bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-07-24: The role of glucocorticoid receptor (GR) expression in predicting pathological complete response (pCR) to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC)
Authors: Saha P , Turk A , Lurain K , Baker G , Conzen S , Nanda R
Published: May 2016

Background

Up to 40% of breast cancers have moderate to strong expression of GR, and activation of GR is associated with poor prognosis in ER-negative breast cancer. GR activation in breast cancer cells initiates anti-apoptotic signaling, contributing to chemotherapy resistance. We hypothesize that GR highly expressing TNBCs will have a suboptimal response to neoadjuvant chemotherapy.

Methods

We identified patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy at the University of Chicago between 2002 and 2014 under IRB approved protocols. Those patients for whom pre-treatment and post-treatment tissue was available were included in this study. Unstained sections of formalin-fixed paraffin-embedded primary tumor were obtained. Percentage tumor cell GR expression was determined via immunohistochemical (IHC) examination using two different antibodies: the anti-GR rabbit monoclonal XP antibody (Cell Signaling, D8H2, 1:500 dilution) and the polyclonal rabbit anti-GR antibody (1:80). Staining was performed according to methods previously published by Belova et al. TNBCs were considered GR positive if greater than 10% of cancer cells stained moderately to strongly positive for GR.

Results

Fifty paired tissue samples were identified and pre- and post-treatment tissue was stained for GR using two anti-GR antibodies as above. Of these 50 cases, 80% had moderate to strong expression of GR using the XP antibody; results with the polyclonal ab will be compared. Percentage GR expression did not change in the setting of treatment. Work to correlate GR expression using the monoclonal versus the polyclonal antibody and clinicopathological features is ongoing.

Conclusions

To our knowledge, this is the first study attempting to evaluate percentage GR expression as a biomarker of response to neoadjuvant chemotherapy in TNBC. If higher GR expression correlates with a lower pCR rate in TNBC as hypothesized, then GR blockade in conjunction with chemotherapy may overcome chemotherapy resistance and lead to improved response to treatment in patients with GR expressing TNBCs.

Citation Format: Saha P, Turk A, Lurain K, Baker G, Conzen S, Nanda R. The role of glucocorticoid receptor (GR) expression in predicting pathological complete response (pCR) to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). [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 P3-07-24.
Abstract P3-07-59: Stem cell markers are overexpressed in tumorspheres cultured from circulating epithelial tumor cells (CETCs) in patients with breast cancer
Authors: Zimon D , Pizon M , Mayer V , Pachmann K
Published: May 2016

Background:

Breast malignancies continuously shed tumor cells which may enter the circulation, spread to other tissue and initiate metastases, but only a small subpopulation among CETCs is capable of metastasis formation. The subpopulation of CETC capable of forming tumorspheres in vitro and carrying stem cells properties is assumed to have metastatic potential. The aim of this study was to characterize the pattern of expression of the tumorspheres as compared to CETCs.

Methods:

Blood samples were obtained from patients diagnosed with breast tumors. CETCs were enumerated with maintrac method and subsequently cultivated in stem cell-selective medium. The expression of stem cell marker genes EpCAM, Nanog, Okt4 Sox2, ALDH and CD133 were detected by RT-PCR in single CETCs and tumorspheres.

Results:

0.1- 10% of CETCs could form non-adherent tumorspheres under stem cell- selective conditions after a period of 14 days. Array qRT-PCR analysis revealed that putative stem cell markers, such as Oct4, Sox2, Nanog, EpCAM, ALDH1 and CD133 are overexpressed in relation to house-keeping genes RPL13a and GAPDH in tumor spheres in contrast to the significantly lower expression level of these stem cell markers in individually isolated CETCs. High expression level of pluripotency genes in tumorspheres was associated with aggressive tumor behaviour in terms of tumor progression and type of cancer.

Conclusion:

Thus, differential expression of stem cell markers in CETCs and tumorspheres substantiates the hypothesis that only a small population of circulating tumor cells possess the stem cell properties and are responsible for metastasis formation.

Citation Format: Zimon D, Pizon M, Mayer V, Pachmann K. Stem cell markers are overexpressed in tumorspheres cultured from circulating epithelial tumor cells (CETCs) in patients 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 P3-07-59.
Abstract P3-07-60: Impact of high SPARC expression of a primary tumor as a strong risk factor for disease recurrence and overall survival in patients with triple-negative breast cancer
Authors: Zhu A , Yuan P , Du F , Ding X , Xu B
Published: May 2016

Background: SPARC (secreted protein acidic and rich in cystein) is a secreted glycoprotein that interacts with extracellular matrix protein and acts as a regulator of critical cellular functions such as proliferation and cell migration. An increasing number of studies have shown altered expression of SPARC in several malignancies. However, the role of this potential biomarker in breast cancer development and progression is controversial. Triple-negative breast cancer (TNBC) is known for its poor prognosis and high recurrence probability. There is a need for prognostic biomarkers to guide treatment decisions for this subtype.

Objective: To explore the association between SPARC and the prognosis of triple-negative breast cancer.

Methods: In this study, a total of 211 samples of triple-negative breast lesions from 2004 to 2008 were collected in Cancer Hospital, Chinese Academy of Medical Sciences. SPARC expression was evaluated by immunohistochemistry using an immunoreactive score (IRS) from patients with up to 10 years clinical follow-up data. The current study set out to examine both the expression of SPARC in primary tumor tissue and to demonstrate if a link existed between the levels of SPARC and the clinical outcome. Cox proportional hazards model was used to estimate HRs and 95%CI, stratified on tumor grade, TNM stage, lymph node status and vascular invasion.

