bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-04-08: Expression of hormone-responsive genes in benign breast tissue varies with menstrual cycle phase and menopausal status
Authors: Hu H , Wang J , Lee O , Shidfar A , Iyer S , Ivancic D , Chatterton RT , Stearns V , Sukumar S , Khan SA
Published: August 2014

Background: The expression of many genes is known to be regulated by ambient hormone levels. In a preliminary study of random fine-needle aspirate (rFNA) samples from benign breast tissue, we found several genes that were highly correlated with the serum levels of progesterone (P4) and estradiol (E2). We now present data to further validate these genes as markers of menstrual cycle phase (MCP) and menopausal status (MPS) in benign breast tissue which may allow retrospective classification of archived breast samples with respect to MCP and MPS at the time of sampling.

Methods: 240 rFNA samples from healthy women with recorded hormonal data at the time of sampling were analyzed. We divided these subjects by menstrual cycle phase (MCP) and menopausal status (MPS): 41 early follicular: (low circulating E2 and P4); 48 mid-cycle (high E2 and low P4); 31 luteal (moderate E2 and high P4). 120 post-menopausal (low E2 and low P4). 100 ng of RNA from rFNA samples of the breast was reverse transcribed. Amplicons of interest were linearly amplified to 14 cycles for 35 genes related to hormone responsiveness. qPCR reactions were carried out using the TaqMan OpenArray (Applied Biosystems). For each gene of interest, expression levels were normalized to the average expression of GAPDH. Gene expression difference between groups were conducted using the Mann-Whitney Test. P-values from gene expression difference were adjusted via the Benjamini-Hochberg (1995) approach.

Results: The mean value of TNFSF11 expression level was 13.19 fold higher in luteal phase subjects than in post-menopausal subjects (p = 0.0003) where there was also the biggest difference of serum P4 level between groups. The expression of DIO2 and MYBPC1 was also significantly higher in luteal phase group than in the post-menopausal group (p = 0.005, p = 0.02, respectively). These 3 genes also demonstrated a higher expression pattern in luteal phase than mid-cycle and follicular phase but analysis is still ongoing. All comparisons between these groups will be presented at the meeting.

Conclusion: The expression levels of TNFSF11, DIO2 and MYBPC1 vary with MCP and MPS. These hormone-responsive genes are candidate MCP classifiers which could be applied to archived breast samples to assess whether biomarkers of breast cancer risk are stable across the menstrual cycle, since MCP and MPS variation is likely an important source of biological noise in studies of archived breast biopsy material.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-04-08.
Abstract P3-04-12: BreastMark: An integrated approach to mining publically available Transcriptomic Datasets relating to Breast Cancer Outcome
Authors: Madden S , Gaule P , Clarke C , Aherne ST , O'Donovan N , Clynes M , Crown J , Gallagher WM
Published: August 2014

Background: Breast cancer is a complex heterogeneous disease for which a substantial resource of transcriptomic data is available. Indeed, gene expression data have facilitated the division of breast cancer into, at least, five molecular subtypes, Luminal A, Luminal B, Her2, Normal-like and Basal. Once identified, breast cancer subtypes can inform clinical decisions surrounding patient treatment and prognosis. It is important to identify patients at risk of developing aggressive disease so as to tailor the level of clinical intervention.

Methods: We have developed a user-friendly web-based system to allow the identification and evaluation of genes that are significantly associated with disease progression and survival for breast cancer in general and also with respect to molecular subtype. The underlying algorithm combines gene expression data from multiple DNA microarray experiments and detailed clinical data to correlate outcome with gene expression levels. This algorithm integrates gene expression and survival data from 21 datasets on 10 different microarray platforms corresponding to 20,017 gene sequences across 3,519 samples.

Results: We demonstrate the robustness of our approach in comparison to two commercially available prognostic tests in breast cancer. Our algorithm complements these prognostic tests and is consistent with their findings. In addition, BreastMark can act as a powerful reductionist approach to these more complex gene signatures, eliminating superfluous genes, potentially reducing the complexity and cost of these multi-index assays. We also applied the algorithm to examine expression of 58 receptor tyrosine kinases in the basal-like subtype of breast cancer, identifying seven receptor tyrosine kinases associated with poor disease-free survival and/or overall survival in this subtype (EPHA5, FGFR1, FGFR3, VEGFR1, PDGFRβ, ROS, TIE1). A web application for using this algorithm is currently available at http://glados.ucd.ie/BreastMark/index.html.

