bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract OT3-02-10: Nordic trip, a randomized phase 3 study in early triple negative breast cancer
Authors: Loman N , Linderholm B , Joensuu H , Ejlertsen B , Johannsson OT , Geisler J , Bendahl P-O , Ahlgren J , Lindman H
Published: May 2016

Background: Adjuvant treatment among the heterogeneous group of triple negative breast cancers (TNBC) is still a challenge. Recently published data indicate that platinum salts may have a role in the treatment of TNBC (v Minckwitz 2014), especially in BRCA-associated cases (Tutt 2014). Subgroup analyses from two large adjuvant studies indicate that also oral capecitabine may add a significant value in this subset of BC (Lindman 2010, O'Shaughnessy, 2010).

As a planned collaboration between the nordic countries, we are currently preparing a three-armed randomized phase 3 study of the addition of carboplatin and capecitabine respectively to a chemo backbone consisting of a taxane-antracycline based treatment in both the adjuvant and the neoadjuvant setting.

Objectives: The primary endpoint will be invasive disease-free survival (IDFS). Secondary endpoints will include IDFS in subsets of TNBC, eg according to gene-expression-based subtypes of TNBC(Lehmann 2011), and BRCA-mutation status. In the cohort treated neoadjuvant, biomarkers predicting pathological response will be identified with the purpose to validate them in the adjuvant cohort.

Method: 1800 patients (pts) with early TNBC stage 1 (>10 mm) - 3 will be randomized 1:1:1 to three treatment arms.

A: nab-paclitaxel (nP) followed by epirubicine-cyclophosphamide (EC)

B: nP-capecitabine followed by EC-capecitabine.

C: nP-carboplatin followed by EC

Treatment will be given either in the adjuvant or in the neoadjuvant setting, the primary endpoint will include all randomized pts from both cohorts.

Statistical considerations: We assume a 75% five-year IDFS with standard treatment (A), and that a relative reduction of the event incidence of 30% for each of the two experimental treatments (B and C) would be a clinically relevant finding (HR=0.7). In order to achieve 80% power at a 0.05 significance level for each of the two comparisons A vs. B and A vs. C, 600 patients need to be evaluated in each of the three treatment arms. Stratification factors: pre- vs postoperative treatment, nodal status and treatment site.

Citation Format: Loman N, Linderholm B, Joensuu H, Ejlertsen B, Johannsson OT, Geisler J, Bendahl P-O, Ahlgren J, Lindman H. Nordic trip, a randomized phase 3 study in early triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-10.
Abstract P1-05-06: Essential role of notch-4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer
Authors: Bui QT , Kang KW
Published: May 2016

Epithelial-mesenchymal transition (EMT) is process in which epithelial cells undergo unique morphologic changes characterized by a transition from epithelial cobblestone phenotype to elongated fibroblastic phenotype (mesenchymal phenotype) leading to increased motility and invasion. Our previous study demonstrated that tamoxifen (TAM)-resistant human breast cancer (TAMR-MCF-7) cells showed the increased expression of mesenchymal marker proteins compared to the parent MCF-7 cells. Notch plays a crucial role in the promotion of EMT during both development and tumor progression. Especially, Notch-1 and Notch-4 were reported as prognostic markers in human breast cancer. Here, we found that the basal expression and activity of Notch-4 were significantly increased in TAMR-MCF-7 cells compared to control MCF-7 cells. Suppression of Notch-4 by either Notch inhibitors or Notch-4 siRNA significantly attenuated the EMT signaling. Interestingly, long-term treatment with DAPT, a Notch inhibitor, eventually led to partial reversal of EMT by up-regulating E-cadherin expression. Activated or tyrosine-phosphorylated STAT3 (pYSTAT3) protein is supposed as a critical signaling molecule in the regulation of tumorigenesis and metastasis of cancer cells. We further found that TAMR-MCF-7 cells exhibited constitutive STAT3 phosphorylation. Suppression of Notch-4 activation attenuated the activated STAT3 elevation in TAMR-MCF-7 cells. We hypothesized that Notch-4 regulated EMT in TAMR-MCF-7 cells via STAT3 signaling. Intrasplenic injection model of liver metastases was performed using TAMR-MCF-7 cells. Mice were received subcutaneous injections daily with DAPT (10 mg/kg) formed smaller tumor size in spleens and showed less micrometastatic tumor burden in livers compared to group treated with vehicle. In conclusion, inhibition of Notch signaling may have efficacy in the treatment of breast cancer metastasis.

Citation Format: Bui QT, Kang KW. Essential role of notch-4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human 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 P1-05-06.
Abstract P1-07-02: 5-year overall survival of early breast cancer during pregnancy: A multicenter French case control study
Authors: Vanlemmens L , Ploquin A , Delaloge S , Rouzier R , Lesur A , Frenel J-S , Loustalot C , Bachelot T , Provansal M , Ferrero J-M , Coussy F , Debled M , Kerbrat P , Vinceneux A , Djelila A , Baron M , Jebert S , Decoupigny E , Tresch E , Bonneterre J
Published: May 2016

Background: Breast cancer (BC) during pregnancy (BCP) is a rare situation that requires collaboration between oncologists, surgeons and obstetricians. The main objectives of this study were to compare the overall survival (OS) and disease free survival (DFS) of a multicenter cohort of pregnant patients (pts) with those of matched control pts.

