Research UK.

Eng-wong J.,Georgetown University | Costantino J.P.,National Surgical Adjuvant Breast and Bowel Project | Costantino J.P.,University of Pittsburgh | Swain S.M.,National Surgical Adjuvant Breast and Bowel Project | Swain S.M.,Washington Hospital Center
Journal of the National Cancer Institute - Monographs | Year: 2010

Following local therapy for ductal carcinoma in situ (DCIS), tamoxifen reduces the risk of ipsilateral and contralateral breast cancer by 30%-50%. Studies of tamoxifen in women with resected DCIS have not shown any effect on overall or cancer-specific survival. The adverse event profile of tamoxifen is well characterized, and individual risks and benefits should be assessed to guide decision making. We review the results of the phase III trials of tamoxifen in DCIS as well as the emerging risk reduction therapies. © The Author 2010. Published by Oxford University Press. All rights reserved.

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