bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract OT1-1-01: A phase II study of neoadjuvant epirubicin/cyclophosphamide (EC) followed by weekly nanoparticle albumin-bound paclitaxel with or without trastuzumab for node-positive breast cancer
Authors: Hirano A , Hattori A , Kamimura M , Ogura K , Kim N , Setoguchi Y , Okubo F , Inoue H , Jibiki N , Miyamoto R , Kinoshita J , Kimura K , Fujibayashi M , Shimizu T
Published: August 2014

Background: Paclitaxel is considered standard treatment for metastatic breast cancer (MBC) and is often used as adjuvant and neoadjuvant chemotherapy for patients with early-stage disease. Conventional paclitaxel requires solvents such as polyoxyethylated castor oil; however, such solvents are associated with toxicity including peripheral neuropathy and hypersensitivity reaction. Moreover, the use of the drug requires special tubing and in-line filters. Therefore, nanoparticle albumin-bound paclitaxel (nab-PTX) requiring no solvent has been developed. Nab-PTX was effective in patients with MBC and as a neoadjuvant therapy. A comparison between weekly and triweekly nab-PTX suggested that weekly nab-PTX was superior in progression-free survival.

Trial design: This is a phase II trial to evaluate the efficacy and toxicity of neoadjuvant epirubicin/cyclophosphamide (EC) (epirubicin/cyclophosphamide) followed by weekly nab-PTX with or without trastuzumab for node-positive breast cancer. Patients receive four cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by four cycles of nab-PTX (125 mg/m2) on days 1, 8 and 15 in a 28-day cycle. Fifteen cycles of trastuzumab (2 mg/kg, loading 4 mg/kg) are added to the nab-PTX regimen in HER2-positive patients every week.

Eligibility criteria: Patients with histologically diagnosed invasive breast cancer based on a core needle biopsy of the T1-4 N1-3 without previous operation or chemotherapy are included in this trial. Eligible patients are aged between 20 years and 70 years with a performance status of 0 to 2 and adequate organ functions.

Specific aims: The primary endpoint is the pathologic complete response (pCR) rate in the breast and axilla, and the secondary endpoints are the breast conserving rate, toxicities, feasibility and overall survival.

Statistical methods: The sample size was calculated using the Simon method, with a type I error of 10% and a study power of 80%. 1. HER2-negative patients

The expected rate of pCR was 25% and the required number of patients was estimated to be 33. 2. HER2-positive patients

The expected rate of pCR was 50%, and the required number of patients was estimated to be 21.

Present and target accrual: Patient accrual within two medical centers started in April 2011 with 20 patients being on study to date (2012, June 12). A total of 56 patients (22 are HER2-positive and 34 are HER2-negative) are planned to be enrolled in the trial.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-01.
Abstract OT1-1-03: PERSEPHONE: Duration of Trastuzumab with Chemotherapy in women with HER2 positive early breast cancer.
Authors: Earl HM , Cameron DA , Miles D , Wardley AM , Ogburn ERM , Vallier A-L , Loi S , Higgins HB , Hiller L , Dunn JA
Published: August 2014

Background: Persephone is a phase III randomised controlled trial comparing six months of trastuzumab to the standard 12 month duration in patients with HER2 positive early breast cancer in respect of disease free survival, safety and cost-effectiveness. A Persephone sister study, the PHARE trial run by the National Institute for Cancer, successfully closed to recruitment in 2010. A prospective meta-analysis is planned once each trial has reported individually.

Methods: A total of 4000 patients will be randomised into each of the two treatment groups. Eligible participants must be Her2 positive with a histological diagnosis of invasive breast cancer and no evidence of metastatic disease. Patients will receive neo-adjuvant or adjuvant chemotherapy and have no previous diagnosis of malignancy unless managed by surgical treatment only and disease-free for 10 years. Patients can be randomised at any time prior to receiving their 10th cycle of trastuzumab.

The power calculations assume that the disease-free survival (DFS) of the standard treatment of 12 months trastuzumab will be 80% at 4 years. On this basis, with 5% 1-sided significance and 85% power, a trial randomising 2000 in each arm will have the ability to prove non-inferiority of the experimental arm defining non-inferiority as ‘no worse than 3%’ below the control arm 4 year DFS. Primary outcome is disease-free survival non-inferiority (equivalence) of 6 months trastuzumab compared with 12 months in women with early breast cancer. Secondary outcomes are overall survival non-inferiority (equivalence); expected incremental cost effectiveness; cardiology function and analysis of predictive factors for development of cardiac damage. Two mandatory sub-studies are: Tumour block collection to discover molecular predictors of survival with respect to duration of trastuzumab treatment and blood sample collection, used to discover single nucleotide polymorphisms (SNPs) as genetic/pharmaco-genetic determinants of prognosis, toxicity and treatment outcome. A third optional sub-study is the quality of life questionnaires.