Methods: Patients from 27 centers and diagnosed between 2000 and 2006 with histological confirmed M0 invasive BC were included in this retrospective study. For the cohort of BCP, pts whose pregnancy was interrupted were not eligible. Controls were matched to BCP pts on 5 criteria: clinical T (of TNM), hormonal receptor (HR) status, HER2 status, administration of neo-adjuvant chemotherapy and pathological nodal status in the absence of neo-adjuvant chemotherapy. Survival times were estimated from the date of diagnosis using Kaplan-Meier method. OS was calculated until death from every cause, DFS was calculated until relapse or death from every cause; patients alive were censored at the date of last news.

Results: 100 BCP pts were identified. Their clinical and pathological characteristics were described on a previous presentation (SABCS 2013 P6-06-07). Matched controls could not be found for 12 BCP pts. 88 BCP pts were matched with 204 controls. The only differences between the 2 populations in terms of characteristics or treatment were more radical mastectomy (p=0.036) and fewer taxane administrations in the BCP group (p=0.06). The median duration of follow-up was 8.2 years for cases and 7.7 years for controls. There were no differences between BCP pts and controls in 5-year OS: 83.4%, IC 95% (73.5-89.8) vs 83.8%, IC 95% (77.9-88.3) nor 7-year OS: 76.5% (65.5-84.4) vs 78.1% (71.5-83.3) (p=0.52). The 5-year DFS was 58.6% IC 95% (47.3-68.3) vs 67.2% IC 95% (60.2-73.2) (p= 0.16). However, 5-year DFS was lower in HR+ BCP pts subgroup than in HR+ control group (56.7% IC 95% (40.7-69.8) vs 70.9% IC 95% (61.4-78.5) (p=0.023).

Conclusion: This multicenter French large study confirmed that there are no differences on OS and DFS between pregnant and no pregnant pts, though this might not be true for HR subgroup.

Citation Format: Vanlemmens L, Ploquin A, Delaloge S, Rouzier R, Lesur A, Frenel J-S, Loustalot C, Bachelot T, Provansal M, Ferrero J-M, Coussy F, Debled M, Kerbrat P, Vinceneux A, Djelila A, Baron M, Jebert S, Decoupigny E, Tresch E, Bonneterre J. 5-year overall survival of early breast cancer during pregnancy: A multicenter French case control study. [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 P1-07-02.
Abstract P1-07-03: Reproductive factors and subtype specific breast cancer risk
Authors: Anderson WF , Pfeiffer RM , Wohlfahrt J , Ejlertsen B , Jensen M-B , Kroman NT
Published: May 2016

Introduction: Reproductive history and breast cancer risk reportedly differ by the estrogen receptor (ER±) and by the joint expression of ER and the human epidermal growth factor-2 receptor (ER±/HER2±). However, large sample sizes are needed to identify risk factor associations for the relatively less common ER- subtypes.

Material and Methods: We, therefore, linked two large-scale and population-based Danish registries to assess the associations for parity, number of live births, and age at first live birth (AFLB) with receptor-specific breast cancer risk. Relative risks (RRs) and 95% confidence intervals (CIs) for associations were estimated with Poisson regression models.

Results: With nearly 31 million women-years of follow-up, there were 45786 Danish women between the ages 20-84 years who developed an invasive breast cancer during the study period 1992-2011. Parity significantly reduced risk for ER+ and ER+/HER2- subtypes (RR for ER+/HER2- = 0.92; 0.87, 0.98) and suggestively increased risk for ER- and ER-/HER2- subtypes (RR for ER-/HER2- = 1.16; 0.99, 1.36). RRs increased with advancing AFLB for ER+ cancers, especially among premenopausal women; and were elevated for ER- cancers among age groups 12-19 years and 30-34 years compared to the reference age group 20-24 years.

Conclusion: Associations of breast cancer risk and reproductive history varied among Danish women by ER± and by ER±/HER2±, consistent with receptor-specific etiological heterogeneity. Risk estimates for ER+ and ER+/HER2- cancers were similar to the well-established associations for breast cancer overall, whereas relative risks for ER- and ER/HER2- cancers tended to be null or the inverse of ER+ associations.

Citation Format: Anderson WF, Pfeiffer RM, Wohlfahrt J, Ejlertsen B, Jensen M-B, Kroman NT. Reproductive factors and subtype specific breast 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 P1-07-03.
Abstract P1-07-19: Spatial analyses of breast cancer in women 15-49 years-old in Rio Grande do Sul, southern Brazil
Authors: Vianna FSL , Vargas F , Gross LG , Nunes LN , Ashton-Prolla P , Camey SA
Published: May 2016

