bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-02-02: Use of contrast-enhanced computed tomography in clinical staging of asymptomatic breast cancer patients to detect asymptomatic distant metastases.
Authors: Tanaka S , Sato N , Fujioka H , Takahashi Y , Kimura K , Iwamoto M , Uchiyama K
Published: August 2014

Objective: The use of computed tomography (CT) with regards to the clinical staging of breast cancer (BC) patients has been on the increase in clinical practice. However, NCCN guidelines recommended the use of imaginng only in cases with locally advanced disease or signs of distant metastases (DM), and the benefits of routine CT have yet to be fully clarified. This study investigated the value of employing contrast-enhanced CT (CECT) to screen for DM in patients with asymptomatic BC.

Methods: The clinical records of 483 patients with asymptomatic BC who underwent CECT, also in order to detect BC spread, between April 2006 and January 2011 were reviewed. The CECT results were classified into normal, true-positive (metastases) or false-positive findings.

Results: Abnormal CECT findings, including true- and false-positive results, were detected in 65 patients (13.5%). Of these, 26 patients (5.4%) showed confirmed true metastatic disease, including 18 lung metastases, 11 liver metastases and 13 bone metastases. Upstaging to stage IV due to the results of the CECT was significantly associated with only larger tumos size (odds ratio, 33.4; 95% CI 12.1–92.5; P < 0.0001) and lymph node status (odds ratio, 37.1; 95% CI 14.2–96.8; P < 0.0001.)

Upstaging to stage IV occurred in 0 of 155 patients at stage I, 5 of 261 patients (1.9%) at stage II and 21 of 67 patients (31.3%) at stage III.

Conclusions: Routine CECT did not appear to be useful for detecting DM in completely asymptomatic patients. Conversely, a small number of patients were upstaged from early to stage IV and a predictive factor beyond T and N stage alone appears to be needed in order to predict which asymptomatic patients have DM.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-02-02.
Abstract P3-05-04: Intra-tumor heterogeneity as a predictor of therapy response in HER2 positive breast cancer
Authors: Rye IH , Helland Å , Sætersdal A , Naume B , Almendro V , Polyak K , Børessen-Dale A-L , Russnes HG
Published: August 2014

Background: Breast cancer is known to be a heterogeneous disease both at the clinical and molecular level. In addition, heterogeneity can also exist within a given tumor, and subpopulations can have distinct phenotypic and genomic features. Little is known about the relationship between intra-tumor heterogeneity and prediction of response to treatment. This study aimed at using a combination of immunofluorescence and fluorescence in situ (FISH) technique (“double immunoFISH”) to identify intra-tumor heterogeneity in tumors from neo-adjuvant treated patients prior to and after therapy, searching for features predicting the response to neo adjuvant treatment.

Material and methods: Twentytwo patients diagnosed with HER2 positive, neo-adjuvant treated breast cancer ((3–4 FEC100 followed by 4 docetaxel plus trastuzumab, 3qw) were selected. Half of the patients had complete response and the others had partial response. By double immunoFISH both phenotypic (ER and HER2 protein) and genomic changes (copy number of HER2 gene and centromere 17) were assessed in the same cells simultaneously on biopsies before and after treatment. The samples were photographed in a Zeiss Axio Imager M1 with 5 fluorescence channels and analyzed with axiovision software. The intensity and localization of HER2 and ER immunofluorescence were semi-quantitatively estimated while the HER2 and centromere 17 FISH signals were counted in 100 cells.

Results: The patients with partial response displayed a high grade of cell-to-cell diversity regarding HER2 copy number, nuclear shape and size and the expression of the membrane protein HER2. This was in contrast to the results from the complete responders who showed a reduced diversity and were more frequently ER negative. In the patients with partial response, a higher diversity was seen after treatment.

