bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract OT1-1-11: DETECT III - A multicenter, randomized, phase III trial to compare standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells
Authors: de Gregorio N , Schochter F , Melcher C , Hagenbeck C , Friedl TWP , Jäger B , Rack BK , Müller V , Fasching PA , Janni W , Fehm T 
Published: August 2014

Abstract
Background: In metastatic breast cancer (MBC) patients, HER2 status may be subject to change and it has been shown that 20-30% of initially HER2-negative patients have HER2-positive metastases. The discordance of the HER2 status between primary tumor and circulating tumor cells (CTCs) may be an important factor affecting the response to HER2-targeted treatments; however, it is unclear if therapy based on the HER2 status of CTC offers a clinical benefit for patients.
Trial Design: DETECT III is a recruiting prospective, multicenter, open-label, two-arm, phase-III study for patients with HER2-negative MBC. Patients with HER2-positve CTCs are randomized to receive either a standard therapy of the physician's choice alone or a standard therapy plus additional HER2-targeted treatment with Lapatinib.
Main Eligibility criteria:
- Metastatic breast cancer;
- HER2-negative primary tumor tissue and/or biopsies from metastatic sites;
- Evidence of at least 1 HER2-positive CTC out of 7.5 ml blood;
- Indication for systemic treatment
- ≥1 lesion evaluable according to RECIST
Specific aims: The objective of the DETECT III trial is to estimate the clinical efficacy of standard therapy plus lapatinib as assessed by progression free survival (PFS) in patients with initially HER2-negative MBC and HER2-positive CTCs. Additional research will be performed on CTC dynamic and characteristics.
Present accrual and target accrual: The DETECT III – trial started February 2012 and has analyzed so far (2013-06-06) 506 patients. We found CTCs in 336 (66.4%) patients (median 7 CTCs, range 1-35078). 67 of these patients (19.9%) had at least one HER2 positive CTC. Estimated patient enrollment is 228.
Methods: The primary endpoint progression-free survival will be estimated using the Kaplan-Meier method. Prevalence and number of CTCs at various time points as well as the HER2 status of CTCs will be determined using the FDA-approved CellSearch System (Veridex, USA). In addition, different measures of CTC dynamics and their value for evaluating therapy efficacy or as a prognostic tool will be examined in detail by explorative data analyses.
Perspectives: The DETECT III-Trail is the first study where treatment is based on phenotypic characteristics of CTCs. If this trial succeeds in proving efficacy of lapatinib in patients with initially HER2-negative primary tumor but HER2-positive CTCs, it may lead to a new strategy for the treatment of metastatic breast cancer.
Contact information: nikolaus.de-gregorio@uniklinik-ulm.de.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-11.
Abstract OT1-4-02: Phase I study of the combination of BKM120 and olaparib for the treatment of high grade serous ovarian cancer (HGSC) and triple negative breast cancer (TNBC)
Authors: Matulonis UA , Wulf G , Cantley L , Mills G , Lasonde B , Atkinson T , Whalen C , Isakoff SJ , Westin S , Bell-McGuinn K , Winer E 
Published: August 2014

Abstract
Background: In vivo synergy of the PI3-kinase inhibitor BKM120 with the PARP inhibitor olaparib has been observed using a mouse model of BRCA1-related breast cancer and sporadic TNBC (Juvekar et al and Ibrahim et al, Cancer Discovery 2012). In addition, olaparib has single agent activity in both HGSC and BRCA-associated breast cancer. The PI3kinase pathway is activated in both TNBC and HGSC (www.cancergenome.nih.gov). These preclinical and clinical data have served as the rationale for this phase I, multi-center study (NCT01623349) combining the oral PARP inhibitor olaparib with the oral PI3-kinase inhibitor BKM120 in patients with recurrent HGSC or recurrent TNBC. This study is being conducted through the Stand Up to Cancer (SU2C)'s Targeting PI3-kinase in Women's Cancers Dream Team.
