bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-14-02: Clinical predictors of benefit from fulvestrant in advanced breast cancer: A meta-analysis of randomized controlled trials
Authors: Niraula S , Pitz M , Gordon V , Grenier D , Amir E , Brandes L
Published: May 2016

Background: While fulvestrant is approved by the United Stated Food and Drug Administration as an alternate endocrine therapy for treatment of advanced breast cancer, data on its efficacy compared to other endocrine treatments are inconsistent. Clinical markers predictive of greater benefit from fulvestrant compared to the alternate endocrine agents have not been identified.

Methods: We searched the literature from inception to May, 2015 from MEDLINE, EMBASE, and major conference proceedings. We included randomized controlled trials that evaluated Fulvestrant compared to either tamoxifen or an AI. We collected the efficacy data reported as Time to Progression (TTP) or Progression Free Survival (PFS) on 7 distinct subgroup of patients from the RCTs defined by: age, time to cancer reoccurrence from primary diagnosis, presence of visceral metastasis, previous chemotherapy exposure, presence of measurable disease, hormone receptor status and, HER-2 status. Data on rates of occurrences of 9 most frequently reported adverse events were also collected from both arms of the studies. Data on both efficacy and toxicity were then weighted using generic inverse variance approach and pooled in a meta-analysis using RevMan 5.3 software.

Results: We identified 8 RCTs that fulfilled our criteria and involved 4,024 patients (2,032 on fulvestrant and 1,992 on control arms). TTP/PFS was the primary endpoint in 7 out of 8 RCTs and secondary endpoint in one. Compared to an AI or tamoxifen, there was a statistically significant improvement in TTP favoring fulvestrant in patients who had visceral metastasis [Hazards Ratio (HR) 0.86; 95% Confidence Interval (CI) 0.77 to 0.96, p<0.01], measurable disease [HR 0.74; 95% CI 0.58 to 0.93, p=0.01], and HER-2 overexpression [HR 0.43; 95% CI 0.27 to 0.70, p<0.001]. Similar effect sizes were observed in a sensitivity analysis excluding the trials of combinations of fulvestrant and AI in the experimental arm. Rates of occurrences of adverse events were similar between fulvestrant and other endocrine agents.

Conclusion: Patients with advanced breast cancer that have visceral disease, measurable disease, or HER-2 driven disease are likely to derive higher benefits from treatment with fulvestrant compared to tamoxifen or an AI. These results may have implications for selection of patients in the design of future clinical trials and to inform treatment decisions in clinical practice.

Citation Format: Niraula S, Pitz M, Gordon V, Grenier D, Amir E, Brandes L. Clinical predictors of benefit from fulvestrant in advanced breast cancer: A meta-analysis of randomized controlled trials. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-02.
Abstract P5-15-04: Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients
Authors: El-Ibrashi MM , El-Sadda WM , Abdel-Halim II , Elashri MS
Published: May 2016

Background:

Bisphosphonates can delay the onset and reduce the risk of skeletal related events in patients with bone metastatic breast cancer; it can prevent and controlcancer treatment-induced bone loss. Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease free survival. The aim of the study is to evaluate the benefits of ZOL combined with adjuvant therapy in premenopausal early breast cancer patients.

Patients and methods:

Patients were premenopausal females who had undergone primary surgery for stage I, II ER +ve and/or PR +ve breast cancer with < 10 positive lymph nodes. All 300 patients were scheduled for standard tamoxifen 20mg/day for five years plus goserelin 3.6 mg every 28 days and were randomized to ZOL 4mg every 6 months for 3 years (group A) and without ZOL (group B). The primary end points were toxicity and disease-free survival (DFS), while overall survival (OS) was the secondary end point.

Results:

Between April 2005 and March 2012, 300 patients were enrolled, the median follow up duration was 98.4 months (range 14-120 months), adding ZOL to endocrine therapy strongly suggests improved DFS versus endocrine therapy alone (90% versus 85% for an absolute increase of 5%). There were fewer disease recurrences in the ZOL group versus no ZOL group (12% vs. 16%) with the greatest reductions in the loco-regional recurrence (3% vs. 5%), distant metastasis (6% vs. 7%) and bone metastasis (3% vs. 5%).

Conclusion:

ZOL with adjuvant endocrine therapy were generally well tolerated with no reports of renal failure or osteonecrosis of the jaw. So, a twice yearly ZOL enhanced the efficacy of adjuvant endocrine treatment, and this benefit is maintained for long time.

