bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-11-06: A phase Ib study of LCL161, an oral inhibitor of apoptosis (IAP) antagonist, in combination with weekly paclitaxel in patients with advanced solid tumors
Authors: Dienstmann R , Vidal L , Dees EC , Chia S , Mayer EL , Porter D , Baney T , Dhuria S , Sen SK , Firestone B , Papoutsakis D , Cameron S , Infante JR
Published: August 2014

Background: Impaired apoptosis is a common feature of cancer cells and may contribute to chemoresistance. LCL161 is an oral small molecule antagonist of Inhibitor of Apoptosis Proteins (IAPs) that sensitizes a subset of tumors from diverse lineages to treatment with cytotoxic therapies, including paclitaxel. Multiple breast cancer models are sensitive to LCL161 as a single agent and LCL161 acts synergistically with paclitaxel in these models. A phase I study established an LCL161 dose of 1800 mg once weekly as well tolerated, with strong evidence of pharmacodynamic activity at doses ≥320 mg. This ongoing phase Ib study defines the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) of LCL161 in combination with weekly paclitaxel.

Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m2 each week followed by escalating doses of LCL161 administered once weekly immediately following paclitaxel. PK and biomarker sampling was performed.

Results: Thirty-two patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 4), and 1800 mg (n = 20). The most frequent adverse events considered LCL161-related included diarrhea (n = 11; 1 Grade 3), nausea (n = 8), fatigue (n = 7; 2 Grade 3), peripheral neuropathy (n = 6; 1 Grade 3), vomiting (n = 6), decreased appetite (n = 5), alopecia (n = 4), and anemia (n = 4). The principal DLTs were neutropenia, fatigue, and neuropathy. Significant cytokine release syndrome, the DLT of single-agent LCL161, has not been observed likely due to the use of dexamethasone as a premedication. No PK interaction between LCL161 and paclitaxel was observed. RECIST partial responses have been observed in 4 patients with diverse tumor types, including breast cancer. Preliminary antitumor activity in the expansion cohort with breast cancer patients will be presented.

Discussion: LCL161 and paclitaxel combination therapy is well tolerated, with manageable toxicities and no evidence of a PK interaction that might interfere with the activity of either agent. Enrollment of additional patients with breast and ovarian cancer into an expansion cohort is ongoing, utilizing an approach to identify those more likely to respond to treatment with IAP antagonists.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-06.
Abstract P6-13-02: Overcoming therapy resistance of metastatic breast cancer by enhanced tumor delivery of polymeric doxorubicin
Authors: Shen H , Xu R , Mai J , Huang Y , Ferrari M
Published: August 2014

Metastatic breast cancers are treated with chemotherapy drugs in clinic. However, patients usually develop therapy resistance quickly due to intrinsic and acquired mechanisms. Poor drug delivery to tumor cells may also contribute to therapy resistance. To address both biological and mass transport barriers to effective therapy, we developed a new doxorubicin-based formulation, polymeric doxorubicin (pDox), to be delivered using a porous silicon drug carrier, the multistage vector (MSV). We show the novel, rationally designed MSV/pDox drug enriches in tumor tissues and has considerable therapeutic efficacy in two animal models of triple negative breast cancer lung metastasis, conferring a significant survival advantage to animals treated with MSV/pDox over all other control groups (80% survival for the MSV/pDox group at 24 weeks post treatment vs. 0% survival for all others, log-rank test, p < 0.001). Mechanistically, pDox is released from the MSV as nanoparticles by controlled, sustained kinetics, and enters tumor cells by vesicular transport. The active doxorubicin is released in the acidic environment in lysosomes, exits vesicles in the perinuclear region, and enters the nucleus for drug action. This effective mass transport mechanism kills both the bulk and therapy resistant cells, but avoids cardiac damage. As a result, this new nanodrug has a significantly higher therapeutic window over doxorubicin and Doxil.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-02.
Abstract PD01-03: Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment
Authors: Beelen KJ , Opdam M , Severson TM , Koornstra RHT , Vincent A , Wesseling J , Muris JJ , Berns EMJJ , Vermorken JB , van Diest PJ , Linn SC
Published: August 2014

BACKGROUND: Activation of the PI3K/MAPK pathways results in anti-estrogen resistance in vitro, however a biomarker that can predict clinical resistance has not yet been identified. Common drivers of these pathways are PIK3CA mutations, loss of PTEN and over-expression of HER2 and IGF-1R. We aimed to test the prognostic and predictive value of PI3K/MAPK pathway drivers as well as downstream activated proteins in postmenopausal breast cancer patients.

METHODS: We collected primary tumor tissue from 563 ERα positive breast cancer patients who were randomized between tamoxifen (1–3 years) versus no adjuvant systemic therapy. PIK3CA hotspot mutations were assessed by Sequenom Mass Spectrometry. Immunohistochemistry was performed for expression of PTEN, IGF-1R and the downstream markers p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interaction between these markers and treatment.