Conclusions: BreastMark is a useful tool for examining putative prognostic markers at the RNA level in breast cancer. The value of this tool will be in the preliminary assessment of putative biomarkers in breast cancer as a whole and within its molecular subtypes. It will be of particular use to clinical and academic research groups with limited bioinformatics facilities.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-04-12.
Abstract P3-06-04: Role of pMAPkinase, pAKT, p27 & IGF-IR as predictive markers of response to trastuzumab in patients with HER2-positive invasive breast cancer treated with neoadjuvant chemotherapy + trastuzumab in the REMAGUS02 trial
Authors: Mathieu MC , Goubar A , Sigal B , Bertheau P , Guinebretière JM , André F , Pierga JY , Delaloge S , Giacchetti S , Brain E , Marty M
Published: August 2014

Background: Predicting a benefit from trastuzumab in patients with HER2+ breast cancer remains an important goal. Possible mechanisms of resistance include altered receptor antibody interaction, Akt and MAPK pathways, and loss of p27. The objective of this study was to determine the correlation between pMAPkinase (pMAPK), pAKT, p27, IGF-IR protein expression and the benefit of trastuzumab for patients randomized to chemotherapy (CT) alone and CT with trastuzumab.

Patients and methods: From May 2004 to October 2007, 120 patients with stage II and III HER2+ breast carcinomas were enrolled in a phase II trial of neoadjuvant chemotherapy (CT) with epirubicin-cyclophosphamide (4 courses) followed by docetaxel ± trastuzumab (T) (4 courses). A complete pathological response (pCR) was defined by the absence of residual invasive carcinoma in the breast and axillary lymph nodes. A tissue microarray was constructed from paraffin-embedded tumor samples collected prior to neoadjuvant chemotherapy. Patients' tumours were scored HER2 3+ immunohistochemically (IHC) or 2+ IHC with HER2 amplification by FISH. Immunohistochemical analysis of pMAPK, pAKT, p27 and IGF-IR was performed on tumor tissue microarrays before CT. The H-score (intensity × %) was evaluated. Specimens were classified as exhibiting high or low expression based on a median value as the cut-off point for each marker. A logistic regression model, including the marker and its interaction with treatment, was used to analyse the markers predictive of a treatment effect on the pCR. The independent predictive value was analysed in a multivariate logistic regression adjusting on the lymph node and ER status.

Results: 117/120 (97.5%) patients had sufficient tumor for the analysis. The pCR rate was 19% in the CT arm and 25% in the CT+T arm. The median H-score was: pMAPK = 28, pAKT= 25, p27= 50 and IGF-IR = 15. No significant difference was observed in the pCR rate between the two arms according to pAKT, p27, IGF-IR expression. The pCR rate was higher in CT+T compared to CT alone in patients with high pMAPK expression (OR = 4.7 (0.9–24.2); interaction p = 0.03). No difference was observed in the pCR rate in patients with low pMAPK expression (OR = 0.5 (0.1–1.8).

Conclusions: In HER2-positive breast cancers, pMAPK expression evaluated by IHC was significantly associated with a pathological response in the arm with neoadjuvant trastuzumab. High pMAPK expression could be a predictive marker of response to trastuzumab in a CT +T regimen.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-04.
Abstract P3-06-05: Expression of SPARC in human breast cancer and its predictive value in the GeparTrio neoadjuvant trial.
Authors: Untch M , Prinzler J , Fasching P , Müller BM , Gade S , Meinhold-Heerlein I , Huober J , Karn T , Liedtke C , Loibl S , Müller V , Rack B , Schem C , Darb-Esfahani S , von Minckwitz G , Denkert C
Published: August 2014

Background: Secreted protein acidic and rich in cysteine (SPARC) is an albumin-binding protein and associated with poor prognosis in multiple cancers.

The aim of this analysis was to determine the frequency of SPARC expression among different molecular breast cancer subtypes and to evaluate its predictive value for therapy response after neoadjuvant anthracycline/taxane based chemotherapy (CTX) in participants of the GeparTrio trial.

Methods: We evaluated tumoral SPARC expression by immunohistochemistry on tissue microarrays (TMAs) constructed from formalin-fixed paraffin-embedded (FFPE) pre-treatment core biopsies from 667 patients (pts) of the GeparTrio trial. The details of the GeparTrio study design are described elsewhere (von Minckwitz, JNCI 2008). Cutoffs for SPARC expression were determined using the web-based software Cutoff Finder (http://molpath.charite.de/cutoff/).

Results: SPARC protein expression was measurable by IHC on the TMAs and 176 (26.4 %) of 667 tumors were SPARC positive. SPARC expression was increased in pts with triple-negative breast cancer (TNBC) compared to hormone receptor or HER2 positive subtypes (p = 0.039).

SPARC positivity was associated with an increased pCR rate in the overall population (p < 0.001). SPARC negative tumors had a pCR rate of 15%, which increased to 27% in SPARC positive tumors. Similarly, in TNBC the pCR rate increased from 26% in SPARC negative tumors to 47% in SPARC positive tumors (p = 0.032).

In multivariate logistic regression analysis adjusted for standard clinicopathological factors, SPARC was independently predictive in the overall population (p = 0.010) as well as the subgroups of pts with TNBC (p = 0.036).

Conclusions: SPARC is expressed in all biological breast cancer subtypes with TNBC revealing the highest expression rate. Our data suggest that SPARC expression may provide predictive information for response to neoadjuvant CTX.

