bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-06-07: Combination of doxorubicin with S1P signaling modulator FTY720 significantly suppressed obesity-associated breast cancer
Authors: Katsuta E , Takabe K
Published: March 2017

Background:

Obesity is one of the biggest health issues in the US. It has been shown that obesity-associated breast cancer is more aggressive with poor prognosis, which is partly explained by the low-grade inflammation caused by obesity. Recently we have published that sphingosine-1-phosphate (S1P), a signaling lipid mediator, link inflammation and cancer in colitis-associated colon cancer model. We hypothesized that addition of S1P modulator that block S1P signaling thus suppress the effect of obesity-mediated inflammation should enhance anti-cancer effect of doxorubicin, which is a typical anti-cancer drug for breast cancer used as a standard of care.

Methods:

Female B6.cg-Lepob (OB/OB) mice fed with high fat diet for 2 weeks prior to implantation of cancer cells were used as an obesity model, and litter mate control mice fed with normal diet were used as a control. 1 x 106 murine mammary adenocarcinoma E0771 cells were inoculated into #2 rt. fat pads as previously described (Katsuta et al JSR 2016). 9 days after inoculation, both OB/OB and control mice were randomized into 4 groups in each group; vehicle, Doxorubicin, FTY720 and Combination of Doxorubicin and FTY720. Doxorubicin was administrated by i.p. injection at a dose of 5 mg/kg on Day 0 and 3. FTY720 was administered everyday by gavage at a dose of 1 mg/kg during the entire course. Tumor growths were measured daily by caliper measurements. Tumor weights were measured on 21 days after cell inoculation.

Results:

The body weight of obesity model was significantly heavier than control mice at the time of cancer cell inoculation (44.1 g vs 19.4 g; p < 0.001). In non-treatment group, tumor weight in obesity group was significant heavier than control mice[KT1] (1232 mg vs 966 mg; p = 0.049), which is consistent with the dogma that obesity worsen cancer progression. As expected, tumor weight in non-treatment group is heavier than any treatment group, and that in combination treatment of doxorubicin and FTY720 is lightest in both of obesity group and control group. Interestingly, tumor reduction rate in obesity group compared with non-treatment group is significant greater than control group (Doxorubicin: 83% vs 19%, p = 0.001; FTY720: 80% vs 46%, p = 0.027, Doxorubicin + FTY720: 93% vs 64%, p = 0.011). Over 15 % weight loss were seen in obesity doxorubicin group and obesity combination treatment group.

Conclusion:

Modification of S1P signaling by FTY720 was shown to enhance the effect of doxorubicin particularly in obese mice, which implicate a novel approach to treat obesity-associated breast cancer.

Citation Format: Katsuta E, Takabe K. Combination of doxorubicin with S1P signaling modulator FTY720 significantly suppressed obesity-associated breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-06-07.
Abstract P3-09-04: Beyond CHEK2 in breast cancer: Search for additional moderately penetrant risk gene variants by analyzing the oligogenic disease course in CHEK2 mutation carriers
Authors: Pohl E , Richters L , Hauke J , Ernst C , Kröber S , Niederacher D , Arnold N , Ramser J , Groß E , Gehrig A , Schmidt G , Dutrannoy V , Kast K , Hahnen E , Schmutzler R
Published: March 2017

This abstract was not presented at the symposium.
Abstract P3-11-01: Prophylactic contralateral mastectomy - A valid choice?
Authors: Subramanian A , Cant G , May S , Jenkins V , Lesley F
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P3-11-04: Adapting evidenced based strategies for effective communication in cancer genetic counseling
Authors: Joseph G , Guerra C , Cheng JKY , Lee R
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P3-12-04: Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit
Authors: Karmali S , Hughes N , Galiauskas R , Cook J , Murphy K , Bird BR , Murphy CG
Published: March 2017

Background: Subcutaneous (sc) trastuzumab has demonstrated non-inferiority to intravenous (iv) trastuzumab and is preferred by patients and providers. Serious administration related reactions (ARRs) such as hypotension, respiratory distress etc. were not reported in the pivotal HannaH study. However, the summary of product characteristics (SPC) advises that patients should be observed for ARRs for 6 hours post the first injection (and 2 hours post subsequent injections), similar to the iv formulation.