RESULTS: No significant interaction between any of the tested PI3K/MAPK pathways drivers and tamoxifen was found. [/bold]However, interactions were identified between tamoxifen and the downstream activated proteins (p-AKT(Thr308), p- mTOR, p-p70S6K and p-ERK1/2). After correcting for multiple testing, p-p70S6K remained significantly associated with tamoxifen resistance. Patients whose tumor did not express p-p70S6K did derive significant benefit from tamoxifen (HR 0.24, 95 % CI= 0.12–0.47, p < 0.0001), while patients whose tumor did express p-p70S6K did not (multivariate HR=1.02, 95% CI=0.48–2.21, p = 0.95), p for interaction 0.003.

CONCLUSION: We conclude that the downstream marker of PI3K/MAPK activation p-p70S6K predicts tamoxifen resistance in ERα positive postmenopausal breast cancer patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-03.
Abstract PD02-02: The effect of HER2 expression on luminal A breast tumors
Authors: Ellsworth RE , Valente AL , Shriver CD
Published: August 2014

Background: Luminal A (LumA) tumors are the most common subtype of breast cancer and have been associated with favorable prognosis. Although tumors can be considered LumA if they have >1% expression of ER, negative HER2 status ranges from 0+ (no expression) to 2+ (weak to moderate expression in >10% of cells) without concurrent genomic amplification. It is not clear how moderate levels of HER2 expression influence tumor biology in LumA tumors.

Methods: The Clinical Breast Care Project database was queried to identify all hormone receptor positive cases with HER2 status defined as 0+ (n = 89) or 2+/not amplified (n = 154). Clinicopathological characteristics were compared between groups using chi-square analysis. Twenty-five 0+ and 25 2+ tumors were subjected to laser microdissection and hybridized to U133 2.0 microarrays (Affymetrix). Gene expression data was analyzed using Partek Genomics Suite.

Results: Age at diagnosis did not differ between patients with no (58.5 years) or moderate (59.3 years) HER2 expression. Patient groups did not differ by ethnicity, tumor stage, grade or size, or lymph node status. Although breast cancer mortality was low, all patients who died of disease (n = 7) had moderate levels of HER2 expression (p = 0.016). At the molecular level, four genes were differentially expressed (p < 0.01, >2x-fold change): ESRRG expressed at significantly higher levels and DHRS2, SCUBE2 and SERPINA6 expressed at significantly lower levels in tumors with moderate HER2 expression.

Discussion: LumA (2+) tumors are dissimilar from LumA (0+) tumors. Increased expression of ESRRG has been associated with increased cellular proliferation and tamoxifen resistance, while decreased expression of SCUBE2 and SERPINA6 have been associated with inhibition of growth and proliferation. Together, these molecular differences suggest that LumA tumors with moderate HER2 expression, although classified as HER2 negative, have more aggressive characteristics than those without HER2 expression which may contribute to the significantly higher mortality rate seen in patients with LumA tumors expressing HER2.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD02-02.
Abstract PD02-03: Added value of HER-2 amplification testing by multiplex ligation-dependent probe amplification (MLPA)
Authors: van Slooten H-J , Kuijpers CC , Moelans CB , Horstman A , Al-Janabi S , Hinrichs JW , van Diest PJ , Jiwa M
Published: August 2014

Introduction Accurate determination of HER-2 status is critical for selection of breast cancer (BC) patients for trastuzumab treatment. According to the most commonly used testing protocol, patients with 3+ immunohistochemistry (IHC) are considered for trastuzumab. In addition, 2+ IHC cases are tested for gene amplification and, when amplified, these patients are considered for trastuzumab treatment as well. Because in our experience IHC results have been proven to be sensitive to pre-analytical variation and inter- and intra-observer variation, we apply amplification testing not solely to 2+, but also to 1+ and 3+ cases. At Symbiant Pathology Expert Centre, a validation study (n = 99) comparing MLPA with chromogenic in situ hybridization (CISH) showed 100% concordance. Starting from April 2011, MLPA has been used as the method for HER-2 amplification testing, because in our hands this technique is more time- and cost-effective than CISH for analyzing large sample numbers. CISH was performed when MLPA was inconclusive, IHC score was heterogeneous or when invasive carcinoma could not be physically separated from DCIS. Here we report the results of a comparison between HER-2 amplification tests and IHC in a cohort of 928 BC patients.

Methods Pathology reports of 928 BC patients from 4 pathology laboratories were retrospectively reviewed. 728 patients were diagnosed between April 2011 and February 2012 in one of three laboratories of Symbiant Pathology Expert Centre. The other 200 patients were diagnosed in University Medical Centre Utrecht between January 2010 and December 2011. 18 patients had multiple tumors that were included as separate cases. In total, 949 tumors were reviewed.

Results With IHC, major differences are observed between the 4 pathology laboratories concerning the percentage of cases scored as 0–1+ and 2+ (Table 1). A considerable number of 3+ cases (6.4%) failed to show gene amplification by MLPA and/or CISH. A smaller percentage of 0–1+ cases (1.8%) did show gene amplification (Table 2). 90 equivocal cases were double tested by CISH and MLPA. In 52/90 of these cases (58%) at least one test was inconclusive. The other 38 (42%) cases showed 100% concordance between MLPA and CISH.