As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of nab-Paclitaxel, prospective analysis of SPARC expression is planned in the GeparSepto trial.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-05.
Abstract P3-06-06: Lactate dehydrogenase B in breast cancer contributes to glycolytic phenotype and predicts response to neoadjuvant chemotherapy
Authors: Dennison JB , Molina JR , Mitra S , Gonzalez-Angulo AM , Brown RE , Mills GB
Published: August 2014

Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic heterogeneity is less well understood. This study aimed to identify and evaluate metabolic biomarkers in breast cancers and determine their ability to predict outcomes.

Methods: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes, those with the highest potential for robust high/low classification in a clinical setting. Using a panel of breast cancer cell lines, expression and activity of the highest scoring bimodal metabolism gene, lactate dehydrogenase B (LDHB), was quantified and associated with glycolytic phenotype. The contribution of LDHB to glycolysis was evaluated using MDA-MB-231 and HCC1937 cell lines with stable lentiviral knockdown of LDHB. mRNA expression of LDHB was evaluated for association with neoadjuvant chemotherapy response within clinical and PAM50-derived subtypes.

Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using four independent patient datasets, LDHB mRNA expression was positively associated with basal subtype and negatively associated with luminal and HER2 subtypes. Furthermore, LDHB predicted basal phenotype independently of hormone-receptor (HR) clinical status (OR = 21.6 for HR-positive/HER2-negative and OR = 18.2 for triple-negative). While LDHB expression could predict basal phenotype, high LDHB expression identified aggressive breast cancer tumors that were primarily but not exclusively basal. Importantly, high LDHB expression predicted pathological complete response to neoadjuvant chemotherapy for both hormone receptor (HR) positive/HER2-negative (OR = 4.0, P = .0002) and triple-negative (OR = 3.0, P = .003) cancers. Consistent with increased response to chemotherapy, LDHB expression in basal cancers within the triple-negative group was associated with the proliferative marker CCNB1 (P < .0001).

Conclusion: mRNA expression of LDHB as a single marker predicted glycolytic phenotype in cell lines and response to neoadjuvant chemotherapy in breast cancers independently of HR status. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for breast cancer patients treated with neoadjuvant chemotherapy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-06.
Abstract P3-06-12: Effect of TOP2A and cMYC gene copy number on outcome in a Phase II trial of adjuvant TC (Docetaxel/Cyclophosphamide) plus trastuzumab (HER TC) in HER2-positive early stage breast cancer
Authors: Jones S , Collea R , Paul D , Sedlacek S , Favret A , Gore I , Lindquist DL , Holmes FA , Allison MAK , Steinberg MS , Stokoe C , Portillo RM , Crockett M , Wang Y , Lina A , Robert NJ , O'Shaughnessy J
Published: August 2014

Introduction: Approximately one-third of HER2+ early stage breast cancer (ESBC) patients have TOP2A-amplified breast cancer, the subpopulation known to benefit from anthracycline use (Press et al, JCO 2011). Data are needed to evaluate whether outcomes in ESBC patients treated with nonanthracycline-based regimens like docetaxel and cyclophosphamide + trastuzumab (HER TC) are affected by TOP2A or cMYC gene copy number.

Methods: This was an open-label, phase II study of HER TC in HER2+ breast cancer patients. Outcome data have been previously reported (Jones et al, SABCS 2011, PD07-03). Tissue was collected to review HER2, cMYC, and TOP2A gene copy number at a central reference laboratory. HER2, cMYC, and TOP2A amplification was defined as FISH ratio >2, and deletion was defined as FISH ratio <1. Every 21 days, patients received T 75mg/m2 IV and C 600mg/m2 IV, plus weekly H 4mg/kg IV (loading dose) and 2mg/kg IV thereafter for a total of 4 cycles. After 4 cycles of TC+H, patients continued on H for 1 year on a 3-week schedule. The primary endpoint was disease-free survival (DFS) at 2 years with continued follow-up for 3 years. Secondary endpoints were overall survival (OS) and safety.

Results: 493 patients with HER2+ ESBC were enrolled. From the 493 patients, 438 (89%) tissue samples were available and analyzed at Caris Diagnostics (Phoenix, AZ) to test for TOP2A, cMYC, and HER2 gene copy number by FISH. HER2 status was confirmed as positive in 87% of samples. Results for TOP2A, cMYC, and HER2 were generated in 438, 436, and 438 samples, respectively. TOP2A was classified as amplified in 43%, normal in 30%, deleted in 27%. cMYC was classified as amplified in 99(23%), normal in 246(56%), and deleted in 91(21%). Three-year DFS and OS in TOP2A and cMYC status as well as ER and Nodal status are depicted in Table 1. Multivariate analyses of age, nodal status, ER status, and gene expression shown below in Table 2 indicate that neither cMYC nor TOP2A status had an effect on outcome. Only nodal and ER status affected outcome.

