bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-07-05: Development of individual adjuvant chemotherapy benefit estimating program for breast cancer patients management
Authors: Rouzier R , Stevens D , Bonneau C , Falcou M-C , Hequet D , Pierga J-Y , Lerebours F
Published: May 2016

Background

To predict the individual benefit of adjuvant chemotherapy (CT) is challenging especially in estrogen receptor tumors HER2 negative tumors. Existing tools are based on data from randomized trials or on genomic tests with benefit calculated for outmoded CT. The aim of this study was to develop an exportable model to predict from real life data the invidual benefit of adjuvant anthracyclines/taxanes based CT.

Patients and methods

Women with estrogen receptor-positive HER2-negative tumors without metastasis at the time of the diagnosis treated at the Institut Curie - Centre René Huguenin (St Cloud, France) between 2000 and 2008 were included. Clinical characteristics, pathological data and information concerning the treatments and outcomes had been prospectively registered. We divided the study population into 2 groups: patients who did not receive adjuvant CT and patients who did. Multivariate survival analysis and prediction were performed according to the Cox model (proportional hazard model). Non-informative variables in the Cox model were excluded from the final model. The individual benefit of CT was calculated by comparing predicted distant disease-free survival without chemotherapy (using a model constructed in patients treated without adjuvant CT) and modeled distant disease-free survival with CT. Benefit of chemotherapy was validated by cross validation and compared to Adjuvant online predictions.

Results

Data from 3385 women were available: 2137 treated without adjuvant chemotherapy and 1248 with. The models to predict survival without and with CT were based on tumor size, number of metastatic nodes, grade and KI67 (all patients had ER-positive-HER2 negative tumors). The discrimination and the calibration of the models were excellent: C-index were 0.81 and 0.76 for patients treated without and with CT. In this population, the mean 10-year benefit provided by CT was 6.2% (median: 1.5%, min: -4%, max: 35%). The accuracy of the model was internally validated and over-performed predictions of adjuvant online because Ki67 and HER2 status are included in our model (p<.05). A web-based interface is available.

Conclusion

We constructed a tool to evaluate the benefit of adjuvant anthracycline / taxane at an individual level. This tool is based on a model that outperform currently availble methods.

Citation Format: Rouzier R, Stevens D, Bonneau C, Falcou M-C, Hequet D, Pierga J-Y, Lerebours F. Development of individual adjuvant chemotherapy benefit estimating program for breast cancer patients management. [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 P5-07-05.
Abstract P5-08-20: Breast cancer patient survival prediction based on the signature derived from DNA methylation and mRNA expression
Authors: Yang HH , Lee MP
Published: May 2016

We analyzed a subset in the TCGA breast cancer data set for the samples with both expression and methylation assays. We first used the three Immunohistochemistry (IHC) markers for ER, PR and HER2 to find methylation sites that showed significant association to the IHC markers with Bonferroni adjustments. We obtained 2616 methylation sites in 2148 genes in the union of these significant methylation sites. On the other hand, based on the gene expression of samples, we selected top one percent most variable genes (179 genes). Intersection of the 2616 methylation markers with the 179 genes resulted in 58 methylation markers in 43 genes. We found 339 samples which have both expression and methylation data from which we can compute the correlation between the expression of a gene and the methylation of a marker in this gene. We defined a methylation expression index (MEI) which was a weighted sum of the expression of the 43 genes using the negative Spearman correlations as the weights. The expression index was applied in the survival analysis in three independent data sets GSE6532, NKI and METABRIC using Kaplan-Meier method and found the significant difference between the patient groups with high and low MEI index. Compared to the signature derived from the first principal component, the MEI gave better survival prediction across different data sets. We used Cox proportional hazards regression model to evaluate the hazard ratio of the MEI with adjustment of the other variables including age, grade, tumor size, ER and node and found HR=1.58 for the MEI with 95% confidence interval [1.06, 2.35].

Citation Format: Yang HH, Lee MP. Breast cancer patient survival prediction based on the signature derived from DNA methylation and mRNA expression. [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 P5-08-20.
Abstract P5-08-22: DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer
Authors: Györffy B , Munkacsy G , Esteva FJ , Miquel TP , Menyhart O
Published: May 2016

Background. The majority of patients develop resistance against suppression of HER2-mediated signaling by trastuzumab in HER2 positive breast cancer (BC). HER2 overexpression activates multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade. MAPK phosphatases (MKPs) are essential regulators of MAPKs and participate in many facets of cellular regulation, including proliferation and apoptosis. We aimed to identify whether differential MKPs are associated with resistance to targeted therapy in patients previously treated with trastuzumab.

