bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency of EGFR mutations in Greek non-small-cell lung cancer (NSCLC) patients.
Authors: Murray Samuel , Papadopoulou Eirini , Nasioulas George
Published: March 2020

e21141

Background: NSCLC patients harboring activating somatic mutations within the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) significantly benefit from EGFR targeted therapy. Treatment with the recently approved EGFR inhibitor IRESSA (gefitinib) leads to improved response and survival outcomes, therefore screening for EGFR mutations has entered routine clinical practice. Several clinico-pathological factors correlate with these mutations including gender, smoking history, and histology. The frequency of EGFR mutations is also ethnicity-dependent, wherein the incidence in Asian populations is ~30%, while in Caucasians (Whites) it is lower, ~ 15%. However, limited data is available on intra-ethnic differences throughout Europe. Aim: The aim of this study was to determine the frequency and spectrum of EGFR mutations in an unselected group of Greek NSCLC patients and investigate technical aspects of analysis. Methods: We set up High Resolution Melting Analysis (HRMA) assays to identify mutations in exons 18-21 of the EGFR gene and validated their analytical sensitivity by making serial dilutions of samples with known mutations and tumor cell content (TCC). A total of 698 NSCLC patients were screened with HRMA for somatic EGFR mutations in exons 18-21 and mutation status was verified by bi-directional sequencing. Pathological review was obtained for all samples and macro-dissection was used to ensure a %TCC of >75% in all possible cases. Results: The sensitivity of our HRM assays was found to be ≤1.5% Using HRMA and bi-directional sequencing a frequency of 19.05% was obtained; 105 x exon 19, 21 x exon 21, 6 x exon 20 and 1 x exon 18 . Conclusions: Applying a very sensitive mutation detection technique in a large cohort of unselected Greek NSCLC patients in routine diagnostic practice, we obtained an overall mutation frequency of 19.05%. This mutation frequency is similar to that found by the SLADB and EURTAC studies in European populations. Differences in sensitivity between techniques suggest that more than one technique should be advised in routine diagnostic practice.
A review of chromosome 3q abnormalities in lung cancer.
Authors: Subramonia-Iyer Subramony , Hrinczenko Borys
Published: March 2020

e21154

Background: With the refinement of genetic analytic techniques more detailed and precise information about 3q abnormalities has become available. The aim of this study was to review and summarize the literature about chromosome 3q in the pathogenesis, classification, treatment and prognosis of lung cancer. Methods: A MEDLINE search was conducted with the terms “lung cancer” and “3q”. Papers that described 3q abnormalities in the context of lung cancer were included in this review. Results: From 1990-2011, 61 papers were identified that described chromosome 3q changes in lung cancer. Initial studies showed 3q amplification in premalignant lesions, bronchial dysplasia, NSCLC and SCLC tumor tissue. Similar 3q amplifications were found in lung cancer cell lines at the 3q26-q28 region, including the gene for telomerase (hTR). Amplification of 3q segments were more prevalent in squamous (40 -100%) than in adenocarcinoma (6 - 25%) and in smokers than in non-smokers. However, malignant cells from pleural effusions of adenocarcinoma showed 3q gains in nearly 40% of cases. Genes located on 3q such as RAP2B, CLDN1 and TBL1XR1 were overexpressed in squamous carcinoma. High gain levels were also found at PIK3CA, EVI1 (3q26.2), LPP (3q27-28) and FHF-1 (3q28) gene loci. Also, 3q gains were associated with EGFR mutations in squamous carcinoma and TP53 mutations in adenocarcinoma. Prognostic importance of several chromosomal changes in lung cancer has also been examined. In one study, overexpression of eIF5A-2, located on 3q, was found to correlate with gene amplification, increased cell proliferation, local invasion, advanced T stage, and poor prognosis in stage I NSCLC [He, Int J Cancer, 2011]. Conclusions: Genetic abnormalities and changes in chromosome 3q have been increasingly well characterized with specific genes identified. Differential expression in various histological types of NSCLC indicates that these genes may contribute to the pathogenetic pathway in squamous carcinoma, and also in locally advanced adenocarcinoma with pleural effusions. These genes have also been shown to be prognostically important. With these promising results, further identification of specific 3q gene products may lead to the development of novel therapeutic targets in lung cancer.
Contribution of platelets to tumor aggressivity.
Authors: Delage Judith , Li Hong , Lu He , Cazin Lionel , Soria Jeannette , Dupuy Evelyne , Drouet Ludovic , Vannier Jean-Pierre , Varin Rémi , Soria Claudine
Published: March 2020