Citation Format: El-Ibrashi MM, El-Sadda WM, Abdel-Halim II, Elashri MS. Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-15-04.
Abstract P5-15-06: 10-year follow-up of adjuvant ovarian suppression in high risk premenopausal breast cancer
Authors: Recchia F , Candeloro G , Rosselli M , Bratta M , Rea S
Published: May 2016

Background: A large randomized study has shown the value of temporary ovarian suppression during the administration of chemotherapy in the treatment of high risk estrogen receptor positive (ER+) breast cancer (BC) (Pagani et al. N Engl J Med 2014). In another study ovarian suppression added to chemotherapy appeared to protect ovarian function (Moore et al. N Engl J Med 2014) and improve the expected outcome of estrogen receptor negative (ER-) BC. Nevertheless, both these studies have a median follow-up time limited to 68 months and 49 months, respectively. Here we present the data of a large non randomized phase II study of adjuvant ovarian suppression in ER+ and ER- breast cancer with a median follow-up of 120 months (range 90-220 months). The primary end point was the ovarian function preservation rate, secondary end points were disease-free survival (DFS) and overall survival (OS). Methods: Between 06-1997 and 06-2007, 200 premenopausal, high risk early BC patients entered the study. All patients received the LH-RH analogue before starting chemotherapy. Breast conserving and radical surgery were performed in 74% and 26% of patients, respectively. Systemic therapy was tailored to the biological characteristics of each patient, and followed by radiation therapy and hormonal therapy in ER+ tumors. Results: The median patient's age was 43 years (range 26-45). The mean number of positive axillary nodes was 3.2 (range 1-25). Seventy-one % of patients were ER+ and/or progesterone receptor positive (PGR+), 29% were ER - and PGR-. The median KI-67 was 30% (range 15% -100%). Twenty-one % of patients were c-ErbB-2 positive. After a median follow up of 120 months (range 90-220), normal menses returned in 90% of patients younger than 40 years and in 56% of patients older than 40 years. The 10 and 15-year DFS rate were 85.5% and 71%, respectively, while the 10 and 15-year OS rate were 91%, and 71%, respectively. The standard pattern of toxicity of chemotherapy was observed. Hot flashes and G1 osteopenia occurring after LH-RH analogue administration were temporary and subsided after the cessation of therapy. Conclusions: LH-RH administration, concurrent with chemotherapy is tolerable and effective. Five full term pregnancies were documented. A favourable impact on the expected DFS and OS was observed. ER- patients had late new primaries, but no recurrence after 5 years, while ER+ patients had disease recurrence even after 13 years.

Citation Format: Recchia F, Candeloro G, Rosselli M, Bratta M, Rea S. 10-year follow-up of adjuvant ovarian suppression in high risk premenopausal breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-15-06.
Abstract P5-17-04: Breast conserving surgery alone for ductal carcinoma in situ: Factors associated with increased risk of local recurrence
Authors: Recht A , Mele A , Mehta P , Brook A , Slanetz P , Sharma R
Published: May 2016

Background: There is ongoing debate regarding the added benefit of radiation therapy (RT) for patients with ductal carcinoma in situ (DCIS) believed to be at low risk for recurrence after wide local excision (WLE) alone since RT is costly and can cause significant adverse effects. In this retrospective study we aimed to identify clinicopathological characteristics associated with an increased risk for ipsilateral local recurrence (LR) in patients not undergoing RT.

Methods: All patients with DCIS treated with WLE alone at the Beth Israel Deaconess Medical Center, Boston between 2000 and 2010 were identified. We collected data on demographics, parity, personal or family history of breast cancer, exogenous hormone use, tobacco use, comorbidities, genetic mutation carrier status, imaging interval, and tumor-specific characteristics (size, margins, grade, architectural subtype, presence of necrosis, estrogen receptor status). We analyzed their effects on the risk of LR.

Results: The study cohort included 281 eligible patients (mean age at diagnosis 59 years, range 33-90). Median follow-up time was 8 years (range 0.11-16.59 years); 59 patients were excluded because they were not followed in our institution after undergoing WLE. LR occurred in 19 of 222 patients (9%), with a recurrence rate of 11.3 per 1000 person-years. The median time from excision to LR was 4.2 years (range, 0.8-11.7). The risk of recurrence was lower for the 64 patients with nuclear grade (NG) I tumors than for the 110 patients with a NG II or 20 patients NG III tumors (3%, 9%, and 20%, respectively, p for trend = 0.01). The mean margin width was 1.8 mm in patients experiencing LR, versus 2.5 mm in patients without LR (p=0.4). Patients who had used hormone replacement therapy or oral contraceptives (n=61) or patients with a history of tobacco use (n=41) had higher rates of LR than those who did not, although these did not reach statistical significance (15% versus 6%, p=0.06; and 17% versus 7%, p=0.07 respectively). There was no significant correlation between the use of tamoxifen or aromatase inhibitors and the risk of LR.

Conclusions: Our data indicate that higher nuclear grade, narrower margin width, use of exogenous hormones, and smoking history may be associated with an increased risk of LR. The evaluation of these factors may be helpful when considering whether to use adjuvant RT or not for patients with DCIS.