Methods. Using Affymetrix HGU133plus2 gene chip data of 88 HER2-positive, trastuzumab treated BC patients, candidate MKPs were identified by Receiver Operator Characteristics analysis performed in R. Genes were ranked using their achieved area under the curve (AUC) values and were further constricted to those markers significantly associated to worse survival. Functional significance of the two strongest predictive biomarkers was evaluated in vitro experiments after gene silencing in the HER2 overexpressing, trastuzumab resistant breast cancer cell lines SKBR-3-TR and JIMT-1.

Results. Out of 10 investigated MKPs, the strongest predictive genes were DUSP4/MKP2 (AUC=0.75, p=0.0096) and DUSP6/MKP3 (AUC=0.77, p=5.29E-05). Furthermore, higher expression for these correlated to worse survival in 221 HER2 positive BC patients (DUSP4: HR=1.6, p=0.04 and DUSP6: HR=1.8, p=0.0053). Silencing of DUSP4 had significant sensitization effects - viability of DUSP4 siRNA transfected, trastuzumab treated cells decreased significantly compared to scramble-siRNA transfected, trastuzumab treated controls (SKBR-3-TR: p=0.016; JIMT-1: p=0.016). In contrast, simultaneous treatment with DUSP6 siRNA and trastuzumab did not alter cell proliferation.

Conclusions. Our findings suggest that DUSP4 is involved in the development of trastuzumab resistance in HER2 positive BC.

Citation Format: Györffy B, Munkacsy G, Esteva FJ, Miquel TP, Menyhart O. DUSP4 is associated with increased resistance against anti-HER2 therapy 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 P5-08-22.
Abstract P5-08-23: Ki-67 expression is not a valuable predictive prognostic factor when progesterone receptor expression is high in estrogen receptor-positive breast cancer
Authors: Han JH , Kang YJ , Han W , Lee H-B , Kim Y , Yoo T-K , Moon H-G , Noh D-Y
Published: May 2016

Background

Immunohistochemistry markers are recognized as a predictive prognostic factor for women with breast cancer. Ki-67 and progesterone receptor (PgR) expression are reported to be independently associated with breast cancer prognosis. Some studies report high Ki-67 expression as a negative predictive marker. Whereas other studies report tendency of similar survival between high and low Ki67 cancers when PgR expression is high. In this study, we examined the prognostic significance of Ki-67 expression under PgR expression status.

Methods

The records of 2,366 patients were retrospectively reviewed. The patients underwent surgery for primary breast cancer from July 2009 to December 2012 at a single institution. We studied the prognostic significance of Ki-67 expression under PgR expression. We used 20% and 10% as the cut-off value for PgR and Ki-67, respectively. The end point was recurrence-free survival (RFS) evaluated by use of Kaplan-Meier analysis.

Result

Of the 2,366 analyzed patients, the median follow-up time was 43 months. During follow-up, 44 patients had recurrence, loco-regional recurrence developed in 23 patients and distant recurrence developed in 21 patients. In patients with low PgR expression, high Ki-67 expression group showed significantly worse prognosis compared to low Ki-67 expression group (p=0.005). On the other hand, no significant difference was shown between low and high Ki-67 expression group when PgR expression was high (p=0.637). Also multivariate analysis demonstrated that high Ki-67 expression was an independent prognostic factor only when PgR expression was low. (95% confidence interval [CI], 1.35-10.48; p=0.011)

Conclusion

This is the largest reported study that prognostic significance of Ki-67 expression is defined by PgR expression. Our study presents that high Ki-67 expression is inversely correlated with recurrence risk in early breast cancer patients only under low PgR expression. At high PgR expression, Ki-67 expression has no influence on breast cancer prognosis. Therefore, attention should be paid to correlation between PgR and Ki-67 expression.

Citation Format: Han JH, Kang YJ, Han W, Lee H-B, Kim Y, Yoo T-K, Moon H-G, Noh D-Y. Ki-67 expression is not a valuable predictive prognostic factor when progesterone receptor expression is high in estrogen receptor-positive 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 P5-08-23.
Abstract P5-08-25: CKAP2 (cytoskeleton associated protein 2) is a new prognostic marker in HER2-negative luminal breast cancer
Authors: Sim SH , Bae C-D , Kwon Y , Park IH , Lee KS , Jung S-Y , Lee S , Kang H-S , Lee ES , Kim H-S , Hong K-M , Ro J
Published: May 2016

Background: Ki-67 has been increasingly used as a prognostic marker in spite of debates on the evaluation methods and inconsistent results on its clinical values. CKAP2 is a microtubule-associated protein which plays key roles in microtubule assembly and disassembly. In the present study, the clinical significance of CKAP2-positive cells was evaluated and compared with the results of Ki-67 positive cells.

Methods: A total of 579 early breast cancer patients who underwent surgery at the National Cancer Center Hospital between 2001 and 2005 were accrued. The proliferation activity was measured by CKAP2-positive cell count (CPCC) and Ki-67 labeling index (Ki-67 LI) using CKAP2 and Ki-67 antibodies, respectively, by immunohistochemcial staining on FFPE tumor tissue. The correlation of CPCC or Ki-67 LI with recurrence free survival (RFS) was analyzed. The immunofluorescent staining was performed on HeLa cells after synchronization by double thymidine block to compare the patterns between CKAP2 and Ki-67.