e21156

Background: The interaction between cancer and coagulation process has been shown since many years. The aim of our study is to understand the mechanisms implicated and to propose new therapeutic approaches. Methods: Two breast cancer cell lines were used: a very aggressive (MDA-MB231) and a much less aggressive (MCF-7). Platelet aggregation tests were done with washed platelets, normal or fibrin removed plasma and cancer cells (20 to 2.105 cells/ml). Procoagulant activity of cancer cells was studied. Aspirin, Apyrase (ADPase), a direct thrombin inhibitor (Hirudin), two Xa inhibitors (Fondaparinux, Rivaroxaban) were the inhibitors tested. Interaction between platelets and cancer cells was visualized by confocal microscopy. Angiogenic effect of supernatants from platelets-cancer cells co-incubation was investigated. Results: The data obtained show that a platelet aggregation is induced by cancer cells in the presence of a small amount of plasma. This aggregation depends on both the type and number of cancer cells. Aggressive MDA-MB231 cells have a more potent pro-aggregating activity than MCF-7. This aggregation appears to be due to thrombin generation since it is inhibited by Hirudin. Rivaroxaban, a direct inhibitor of factor Xa, inhibits platelets aggregation but not Fondaparinux, an indirect anti Xa inhibitor which binds to Antithrombin III. Aspirin and Apyrase have no effect. Moreover, the procoagulant activity of cancer cells with plasma is inhibited by Hirudin and Rivaroxaban but not by Fondaparinux. This suggests that the Fondaparinux-Antithrombin III complex cannot access to cell membrane-bound factor Xa. It may be due to its steric hindrance since thromboplastin induced coagulation is inhibited by Rivaroxaban but not by Fondaparinux. The confocal microscopic study shows that platelets protect tumor cells from immune attack via the formation from a protective envelope around cancer cells. Angiogenesis assays show that activation of platelets by cancer cells releases angiogenesis stimulating factors and cytokines. Conclusions: The present work confirms the crucial role of platelets in cancer aggressiveness and reveals that Rivaroxaban or Thrombin inhibitors could be efficient drugs to reduce cancer progression, metastasis and thrombosis.
Integrated laboratory networks for a successful biomarker implementation strategy in personalized medicine.
Authors: Paz Maria fe , Ferreiro Jose Luis , Keeling Peter
Published: March 2020

e21158

Background: Much work has been done to ensure that biomarkers research and the development of targeted therapies in Oncology can be translated into a better stratification of patients. However, when it comes to the implementation of those biomarkers into the clinical setting, laboratories are not commonly consider an essential stakeholder. Unfortunately, the laboratories are often the forgotten third arm of a successful foundation in personalized medicine (PM), for molecular diagnostics in oncology. In order to truly enhance the power of companion diagnostics, and to better meet healthcare demands and finally, patient needs, superior integrated laboratory services are crucial. This presentation will provide a brief introduction from Labceutics highlighting the need for highest quality laboratory networks across Europe. In addition it would feature results of a Delphi survey of leading EU laboratories on the gaps and shortfalls they face in implementing companion diagnostics Methods: Delphi survey study conducted over a representative sample of the +120 partners in the Labceutics European Laboratory network. Statistical analysis was performed with SPSS software. Results: this research reveals that that fewer than 10% of these laboratories had been contacted directly by pharmaceutical companies to discuss the future implementation issues they may face in introducing companion diagnostics in their Lab. Additionally, the study confirmed that 25% of the laboratories surveyed, preferred to begin their testing service of a novel diagnostics with an IVD kit purchased from a diagnostic company. On the other hand, 77% either preferred to develop their own in house method or consider the business case, since so many of the new diagnostics have very low volumes in the initial 3 to 5 years. Conclusions: this exhaustive will provide the audience with insights into the main issues about best practices for laboratories to ensure appropriate implementation of testing services. It will reveal as well, the importance and sequence of "early prelaunch" engagement with a laboratory network to accelerate post launch diffusion of testing.
Disruption of protocadherin function as an indicator of cancer progression.
Authors: Shima James , Delaney Joseph , Umesh Anita , Park Jenny , Wall Gregory , Su Qiaojuan , Shekar Mamatha , Kupershmidt Ilya
Published: March 2020

e21159

Background: Protocadherins (PCDH) are a large family of calcium-dependent cell–cell adhesion molecules that are involved in tissue morphogenesis, in particular the development of the central nervous system. Recently, alteration of PCDH alpha/beta/gamma locus genes have been implicated in a number of oncogenic processes: hypermethylation of the PCDH locus in Wilms’ tumor progression and metastasis, differential expression of some PCDH genes between bone and brain metastases in breast cancer patients, and epigenetic silencing of PCDH gamma A11 in astrocytoma invasion of the adjacent parenchyma. Assessment of PCDH function could help guide treatment decisions by aiding in the identification of cancer patients who are more likely to develop metastases. Methods: Identification of altered PCDH locus genes in cancer patient samples was performed using the NextBio platform which incorporates curated public genomic data from numerous sources, including TCGA, GEO, COSMIC, and others. Correlation of numerous data types was used to identify deleterious mutations, altered RNA expression, and copy number changes that were indicative of metastasis or a more advanced disease state. Results: A nearly 3-fold increase in the frequency of potentially detrimental somatic mutations in the PCDH gamma locus was observed in breast and ovarian cancer patients with extensive lymph node metastases (N3) compared to patients with a lower degree of lymph node metastasis (N0-N2). Similarly, expression of PCDH locus genes was down-regulated in cases of lymphoma, in metastatic samples across a number of diseases, and in diseases that commonly result in lymph node metastases including breast and lung cancer. Conclusions: Stratification of patient subgroups based on molecular signatures has become increasingly important for both assigning patients to appropriate clinical trials as well as providing insight into effective treatment options. Examination of PCDH perturbations may provide insight into a patient’s risk of developing a metastatic disease, in particular metastases to lymph nodes, and help identify patients who may benefit from a more aggressive treatment regimen.
Breast density change as a predictive surrogate for response to adjuvant endocrine therapy in estrogen receptor-positive breast cancer.
Authors: Kim Ji sun , Han Wonshik , You Jee Man , Shin Hee-Chul , Ahn Soo Kyung , Moon Hyeong Gon , Im Seock-Ah , Kim Tae-You , Cho Nariya , Moon Woo Kyung , Noh Dong Young
Published: March 2020