Conclusion: The genomic variability prior to therapy was higher in the partial-responders vs. the complete responders, and the remaining tumor was even more heterogeneous after treatment than prior to treatment. Double immunoFISH is a valuable tool for visualization of both phenotypic and genomic alterations in the same cell in FFPE sections. The cohort will be expanded to explore the diversity further, and the results will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-04.
Abstract P3-06-09: Test of association between Ki67 index of early breast cancer and local relapse after adjuvant hypofractionated radiotherapy.
Authors: Rodrigues DN , Somaiah N , Daley F , Davies S , Rakha E , A'Hern R , Haviland J , Sydenham M , Owen R , Reis-Filho J , Yarnold JR
Published: August 2014

Introduction: There is a strong inverse association between the proliferation indices of early- and late-responding normal tissues and their sensitivity to radiotherapy fraction size. The aim of this study is to test for association between Ki67 index and the fractionation sensitivity of breast cancer. The hypothesis is that tumours with high Ki67 indices are relatively insensitive to fraction size and be over-represented in tumours relapsing after hypofractionated, radiotherapy.

Methods: Between 1986 and 2003, the START pilot and START A trials tested 2 test dose levels of a 13-fraction regimen (3.0 or 3.3 Gy & 3.0 or 3.2 Gy fractions, respectively) in 5 weeks against 25 fractions of 2.0 Gy following primary surgery for early breast cancer. Primary tumour blocks of patients with local tumour relapse were collected for immunohistochemistry (IHC) for Ki67 (manual counting in whole sections), HER2, ER & PR (Allred quick scores in tissue sections). Ki67 was assumed to be log normally distributed with a standard deviation of 0.5–0.9. Assuming evaluable blocks for 240 patients, a standardised detectable difference of 0.45 (90%+ power, 5% significance level) corresponded to a detectable difference in geometric means of 5–10%.

Results: From a total of 3646 patients entered into the START pilot and START A trials, 261 local tumour relapses were recorded at a median follow up of 8.4 years (range 0.9–17.5) and 7.2 (range 0.7–11.9) years respectively. Blocks from 213 patients were recovered, of which 176 were evaluable by IHC. There was no significant difference in proliferation between tumours relapsing after conventional and hypofractionated radiotherapy, with mean Ki67 scores of 7.63 (95%CI: 5.06–11.5) and 5.33 (95CI%: 3.86–7.35), respectively. Mean Ki67 scores in 48 primary triple negative tumours (TNT) that relapsed locally were 15.74 (95%CI: 8.53–29.06) after conventional and 7.52 (95%CI: 3.51–16.1) after hypofractionated radiotherapy, but TNT were equally represented (28%) in both groups.

Conclusion: An association between proliferative indices and fractionation sensitivity in breast tumours has not been demonstrated. If confirmed, it suggests that genetic and epigenetic features unrelated to proliferation are sources of inter-tumour variation in fractionation sensitivity.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-09.
Abstract P3-06-32: Topoisomerase 1 gene copy aberration is a frequent finding in clinical breast cancer samples
Authors: Stenvang J , Smid M , Nielsen S , Balslev E , Timmermans M , Rømer M , Nygaard S , Christensen I , Nielsen D , Foekens J , Brünner N , Martens J
Published: August 2014

Background: The topoisomerase-1 (TOP1) targeting drug irinotecan may be a new effective drug in the treatment of metastatic breast cancer patients1,2. However, the use of irinotecan should be guided by predictive biomarkers to avoid drug-induced site effects in the non-responding subgroup of patients. A newly developed TOP1 fluorescence in situ hybridization (FISH)3 probe mix (Dako, Denmark) may represent such a novel predictive biomarker assay.

Materials and Methods: The TOP1/CEN-20 FISH probe mix was applied to normal breast tissue (n = 100) and human breast cancer biopsy material (n = 42). TOP1 copy number variations (Affymetrix GeneChip 100k SNP array) and TOP1 mRNA levels (Affymetrix u133a GeneChip) were studied in 313 breast cancer samples4.