Conclusion: Outcome (DFS + OS) in a phase II study of a nonanthracycline regimen (TC) coupled with H was unaffected by cMYC or TOP2A gene copy number status. Only ER and nodal status showed an effect in a multivariate analysis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-12.
Abstract P3-06-17: Detection and monitoring of circulating endothelial cells, circulating tumor cells and disseminated tumor cells during neoadjuvant treatment including an anti-angiogenic agent
Authors: Mathiesen Randi R , Borgen Elin F , Schirmer Cecilie B , Johanssen Ingunn S , Sætersdal Anna B , Wist Erik A , Engebråten Olav
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-17.
Abstract P3-06-22: Mechanisms behind trastuzumab resistance as neoadjuvant therapy in HER2-positive operable breast cancer
Authors: Jinno H , Sato T , Hayashida T , Takahashi M , Hirose S , Kitagawa Y
Published: August 2014

Background: The development of trastuzumab has had a major impact in treatment of breast cancer patients with HER2 overexpression. Despite clinical usefulness, intrinsic or acquired resistance to trastuzumab is a common clinical phenomenon. However, the mechanisms of resistance to trastuzumab have not been fully elucidated. Potential mechanisms include aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4. The objective of this study was to determine the possible mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer.

Patients & methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel (80 mg/m2 IV) plus weekly trastuzumab (4mg/kg loading dose followed by 2 mg/kg IV) for 12 weeks before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. ER and PgR status was assessed using Allred score. For Ki67 labeling index, a total of 400 cells were counted from three consecutive high-power magnifications. PTEN, pIGF-1R and MUC4 expression level was scored semiquantitatively based on staining intensity. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. pCR was defined as no residual invasive carcinoma in the breast.

Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. ER and PgR were positive in 18 (48.6%) and 16 (43.2%) patients, respectively. The overall response rate was 86.5%, including a complete response in 21 patients and a partial response in 11 patients. The pCR rate was 48.6% (18/37). Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 and pIGF1-R status did not affect the pCR rate. PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. pCR rate was significantly correlated with PgR negativity (p = 0.004) and higher Ki67 (p = 0.01).

Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-22.
Abstract P3-06-23: Predicting response to neoadjuvant letrozole
Authors: Larionov A , Turnbull A , Sims A , Renshaw L , Kay C , Harrison D , Dixon JM
Published: August 2014

Background: Approximately 75% of older postmenopausal patients with large operable or locally advanced oestrogen receptor positive breast cancer respond to treatment with neoadjuvant letrozole. Prediction of response is required as approximately 25% fail to respond. The aim of this study was to design a response predicting classifier with two data sets, one published previously [1] and secondly a new dataset.

Methods: Patients were treated with Letrozole (Femara, 2.5 mg daily) and tissues were collected before treatment, 2 or 3 weeks on treatment, and between 3 and 5 months on treatment. Response was based on a 3D ultrasound, with response being classified as a 50% reduction in tumour volume at 3 months. To ensure biological relevance of the response groups we also separated patients into Quick Stable Responders (QSR) and Long-Term Non-responders (LNR), as summarised in Table 1.

Illumina HT-12 BeadArrays were used for gene expression profiling, allowing platform-independent cross-validation with our previous study using Affymetrix HGU-133 chips [1]. The probe IDs were re-annotated to Ensemble gene IDs and XPN batch correction has been applied to make the datasets directly comparable. A combination of Rank-Product, SAM and Random Forrest analyses have been used to design several alternative signatures separating extreme response groups, the patients who responded rapidly vs those who did not respond for a long time. One of the best performing signatures included 48 informative features: 24 at baseline, 12 at 2-weeks and 12 changes between 0 and 2 weeks. This signature was validated on the independent previously published test set by classifying extreme responses (quick stable responders vs long term non responders) using Support vector machines (SVM) with different kernel functions.

Results Are summarised in Table 2.

Conclusions  – A new sample series has been collected to study neo-adjuvant endocrine response. It can be used for independent validation of previous results [1] and for design of new platform-independent response predictors.– Multi-gene predictors based upon change in gene expression outperform those from baseline or 14 day measurements alone. The best classifiers include all 3 time points.– A classifier has been derived with a 91% accuracy rate of predicting extreme response group in 21 of 23 patients.

References

[1] Miller 2009 J Clin Oncol 27:1382.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-23.
Abstract P3-06-26: Serum anti-p53 antibody titers predict pathological response to preoperative chemotherapy in women with HER2 positive or triple negative breast cancer.
Authors: Yoshiyama T , Nakamura Y , Igawa A , Saruwatari A , Shigechi T , Ueda N , Kuba S , Ishida M , Nishimura S , Nishiyama K , Ohno S
Published: August 2014

Background: In SABCS 2009, we reported that the high level of serum anti-p53 antibody titers was associated with response to preoperative chemotherapy in cases with primary breast cancer (SABCS 2009). Prognostic meaning of pathological complete response (pCR) after preoperative chemotherapy differs among various subtype, and there is a close relationship between pCR and prognosis in cases with HER2 positive or triple negative disease. The aim of this study is to evaluate the association between the high level of serum anti-p53 antibody titers and pCR in patients with HER2-positive or triple negative breast cancer.