e21160

Background: Previous studies showed that anti-estrogen therapy lowers mammographic breast density (MD). We hypothesized that the short-term change of breast density can be a surrogate marker predicting response to adjuvant endocrine therapy (ET) for breast cancer. Methods: We analyzed data of 1,065 estrogen receptor (ER)-positive breast cancer patients who underwent surgery between 2003 and 2006 and received at least 2 years of ET including tamoxifen and aromatase inhibitor. MD was measured using Cumulus software 4.0 and expressed as a percentage. MD reduction was defined as an absolute difference between the MD of two mammography images: taken preoperatively and 8-20months after the start of adjuvant ET.. Results: After median follow up of 68.8 months, overall recurrence rate was 7.5% (80/1065). Mean MD reduction was 5.9% (-17.2 to 36.9). In a logistic regression analysis, age<50, high preoperative MD, and longer interval between start of ET to the 2nd mammogram were significantly associated with higher MD reduction (p value<0.05). In a survival analysis using Cox model, tumor size (>2cm), lymph node positive, high Ki-67 (≥10%), and lower MD reduction were independent factors significantly associated with recurrence-free survival (p<0.05). The hazard of recurrence increased proportionally according to the less degree of MD reduction. Conclusions: MD change during short-term use of adjuvant ET was a significant predictive factor for long-term recurrence in ER-positive breast cancer. It is urgent to develop effective treatment strategy in patients who have less MD reduction in spite of about 1 year of ET.
Randomized phase III, multicenter, open-label study comparing TH-302 in combination with doxorubicin versus doxorubicin alone in subjects with locally advanced unresectable or metastatic soft tissue sarcoma.
Authors: Chawla Sant P. , Reinke Denise K. , Saks Sam , Kroll Stew , Tap William D.
Published: March 2020

TPS10100

Background: A hypoxic microenvironment characterizes solid tumors including soft tissue sarcoma (STS) and is associated with chemotherapy resistance. TH-302, a prodrug of the alkylating agent bromo-isophosphoramide mustard (BR-IPM) is reduced in hypoxic environments, releasing Br-IPM. Combining D with TH-302 should effectively target both the normoxic and hypoxic regions of STS. TH-302 was investigated with full-dose D (75 mg/m2). The regimen was well tolerated, >60% completed 6 cycles. DLTs at higher doses were infection with neutropenia and grade 4 thrombocytopenia. The efficacy was higher than generally reported with single agent D (Sleijfer, The Oncologist, 2005). At MTD (75 mg/m2 D and 300 mg/m2 TH-302) best response were 2 (2%) CR, 30 (34%) PR, 43 (48%) SD. Median PFS and OS were 6.7 and 17.5 months, respectively. Based upon these data, a study (NCT01440088) is ongoing to assess the benefit of adding TH-302 to the standard D as first-line therapy of STS. Methods: The randomized (1:1) phase III study of TH-302 (300 mg/m2) with D versus D alone was initiated September 2011. Target goal is 450 patients. TH-302 is administered IV over 30-60 minutes on Days 1 and 8 (21-day cycle). D (75 mg/m2, bolus or continuous) is administered Day 1 starting 2-4 hrs after TH-302 when used in combination. Patients receiving TH-302 plus D without progression after 6 cycles may continue on TH-302 alone. Key eligibility criteria: locally advanced unresectable or metastatic STS untreated with chemotherapy (adjuvant allowed), ECOG 0/1, measurable disease (RECIST 1.1) and adequate hematologic, hepatic, renal function. A FDA Special Protocol Agreement was reached on study design and analyses. Primary efficacy endpoint is overall survival (OS) comparison of the combination vs D. The study is designed to detect a 40% improvement in OS with 85% power and one-sided alpha of 2.5%. An interim futility PFS analysis is scheduled after 113 PFS events. Significant improvement in PFS (one-sided p < 0.10) is required to continue. A further analysis for early efficacy stoppage is scheduled after 175 OS events. IDMC will monitor safety and efficacy.
Masitinib in comparison to imatinib as first-line therapy of patients with advanced gastrointestinal stromal tumor (GIST): A randomized phase III trial.
Authors: Adenis Antoine , Chaigneau Loic , Michel Pierre , Isambert Nicolas , Bertucci François , Bui Nguyen Binh , Bouche Olivier , Mineur Laurent , Bekaii-Saab Tanios S. , Penel Nicolas , Acin Yolene , Moussy Alain , Hermine Olivier
Published: March 2020