Results: High SPARC expression (IRS≥3) was observed in 52.1% of all primary tumors. Patients expressing low levels of SPARC had better disease-free survival (DFS) (HR=0.632, 95%CI:0.405-0.987, P = 0.044) as well as overall survival(OS)(HR=0.576, 95%CI:0.351-0.946, P = 0.029) compared to those with high SPARC expression levels.Furthermore, the presence of high SPARC expression was an independent prognostic factor for both DFS (HR=1.67, 95%CI:1.04-2.69, P=0.034) and OS(HR=1.77, 95%CI:1.04-3.01, P=0.037) of triple-negative breast cancer patients, stratified on tumor grade, TNM stage, lymph node metastasis and vascular invasion, with adjustment for age, hormonal status, tumor size, adjuvant radiotherapy and adjuvant chemotherapy.

Conclusion: Our results suggest that the presence of higher SPARC expression could be an indicator of high aggressiveness and may be a strong prognostic factor for triple-negative breast cancer.

Citation Format: Zhu A, Yuan P, Du F, Ding X, Xu B. Impact of high SPARC expression of a primary tumor as a strong risk factor for disease recurrence and overall survival in patients with 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 P3-07-60.
Abstract P3-09-02: Early life residence, fish consumption and risk of breast cancer
Authors: Haraldsdottir A , Torfadottir JE , Valdimarsdottir UA , Aspelund T , Tryggvadottir L , Launer LJ , Harris TB , Gudnason V , Steingrimsdottir L
Published: May 2016

Introduction: Few studies exist on the effect of diet during different periods of life, on breast cancer risk later in life. Great differences existed in food consumption between the capital and rural areas in Iceland in the middle of the 20th century, with very high fish consumption in coastal areas.

Objectives: Our aim was to explore the effect of diet and residence during early life and midlife on breast cancer risk later in life.

Methods and data: We used data from the Reykjavik Study, a population-based Icelandic cohort of 10049 women born between 1907 and 1935, and examined the association of residence in early life, used as a proxy for dietary habits, and risk of breast cancer. To further explore this association, we also used food frequency data at different periods of life, including adolescence, from the AGES-Reykjavik cohort, a subgroup of the Reykjavik Study, established in 2002. Participants provided information on residence in early life. By linkage with the Icelandic Cancer Registry, information on breast cancer diagnoses was available throughout 2013. Adjustments were made for a series of potential confounders, including residence for dietary analysis.

Results: During a mean follow-up of 27.3 years, 744 women were diagnosed with breast cancer. We found a significant inverse association for breast cancer diagnosis among women who lived though the puberty period (20 years or more) in coastal villages compared with women residing in the capital area (HR = 0.74, 95% CI: 0.58, 0.94). In the subgroup analysis, we found that women with high fish consumption in midlife had lower risk of breast cancer in older age, compared with women with lower consumption, (OR = 0.60, 95% CI 0.38, 0,94). However, we did not observe a statistically significant association between high fish intake in adolescence and breast cancer (OR = 0.84, 95% CI 0.62 - 1.13).

Conclusions: Our results suggest that high fish consumption in early- to midlife may be associated with reduced risk of breast cancer.

Citation Format: Haraldsdottir A, Torfadottir JE, Valdimarsdottir UA, Aspelund T, Tryggvadottir L, Launer LJ, Harris TB, Gudnason V, Steingrimsdottir L. Early life residence, fish consumption and risk 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 P3-09-02.
Abstract P3-12-03: Utilizing the genomically adjusted dose (GAD) to personalize radiotherapy in adjuvant breast cancer management
Authors: Ahmed KA , Venkat PS , Scott JG , Diaz RJ , Fulp WJ , Torres-Roca JF
Published: May 2016

Background: We have previously validated a multi-gene model of tumor radiosensitivity (RSI) with validation in multiple independent cohorts including breast, rectal, esophageal, head and neck, glioblastoma, and prostate malignancies. Utilizing the linear quadratic model and RSI, we derived an expression for the genomically adjusted dose (GAD) to model radiation dose effect for individual patients.

Methods: As RSI models the surviving fraction of cells at 2 Gy (SF2), we are able to derive a patient specific alpha. These terms were used in the linear quadratic model to calculate a GAD to model radiation effect and its association with local control. A higher GAD implies a higher predicted radiation therapy effect. Clinical and array-based gene expression were obtained from 75 ER negative patients from the Netherlands Cancer Institute (NKI) and the Institut Curie treated with breast conservation therapy.

Results: Median follow-up for all patients was 10 years with a median age of 42 years (range: 23-50 years). Adjuvant radiation dose to the whole breast was 50 Gy (range: 45-55 Gy). When assessing local recurrence on multivariate analysis, we found GAD to be a significant predictor of local recurrence when dichotomized at the median (GAD-low vs GAD-high Hazard Ratio (HR) 4.5; 95% CI 1.7-13.5; p=0.0031). GAD was also significant per unit change (HR 0.91; 95% CI 0.83-0.99; p=0.021). We then modeled GAD for an escalated dose up to 60 Gy and found an additional 48% of GAD-low patients could achieve a GAD-high with dose escalation.