Breast cancer (BC) rates under 50 years have been increasing over time in several countries. Although the exact impact of BC is not know in low and middle income countries, it's estimated that at least 20% of deaths caused by BC affect women under the ahe of 50 years. In Porto Alegre, the capital of Rio Grande do Sul (RS), Brazil's southernmost state, the incidence of BC in women aged 40-49 years is 165 cases per 100,000, while the mortality rate reaches 25 in 100,000 women. In order to understand BC profile in this age group in the entire state of RS, we established incidence, morbidity and mortality between 2002-2011 through crude and smoothed rates for each municipality. Furthermore, we perform the spatial analysis of these indicators. Incidence data were only available for the state capital, where the rate incidence was 19 and 160 cases per 100,000 women in the age groups of 15-39 and 40-49, respectively. Statewide mortality was 2 and 21 per 100,000 women in the age groups of 15-39 and 40-49, respectively. Hospitalar morbidity associated with BC was 0.6% and 2% in women 15-39 and 40-49 years, respectively. The distribution of morbidity and mortality showed regions with continuously high rates throughout this period with result above 3% and 20 deaths per 100,000 women. In the same areas we did not identified centers specialized in cancer treatment and care. Although there is specific epidemiological surveillance for cancer in Brazil, the coverage is insufficient, especially when it comes to incidence. Morbidity and mortality data showed regions continually affected by high rates, suggesting that specific measures as well as specialized care for women in these regions are necessary. This result is particularly important since current guidelines of the Ministry of Health in Brazil recommend mammographic screening starting at the age of 50 years. The expansion of coverage and access to appropriate treatment is essential for the recognition of risk factors, adoption of effective strategies and reduction of cases and deaths in this group of women. Knowledge of the age distribution of BC cases and BC related deaths is important for the definition of health care policies, which will likely be different in different regions of the world.

Citation Format: Vianna FSL, Vargas F, Gross LG, Nunes LN, Ashton-Prolla P, Camey SA. Spatial analyses of breast cancer in women 15-49 years-old in Rio Grande do Sul, southern Brazil. [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 P1-07-19.
Abstract P1-08-05: Expression levels of sialyl transfereases and fucosyl transferases in breast cancer and their prognostic significance
Authors: Yu AL , Liao K-H , Chang C-H , Lin Y-C , Fan T-C , Hung J-T , Yeo H-L , Lin R-J , Yu J-C
Published: May 2016

Aberrant expression of fucose or sialic acid containing glycans is prevalent in various cancers, including breast cancer. The addition of fucose and sialic acid to glycans is mediated by fucosyl transferases (FUTs) and sialyl transferases (STs), respectively. To explore the roles of these FUTs and STs in breast cancer, we collected 123 paired breast cancer specimens (tumor tissue and non-tumor tissue) and determined the RNA expression levels of 13 FUTs (FUT1-13) and 13 STs (ST3Gal1-6, ST6Gal1, ST6GalNAc1-4, ST6GalNAc6, ST8Sia1 and ST8Sia4) by q-PCR. The expression of 10 FUTs and 10 STs is significantly higher in tumor tissue than in non-tumor tissue by 1.2-4.09 folds. Notably, expression of FUT1 and ST3Gal1 appeared to be highest in triple negative subtype. Further multivariate Cox regression analysis showed a significant correlation between higher hazard ratios (HRs) for five-year relapse-free survival (RFS) and higher ST3Gal1 expression (N = 16, HR = 2.54, p = 0.02) or lower ST3Gal3 expression (N = 88, HR = 3.44, p < 0.001). As to the joint effects of high expression of ST3Gal1 and low expression of ST3Gal3 (N = 10) compared with low expression of ST3Gal1 and high expression of ST3Gal3 (N = 82), the HR was 5.5 (95% CI = 2.16-14.02, p = 0.0004) for RFS. The two gene additive model displayed a statistically significant HR of 2.33 for RFS (95% CI = 1.48-3.69, p = 0.0003). These results suggest that FUTs and STs play important roles in tumor progression.

Citation Format: Yu AL, Liao K-H, Chang C-H, Lin Y-C, Fan T-C, Hung J-T, Yeo H-L, Lin R-J, Yu J-C. Expression levels of sialyl transfereases and fucosyl transferases in breast cancer and their prognostic significance. [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 P1-08-05.
Abstract P1-09-04: New Orleans has the highest incidence rates of triple negative breast cancer
Authors: Loch MM , Li X , Hsieh M-C , Chen VW , Wu X-C
Published: May 2016

Background: We previously demonstrated increased incidence rates of triple negative breast cancer (TNBC) in Black women (BW) in New Orleans (NO) and Louisiana (LA) compared with SEER 17. We explored the hypothesis that BW in NO had a higher incidence of TNBC than in BW other metro areas in the SEER Program.

Methods: We analyzed tumor characteristics of invasive female breast cancers diagnosed 2010-12 from SEER, focusing on racial disparities. We compared LA data with SEER 17 and metropolitan areas (Atlanta, Detroit, Los Angeles and San Francisco). Predictors of TNBC were identified in multivariate logistic regression.

Results: Overall incidence rate of TNBC in BW was significantly higher in NO (32 per 100,000) than in the rest of LA (24 per 100,000) and the SEER metro areas combined (23 per100,000). Detroit had the 2nd highest rates (27.3 per 100,000) followed by Los Angeles, San Francisco and Atlanta (23.2, 23, 22.4 respectively). Compared with SEER 17, the rate ratio of TNBC was 38% higher for BW in NO (CI: 1.17-1.61) and 17% higher for BW in Detroit (CI: 1.06-1.29). Compared with other LA metro areas, the rate ratio of TNBC was 44% higher for BW in NO (CI: 1.10-1.91). Young age (<65) and black race predicted TNBC after adjusting for insurance status, tumor size, lymph node status, grade and derived AJCC stage.

Conclusions: The incidence rates and rate ratios of TNBC in BW in NO and LA are not only significantly higher than in SEER 17 but also higher than any other SEER metro area. We will explore this dataset further by analyzing BMI, comorbidities and SES. This disparity in BW in NO has clinical implications and translational research potential as it enables us to broaden the understanding and treatment of this aggressive disease.