Results: Persephone opened to recruitment in October 2007. To date, 2152 patients (54%) of its total have been randomised from 147 UK sites. Recruitment is due to complete by December 2013 and the first planned interim analysis of the primary outcome will be mid-2016.

Conclusion: The IDSMC last reviewed the trial in December 2011 and congratulated the Trial Management Group on the conduct of the trial and the quality of the data. No safety concerns were identified, and the IDSMC proposed that the trial continue to planned recruitment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-03.
Abstract OT1-1-04: ALTERNATIVE: safety and efficacy of lapatinib (L), trastuzumab (T), or both in combination with an aromatase inhibitor (AI) for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer
Authors: Johnston S , Wroblewski S , Huang Y , Harvey C , Nagi F , Franklin N , Gradishar W
Published: August 2014

Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) gene in breast cancer is associated with an aggressive phenotype, poor prognosis, and resistance to endocrine therapies. Of HER2+ patients, ∼50% are also hormone receptor-positive (HR+). For patients who are both HER2+ and HR+, combining the AI letrozole with the dual tyrosine kinase inhibitor L has been shown to improve outcomes compared with letrozole alone. The combination of L and T, a humanized monoclonal antibody-targeting HER2, has been shown to improve outcomes compared with L alone.

Trial design: The ALTERNATIVE study is a Phase III, randomized, open-label, multicenter trial, which will examine the efficacy of L/T/AI in combination versus T/AI alone. Patients will be randomized to 1 of 3 treatment arms: L 1000 mg po QD plus T (loading dose of 8 mg/kg followed by maintenance with 6 mg/kg IV q3w plus an AI po QD); T plus an AI; or L 1500 mg po QD plus an AI. Choices of AI include letrozole, anastrozole, or exemestane.

Eligibility criteria: Postmenopausal female patients with HER2+/HR+ metastatic breast cancer (MBC) who have received neo/adjuvant T and endocrine therapy, are treatment naïve for MBC, and are not candidates for chemotherapy.

Specific aims: The primary efficacy endpoint is overall survival (OS), defined as the time from randomization until death due to any cause, for L/T/AI compared with T/AI alone. Secondary efficacy objectives include comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI in addition to comparisons of progression-free survival, overall response rate, time to response, and duration of response. The safety objective is to evaluate the safety and tolerability for all 3 treatment groups.

A 4-year recruitment is anticipated. More than 200 centers across 37 countries are planned; approximately 110 centers are currently open for enrollment.

Statistical methods: The study is powered to detect a 42% reduction in risk of death (hazard ratio=0.70) in patients who receive L/T/AI (median 28.5 months) versus T/AI (median 20 months) using a 1-sided test for superiority with α=0.025. The required number of total events to achieve a power of 80% is 249. Secondary comparisons are not powered and will be based on the intent-to-treat population.

Present and target accrual: Twenty-six (26) of 525 patients have been randomized. Patients who have participated in previous neo-/adjuvant trials including a T regimen are eligible, provided they meet all other inclusion criteria.

The study is currently recruiting patients, with an anticipated target accrual of 525 patients by March 2016.

Clinical trial registry number: NCT01160211

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-04.
Abstract OT1-1-05: A Phase I pharmacokinetics trial comparing PF-05280014 and trastuzumab in healthy volunteers (REFLECTIONS B327-01)
Authors: Ricart AD , Zacharchuk C , Reich SD , Meng X , Barker KB , Taylor CT , Hansson AG
Published: August 2014

Background: Trastuzumab is a humanized recombinant monoclonal antibody that selectively binds the extracellular domain of human epidermal growth factor receptor 2 (HER2) and is approved for treatment of breast and gastric cancers. PF05280014 is being developed as a potential biosimilar to trastuzumab. In nonclinical evaluations, PF-05280014 has an identical amino acid sequence to trastuzumab and similar physicochemical and in vitro functional properties. The goal of this phase I trial is to demonstrate the pharmacokinetic similarity of PF-05280014 to trastuzumab sourced from both the United States (trastuzumab-US) and European Union (trastuzumab-EU).

Trial design: In this double-blind, parallel group, single dose trial, subjects will be randomized 1:1:1 into 3 arms: PF-05280014; trastuzumab-US, and trastuzumab-EU (NCT01603264).

Eligibility: Healthy male volunteers, 18–55 years of age with normal left ventricular ejection fraction are eligible. Multiple exclusion criteria common to Phase 1 trials are in effect. All subjects must provide informed consent.

Aims: The primary objectives are to demonstrate the pharmacokinetic similarity of PF-05280014 to trastuzumab-US and trastuzumab-EU. Secondary objectives include evaluating the safety, tolerability, and immunogenicity of PF-05280014 compared with US-licensed and EU-approved trastuzumab products.