Conclusions: We found GAD to be significantly correlated with local control following breast conservation therapy. Modeling dose escalation with GAD, we identified a select population of patients whom we hypothesize may benefit from genomically guided increased dose in the adjuvant setting. This population may represent a cohort for future clinical trial enrollment.

Citation Format: Ahmed KA, Venkat PS, Scott JG, Diaz RJ, Fulp WJ, Torres-Roca JF. Utilizing the genomically adjusted dose (GAD) to personalize radiotherapy in adjuvant breast cancer 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 P3-12-03.
Abstract P3-14-04: Effects of the dual selective CYP17 lyase inhibitor and androgen receptor (AR) antagonist, VT-464, on AR+ and ER+ tumor models in vitro and in vivo
Authors: Ellison SJ , Norris JD , Wardell S , Eisner JR , Hoekstra WJ , Stagg DB , Alley HM , Moore WR , McDonnell DP
Published: May 2016

VT-464 is a lyase-selective inhibitor of the dual-activity CYP17A1 enzyme that is required for the synthesis of androgens and estrogens in the gonads, adrenals, and tumors. In addition to its role as a CYP17A1 lyase inhibitor, we previously showed that VT-464 also functions as a direct and effective AR antagonist in prostate cancer models. In our current study, we evaluated the therapeutic potential of VT-464 in breast cancer by analyzing its effectiveness in several AR-positive breast cancer cell lines, including those that are ER-positive and ER-negative. Through in vitro assays and xenograft analysis, we compared the activity of VT-464 to enzalutamide, a second generation AR antagonist that is approved for the treatment of castration resistant prostate cancer and is in multiple Phase 2 breast cancer studies. Our results showed that VT-464 was highly effective in preventing proliferation of both ER-positive and ER-negative breast cancer cell lines in vitro. Importantly, significant inhibition was also observed in soft agar assays that assesses anchorage-independent growth. In mechanistic studies, VT-464 and enzalutamide both inhibited induction of AR target genes and recruitment of AR to target promoters, verifying direct AR antagonistic activity observed previously in prostate cancer cells. Furthermore, we evaluated the ability of VT-464 and enzalutamide to inhibit tumor formation in a tamoxifen-resistant model of breast cancer. Oral administration of either enzalutamide or VT-464 significantly decreased tumor growth in mice, with VT-464 achieving greater growth inhibition than enzalutamide. Together, these data provide further rationale for the future study of the AR as a viable therapeutic target in breast cancer, and importantly, suggest that AR inhibition can impact tamoxifen-resistant tumor growth. The dual effects of CYP17A1 lyase inhibition and AR antagonism that are achieved with VT-464 further supports its development as an effective oral therapy option for AR-positive breast cancer. A phase 1 / 2 clinical study of oral VT-464 in women with AR+ triple-negative breast cancer or ER+ cancer resistant to aromatase inhibitors will commence in 2015.

Citation Format: Ellison SJ, Norris JD, Wardell S, Eisner JR, Hoekstra WJ, Stagg DB, Alley HM, Moore WR, McDonnell DP. Effects of the dual selective CYP17 lyase inhibitor and androgen receptor (AR) antagonist, VT-464, on AR+ and ER+ tumor models in vitro and in vivo. [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 P3-14-04.
Abstract P4-02-09: Can MRI be used to determine pathological complete response following neo-adjuvant chemotherapy for breast cancer?
Authors: Sharma N , Dave R , Millican-slater R , Dodwell D , Horgan K
Published: May 2016

Intro

Neo-adjuvant chemotherapy (NACT) is increasingly offered to patients with breast cancer, and it understood that patients with pathological complete response (PCR) have improved survival. It has been suggested that patients with radiological complete response may be spared surgery. We aimed to determine whether MRI findings can predict PCR following NACT.

Methods

This was a retrospective analysis of a prospectively maintained database. Most patients had NACT with 6 cycles of EC/DC+/-Traztuzumab and response was monitored using MRI. For univariate analysis χ2 and Fisher's exact test was used for categorical data. Log rank test by Kaplan Meier method was used for survival analysis.

Results

310 patients had NACT from December 2007 to December 2014. Baseline MRI prior to embarking on NACT was achieved in 251 patients. MRI concorded with size on mammography/USS in the majority of cases (83%) and upgraded the overall size of the lesion in 16% (50% of unifocal lesions on USS upgraded to multifocal).

In the 247 patients who had baseline MRI, a radiological response seen on the 2nd MRI (early responders, n=138), was predictive of eventual PCR (p=0.000, sensitivity = 77%). Patients with Her2+ve non-luminal (65%), triple negative (TNBC) (64%) and Luminal B Her2-ve (65%) tumours were more likely to be early responders on MRI. The non-early responders with Her2+ve tumours all had late radiological response, however, the TNBC tumours had low rates of late radiological response. Complete radiological response on the final MRI correlated strongly with PCR; p=0.000, specificity=98%. Tumour vascularity correlated positively and significantly with PCR. There was no difference in survival between those with early and late radiological response (median survival 66.2 months and 66.9 months), but those with no radiological response had significantly poorer survival 53.2 months, p=0.012).