Conclusion MLPA is an accurate and cost-effective method for the determination of HER-2 status. We recommend the use of a gene amplification test to confirm HER-2 status in all IHC scores, not just the 2+ cases. However, it is still unclear whether the small subgroups of patients showing only HER-2 protein overexpression or only HER-2 gene amplification would benefit from trastuzumab. Follow-up data are therefore needed to determine the clinical value of HER-2 status assessed by each technique in order to improve the current standard of care for HER-2 testing.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD02-03.
Abstract PD02-06: Concordance between immunohistochemistry and FISH(fluorescence in sity hybridization) & SISH(silver in situ hybridization) for assessment of the HER2
Authors: Lee M-R , Cho S-H , Kim D-C , Lee K-C , Lee J-H , Kwon H-C , Lee H-W , Lee S-e
Published: August 2014

Goals: Accurate assessment of the human epidermal growth factor receptor 2 (HER2) of invasive breast cancer with Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) & Silver in situ hybridization(SISH) is very important to decide treatment of targeted therapy with the humanized monoclonal antibody trastuzumab and the dual tyrosine kinase inhibitor lapatinib. The accuracy of these three testing methods can be adversely affected by various factors. We performed a retrospective analysis of the concordance of IHC and FISH & SISH analysis for HER2/neu at Donga-A Medical Center and reviewed possible causes of disparity between these two methods.

Methods: We performed retrospective review of a total of 416 invasive ductal carcinomas evaluated for HER2/neu at the Department of Surgery in Dong-A Medical Center between 2005 and 2011. We reviewed this data retrospectively and evaluated the concordance between IHC and FISH & SISH.

Results: Comparison of the routinely assessed immunohistochemical HER2 status and FISH & SISH revealed that ten invasive carcinomas diagnosed immunohistochemically as highly overexpressed (score 3+) did not show amplification of the HER2 gene by FISH n that these are false positives (SISH: false positive: 7 cases). Eight invasive carcinomas diagnosed immunohistochemically as Negatively expressed (score 0) showed amplification of the HER2 gene by SISH on that these are false negative. Fourteen tumor, which scored as 2+ by IHC, was proven to be amplified on initial testing with FISH (SISH: 6 cases). Concordance between IHC and FISH analysis was good (171/181= 94.5%) (false positive: 5.5%) (SISH: 228/235=97.0%, false positive 3.4%, false negative 2.9%) and within the published range.

Conclusion: IHC as first-line testing for HER2 may result in false positive and false negative results. The novel ASCO/CAP criteria for the immunohistochemical evaluation of the HER2 status may prevent some false positive results. The discordant cases between IHC and FISH & SISH represent a well-recognized subset of genetic heterogeneity in HER2/neu, which is known to contribute to positive IHC and negative FISH & SISH tests. The most powerful method for studying HER2 status is ISH. However, in heterogeneous carcinomas even FISH may not succeed in a correct evaluation of HER2.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD02-06.
Abstract PD04-03: Is breast conservation therapy an option for young women with operable breast cancer? Local recurrence rates in young women following surgery: a single centre experience.
Authors: Lewis CR , Smith R , Matthews A , Choo E , Lee C
Published: August 2014

Background: Breast cancer (BC) is less common in young women (defined here as ≤ 40 years age), but is associated with more aggressive biological features, higher risk of local recurrence (LR) and poorer overall survival. This study examines and compares the incidence of LR following breast conservation therapy (BCT) versus mastectomy in women with operable BC treated at our centre.

Methods: The POWCC breast cancer database was retrospectively reviewed for the period January 1995 to December 2008. 2250 eligible women with BC undergoing primary breast surgery were identified. LR rate was compared between young women and older women (age > 40 years), and according to type of surgery. Data were analysed using a competing risk Cox model to account for distant recurrence and death as competing events for local recurrence.

Results: Median follow-up was 70 months. Of 2250 women, 246 (11%) were young women, and the mastectomy rate was 49.2%. In older women (89%), mastectomy rate was 41.7%. LR occurred in 17 (6.9%) and 57 (2.8%) in young and older women respectively (p = 0.001). Amongst the young women, 12 (9.6%) and 5 (4.1%) patients recurred locally in BCT and mastectomy respectively (p = 0.09). Amongst the older women, 43 (3.7%) and 14 (1.7%) patients recurred locally in BCT and mastectomy respectively (p = 0.008). In univariate Cox analysis, significant risk factors for LR were BCT (p = 0.003), positive surgical margins (p = 0.03), age ≤ 40 years (p = 0.001), premenopausal status (p = 0.003) and no adjuvant systemic therapy (0.02). Age remains a significant predictor of LR in multivariate Cox analysis (Table). There was no significant interaction between age and type of surgery on LR (p = 0.72).