Statistical methods: Pharmacokinetic similarity will be demonstrated if the 90% confidence interval of the ratio of the area under the concentration-versus-time curve from time 0 to the last time point with quantifiable concentration (AUCT) and maximum concentration (Cmax) of PF-05280014 to both trastuzumab-US and trastuzumab-EU are within 80%–125%. At least 93 subjects, 31/arm, will be needed to provide >81% power to demonstrate pharmacokinetic similarity for all comparisons. The planned enrolment is 105 subjects to account for subjects who may not complete the full follow-up period. The intent-to-treat (ITT) population is defined as all subjects who are randomized to receive treatment. The modified ITT population is defined as all subjects who are randomized and receive at least one dose of treatment and will be used to assess safety, tolerability, and immunogenicity. The per-protocol population is defined as all subjects who are randomized to and receive treatment and do not have any major protocol violations and will be used for the primary evaluation of pharmacokinetic parameters.

Accrual: The target accrual is 105 subjects; present accrual is 17subjects.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-05.
Abstract OT2-2-03: Dovitinib (TKI258) or placebo in combination with fulvestrant in postmenopausal, endocrine-resistant HER2–/HR+ breast cancer: a phase II study
Authors: Andre F , Greil R , Denduluri N , Barrios C , Campone M , Cortes J , Neven P , Reddick C , Squires M , Zhang Y , Yovine A , Blackwell K
Published: August 2014

Background: Overcoming endocrine resistance is a critical goal in the treatment of hormone receptor-positive (HR+) breast cancer. Molecular mechanisms associated with endocrine resistance include adaptive cross-talk between the estrogen receptor and the fibroblast growth factor receptor (FGFR). Up to 8% of HR+/ human epidermal growth factor receptor 2 negative (HER2–) breast cancer patients have amplification of the FGFR1 gene, which is associated with resistance to endocrine therapy. In preclinical models, resistance to endocrine therapy can be overcome via FGFR1 inhibition. Dovitinib is a potent oral inhibitor of receptor tyrosine kinases, including FGFR, vascular endothelial growth factor receptor (VEGFR), and platelet derived growth factor receptor (PDGFR), that demonstrated antitumor activity in heavily pretreated breast cancer patients with FGF-pathway amplification (FGFR1, FGFR2, or ligand FGF3; Andre et al, ASCO 2011). Dovitinib may reverse resistance to endocrine therapy related to FGF-pathway amplification and may also inhibit angiogenesis, which plays an essential role in breast cancer development. Dovitinib is studied here in combination with fulvestrant to determine if it can improve outcomes in postmenopausal patients with endocrine resistant HER2−/HR+ breast cancer.

Methods: This is a multicenter, randomized, double-blind, placebo-controlled, phase II trial that will enroll postmenopausal HER2–/HR+ locally advanced or metastatic breast cancer patients (N ≈ 150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting. Patients prospectively undergo molecular screening to enrich for FGF amplification (FGFR1, FGFR2, or FGF3 amplification by qualitative polymerase chain reaction (qPCR); 45 amplified and 30 nonamplified patients per arm). Patients are randomized 1:1 (stratified by FGF-amplification and presence of visceral disease) to receive fulvestrant intramuscularly (500 mg q4w [with an additional dose 2 weeks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or placebo until disease progression, unacceptable toxicity, death or discontinuation due to any reason (eg, withdrawal). Crossover is not permitted. The primary endpoint is progression-free survival, with tumor assessments performed q8w. Secondary endpoints include overall response rate per RECIST v1.1, duration of response, overall survival, Eastern Cooperative Oncology Group performance status and patient-reported outcome scores over time, and safety. Additionally, the pharmacodynamic effect of dovitinib on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to dovitinib will be explored.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-2-03.
Abstract OT2-3-03:

D

enosumab versus placebo as adjuvant treatment for women with early-stage breast

ca

ncer at high risk of disease

re

currence (D-CARE): An international, randomized, double-blind, placebo-controlled phase 3 clinical trial
Authors: Goss PE , Barrios CH , Chan A , Finkelstein DM , Iwata H , Martin M , Braun A , Ke C , Maniar T , Coleman RE
Published: August 2014

Bone represents approximately 40% of all first recurrences in women with early-stage breast cancer and is a common site of distant recurrence. In preclinical studies, RANKL inhibition significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors.

Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints are safety, breast density, incidence of SREs (following the development of bone metastasis) patient reported outcomes, and biomarkers.

Methods: In this international, randomized, double-blind, and placebo controlled phase 3 trial, approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm, (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except ductal carcinoma in situ or lobular carcinoma in situ) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, are not eligible. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) will be administered. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete enrollment in late 2012.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-03.
Abstract OT2-3-07: A randomized, phase 2 study of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) in combination with temozolomide (TMZ) or in combination with carboplatin (C) and paclitaxel (P) versus placebo plus C/P in subjects with BRCA1 or BRACA2 mutation and metastatic breast cancer
Authors: Isakoff SJ , Pulhalla S , Shepherd SP , Falotico N , Kaufman B , Friedlander M , Robson M , Domchek S , Garber J , McKeegan E , Chyla B , Qian J , Giranda VL
Published: August 2014

Background: Veliparib is a potent, oral PARP inhibitor that inhibits DNA repair, primarily through single strand break repair. BRCA1/2 mutated tumors are defective in homologous recombination, leading to more error prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. Veliparib and TMZ recently demonstrated promising activity in BRCA1/2 mutation carriers, and veliparib and C/P is being evaluated in a CTEP Phase 1 study. This Phase 2 multinational study will evaluate veliparib in combination with TMZ and in combination with C/P compared to an active, placebo-controlled arm of C/P in subjects with BRCA1 or BRCA2 mutation and metastatic breast cancer.