Results: The CPCC (median, 8 with the range of 0- 170) and Ki-67 LI (median, 10.2 with the range of 0%- 91.7%) were highly correlated (R = 0.754, P < 0.001). While CPCC was marginally significant in multivariate analysis for RFS in all cases, it was a significant variable for RFS in the subset analysis with HER2-negative luminal breast cancer patients (HR, 3.154; 95% CI, 1.154-10.693; P = 0.027). On the contrary, Ki-67 LI failed to show any correlation with RFS in all or any subgroups. In the analysis on HeLa cells, CKAP2 staining was more specific to cells in metaphase than Ki-67 staining.

Conclusions: CPCC can be an independent prognostic factor specifically in a HER2-negative luminal type of breast cancer. In addition, CPCC appears to be superior to Ki-67 LI as a survival indicator which may be related to the restricted expression pattern of CKAP2 in metaphase cells. Further study is warranted.

Citation Format: Sim SH, Bae C-D, Kwon Y, Park IH, Lee KS, Jung S-Y, Lee S, Kang H-S, Lee ES, Kim H-S, Hong K-M, Ro J. CKAP2 (cytoskeleton associated protein 2) is a new prognostic marker in HER2-negative luminal 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 P5-08-25.
Abstract P5-08-42: Development and validation of personalized ex vivo platform mimicking patient heterogeneous tumor microenvironment to enable personalized treatment for breast cancer
Authors: Majumder PK , Majumder B , Mehrotra DG , Radhakrishnan P , Baraneedharan U , Agarwal S , Sengupta S , Babu G
Published: May 2016

Tumour heterogeneity is emerging as a key driver of drug response. Understanding the heterogeneity is therefore a critical milestone towards the prediction of clinical outcome of anti-cancer drugs. There is a need for technology that can predict treatment outcome with high fidelity by contextually integrating tumor heterogeneity and phenocopying the tumor microenvironment.

Tumor grade-matched matrix support, activated immune compartments and autologous ligands from individual patients were used to engineer a novel personalized ex vivo platform named CANScript. We evaluated functional outcomes as a measure of response to a panel of anticancer drugs in this CANScript platform. Histopathological and molecular characterization of the tumor explants cultured in CANScript revealed a close approximation to the parental tumor at baseline as confirmed by tumor cell viability, proliferation, critical phosphoproteomic status, global transcriptomic profiles and balance in active components of tumor and stromal phenotypes (Majumder. B et al Nat. Commun, 2015). Using more than 100 patients clinical outcome of anticancer drugs (training set) we have further built a machine learning algorithm that takes all functional outcome data from the CANScript platform and provides outcome data in a linear scale showing clinical prediction. This algorithm when applied to the test cohort of more than 40 patients with refractory breast cancer assessed in the CANScript achieved more than 90% sensitivity while keeping specificity in a desired high range for predicting short term clinical outcome.

The high specificity and sensitivity observed in predicting clinical outcomes using the CANScript support the use of this novel platform to select treatment for patients with breast cancer.

Citation Format: Majumder PK, Majumder B, Mehrotra DG, Radhakrishnan P, Baraneedharan U, Agarwal S, Sengupta S, Babu G. Development and validation of personalized ex vivo platform mimicking patient heterogeneous tumor microenvironment to enable personalized treatment 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 P5-08-42.
Abstract P5-08-47: Clinical outcome of pathological T1N0 breast cancer according to the hormone receptor and HER2 status and adjuvant therapy
Authors: Tokunaga E , Akiyoshi S , Koga C , Nakamura Y , Taguchi K , Ishida M , Ohno S
Published: May 2016

Background: The outcome of T1N0 breast cancer is relatively good, however, a subpopulation of this stage has a high population of relapse. It is important to clarify the factors associated with the outcome in order to determine the adequate adjuvant systemic therapy for T1N0 breast cancer.

Aims: To investigate the prognosis of pathological T1N0 (pT1N0) breast cancer by receptor (estrogen receptor; ER, progesterone receptor; PgR, human epidermal growth factor receptor 2; HER2) status and adjuvant systemic therapy, and thus to identify the factors associated with the outcome.