Discussion: Our results demonstrate that young women who undergo BCT have the highest risk of early LR. Adjuvant systemic therapy is protective of early LR. This study is hypothesis-generating and a definitive prospective clinical trial is required to better determine the optimal type of breast surgery in young women.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD04-03.
Abstract PD04-05: Molecular predictors for type of recurrence following conservative treatment for DCIS
Authors: Sakr RA , Andrade VP , Chandarlapaty S , Giovanni C , Giri D , Heguy A , De Brot M , Olvera N , Muhsen S , Koslow S , Van Zee KJ , Morrow M , Rosen N , King TA
Published: August 2014

Background: The identification of molecular predictors of type of recurrence (non-invasive vs invasive) after local therapy for ductal carcinoma in situ (DCIS) remains a challenge. We hypothesized that gene expression profiling using a panel of 32 breast cancer-related genes could identify a signature predictive of type of recurrence.

Methods: From a prospectively maintained database of 1873 pts treated with conservative surgery +/− radiation for DCIS (1991–2006), we identified 190 (10%) patients who recurred. Original DCIS archival blocks were available for 108 (57%) of these cases. Freshly cut sections were obtained for microdissection of pure DCIS lesions, RNA was extraction and mRNA transcript quantification was performed with the Nanostring™ nCounter® system. Data were normalized using the nCounter® digital analyzer software for analysis.

Results: Among the 108 studied cases, 66 (61%) recurred as DCIS and 42 (39%) recurred as invasive cancer. Median time to recurrence was 40 months (range 7–156 mo) and did not differ by type of recurrence. Similarly, patient age, grade of DCIS, ER status, use of radiation or tamoxifen therapy did not differ. Unsupervised hierarchical clustering using all 32 genes demonstrated two predominant groups, one enriched for recurrent-as-invasive (RI) tumors, and the other enriched for recurrent-as-DCIS (RD) tumors. Refined analysis by selection of 14 genes with significant differential expression between the RI and the RD tumors identified four main groups. The first cluster was dominated by ERBB2 over-expression and is equally composed of RI and RD tumors. The second cluster was composed almost exclusively of RI tumors and showed high level of COX2 and CCND1 and low level of CDKN2A (p16). The clusters 3 and 4 were enriched for RD tumors, with the fourth cluster completely devoid of RI cases. This RD-only group showed the lowest level of CCND1, but highest level of AKT3, EGFR, CDKN2A, and MKI67, thus displaying molecular traits typical of basal-like tumors.

Conclusion: In this cohort of patients who recurred following conservative treatment for DCIS, HER2 expression was not predictive, however gene expression analysis demonstrated that high COX2 and CCND1 and low CDKN2a (p16) levels were strongly associated with invasive recurrences (RI), whereas increased AKT3 and MKI67 were associated with non-invasive recurrences (RD). Although the optimal combination of predictive markers requires validation, these data suggest that molecular alterations associated with RI differ from those associated with RD and warrant further investigation.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD04-05.
Abstract PD04-08: Cell cycle algorithm correlates with grade of DCIS and p53 status, allows elimination of ‘intermediate grade’ disease and gives clinically meanignful information.
Authors: Sainsbury R , Loddo M , Proctor I , Stoeber K , Williams G , Thorat M , Cuzick J
Published: August 2014

We have previously shown that multi-parameter analysis of the DNA replication initiation machinery (Mcm2-7, geminin) and mitotic proteins (Plk1, Aurora A, H3S10ph), expressed during various phases of the cell division cycle, provides a method to accurately assess the proliferative state of dynamic tumour cell populations. We have shown that this novel form of cell cycle biomarker analysis allows separation of breast cancers into three discrete cell cycle phenotypes of major prognostic significance including (i) an out-of-cycle state, (ii) a G1-delayed/arrested state and (iii) an actively cycling state. Importantly, we identified groups of patients with apparently good grade cancers on routine clinicopathological criteria but who nevertheless exhibited the poor prognostic actively cycling phenotype (iii) and might therefore benefit from adjuvant chemotherapy. Additionally, we identified patients with typically poor prognosis tumours but which were actually cycling slowly (phenotype i or ii) and therefore likely not to have benefited from chemotherapy. Notably, when this cell cycle algorithm was used in a multi-variate analysis, the effect of Ki-67 disappeared.

We have now applied the algorithm to 72 cases of DCIS (all of which were re-graded by one pathologist for consistency) and also to a TMA of 136 cases with known outcome from the UK DICS trial. There was excellent correlation between tumour grade and p53 status. The high grade DCIS was positively associated with a high cell cycle score (actively cycling phenotype iii; 28 out of 34 tumours) and low grade DCIS was associated with a low score (namely phenotypes i and ii; 13 out of 19). Interestingly, 7 of the 10 intermediate grade DCIS could be classified as phenotype, i or iii suggesting that the algorithm may be useful in stratifying this group of patients.