TPS10102^

Background: Masitinib is an oral tyrosine kinase inhibitor (TKI) that has greater in vitro kinase activity and/or selectivity than imatinib against KIT and PDGFRA/B. A phase 2 study has previously reported that masitinib treatment produced clinically relevant activity in imatinib-naïve patients with advanced GIST. Considering the promising long term response observed in overall survival (OS) (see Table) there is compelling evidence to compare masitinib against imatinib (the current standard of care) in the first-line setting. Methods: A multicenter, randomized, open label, phase 3, 1:1 study to compare efficacy and safety of masitinib (7.5 mg/kg/day) to the active control of imatinib (400 or 600 mg/day) in first-line treatment of patients with advanced GIST. Primary endpoint is progression-free survival (PFS), with secondary endpoints including OS, time to progression (TTP), and clinical response rates (RECIST). Based on a planned sample size of 222 patients (111/arm) this 15% non-inferiority study was designed to have an 85% power using a 95% two-sided CI of the hazard ratio. Patient eligibility criteria include: histologically proven, metastatic or locally advanced nonresectable, or recurrent post-surgery GIST; TKI naïve patient or patient previously receiving imatinib only as a neoadjuvant or adjuvant therapy; and confirmed KIT-positive or PDGFRA-positive tumors. Recruitment is ongoing. On 09/2011, the DMC recommended continuation of this study. Clinicaltrial.gov: NCT00812240. [Table: see text]
The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer patients using ColoPrint.
Authors: Salazar Ramon , Marshall John , Capdevila Jaume , Glimelius Bengt , de Waard Jan Willem , Van Der Hoeven Jacobus , Klaase Joost , Bibeau Frédéric , Bachleitner-Hofmann Thomas , Midgley Rachel A , Levine Edward Allen , Law Wai Lun , Asano Michio , Chang George J. , Cohen Stephen M , Beart Robert W. , Goldfarb Paul M. , McCarter Martin , Stork-Sloots Lisette , Rosenberg Robert
Published: March 2020

TPS10632

Background: An 18-gene expression profile, ColoPrint, has been developed for identifying colon cancer patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature was validated in public datasets and independent patient cohorts (stage II and III patients). Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) (median follow-up 70 months). ColoPrint classifies 65% of stage II patients as Low Risk. The 3-year RFS was 91% for Low Risk and 74% for High Risk patients with a HR of 2.9 (p=0.001). ColoPrint was the only significant prognostic marker in the subgroup of patients with T3-MSS phenotype (Tabernero, ASCO GI 2012). Methods: A blinded prospective trial, PARSC (Prospective study for the Assessment of Recurrence risk in Stage II colon cancer patients) using ColoPrint has been initiated. Objectives are: (1)To validate the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage II colon cancer. (2) To compare the risk assessment in stage II patients using the ColoPrint profile vs a clinical risk assessment based on Investigator’s assessment of risk and ASCO high-risk recommendations. (3) To investigate therapy as a potential confounding factor for ColoPrint results. (4) To assess the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage III colon cancer. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II and III, no prior neo-adjuvant therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician adhering to National Comprehensive Cancer Network (NCCN)-approved regimens or a recognized alternative (blinded for ColoPrint result). The trial started in Sept. 2008 with currently 32 participating sites in 11 countries. Thus far, 340 eligible stage II and 280 stage III patients have been enrolled. The aim is to enroll 575 stage II patients. Clinical trial registry number: NCT00903565.
ACRIN 6684 assessment of tumor hypoxia in glioblastoma using 18F-fluoromisonidazole with PET and MRI.
Authors: Gerstner Elizabeth Robins , Zhang Zheng , Fink James R , Sorensen Gregory A , L'Heureux Darryl , Heckel Martha L. , Dunning Bernadine , Muzi Mark , Mankoff David A. , Barboriak Daniel
Published: March 2020

TPS10635

Background: Glioblastoma (GBM) is an aggressive type of primary malignant brain tumor and despite treatment with surgery, radiation, and temozolomide (TMZ) chemotherapy, median overall survival (OS) remains poor. A pathologic hallmark of GBM is tumor necrosis, a suspected result from endogenous tumor hypoxia. Angiogenesis is stimulated by hypoxia-driven signaling cascades and is required for tumor proliferation. The inefficient blood supply of these hypoxic tumors also limits the efficacy of chemotherapy and radiotherapy. Surviving hypoxic tumor cells may be selected out and proliferate as a more aggressive tumor subtype, therefore hindering OS. 18F-Fluoromisonidazole (FMISO) is a PET radiotracer whose uptake in hypoxic tissues can be measured radiographically. The degree of tumor hypoxia has been negatively associated with time to tumor progression and survival (Spence et al, 2008). Knowledge of the degree/distribution of tumor hypoxia by PET uptake and perfusion MRI parameters may provide prognostic information and help guide therapy for patients with GBM. Methods: In this phase II prospective single arm multi-institution study, patients will undergo baseline FMISO PET and MR imaging two weeks prior to chemoradiotherapy (CRT). A subset of patients will receive a second FMISO PET one week prior to CRT to assess reproducibility. Clinical outcomes of OS and 6-month progression-free survival (PFS-6) will be correlated to PET and MRI parameters. Eligibility: Pathologically confirmed GBM with residual tumor after surgery (including T2/FLAIR hyperintensity consistent with tumor) scheduled to receive standard fractionated radiation therapy and temozolomide alone or with an anti-VEGF agent or PARP inhibitor. Current enrollment: 22 patients of 50 sample size Contact information: Please contact the PI, Elizabeth R. Gerstner, MD ( egerstner@partners.org ) for additional information. Significance: With a better understanding of the extent of tumor hypoxia and changes in hypoxia levels from treatment, more effective therapies could be developed to inhibit GBM growth, target hypoxic areas and individualize patient care.
Phase II neoadjuvant trial with carboplatin and eribulin mesylate in patients with triple-negative breast cancer.
Authors: Barnato Sara E. , Jeruss Jacqueline Sara , Bethke Kevin P. , Hansen Nora M. , Khan Seema Ahsan , Von Roenn Jamie H. , Rosen Steven T. , Gradishar William John , Siziopikou Kalliopi P. , Meservey Caitlin , Kaklamani Virginia G.
Published: March 2020