Citation Format: Loch MM, Li X, Hsieh M-C, Chen VW, Wu X-C. New Orleans has the highest incidence rates of triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-04.
Abstract P1-10-11: Prognostic value of non-alcoholic fatty liver disease in stage II/III breast cancer patients who received neoadjuvant chemotherapy
Authors: Yang Y , Lee K-H , Kim T-Y , Han S-W , Oh D-Y , Kim T-Y , Han W , Moon H-G , Park IA , Noh D-Y , Im S-A
Published: May 2016

Background

Metabolic syndrome is associated with various malignancies, including breast cancer. Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. NAFLD is frequently observed during chemotherapy, but its clinical implication is unclear. The purpose of this study is to evaluate the prognostic value of NAFLD in patients with stage II/III breast cancer who received neoadjuvant chemotherapy (NAC Tx).

Methods

The patients with clinical stage II/III breast cancer who received NAC Tx with docetaxel and doxorubicin were enrolled. Treatment sequences were: 3 cycles of NAC Tx → surgery → 3 cycles of adjuvant chemotherapy (AC Tx), or 6 cycles of NAC Tx → surgery, allowing AC Tx at the physician's discretion. NAFLD was determined by ultrasonography (radiologists' decision), non-constrast computed tomography [CT] (the attenuation of liver is less than that of spleen or <49 hounsfield unit [HU]) or contrast CT (the difference between liver and spleen attenuation < -18.5 HU). The presence of NAFLD was evaluated 3 times, at diagnosis, after NAC Tx and after the completion of AC Tx. Improvement of NAFLD was defined as the disappearance of NAFLD after NAC Tx.

Results

Between 2002 and 2008, 269 patients were enrolled. The median age was 45 (range 18-69), and 51.7% and 28.6% were with hormone receptor and HER2 positive tumors, respectively. The median number of NAC Tx was 3 cycles (range 1-6). NAFLD was observed in 33 (12.4%) patients at diagnosis, 52 (19.3%) after NAC Tx and 71 (26.4%) at the completion of AC Tx. The patients with NAFLD at diagnosis showed shorter overall survival than those without NAFLD (HR=2.688, 95% CI 1.259-5.747, P=0.011). The improvement of NAFLD during NAC Tx was observed in 28 (10.4%, group A) and persistence of NAFLD observed in 24 (8.9%, group B). Group A showed better prognosis in both PFS (HR 0.125, 95 % CI 0.016-0.962) and OS (no event), whereas group B showed worse PFS (HR 2.329, 95% CI 1.280-4.237) and OS (HR 3.721, 95% CI 1.727-8.015) compared to the patients without NAFLD at diagnosis.

Conclusions

NAFLD at diagnosis was a poor prognostic marker of OS in patients who received NAC Tx. Improvement of NAFLD during NAC TX was associated with good prognosis in terms of PFS and OS.

Citation Format: Yang Y, Lee K-H, Kim T-Y, Han S-W, Oh D-Y, Kim T-Y, Han W, Moon H-G, Park IA, Noh D-Y, Im S-A. Prognostic value of non-alcoholic fatty liver disease in stage II/III breast cancer patients who received neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-11.
Abstract P1-10-12: Biopsychosocial concerns of adolescent young adults (AYA) with breast cancer
Authors: Smith R , Mortimer J , Loscalzo M , Clark K
Published: May 2016

Background: The natural history of breast cancer in the AYAs with breast cancer is reported to be more aggressing than that observed in older women. We wanted to determine the level of biopsychological distress in this population compared with women in other age groups.

Methods: All new patients seen at City of Hope complete a tablet-based self report biopsychosocial screening questionnaire (SupportScreen®). Patients are asked to score a series of problems on a 5-point Likert scale ("not a problem" to "very severe problem") and are asked if they are interested in obtaining help for that problem. Results: To date 1,159 women have undergone screening; 79 pts (6.9%) were age 18-39 yrs (AYA), 807 (69.6%) age 40-64 yrs, and 273 (23.6%) > 65 yrs. The concerns that were unique to the AYA population included: Ability to have children (p=0.001) and physical appearance (p=0.047 for 40-64 yrs and p=0.018 for age > 65 yrs). Older women were more concerned that AYAs or middle aged women about transportation (p=0.008), walking, climbing stairs (p=0.000). Compared to older women, those age 40-64 yrs were more likely to identify feeling anxious or fearful (p=0.032) and managing work, school or home life (p=0.018). In comparison to AYAs, those age 40-64 yrs had more distress related to recent weight change (p=0.034) and difficulty sleeping (p=0.006).

Conclusions: Biopsychosocial concerns change over the continuum of age. Compared to other age groups, the AYA population was more concerned about their ability to have children and their physical appearance. In other domains of distress, they were comparable to women age 40-65 yrs.