Methods: Approximately 240 subjects will be randomized in a 1:1:1 ratio to: 1) Veliparib 40 mg BID D1-7 + TMZ (150–200 mg/m2 QD D1-5) of every 28 day cycle; or 2) Veliparib 120 mg BID D1-7 + C (AUC 6, D3) and P (175 mg/m2, D3) of every 21 day cycle or 3) placebo BID D1-7 + C/P. Key eligibility includes known deleterious BRCA1/2 mutation, ≤1 prior chemotherapy for metastatic disease, and no prior platinum agent. Randomization will be stratified by hormone receptor positive versus negative, prior vs. no prior cytotoxic therapy, and ECOG 0–1 vs 2.

The primary objective is progression-free survival (PFS) using RECIST 1.1. Secondary objectives include overall survival, objective response rate, duration of response and safety/tolerability. Optional paired tissue biopsies will be obtained at baseline and at progression to evaluate markers of response and resistance. Additional correlatives for response include assessment of peripheral blood, CTCs, and archived tissue for markers of disease status, gene methylation and mutational status, and tumor-specific alteration of cellular proteins/peptides and/or nucleic acids. Using the log-rank test for PFS, with 150 PFS events the study will have ≥ 80% power at 2-sided α level of 0.05 to detect a statistically significant treatment effect assuming a true hazard ratio of 0.58 favoring the 2 treatment groups containing veliparib. As of June 11, 2012, 5 subjects have been enrolled.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-07.
Abstract OT3-2-02: The PREDICT Study (Prospective, Randomized Early Detection and Intervention after Breast Cancer-Treatment, for women at risk of lymphedema)
Authors: Taghian AG , Skolny MN , O'Toole J , Miller CL , Jammallo LS , Specht MC
Published: August 2014

Introduction: It is well-documented that lymphedema is one of the most feared long-term side effects of breast cancer (BC) treatment. However, to date, a standardized approach for the quantification and treatment of breast cancer-related lymphedema (BCRL) has yet to be established.

Aims: We propose a screening and intervention trial that will assess the efficacy of early detection and intervention for BCRL. Intervention comprises the use of compression garments for mild lymphedema and compression garments +/− nighttime bandaging for moderate lymphedema. Other factors to be evaluated include: symptom clusters, treatment adherence, fear avoidance behavior, quality of life (QOL), upper extremity function, and risk factors for BCRL.

Eligibility Criteria: Women 18 years + with a confirmed BC diagnosis, no history of BC, no known metastatic or locally advanced disease, no history of primary lymphedema, sentinel lymph node biopsy or axillary lymph node dissection as part of definitive breast surgery.

Study Design: A two-stage study which includes a Screening and an Intervention trial. The screening arm will evaluate arm volume change during and after BC treatment with target accrual of 8000. Patients will undergo measurements via perometry and complete the MGH Lymphedema Evaluation Following Treatment for Breast Cancer (LEFT-BC) Survey at each screening appointment to evaluate changes in functionality, upper extremity utilization (fear associated avoidance), and QOL. Screening visits will occur pre- and post - operatively, at the conclusion of chemotherapy and radiation therapy and every 3–7 months thereafter. Patients will become eligible for enrollment into the intervention trial if, during the course of screening, they develop a relative arm volume change (RVC) of ≥ 5% which persists at a verification measurement within 4–8 weeks. Eligible subjects are enrolled into one of two groups based on verification RVC: Group I – Mild Lymphedema (5–10% RVC) or Group II – Moderate Lymphedema (11–20% RVC). Subjects are then randomized within each group. Group I subjects are randomized to one of two arms: I-A – Observation, I-B – Compression, and Group II subjects are randomized to one of two arms: II-A – Compression, II-B – Compression + Night Compression Bandaging. Target accrual for the intervention trial is 336 subjects (Group I: 208, Group II: 128).

Clinical Relevance: The results of this study will yield level I evidence on the effectiveness of early detection and intervention for BCRL. Findings may shape clinical practice in diagnosis and treatment, as well as provide insight regarding the risk factors, symptoms, upper extremity function, and quality of life (QOL) associated with BCRL.