Methods: Among 2164 women who underwent surgery for primary breast cancer in our department, 925 had pathological T1N0 tumors (130 T1a, 234 T1b and 561 T1c). The associations between clinicopathological characteristics, adjuvant therapy and relapse-free survival (RFS) were examined

Results: Of 908 patients with known hormone receptor (HR; ER and PgR) and HER2 status, 675, 79, 64 and 90 had HR+/HER2-, HR+/HER2+, HR-/HER2+ and HR-/HER2- (triple negative; TN) tumors, respectively. The prognosis of patients with T1c tumors was significantly poorer than that of the patients with T1a and T1b tumors (5-year DFS of T1a, T1b and T1c: 97.5%, 97.9%, 94.5%, p=0.0201). HR+/HER2- subtype was significantly associated with better prognosis than other subtypes (5-year DFS: 96.9% vs. 93.6%, p=0.0194). Patients younger than 40 year old or older than 74 years old had significantly shorter PFS (p=0.0039). Lymphovessel invasion (ly), high histological grade (HG2, 3) were associated with poor outcome in all cohort (p=0.0026, p=0.0356). In HR-positive tumors, ly, high HG and omission of the adjuvant endocrine therapy were associated with shorter RFS (p=0.0009, p=0.0306 and p=0.0016, respectively). Adjuvant chemotherapy was not associated with RFS regardless of HR and HER2 status. However, in T1c with nuclear grade (NG) 3 tumors, use of the adjuvant chemotherapy was associated better prognosis. The prognosis of patients with HER2+ tumors was not significantly different among patients with or without trastuzumab in this cohort.

Conclusion: In spite of the excellent prognosis of pT1N0 breast cancer, adjuvant endocrine therapy is important for patients with HR+ tumors. However, the use of adjuvant chemotherapy or trastuzumab did not significantly improve the prognosis. Thus, the indication of chemotherapy or anti-HER2 therapy should be determined in consideration of the several prognostic factors for pT1N0 breast cancer.

Citation Format: Tokunaga E, Akiyoshi S, Koga C, Nakamura Y, Taguchi K, Ishida M, Ohno S. Clinical outcome of pathological T1N0 breast cancer according to the hormone receptor and HER2 status and adjuvant therapy. [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 P5-08-47.
Abstract P5-10-04: Care guidelines for young women diagnosed with breast cancer
Authors: DeCoteau MJ
Published: May 2016

Background: Rethink Breast Cancer has been offering educational resources and front-line psychosocial and practical support to younger women with breast cancer for over ten years. We have heard first-hand the unique issues that these women face. Some of these challenges include diagnosis during pregnancy, effects of chemotherapy on fertility, risk of menopausal symptoms or osteoporosis, feelings of isolation, questions about sexuality, childcare, relationships, dating, employment and money.

Purpose: Health Canada and the Canadian Medical Association have established comprehensive Clinical practice guidelines for the care and treatment of breast cancer and our Provincial Cancer Agencies, the Canadian Association of Nurses in Oncology (CANO) and the Canadian Association of Psychosocial Oncology (CAPO) all have developed excellent Standards of Care. However, our report, Breast Cancer in Young Women in Canada – A Needs Assessment, finds that younger women's needs continue to fall through the cracks. The report also shows that despite a growing array of peer support based interventions and community resources for young women with breast cancer, their needs are often not being met by current healthcare systems.

In response to the feedback from young women experiencing breast cancer in Canada provided in our report, Rethink Breast Cancer has developed a set of recommended Care Guidelines for Young Women with Breast Cancer to ensure their special needs are addressed (in a timely matter). They serve as a compliment to the guidelines mentioned above.

Methods: The care guidelines have been developed in consultation with Rethink's Young Women's Network, a group comprised of young women across the Canada that have personal experience with breast cancer and are interested in Rethink's unique role within the breast cancer community. The network provides important input and feedback on our resources and campaigns for young women dealing with breast cancer. The care guidelines were also developed through consultation with our professional advisors in oncology, nursing and psychosocial support. They are based on original work by UK specialist breast cancer support charity Breast Cancer Care.

Results & Conclusions: These guidelines provide information about key issues individuals may want to discuss with their healthcare providers involved in their breast cancer treatment and care. They are recommendations on the kind of information and support to which individuals should be given access to as a younger woman with breast cancer. They will also serve to guide the care these individuals receive from healthcare professionals.

Citation Format: DeCoteau MJ. Care guidelines for young women diagnosed with 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 P5-10-04.
Abstract P5-14-05: Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12)
Authors: Schoenfeld W , Zweifel M , Thuerlimann B , Riniker S , Weder P , von Moos R , Pagani O , Bigler M , Rothgiesser KM , Pilop C , Brauchli P , Tapia C , Sessa C
Published: May 2016

Background: CR1447 (4-OH-testosterone, 4-OHT), a steroidal small molecule, strongly binds to the androgen receptor (AR) and has aromatase inhibiting activity. Pre-clinical studies show that CR1447 given as an ointment is efficiently absorbed and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells. Methods: CR1447 was administered topically on a daily basis to patients with ER-positive/HER2-negative or ER-negative/PR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. One cycle was defined as 21 days of treatment. Disease evaluation was performed at 3 and 6 months in order to determine tumor response (i.e. complete/partial remission and stable disease) in 3 cohorts of 3 evaluable patients each plus 3 confirmatory patients (dose escalation 100, 200, 400 mg). Results: 14 patients have been treated for a total of 38 cycles. Two patients are still on treatment at the time of analysis. Two patients, one in cohort 1 and one in cohort 2, showed early tumor progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447, resulting in sufficient plasma concentrations of 4-OHT. 4-OH-androstenedione, a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Conclusions: CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative and ER-negative/PR-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day.