A clinical correlation between phenotype III and recurrence and/or progression to invasive disease was evident. Further analysis of this from data derived from the TMAs generated from the UK DCIS trial will be presented. If the early findings are confirmed we may be able to solve the dilemma of which cases of DCIS need treatment and which we currently overtreat.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD04-08.
Abstract PD10-04: Predictive genomic markers to chemotherapy and adjuvant trastuzumab via whole genome expression DASL profiling in the N9831 adjuvant study
Authors: Perez EA , Eckel-Passow JE , Ballman KV , Anderson SK , Thompson EA , Asmann YW , Jen J , Dueck AC , Lingle WL , Sledge GW , Winer EP , Gralow J , Jenkins RB , Reinholz MM
Published: August 2014

Background: Adding adjuvant trastuzumab to chemotherapy for patients (pts) with resected HER2+ breast cancer (BC) improves disease free and overall survival (Perez EA, et al. J Clin Oncol 2011). Understanding which pts are most likely to benefit from these therapies is a goal of our team.

Methods: Baseline 1639 annotated tumor specimens from pts enrolled in the phase III N9831 adjuvant trastuzumab trial (NCT00005970) were processed via the >29,000 gene probe DASL technology (Illumina) to identify genomic predictors of pt outcome to Arm A chemotherapy or Arm C chemotherapy plus concurrent trastuzumab. Samples were spotted in 96 well plates, with appropriate replicates. Extensive quality control and internal validation were performed. The association of each gene with recurrence-free survival (RFS) was determined for each treatment arm separately using CoxPH models adjusted for clinical and tumor risk factors. A p < 0.0001 was used to define significance. A geneset analysis (using 408 Kegg/BioCarta genesets) was performed to determine pathways associated with RFS.

Results: PRPF4B, EWSR1, BMI1, CNNM1, FOXO4, CLIP2, MCCC1, CHRM2 were found to be significantly associated with RFS for Arm A and AAK1, DAZAP2, TP53INP1, MACF1 and ADHFE1 were associated with RFS for Arm C. The most significant pathway associated with RFS in Arm A was the KEGG hypertrophic cardiomyopathy pathway and for Arm C, the BioCarta pertussis toxin-insensitive CCR5 signaling in macrophage pathway.

Conclusions: We have identified 8 genes associated with RFS for pts treated with adjuvant chemotherapy, and 5 genes associated with RFS for pts treated with concurrent trastuzumab and chemotherapy in pts with HER2 early stage BC. In addition, geneset analysis identified BioCarta and Kegg pathways associated with RFS for each arm. Validation in an independent cohort is expected to be completed by the end of 2012.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-04.
Abstract PL-2: Estrogen Receptor Cistrome: Implications for 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 (HNF3α) 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 map ER binding events in primary breast cancers and distant metastases. We find context dependent ER cis-regulatory elements (cistromes) that give insight into underlying transcriptional networks. These differential ER binding profiles correlate with clinical response in ER+ breast cancers. We experimentally explore the binding dynamics between drug sensitive and resistant contexts and identify properties that govern ER binding differences. These data suggest that ER-DNA interactions are dynamic and can be modulated by changes in FOXA1. We are currently exploring mechanisms that mediate FOXA1-DNA interactions, in order to better understand ER transcriptional activity in breast cancer biology.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PL-2.
Abstract S4-3: The EndoPredict score identifies late distant metastases in ER+/HER2− breast cancer patients
Authors: Dubsky P , Brase JC , Fisch K , Jakesz R , Singer CF , Greil R , Dietze O , Weber KE , Petry C , Kronenwett R , Rudas M , Knauer M , Gnant M , Filipits M
Published: August 2014

Background: ER+/HER2− negative (ER+) breast cancers have a proclivity for late recurrence. A first step to an improved adjuvant treatment of late metastasis is to identify women at risk and understand the underlying biology. Several prognostic multigene tests have been developed for ER+ breast cancer patients. Some of these tests have been validated to predict early recurrence events. However, few gene expression assays have been shown to predict late metastases.

Here, we assess whether the prognostic EndoPredict (EP) score, which incorporates both the expression levels of proliferative - and ESR1-related genes, can be used to identify late relapse events in ER+ breast cancer patients.

Methods: Patients included in this study participated in the ABCSG-6 (tamoxifen-only arm) or ABCSG-8 phase III adjuvant trial and received either tamoxifen for 5 years or tamoxifen for 2 years followed by anastrozole for 3 years. All 1702 ER+/HER2− breast cancer patients were retrospectively assigned into risk categories based on the EP and on common clinical parameters. The primary endpoint was distant metastasis. Ongoing collection of follow-up events allowed estimation of metastasis rates using the Kaplan–Meier method in an early and late time cohort: 0–5 years/early recurrence and 5–10 years/late recurrence.

Results: 49% of all patients were classified as low-risk according to the EP score. Kaplan Meier analysis demonstrated that the EP low-risk group had a significantly improved clinical outcome in the first (0–5 years; p < 0.0001) and second time interval (5–10 years; p = 0.002). Nodal metastasis was also significantly associated with the clinical outcome in both time intervals, with node-positive tumors showing a considerably higher rate of late recurrence events. In contrast, Ki67 levels and grading were not significantly associated with late metastasis. Multivariate analysis showed that EP was an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size and Ki67 in both the first and second time interval. The EPclin – a combination of the EP and the clinical risk factors nodal status and tumor size – showed the best performance in predicting late relapse events. Exploratory analyses of proliferative - versus ESR-1 related genes as contributors to early and late distant metastases show differential effects.