Citation Format: Recht A, Mele A, Mehta P, Brook A, Slanetz P, Sharma R. Breast conserving surgery alone for ductal carcinoma in situ: Factors associated with increased risk of local recurrence. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-17-04.
Abstract P6-02-04: Screen detected and interval cancers; genomic analysis points to different molecular etiology?
Authors: Gorringe KL , Hunter SM , Byrne D , Devereux L , Rowley SM , Elder K , Huynh R , Pridmore V , Hopper J , Kavanagh A , Mitchell G , Mann BG , Fox SB , Campbell IG
Published: May 2016

Breast cancers diagnosed after a negative mammogram but prior to the next screening episode are termed "interval cancers" and comprise as many as 25% of all cancers detected in women attending population-based screening programs. The high interval cancer rate is a major problem affecting the effectiveness of mammographic screening. It is unclear whether interval cancers represent a distinct biological entity compared to screen-detected cancers or whether their designation is simply an arbitrary outcome of screening timing. Using an Australian prospective population-based cohort of over 53,000 women (lifepool), 537 cases of breast carcinoma (in situ and invasive breast cancer) were identified, of which 293 had known screening status at time of diagnosis. Pathology reports, mammographic density data, germline DNA and tumor tissue were available for analysis.

Screen and interval cases showed no significant differences in mammographic density or PR status but there were trends towards higher proportions of ER negative and HER2 positive cases in interval cancers (p<0.1). Interval cancers also had a younger age at diagnosis (p<0.01), increased tumor size (p<0.01) and higher grade (p<0.01). Copy number analysis was performed on a subset of invasive breast cancer cases using OncoScan MIP arrays. No difference in the overall number of copy number aberrations or fraction of the genome altered were observed, however specific differences were noted between interval and screen detected cases. These included copy number changes on chromosomes 8 and 11. Analysis of germline DNA was performed using a panel sequencing approach of known breast cancer genes as well as lower-penetrance SNPs. Pathogenic mutations in BRCA1, BRCA2, TP53 and PALB2 were identified in 1/13 interval cases (in BRCA2), 1/66 screen-detected cases and 8/74 cases with currently unknown screen/interval status. Screen detected cancers may thus have a reduced contribution from high-penetrance predisposing variants.

Citation Format: Gorringe KL, Hunter SM, Byrne D, Devereux L, Rowley SM, Elder K, Huynh R, Pridmore V, Hopper J, Kavanagh A, Mitchell G, Mann BG, Fox SB, Campbell IG. Screen detected and interval cancers; genomic analysis points to different molecular etiology?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-02-04.
Abstract P6-03-03: The Q-CROC-3 project reveals novel genomic alterations in triple negative breast cancers in residual tumors after neoadjuvant chemotherapy
Authors: Basik M , Aguilar-Mahecha A , Lafleur J , Bareke E , Przybytkowski E , Alirezaie N , Discepola F , Légaré S , Kovacina B , Lan C , Mihalcioiu CL , Robidoux A , Marcus E , Roy J-A , Pelmus M , Aleynikova O , Nabavi S , Tonellato P , Majewski J
Published: May 2016

The prognosis of triple negative breast cancer that shows resistance and/or incomplete response to cytotoxic chemotherapy is poor. In order to understand the mechanisms of resistance to chemotherapy and the genomic evolution of TNBCs treated with chemotherapy, an international multi-center biopsy-driven clinical trial was created for the collection and study of drug-resistant primary and metastatic freshly frozen tumors (Q-CROC-03: NCT01276899). We consented 60 patients with operable TNBC undergoing neoadjuvant Anthracycline/Taxane-based chemotherapy for pre and post-treatment biopsies as well as collection of residual tumor at the time of surgery and serial blood sampling. In 12-15 patients, adequate residual tumor material was available for genomic studies, which included whole exome sequencing, array CGH, gene expression microarray profiling and RNAseq of paired tumors. Whole exome sequencing revealed clonal shifts as well as the relatively infrequent appearance of novel mutations in individual tumors, without any recurrently detected variants. Array CGH revealed a remarkable stability in the number of DNA copy number alterations with a few functional alterations enriched for in the residual tumor, including an amplicon involving the NFIB gene. Finally, gene expression profiling showed shifts towards the immune-modulatory and basal TNBC subtypes after chemotherapy as well as an increase in the expression of several targetable genes, including DUSP1, a dual specificity phosphatase. In the 4 cases of primary and matching metastatic tumors, the post-NAC residual tumor had acquired changes many of which persisted in the metastatic sites, indicating that the analysis of the residual tumors can provide a partial picture of genomic changes present in metastases but not in the primary tumor. In summary, the genomic characterization of residual post-NAC tumor tissue provides important information for the development of novel therapeutic strategies for drug-resistant TNBCs as well as a portrait of genomic evolution of TNBCs subjected to chemotherapy.

Citation Format: Basik M, Aguilar-Mahecha A, Lafleur J, Bareke E, Przybytkowski E, Alirezaie N, Discepola F, Légaré S, Kovacina B, Lan C, Mihalcioiu CL, Robidoux A, Marcus E, Roy J-A, Pelmus M, Aleynikova O, Nabavi S, Tonellato P, Majewski J. The Q-CROC-3 project reveals novel genomic alterations in triple negative breast cancers in residual tumors after neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-03.
Abstract P6-03-04: Amplification of the WHSC1L1 oncogene regulates expression and estrogen-independent activation of ERα in SUM-44 breast cancer cells and is associated with ERα over expression in breast cancer
Authors: Ethier SP , Irish J , Mills J , Ivey B , Hardiam G , Wilson R , Domkowski A , Guest S
Published: May 2016