Citation Format: Schoenfeld W, Zweifel M, Thuerlimann B, Riniker S, Weder P, von Moos R, Pagani O, Bigler M, Rothgiesser KM, Pilop C, Brauchli P, Tapia C, Sessa C. Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12). [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 P5-14-05.
Abstract P5-15-05: The expression of genes involved in cholesterol biosynthesis is heterogeneous in breast cancer and may predict sensitivity to statin treatment and clinical outcome
Authors: Kimbung S , Feldt M , Bosch A , Borgquist S
Published: May 2016

Background: Epidemiological evidence supports a protective role of cholesterol lowering drugs against breast cancer recurrence. Preclinical studies also support this role since statins can suppress breast cancer progression in various models. The response of breast cancer cells to statin treatment is however heterogeneous. We performed a comprehensive molecular characterisation of the anti-cancer mechanisms of statins in-vitro in view of identifying biomarkers of statin sensitivity in breast cancer.

Methods: Breast cancer cell lines were treated with atorvastatin and the effects on cell proliferation were determined. A panel of cell lines displaying a diverse range of sensitivity to atorvastatin treatment were selected for gene expression microarray profiling following treatment. Differentially expressed genes were identified and subjected to gene ontology analysis and links to outcome following breast cancer diagnosis were explored.

Results: Statin treatment elicited a more potent inhibition of proliferation in estrogen receptor (ER) negative cell lines. This was reflected on the whole genome transcriptional scale as the ER negative cells also displayed a more robust dysregulation of mRNA transcripts relative to the less-sensitive ER expressing cells. Down-regulation of DNA replication, regulation of cell cycle progression, and other proliferation-associated biological processes via mechanisms influencing the transcriptional activity of E2F was observed in the statin-sensitive cells. Importantly, cholesterol biosynthesis via the mevalonate pathway was upregulated in all cell lines following statin treatment. This effect was directly correlated with the pre-treatment expression levels of target genes involved in this biological process, suggesting a link with sensitivity to statin treatment. The expression of cholesterol biosynthesis genes was also found to be variable in primary breast tumors and a significant association was observed between decreased expression and an improved recurrence-free and overall survival, especially in ER positive tumors.

Conclusions: These data suggest that the normal feedback regulation of the mevalonate pathway induced by statins may be compromised in a subset of breast cancer cells and may be exploited to predict breast cancer prognosis and sensitivity to statin treatment.

Citation Format: Kimbung S, Feldt M, Bosch A, Borgquist S. The expression of genes involved in cholesterol biosynthesis is heterogeneous in breast cancer and may predict sensitivity to statin treatment and clinical outcome. [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 P5-15-05.
Abstract P6-03-19: Rs1008805 polymorphism in the CYP19A1 gene is related to the prognosis of stage I–II and operable stage III breast cancer
Authors: Shao X , Zheng Y , Shi L , Huang Y , Wang X
Published: May 2016

Purpose Aromatase, encoded by CYP19A1 gene, is a rate-limiting enzyme in the conversion of androgens into estrogens. It has been demonstrated that genetic polymorphisms in CYP19A1 gene were significantly correlated with altered hormone levels in urine and serum, providing an explication for an elevated risk for progression in relation with increasing estrogen exposure. Consequently, it is biologically plausible that CYP19A1 gene polymorphisms may be related to the prognosis of breast cancer.

Methods CYP19A1 gene rs1008805 polymorphism were genotyped on 406 Chinese Han women with stage I-II and operable stage III breast cancer. Associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS).

Results Totally, there were 200 (49.3%) patients with AA genotype, 169 (41.6%) with AG variant, and 37 (9.1%) carrying GG variant. No significant differences were found in DFS among the whole population with these three genotypes. However, postmenopausal women with GG variant had a poorer DFS when compared with those carrying AG or AA genotype (13.7 months versus 56.3 months; HR, 2.462; 95 % CI, 1.310-4.628; P = 0.004). And what's more, being adjusted by patients features in multivariate analyses, GG genotype remained an independent prognostic factor for DFS (HR, 2.706; 95 % CI, 1.393-5.257; P = 0.003). Premenopausal women with GG variant had a marginally improved DFS when compared with those carrying AG or AA genotypes (87.0 months versus 48.7 months; HR, 0.544; 95% CI, 0.295-1.003; P = 0.051). However, this difference was not confirmed by multivariate analyses.