Study Design: This study has a 3 + 3 design, escalating if 0/3 or 1/6 participants have a dose limiting toxicity (DLT) during the first cycle of therapy (first 28 days). The study objectives are to determine the recommended phase II dose (RP2D) of daily continuous oral olaparib (using the tablet formulation) and BKM120, assess toxicities, safety, and preliminary activity of this combination, and determine pharmacokinetic profiles of both agents. In addition, there are several translational endpoints including elucidation of downstream signaling effects of the PI3-kinase pathway, examination of BRCA1 immunostaining, and assessment of BRCA1 promoter hypermethylation and somatic mutations in BRCA1 and BRCA2 using archived formalin fixed paraffin embedded (FFPE) tissue. Serial IL-8 and circulating DNA levels are also being monitored as well. Eligibility includes a diagnosis of recurrent TNBC or HGSC, PS 0 or 1, measurable or evaluable cancer, and normal lab values and organ function. Prior PARP inhibitor exposure is allowed. In addition, breast cancer or ovarian cancer patients with any histologic subtype are eligible if they have a known germline BRCA1 or BRCA2 mutation. At the RP2D, 10 pts each with a diagnosis of TNBC or HGSC will be enrolled to further determine safety and efficacy profiles in addition to more thoroughly studying translational endpoints. As of June 7, 2013, 16 patients have been enrolled into this study with a planned accrual of approximately 50 patients which may change based on number of dose levels tested during dose escalation. In addition, an amendment is pending that will add a second cohort studying the combination of olaparib and BYL719 based on robust pre-clinical activity observed in murine models which will increase our total accrual. Once this new cohort is open, both arms will enroll simultaneously.
For further information, contact Ursula Matulonis at: umatulonis@partners.org.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-02.
Abstract OT3-1-01: A randomized phase II study of maintenance hormone therapy with or without capecitabine after induction chemotherapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214)
Authors: Yoshinami T , Nakayama T , Ikeda M , Iwamoto M , Komoike Y , Takashima T , Tsurutami J , Yoshidome K , Morita S , Masuda N 
Published: August 2014

Abstract
Background: The combination therapy of Bevacizumab (B) and Paclitaxel (P) has demonstrated to prolong progression free survival (PFS) in E2100 study. Because its PFS is very long, developing optimal therapeutic strategy of B+P, including management of toxicity is crucial. At the 1st International Consensus Conference for Advanced Breast Cancer, most experts agreed the maintenance endocrine therapy after effective induction chemotherapy. In KBCSG-TR 1214 study, we planned to examine the following clinical questions. 1. As a maintenance therapy, which is more effective either endocrine therapy alone (E) or endocrine therapy with Capecitabine (E+C)? 2. Can maintenance therapy reduce toxicity of B+P and restore patient's QOL.? 3. How effective is B+P re-challenge after failure of maintenance therapy?
Methods: KBCSG-TR 1214 study is multicenter open-labeled randomized phaseII trial for HR-positive and HER2-nagative metastatic breast cancer(MBC) patients. Patients will receive B (10mg/kg q2w) in combination with P (90mg/m2 on day 1, 8, and 15 q4w) as an induction therapy. Patients without progression after 6 cycles of B+P will be randomized to E or E+C. Endocrine therapy will be chosen by their physician (treatment of physician's choice). Patients in E+C will receive endocrine therapy with Capecitabine 1657mg/m2 on day1 to 21 q4w. Stratification factors for randomization are menopausal status, presence of target lesion, number of prior endocrine therapies for MBC, with or without 1st line chemotherapy for MBC. After progression of maintenance therapy (E or E+C), B+P will be started again as a reintroduction therapy. Primary end point is PFS of maintenance therapy. Secondary end points include time to failure of strategy from randomization, efficacy of reintroduction therapy, overall survival and safety of induction therapy. Translational research is also planned. VEGF, angiopoetin-1, and apelin in plasma will be measured at four points (before induction therapy, at the beginning of the maintenance therapy and the re-induction therapy, and at the end of the trial). This study has just begun and planned 120 patients will be enrolled. (UMIN000008662).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-01.
Abstract OT3-1-03: DIRECT: A phase II/III randomized trial with dietary restriction as an adjunct to neoadjuvant chemotherapy for HER2-negative breast cancer
Authors: de Groot S , Vreeswijk MPG , Smit VTHBM , Heijns JB , Imholz ALT , Kessels LW , Jager A , Los M , Weijl NI , Smorenburg CH , Portielje JEA , Liefers GJ , van de Velde CJH , Meershoek EM , van Leeuwen E , Fischer MJ , Kaptein AA , Putter H , Longo V , Nortier HWR , van der Hoeven KJM , Pijl H , Kroep JR 
Published: August 2014

Abstract
Background:
Preclinical evidence shows that short-term fasting protects normal cells, while cancer cells are sensitized to chemotherapy. Furthermore, a specifically designed very low calorie, low amino acid substitution diet (“Fasting Mimicking Diet”, FMD) has similar effects on chemotherapy as short-term fasting. This trial evaluates the impact of FMD on tolerance to and efficacy of neoadjuvant chemotherapy in women with HER2-negative early breast cancer.