*Funding by awards R01CA139118 & 3P5OCA089393, AGT

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-2-02.
Abstract OT3-3-03: Silent risk? Cardiovascular risk factors in survivors of breast cancer treated with anthracyclines.
Authors: Murtagh Gillian , Lyons Tomas G , Geraghty Lucy , Conlon Carmel , Tallon Elaine M , Ballot Jo , Patel Anil , Badabhagni Mallikarjuna , Ledwidge Mark T , Fennelly David , Gullo Giuseppe , Walshe Janice , Crown John , McDonald Kenneth M
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-03.
Abstract OT3-3-09: ARTemis trial - randomised trial with neo-adjuvant chemotherapy for patients with early breast cancer
Authors: Earl HM , Blenkinsop C , Grybowicz L , Vallier A-L , Cameron DA , Bartlett JMS , Murray N , Caldas C , Thomas J , Dunn JA , Higgins HB , Hiller L , Hayward L
Published: August 2014

Background: Bevacizumab, a humanised monoclonal antibody which targets vascular endothelial growth factor (VEGF), has shown promising anti-tumour effect when given concurrently with taxane-based chemotherapy in breast cancer. However two neoadjuvant breast cancer trials have produced conflicting results. The GEPARQUINTO trial reported significant benefit only in the triple negative patients (pCR 27.8% vs 36.4% p = 0.021). The NSABP-B40 study showed significant benefit for bevacizumab only in the ER+ve patients (pathological complete response (pCR) in ER+ve population 15.2% vs 23.3%, p = 0.008).

Trial design: ARTemis is a phase III randomised trial to determine whether the addition to neo-adjuvant chemotherapy of bevacizumab is more effective than standard chemotherapy alone in patients with HER2-negative early breast cancer. A total of 400 patients will be randomised into each of the two treatment arms which will allow an absolute difference in the pCR rates in excess of 10% to be detected at the 5% (2-sided) level of significance with an 85% power. Primary outcome is pathological complete response rates after neo-adjuvant chemotherapy, i.e. no residual invasive carcinoma in the breast, and no evidence of metastatic disease within the lymph nodes. Secondary outcomes are disease free survival, overall survival, complete pathological response rates in breast alone, radiological response after 3 and 6 cycles of chemotherapy and rate of breast conservation and toxicities. Translational work (ARTemis-Science): collection of blood samples, and paraffin-embedded formalin-fixed and fresh tissue samples to investigate whether markers for chemotherapy response/resistance, and pharmacogenetic and pharmacogenomic markers can be correlated with outcomes (pathCR and RFS) in patients randomised to receive bevacizumab versus those that do not.

Eligibility criteria: Histologically confirmed HER2-negative invasive breast cancer; T2 to T4 tumour and/or large/fixed axillary nodes (>20mm/clinical N2 or N3), or inflammatory disease; suitable for, and fit to receive neo-adjuvant chemotherapy and an anti-angiogenic.

Results: Recruitment into ARTemis began in April 2009 and as of June 2012 had recruited 600 (75%) patients and 65 sites are open for recruitment. ARTemis is due to complete recruitment by first quarter of 2013 and the first planned interim analysis of the primary outcome will be December 2013.

Conclusion: The IDSMC reviewed the trial in June 2012 and recommended continuation of recruitment to this important trial given there were no safety concerns.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-09.
Abstract OT3-4-05: Use of early CIRculating tumor CElls count changes to guide the use of chemotherapy in advanced metastatic breast cancer patients: the CirCe01 randomized trial
Authors: Bidard F-C , Asselain B , Baffert S , Brain E , Campone M , Delaloge S , Bachelot T , Tubiana-Mathieu N , Pelissier S , Pierga J-Y
Published: August 2014

Background: After the SWOG0500 trial, the CirCe01 trial (NCT01349842) is the second randomized attempt to demonstrate that patients who received a first cycle of chemotherapy and whose CTC count did not drop should be switched off this chemotherapy.

The clinical setting used here is a population with high chemoresistance prevalence, i.e. patients starting a third line chemotherapy; the CTC test will be also repeated at the beginning of every new chemotherapy line in patients randomized in the CTC arm (i.e. to evaluate the 3rd, 4th, 5th … lines).

In the CTC arm, it has been hypothesized that many patients with chemoresistant tumor will experience repeated early chemotherapy changes (e.g. 3 chemotherapy regimens tested in 9 weeks), giving support to the discontinuation of inefficient, toxic and costly chemotherapies and the start of palliative care. It is believed, for this subgroup of patients, that such de-escalating management will benefit both patients and healthcare systems. For some other patients, it is also expected that they will benefit from the early chemotherapy turn-around and find earlier an efficient therapy among all those tested.

Methods: The main inclusion criteria are metastatic breast cancer patients starting a third line of chemotherapy and an elevated CTC count at baseline.

304 metastatic breast cancer patients will be randomized between the standard arm, in which the treatment management is made following the current standard of care, and the CTC-driven arm, in which the “response” after every first cycle of any new chemotherapy line is assessed by CTC count made before the second cycle. Chemotherapies which did not lead to a significant reduction of CTC count are discontinued, and the patient might be offered another chemotherapy regimen (which will be also evaluated by CTC).