Conclusion

Response on MRI is predictive of PCR, particularly within the non-luminal Her2+ve and TNBC molecular subtypes. Early response has high sensitivity, and complete response on final MRI has high specificity. Further work on larger data-sets is required before we confidently spare patient from surgery in the event of complete response on MRI.

Citation Format: Sharma N, Dave R, Millican-slater R, Dodwell D, Horgan K. Can MRI be used to determine pathological complete response following neo-adjuvant chemotherapy 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 P4-02-09.
Abstract P4-02-11: Value of magnetic resonance imaging in preoperative predicting tumor extent in each subtypes of breast cancer
Authors: Yang BS , Lee HW , Park JT , Lee HM , Ahn SG , Jeong J
Published: May 2016

Background: It is well known that patients with triple-negative breast cancer (TNBC) have a high risk of local tumor recurrence in ipsilateral breast. To know the additional value of breast magnetic resonance imaging (MRI) in preoperative prediction of tumor extent for TNBC, we tested the accuracy of MRI in correlation with pathologic tumor size according to subtypes. In addition, we investigated the margin-positive rates by subtypes among the patients receiving breast-conservative surgery (BCS).

Methods: We retrospectively identified patients with invasive breast cancer who had preoperative breast MRI and ultrasound between 2011 and 2014. We excluded patients having large tumor more than 5cm or multiple tumors. Patients were classified into 4 subtypes (luminal A, luminal B/HER2, HER2, triple-negative breast cancer (TNBC)) based on the immunohistochemistry. Lin's concordance correlation coefficient was used to measure the agreement between the MRI or ultrasound and tumor extent. Also, patients were classified into three groups according to the accuracy of MRI in correlation with tumor extent (concordance, underestimation, and overestimation). Tumor extent was defined as pathologic tumor size including in situ carcinoma.

Results: In a total of 589 patients, 397(67.4%) women received BCS. Means of tumor size were 1.99 ± 0.91 cm by pathologic review, 1.91 ± 1.01 cm by MRI, and 1.76 ± 0.92 cm by ultrasonography, respectively. Correlation analysis revealed a similar concordance rate between MRI and ultrasound to pathologic tumor size (r= 0.622 and 0.573). Lin's concordance analysis showed that MRI showed more significant correlation with pathologic tumor size than ultrasound in patients with TNBC (r= 0.735 VS 0.593, p=0.0052). However, the proportion of concordant group did not differ significantly according to subtypes (p=0.279).

Conclusions: Our findings suggest that preoperative MRI does not increase the accuracy in predicting tumor extent or reduce the margin-positive rates in breast cancer.

Citation Format: Yang BS, Lee HW, Park JT, Lee HM, Ahn SG, Jeong J. Value of magnetic resonance imaging in preoperative predicting tumor extent in each 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 P4-02-11.
Abstract P4-07-04: PARP1/2 inhibition in a subset of triple negative breast cancer (TNBC) patient-derived tumor xenografts (PDX) identifies predictive biomarkers of response
Authors: Serra V , Cruz C , Bruna A , Ibrahim YH , Vivancos A , Vivancos A , Nuciforo P , Bellet M , Gómez P , Pérez JM , Saura C , Vidal M , Serres X , Rueda OM , Peg V , Caldas C , O'Connor MJ , Baselga J , Cortés J
Published: May 2016

Background: BRCA1/2 mutation carriers (gBRCA) have a higher risk of breast or ovarian cancer, since BRCA1/2 mutation results in impaired high-fidelity DNA repair by homologous recombination (HR) and subsequently genetic instability. In non-gBRCA TNBC, HR deficiency occurs at the somatic level, by means of BRCA1 mutation, BRCA1 epigenetic loss or mutation in other HR-associated genes. Because PARP1/2 inhibitors (PARPi) are well-tolerated and active anti-cancer agents in the advanced setting of gBRCA tumors, we sought to expand their applicability by identifying response biomarkers in TNBC.

Methods: We have assessed the antitumor response of the PARP1/2 inhibitor olaparib as single agent in a panel of 12 primary and advanced TNBC PDX models. On PDXs exhibiting primary sensitivity to olaparib, we have developed models of acquired resistance by continuous exposure to the drug and identifying progression on treatment. We have characterized the models through targeted sequencing and the analysis of the hypermethylation and expression levels of BRCA1 transcript to find potential correlates of drug-sensitivity.

Results: Three out of 12 PDXs (25%) treated with single agent olaparib, exhibit tumor regression or disease stabilization. BRCA1 is hypermethylated in two of these PARPi-sensitive TNBC PDX models and is associated with loss of BRCA1 mRNA expression. The third PARPi-sensitive TNBC PDX harbors a frameshift, heterozygous PALB2 mutation, which is no longer detected in the acquired resistance PDX model. Acquired resistance in the hypermethylated PDXs is under study as well as the duration of response compared to gBRCA PDX models.

Conclusions: Our study highlights that somatic HR-deficiency is frequent in TNBC and provides the basis of sensitivity to PARPi.

