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Pogue-Geile K.L.,NSABP | Kim C.,NSABP | Jeong J.-H.,Bowel Project Operations and Biostatistical Centers | Jeong J.-H.,University of Pittsburgh | And 39 more authors.
Journal of the National Cancer Institute | Year: 2013

Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene- by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; Pinteraction between the model and trastuzumab < .001). Conclusions We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47). © The Author 2013.


PubMed | Cornell College, McMaster University, Royal Prince Alfred Hospital, Harvard University and 25 more.
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2016

Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss kappa value for <60 vs 60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.


LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, announced publication of abstracts on neratinib for the American Association for Cancer Research (AACR) Annual Meeting 2017. The AACR Annual Meeting will be held at the Walter E. Washington Convention Center in Washington, D.C. from April 1 to April 5. Full abstracts of the following presentations are available online at www.aacr.org: Apr. 4, 2017, 1:00 - 5:00 p.m. EDT – Abstract 4818 (Poster): Neratinib/fulvestrant but not fulvestrant alone maintain complete tumor responses after treatment with trastuzumab + paclitaxel of mice bearing ER+/HER2+ xenografts. L.J. Schwarz et al, Vanderbilt University Medical Center. April 4, 2017, 1:00 - 5:00 p.m. EDT – Abstract 4157 (Poster): Co-blockade of mTORC1, ERBB and estrogen receptor signaling pathways in endocrine resistant breast cancer: combating tumour plasticity. R. Ribas et al, Institute of Cancer Research. April 4, 2017, 1:00 - 5:00 p.m. EDT – Abstract 4038 (Poster): Exploring optimal targeted combination therapies with neratinib for HER2+ breast cancer. M. Zhao et al, MD Anderson Cancer Center. April 5, 2017, 8:00 - 12:00 p.m. EDT – Abstract 5167 (Poster): Stem-like colorectal cancer cell lines show response to the ERK1/2 inhibitor, SCH772984, alone and in combination with neratinib while the combination of MEK-162 and neratinib work to decrease tumor growth in inflammatory colorectal cancer subtypes. R. Pal et al, NSABP. April 5, 2017, 8:00 - 12:00 p.m. EDT – Abstract 5684 (Poster): NSABP FC-7 Correlative Study: HER2 amplification in circulating cell-free DNA (cfDNA) in metastatic colorectal cancer (mCRC) resistant to anti-EGFR therapy. S. Rim Kim et al, NSABP. Full abstracts of the following presentations are expected to be available online March 31, 2017, after 4:00 p.m. EDT: April 2, 2017, 12:45 - 3:00 p.m. EDT – Abstract CT001 (Oral, Clinical Trials Plenary Session): Neratinib in HER2 or HER3 mutant solid tumors: SUMMIT, a global, multi-histology, open-label, phase 2 ‘basket’ study. D. Hyman et al, Memorial Sloan Kettering Cancer Center. April 2, 2017, 3:00 - 5:00 p.m. EDT – Abstract CT011 (Oral, Minisymposium): Circulating tumor DNA (ctDNA) sequencing for HER2 mutation (HER2mut) screening and response monitoring to neratinib in metastatic breast cancer (MBC). C. Ma et al, Washington University School of Medicine. April 2, 2017, 3:00 - 5:00 p.m. EDT – Abstract CT013 (Oral, Minisymposium): NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DM1) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC). J. Abraham et al, NSABP. April 3, 2017, 10:30 a.m. – 12:45 p.m. EDT – Abstract LB103 (Oral, Major Symposium): Landscape of Somatic ERBB2 Mutations - Findings from AACR GENIE and Comparison to Ongoing ERBB2 Mutant Basket Study. A. Schram et al, Memorial Sloan Kettering Cancer Center. April 4, 2017, 1:00 - 5:00 p.m. EDT – Abstract CT128 (Poster): Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients (pts) with HER2+ early-stage breast cancer (eBC): the CONTROL trial. E. Ibrahim et al, Beaver Medical Group LP. Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. The Company in-licenses the global development and commercialization rights to three drug candidates—PB272 (neratinib (oral)), PB272 (neratinib (intravenous)) and PB357. Neratinib is a potent irreversible tyrosine kinase inhibitor that blocks signal transduction through the epidermal growth factor receptors, HER1, HER2 and HER4. Currently, the Company is primarily focused on the development of the oral version of neratinib, and its most advanced drug candidates are directed at the treatment of HER2-positive breast cancer. The Company believes that neratinib has clinical application in the treatment of several other cancers as well, including non-small cell lung cancer and other tumor types that over-express or have a mutation in HER2. Further information about Puma Biotechnology may be found at www.pumabiotechnology.com. This press release contains forward-looking statements that involve risks and uncertainties that could cause the Company's actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are based on current expectations, forecasts and assumptions, and actual outcomes and results could differ materially from these statements due to a number of factors, which include, but are not limited to, the risk factors disclosed in the periodic reports filed by the Company with the Securities and Exchange Commission from time to time. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. The Company assumes no obligation to update these forward-looking statements, except as required by law.


LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, announced that a biomarker analysis of the NSABP FB-7 Phase II clinical trial of Puma's investigational drug PB272 (neratinib) was presented at the 2016 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas. The presentation entitled “An exploratory correlative biomarker analysis of NSABP FB-7, a phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer” was presented as a poster presentation. This trial was sponsored by the NSABP Foundation, Inc. The FB-7 trial is a randomized Phase II clinical trial for women with HER2-positive locally advanced stage IIB-IIIC invasive breast cancer. Patients were randomly assigned to receive trastuzumab (T) or neratinib (N) or the combination (T+N) with weekly paclitaxel (P) followed by standard doxorubicin and cyclophosphamide chemotherapy (AC) administered prior to surgery. 126 U.S., Canadian, and European patients were randomly assigned to Arm 1 (T+P followed by AC), Arm 2 (N+P followed by AC) or Arm 3 (T+N+P followed by AC). The primary endpoint of the trial was pathological complete response rate (pCR) in the breast and lymph nodes. The clinical safety and efficacy data from this trial was presented at the 2015 SABCS. A key secondary endpoint of the FB-7 trial was to evaluate molecular and genetic markers for correlation with response. Pre-treatment core biopsy samples (n=59) and post treatment surgical samples (n=17) were obtained from a subset of patients treated in the FB-7 trial. pCR data were available for 51 patients from the biomarker cohort. After excluding low tumor content non-evaluable samples, correlative biomarker analysis was performed in 42 patients. Expression levels and the activation status of EGFR/HER2 signaling proteins were investigated. The results of the phosphorylated HER2 (phosphoHER2) showed that median levels of phosphoHER2 were higher in the patients who achieved a pCR with neratinib (n=7) than in the patients who did not achieve a pCR who received either trastuzumab (n=8, p=0.07) or the combination of trastuzumab plus neratinib (n=4, p=0.035). There was not a significant difference in the median levels of phosphoHER2 in the patients who achieved a pCR with neratinib (n=7), trastuzumab (n=8, p=0.16) or the combination of trastuzumab plus neratinib (n=4, p=0.10). The truncated form of HER2 known as p95HER2 was measured by the proprietary assay of Pierian Bioscience. p95HER2 represents a truncated form of the HER2 receptor that lacks the extracellular trastuzumab binding domain. It is believed to represent a mechanism of trastuzumab resistance. Median p95HER2 levels were higher in samples from patients who achieved a pCR with neratinib than in the patients who did not achieve a pCR who received either trastuzumab (p=0.027) or the combination of trastuzumab plus neratinib (p=0.009). There was not a significant difference in the median levels of p95HER2 in the patients who achieved a pCR with neratinib (n=7), trastuzumab (n=8, p=0.16) or the combination of trastuzumab plus neratinib (n=4, p=0.35). The MammaPrint assay was performed on 59 samples to determine if there was any imbalance between arms. This assay is a genomic test that analyzes the activity of 70 genes and then calculates a recurrence score that is either low risk or high risk. The results of the MammaPrint showed that the patients in all three arms of the FB-7 trial were balanced with the median MammaPrint risk score being similar across arms. There were only three patients with a MammaPrint low score. Dr. Samuel Jacobs, Emeritus Clinical Professor in the Department of Medicine, University of Pittsburgh School of Medicine, and the Director of Medical Affairs for the NSABP Foundation, Inc., said, “We are pleased to see the results of this exploratory biomarker analysis which suggests that activation of the HER pathway based on p95HER2 and phosphoHER2 may correlate with pCR to neratinib. Further biomarker analysis in additional datasets will be needed to determine which patients may derive the greatest benefit from neratinib.” Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, “We are pleased to complete this biomarker analysis of neratinib. Further results of the biomarker analysis should help us to determine the best path forward for neratinib in the neoadjuvant treatment of HER2-positive early stage breast cancer.” Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. The Company in-licenses the global development and commercialization rights to three drug candidates—PB272 (neratinib (oral)), PB272 (neratinib (intravenous)) and PB357. Neratinib is a potent irreversible tyrosine kinase inhibitor that blocks signal transduction through the epidermal growth factor receptors, HER1, HER2 and HER4. Currently, the Company is primarily focused on the development of the oral version of neratinib, and its most advanced drug candidates are directed at the treatment of HER2-positive breast cancer. The Company believes that neratinib has clinical application in the treatment of several other cancers as well, including non-small cell lung cancer and other tumor types that over-express or have a mutation in HER2. Further information about Puma Biotechnology can be found at www.pumabiotechnology.com. This press release contains forward-looking statements, including statements regarding the development of the Company’s drug candidates. All forward-looking statements included in this press release involve risks and uncertainties that could cause the Company's actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are based on current expectations, forecasts and assumptions, and actual outcomes and results could differ materially from these statements due to a number of factors, which include, but are not limited to, the fact that the Company has no product revenue and no products approved for marketing, the Company's dependence on PB272, which is still under development and may never receive regulatory approval, the challenges associated with conducting and enrolling clinical trials, the risk that the results of clinical trials may not support the Company's drug candidate claims, even if approved, the risk that physicians and patients may not accept or use the Company's products, the Company's reliance on third parties to conduct its clinical trials and to formulate and manufacture its drug candidates, the Company's dependence on licensed intellectual property, and the other risk factors disclosed in the periodic and current reports filed by the Company with the Securities and Exchange Commission from time to time, including the Company's Annual Report on Form 10-K for the year ended December 31, 2015. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. The Company assumes no obligation to update these forward-looking statements, except as required by law.