Results: Employing FISH, the mean diploid TOP1 copy number in normal breast epithelium was 1.7 (range 1.45–1.90) and the diploid CEN-20 number was 1.6 (range 1.38–1.82). The normal diploid range was defined as the mean plus/minus 0.5 times the haploid gene copy number (Table 1 and 2). Using these values as cut-off, 13 (30.9%) of the 42 breast cancer samples had TOP1 gene copy number in the diploid range, 18 (42.9%) had 1 extra copy and 11 (26.2%) had ≥ 2 extra copies. CEN-20 counts showed that 19 (45.5%) had CEN-20 values within the diploid range, 21 (50%) had 1 extra copy and 2 (4.8%) had ≥ 2 extra copies. Calculating the TOP1/CEN-20 ratio showed that 6 (14.3%) of the patients samples had a ratio above 1.5, while none had a ratio < 0.8. The Pearson correlation between TOP1 and CEN-20 counts in the 42 breast cancer samples analyzed with FISH was 0.73. In the 313 breast cancer samples 34/313 (10.9%) had TOP1 copy gain and a significant association (p < 0.0001) was observed between TOP1 copy number and TOP1 mRNA.

Conclusions: This study shows that about 25% of breast cancers have ≥2 extra copies of TOP1 as determined by FISH analyses. The high correlation between TOP1 and CEN20 in the 42 breast cancer samples challenges the use of the ratio. Moreover, the significant association between TOP1 gene copy number (SNP array) and TOP1 mRNA expression in breast cancer biopsies suggests that TOP1 FISH results will correlate with TOP1 protein amounts and may therefore be used to predict sensitivity to the TOP1 targeting drug irinotecan in breast cancer. However, a prospective clinical study is needed to prove or disprove this hypothesis.

References

1. Perez EA et al. J Clin Oncol. 2004, 22(14):2849–55. 2. Lee KS et al. Invest New Drugs. 2012 May 5. 3. Rømer MU et al. Scand J Gastroenterol. 2012, 47(1):68–79. 4. Zhang Y et al. Cancer Res 2009, 69(9):3795–3801.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-32.
Abstract P4-14-14: Phyllodes tumour of the breast: A retrospective analysis of 87 cases
Authors: Walter HS , Esmail F , Krupa J , Ahmed SI
Published: August 2014

Background: Phyllodes tumour is a rare fibroepithelial tumour of the breast that accounts for only 0.5% of all breast neoplasms.

Methods: We retrospectively reviewed the case notes of all patients with phyllodes tumour treated between 1987–2010. Clinical data was analysed with respect to pathological and treatment outcome data.

Results: Between 1987–2010, 87 patients were treated for tumours, histologically classified as benign (60), borderline (10) and malignant (17). Median age at presentation was 55 years for patients with malignant phyllodes, 45 years for benign phyllodes and 48 years for patients with borderline tumours. Primary surgery for patients with benign or borderline phyllodes in 68 cases was breast conserving with 2 patients undergoing mastectomy. Of those with malignant phyllodes, primary surgery for 6 patients was mastectomy and 11 patients had breast conserving surgery. 2 patients with malignant phyllodes received adjuvant radiotherapy, to the chest wall for recurrence following mastectomy in one patient and following local excision in the other patient. 2 patients with malignant phyllodes proceeded to axillary surgery, with no involvement of lymph nodes. 6 patients (8.6 %) with benign disease and 4 (23.5 %) with malignant phyllodes had a local recurrence. Of those with malignant phyllodes who had a recurrence, 2 had systemic metastases and all had had a local excision at presentation. Median time to development of metastatic disease from initial presentation was 2.5 years. 1 patient received 1 cycle of palliative doxorubicin but progressed through treatment. Relapse free survival to date for patients with benign, borderline and malignant phyllodes was 91.7 %, 90 % and 70.6 % respectively.