Conclusions The present study indicated that GG genotype of rs1008805 SNP in the first exon of CYP19A1 gene was significantly related to a worse DFS in postmenopausal women with early breast cancer. This founding is novel, if confirmed, CYP19A1 rs1008805 genotypes may turn to be a prognostic biomarker for early breast cancer.

Citation Format: Shao X, Zheng Y, Shi L, Huang Y, Wang X. Rs1008805 polymorphism in the CYP19A1 gene is related to the prognosis of stage I–II and operable stage III 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 P6-03-19.
Abstract P6-04-03: Transcriptome profiling reveals enrichment of luminal feature in aged basal cell population in murine mammary gland
Authors: Gu X , Gao H , Wu A , Bandyopadhyay A , Dong Q , Sun L-Z
Published: May 2016

Aging is the number one risk factor for breast cancer development. Increasing evidence suggests the potential of mammary stem cells (MaSCs) and their progenitors to generate certain types of breast cancers through neoplastic transformation. Our previous study has shown increased percentage of MaSC-enriched basal cell population (Lin-CD49fhighCD24med) and increased MaSC frequency during aging in murine models. On the other hand, a recent study from another group showed an increased frequency of CD49fhigh cells in the human luminal population (CD227+) during aging, indicating possible aberrant expression of CD49f in the aged luminal cells. However, how these age-related luminal cells with basal markers are generated and how they contribute to potential breast cancer development remains unknown. Here we apply bioinformatics analysis on Next Generation Whole Transcriptome Sequencing data of MaSC-enriched basal cell population (Lin-CD49fhighCD24med) and luminal progenitor-enriched cell population (Lin-CD49flowCD24high) of both young (4 to 6 months) and old (26 to 31 months) mouse mammary gland to test the hypothesis that age-associated increase of basal cell population and MaSCs may be due to the gain of basal cell markers and features by luminal cells. By Gene Set Enrichment Analysis (GSEA) we found a significant loss of basal cell and basal mammosphere signatures and a significant enrichment of luminal cell and luminal mammosphere signature in the old basal cell population and mammospheres in comparison with the young basal cell population and mammospheres. The core enrichment luminal genes from GSEA are able to cluster the old MaSC-enriched basal cell population as well as mammospheres closer to the cluster of luminal population than to the young basal population. These analyses indicate that aging may be associated with an expansion of aberrant MaSCs with both basal and luminal markers in mice, which may be the precursors of certain types of breast cancer. We are now studying the potential function of the basal-like luminal cells in the aged basal population.

Citation Format: Gu X, Gao H, Wu A, Bandyopadhyay A, Dong Q, Sun L-Z. Transcriptome profiling reveals enrichment of luminal feature in aged basal cell population in murine mammary gland. [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 P6-04-03.
Abstract P6-04-08: Expression profile of long non-coding RNAs characterizes different subtypes of breast cancer
Authors: Barton M , Santucci-Pereira J , Russo J
Published: May 2016

Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are not translated into proteins, but regulate the transcription of genes involved in different cellular processes, including differentiation, cancer initiation and progression. The relevance of several lncRNAs in the transcriptional and post-transcriptional field is now well established. Their roles have been found to vary from forming complexes needed for gene transcription to having critical roles in the cytoplasm where they regulate protein localization, mRNA translation and stability. Microarray analysis of normal breast of parous and nulliparous postmenopausal women revealed that lncRNAs are up-regulated in the parous breast [Int. J. Cancer: 131, 1059-1070, 2012]. Subsequently, RNA sequencing was performed to a subset of these samples to understand the role of lncRNAs in the regulation of transcription and their potential function in pregnancy's effect in reducing the lifetime risk of developing breast cancer. In this work, RNA sequencing of healthy postmenopausal breast tissue biopsies from 8 parous and 8 nulliparous women using Illumina platform was performed. The sequencing results show that there are 42 lncRNAs differentially expressed between parous and nulliparous breast tissue. After analysis of these 42 lncRNAs using bioinformatics and thermodynamic filters, 10 lncRNAs were selected to be tested in vitro. Using RT-qPCR, we have demonstrated that the expression profile of at least 10 lncRNAs is characteristic of each epithelial breast cancer cell subtype (luminal, triple negative and cells that overexpress HER2). Moreover, these lncRNAs are differentially expressed in breast tumors when compared to its adjacent normal tissue. Overexpression and knock out experiments of several of these lncRNAs are underway to prove their relevance in breast differentiation and cancer initiation. The results in cancer/normal immortalized breast cell lines and tumor/adjacent normal breast tissue point to the potential of these lncRNAs as targets, not only for therapeutic approaches against breast cancer, but also as preventive measures for nulliparous women.

(This work was supported by NIH core grant CA06927 to Fox Chase Cancer Center).