Trial design:
DIRECT is a Dutch, randomized, open-label multicenter phase II/III trial. Women receiving neoadjuvant TAC courses (docetaxel/adriamycin/cyclophosphamide; day 1, q 3 weeks with G-CSF support at day 2) will be randomized with or without FMD for 3 days prior to and the day of chemotherapy and 3 days prior to surgery.
Eligibility criteria:
Eligible women are WHO 0-2, age ≥18 years, HER2-negative, stage II or III breast cancer and adequate bone marrow, liver and renal function, BMI &gt; 19kg/m2 and absence of diabetes mellitus.
Study endpoints:
The primary endpoints are grade III/IV toxicity (phase II) and the pathologic complete response rate (pCR) (phase III). Secondary endpoints are grade I/II toxicity, metabolic and inflammatory response to chemotherapy, DNA damage, apoptosis, immunology and nutrient sensing pathways in the tumor, biomarkers as single nucleotide polymorphisms, Ki67 and tumor stroma/ratio, patient's quality of life and (disease free) survival. Optional side studies include chemotherapy-induced DNA damage and nutrient sensing pathways in leukocytes and proteomics.
Statistical Methods:
Using a 5% significance level based on the two-sided Fisher's exact test with a power of 80%, 128 patients (64/arm) will be enrolled to show a 50% decrease of grade III/IV adverse events in the experimental arm (phase II) and 250 patients (125/arm) are needed to show an improvement of the pCR rate from 18% to 36% (phase III).
Target accrual:
Recruitment will start in September 2013. The expected end of accrual of 250 patients from multiple centers in the Netherlands will be the last quarter of 2015.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-03.
Abstract OT3-2-03: An efficacy and safety trial of preoperative chemo-endocrine therapy in luminal B (HER2-negative) breast cancer: A prospective multi-institutional study
Authors: Matsunuma R , Ogura H , Ide Y , Hosokawa Y , Taki Y , Yoshida M , Tokunaga Y , Koizumi K , Sato T , Hozumi Y , Mori H , Miyamoto Y , Watanabe T , Shiiya N 
Published: August 2014

Abstract
Background: The St.Gallen consensus guideline recommends the sequential administration chemotherapy followed by of endocrine therapy as postoperative therapy for the higher risk ER-positive breast cancer patients based on results of a single study (Albain et al, Lancet 2009). In metastatic settings however, several trials conducted in the 1980's demonstrated that tumor response rates were higher when chemotherapy and tamoxifen were concomitantly administered, than when chemotherapy and tamoxifen administered were given sequentially. In the preoperative settings, pathological complete response (pCR) rate can be used a surrogate marker to predict event-free survival or overall survival in Luminal B(HER2-negative) breast cancer. We therefore designed a prospective randomized safety and efficacy trial in order to test a hypothesis that the concomitant administration of an aromatase inhibitor and chemotherapy improves pathological complete response(pCR) rate than chemotherapy alone in the preoperative setting.
Trial design: The trial is a prospective, multi-center, randomized comparison of chemotherapy alone versus concomitant chmo-endocrine therapy evaluating the efficacy in terms of pCR rate and safety in preoperative settings in patients with Luminal B (HER2-negative) breast cancer. 94 patients were to be accrued into this trial.
- arm A (control): 12 cycles of weekly paclitaxel(80mg/m2) followed by 4 cycles of every 3-week AC(Doxorubicine 60mg/m2, Cyclophosphamide 600mg/m2).
- arm B (experimental): The same chermotherapy as arm A and anastrozole in postmenopausal patients or anastrozole+leuprolerine in premenopansal patients.
Eligibility criteria: 1)Female patients with operable and histologically confirmed invasive breast cancer; 2)HER2-negative; 3)Either ER -positive or PgR-positive; 4)Either Ki67-LI&gt; = 14% and NG&gt; = 2 or NG = 3 regardless of Ki67-LI.