Conclusion: Phyllodes tumours form a heterogenous group with a spectrum of behaviour in terms of risk of local recurrence and metastases. From this series, malignant phyllodes have a higher recurrence rate than benign and borderline tumours. Local excision in this group was associated with a 36.4 % local failure rate and 18.2 % risk of systemic metastasis. Treatment for malignant phyllodes should be individually based, but the greater risk of relapse both locally and systemically, should be taken into consideration and the options of mastectomy or oncoplastic techniques considered.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-14-14.
Abstract AL-1: AACR outstanding investigator award for breast cancer research: Understanding estrogen receptor transcription in breast cancer
Authors: Carroll JS
Published: August 2014

Estrogen Receptor (ER) is the defining feature of luminal breast cancers, where is functions as a transcription factor. The traditional view of ER getting recruited to promoters of target genes is too simplistic. The recent discovery of ER-DNA interaction regions from ER+ breast cancer cell lines has revealed that ER rarely associates with promoter regions of target genes and instead associates with enhancer elements significant distances from the target genes. The genomic mapping of ER binding events also revealed the enrichment of DNA motifs for Forkhead factors. The Forkhead protein FoxA1 (HNF3a) was subsequently shown to bind to half of the ER binding events in the genome and was required for ER to maintain interaction with DNA. We have extended on these findings to explore ER and FoxA1 functional interactions in breast cancer, with a specific focus on changes in binding dynamics that occur during endocrine resistance. To this end, we have established transcription factor mapping approaches (ChIP-seq) in primary tumor material, to investigate differential ER/FoxA1 binding that occurs during tumor progression. We have functionally explored underlying factors that contribute to altered transcription factor binding and activity. In addition, we have recently established a method for rapid unbiased discovery of protein interacting complexes, which we have applied to discover ER associated proteins. We find an unexpected interaction between ER and progesterone receptor (PR) in ER+ breast cancer. We show that PR is a negative regulator of the ER complex, where it is important for modulating ER-DNA interactions and cellular growth. These findings help delineate the complexes that influence ER transcriptional activity and ultimately impinge on tumor progression and drug sensitivity.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr AL-1.
Abstract BS02-1: Hypoxia metabolism in breast cancer – How to overcome resistance to anti-angiogenic therapy
Authors: Harris AL , Buffa FM , Haider S , Bensaad K , McIntyre A , Lord S , Mehta S , Choudhry H , Favaro E , Ledaki I , Singleton D
Published: August 2014

Background. Hypoxia is recognised to induce a multigene programme mainly via HIF1a and also HIF2a transcription factors. Bioinformatics analysis of multiple gene array data sets in breast cancer showed a core hypoxia response programme of approximately 90 genes associated with poor outcome independently of other factors. This core response was significantly over-expressed in triple receptor negative cancers. Additionally, microRNAs associated with hypoxia were shown to give additional worse prognosis associations (mir-210). mir-210 targeted the mitochondrial iron chaperone responsible for regulation of key enzymes in the Krebs cycle and showed an adaptive response to hypoxia involving switching off the mitochondrial metabolism.

Aims and methods. To assess in human breast cancer the hypoxia transcriptome we conducted gene microarray studies before and after 2 weeks of bevacizumab 15mg/kg single dose before neoadjuvant chemotherapy. This was correlated with imaging by DCE-MRI Ktrans analysis.

Results. The study showed that high Ktrans was an excellent predictor for the biological affect of VEGF inhibition and extensive gene induction occurred, including many components of the HIF pathway, but also glycogen metabolism and lipid metabolism.

We investigated these further in xenograft models to see which of the adaption pathways may be most important for survival under hypoxic conditions. We showed that induction of CA9, a key enzyme regulating extracellular pH, was critical for survival under anti-angiogenic therapy and blocking CA9 could synergise and also produce radiosensitivity. Reactivating mitochondria under hypoxic conditions induced by angiogenesis also showed additional anti-cancer benefits and is the basis now for a new phase I study in our department.

Additionally, surprisingly, induction of glycogen and lipid storage occurred and this was essential for survival on reoxygenation and for protection against free radical damage, which greatly increased when either pathway was inhibited.

We investigated, by bioinformatic approaches, the expression of 133 key enzymes in metabolism, showed that they were strongly associated with different subtypes of breast cancer, which may help in selection of patients for future intervention studies.