The 8p11-p12 amplicon occurs in approximately 15% of breast cancers and occurs almost exclusively in aggressive luminal B type tumors. Our lab and other labs have identified the WHSC1L1 oncogene as a driving oncogene from this region with potent transforming activity. In the present studies, we found that over expression of WHSC1L1 is linked to over expression of the ESR1 and ERα protein in the SUM-44 breast cancer cell line, and also in primary human breast cancer specimens. Knockdown of WHSC1L1, and particularly the short isoform of WHSC1L1, had a dramatic effect on ESR1 mRNA and ERα protein levels. SUM-44 cells do not require exogenous estrogen for continuous growth in vitro; however these cells are dependent on ERα expression as determined from ESR1 knockdown experiments, and potent growth inhibition and ERα degradation following exposure to the selective estrogen receptor degrader (SERD) fulvestrant. ChIP-Seq experiments utilizing ERα antibodies demonstrated potent ERα binding to chromatin in SUM-44 cells under estrogen-free conditions. ERα bound to ERE and FOXA1 binding motifs under estrogen-free conditions and regulated expression of number of well-known estrogen responsive genes. Short term treatment with estradiol enhanced binding of ERα to chromatin and influenced expression of many of the same genes expressed and to which ERα was bound under estrogen-free conditions. Finally, knockdown of WHSC1L1 in SUM-44 cells resulted in loss of ERα binding to chromatin under estrogen-free conditions; however treatment estradiol restored ERα binding to chromatin at key estrogen-response elements and genes. These results indicate the SUM-44 cells are a good model for a subset of luminal B breast cancers that have the 8p11-p12 amplicon, over express the WHSC1L1 oncogene, and over express ERα that is independent of estrogen for binding to chromatin and regulation of gene expression. Dependence on ERα activity for growth and survival of breast cancer cells but independence of estradiol is a major cause of breast cancer mortality as such cells become non-responsive to current hormonally based therapies.

Citation Format: Ethier SP, Irish J, Mills J, Ivey B, Hardiam G, Wilson R, Domkowski A, Guest S. Amplification of the WHSC1L1 oncogene regulates expression and estrogen-independent activation of ERα in SUM-44 breast cancer cells and is associated with ERα over expression in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-04.
Abstract P6-04-05: Genotype-phenotype classification of triple negative breast cancers (TNBC) in women of African descent using the PAM50 NanoString platform and genomic data
Authors: Olayiwola OA , Ogundiran TO , Hardeman A , Yoshimatsu TF , Clayton W , Adeoye A , Ademola A , Ajani MA , Khramtsova G , Grushko TA , Huo D , Zheng Y , Parker J , Perou C , Olopade OI
Published: May 2016

Introduction: TNBC has the highest mortality rate amongst all other breast cancer types due to its complex tumor heterogeneity and lack of well-defined molecular targets. It is known that women of African descent are two to three times more likely to develop TNBC compared to women of European ancestry, yet wide-scale genomic studies of African and African American breast tumors are limited. To elucidate genotypes and molecular subtypes associated with the most aggressive forms of breast cancer, we used the PAM50 NanoString platform to reclassify Nigerian (NG), African American (AA) and Caucasian (CA) tumors previously annotated by Immunohistochemistry (IHC), and correlated our findings to their germline genotype data obtained using high-throughput technologies.

Methods: RNAs were isolated from formalin-fixed, paraffin embedded (FFPE) tumor tissues using the High Pure Paraffin Kit (Roche) following manufacturer's protocol, and assayed on NanoString nCounter Analysis System using a custom Nano110 (PAM50 + claudin-low & VEGF signatures) probe set. Intrinsic subtyping and gene-expression data were evaluated using R statistical software. All study samples were previously annotated and subtyped by the ER/PR/HER2 IHC classifier. Genotypes were obtained from next generation sequencing or Illumina Human2.5M BeadChip platform using germline DNA from more than 2000 breast cancer cases and 2000 controls were studied.

Results: To date, Intrinsic molecular subtyping by Nano110 has been completed on 69 NG, 81 AA and 74 CA tumors. Concordance between IHC and PAM50 was 59%, which is adequate and comparable to previous studies. Basal-like subtype was overrepresented and accounted for nearly 30% of NG and AA cases, compared to 17% in CA cases. HER2-enriched subtype was overrepresented only in NG cases (9%). The proportion with Luminal A tumors were 44% NG, 56% AA and 68% CA, respectively.

Conclusions: PAM50 NanoString assay is reliable and high-throughput for molecular subtyping breast cancer using RNA extracted from FFPE tumors. Ongoing work will correlate PAM50 intrinsic subtypes to genotype data.