Conclusions: The EndoPredict test identified a subgroup of patients that have a low likelihood of developing late metastases. The eight genes contained in the test provide complimentary prognostic information to clinico-pathologic parameters. Both the expression of proliferative - and ESR1-related genes contributes to the underlying biology of late distant metastases.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-3.
Abstract S5-3: PHARE Trial results of subset analysis comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer
Authors: Pivot X , Romieu G , Bonnefoi H , Pierga J-Y , Kerbrat P , Guastalla J-P , Lortholary A , Espié M , Fumoleau P , Khayat D , Pauporte I , Kramar A
Published: August 2014

Background: Since 2005, One year trastuzumab (T) treatment has been providing survival beneﬁt to patients with early breast cancer and HER2 overexpression. However, the optimal duration of T has been debatable due to concerns for cardiac toxicity and results from the FinHer trial which showed that 9 weeks of T provided a similar magnitude of benefit than the 1-year treatment. The French National Cancer Institute (INCa) initiated an academic randomised non-inferiority trial aiming to compare a shorter T exposure of 6 months versus the standard 12 months. This trial, named PHARE for ‘Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure’ [NCT00381901] was approved byan independent ethics committee with regularly planned IDMC meetings.

Patients and methods: Patients with HER2 + early breast cancer who received at least 4 cycles of (neo)-adjuvant chemotherapy were eligible. Randomization 1:1 using a minimisation algorithm was stratified on concomitant or sequential T administration with chemotherapy, oestrogen receptors (ER) status and center. The primary objective was to compare disease free survival (DFS). Overall survival (OS) and cardiac toxicity were investigated as secondary aims. An absolute loss of 2% in DFS in the experimental arm was defined as the non-inferiority margin (1.15 in relative terms) and required 3400 patients with alpha=0.05 and 80% power.

Results: Between 5/2006 and 7/2010, 3382 patients were randomized to 6 or 12 months of T following the IDMC recommendation for accrual interruption and extended follow-up. Disease and treatment characteristics were well balanced between the 2 arms: median age 55 years (range 21–86), median tumour size 20 mm (0–270), node involvement 45%, SBR grade III 56%, ER positive 58%, radiotherapy 88%; concomitant T administration 58%, anthracyclin and taxane containing chemotherapy 73%. The data-base was locked on July 30th, 2012. The 95% HR confidence interval was ranged between 1.09–1.66 for DFS between the 2 arms and it included the pre-specified non-inferiority margins of 1.15. Thus the results were inconclusive regarding the non-inferiority (p = 0.14). A subset analysis based on stratification factors will be presented at SABCS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-3.
Abstract CS01-2: The role of radiation in the treatment of the axilla in the setting of neoadjuvant chemotherapy
Authors: Fowble B
Published: August 2014

There is considerable controversy regarding the appropriate surgical procedure and its timing for evaluating the status of the axillary nodes in the neoadjuvant setting. Sentinel lymph node (SLN) surgery following initial chemotherapy avoids an axillary dissection and its associated morbidity in clinical N0 patients who have pathologic negative SLN. SLN identification and false negative rates (FNR) have been acceptable in these women and axillary recurrence rates without radiation directed to the axilla are £1%. For clinical N1 disease, 2 recent studies (SENTINA, ACOSOG 1071) reported SLN identification rates of 80% and 91%, FNR of 12.8 and 14% and ypN0 rates of 52% and 40% respectively. The SLN was the only positive node(s) in 58% and 40% of the ypN1 patients. Several studies have evaluated the role of regional node (RN) irradiation in clinical N1 patients who are ypN0 following neoadjuvant chemotherapy and have found no improvement in local-regional disease free survival. RN failure rates are low as reported by the NSABP B18 and 27 trials in the absence of post mastectomy radiation or with breast only radiation. The question of RN radiation is being addressed by an NRG (NSABP-RTOG) randomized trial. For women with clinical N1 disease who remain ypN1, axillary radiation may substitute for axillary dissection. Axillary radiation has been shown in randomized trials to be equivalent to axillary dissection in the adjuvant setting for clinical N0 women (NSABP B04) including those with positive SLN (Dutch Mirror, IBCSG 23-01, AMAROS). The Alliance trial will address this question. The potential advantage of neoadjuvant chemotherapy is the ability to adjust surgical and radiation treatment based on pathologic response and thereby minimize the morbidity of combined therapy. Various clinical scenarios will be presented with treatment options.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr CS01-2.
Abstract ES04-1: Basic science 101 – Targeting cell signaling in breast cancer
Authors: Yee D
Published: August 2014