Citation Format: Smith R, Mortimer J, Loscalzo M, Clark K. Biopsychosocial concerns of adolescent young adults (AYA) 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 P1-10-12.
Abstract P1-15-07: The neuroprotective aminopropyl carbazole, P7C3-A20, prevents paclitaxel-induced pain
Authors: LoCoco PM , Risinger AL , Mooberry SL , Berg KA , Clarke WP
Published: May 2016

Paclitaxel (PTX), a microtubule-targeting anticancer agent, produces a debilitating peripheral neuropathy that is accompanied by neuropathic pain. Currently, there are only marginally effective therapeutic interventions available. Consequently, patients are forced to reduce or discontinue life-saving chemotherapy to cope with the pain. Recently, a newly identified agent, P7C3-A20, was found to be protective in several models of neurodegeneration, including Parkinson's disease and traumatic brain injury. Given that PTX triggers progressive degeneration of peripheral afferent neurons, this study was performed to evaluate the potential neuroprotective efficacy of P7C3-A20 in rodent models of PTX-induced peripheral neuropathy. P7C3-A20 (10 mg/kg) or vehicle (Cremophor EL/DMSO/5% Dextrose; 1:1:3) was administered intraperitoneally (i.p.) to Sprague-Dawley rats (250-300 g) everyday over a 28-day experimental paradigm. Following two days of treatment with P7C3-A20 or vehicle, rats also received 3 injections of PTX (11.7 mg/kg, i.p.) or vehicle (Cremophor EL/DMSO/5% Dextrose; i.p.) administered every other day. Treatment with P7C3-A20 did not alter body weights or leukocyte counts in control or PTX-treated rats. PTX treatment increased sensitivity to mechanical and cold stimulation (allodynia) of the hindpaw, evidence of peripheral neuropathy. Notably, P7C3-A20 treatment prevented the development of allodynia in response to PTX. Immunohistochemical analysis of paw biopsies indicated that P7C3-A20 prevented PTX-mediated degeneration of terminal nerve endings. Collectively, these data suggest that P7C3-A30 prevented the neurotoxic effects of PTX on peripheral sensory neurons. A xenograft tumor model of triple negative breast cancer was then used to determine whether P7C3-A20 diminished the antitumoral efficacy of PTX. MDA-MB-231 tumors were bilaterally implanted into flanks of female athymic nude mice and allowed to grow for 3 weeks prior to treatment. Using the same treatment protocol as the rats, tumor-bearing mice received daily treatment with P7C3-A20 (20 mg/kg, i.p.) or vehicle for 16 days. P7C3-A20 did not alter PTX-mediated inhibition of tumor growth. Furthermore, P7C3-A20 prevented PTX-induced mechanical allodynia in the mice. Taken together, this work indicates that P7C3-A20 prevents PTX-induced neuropathic damage without diminishing its antitumoral efficacy. P7C3-A20 may be an exciting new candidate to prevent peripheral neuropathy in patients undergoing cancer treatment with PTX.

Citation Format: LoCoco PM, Risinger AL, Mooberry SL, Berg KA, Clarke WP. The neuroprotective aminopropyl carbazole, P7C3-A20, prevents paclitaxel-induced pain. [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 P1-15-07.
Abstract P2-04-01: The role of Jmjd1a in mammary gland development and breast tumor growth
Authors: Qin L , Xu Y , Wu Y , Yu X , Toneff MJ , Liao L , Li Y , Xu J
Published: May 2016

Histone modification alters chromatin architecture and thereby influences gene transcription. Histone methylation status is reversible and counter-regulated by methyltransferases and demethylases. Jmjd1a (also known as KDM3A, TSGA, JMJD1, JHDM2A and JHMD2A) is a histone demethylase. It belongs to JmjC domain-containing protein family and could specifically remove di- and mono- methyl residues from di or mono-methylated histone H3K9 (H3K9me2/me1). Recent studies showed that Jmjd1a plays an important role in embryonic stem cell self-renewal, spermatogenesis, regulation of metabolic gene expression and body weight, sex determination, tumor angiogenesis, and macrophage infiltration. However, its role in mammary gland (MG) development, breast carcinogenesis and breast cancer progression hasn't been systemically investigated. In this study, we found that Jmjd1a is expressed in mouse luminal epithelial cells. Genetic disruption of the Jmjd1a gene significantly slowed down MG development as indicated by retarded MG elongation and decreased ductal density in virgin mice observed at the ages of 4, 6 and 8 weeks. In agreement with the retarded MG development, the expression of Ki67 and cyclinD1 in epithelial cells of MGs from Jmjd1a knockout (KO) mice dramatically reduced compared with that from wild type (WT) mice. H3K9me1 and H3K9me2 levels in the epithelial cells of KO MGs are much higher than that in WT MGs. To assess the role of Jmjd1a in breast cancer progression, we crossbred Tg(Jmjd1a-/-) mice with MMTV-TVA(RCAS-PyMT) mice and obtained Tg(Jmjd1a-/-)×MMTV-TVA(RCAS-PyMT) mice. Infection of the TVA-expressing MG epithelial cells with the RCAS-PyMT virus induced mammary tumors in these mice and MMTV-TVA(RCAS-PyMT) control mice. We found that KO of Jmjd1a slightly accelerated mammary tumor initiation but significantly decreased tumor growth. Ki67 and cyclinD1 expression statistically reduced in KO tumors versus WT tumors. At the molecular level, Jmjd1a expression positively correlated with cyclin D1 expression in mammary epithelial cells and mammary tumors. Knockdown of Jmjd1a in MCF-7 cells significantly reduced cyclin D1 expression, while ectopic expression of Jmjd1a in MCF-7 cells increased cyclin D1 expression. ChIP assay revealed that Jmjd1a is associated with a promoter region of cyclin D1. Co-expression of c-Myc and Jmjd1a boosted the activity of the cyclin D1 reporter. In conclusion, our study indicated that Jmjd1a plays an important role in promoting mammary gland development and breast tumor growth by up-regulating cyclin D1 expression. Targeting Jmjd1a may inhibit breast cancer progression.