Citation Format: Olayiwola OA, Ogundiran TO, Hardeman A, Yoshimatsu TF, Clayton W, Adeoye A, Ademola A, Ajani MA, Khramtsova G, Grushko TA, Huo D, Zheng Y, Parker J, Perou C, Olopade OI. Genotype-phenotype classification of triple negative breast cancers (TNBC) in women of African descent using the PAM50 NanoString platform and genomic data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-05.
Abstract P6-08-05: Protein tyrosine kinase activity and miRNA expression profiling reveals differences according to progesterone-receptor-status in HER-2 negative breast cancer
Authors: Tahiri A , Satheesh SV , de Wijn R , Lders T , Aure MR , Quigley DA , Bukholm IR , Hurtado A , Kristensen VN , Geisler J
Published: May 2016

Background: Kinases are considered as promising source of biomarkers for diagnostic, prognostic and therapeutic purposes in cancer patients. We assessed tyrosine kinase activity in 39 primary breast cancer samples that were all hormone receptor positive (ER+ and/or PR+) with differential HER-2 status, using microarray technology. Methods: Pamchip® peptide microarrays were used to measure the activity of protein tyrosine kinases in 32 breast cancer samples. The breast cancer cell lines MCF-7, BT474 and ZR75-1, was studied for kinase activity, both untreated and treated with estradiol. Results: Results showed differences in phosphorylation amongst breast cancer samples. A total of 37 peptide kinases were highly phosphorylated in a group of breast cancer samples representing 33 protein tyrosine kinases involved in cancer pathways and immunological responses. In vitro studies with breast cancer cell lines exhibited the same phosphorylation profiles, but increased phosphorylation was only observed in one cell line, ZR75-1. Eliminating HER-2 positive samples, we obtained differences in phosphorylation profiles based on PR-status only. Samples lacking PR-expression exhibited higher kinase activity of downstream kinases compared to PR-positive samples. Similar results were obtained with miRNA expression profiles of 31 breast cancer samples. Five miRNAs were identified to be significantly differentially expressed (p < 0.05) between PR-negative and PR-positive samples. This effect was even stronger when eliminating HER-2 positive samples, with 13 miRNAs exhibiting significant differential expression based on PR-status. Conclusion: Although our data are based on a small dataset, the lack of PR expression seems to have a profound effect on tyrosine kinase activity and miRNA expression in HER-2 negative breast cancers without any effect on gene expression. This indicates that regulatory and functional molecules might exhibit phenotypical features of cancer that cannot be explained by gene expression alone.

Citation Format: Tahiri A, Satheesh SV, de Wijn R, Lders T, Aure MR, Quigley DA, Bukholm IR, Hurtado A, Kristensen VN, Geisler J. Protein tyrosine kinase activity and miRNA expression profiling reveals differences according to progesterone-receptor-status in HER-2 negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-08-05.
Abstract P6-09-03: Time-dependent nomogram for risk of locoregional recurrence in early breast cancer patients: 10 year extension
Authors: Witteveen A , Vliegen IMH , Sonke GS , Klaase JM , IJzerman MJ , Siesling S
Published: May 2016

Background

The objective of this study was to extent the recently developed and validated time-dependent logistic regression model and web-based nomogram. This nomogram is suitable for the annual long term risk prediction of locoregional recurrence (LRR) in individual breast cancer patients and clinical decision support with regard to the follow-up.

Methods

Women first diagnosed with early breast cancer between 2003-2006 in all Dutch hospitals were selected from the Netherlands Cancer Registry with five year of recurrence follow-up (n=37,230). Of the year 2003 follow-up was retrieved for ten years. In the first five years following primary breast cancer treatment 3.7% of the selected patients developed a LRR as a first event, in ten years 6.2%. Risk factors were determined using logistic regression and the risks were calculated per year, conditional on not being diagnosed with recurrence in the previous year. Discrimination and calibration were assessed. Bootstrapping was used for internal validation. Data on primary tumors diagnosed between 2007-2008 in 43 Dutch hospitals was used for external validation of the performance of the nomogram (n=12,308).

Results

The final model included the variables grade, size, multifocality, and nodal involvement of the primary tumor, and whether patients were treated with radio-, chemo- or hormone therapy. Model predictions were well calibrated. Estimates in the validation cohort did not differ significantly from the index cohort. The results were incorporated in a web-based nomogram. In 0.7% of the patients, the risk of LRR between year 5-10 was higher than the average risk of all patients in the first five years. All of these patients were aged below 50, had a tumour size larger than 2 cm, non-negative hormone status, received radiotherapy, but no hormone therapy and 19% developed a recurrence during ten years.

Conclusion/discussion

This validated and time-dependent nomogram for the prediction of annual LRR risks over ten years is simple to use and shows a good predictive ability in the Dutch population. It can be used as an instrument to identify patients with a low or high risk of LRR who might benefit from a less or more intensive and longer follow-up after breast cancer and to aid clinical decision-making for personalized follow-up.