To additionally define the hypoxia transcription, we conducted RNA sequencing of MCF7 cells in normoxia and mild hypoxia. This revealed marked induction of many long non-coding RNAs, suppression of all transfer RNAs and induction of novel antisense RNAs.

Conclusions. Overall, therefore, although anti-angiogenic therapy alone is now withdrawn from clinical utility in breast cancer, the massive induction of hypoxic microenvironment and synergy with many other therapeutics, suggests that as new approach using induced essentiality should be reassessed in breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS02-1.
Abstract BS02-2: Alterations in tumor metabolism to support breast tumor growth and progression
Authors: Vander Heiden M
Published: August 2014

Breast cancer cells must adapt metabolism to support anabolic processes and allow the accumulation of biomass to allow proliferation. However, tumor cells also experience periods of stress, and metabolic plasticity to shift metabolism to maximize efficiency and survive nutrient limitation is also needed for cancer progression. The M2 pyruvate kinase isoform (PKM2) is expressed in cancers and plays a role in regulating metabolism. To determine whether PKM2 is required for the development and growth of primary breast tumors, we generated mice harboring a conditional allele for PKM2. PKM2 deletion selectively abolishes PKM2 protein production while continued production of PKM1, the other major pyruvate kinase isoform. We crossed PKM2 conditional mice to a model of human breast cancer driven by loss of the Brca1 tumor suppressor gene. Contrary to prior expectation, mammary tumor formation and progression was accelerated despite PKM2 deletion. PKM2-null tumors displayed heterogeneous compensatory PKM1 expression, and expression of PKM1 was observed only in non-proliferating tumor cells. In contrast, proliferating cells in the tumor had no detectable pyruvate kinase expression. This suggests that PKM2 protein is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, while cells with active pyruvate kinase are involved in aspects of tumor progression that do not involve proliferation. Consistent with these findings, variable expression of PKM2 was observed across a panel of human breast tumors, and recurrent mutations resulting in disruption of one PKM2 allele are found in multiple human cancers. Together, these data support a model where regulation of PKM2 activity allows the enzyme to support the differential metabolic requirements of both proliferating and non-proliferating tumor cells.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS02-2.
Abstract ES04-2: Understanding nuclear receptor in breast cancer
Authors: Fuqua SAW
Published: August 2014

Breast cancer cells have receptors on the surface, in the cytoplasm and in the nucleus. Chemical messengers such as steroid hormones bind to receptors, and this causes changes in the transcriptional program of the cells. Breast cancer cells may express two important steroid receptors: estrogen receptor s alpha and beta (ERs a and b, respectively), and/or progesterone receptor (PR). ER-positive cancer cells depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g. tamoxifen), or which block estrogen synthesis (Cyp19 [aromatase] inhibitors or Cyp19 inhibitors which block both androgen and estrogen synthesis. Cells which express more of these receptors generally respond better to hormonal therapies.

The ERs are from a large family of nuclear receptor transcription factors (TFs). When bound by hormone (they bind to DNA directly or they can interact with other transcription factors bound to DNA to regulate gene expression. ER and PR acts by recruiting a complex of coactivator or corepressor proteins that modulate ER functions. These coactivators are important regulatory molecules, and evidence suggests that some are oncogenes, capable of causing breast cancer and showing gene amplification and/or over-expression in a ER-psositiv breast cancers, thus affecting tumor growth and treatment.

Many mechanisms for resistance to endocrine therapies have been postulated and the loss of ER over time although not common can happen. The evolution of receptor mutations over time perhaps in tumor subpopulations has also been postulated, and recent evidence suggests that they occur more frequently than once thought in ER-positive metastatic gtumors. In addition, the PR is frequently lost or altered, which can result from its activation from upstream growth factor receptors. Coactivators that are overexpressed can also modulate ER function so that tumors fail to respond to blocking ER therapies. The basic biology, function, and altered mechanism of action of ER/PR which occur during tumor evolution will be discussed in this educational session.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES04-2.
Abstract ES05-1: Global trends in breast cancer incidence and mortality
Authors: Porter PL
Published: August 2014