Citation Format: Serra V, Cruz C, Bruna A, Ibrahim YH, Vivancos A, Vivancos A, Nuciforo P, Bellet M, Gómez P, Pérez JM, Saura C, Vidal M, Serres X, Rueda OM, Peg V, Caldas C, O'Connor MJ, Baselga J, Cortés J. PARP1/2 inhibition in a subset of triple negative breast cancer (TNBC) patient-derived tumor xenografts (PDX) identifies predictive biomarkers of response. [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 P4-07-04.
Abstract P4-09-21: Dual expression of aquaporin 3 and 5 in patients with early breast cancer
Authors: Lee SJ , Chae YS , Kwon TJ , Chung JH , Lee J , Jung JH , Kim WW , Park HY , Jeong JY , Park S-H , Park S
Published: May 2016

Background: We reported separately that AQP5 or AQP3 expression in tumor tissue may predict survival after surgery for the specific types of early breast cancer (EBC). However, there is no definitive evidence for the role of dual expression of the two AQPs. Therefore, the current study focused the association and its prognostic impact of their tumoral expressions in the same patients.

Patients and Methods: AQP3 and AQP5 expressions were investigated on the basis of the immunohistochemistry of tissue microarray specimens from 447 EBC patients who underwent surgery between 2003 and 2008 as described in previous studies. Patients were divided into 4 subgroups based on AQP3 and AQP5 expressions: group1 for (-/-), group2 for (-/+), group 3 for (+/-), and group 4 for (+/+), respectively.

Results: Among 477 patients, the number of patients for each group was as follows: group 1 (n=193, 43.2%), group 2 (n=74, 16.6%), group3 (n=110, 24.6%) and group 4 (n=70, 15.7%), respectively. In the current study a positive correlation was identified between AQP3 and 5 expressions (P=0.017 by a χ2- test) in particular for HER2- overexpressing and ER-positive tumors (P=0.009 and 0.044, respectively). Multivariate survival analysis showed that dual expression of AQP3 and AQP5 was a negative prognostic factor for relapse-free or distant disease-free survival for patients with HER2-overexpressing EBC (HR=3.107 and 3.683; P=0.043 and 0.027, respectively), statistically more prominent compared in case with AQP3 expression alone (HR=3.137 and 2.784; P=0.036 and 0.070, respectively).

Conclusion: Dual expression of AQP3 and AQP5 in tumor tissue may be considered as a potential prognostic marker in patients with HER2-overexpressing EBC after curative surgery.

Citation Format: Lee SJ, Chae YS, Kwon TJ, Chung JH, Lee J, Jung JH, Kim WW, Park HY, Jeong JY, Park S-H, Park S. Dual expression of aquaporin 3 and 5 in patients with early 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 P4-09-21.
Abstract P5-01-06: 18F-radiolabeled PARP-1 inhibitor uptake as a marker of PARP-1 activity in breast cancer
Authors: Edmonds CE , Lieberman BP , Xu K , Zeng C , Makvandi M , Li S , Hou C , Lee H , Greenberg RA , Mankoff DA , Mach RH
Published: May 2016

Objectives: The nuclear enzyme PARP-1 plays a central role in sensing DNA damage and facilitating repair. Tumors with BRCA1/2 mutations are highly dependent on PARP-1 as an alternative mechanism for DNA repair, and PARP inhibitors generate synthetic lethality in tumors with BRCA mutations, resulting in cell cycle arrest and apoptosis. Zhou et al. recently synthesized an 18F-labeled PARP-1 inhibitor (18F-FluorThanatrace) for PET, and demonstrated high specific tracer uptake in a xenograft model of breast cancer (Zhou, Bioorg Med Chem, 22:1700, 2014). The current study seeks to quantify the relationship between 18F-FluorThanatrace binding (both in vitro and on PET imaging of human tumor xenografts) and the level of constitutively active PARP-1, using multiple human breast cancer cell lines, including a BRCA1 defective line.

Methods: BRCA1 defective HCC1937, triple negative MDA-MB-231, and luminal A MCF-7 human breast cancer lines were assessed for constitutive PARP-1 activity via a chemiluminescent ELISA assay for PAR and by Western blot. The same cell lines were incubated with 18F-FluorThanatrace over various time increments, and tracer uptake was assayed via a gamma counter. Specificity of tracer binding was verified via co-incubation with competitive inhibitor Olaparib, and specific tracer uptake was calculated as the difference between uptake with and without Olaparib. Specific tracer uptake was compared to levels of constitutive PARP-1 activity in all cell lines. In addition, HCC1937 and MDA-MB-231 xenograft tumor models were imaged via 18F-FluorThanatrace-PET/CT, and PET uptake was correlated with PARP-1 activity.

Results: BRCA1-defective HCC1937 had higher constitutive PARP-1 activity than cell lines with intact BRCA1. In vitro levels of 18F-FluorThanatrace uptake correlated with constitutive PARP-1 activity across cell lines. In addition, 18F-FluorThanatrace measured by PET in xenograft breast cancer tumor models correlated with constitutive PARP-1 activity.

Conclusions: Tumor uptake of 18F-FluorThanatrace, both in vitro and on PET imaging of xenograft tumor models, quantitatively reflects differences in PARP-1 activity across different breast cancer cell lines, including BRCA1 defective. This motivates further studies of 18F-FluorThanatrace as an in vivo measure of PARP-1 activity and possibly as a predictive marker for PARP-1 therapy in patients, including those with BRCA1/2 mutations.