Citation Format: Witteveen A, Vliegen IMH, Sonke GS, Klaase JM, IJzerman MJ, Siesling S. Time-dependent nomogram for risk of locoregional recurrence in early breast cancer patients: 10 year extension. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-03.
Abstract P6-09-08: Exposure to multiple sources of polycyclic aromatic hydrocarbon and breast cancer incidence
Authors: White AJ , Bradshaw PT , Herring AH , Teitelbaum SL , Beyea J , Stellman SD , Steck SE , Mordukhovich I , Eng SM , Engel LS , Conway K , Hatch M , Neugut AI , Santella RM , Gammon MD
Published: May 2016

Background. Previous epidemiologic studies, including our own, have consistently linked long-term exposure to single-source polycyclic aromatic hydrocarbons (PAHs) to increased breast cancer incidence. It is unclear whether single sources, specific groups, or all PAH sources should be targeted for breast cancer risk reduction. This study considers the impact on breast cancer incidence from multiple PAH exposure sources in a single model, which better reflects exposure to these complex mixtures.

Methods. In a population-based case-control study conducted on Long Island, New York (N=1,508 breast cancer cases/1,556 controls), a Bayesian hierarchical regression approach was used to estimate adjusted posterior means and credible intervals (CrI) for the adjusted odds ratios (ORs) for PAH exposure sources, considered singly and as groups: active smoking; residential environmental tobacco smoke (ETS); indoor and outdoor air pollution; and grilled/smoked meat intake.

Results. Most women were exposed to PAHs from multiple sources. In a hierarchical model, breast cancer incidence was positively associated with ETS from a spouse (OR=1.20, 95%CrI=1.03, 1.42) and residential synthetic firelog burning (OR=1.30, 95%CrI=1.06, 1.60). Additionally, PAH exposure groups, including ingestion (OR=1.45, 95%CrI=1.16, 1.79), indoor stove/fireplace use (OR=1.30, 95%CrI=1.02, 1.62), and total indoor sources (active smoking, ETS from spouse, grilled/smoked meat intake, stove/fireplace use, OR=1.46, 95%CrI=1.03, 2.05), were associated with increased breast cancer incidence.

Conclusions. Groups of PAH sources, especially those for ingestion and indoor sources, were associated with a 30-50% increase in breast cancer incidence. PAH exposure is ubiquitous and a potentially modifiable breast cancer risk factor.

Citation Format: White AJ, Bradshaw PT, Herring AH, Teitelbaum SL, Beyea J, Stellman SD, Steck SE, Mordukhovich I, Eng SM, Engel LS, Conway K, Hatch M, Neugut AI, Santella RM, Gammon MD. Exposure to multiple sources of polycyclic aromatic hydrocarbon and breast cancer incidence. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-08.
Abstract P6-10-02: Patient rather than physician-related barriers to tamoxifen uptake for breast cancer prevention in high-risk women
Authors: Skandarajah AR , Thomas S , Chin-Lenn L , Mann B , Lindeman G
Published: May 2016

Background: Tamoxifen use for 5 years confers 35% risk reduction in breast cancer at 15 years, although the evidence to support its use for BRCA1 or BRCA2 mutation carriers is less clear. Since 2014, it has been our policy to discuss and recommend endocrine prevention to every eligible individual who attends the risk management clinic (for gene carriers or women with a strong family history) at our institution.

Aim: To assess the uptake of endocrine prevention in a high risk population when uniformly recommended and reasons for declining prevention.

Methods: All patients attending risk management clinic between February 2014 until May, 2015 received both verbal and written evidence-based information on endocrine prevention and were registered prospectively. Endocrine prevention use and cessation was captured. Reasons for declining or ineligibility for tamoxifen use were recorded.

Results: During the study period, 314 consultations were carried out on 248 women. They comprised 38 BRCA1 and 42 BRCA2 mutation carriers, 4 Peutz-Jegher syndrome patients, 155 women with strong family history, 9 with moderate family history. Their median age was 39.7 (range: 21-70 years). Despite routine policy, Tamoxifen prevention was routinely discussed, except where a patient required biopsy or was given biopsy results n=14 (7%). One patient had a new cancer diagnosis during this period. In 52 women, tamoxifen was not recommended for the following reasons: patients re-assessed as moderate risk (9), on other prevention trials (2), very young/old age (28), pregnant or breast-feeding (10) and previous mastectomy/cancer/DCIS (3). Of the remaining 182 eligible patients, 14 (8%) were on tamoxifen (median duration 12 months, range= 1-20 months), 8 (4%) had ceased tamoxifen due to side effects. Main reasons for declining were 25 (14%) were trying to conceive, 34 (19%) prefer prophylactic mastectomy, 15 (8%) were concerned regarding the side effects, 5 (3%) were currently suffering from menopause and 4 (2%) wished to await salpingo-oophorectomy. 66 (36%) indicated that they were ‘not interested’.

Conclusions: Physician-reluctance is not the reason for poor uptake of endocrine prevention in a specialized risk management clinic. Contraindications are common, many women elect for alternative risk reducing strategies and despite supportive evidence, many women prefer to choose surveillance alone over medical prevention.