Patients and Methods: In this study, we analyzed 196 women with operable early stage breast cancer (T1-T3, N0-1) treated with preoperative chemotherapy and definitive curative surgery since 2002 to 2011. All of the patients received four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w). The serum anti-p53 antibody titers were assessed by ELISA with the anti-p53 EIA Kit II (MESACUP anti-53 Test: MBL) in the pre-treatment serum samples. The test's cut-off value was determined to be 1.3 IU/ml based on reference distribution in healthy control individuals. The association between serum anti-p53 antibody titers and pCR was analyzed.

Results: The subtype of tumors of 196 patients were classified to 86 of ER+/HER2−, 24 of ER+/HER2+, 29 of ER−/HER2+ and 57 of ER−/HER2−. The pCR was achieved 49 of 196 patients (25%). The pCR rate were 7%(6/86), 33%(8/24), 48%(14/29) and 37%(21/57) in the subtype of ER+/HER2−, ER+/HER2+, ER−/HER2+ and ER−/HER2− respectively. The range of serum anti-p53 antibody titers in the serum samples of 196 patients was between 0.40 and 5610 (the median was 0.40 and the average was 85.2). Excluding 86 cases with ER+/HER2−, relationship between serum anti-p53 antibody titers and pCR was evaluated. According to serum anti-p53 antibody titers with the patients of pCR, cut-off value of serum anti-p53 antibody titers was set to be 6 IU/ml. The pCR was observed in nine of 12 cases (75%) with high serum anti-p53 antibody titers, which was significantly higher than those with low titers (35%: 34/98; p = 0.01). Multivariate analysis showed that the only high anti-p53 antibody titer was an independent predictive factor for pCR due to preoperative chemotherapy (p = 0.01).

Conclusion: p53 mutation analysis using serum anti-p53 antibody titers might be a useful predictive test for response to preoperative chemotherapy in patients especially with HER2 positive or triple negative breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-26.
Abstract P3-07-08: Recent trends in the characteristics of patients with distant stage breast cancer in the United States Surveillance, Epidemiology and End Stage Disease (SEER) program
Authors: Li J , Dalvi T , Pawaskar M , Tsai K , Caspard H , Fryzek J
Published: August 2014

Objectives. Even though advances in screening and contemporary diagnostic techniques have led to earlier detection, a proportion of breast cancer patients are still diagnosed with distant stage disease. The objective of this research was to describe the changing demographic and clinical characteristics of patients with distant stage breast cancer.

Methods. We identified women aged 20 years or older who were diagnosed with distant stage primary breast cancer between 1995 and 2009 with non-missing hormone receptor (HR) status in the SEER 18 Registry (1973–2009) database. As staging systems changed across the years of the study, we opted to use the SEER historic stage in our analyses. Trends in demographic and clinical characteristics were evaluated by time period of diagnosis (1995–1999, 2000–2004, 2005–2009) and HR status (HR+ includes ER+/PR+, ER+/PR- and ER−/PR+; HR− includes ER−/PR− only). Statistically significant changes were examined using the Cochran Armitage test.

Results. A total of 30,161 women with distant stage breast cancer were identified. Over the 15 years, the incidence rate (IR) of distant stage disease was stable (10.6 to 10.9 per 100,000 pys), as well as the proportion of HR+ cases (68%).

Age did not vary significantly over time; 55% of the HR+ cases and 45% of the HR- cases were 60 years or older. The proportion of Black and Hispanic patients increased significantly over time (18 to 24% for HR+; 24 to 33% for HR−) -as did the proportion of patients diagnosed with grades I and II cancers (44 to 54% for HR+; and 16 to 20% for HR−). The proportion of ductal histologic diagnoses was stable over time, at 77% among HR+ cases and 93% among HR- cases in 2005–2009. Cancer-directed surgeries (from 63 to 47% for HR+; 72 to 56% for HR−) and radiation therapies (43 to 37% for HR+; 42 to 38% for HR−) became less common over the time. Information on chemotherapy/systemic therapies is unavailable in this dataset.

Conclusions. Although, incidence rate of distant stage breast cancer was stable over a time, there was a higher proportion of diagnosis of grade I/II stage cancer cases potentially due to earlier cancer detections by screening programs. The growing proportion of minorities suggested that screening programs be adjusted to the changing demographics in the United States.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-08.
Abstract P3-07-09: Prevalence and effects of off-label use of chemotherapeutic agents in elderly breast cancer patients: estimates from Surveillance, Epidemiology and End Results-Medicare data
Authors: Eaton AA , Sima CS , Panageas KS
Published: August 2014

Purpose: To gain FDA approval, drug companies submit evidence from clinical trials demonstrating that a drug is safe and efficacious in a certain setting. Current regulations allow oncologists to prescribe approved drugs for uses other than those for which the drug was approved (off-label use). While there seems to be a consensus that off-label use is common in oncology, there is a lack of published data on recent trends and on utilization in different populations.

The strength of evidence demonstrating safety and efficacy varies for drugs used in the off-label setting, and patients may be at risk for unacceptable toxicity. The risk of toxicity may be higher among older patients, whose ability to tolerate chemotherapy is compromised by age-related organ decline and comorbidities. Our objective was to describe the prevalence of off-label use of chemotherapeutic agents in elderly breast cancer patients with Medicare coverage and to compare toxicity between patients using off-label drugs and patients using only approved drugs.