The medical primary endpoint of the trial is the overall survival, whereas a medico-economic study as a co-primary endpoint. Several secondary endpoints are pre-planned, including progression-free survival, quality of life, anxiety/depression and comparison with serum markers.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-4-05.
Abstract OT3-4-06: Circulating tumor cells to guide the choice between chemotherapy and hormone therapy as first line treatment for hormone receptors positive metastatic breast cancer patients: the STIC CTC METABREAST trial
Authors: Bidard F-C , Baffert S , Hajage D , Brain E , Armanet S , Simondi C , Mignot L , Asselain B , Tresca P , Pierga J-Y
Published: August 2014

Background: Baseline CTC count already demonstrated its accuracy as an independent prognostic marker in metastatic breast cancer (MBC), before the start of any treatment (Cristofanilli, NEJM 2004; Pierga Ann Oncol 2011) for progression free survival and overall survival. Multivariate analyses performed in both a pooled analysis (Liu, ASCO 2011) and in the IC 2006–04 study showed that the other independent prognostic factors were the performance status and hormone-receptor (HR) status. Oppositely, the other criteria that are frequently used to choose between hormone therapy and chemotherapy for the treatment of first line hormone receptor-positive MBC patients (e.g. number of metastatic sites, visceral disease, metastasis-free interval…) were not independent prognostic factors. As CTC count is highly correlated to PFS, we designed a large pivotal phase III trial to evaluate the use of CTC to determine the disease aggressiveness and the choice of first line treatment in potentially hormonosensitive MBC.

Trial design: First line metastatic breast cancer patients will be randomized between the clinician choice and CTC count-driven choice. In the CTC arm, patients with ≥5 CTC/7.5ml will receive chemotherapy whereas patients with <5 CTC/7.5ml will receive endocrine therapy as first line treatment.

Eligibility criteria: Main inclusion criteria include hormone receptor-positive metastatic breast cancer patients with no previous treatment for the metastatic disease, and who can receive either hormone therapy or chemotherapy as first line treatment.

Statistical methods: As every patient will receive a treatment, this pivotal trial has been designed to show a non-inferiority of the CTC arm for PFS (primary clinical endpoint) and a superiority of the CTC arm for the medico-economics study (co-primary endpoint).

Present accrual and target accrual: This trial began in March 2012 and more than 15 French cancer centers participate to this study. The accrual of 996 metastatic breast cancer patients should be completed in 2 to 3 years. 20 patients have been included in 2 months in the first opened center.

Contact information for people with a specific interest in the trial

The STIC CTC METABREAST trial has been funded by the French Ministry of Health (STIC program) and Veridex. The promoter is the Institut Curie (Paris).

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-4-06.
Abstract P1-01-02: Axillary Reverse Mapping: A Prospective Study on Feasibility, Oncologic Safety, and Lymphedema Prevention.
Authors: Connor Carol S , McGinness Marilee K , Mammen Joshua MV , Ranallo Lori B , LaFaver Stephanie M , Klemp Jennifer R , Fan Fang , Mahnken Jonathan D
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-02.
Abstract P1-01-03: Comparison of sentinel lymph node biopsy guided by the multi-modal method of indocyanine green fluorescence, radioisotope and blue dye versus the radioisotope in breast cancer; A randomized phase II trial
Authors: Jung S-Y , Kim S-K , Kim SW , Lee S , Lee J , Shin I-s , Kwon Y , Lee E
Published: August 2014

Background: Sentinel lymph node (SLN) biopsy is a standard surgery for axillary staging of early breast cancer. This study aimed to evaluate the identification rate and surgery time of SLN biopsy with the multi-modal method using the mixture of indocyanine green (ICG) fluorescence, RI and blue dye as a new method, in comparison with the RI, in clinically node negative breast cancer patients.

Materials and methods: In this phase-II randomized study, 86 patients with clinically node negative breast cancer were randomized to receive periareolar injection of the mixture including ICG fluorescence, RI and blue dye or the only RI for SLN biopsy. We compared the identification rate, the number of SLN, and detections time of SLN biopsy between these two groups.

Results: The mean age of the multimodal group and the only RI group was 48.2 years and 51.0 years (p = 0.12), respectively. There were no differences of histopathologic factors including tumor size, node positivity, hormone receptor positivity and HER2 positivity between two groups. Sentinel lymph nodes were identified in all patients of both groups (100% in the multimodal group vs 100% in the RI group). The average number of SLN in the mixture group was more than that of the RI group (3.4 ±1.37 vs 2.3 ± 1.04; p < 0.001). The time to excise the first SLN was similar in each group (6.5 ± 5.16 min vs 8.0 ± 4.35 min; p = 0.13). In multimodal group, percutaneous lymphatic drainage was visualized by fluorescent imaging in 90.7% (39 of 43 patients) and all of the first SLN were detected by both ICG fluorescent and RI. After operation, there was no complication including skin staining or necrosis.