Citation Format: Skandarajah AR, Thomas S, Chin-Lenn L, Mann B, Lindeman G. Patient rather than physician-related barriers to tamoxifen uptake for breast cancer prevention in high-risk women. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-02.
Abstract P6-12-05: Impact of the Middle East unrest on management of breast cancer – A single institution experience
Authors: Khalifa A , Abdul-Hadi M , Al-Haddad H , Abu-Rida L
Published: May 2016

King Fahad University Hospital of Dammam (KFHU) is a major referral teaching Hospital in the Eastern province in Saudi Arabia. With permission, The Breast Division at KFHU accepts expatriate patients for treatment of breast cancer free of charge. Between Jan 2010 and June 2015 the unit has received 435 new and previously treated breast cancer patients, 35% of them were expatiates. We have noticed that most of these patients had an out of their hand delay in initiating either their investigations for a breast lump or start of active treatment; this has resulted in less than optimum prognosis in many cases. We reported that 75% of these patients had an average of 6-19 months delay before they presented for investigations of a breast mass, 25% had received previous irregular treatment and did not complete their management due to war unrest and travelling. More than 70% of patients who needed radiotherapy did not receive it due to unavailability of treatment facility. Conclusion: In spite of the dramatic improvement in diagnosing early breast cancer, after the wide spread of screening programs in the last decade, we are faced again with recent increase in advanced presentations and poor outcome due to war unrest. With the expected increase in the number of similar cases we think that this category of patients should be addressed as a special category.

Citation Format: Khalifa A, Abdul-Hadi M, Al-Haddad H, Abu-Rida L. Impact of the Middle East unrest on management of breast cancer – A single institution experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-12-05.
Abstract P6-12-06: Preoperative chemotherapy regimens and breast cancer subtype in an underinsured Hispanic population
Authors: Mehta D , Winton L , Walters J , Hsu C-H , Nodora J , Martinez ME , Bouton M , Komenaka IK
Published: May 2016

Background: Although the Hispanic population is among the fastest growing in the United States, however, less is known about them then other populations. Breast cancer in different racial/ethnic populations display different behaviors. The current study was performed to examine response to preoperative chemotherapy regimen and by breast cancer subtype in a Hispanic safety net population.

Methods: A retrospective review of Hispanic breast cancer patients who underwent preoperative chemotherapy from July 2001 to February May 2015 at a safety net hospital. Sociodemographic, clinical, and treatment variables were evaluated. Response to chemotherapy regimen was recorded. Breast cancer subtypes were divided based on IHC and FISH testing. Luminal B subtype was classified based on Ki67 (>15%) and PR (<20%).

Results: The average age of the 133 patients was 45 years. 93% of the patients were insured with Medicaid or uninsured (70%). The average size of the cancers at presentation was 5cm. Overall 86% of patients had a clinical response to preoperative chemotherapy and 35% had pathologic complete response (pCR). AC and TC regimens had the lowest rate of pCR at 16%. AC/T (every 3 week and weekly) had similar rates of pCR 23% and 29%, while dose dense regimens showed pCR 40%. Herceptin containing regimens had pCR 57%. 7 patients received TAC and 71% had pCR.

By subtype, Luminal A and B patients had low rates of pCR 9% and 14% respectively. Luminal B patients did benefit from preoperative chemotherapy as 86% of patients who were not candidates for breast conservation at presentation were able to undergo lumpectomy after preoperative chemotherapy. Her2 subtype patients who got Herceptin had pCR 57%. Triple negative patients had pCR 54%.

Conclusions: In this underinsured, Hispanic population who presented at advanced stages, differences in response to preoperative chemotherapy were seen based on breast cancer subtype. Differences were also seen based on chemotherapy regimen. TAC maybe a particularly effective regimen in triple negative Hispanic women.

Citation Format: Mehta D, Winton L, Walters J, Hsu C-H, Nodora J, Martinez ME, Bouton M, Komenaka IK. Preoperative chemotherapy regimens and breast cancer subtype in an underinsured Hispanic population. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-12-06.
Abstract P6-12-13: Awareness and acceptability of skin application of preventive medications for breast cancer
Authors: Karavites LC , Allu S , Khan SA , Kaiser K
Published: May 2016

OBJECTIVE: To better understand women's knowledge and perceptions of breast cancer prevention medications and determine if a topical administration of these medications would increase acceptability.

METHODS: Focus groups were conducted with healthy women identified through the breast center of a single institution. An experienced moderator led participants through a discussion of breast cancer risk perceptions, knowledge of and concerns about risk reduction medications, and their views of a skin application of risk reducing medication. Participants provided sociodemographic information, breast cancer risk factors, and prior physician recommendations to take risk-reducing medicines. Trained research personnel examined all qualitative results systematically. Participants' breast cancer risk was estimated using the Gail Model.

RESULTS: Four focus groups (N=32) were conducted. Most participants had at least a college degree (78.2%) and were of either European (50%) or African ancestry (31%). The majority (72%) were at elevated risk for breast cancer, just over half of these women perceived themselves to be at higher than average risk. Only 19% of participants had prior knowledge of preventive medications. Women who perceived themselves to be at high risk were more likely to know about preventive medications than those who did not, 38% vs 0% respectively. Over 90% of the focus group participants stated that they would prefer a topical application of a preventive medication to a pill if their physician advised them to take preventive medication.