TPS1134

Background: Several neoadjuvant trials have been conducted in triple negative breast cancer (TNBC) with platinum agents with pathologic complete response (pCR) ranging from 16%-32%. Eribulin mesylate, a nontaxane microtubule dynamics inhibitor, has clinical activity as monotherapy in breast cancer and other solid tumors. A recent phase I trial found the combination of eribulin mesylate with carboplatin was well tolerated and showed activity in advanced solid tumors. The recommended dose for future trials was eribulin mesylate 1.1 mg/m2 and carboplatin AUC6. We proposed a neoadjuvant phase II trial with the combination of carboplatin and eribulin in patients with TNBC. Methods: This is a non-randomized, open-label, multi-center, phase II clinical trial of eribulin and carboplatin enrolling histologically-confirmed TNBC patients. Our primary endpoint is to determine the pCR in TNBC patients treated with the combination of carboplatin and eribulin. Secondary endpoints include determination of the clinical response rate, toxicity evaluation and measurement of stem cell and TLE3 as a biomarker of response to eribulin therapy. To obtain an alpha of 0.10 and a power of 0.90, a sample size of 30 patients is required to detect a pCR rate >=30%. 10 of the planned 30 patients have been enrolled to date. Treatment will be given every 3 weeks for a total of 4 cycles of therapy. There will be an initial safety run-in to evaluate the appropriate dose of eribulin in this population. The first 10 patients will receive eribulin at 1.4 mg/m2 (intravenously over 2-5 minutes) followed by carboplatin AUC=6 (intravenously over 30 minutes). After the 10th patient has been enrolled, the study will be temporarily suspended pending review; toxicity will be assessed for these first 10 patients (cycle 1 only) to assess whether this dose of eribulin will be used for the remaining patients or if a reduction to a dose of 1.1 mg/m2 will be required. Definitive surgery will be performed 3-8 weeks after completion of therapy, which will conclude the duration of the study. Clinical Trial Registry Number NCT01372579.
Neoadjuvant bevacizumab with weekly nab-paclitaxel plus carboplatin followed by doxorubicin plus cyclophosphamide (AC) for triple-negative breast cancer.
Authors: Snider Jessica N. , Young Robyn R. , Schwartzberg Lee Steven , Allen Jeffrey Warren , Javed Yasir Ahmed , Jahanzeb Mohammad , Sachdev Jasgit C.
Published: March 2020

TPS1137

Background: Triple negative breast cancer (TNBC) predominantly clusters with “basal like” subtype on genomic profiling. Over-expression of Secreted Protein Acidic and Rich in Cysteine (SPARC) has been observed in basal like breast cancer (Charaffe-Jaufrett et al. Oncogene 2006; 2273-84). Endothelial transcytosis of nab- paclitaxel occurs via albumin- gp60 receptor-caveolin 1 interaction. SPARC entraps the albumin resulting in higher intratumoral accumulation, which may explain the increased efficacy of nab-paclitaxel (Desai et al. Translational Oncology 2009; 59-63). Exploiting this mechanism and the dysfunctional BRCA mediated DNA repair in basal tumors, we hypothesize that nab-paclitaxel + the DNA damaging drug carboplatin would produce high response rates in TNBC. Adding bevacizumab may enhance efficacy by blocking angiogenesis. In TNBC, pathologic complete remission (pCR) to neo-adjuvant therapy correlates with better disease-free survival (DFS). We hypothesize that high pCR rates can be achieved for patients with TNBC with this combination translating to an improved DFS than seen historically. Methods: Patients with palpable and operable TNBC ≥ 2 cm are eligible for this single stage phase II trial. pCR (defined as the absence of invasive tumor cells) in the breast is the primary end point, while pCR in the breast + axillary nodes and pCR + near pCR (residual tumor < 5mm) in the breast are secondary end points. 57 evaluable patients are needed, assuming a pCR rate of 25% vs. 40% for the null and alternate hypotheses respectively. 34 patients have been accrued to date. Patients receive carboplatin AUC 6 day 1 and nab-paclitaxel 100mg/m2 days 1, 8 and 15 of a 28 day cycle for 4 cycles and then dose dense AC for 4 cycles. Bevacizumab is given at 10mg/kg Q 2 weeks with chemotherapy for the first 6 cycles. Surgery and radiation are per institutional standards. Bevacizumab is continued postoperatively to complete 1 year of treatment. A core biopsy for collection of fresh tumor tissue is required prior to the start of study treatment. Blood is collected at baseline, and after 4 and 8 cycles for biomarker analysis. Gene expression profiling will be undertaken for correlation with response.
Randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer.
Authors: Kohno Norio , Hasegawa Yoshie , Horiguchi Jun , Ishikawa Takashi , Miura Daishu , Hayashi Mitsuhiro , Takao Shintaro , Kim Seung Jin , Tanino Hirokazu , Akazawa Kohei
Published: March 2020