Endpoints : Primary endpoint is the pCR rate. Secondary endpoints are the clinical response rate(RECIST), the adverse events(CTC-AE ver.4.0), the breast conserving rate and the health related quality of life.
Statistical Considerations : The pCR rates in the control arm and the experimental arm are expected to be 10% and 25%, respectively. In order to show the superiority of the experimental arm with an alfa error at 5% and beta error at 20%, calculated number of patients needed were 96.
Present Accrual and Target Accrual: As of June 06, 2013, 18 patients were enrolled from 8 institutions.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-03.
Abstract OT3-2-05: Randomized phase II study of fulvestrant with or without ganetespib in patients (pts) with hormone receptor (HR)-positive metastatic breast cancer
Authors: Lin NU , Whitesell L , Gelman R , Mayer E , Krop IE , Santagata S , Lowe A , Proia D , Farooq S , Brown M , Iannone M , Lindquist S , Winer EP 
Published: August 2014

Abstract
Background: In pts with HR-positive metastatic breast cancer, endocrine resistance is a major clinical problem. Ganetespib is a small molecule inhibitor of heat shock protein 90 (HSP90), a molecular chaperone protein that regulates post-translational folding of numerous client proteins including estrogen and progesterone receptor. In preclinical HR-positive breast cancer models, ganetespib impairs endocrine resistance and reduces heterogeneity in the disease control achievable by hormonal therapies.
Trial Design and Eligibility: This is a randomized phase II study designed to evaluate the efficacy of ganetespib in combination with fulvestrant compared to fulvestrant alone. Pts with endocrine-resistant, HR-positive metastatic breast cancer and up to 1 prior line of metastatic chemotherapy are eligible. Endocrine resistance is defined as relapse while on or within 1 year of completion of adjuvant endocrine therapy (ET) or progression through at least one line of ET for advanced disease. Patients are treated with fulvestrant 500 mg IM on Cycle 1 Day 1 (C1D1) and C1D15, C2D1, and D1 of each subsequent 28-day cycle. Ganetespib is administered at a starting dose of 200 mg/m2 IV on Days 1, 8, and 15 of each cycle. Pts undergo optional research biopsies at baseline and time of progression. Pts with accessible disease undergo a required research biopsy on C2D9. Circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMCs) are collected at baseline, C2D8, C2D9, and time of progression. Pts who progress on fulvestrant may cross over to the combination.
Aims: The primary endpoint is progression-free survival. Secondary endpoints include safety and tolerability, objective response rate by RECIST 1.1, clinical benefit rate, and overall survival. Correlative aims include comparison of biomarkers on the C2D9 biopsy in pts treated with fulvestrant alone versus the combination of fulvestrant plus ganetespib, analysis of CTCs and pharmacodynamic markers in PMBCs.
Statistical Methods: Pts will be randomized 1:2 to receive fulvestrant alone or the combination of fulvestrant plus ganetespib. The total accrual goal is 71 pts. The expected accrual rate is 3.5-4.5 pts per month over a period of ∼20 months; it is anticipated at ∼15% of pts may be censored for PFS, with similar probability on both arms. There will be 80% power to detect a prolongation of true median PFS from 4.0 months to 8.0 months, using a one-sided 0.05 log-rank test.
Acrrual: To date, 15 of 71 planned pts have been enrolled.
Funding: The trial is supported by a grant from the Susan G. Komen foundation and funding from Synta Pharmaceuticals.
Contact information: nlin@partners.org.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-05.
Abstract P1-01-01: The value of isosulphan blue dye in addition to isotope scanning in the identification of the sentinel lymph node in breast cancer patients with a positive lymphoscintigraphy: A randomised controlled trial (ISRCTN 98849733)
Authors: O'Reilly EA , Aucharaz N , Kelly G , Al Azawi D , Prichard RS , Evoy D , Rothwell J , Geraghty J , O'Doherty A , Skehan S , Quinn C , McDermott E 
Published: August 2014

Abstract
Introduction
The advent of multimodal and targeted breast cancer treatment has seen a radical shift from aggressive surgical intervention to a more minimalist approach, both within the breast and axilla. Primary among these changes is the utilisation of the sentinel lymph node biopsy (SLNB) to detect disease within the axilla and a move away from an obligatory axillary clearance when the sentinel node is positive. This depends on the accurate identification of the SLN and initial studies describe a higher identification rate and a lower false negative rate with a dual tracer identification technique. This encompasses a combination of a blue / green dye and radio-labelled isotope. The use of blue dye has been, of itself, associated with significant morbidity and therefore many clinicians may opt for single tracer identification.