Citation Format: Edmonds CE, Lieberman BP, Xu K, Zeng C, Makvandi M, Li S, Hou C, Lee H, Greenberg RA, Mankoff DA, Mach RH. 18F-radiolabeled PARP-1 inhibitor uptake as a marker of PARP-1 activity 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 P5-01-06.
Abstract P5-02-01: Diagnosis of pathological complete response by vacuum-assisted minimal invasive biopsy after neoadjuvant chemotherapy in breast cancer - Results from a prospective pilot study
Authors: Hennigs A , Heil J
Published: May 2016

Purpose:

To explore the ability of vacuum-assisted-biopsy (VAB) to diagnose pathological complete response (pCR) or residual tumor in breast cancer patients after neoadjuvant chemotherapy (NACT).

Patients and methods: 50 patients (22 with clinical / imaging complete response 28 with clinical / imaging residual tumor) were included in this review-board approved prospective pilot study between 08/14 and 02/15. Vacuum-assisted-biopsy (VAB) was performed after NACT and before surgery. Negative predictive values (NPV) and false-negative-rates (FNR) to predict a pCR in surgical specimen (=diagnose pCR through VAB) were the main outcome measures.

Results:

The cohort (n=50) consisted of 15 (30%) triple negative (TNBC), 13 (26%) HER2 positive (HER2+) and 22 (44%) hormone receptor positive / HER2 negative (HR+/HER2-) cancers. pCR in surgical specimen was diagnosed in 23 (46%) cases of the whole cohort. The NPV of the VAB diagnosis of pCR was 94.4% (95% CI: [0.84; 1.00]). The FNR was 3.7% (95% CI: [0; 0.12]) and specificity 73.9% (95% CI: [0.54; 0.94]). Taking only those biopsies into account that pathology confirmed to be representative of the (former) tumor region, improved the outcome of VAB to a specificity of 100% while the NPV (94.4% (95% CI: [0.84; 1.00]) and the FNR (4.8% (95% CI: [0.00; 0.15]) stayed the same.

Conclusion:

Overall accuracy of VAB diagnosis of pCR questions the necessity of surgical intervention to diagnose a pCR. A confirmative, multi-center, intra-individually-controlled clinical trial including patients with clinical complete, near complete or partial response to NACT to validate the above mentioned results is warranted.

Citation Format: Hennigs A, Heil J. Diagnosis of pathological complete response by vacuum-assisted minimal invasive biopsy after neoadjuvant chemotherapy in breast cancer - Results from a prospective pilot 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 P5-02-01.
Abstract P5-03-03: Designing a novel platinum chemotherapeutic (IO-125) for treatment of breast cancer
Authors: Sengupta A , Roy M , Sarkar A , Mylavarapu S , Modi S , Gupta N , B H , Hossain S , Ansari A , Pandey M , Yadav Y , Sengupta S
Published: May 2016

Triple-negative breast cancer (TNBC) is an aggressive form of cancer occurring in 15-20% of breast cancer patients, with most patients relapsing on currently approved therapy. Recent studies have shown activity of platinum chemotherapy in this class of patients. IO-125 is a novel platinum (II) chemotherapeutic agent with an unique coordination environment. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC.

The coordination environment in IO-125 facilitates supramolecular assembly and releases diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. In vitro cell viability studies using an array of breast cancer cell lines shows IO-125 exerts increased potency compared to carboplatin or oxaliplatin. The maximum tolerated (platinum-equivalent) dose (MTD) of IO-125 in mice was 8-fold higher than the MTD (platinum-equivalent) dose of oxaliplatin. The biodistribution and pharmacokinetic profile of IO-125 in plasma and tumor revealed preferential tumor accumulation, significantly increased area-under-the-curve (AUC), a reduction in clearance (CL) and a longer terminal half-life (42 hours) in comparison to oxaliplatin (18 hours). In addition, DNA-Pt adduct formation in tumors was significantly higher for IO-125. When administered at their respective MTDs, IO-125 led to sustained regression of the tumor in a 4T1 syngeneic breast cancer model. Based on these observations, we conclude that IO-125 may emerge as a novel therapeutic against triple negative breast cancer.

Citation Format: Sengupta A, Roy M, Sarkar A, Mylavarapu S, Modi S, Gupta N, B H, Hossain S, Ansari A, Pandey M, Yadav Y, Sengupta S. Designing a novel platinum chemotherapeutic (IO-125) for treatment 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 P5-03-03.
Abstract P5-05-02: Regulation of glucose metabolism by the RUNX2 transcription factor has a negative impact on mitochondrial function in breast cancer cells
Authors: Kim MS , Choe M , Cho H , Polster BM , Girnun GD , Passaniti A
Published: May 2016

The RUNX2 transcription factor regulates breast cancer (BC) metastasis to bone and is itself a target of IGF-1 signaling pathways. We have shown that glucose can activate RUNX2 phopshorylation through IGF-1 receptor signaling and that RUNX2 was associated with inhibition of pyruvate dehydrogenase (PDHA1) activity and repression of mitochondrial respiration in BC cells. However, the mechanisms by which RUNX2 alters mitochondrial function and supports an oncogenic phenotype are not completely known. RUNX2 expression in a luminal BC cell line increased expression of glycolytic genes, and sensitivity to glucose starvation. However, RUNX2 knockdown in a triple-negative BC cell line inhibited expression of glycolytic genes. RUNX2 also repressed mitochondrial oxygen consumption rates (OCR), a measure of oxidative phosphorylation while overexpression of SIRT6, a NAD-dependent histone deacetylase, increased respiration in RUNX2-positive cells. RUNX2 repressed SIRT6 expression directly at the transcriptional and post-translational levels. High SIRT6 expression was observed in normal mammary tissue and cells that did not express RUNX2 but endogenous SIRT6 expression was low in malignant BC tissues or cell lines, which expressed high levels of RUNX2. These results suggest that SIRT6, a known tumor suppressor, was a critical mediator of these RUNX2-regulated metabolic changes. These results support a hypothesis whereby RUNX2 upregulation during BC progression leads to inactivation of the SIRT6 tumor suppressor to promote tumorigenesis. It will be important to investigate further changes in mitochondrial function to understand the precise mechanisms by which RUNX2 regulates BC metabolism.