TPS1141

Background: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate, and it induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. ZOL has also been found to have antitumor effects that include an angiogenesis inhibiting action, an inhibitory effect on tumor cell adhesion to and invasion of the extracellular matrix, and activation of a gdT cells. In addition, it has been found to have a synergistic apoptosis-inducing effect when used in combination with antitumor drugs. In this study we will investigate the pCR rate when ZOL is added to anthracycline followed by taxane to treat T2 and T3 breast cancer patients. Methods: Women with resectable invasive StageIIA-IIIB (T ≥ a3 cm or T ≥ a2 cm and lymph node positive) breast cancer who are HER-2-negative, between 20 and 70 years of age, and ECOG PS 0-1 are eligible. Patients with distant metastasis, patients who have had received chemotherapy, hormone therapy, or radiotherapy for breast cancer, patients with serious complications, such as heart disease or an infection, patients with a complicating dental or jaw infection or traumatic condition of the teeth, and patients with a history of treatment with a bisphosphonate within the previous 12 months are excluded. A total of 4 courses of FEC100 are administered every 3 weeks followed by weekly paclitaxel for 12 courses. ZOL 4mg is administered every 3-4 weeks a total of 7 times. Patients are randomized 1:1 to chemotherapy + ZOL group or chemotherapy alone group, according to the presence or absence of lymph node metastasis, estrogen receptor (ER) status, and their menopausal status. The primary endpoint is pCR. Secondary endpoints are tumor response rate, the breast-conserving surgery ratio, and disease-free survival (DFS). We calculated the sample size on the basis of a pCR rate of 18% in the chemotherapy alone group and 35% in the chemotherapy + ZOL group, at a one-sided significance rate of 5%, and test power of 80%, and as a result we will target a patient sample size of 180 patients. 162 of planned 180 patients have been enrolled as of January 24, 2012.
IBL2001: Phase (ph) I/II study of a novel dose-dense (dd) schedule of indibulin for the treatment of metastastic breast cancer.
Authors: Traina Tiffany A. , Hudis Clifford , Gonzalez Joseph , Anthony Stephen Patrick , Smith David A. , Chandler Jason Claud , Jac Jaroslaw , Youssoufian Hagop , Norton Larry
Published: March 2020

TPS1143

Background: Indibulin (Zybulin, ZIO‑301) is a new, synthetic agent that inhibits tumor cell growth at the G2/M phase through destabilization of microtubule dynamics. It binds tubulin at a different site than taxanes and vinca alkaloids. Indibulin does not interact with acetylated (neuronal) tubulins and has not exhibited the neurotoxicity associated with other tubulin binders. Indibulin has potent antitumor activity in human cancer cell lines, including multidrug-, taxane-, and vinblastine-resistant lines. Norton-Simon modeling based on cell line data suggested that dd administration could optimize efficacy while limiting toxicity. Methods: Eligible are patients (pts) with metastatic or unresectable locally advanced breast cancer, measurable or non-measurable disease, and any number of prior therapies. The objective of the Ph I portion is to determine the maximum tolerated dose (MTD) of indibulin when given in a dd fashion (5 days treatment, 9 days rest (14 total) using standard 3+3 dose escalation schema. Ph II will seek to estimate the proportion of pts progression free at 4 months when treated with indibulin at the dose determined in the Ph I. Secondary endpoints are overall response rate, proportion of subjects with stable disease >6 months and toxicity profile of indibulin. Optimal Simon two-stage design with an unpromising rate of pts who have not progressed at four months as 20% and a promising rate of 40% with a type I error of 5% and power of 80% will be used. 13 pts will initially enter the 1st stage of the ph II portion. If there are 3 or fewer pts who do not experience disease progression at 4 months in the first stage of ph II, the study will be terminated and declared to have a negative result. If 4 or more pts do not progress at 4 months, enrollment in the ph II of the study will be extended to 43 pts. A total of 45 pts will be enrolled to allow for a 5% drop out rate to account for pts who may not be evaluable for the primary endpoint due to toxicity or study withdrawal rather than progression of disease or death prior to 4 months. If ≥13 out of 43 pts are progression-free at 4 months, the study will be considered to have a positive result and indibulin would be considered worthy of further testing in this disease.
A phase II, single-arm, feasibility study of dose-dense doxorubicin and cyclophosphamide (AC) followed by eribulin mesylate for the adjuvant treatment of early-stage breast cancer (EBC).
Authors: Traina Tiffany A. , Hudis Clifford , Lehman Robert , Rege Jessicca , Wang Wenquan , Cox David , Seidman Andrew David
Published: March 2020

TPS1145

Background: Randomized trials have confirmed the benefit of the combination of an anthracycline (A) and cyclophosphamide (C) for the adjuvant treatment of EBC. The addition of taxane therapy to AC therapy has further improved survival. Despite the improvement in adjuvant therapies for BC, new approaches for improving outcomes are of significant importance and may involve developing improved combination regimens. Eribulin mesylate has demonstrated antitumor activity and significant improvement in overall survival (OS) in patients with heavily pretreated locally advanced or metastatic breast cancer (MBC) and may improve outcomes in EBC as well. Methods: This study will determine the feasibility of eribulin as adjuvant therapy following dose-dense AC for HER2 normal EBC. A completion rate of >80% was set as a threshold for feasibility as established adjuvant regimens have shown feasibility rates ranging from ~65% for trastuzumab to >80%. This is a phase 2, single-center, feasibility study of dose-dense adjuvant chemotherapy in patients with EBC. Dose-dense AC (Doxorubicin 60 mg/m2 IV plus C 600 mg/m2 IV) on day 1 of every 14-day cycle is given for 4 cycles, followed by 4 cycles of eribulin mesylate at 1.4 mg/m2 over 2-5 minutes IV on days 1 and 8 every 21 days. Growth factors are given on day 2 of AC cycles and only for neutropenia events with eribulin treatment. Feasibility is determined by the ability to complete the eribulin portion of the regimen without a dose delay or reduction. Exploratory objectives include efficacy endpoints of 3-year disease-free survival (DFS) and OS. Patients have histologically confirmed HER2 normal stage I-III invasive disease and adequate bone marrow, liver, and renal function. Thirty two of approximately 80 planned patients are currently enrolled. Feasibility rates will be calculated with growth factor support (ie, the successful use of growth factor support following a neutropenia event is not considered a dose delay)and without growth factor support (ie, where need for growth factors is considered a delay). Secondary endpoints include DFS and OS and will be estimated by Kaplan-Meier method.
A multicenter prospective study of image-guided radiofrequency ablation for small breast carcinomas.
Authors: Kinoshita Takayuki , Yamamoto Naoto , Fujisawa Tomomi , Takabatake Daisuke , Wada Noriaki , Masuda Norikazu , Tsuda Hitoshi , Doihara Hiroyoshi , Takahashi Masato
Published: March 2020