Conclusions: This study is the first randomize trial which compared the multimodal method using the mixture of ICG fluorescence, RI and blue dye and the conventional RI method for SLN biopsy. The multimodal method is an available method for SLN biopsy, which allows percutaneous visualization of lymphatic vessels and intraoperative lymph node detection.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-03.
Abstract P1-01-06: Evaluation of the stage IB designation of the 7th edition of the AJCC staging system: Biologic factors are more important
Authors: Mittendorf EA , Ballman KV , McCall LM , Hansen N , Lucci A , Gabram S , Urist M , Crow J , Hurd T , Hunt KK , Giuliano AE
Published: August 2014

Purpose: The stage IB designation was added to the AJCC 7th edition staging system to denote micrometastasis in patients with T1 tumors. We have previously examined this group and found that receptor status and nuclear grade were better survival discriminates than the presence of micrometastases. The current study was undertaken to validate this finding in a larger cohort from the American College of Surgeons Oncology Group (ACOSOG) Z0010 study.

Methods: Clinicopathologic and outcomes data from patients enrolled on ACOSOG Z0010 were recorded. All patients underwent breast conserving surgery, sentinel lymph node biopsy and whole breast radiation for clinical T1-2, N0 breast cancer. Sentinel lymph nodes were evaluated by H&E locally and if negative, by immunohistochemistry (IHC) at a central laboratory. Patients were staged according to the 7th edition AJCC system and recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were determined using the Kaplan-Meier method and compared using the log-rank test.

Results: There were 5210 eligible and evaluable patients enrolled on ACOSOG Z0010. AJCC stage distribution was known in 4590 and included: 2849 (62.0%) stage IA, 376 (8.2%) stage IB, 878 (19.1%) stage IIA, 322 (7.0%) stage IIB, and 170 (3.7%) stage III. Median follow-up for the cohort was 9.0 years (range 0–12.6). Five and 10-year RFS, DSS and OS rates for patients with stage IA versus IB disease are shown in table 1.

There were no significant differences between groups. When all stage I patients (stage IA and IB) were evaluated by ER status (positive vs negative) or grade (grade 1 vs 2 vs 3), these biologic factors were able to significantly discriminate patients with respect to RFS, DSS and OS (table 2).

Conclusion: Differentiating patients with micrometastases (stage IB) from node negative patients (stage IA) does not stratify patients well with respect to survival. Biologic factors including ER status and grade are better discriminants of survival than the presence of small volume nodal metastases in patients with early stage breast cancer. Breast cancer staging should include biologic factors from the primary tumor.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-06.
Abstract P1-01-09: Which nomograms may be the best for predicting nonsentinel lymph node metastasis in breast cancer patients: a meta-analysis.
Authors: Chen K , Jin L , Zhu L , Shan Q , Su F
Published: August 2014

Background: Axillary lymph node dissection (ALND) is the standard treatment for breast cancer patients with positive sentinel lymph nodes (SLNs). Several nomograms were developed to identify SLN-positive patients with low risk of nonsentinel lymph nodes (NSLNs) metastasis. These nomograms were validated in different populations and it is still unknown which is the best. This study is to present a systemic review and perform a meta-analysis to obtained the pooled AUC (Area Under the receiver-operator Curve) value of each models.

Methods: This review focused on six models: Cambridge, MSKCC, Mayo, MDA, Tenon and Stanford models. A “Pubmed” search and “Web of science” search were conducted and 35 literatures were ultimately included. AUC and the number of patients with positive NSLNs were extracted. Publication bias and heterogeneity were analyzed. AUCs were converted to odds ratios (ORs) for combination. The combined ORs were converted back to AUCs to represent the integrated discriminative capabilities of each models.

Findings: In total, the Cambridge, Mayo, MDA, MSKCC, Stanford and Tenon models were validated in 8, 6, 4, 39, 14 and 15 studies, with 2156, 2431, 843, 8143, 3700 and 3648 patients included, respectively. There were no publication bias or heterogeneity observed in the Cambridge, Mayo, MDA and Tenon models (Table 1). The combined ORs and the corresponding AUCs of each models were listed as follow: Cambridge (OR = 3.86, AUC = 0.71), Mayo (OR = 3.71, AUC = 0.71), MSKCC (OR = 3.47, AUC = 0.70), MDA(OR = 3.44, AUC = 0.70), Tenon (OR = 3.46, AUC = 0.70) and Stanford (OR = 2.92, AUC = 0.67). For each of the predictive models, both fixed and random effect models were used to calculate the combined OR. The presence of larger difference between the fixed and random effect analysis suggests small study effects, rendering the meta-analysis relatively less reliable. The combined ORs were identical when fixed and random effect models were used in the Cambridge and MDA models, suggesting that there was no small study effects in these two models.