Although breast cancer remains a disease most prominent in affluent countries, there is clear evidence that the risk of breast cancer, and most troubling, the risk of death from breast cancer is now a global concern. Data from global databases show incidence rates of breast cancer increasing in virtually all geographical regions since 1973. There are over 1 million new cases of breast cancer worldwide each year, and forty five percent of those cases occur in the less developed countries. Virtually all emerging countries are faced with the challenge of detecting, registering and treating a disease that in the past was considered too infrequent or too low on the list of deadly threats to waste precious health dollars.

The presentation will address global and regional trends in breast cancer incidence and mortality as well as reasons for disparities in mortality and strategies to alter current trends.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES05-1.
Abstract OT1-1-01: Optimizing neoadjuvant systemic treatment in HER2 positive breast cancer - The TRAIN-2 study
Authors: van Ramshorst MS , van Thienen JV , Stouthard JM , Rodenhuis S , Linn SC , Sonke GS
Published: August 2014

Background Anthracycline-based regimens are still commonly used in HER2 positive (HER2+) breast cancer (BC), despite added toxicity compared to non-anthracycline containing regimens. The benefit of antracyclines in the era of trastuzumab containing regimens is controversial. Moreover, the value of anthracyclines in combination with dual-HER2 blockade is uncertain. We recently showed high pathologic complete response (pCR) rates with a weekly neoadjuvant paclitaxel-trastuzumab-carboplatin (PTC) regimen. We now aim to evaluate the effect of replacing 3 PTC cycles in this regimen with 3 FE90C-trastuzumab cycles, while adding pertuzumab to all cycles in both arms.

Secondly, combined blockade of the estrogen-receptor (ER) pathway and the HER2-pathway in the presence of chemotherapy has not previously been investigated in HER2+/ER+ tumors.

Trial design This is a randomized comparative trial evaluating pCR rate (ypT0/is ypN0) at surgery as primary endpoint after neoadjuvant systemic therapy with 9 cycles PTC plus pertuzumab q3w (paclitaxel 80mg/m2 day 1, 8 – trastuzumab 6mg/kg (loading dose 8mg/kg) day 1 – carboplatin AUC = 6 day 1 – pertuzumab 420mg (loading dose 840mg) day 1) versus 3 cycles FE90C-T plus pertuzumab q3w followed by 6 cycles PTC plus pertuzumab q3w.

An optional second randomization (2×2 factorial design) will compare concurrent endocrine treatment with an aromatase inhibitor (and ovarian function suppression in premenopausal women and men) during neoadjuvant chemotherapy in combination with dual HER2-blockade, in patients with HER2+/ER+ tumors.

Eligibility criteria Patients aged ≥18 year with histologically confirmed invasive HER2+ BC, stage II or III. Eligible patients have a performance status of 0 to 1 and adequate cardiac and organ function.

Specific aims The primary objective is to compare the efficacy of 6 cycles neoadjuvant PTC plus pertuzumab preceded by either 3 cycles FE90C-T plus pertuzumab or 3 cycles PTC plus pertuzumab in stage II and III HER2+ BC.

Secondary objectives are to describe the efficacy of combined HER2 and ER pathway blockade in HER2+/ER+ BC, to describe the safety of the various regimens and to identify prognostic and predictive biomarkers for pCR.

Statistical methods The sample size of the study will be based on the primary objective. To detect an increase in pCR rate from 44% in the PTC arm to 58% in the FE90C-T arm at the 5% (2-sided) level of significance with an 80% power 437 patients need to be randomized (assuming ∼10% of patients will be not evaluable).

Target accrual Recruitment will start in the summer of 2013 across ∼30 sites in the Netherlands. Unrestricted research support and pertuzumab are kindly provided by Roche Netherlands. The trial is sponsored by the Dutch Breast Cancer Trialists’ Group (BOOG).

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-01.
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

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

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

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

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 > 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

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> = 14% and NG> = 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

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

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.