TPS1147

Background: As the management of breast carcinoma evolves toward less invasive treatments, the next step is the possibility of removing the primary tumor without surgery. The most promising noninvasive ablation technique is radiofrequency ablation (RFA), which can effectively kill tumor cells with a low complication rate. Our preliminary studies of RFA followed by standard surgical resection have indicated that this technique is effective for surgical ablation of small (≤ 2cm) breast tumors without extensive intraductal components (EIC). Methods: To determine if RFA is oncologically and cosmetically appropriate for the local treatment of primary breast carcinoma, this multi-center prospective study used RFA as the sole local treatment of breast tumors ≤ 1.5cm in size on ultrasound and MRI. Exclusion criteria include receiving of preoperative chemotherapy, or the presence of invasive lobular carcinoma or invasive ductal carcinoma with suspicious EIC. After confirmation that the standard baseline core biopsy for diagnosis and measurement of tumors markers (ER, PgR, HER-2/neu expression and the presence of the Ki-67 proliferative marker) have been obtained, consent will be obtained and the patient scheduled RFA. All patients received adjuvant radiation therapy. The use and choice of systemic therapy will be based on the information from the baseline core biopsy and imaging studies. The first primary endpoints of this study is successful tumor ablation, as evidenced by negative findings on vacuum-assisted or core biopsies and imaging studies after RFA. The second primary endpoints is the incidence of procedure related adverse events. Forty patients with small tumors that are clearly identifiable and measurable by ultrasound and MRI were enrolled. The response to ablation was evaluated with both vacuum-assisted or core biopsies and imaging studies every 3 months during the first year. The long-term outcomes were assessed using quality of life measurement scales and imaging studies every 6 months thereafter through year 5.
The MIRACLE trial: A randomized, controlled trial comparing green tea extract versus placebo for the prevention of metachronous colon adenomas in a screening population.
Authors: Ettrich Thomas , Stingl Julia , Muche Rainer , Berger Andreas , Seufferlein Thomas
Published: March 2020

TPS1612

Background: Prevention of colorectal cancer is a major health care issue. After polypectomy there is an increased risk of polyp recurrence and various means of chemoprevention have been tried to prevent this. NSAIDs have been shown to be effective but confer side effects such as gastrointestinal bleeding. Nutraceuticals such as polyphenols from tea plants have demonstrated remarkable therapeutic and preventive effects in molecular, epidemiological and some clinical trials. However, their value in preventing colorectal polyps has not been demonstrated in a large, randomized trial. The beneficial safety profile of decaffeinated green tea extract and accumulating evidence of its cancer preventive potential justify and require, in our view, a validation of this compound for the nutriprevention of colorectal adenoma. Good accessibility and low costs might render this neutraceutical a top candidate for wider use as nutritional supplement in colon cancer prevention. Methods: Randomized, double blinded, placebo-controlled, multicenter trial. After a one month run-in period with verum, 2534 patients (age: 50-80 years) who have undergone polypectomy within the last 6 months will be randomized to receive either decaffeinated green tea extract (containing 150 mg epigallocatechin gallate (EGCG) two times daily) or placebo over a period of three years. 2028 patients are expected to complete the whole study course. Primary outcome: Incidence of metachronous colorectal adenomas (tubulovillous, tubular, villous, serrated lesions) at the 3 year follow-up colonoscopy Secondary outcomes: Occurrences, number, localization, size and histological subtypes of adenomas, frequency of colorectal carcinoma. In addition, genetic and biochemical biomarkers in blood samples and genetic alterations (e.g. K-ras, B-raf, specific microRNAs) in tissue samples of adenomas will be analyzed (biobanking subprojects). Additionally, nutrikinetics and nutrigenetics of EGCG and other catechins will be assessed in healthy volunteers. Patient recruitment has started in November 2011. We expect the last patient out in fall 2017. (Trial identifier: NCT01360320)
Mitigation of iatrogenic risk in young women Hodgkin’s survivors, acceptability of a structured information process.
Authors: Eisinger François , Boyer-Chammard Agnes , Gonzague Laurence , Coso Diane , Viens Patrice , Bouabdallah Reda
Published: March 2020