CONCLUSION: Awareness of preventive medications was low even in a highly educated sample of high-risk women. If given a choice in the route of administration of chemoprevention, nine out of ten women preferred a gel to a pill. Future work should focus on demonstrating a reduction in side effects of topical over oral medications and raising awareness of chemopreventive options for breast cancer to increase acceptance of preventive medications.

Citation Format: Karavites LC, Allu S, Khan SA, Kaiser K. Awareness and acceptability of skin application of preventive medications for breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-12-13.
Abstract P6-13-07: The taccalonolides are novel microtubule stabilizers that covalently bind tubulin and have in vivo efficacy in drug resistant tumors
Authors: Risinger AL , Li J , Benavides R , Kuhn JG , Mooberry SL
Published: May 2016

Some of the most effective drugs used in the treatment of breast cancer are microtubule stabilizers. However, there are limitations to their clinical efficacy, including inherent and acquired drug resistance. All microtubule stabilizers that are currently approved for clinical use bind within the taxane pocket on β-tubulin in a reversible manner. The taccalonolides are a novel class of microtubule stabilizers that have a similar profile of microtubule stabilization as the taxanes, but circumvent drug resistance mediated by expression of drug efflux pumps, mutations in the taxane binding site, or overexpression of the βIII isotype of tubulin. We have shown that one important difference between the taccalonolides and clinically approved microtubule stabilizers is that the taccalonolides form a covalent bond to β-tubulin. This distinct interaction allows for irreversible binding, which explains their ability to avoid drug efflux mechanisms and likely belies their exquisite potency in in vivo antitumor models which allows for delivery in aqueous solvents. Serum stability and binding studies, microsomal clearance and pharmacokinetic analysis were performed with both taccalonolides AF and AJ to more fully understand the properties of this class of compounds. We found that both taccalonolides had low microsomal intrinsic clearance rates with no evidence of serum binding and had half-lives similar to paclitaxel in vivo. Like other microtubule targeted agents, taccalonolide AF has a narrow therapeutic window with antitumor effects accompanied by body weight loss. Interestingly, direct injection of taccalonolide AF into a xenograft tumor was highly effective with no associated toxicities at low doses, indicating that targeted delivery to the tumor would greatly increase the efficacy and decrease toxicities. To this end, efforts to promote the targeted delivery of taccalonolide AF to the tumor are being evaluated.

Citation Format: Risinger AL, Li J, Benavides R, Kuhn JG, Mooberry SL. The taccalonolides are novel microtubule stabilizers that covalently bind tubulin and have in vivo efficacy in drug resistant tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-07.
Abstract P6-13-18: Triple-negative kinase profile guides in the selection of the multi-kinase inhibitor EC70124 as an active antitumor agent
Authors: Perez-Peña J , Serrano-Heras G , Corrales-Sánchez V , Nieto-Jimenez C , Gascón-Escribano MJ , Montero JC , Moris F , Martin M , Pandiella A , Ocana A
Published: May 2016

Introduction: Identification of the kinase profile of triple negative tumors can guide in the selection of active multi-kinase inhibitors. We describe the preclinical selection of a novel kinase inhibitor based on the kinase profile identified in human samples.

Methods: phosphokinase profiles of human samples were performed using two kinase arrays: human phospho-RTK array kit (# ARY001, R&D Systems, Abingdon, UK) and the PathScan RTK Signaling Antibody Array Kit (# 7982,Cell Signaling Technology). Based on the kinase profile, inhibitors against activated proteins were evaluated in a panel of triple negative cell lines. Proliferation and growth was measured by MTT uptake. Evaluations of apoptosis and cell cycle were performed by flow cytometry using Annexin V and propidium iodide, respectively. Gene-set enrichment analyses were performed to identify relevant functions mediated by the drug and the identified genes were confirmed by RT-PCR. The in vivo antitumoral effect was evaluated using xenografted animals.

Results: Several kinases were constitutive activated in human tumors, including AKT and pS6, among others . Pharmacological screening identified PI3K/mTOR inhibitors as the most active agents. The novel multi-kinase inhibitor, EC-70124 showed clear antitumor activity. Doses of EC70124 in the nanoMolar ranged reduced proliferation and cell growth in a panel of triple negative cell lines including HS578T, BT549, MDA-MB231 and HCC3153. Treatment with EC70124 inhibited the PI3K/mTOR pathway and induced DNA damage. Gene set enrichment analyses showed different cellular functions induced by the compound. EC70124 showed activity in xenografted animals. Pharmacodynamic analyses supported the inhibition of the PI3K/mTOR pathway in vivo.

Conclusion: the kinase profile of human triple negative tumors identified major activated pathways including the PI3K/mTOR route. The novel kinase inhibitor EC70124 inhibited the PI3K/mTOR pathway showing clear antitumor activity. Evaluation of the kinase profile followed by functional studies is an attractive approach to rationally select active antitumoral agents.

Citation Format: Perez-Peña J, Serrano-Heras G, Corrales-Sánchez V, Nieto-Jimenez C, Gascón-Escribano MJ, Montero JC, Moris F, Martin M, Pandiella A, Ocana A. Triple-negative kinase profile guides in the selection of the multi-kinase inhibitor EC70124 as an active antitumor agent. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-18.