Since normal cells require extracellular signals to proliferate, it seems likely that some transformed breast cancer cells can still respond to these signals. This premise is now well established; disruption of estrogen receptor function, important in normal mammary gland biology, by estrogen deprivation (ovarian suppression or aromatase inhibition) or selective estrogen receptor modulators demonstrated the clinical value of interrupting these key signaling pathways. Further advances have included the disruption of the human epidermal growth factor 2 (HER2) by monoclonal antibodies and tyrosine kinases. These successes have generated greater enthusiasm for identifying mechanism of action of cell signaling with the hope of identifying new therapeutic targets. The intracellular signaling pathways that transduce proliferative signals is becoming better understood. Activation of the phosphatidyl 3-kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are required for normal and malignant cell growth. Multiple strategies and drugs have been developed to target these pathways and are in clinical trial. It is also evident that co-targeting of new or established pathways also have utility over targeting only one molecule. For example, the demonstration that estrogen receptor targeting and mTOR inhibition has clinical value has revealed the potential for the inhibition of multiple pathways. Similar advances have been made in targeting HER2 by both trastuzumab and pertuzumab. These clinical strategies have value as combination therapy may more fully suppress cell signaling than single agent therapy. Additional concepts and strategies will be discussed based on the established targets of estrogen receptor and HER2.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES04-1.
Abstract ES08-2: Predicting tumor response by functional imaging, PET imaging as a functional predictive biomarker
Authors: Mankoff D
Published: August 2014

The ability to measure biochemical and molecular processes to guide breast cancer treatment represents a significant advance in individualized breast cancer treatment. These assays have traditionally been performed by analysis of cell culture or tissue samples. More recently, functional and molecular imaging allows in vivo assay of biochemistry and molecular biology that is highly complementary to tissue-based assay. Molecular imaging can help inform drug trial of targeted breast cancer treatment and clinical decision making by (1) measuring regional expression of the therapeutic target, (2) testing the ability of drugs to interact with their intended targets, and (3) by measuring cancer response early in the course of treatment.

This talk will review basic principals of molecular imaging in breast cancer, with an emphasis on those methods that have been tested in patients. The talk will review the current state of molecular imaging in breast cancer patients, including methods in routine clinical use, those undergoing advanced clinical trials, and those in early-phase testing. Current trials and future directions will be highlighted.

The session is designed for a broad audience, ranging from breast cancer translational scientists to practicing physicians caring for breast cancer patients.

References

1. Mankoff DA. Molecular imaging as a tool for translating breast cancer science. Breast Cancer Res. 2008;10 Suppl 1:S3.

2. Specht JM, Mankoff DA. Advances in molecular imaging for breast cancer detection and characterization. Breast Cancer Res. 2012 Mar 16;14(2):206.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES08-2.
Abstract ES09-3: Symptom management and quality of life in metastatic breast cancer
Authors: Niravath P
Published: August 2014

Approximately 40,000 women in the US die each year of metastatic breast cancer. Because the disease is incurable at this stage, effective symptom management and preservation of quality of life are paramount for these patients. For those with brain metastases, consideration of cognition, quality of life, and overall survival are extremely important because some subsets of patients with breast cancer metastases to the brain may now enjoy prolonged survival of almost 2 years. For solitary brain metastasis, surgical resection followed by whole brain radiotherapy is known to prolong survival, though the addition of whole brain radiotherapy is associated with significant cognitive impairment and decreased quality of life without clear improvement in overall survival. Stereotactic radiosurgery (SRS) shows promise as a therapeutic option for patients with asymptomatic, smaller brain lesions. SRS, as compared to open surgery, results in improved quality of life. Bone metastasis is another common management dilemma for breast cancer patients. Commonly used bone agents, such as bisphosphonates and RANK ligand inhibitors, are known to decrease bone pain and increase quality of life, as well as reduce skeletal-related events. However, safe and optimal duration of bisphosphonates or RANK ligand inhibitors remains unclear in the metastatic breast cancer population. Finally, we will discuss quality measures for delivering end of life care, trends in the country, and methods for improving end of life care with goals of earlier hospice referrals and less treatments at end of life which lead to hospitalizations or ICU stays.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES09-3.
Abstract MS01-2: Artificial receptors and the cellular therapy of breast cancer
Authors: Brenner MK
Published: August 2014