Citation Format: Kim MS, Choe M, Cho H, Polster BM, Girnun GD, Passaniti A. Regulation of glucose metabolism by the RUNX2 transcription factor has a negative impact on mitochondrial function in breast cancer cells. [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 P5-05-02.
Abstract P5-06-03: Effect of obesity on molecular characteristics of invasive breast tumors: Gene expression analysis of 405 tumors by BMI
Authors: Ellsworth RE , Toro AL , Costantino NS , Shriver CD , Ellsworth DL
Published: May 2016

Background: Obesity is a risk factor for breast cancer in postmenopausal women and weight gain after diagnosis is associated with decreased survival and less favorable clinical characteristics such as greater tumor burden, higher grade, and poor prognosis, regardless of menopausal status. Despite the negative impact of obesity on clinical outcome, the molecular mechanisms by which excess adiposity influences breast cancer are not well-understood.

Methods: Affymetrix U133 2.0 gene expression data was available for 405 primary breast tumors and 20 tumor-adjacent adipose tissues; RNA was isolated from tumor epithelia or adipose using laser microdissection. Patients were classified as lean (BMI<25), overweight (BMI 25-29.9) or obese (BMI>30). Statistical analysis was performed by ANOVA using Partek Genomics Suite version 6.6.

Results: Obese patients were significantly more likely to be diagnosed >50 years and to be of African American ancestry compared to lean or overweight women, while pathological characteristics including tumor stage, size or grade, lymph node status and intrinsic subtype did not differ significantly between groups. Principal component analysis could not effectively cluster the tumors by weight and no genes were differentially expressed using a false discovery rate <0.05. Using a less stringent unadjusted P-value of <0.01, 329 genes were differentially expressed, however, this gene expression profile could not discriminate patient tumors by BMI. In contrast, BMI was effective in clustering tumor-adjacent adipose samples by BMI based on differential expression of 156 genes.

Conclusions: Although tumor epithelial cells from obese women do not differ significantly from those of lean and/or overweight women at the gene expression level, tumor-adjacent adipose did differ by weight. These data demonstrate that less favorable outcomes in obese patients are not be attributable to the tumor itself but to influences from the microenvironment and suggest that decreasing breast adiposity may be an effective strategy to reducing risk and improving outcomes in obese women.

Citation Format: Ellsworth RE, Toro AL, Costantino NS, Shriver CD, Ellsworth DL. Effect of obesity on molecular characteristics of invasive breast tumors: Gene expression analysis of 405 tumors by BMI. [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 P5-06-03.
Abstract P5-08-19: A single-nucleotide polymorphism in the 3'-UTR region of the adipocyte fatty acid binding protein 4 gene is associated with prognosis of triple negative breast cancer
Authors: Yuan P , Wang W , Wu C , Lin D , Xu B
Published: May 2016

Objective Triple negative breast cancer (TNBC) is a subtype with poor prognosis and high heterogeneity. The aim of this study was to screen single nucleotide polymorphisms (SNPs) associated with the prognosis of TNBC patients and to explore the potential mechanism.

Methods We selected SNPs(MAF≥1%) located on the 3' untranslated region (3'UTR) of differentially expressed genes in breast cancer through databases (Nextbio,ensemble,NCBI,MirSNP). We investigated the possible associations between 111 SNPs and progression risk among 323 TNBC patients using two-step case-control study with discovery cohort (n=162) and validation cohort (n=161). The Benjamini Hochberg false discovery rate (FDR) method was used to assess the statistical significance after correction for multiple comparisons. Kaplan-Meier analysis was applied in order to assess the association between disease free survival (DFS) and positive SNPs, as well as Body Mass Index(BMI). We also investigated the expression of FABP4 in adipocytes adjacent to TNBC tissues (n=35) using immunohistochemistry. The integrated optical density (IOD) was measured as an approximation of FABP4 expression. Mann-Whitney U test was used in an attempt to assess the correlations among SNPs in FABP4, FABP4 expression and TNBC prognosis.

Results SNPs in FABP4, KRAS and NTRK2 genes associated with the recurrence risk of TNBC throughout the discovery cohort and validation cohort, while the statistical significance was retained after multiple comparisons only for FABP4 rs1054135. The G allele of rs1057035 was associated with decreased risk of disease progression (aHR 0.14, 95%CI0.03-0.66), as well as an increased DFS (P<0.05). Furthermore, the expression of FABP4 was statistically significant lower in patients with rs1054135-GG genotype and those in disease-free group(P=0.0464,P=0.0061 respectively).

Conclusions Our study found a lipid metabolism related gene and an important SNP in the 3'UTR of FABP4 associated with TNBC prognosis, which may aid the screening of high-risk patients with TNBC recurrence and the development of novel chemotherapeutic agents.