Materials and Methods: We identified women 65 and older with a first primary breast cancer diagnosed in 2000–2007 from Surveillance, Epidemiology and End Results (SEER) cancer registry data linked with Medicare claims. Specific chemotherapeutic agents used following diagnosis were identified in Medicare claims and classified as on- or off-label use based on whether the drug was approved for breast cancer as of May 2012. Thirty-day toxicity (ER visit, hospitalization or death) was compared between patients whose first line regimen contained only approved drugs and patients whose first line regimen contained at least one off-label drug using the Cochran-Mantel-Haenszel test.

Results: The most commonly-used approved drugs were cyclophosphamide (used in 14% of patients), doxorubicin (10%), docetaxel (5%), fluorouracil (5%), and paclitaxel (5%).

In total, forty-five off-label agents were used. Vinorelbine and carboplatin were each used in 1% of patients. No other off-label drug was used in more than 109 (0.11%) of patients.

Toxicity was significantly higher for patients treated with off-label agents compared to patients treated with only approved drugs, after adjusting for stage at diagnosis (p = 0.01).

Conclusions: In this population-based cohort, rates of chemotherapy use were generally low, and rates of off-label use were even lower, with only 3% of patients treated off-label. Off-label use became more common as stage at diagnosis increased, with use increasing from 1% in stage 0/1 patients to 12% in stage 4 patients. The higher toxicity rates observed in patients treated with off-label drugs may indicate that these drugs are less safe than approved agents. This result will be confirmed in a matched analysis accounting for age, stage and comorbidities.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-09.
Abstract P3-07-12: Risk Factors for Breast Cancer in Women Served in Odete Valadares Maternity, Belo Horizonte-MG
Authors: Sediyama CMNO , Peluzio MCG , Abranches MV
Published: August 2014

With changes in lifestyle of the population and changes in women reproductive patterns in the last century, the profile of mortality among women has changed, today the prevailing non-infectious chronic diseases, like cancer, including breast cancer. This paper is a case-control population-based, with the objective of evaluating the risk factors and their association with breast cancer in a population of women seen in Odete Valadares Maternity, in the Hospital Foundation of the State of Minas Gerais, in Belo Horizonte, between January and July 2006. Inclusion criteria were age over 18 years and referral for mammography service. Women with abnormal mammography and confirmation of malignancy of the breast were invited to participate in the study, and those with normal mammography were invited to compose the control group. We evaluated 710 women and 456 selected to participate in the study, 261 with breast cancer and 195 healthy controls.

The participants were interviewed, answered a questionnaire on reproductive aspects and lifestyle habits (smoking, alcohol consumption, physical activity, children, age at menarche and menopause, oral contraceptive use and hormone replacement therapy and breast-feeding) and was measured anthropometric data. The association between several independent variables and the presence of breast cancer was evaluated by Student's t test, Mann-Whitney and chi square test. We estimated odds ratio and their respective confidence intervals.

This study found a positive association between physical inactivity, menopause, nulliparity, lack of breastfeeding and family history of breast cancer and the diagnosis of breast cancer, and alcohol conferred a protective effect in this population.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-12.
Abstract P3-08-01: The prospective risk of ovarian cancer in 1433 women in a breast cancer family history clinic: no increased risk in families testing negative for BRCA1 and BRCA2.
Authors: Evans DGR , Ingham SL , Sahin S , Buchan I , Warwick J , O'Hara C , Moran A , Howell A
Published: August 2014

Since the identification of the BRCA1 and BRCA2 genes speculation has continued regarding the breast and ovarian cancer risk associated with mutations in these genes. Also, as to whether mutations in these genes account for the majority of the association between breast and ovarian cancer. Identification of RAD51C and RAD51D mutations in breast/ovarian cancer families has reawakened the debate as to whether it is safe to reassure women from BRCA negative families that they are not at increased risk of ovarian cancer. 1433 women from breast cancer families that had tested negative for BRCA1/2 were followed for a total of between 0.04 and 25 years and checked against a cancer registry for ovarian cancer incidence. Data was censored at ovarian cancer diagnosis, oophorectomy or death. During 16358 women years of follow up no invasive epithelial ovarian cancer occurred, although 2 borderline tumors were diagnosed. Expected rates for this cohort from cancer registry data were 2.75 epithelial ovarian tumors with 2.52 for invasive cancer and 0.23 for borderline tumors. The upper confidence limit for invasive RR was 1.3 and for borderline tumors 0.97–31. In conclusion this the largest prospective follow up of a BRCA negative cohort has demonstrated that there is no increase in risk of invasive ovarian cancer in families that have tested negative for BRCA1/2.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-01.
Abstract P3-08-03: Urinary levels of prostaglandin E2 metabolite and postmenopausal breast cancer
Authors: Kim S , Taylor JA , Sandler DP
Published: August 2014