It is clear that targeting therapy to the specific molecular lesions of breast cancer affords the best opportunity to obtain effective treatment without adverse effects on normal tissues. The immune system remains one of the most effective targeting systems known, and tumor-directed monoclonal antibodies have already shown significant success in treating this and other malignant disorders. Cellular therapies based on T lymphocytes, by contrast, have not yet made an equivalent impact, even though T cell-based immune responses to tumor have many unique characteristics that should make them highly effective. In this presentation I will discuss one historic success story for cellular immunotherapy -the treatment of EBV-associated lymphoid and epithelial malignancies by tumor specific T cells -and show how the lessons learned from analyzing the mechanisms underlying this success can be implemented to treat other solid tumors including breast cancer Four components are required for effective activity;-. 1) The infused T cells must target strong and unique antigens, presented with ample accessory signals and co-stimulation; 2) The T cells should contain a polyclonal and multispecific memory population directed to tumor; 3) The T cells must be able to overcome potent immune escape mechanisms 4) The environment should favor (homeostatic) lymphoid expansion. We and others are developing a systematic approach to meet these requirements by introducing novel artificial receptors (Chimeric Antigen Receptors – CARs) and other cell engineering components into T lymphocytes. As an increasing level of success becomes documented in hematological malignancy and solid tumors, we can be hopeful that these therapies will become part of the standard of care for breast cancer as well.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr MS01-2.
Abstract OT1-1-08: PERSEPHONE: Duration of trastuzumab with chemotherapy in women with HER-2+ve early breast cancer
Authors: Earl HM , Vallier A-L , Ogburn-Storey E , Cameron DA , Wardley AM , Miles D , Loi S , Hiller L , Higgins HB , Dunn JA
Published: August 2014

Background: PERSEPHONE is a randomised controlled trial comparing six months of trastuzumab to the standard 12 months in patients with HER2 positive early breast cancer. PERSEPHONE is funded by the NIHR HTA programme in the UK.

Methods: 4000 patients (pts) will be randomised into the two arms (1:1). The power calculations assume that the disease-free survival (DFS) of the standard treatment (12 months trastuzumab) is 80% at 4 years. Randomisation of 4000 pts will allow the trial to prove non-inferiority of six months trastuzumab (5% 1-sided significance and 85% power). Non-inferiority is defined as ‘no worse than 3%’ below the control arm (12 month) 4 year DFS. Primary outcome is DFS, and secondary outcomes are overall survival (OS) non-inferiority; cost effectiveness; cardiac function and quality of life. Tumour blocks are collected to research molecular predictors of survival with respect to duration of trastuzumab treatment. Blood samples are analysed for single nucleotide polymorphisms (SNPs) as pharmaco-genetic determinants of prognosis, toxicity and treatment outcome. PHARE, a similar trial from the Institut National du Cancer in France, closed to recruitment in 2010 and presented early data at ESMO 2012. Following this an unplanned interim analysis of PERSEPHONE was presented to the Data Monitoring and Safety Committee (DMSC).

Results: PERSEPHONE commenced recruitment in October 2007. At abstract submission, 2781 pts (70%) had been randomised from 145 UK sites. Recruitment is due to complete in 2015 with the first planned interim analysis of the primary outcome mid-2016. The iDMSC reviewed all data available on HERA and PHARE as well as a PERSEPHONE interim analysis. There were no safety findings or signals that would warrant a change of the study plan and the high quality of data returns was noted.

Conclusion: PERSEPHONE continues the active recruitment phase as planned. Preliminary but inconclusive PHARE data have reinforced interest in the PERSEPHONE trial both nationally and internationally. There has been full support from the Breast International Group (BIG) and the international breast cancer community to answer this important shorter duration question.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-08.
Abstract OT2-3-02: NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx)
Authors: Cobleigh MA , Anderson SJ , Juilan TB , Siziopikou KP , Arthur DW , Rabinovitch RA , Zheng P , Mamounas EP , Wolmark N
Published: August 2014

Background: A significant amount of DCIS is ER negative and/or overexpresses HER2. This provides an opportunity to test targeted therapy in DCIS. In xenograft models and cell lines, T boosts RT effectiveness. In T-treated HER2+ patients, apoptosis occurs within 1 wk of single agent T use, with T found in ductal aspirates. Ample safety evidence for T exists. T given during whole breast irradiation (WBI) may improve results for lumpectomy (Lx) resected HER2+ DCIS. A trial to examine this question will enhance the understanding of breast tumor biology and the prevention of such tumors and could possibly extend breast-conserving surgery benefits for women with DCIS.

Method: After Lx for pure DCIS, each patient's DCIS lesion is centrally tested for HER2 by IHC analysis. HER2 2+ tumors undergo FISH analysis. HER2 3+ or FISH+ patients can be randomly assigned to 2 doses of T, 3 weeks apart during WBI or to WBI alone.

Women ≥18 yrs. with a margin-clear Lx for pure DCIS, with ECOG status 0/1 who are clinically or pathologically node negative are eligible. Centrally tested DCIS must be HER2 +. ER and/or PR status must be known before randomization.

Primary aims are to determine if T decreases ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary aims are to determine the benefit of T in preventing regional or distant recurrence and contralateral invasive breast cancer or DCIS. NSABP B-43 will determine if DFS, recurrence-free interval, and OS can be improved with the use of T. 2000 patients will be accrued over 7.9 yrs, with a definitive analysis of primary endpoints performed at 163 ipsilateral breast cancer events (7.5 - 8 yrs. after protocol initiation) with an 80% power to detect a hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per 100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate. As of 5-31-13, 1,349 patients have been randomized.

NCT00769379

Support: PHS NCI-U10-CA-69651, -12027; NCI P30-CA-14599; Genentech, Inc.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-3-02.