Citation Format: Qin L, Xu Y, Wu Y, Yu X, Toneff MJ, Liao L, Li Y, Xu J. The role of Jmjd1a in mammary gland development and breast tumor growth. [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 P2-04-01.
Abstract P2-05-17: ARGX-111 depletes MET-expressing circulating tumor cells via enhanced ADCC, resulting in inhibition of metastasis
Authors: Morello V , Hultberg A , De Jonge N , Huyghe L , Hanssens V , Brouckaert P , Saunders M , Dreier T , Thibault A , Rolfo C , Aftimos P , Awada A , Michieli P , de Haard H
Published: May 2016

Several lines of experimental evidence suggest that Hepatocyte Growth Factor (HGF) and its receptor MET play an important role in breast cancer progression and drug resistance. To date, targeted MET inhibitors in clinical development have primarily shown cytostatic rather than cytotoxic effects. Development of a cytotoxic MET inhibitor would serve to complement standard breast cancer therapy, especially when administered in the adjuvant/neo-adjuvant setting.

We have developed ARGX-111, a human antibody antagonist of MET function. ARGX-111 blocks both HGF-dependent and -independent signaling, down-regulates tumor cell surface expression of MET and kills MET-overexpressing cells by enhanced antibody-dependent cellular cytotoxicity (ADCC).

ARGX-111 was shown to be more efficacious than an ADCC-inactive control antibody in both HGF-dependent and -independent tumor xenograft models. ADCC reporter assays confirmed the cytotoxic effects of ARGX-111 in patient-derived primary tumor specimens, including MET-expressing breast cancer stem-like cells. In an orthotopic mouse model of metastatic mammary carcinoma (MDA-MB-231), adjuvant or neo-adjuvant treatment with ARGX-111 was significantly more effective in depleting circulating tumor cells (CTCs) and suppressing the development of bone and lung metastases than the ADCC-inactive control.

Taken together, these results provide a rationale for clinical investigation of ARGX-111 in the early breast cancer setting. An ongoing Phase 1 study (NCT02055066) is examining the effects of ARGX-111 on CTCs, alongside the assessment of its safety and efficacy.

Citation Format: Morello V, Hultberg A, De Jonge N, Huyghe L, Hanssens V, Brouckaert P, Saunders M, Dreier T, Thibault A, Rolfo C, Aftimos P, Awada A, Michieli P, de Haard H. ARGX-111 depletes MET-expressing circulating tumor cells via enhanced ADCC, resulting in inhibition of metastasis. [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 P2-05-17.
Abstract P2-05-23: TWIST1 silences FOXA1 transcription to promote breast cancer progression
Authors: Xu Y , Feng Z , Xu Y , Mo Q , Qin L , Sun T , Wu H , Li Y , Liao L , Xu J
Published: May 2016

TWIST1 promotes epithelial-mesenchymal transition (EMT), invasion and metastasis of breast cancer cells, but the underlying mechanism is still not well understood. We generated mammary gland tumor specific Twist1 knock out mouse model and found that TWIST1 does not affect PyMT-induced mammary tumor initiation and growth but promotes tumor lung metastasis. We identified FOXA1 as a novel direct target of TWIST1 in both mouse and human breast cancer. We further found that TWIST1 inhibits FOXA1 expression through direct binding to its proximal promoter region and recruiting Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) transcriptional repressor complex. Moreover, TWIST1 also diminished transcriptional activator AP1 binding to FOXA1 promoter. TWIST1 mediated FOXA1 down-regulation is essential for promoting breast cancer migration, invasion and metastasis. FOXA1 significantly inhibits TWIST1 dependent cell migration and invasion capability of MCF7 cells through inhibiting integrin α5, β1 and MMP9 expression. Importantly, TWIST1high FOXA1low correlates with the poorest prognosis in breast cancer patients.

Citation Format: Xu Y, Feng Z, Xu Y, Mo Q, Qin L, Sun T, Wu H, Li Y, Liao L, Xu J. TWIST1 silences FOXA1 transcription to promote breast cancer progression. [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 P2-05-23.
Abstract P2-06-04: The power of next generation sequencing in the detection of breast and ovarian cancer susceptibility genes other than BRCA
Authors: Eliade M , Skrypski J , Baurand A , Jacquot C , Bertolone G , Loustalot C , Coutant C , Guy F , Fumoleau P , Rivière J-B , Duffourd Y , Ghiringhelli F , Végran F , Boidot R , Lizard S , Faivre L
Published: May 2016

Background : Most cases of breast and ovarian cancer susceptibility remains unexplained. Testing multiple genes in one go with next generation sequencing is then an asset with the recent discovery of new genes involved in breast and ovarian cancer susceptibility.

Methods : We studied 457 patients originated from Burgundy (France) fulfilling the criteria for BRCA1/2 testing using a next generation sequencing 25-gene panel including 17 genes of predisposition for breast and/or ovarian cancer (ATM, BARD1, BRCA 1/2, BRIP1, CHEK2, PALB2, RAD51C, TP53, PTEN, RAD50, MRE11, MLH1, MSH2, MSH6, PMS2, STK11).