Aims
The aim of the current study was to determine whether the addition of blue dye to radio-isotope increased the positive SLN detection rate, where the SLN was identified pre-operatively on a lymphoscintigram.
Methods
A prospective randomised controlled trial comparing the combined techniques of isosulphan blue dye and isotope scanning versus isotope scanning alone was performed at a single tertiary referral centre. Ethical approval was obtained prior to commencing the study from the hospital ethics committee. Enrolment commenced in March 2010 and ceased in September 2012. The study design was a randomised open label controlled parallel group trial. The primary outcome measure was the effect of the omission of the blue dye on the identification of SLN if the lymphoscintigram was positive (1 -3 nodes identified).
Results
A total of 673 patients were included in the final analysis with 344 patients receiving the combination (blue dye and radio-isotope) and 329 patients who received radio-isotope scanning alone. The groups were evenly matched both demographically and pathologically. The mean age was 48 years (48.3 versus 47.7 years; P = 0.47), the mean tumour size was 23.1mm (23.2mm versus 23.0mm; p = 0.89) and there was no statistically significant difference in the grade of the tumours between the two groups (p = 0.58). Overall, there was no difference in the number of nodes retrieved between the two groups (563 versus 523; p = 0.30). Similarly, there was no difference in the number of positive lymph nodes that were identified between the two groups (107 versus 98; 23.8% versus 22%; p = 0.65).
Conclusions
The addition of isosulphan blue dye does not aid in the identification of the SLN in patients who have a positive lymphoscintigram when radioisotope colloid is used.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-01.
Abstract P1-01-06: Elaboration of a nomogram to predict the non sentinel node status (NSN) in breast cancer (BC) patients with positive SN, intra-operatively assessed with OSNA (one step nucleic acid amplification) method
Authors: Di Filippo F , Gianarelli D 
Published: August 2014

Abstract
BACKGROUND
Diagnostic axillary lymph node dissection (ALND) has been replaced by sentinel node biopsy (SNB) in nodal staging. Tumor-positive SNB results in a risk of NSN metastases in case of micro and macro metastases ranging from 10 to 50% respectively. Therefore most of the patients are submitted to an unnecessary ALND. Therefore the development of a mathematical model for predicting patient-specific risk of non sentinel node metastases is strongly warranted. We have developed an European Database with positive SN detected by OSNA molecular method, able to identify intra-operatively patients with micro (CK19 mRNA copies 250-5000) or macrometastases (number of copies &gt; 5000).
MATERIAL AND METHODS
European OSNA database has been developed, only patients whose SN was totally assessed with OSNA were included. The following parameters were recorded:
- Clinical: hospital, age, record number
- Bio-patological: tumor size, grading, multifocality, histological type, LVI, ER-PR status, HER-2, KI67, molecular classification (luminal A, luminal B, HER2 like, triple negative)
- Sentinel and non-sentinel lymph node related: number of removed SNs, number of positive and negative SNs, copy number of positive sentinel node, ratio: number of positive SN to number of removed SN number of removed and number of positive nodes after ALND.
A total of 2351 patients have been included in the database (938 micrometastases and 1413 macrometastases) with the collaboration of 20 European and Italian OSNA centers.
Univariate analysis was performed to determine factors associated with NSN metastases. Chi-square test was used for categorigal variables. All variables with p values less than 0.05 were included in the logistic analysis using backward stepwise method.
RESULTS
Univariate and multivariate analysis for micro and macro metastases are reported. In patients with SN micrometastases, multivariate analysis showed that grading (p&lt;0.006), Tsize (p&lt;0.04) and the number of CK19 mRNA copies (p&lt;0.0001) are strictly related with positivity of NSN status. In patients with macrometastases multivariate analysis selected KI 67 (p&lt;0.04), Tsize (p&lt;0.002), number ofcopies (p&lt;0.0001) and multifocality (p&lt;0.007) as parameters significantly correlated with NSN positivity.
CONCLUSIONS
In our analysis we have evaluated only parameters available at the time of operation because the final nomogram has to be employed by the surgeons as a guide for the surgical decision-making whether to perform or not ALND in BC women. The large population employed and the power of number of copies are the right prerequisites for a reliable nomogram that will be presented at the Meeting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-06.