Citation Format: Yuan P, Wang W, Wu C, Lin D, Xu B. A single-nucleotide polymorphism in the 3'-UTR region of the adipocyte fatty acid binding protein 4 gene is associated with prognosis 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 P5-08-19.
Abstract P5-09-07: Using the power of the internet to deliver breast teaching in Africa
Authors: Shaaban AM , Abdulkareem F , Rotimi O
Published: May 2016

Introduction:

Delivering high quality breast teaching to African countries is of utmost importance. Our previous audit of breast cancer reporting in Africa has identified areas that would benefit from teaching and education. However, time and resource issues limit the ability to deliver teachings to a large number of African pathologists in person.

Method

As part of a comprehensive national in house teaching for senior trainees in Nigeria, a distant module of teaching was delivered by a team of UK pathologists using a freely available internet application.

Results

Distant teaching formed part of a two week residential postgraduate histopathology course that was designed for trainees preparing for their exit Histopathology exam. Sixty African pathologists attended the teaching. Previous auditing of breast cancer reporting indicated the need for education on macroscopic specimen handling, typing and grading of breast cancer. Other topics included an update on inflammatory breast cancer which has a high incidence in Africa and columnar cell lesions that are increasingly being encountered by African pathologists in the context of breast screening. A set of anonymous virtual slides were scanned and distributed to delegates before the course date.

Teaching was delivered using Skype application that only required a computer with internet access at the UK and Nigeria. We utilised video-conferencing which allowed trainees to see their lecturers and vice versa. The new data sharing facility of the application allows simultaneous sharing of Power Point presentations, with annotation which facilitates interactive discussion. A slide seminar using the previously circulated virtual slides, covering areas of diagnostic challenges morphologically and by immunohistochemistry was also delivered. An approach to diagnosing these lesions was delivered with re-focussing on tumor typing and grading. Participants were able to ask questions and interact with the UK-based tutors thorough the sessions. The feedback collected from attendees was excellent.

Conclusion

Distant teaching using freely available internet applications is a valuable, time and cost effective method that allows sharing educational material including lectures and slide seminars in an interactive manner. It is particularly useful in delivering teaching to resource-poor countries.

Citation Format: Shaaban AM, Abdulkareem F, Rotimi O. Using the power of the internet to deliver breast teaching in Africa. [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 P5-09-07.
Abstract P5-14-03: A network meta-analysis of fulvestrant 500 mg versus alternative therapies for second-line treatment of postmenopausal, estrogen receptor-positive advanced breast cancer
Authors: Telford C , Jones N , Batson S
Published: May 2016

Background

A network meta-analysis (NMA) of randomized controlled trials compared overall survival (OS) and serious adverse events (SAEs) of fulvestrant 500 mg with alternative therapies for second-line treatment of postmenopausal, estrogen receptor-positive advanced breast cancer.

Methods

Data were identified by systematic literature review. Study level hazard ratios (HRs) were obtained by modeling survival data using Weibull distribution, based on statistical and visual fit. SAEs were calculated as rate of grade 3/4 adverse events per patient year. Fixed effect Bayesian NMA were conducted for both outcomes.The base case included the following comparators of interest: anastrozole 1 mg, letrozole 2.5 mg, fulvestrant 250 mg, exemestane 25 mg, everolimus 10 mg plus exemestane 25 mg. The first three comparators were included in a subgroup analysis of treatment post-antiestrogen (antiestrogen subgroup), the last three were included in a subgroup analysis of treatment post-aromatase inhibitor (aromatase inhibitor subgroup).

Results

Ten studies were included; all studies reported SAEs, 7 studies reported OS. In the base case, fulvestrant 500 mg improved OS versus all comparators and in the antiestrogen subgroup versus fulvestrant 250 mg (HR 0.74; 95% credible interval [CrI] 0.56, 1.00), anastrozole (HR 0.73; 95% CrI 0.52, 1.03), and letrozole (HR 0.69; 95% CrI 0.44, 1.09). In the aromatase inhibitor subgroup, fulvestrant 500 mg improved OS versus fulvestrant 250 mg (HR 0.89; 95% CrI 0.59, 1.33) and exemestane (HR 0.93; 95% CrI 0.58, 1.47); OS for fulvestrant 500 mg versus everolimus plus exemestane was similar (HR 1.02; 95% CrI 0.62, 1.69). Decreased SAE rates were seen for fulvestrant 500 mg versus letrozole, exemestane, and everolimus plus exemestane (13.22 versus 20.65, 46.63, 67.30 events, respectively) in base case and versus fulvestrant 250 mg and letrozole (14.88 versus 15.67, 23.41 events, respectively) in the antiestrogen subgroup. NMA in the aromatase inhibitor subgroup was not performed (lack of reporting SAEs).

Conclusions

This analysis suggests improved efficacy for fulvestrant 500 mg versus fulvestrant 250 mg and aromatase inhibitors, similar efficacy to everolimus plus exemestane, and decreased toxicity amongst a majority of the comparators. Fulvestrant 500 mg can be considered an efficacious and better tolerated alternative endocrine treatment in this setting.

Citation Format: Telford C, Jones N, Batson S. A network meta-analysis of fulvestrant 500 mg versus alternative therapies for second-line treatment of postmenopausal, estrogen receptor-positive advanced 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 P5-14-03.