Results : A pathogenic BRCA1/2 mutation was found in 8% (n=37) of patients. Besides, we found 39 deleterious or probably deleterious mutations in 13 different genes. The most frequently mutated genes were CHEK2 (n=10 ; 2.1 %), ATM (n=9 ; 2 %), and PALB2 (n=4 ; 0.9%). One patient had deleterious mutations in both TP53 and PALB2, and another one had deleterious mutations in both BRCA2 and CHEK2. The mutation could explain the phenotype in the majority of cases, but a pathogenic mutation was found in a different predisposing gene in 7 patients, and could be considered as incidental findings with the currently published spectrum of cancer locations.

Conclusion : Besides BRCA1/2 mutations, that remain the most frequent susceptibility genes for breast and ovarian cancer, gene panels remain a powerful tool for identifying the other less frequent susceptibility genes. The penetrance and spectrum of cancer associated to these other genes remain sometimes undefined, and further collaborative work is crucially needed to address this question. The possibility of double hits should led to careful genetic counseling.

Citation Format: Eliade M, Skrypski J, Baurand A, Jacquot C, Bertolone G, Loustalot C, Coutant C, Guy F, Fumoleau P, Rivière J-B, Duffourd Y, Ghiringhelli F, Végran F, Boidot R, Lizard S, Faivre L. The power of next generation sequencing in the detection of breast and ovarian cancer susceptibility genes other than BRCA. [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 P2-06-04.
Abstract P2-06-07: PRKCQ regulates taxol sensitivity of triple negative breast cancer cells via IL-6/Stat3 signaling
Authors: Irie HY , Byerly J
Published: May 2016

Background/Rationale. While some patients with triple negative breast cancer achieve long-term remission with chemotherapy, many have cancers that are chemotherapy resistant. The lack of targeted therapies for this subtype also makes some triple negative cancers difficult to treat and control. PRKCQ, a member of the novel protein kinase C family, is preferentially expressed in triple negative breast cancers compared to ER+/Luminal cancers. We previously reported that PRKCQ expression drives growth-factor independent growth, anoikis resistance and migration of breast epithelial cells. In addition, PRKCQ is required for in vivo growth of triple negative breast cancers tumor xenografts. We sought to determine if PRKCQ expression modulates sensitivity of triple negative breast cancer cells to standard of care chemotherapy and whether PRKCQ inhibition could be a strategy to induce death of chemotherapy-resistant triple negative breast cancer cells. Methods. We determined the effects of modulating PRKCQ expression, using PRKCQ cDNA or shRNA vectors, on Doxorubicin or Taxol treatment-induced effects on triple negative breast cancer cells, including those that are relatively chemotherapy resistant at baseline. We determined the mechanisms by which PRKCQ expression regulates sensitivity to Taxol. Results. Increased PRKCQ expression in MCF-10A breast epithelial cells suppresses the apoptosis-inducing effects of Doxorubicin or Taxol treatment. PRKCQ-induced Taxol resistance is dependent on PRKCQ kinase activity. PRKCQ-expressing MCF-10A cells secrete enhanced levels of IL-6, leading to the autocrine activation of Stat3; IL-6/Stat3 activation is necessary for PRKCQ-induced resistance to Taxol. Finally, downregulation of PRKCQ sensitized MDA-231-Luc cells to Taxol treatment and induced apoptosis of these cells which are relatively resistant to Taxol at baseline. Conclusions. PRKCQ regulates sensitivity to standard of care chemotherapies used in the treatment of triple negative breast cancer. IL-6/Stat3 signaling induced by PRKCQ kinase activity is responsible for resistance to the effects of Taxol treatment. Targeting PRKCQ therefore could be an attractive strategy to overcome chemotherapy resistance of a subset of triple negative breast cancers.

Citation Format: Irie HY, Byerly J. PRKCQ regulates taxol sensitivity of triple negative breast cancer cells via IL-6/Stat3 signaling. [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 P2-06-07.
Abstract P2-08-26: Tumor-associated macrophages and platelet-derived growth factor C as a prognostic marker for breast cancer patients
Authors: Yoo T-K , Lee K-M , Jung H , Na YR , Seok SH , Han W
Published: May 2016

Introduction: Tumor related inflammation plays an important role in breast cancer progression, tumor-associated macrophages (TAMs) being a crucial part of this microenvironment. Platelet-derived growth factor-C (PDGF-C) is abundant in the breast cancer microenvironment having an anti-apoptotic effect on macrophages. Previous reports suggest that tumor cell derived PDGF-C promotes TAM survival, enhancing tumor progression. In this study we analyzed the prognostic value of PDGF-C density associated with TAM infiltration in human breast cancer.

Materials and Methods: TAM and PDGF-C density was evaluated by immunohistochemistry of CD163+, CD68+ and PDGF-C myeloid cells in tumor stroma. Tissue microarrays from 140 invasive breast cancer cases were used. Survival analysis to evaluate the impact of TAM and PDGF-C density on disease free survival (DFS) was done using Kaplan-Meier and Cox regression analysis.

Results: Infiltration of CD163+ and CD68+ macrophages into tumor stroma had a tendency, but not significant, for reduced DFS (p=0.204, p=0.314 respectively). Whereas PDGF-C strong density was significantly associated with worse DFS (p=0.024). This inverse correlation with DFS was demonstrated stronger when PDGF-C density was combined with CD163+ and CD68+ macrophage infiltration (p=0.008, p=0.018, respectively). But, CD163+ or CD68+ infiltration with strong PDGF-C density did not demonstrate as an independent prognostic factor when adjusting for tumor size, lymph node metastasis, hormone receptor and histologic grade. This result is probably due to small number of patients having both TAM infiltration and strong PDGF-C density.