Estrogens are considered a key player in the mammary carcinogenesis. In postmenopausal women, peripheral aromatization of androgens is the predominant source of estrogens. Given that prostaglandin E2 (PGE2) is a potent activator of aromatase expression, we hypothesized that endogenous level of PGE2 would influence estrogen bioavailability and subsequent breast cancer risk in postmenopausal women. In addition, because PGE2 synthesis is suppressed by treatment of non-steroidal anti-inflammatory drugs (NSAIDs) via inhibition of cyclooxygenase enzyme activity, we further hypothesized that regular use of NSAIDs may modify the association between PGE2 and postmenopausal breast cancer risk. We carried out a case-cohort analysis within the NIEHS Sister Study, a prospective cohort study of 50,884 women. Postmenopausal women who were aged 50 or older and did not report current use of hormones were eligible for the present analysis (N = 11,338). Urinary levels of a major PGE2 metabolite (PGE-M), which is generally accepted as the most accurate index of endogenous PGE2 formation, were quantified using liquid chromatography/tandem mass spectrometry in 302 incident breast cancer cases and 305 subcohort members who were randomly selected by frequency matching for age among cases. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Prentice's pseudo-likelihood approach with Barlow's weighting scheme. Several factors were associated with higher levels of urinary PGE-M in the multivariable analysis, including current smoking, obesity, high caloric intake from saturated fat and surgical menopause. No associations were observed for dietary intake of omega 3 fatty acids, use of vitamin supplements and physical activity. Overall, there was no association between urinary PGE-M and postmenopausal breast cancer risk. After including the interaction terms between NSAID use and urinary levels of PGE-M in the model, however, high levels of urinary PGE-M were associated with an increased risk of breast cancer in postmenopausal women who did not regularly use NSAIDs (likelihood ratio test p <0.01).

Taking into account use of NSAIDs 1 day prior to urine collection did not change results. NSAID use may modify the conversion of androgens to estrogen and thereby lower breast cancer risk. Expected data on estrogen and estrogen metabolites will help us better understand these findings.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-03.
Abstract P3-08-06: Triple Negative Breast Cancer and BRCA Status: Implications for Genetic Counseling
Authors: Haque R , Alvarado M , Ahmed SA , Shi JM , Chung JWL , Avila CC , Zheng CX , Tiller GE
Published: August 2014

BACKGROUND: Controversy exists whether women newly diagnosed with triple negative breast cancer (TNBC) should be referred to genetic counseling as they may be more likely to be BRCA carriers. However, prior studies included small numbers of carriers and their results have had limited influence on practice guidelines. The objective of this study was to determine the association of breast cancer molecular subtype and BRCA status in a large group of medically insured women.

METHODS: We examined a cohort of 2,105 women with breast cancer history tested for BRCA mutations in a large California health plan from 1997–2011. BRCA test results were recorded in the health plan's clinical genetics registry. Of the 2,105 breast cancer patients, 249 were BRCA mutation carriers (143 BRCA1 carriers, and 106 BRCA2 carriers). We conducted data linkages of all patients with the health plan's NCI-SEER affiliated tumor registry and identified ER, PR, and HER2. HER2 status was also captured from pathology reports using natural language processing. ER, PR, and HER2 status were assessed by immunohistochemical or FISH techniques. Patients were classified into four main biologic subtypes: triple negative (ER−/PR−/HER2−); luminal A (ER+ and/or PR+/HER2−); luminal B (ER+ and/or PR+/HER2+); and HER2-enriched (HER2+/ER−). We examined the association between molecular subtypes (collapsed into TNBC vs. non TNBC categories) and BRCA1/2 mutation status using contingency table analyses. P-values (two-sided) were estimated using chi-square analysis. Multivariable logistic regression was used to estimated adjusted odds ratios (OR) and 95% confidence intervals.

RESULTS: TNBC subtype was strongly associated with BRCA status (P < 0.0001). Women with TNBC tumors were five-fold more likely to be BRCA carriers than women who had non-TNBC breast tumors (OR = 5.6, 95% CI: 4.1–7.5). Specifically, the association of TNBC with BRCA1 was more robust (OR = 12.2, 95% CI: 8.3–17.9). Adjusting for age and stage of breast cancer diagnosis and race/ethnicity did not materially modify the association between TNBC and BRCA1 status. TNBC was not associated with BRCA2 status (OR = 1.6, 95% CI: 0.9–2.7).

CONCLUSION: TNBC was strongly associated with BRCA1 status, but not with BRCA2 status. Statistically significant numbers of patients with BRCA mutations have a TNBC profile. These patients should therefore be referred to clinical genetics for further evaluation and possible testing.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-06.
Abstract P3-08-07: HER2 positive breast carcinomas: trend in evolution between 1998 and 2008 and relationship with clinico-pathological characteristics in a population based study.
Authors: Beltjens F , Bertaut A , Pigeonnat S , Pouget N , Guiu S , Poillot M-L , Charon-Barra C , Coudert B , Dabakuyo S , Fumoleau P , Arveux P , Arnould L
Published: August 2014

Background: Determination of HER2 status in invasive breast carcinomas is now mandatory for the optimal treatment of the patient. A vast majority of initial published studies described positivity in about 20 to 25 % of breast carcinomas, but the proportion of HER2 positive gene expression in women with breast cancer varies in the literature from 9 to 74%. The population of the tumor analyzed (for example histologic types, stage, age), the type of the assays used and the lack of uniformity or quality controls in detection assays may partly explain these differences. Our study describes the evolution of HER2 positive invasive breast cancer proportions during a period of 10 years and identifies clinical and pathological characteristics of these positive tumors.