Citation Format: Barton M, Santucci-Pereira J, Russo J. Expression profile of long non-coding RNAs characterizes different subtypes of 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 P6-04-08.
Abstract P6-06-03: Novel hereditary breast cancer gene mutations: Should there be greater concern regarding ovarian cancer risk?
Authors: Nassikas N , Wilbur JS , Laprise JK , Legare RD
Published: May 2016

INTRODUCTION: As the use of multi-gene breast cancer panel testing increases the phenotype of the included genes continues to evolve. PALB2 and NBN have a well characterized association with breast cancer and are included on many breast cancer gene panels. Germline PALB2 and NBN mutations have been identified in a small percentage of ovarian carcinoma cases with one study reporting a non-significant twofold increase in carriers of the PALB2 mutations amongst ovarian cancer patients (P= 0.4). Similar to BRCA1 and BRCA2 both genes are members of the Fanconi Anemia pathway therefore a potential increased risk for both breast and ovarian cancer could be anticipated. However at present overall the current literature on the association with ovarian cancer is sparse. Here we present the cases of three hereditary breast and ovarian cancer families found to carry pathogenic mutations within the PALB2 and NBN genes. In all three families the proband was diagnosed with ovarian or fallopian tube cancer and carries a pathogenic PALB2 or NBN mutation. Our PALB2 family carries the well-known French Canadian founder mutation, c.2323C>T, and includes the proband who was diagnosed with a stage II-C, grade 3, fallopian tube carcinoma at age 58, her heterozygote sister with ovary cancer at 68 and her mother with ovary cancer at 43 who was not able to be tested. This PALB2 proband has 5 sisters, 7 brothers and 41 nieces and nephews with only one sister diagnosed with breast cancer at 69 who also is PALB2 positive and a maternal grandmother with breast cancer at 48 who was unable to be tested. The NBN Slavic founder mutation, c.657_661del, was discovered in a 66 year old woman with stage IV, high-grade serous ovarian cancer having a mother with breast cancer at 91 and a maternal aunt with ovary cancer at 59 who have not yet been tested. Lastly, our patient from Laos with a diagnosis of a stage II-C endometrioid adenocarcinoma of the ovary diagnosed at 38 years old was found to carry the deleterious NBN mutation, c.1550dupA. She is not aware of any cancer family history and reports a large family including five brothers, four sisters and multiple aunts and uncles on both side of the family. CONCLUSION: These case studies suggest a link between PALB2 and NBN, two known breast cancer susceptibility genes, and hereditary ovarian cancer risk. These observations suggest that further data are needed to accurately evaluate ovarian cancer risk within novel hereditary breast cancer genes now commonly tested as part of multiplex panel analysis.

Citation Format: Nassikas N, Wilbur JS, Laprise JK, Legare RD. Novel hereditary breast cancer gene mutations: Should there be greater concern regarding ovarian cancer risk?. [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 P6-06-03.
Abstract P6-09-14: Awareness of brest cancer risk factors among lay persons and physicians
Authors: Morère J-F , Viguier J , Blay J-Y , Touboul C , Lhomel C , Eisinger F , Pivot X
Published: May 2016

Background

The EDIFICE surveys have been conducted every three years since 2005. The aim of the surveys is to provide a better understanding of the participation of the French population in cancer screening programs. The breast cancer screening program is nowadays widely implemented throughout the female population aged 50-74 years; however, the question of whether it could be adapted according to breast cancer risk factors is currently under debate. This analysis focuses on awareness of the nature of breast cancer risk factors among the lay population and physicians.

Methods

This fourth nationwide observational survey, EDIFICE 4, was conducted by phone interviews using the quota method. A representative sample of 1602 individuals aged between 40 and 75 years old was interviewed between June 12 and July 10, 2014. A mirror survey on a representative sample of 201 general practitioners (adjusted for age and geographical area) and 100 oncologists (adjusted for type of healthcare institution and geographical area) was conducted between July 9 and August 8, 2014. Interviewees were all asked to cite five main risk factors for breast cancer.

Results

For lay persons (737 women with no history of cancer), the breast cancer risk factors reported were: for 54%, heredity and family history; for 29%, unhealthy lifestyle, including smoking, poor diet, stress, alcohol, physical inactivity; for 15%, exposure to exogenous hormone therapy; for 4%, air pollution; for 4%, sunburn on breasts; for 4%, late childbearing or no childbearing, and for 2%, overweight/obesity. Among physicians (70 female general practitioners and 35 female oncologists), the breast cancer risk factors reported were: for 98%, heredity and family history; for 51%, exposure to exogenous hormone therapy; for 39%, late childbearing or no childbearing; for 32%, unhealthy lifestyle, including smoking, poor diet, stress, alcohol, physical inactivity; for 22%, overweight/obesity; for 20%, age; for 22%, no breast feeding, and for 2%, air pollution.