Conclusion: Our results show that PDGF-C infiltration adversely affects DFS and also enhances the inverse correlation between tumor-associated macrophages and DFS. To support these results, a study with larger numbers is on progress.

Citation Format: Yoo T-K, Lee K-M, Jung H, Na YR, Seok SH, Han W. Tumor-associated macrophages and platelet-derived growth factor C as a prognostic marker for breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-26.
Abstract P3-03-01: Intracranial PDX models of breast cancer metastasis
Authors: Nielsen CH , Nedergaard MK , Wick MJ , Papadopoulos K , Tolcher AW , Kjaer A
Published: May 2016

Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is an independent factor for development of brain metastases. Up to 37% of patients with HER2 positive disease relapse intracranially despite control of extra-cranial metastatic disease. Inability of anti-cancer agents to cross an intact blood-brain barrier (BBB) is a possible explanation for the increased incidence of brain metastases.

Subcutaneous (SQ) patient-derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, orthotopic PDX models may confer a translational advantage as the patient tumor microenvironment is more closely mimicked. Especially when targeting brain tumors, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to develop a panel of intracranial PDX models of breast cancer brain metastases for pre-clinical efficacy studies of new anticancer drugs.

Methods: SQ tumors from three different HER2 positive PDX breast cancer models designated ST340, ST1339 and ST1616B were enzymatically digested and used for intracranial stereotactic injection in nude mice. Contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) were used to determine tumor take. Intracranial tumor growth was monitored using MRI and positron emission tomography (PET) in conjunction with the amino acid radio tracer 18F-FET.

Results: MRI confirmed tumor take in one model as early as 2 weeks after intracranial implantation. Increased 18F-FET uptake was detected in all models. MRI could be effectively used to monitor tumor growth and the corresponding 18F-FET PET images demonstrated increased 18F-FET uptake over time.

Conclusion: Three different HER2 positive intracranial PDX breast metastases models were established from low passage SQ PDX models. We suggest, that using these intracranial PDX models of brain metastases, new drugs for advanced breast cancer can be evaluated in preclinical models that more closely mimic the microenvironment and the BBB in patients. In addition, translational imaging techniques can be evaluated during preclinical testing and the potential of tracers like 18F-FET as imaging biomarkers of therapeutic response can be assessed. Together, the established SQ and orthotopic PDX models of breast cancer and brain metastases can be used as a relevant translational platform for testing of new drugs.

Citation Format: Nielsen CH, Nedergaard MK, Wick MJ, Papadopoulos K, Tolcher AW, Kjaer A. Intracranial PDX models of breast cancer metastasis. [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 P3-03-01.
Abstract P3-07-21: Non-alcoholic fatty liver disease induced by selective estrogen receptor modulators is a protective factor for breast cancer survival
Authors: Wang S , Zheng Q , Nie M , Xu F , Xia W , Yuan Z , Peng R , An X , Qin T , Qin G
Published: May 2016

Purpose: Non-alcoholic fatty liver disease (NAFLD) induced by selective estrogen receptor modulators (SERMs) treatment may be related to treatment efficacy for the antagonism of circulating estrogens. We conducted a retrospective study to investigate the relationship between survival outcomes and NAFLD in breast cancer patients treated with tamoxifen or toremifene.

Patients and methods: 785 eligible patients received tamoxifen or toremifene in Sun Yat-sen university cancer center from January 2005 to December 2009 were included in our study. All patients have at less one abdominal ultrasonography measurement at baseline and every year's follow-up. Patients who diagnosed NAFLD by ultrasonography during three-year's follow-up were classified into NAFLD cohort, others were classified into no-NAFLD cohort. Univariate and multivariate Cox regression was utilized to analyse the relationship between NAFLD and disease-free survival (DFS) and overall survival (OS).

Results:158 patients had reported NAFLD in the first 3 years' follow-up. Patients who developed NAFLD had better DFS and OS than those not developing NAFLD. The 5-years DFS was 91.56% and 85.01% at NAFLD and no-NAFLD cohort (univariate hazard ratio [HR]: 0.59 [95%CI 0.37-0.96], P=0.034), respectively. The 5-years OS was 96.64% and 93.31% at NAFLD and no-NAFLD cohort (univariate HR: 0.39 [95%CI 0.16-0.99], P=0.047), respectively. Multivariate analysis revealed that NAFLD is an independent prognostic factor on DFS in breast cancer patients with SERMs treated. Women treated with SERMs experienced NAFLD in the first three-year's follow-up had a reduced risk of DFS of 42% (multivariate HR: 0.58; [95%CI 0.36-0.95], P=0.032) compared with patients without NAFLD.

Conclusion: NAFLD induced by SERMs seems to be associated with better survival outcomes and may therefore be helpful in predicting treatment responses in breast cancer patients treated with SERMs.

Citation Format: Wang S, Zheng Q, Nie M, Xu F, Xia W, Yuan Z, Peng R, An X, Qin T, Qin G. Non-alcoholic fatty liver disease induced by selective estrogen receptor modulators is a protective factor for breast cancer survival. [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 P3-07-21.