Conclusions: All of the included models are all better than random chance but not provide excellent discriminative capabilities. The Cambridge and Stanford models were relatively superior and inferior when compared with the other models, respectively.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-09.
Abstract P1-01-10: Comparison of sentinel lymph node positivity rates pre and post introduction of OSNA molecular analysis
Authors: Rusby J , Agabiti E , Waheed S , Barry P , Roche N , Allum W , Gui G , MacNeill F , Christaki G , Osin P , Nerurkar A
Published: August 2014

Introduction: Intra-operative assessment (IOA) of the axillary sentinel lymph node (SLN) allows immediate completion axillary lymph node dissection (cALND) for a positive SLN. One-step nucleic acid amplification assay (OSNA, (Sysmex)), a molecular technique, is very sensitive and may upstage the axilla compared with other forms of intra-operative assessment and with formal, paraffin-embedded haematoxylin and eosin (H&E) histopathology. This would result in an increased cALND rate at a time when efforts are being made to reduce unnecessary axillary surgery in line with the Z0011 trial (Giuliano et al. 2011).

This study compares node positive rates before and after two changes in practice: the introduction of OSNA and the unit policy to perform cALND for macrometastatic SLN disease only.

Methods: All patients in our unit undergo pre-operative axillary ultrasound with fine needle aspiration cytology of any suspicious nodes. Those with malignant cytology proceed directly to ALND. Radiologically and cytologically node negative patients undergo SLNB. Consecutive electronic records were examined for all SLNB procedures in two groups: Pre-OSNA from June 2006 to December 2010 and OSNA from August 2011 to March 2012. Pre-OSNA, patients were offered cALND for micro-or macroscopic SLN disease identified by H&E histology. Following Z0011, patients in the OSNA group proceeded to cALND for SLN macrometastases but not for micrometastases. The chi-squared test was used to compare results between the two groups.

Results: The groups were similar in terms of age, tumour size, grade and receptor status. Sentinel node and cALND results are shown in table 1.

In summary, testing by OSNA resulted in a higher node positive rate and a greater proportion reported with micrometastases (40% compared with 23% pre-OSNA). The OSNA macrometastasis rate was equal to the pre-OSNA overall node positive rate (22%). Among patients proceeding to cALND (all node-positive pre-OSNA patients and OSNA patients with macrometastases) there was no significant difference in the proportion with additional positive nodes in the cALND or the proportion with a total of four or more positive nodes.

Conclusion: The introduction of OSNA has increased the proportion of patients identified as node positive, and has increased the proportion reported to have macrometastasis. Simultaneously, the decision not to perform cALND for patients with micrometastasis was intended to limit the additional surgery performed in the SLNB group as a whole. However, since this decision was based on data from studies using H&E assessment, we should look for ways to raise the threshold for cALND such that it includes only the patients at the highest risk of axillary recurrence.

Reference

Giuliano AE et al. JAMA 2011; 305(6): 569–75.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-10.
Abstract P1-01-12: The Performance of the One Step Nucleic acid Amplification (OSNA) Assay in Breast Cancer Patients with Receiving Preoperative Systemic Therapy
Authors: Yagata H , Yamauchi H , Horii R , Osako T , Iwase T , Akiyama F , Kinoshita T , Tsuda H , Tsugawa K , Nakamura S
Published: August 2014

Background: The OSNA (One Step Nucleic acid Amplification) assay is a semi-automated lymph node examination method using molecular biological technique. The OSNA assay has been validated for breast cancer patients without receiving preoperative systemic therapy (PST) by several clinical studies and has currently become more popular as sentinel lymph node (SLN) examination method with the following two main advantages; 1) to allow examination of the whole portion of a node, 2) to allow intraoperative judgment of metastasis positive or negative. However, the feasibility of the OSNA assay in breast cancer patients treated by PST has never been confirmed. In this multi-central clinical study, we compared the judgments of the OSNA assay and of pathological examination on lymph nodes dissected after receiving PST to evaluate the performance of the OSNA assay.

Material & Methods: Three hundred two nodes dissected from the 80 breast cancer patients who received PST were examined. Each lymph node was divided at 2mm intervals and the slices were alternately applied to the OSNA assay and pathological examination with H&E staining and CK19 immunohistochemical staining of permanent-section. In pathological examination, judgments of metastasis positive or negative were determined by one central-review pathologist according to the criteria of AJCC 7th edition (“positive” if >0.2mm metastases were detected).

Result: The overall concordance rate between the OSNA assay and pathological examination was 91.1% (275/302) with sensitivity of 88.3% (53/60) and specificity of 91.7% (222/242) (Table). These results are very similar to those of the Japanese clinical validation study in breast cancer patients without receiving PST which was conducted by the almost same protocol (Tamaki Y, et al. Clin Cancer Res, 2009, 15: 2879–2884).

Conclusion & Discussion: These results indicate the OSNA assay can be applicable for breast cancer patients after receiving PST as well as breast cancer patients without receiving PST. The OSNA assay will enable to examine the whole portion of nodes, leading to more detection of metastases (especially micrometastases) and more exact nodal staging for breast cancer patients treated by PST. Also, for the patients who receive sentinel lymph node biopsy after PST, the OSNA assay will be useful as intraoperative examination method of SLNs because it is expected to provide more correct judgments than current intraoperative methods such as frozen-section or touch-print cytology.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-12.