Methods: Based on the regional, population-based breast cancer registry, we identify 2396 patients diagnosed with invasive breast cancer in the Côte-d'Or department and treated in a single institution between 1998 and 2008. The HER2 status was determined by immunohistochemistry and by fluorescence in situ hybridization by a single team that performed regular internal quality controls and participated to multiannual external international quality control programs.

Results: During the 1998–2008 period, 12.8% of invasive breast cancers were identified as HER2 positive, with no trend to annual variations (p = 0.27). During the same period, despite an increase of 45% of the annual diagnosed cancers in the institution, the clinical and pathological characteristics such as age, tumor size, grade, hormonal receptors expression remain stable. We only noticed a slight but significant increase of lobular carcinomas (p = 0.036). In multivariate analysis, HER2 positivity was as expected associated with: hormonal receptor negative status (OR = 1.7 [IC95%: 1.2–2.4], p = 0.0035), metastatic presentation at diagnosis (OR = 2 [IC95%: 1.2–3.4], p = 0.0092), ductal subtype (OR = 1.9 [IC95%: 1.1–3.1], p = 0.0178) and high SRB grade (OR = 2.8 [IC95%: 1.7–4.5] for SBR II, OR = 5.4 [IC95%: 3.2–9.1] for SBR III, p = 0.0035). Conversely, patients older than 75 years presented mostly HER2 negative tumors (OR = 0.5 [IC95%: 0.3–0.8], p < 0.0001).

Conclusions: This population based study on HER2 breast cancer status emphasizes that in a population with stable clinical and tumoral characteristics, when standardized and controlled assays are used, the proportion of HER positive tumors remains stable over a large period and is lower than usually reported (12.8%).

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-07.
Abstract P3-08-09: Clinical and Pathological Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1
Authors: Yap Y-S , Wong J , Chan M , Yong W-S , Ong K-W , Lo S-K , Ngeow J , Tan B , Madhukumar P , Tan M-H , Ang P , Teh B-T , Tan P-H , Lee AS-G
Published: August 2014

Background: Neurofibromatosis type 1(NF1) is an autosomal dominant genetic disorder affecting 1 in 3,000 individuals worldwide. Risk of cancer, including breast cancer, is increased, as NF1 is a tumour suppressor gene. There is limited data on the characteristics of breast cancer in individuals with NF1.

Objectives: To study the clinical and pathological characteristics of breast cancer in women with NF1.

Methodology: Patients with both NF1 and breast cancer were identified retrospectively from hospital records as well as prospectively when seen at National Cancer Centre Singapore (NCCS) and Singapore General Hospital (SGH). All women had histologically proven breast cancer and fulfilled at least 2 of the 7 criteria developed by the NIH Consensus Conference for clinical diagnosis of NF1. Germline NF1 mutation sequencing is being performed on patients with blood specimens available. Details on patient demographics, tumour grade, stage, receptor status and clinical outcome were evaluated. The pathological characteristics of NF1-associated breast cancer were then compared to sporadic breast cancers in our 2001–2004 cohort, with a focus on grade and HER2 positivity rate.

Results: We identified 13 women with NF1 and breast cancer seen at our institutions from 2001 to present date. Average age of breast cancer diagnosis for women testing positive was 48 years (range 30–64). All 13 patients had invasive ductal carcinoma; of which 5 were stage 3 or 4 at diagnosis. To date, 4 out of 12 patients with stage 1–3 breast cancer have relapsed. Grade, estrogen, progesterone and HER2 receptor status were fully available for 12 patients. Ten out of 12 tumours (83%) were grade 3, compared to 45% (705/1578) among our sporadic breast cancers (p = 0.007). Eight out of 12(67%) NF1-associated breast cancers were HER2 positive (IHC 3+ or FISH positive), compared to 27% (367/1367) in sporadic cancers (p = 0.002). Two other NF1-associated tumours were triple negative, and two were hormone receptor positive and HER2 negative. Six out of 12 (50%) NF1-associated cancers were estrogen receptor (ER) positive, compared to 67% (1124/1689) in sporadic cancers (p = 0.2).

Conclusion: Our findings suggest that NF1-associated breast cancer tends to be more aggressive, with a higher frequency of grade 3 and HER2 positive tumours compared to sporadic breast cancer. Further genomic profiling of these tumours (in progress) may elucidate the role of NF1 in breast cancer. This may also have implications for sporadic tumours with somatic NF1 mutations in individuals without NF1.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-09.