PubMed | NSABP, Chonnam National University, Gyeongsang National University, Seoul National University and 6 more.
Type: Clinical Trial, Phase II | Journal: Oncotarget | Year: 2016

The purpose of this study was to investigate the clinical activity, safety and predictive biomarkers of dacomitinib, an irreversible pan-HER inhibitor, in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M-ESCC). Patients, whose diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv 1.1. Predictive biomarker analyses included the characterization of somatic mutations and gene expression using the Ion Torrent AmpliSeq Cancer Hotspot Panel and Nanostring nCounter, and investigation of their relationship with clinical outcomes. Of the 48 evaluable patients, 6 (12.5%) achieved partial responses and 29 (60.4%) had stable disease. The median response duration was 7.1 months. The median progression free survival (PFS) and overall survival (OS) was 3.3 months (95% CI, 2.4-4.3 months) and 6.4 months (95% CI, 4.4-8.4 months). Adverse events were mostly grade 1-2. Gene set enrichment analysis revealed that ERBB signaling pathway is significantly enriched in patients with PFS 4 months (n = 12) than PFS < 4 months (n = 21) (p < 0.001). Upregulation of ERBB signaling pathway was significantly associated with longer PFS (5.0 vs. 2.9 months, P = 0.016) and OS (10.0 vs. 4.8 months, P = 0.022). The most frequent mutations were TP53 (61%) followed by CDKN2A (8%), MLH1 (8%), FLT3 (8%) and EGFR (8%). Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-ESCC. Screening of ERBB pathway-related gene expression profiles may help identify patients who are most likely benefit from dacomitinib.


News Article | December 1, 2016
Site: www.prweb.com

ResearchDx/PacificDx announced today that it will share findings demonstrating the value of DNA microarray comparative genomic hybridization (array CGH) for HER2 genomic subtyping in breast cancer patients at this year’s San Antonio Breast Cancer Symposium. Using molecular test results from tumors with previously documented positive, negative, and equivocal HER2 status, the abstract accepted for presentation will show how high-resolution DNA-based testing can precisely determine a patient’s HER2 status allowing physicians to make decisions about anti-HER2 therapies based on the HER2 genomic subtype of the tumor. Using molecular data generated from tumor-targeted DNA extractions in their CAP/CLIA certified laboratory, the ResearchDx/PacificDx team focused on the patient subset with tumors that had been called “equivocal” for HER2 gene status. The HER2 gene is a known driver of breast cancer and definitive documentation of the HER2 status in a patient's tumor is critically important for predicting response to targeted anti-HER2 therapies. High-resolution HER2 testing accurately classified the HER2 status in 100% of the tumors and defined the HER2-Low genomic subtype most often called “equivocal” by standard testing methods. This subcategory is characterized at the protein level by low expression of the HER2 protein and no amplification of the HER2 gene on chromosome 17. Response to Herceptin in HER2-Low patients is being studied by the NSABP-B47 clinical trial (hyperlink to trial http://www.nsabp.pitt.edu/B-47.asp). “The equivocal HER2 category has become so accepted in breast cancer, people may not recognize the biological reality that this is not a genomic subtype,” said ResearchDx/PacificDx Chief Medical Officer Dr. Shelly Gunn. “In the era of precision medicine, we have clinical laboratory tools to precisely characterize HER2 status as Positive, Negative, or Low in any breast cancer. Our findings show that high resolution testing can provide an accurate HER2 genomic subtype for every tumor so no patient has to endure the uncertainty of HER2 equivocal results.” The abstract, which outlines the high resolution testing used to identify the genomic subtype of breast tumors, will be presented by Dr. Gunn as follows: Title: A clinically validated DNA microarray for high-resolution HER2 testing defines a new genomic subtype in high- risk breast cancer with equivocal results by IHC and FISH Abstract Number: P1-09-18 Date & Time: Thursday, December 7th from 5:00 p.m. to 7:00 p.m. The San Antonio Breast Cancer Symposium will take place December 6-10, 2016 in San Antonio, Texas. ABOUT ResearchDx/PacificDx ResearchDx was founded to equip biopharmaceutical companies with the knowledge and expertise to develop and manufacture the next generation of companion diagnostic products. As the preeminent Companion Diagnostics Organization, ResearchDx offers management services for every stage of the diagnostic development process—from initial assay concept and discovery through clinical research and international regulatory approval. Learn how ResearchDx personalizes medicine at http://researchdx.com/about-us/. Recognized as a leader in the design and implementation of high-complexity testing, the PacificDx Laboratory provides outsourcing services to pathology groups and biopharma allowing seamless integration of molecular assays into their existing test menus http://pacificdx.com


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.

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