Conclusion

We observed a relatively satisfactory level of understanding regarding the different risk factors for breast cancer despite the lack of indication of any qualitative ranking. Although overweight is a known risk factor for breast cancer, this fact is still not clearly understood among physicians and not widely known by the general public. On the other hand, both physicians and also half of the lay population were well aware of the fact that heredity is a risk factor for breast cancer.

Citation Format: Morère J-F, Viguier J, Blay J-Y, Touboul C, Lhomel C, Eisinger F, Pivot X. Awareness of brest cancer risk factors among lay persons and physicians. [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 P6-09-14.
Abstract P6-10-07: Family history and risk of pregnancy-associated breast cancer (PABC)
Authors: Lambe M , Johansson ALV , Andersson TM , Hsieh C-C , Cnattingius S , Dickman PW
Published: May 2016

Background: The risk of breast cancer is at least doubled in young women with a family history of breast cancer. Pregnancy has a dual effect on breast cancer risk; a short-term increase followed by a long-term protection. It has been hypothesized that women with a genetic predisposition for breast cancer are particularly susceptible to physiological changes during childbearing that may influence short term risk.

Materials & methods: We followed a cohort of women aged 15 to 44 years between 1963 and 2009 identified in Swedish registers. Family history was defined as having a mother or sister with breast cancer. In a case-cohort analysis, we estimated incidence rate ratios of breast cancer during pregnancy and time intervals up to 10 years post-delivery.

Results: In 3,452,506 women, there were 15,548 cases of breast cancer (1,208 were pregnancy-associated (PABC), defined as breast cancer during or within 2 years of pregnancy). Compared to nulliparous women, the risk of breast cancer was decreased during pregnancy, similar during 1st year and increased during 2nd year post-delivery. The pattern was similar in women with or without family history of breast cancer. A peak in risk was observed 5-6 years following the first birth regardless of family history. After a second birth, this peak was only present in women with a family history.

Conclusions: Our results indicate that women with a family history of breast cancer do not have a different breast cancer risk during and within 10 years following pregnancy compared to women without a family history.

Citation Format: Lambe M, Johansson ALV, Andersson TM, Hsieh C-C, Cnattingius S, Dickman PW. Family history and risk of pregnancy-associated breast cancer (PABC). [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 P6-10-07.
Abstract P6-10-17: Rates of prophylactic surgeries among BRCA 1 or 2 mutation carriers: A single institution experience
Authors: Raphael J , Hewitt P , Graham T , Ott K , Mancuso T , Lorentz J , Emmerson M , Eisen A
Published: May 2016

Background

Women with identified BRCA1/2 mutation have a substantially increased risk of developing several types of cancer, mainly breast and ovarian, during their lifetime. Management options included close surveillance, chemoprevention and prophylactic surgeries. The aim of this study is to assess the rate of prophylactic surgeries among BRCA1/2 carriers counseled and screened at a single institution in the last 2 decades.

Methods

We retrospectively captured all women with a BRCA1/2 mutation that were identified in our genetic clinic between 2000 and 2015. The incidence of breast and ovarian cancer among all BRCA carriers was reported. The rates of prophylactic surgeries were calculated and analyzed in all identified carriers.

Results

Six hundred and eighty four women were identified to carry a deleterious BRCA mutation, among them 364 BRCA1 (53%) and 320 BRCA2 (47%). Three hundred and twenty seven (48%) were diagnosed with breast cancer and 80 (12%) had either ovarian or fallopian tumor. Forty percent (N=271) of the women assessed were healthy carriers. Prophylactic bilateral salpingo-oophorectomies (BSO) were performed in 342 women (50%) and prophylactic mastectomies (PM) (bilateral or unilateral) in 190 (28%). Furthermore, 154 women (23%) had both BSO and PM. Of note, 79 women (12%) were less than 35 years old and 122 were less than 40 years old (18%), the majority of those were waiting to have BSO later on. If we remove the young women from the analysis, 57 and 61% of the women would have had BSO (less than 35 and 40 years excluded respectively). If we only analyze the women who had a recent follow up in our clinic (2014-2015), 422 women would be eligible. Among those, 58 and 84 were less than 35 and 40 years old (y) respectively. For this cohort, the rates of BSO would be 61% (257/422)(whole cohort), 71% (excluding women less than 35y) and 76% (excluding women less than 40y).

Conclusion

A promising rate of BSO was reported in our cohort of BRCA carriers as compared to the literature. This rate was even higher (from 50 to over 70%) when we only analyzed patients with recent follow up in clinic and when we excluded young women waiting to have BSO. More efforts are needed to determine why the rates of PM are lower, for example limited breast reconstruction resources, in order to reduce the incidence of subsequent invasive breast cancer in this high-risk population.

Citation Format: Raphael J, Hewitt P, Graham T, Ott K, Mancuso T, Lorentz J, Emmerson M, Eisen A. Rates of prophylactic surgeries among BRCA 1 or 2 mutation carriers: 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 P6-10-17.