TPS1613

Background: Long term follow up of cancer survivors uncovers iatrogenic risk. Higher risk for second cancers should be mainly observed for cancer with a high rate of therapeutic efficacy, using aggressive therapeutic and for cancers occurring in young people. Hodgkin lymphoma fits all these criteria. Consistent data about higher risk for breast cancer in these women had been published. However, risk management is not yet often carried out. Methods: We plan to carry out a national program aiming both at offering counselling and screening protocol and to assess key parameters allowing to better estimate risk, and offering acceptable and effective risk management option. Our National program will start in January 2013. We are now in a pilot phase in a single medical institution in which we offered women previously affected with an Hodgkin lymphoma to have access to risk analysis and information and if they agree to a specific breast cancer screening program. We present some of our psychosocial questionnaire analysis based on 27 women (aged 19-50 years old) fulfilled at the end of the information consultation and one month latter. Results: There was few or no negative assessment: no one stated that they express regrets to have been informed, nor they better ignore some delivered information, no one feel that risk management description is unsatisfying and no one will advice an other women against that kind of consultation. Only 4 out 27 i.e. 15% stated that there was in delivered information a source for anxiety. However positive assessment was only fairly high and not stable after one month. Information process to inform women survivors from Hodgkin lymphoma of their higher risk of being affected with a breast cancer and the current recommendation for earlier breast cancer screening reach a high level of satisfaction at the initial stage of the process. However it could decrease with time and thus, need to be monitored. [Table: see text]
Vorinostat to restore sensitivity to aromatase inhibitor therapy in metastatic breast cancer: A phase II clinical trial with ER imaging correlates.
Authors: Linden Hannah M. , Kurland Brenda F , Link Jeanne , Gadi Vijayakrishna K. , Specht Jennifer M. , Gralow Julie , Schubert Erin K , Peterson Lanell , Eary Janet F. , Mankoff David A.
Published: March 2020

TPS3109

Background: Endocrine refractory,Indolent, soft tissue, and bone dominant metastatic breast cancer is a clinical problem, for which alternatives to chemotherapy are needed, Histone deacetylace inhibitors (HDACi) have shown pre-clinical promise in estrogen receptor-modulation and restoring sensitivity to endocrine manipulation, suggesting potential clinical benefit. HDACi restore ER expression in ER-negative cells which are then sensitive to AI treatment in xenografts (Sabnis 2011) and are toxic to ER-positive cell lines (Huang 2000). Vorinostat is an FDA approved HDACi for CTCL, and could have a beneficial role in restoring ER-signaling in endocrine-resistant tumors. We hypothesized that HDACi therapy could restore sensitivity to aromatase inhibitor (AI) therapy, in patients with prior progression on AI, and allow continued endocrine therapy. Recent data suggest clinical benefit of Tamoxifen and vorinostat given continuously (Munster 2011) as well as entinostat and an AI (Yardley 2011). Our prior work has shown the feasibility of monitoring regional ER expression and ER-estrogen binding in vivo using [F-18]fluoroestradiol (FES) PET imaging (Linden 2011) providing a biomarker to interrogate the molecular target. Methods: Patients with metastatic breast cancer with prior clinical benefit from endocrine manipulation who progressed on AI therapy are eligible. Patients must be off ER blocking therapies, and functionally postmenopausal. Baseline FES and FDG PET are performed and patients receive investigational vorinostat treatment at 400 mg po BID for 2 weeks followed by serial FES and FDG PET to assess the impact of vorinostat on ER expression and tumor metabolism. Patients are retreated on their prior AI as a single agent for 6 weeks, followed by paired FES and FDG and clinical assessment. Patients with clinical benefit may continue on treatment: 2 weeks of vorinostat followed by 6 weeks of AI in 8-week cycles until progressive disease or toxicity. We have enrolled 4 of a planned 20 patients.
First-in-human phase I clinical trial of QBI-139, a human ribonuclease variant, in solid tumors.
Authors: Strong Laura E. , Kink John A. , Mei Baigen , Shahan Mark N. , Raines Ronald T.
Published: March 2020

TPS3113

Background: RNA has been recognized as a drug target for cancer therapy, as evidenced by the ongoing clinical trials of RNAi and antisense therapies. An alternative approach that circumvents the delivery and stability issues of RNAi and antisense is to harness the activity of naturally occurring enzymes that degrade RNA. Variants of human ribonucleases (RNase) have been generated with diminished binding to their natural inhibitor inside cells, which allows the new proteins to kill cancer cells. QBI-139, a variant that retains 95% sequence identity to a naturally occurring RNase, has demonstrated efficacy as both a single agent and in combination against multiple tumor types in in vivo models of human cancer. A first in human phase I trial was designed and initiated for QBI-139. Methods: Since QBI-139 showed efficacy against multiple cancers in model systems, a first in human phase I trial was designed for patients with advanced solid tumors (NCT00818831). Patients receive QBI-139 by intravenous infusion once weekly for a cycle of three weeks. In the absence of disease progression or unacceptable toxicity, treatment can continue on the twenty one day cycle. The trial is a standard 3+3 design with cohorts of three to six patients receiving escalating doses of QBI-139 until the maximum tolerated dose (MTD) and/or recommended phase II dose is determined. The inclusion/exclusion criteria are typical for the patient population. Forty three patients have been treated to date (January 2012) without identification of dose limiting toxicity. The starting dose in the clinical trial was 3 mg/m2 while the most recently completed cohort was treated with a dose of 50.4 mg/m2. Dose escalation is ongoing. The primary outcome is to evaluate the toxicity and tolerability of QBI-139 in patients with advanced refractory solid tumors. This information will allow for identification of the maximum tolerated dose. Clinical exposure levels are being monitored by measuring the pharmacokinetics of QBI-139. Tumor response to QBI-139 will be measured using RECIST criteria. Since QBI-139 demonstrated broad efficacy in model systems, another outcome of the phase I trial may be identification of the indications for the next stage of clinical development.