Methods: We conducted an audit of patients commencing sc trastuzumab at our institution. Medical notes of each patient were reviewed to record adverse events reported on the day of first administration or at the subsequent visit. In addition all patients were interviewed by telephone and questioned regarding adverse events with first or subsequent injections.

Results: 39 patients were identified, 32 had received prior iv trastuzumab. Patients received a mean of 12 injections. In total patients received 470 sc trastuzumab injections, associated with a recommended 1,096 hours of observation as per SPC. 3 injections (0.6%) were associated with ARRs within 24 hours, all on the first cycle. 2 patients (5%) experienced injection site reactions immediately post injection and 1 patient had injection site pain during the injection. 1 patient experienced pyrexia and dry cough 24 hours post injection and was hospitalized for respiratory tract infection. No patient experienced a reaction between 2 and 6 hours post first injection. There were no serious ARRs.

Conclusions: ARRs related to sc trastuzumab are usually immediate, mild and self-limiting. Observing patients for 6 hours post first injection and 2 hours post subsequent injections represents an inefficient use of healthcare resources.

Citation Format: Karmali S, Hughes N, Galiauskas R, Cook J, Murphy K, Bird BR, Murphy CG. Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-12-04.
Abstract P3-13-01: Determining the breast tumor margin through genomics of the cancer-stromal interaction
Authors: Dhage S , Ernlund A , Wang J , Axelrod D , Berman R , Roses D , Schneider R
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P3-13-03: Bilateral mastectomy and immediate reconstruction are associated with increased postoperative complications
Authors: Dietch ZC , Nagraj VP , Showalter SL , Schroen AT , Brenin DR
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P3-13-21: Primary surgery in inflammatory breast cancer
Authors: Muzaffar M , Vohra N , Wong J
Published: March 2017

Background: Inflammatory Breast Cancer (IBC) is a rare but very aggressive variant of breast cancer accounting for around 1-5% of all breast cancer cases. Current standard of care is multimodality therapy with preoperative chemotherapy followed by modified radical mastectomy and adjuvant radiotherapy.

Method and Material: We searched the Surveillance Epidemiology and End results Registry to identify female patients diagnosed with Stage III IBC between 1988-2013.We performed descriptive and univariate analyses of the patients with IBC. Variables assessed included patient age, race/ethnicity, histologic subtype, tumor grade, hormone receptor status, surgery type.

Results: We identified 11604 women with IBC from SEER database diagnosed between 1988-2013.The median age was 57 yrs., 80 % ( 9273) of patients were white,14.4 % ( 1667) blacks, and around 73% had nodal involvement. 32.4 % (3756) patients were diagnosed with IBC between 1988-2000, while 67.6 % ( 7848) between 2001-2013.We excluded patients with missing primary surgery information with 7586 patients remaining for analysis. The median age in this final cohort was 56yrs, 80.4 % ( 6097) patients were white, and 13.7 % (1044) were black. The predominant tumor type was invasive ductal carcinoma, majority of the patients had grade 3 tumor 59.4 % ( 4504), grade2 in 23.2 % ( 1757),47.1% were estrogen receptor (ER)positive,43% were ER negative,53% were progesterone receptor negative, and 7% had HER 2 positive tumor. In this cohort 6.4 % (487) patients underwent partial mastectomy and 93.6 % (7099) underwent mastectomy. In the cohort undergoing breast conservation, 15% were during 1988-2000 and 84.4% during years 2001-2013 (p value=0.06).

Surgery in non-metastatic inflammatory Breast CancerType of Surgery1988-20002001-2013p-valuePartial Mastectomy76 (6.7%)1140(93.3%)0.06Mastectomy411 (6.9%)5959(93.1%)

The median survival was 46 months among patients diagnosed between 1988-2000 and 61 months for 2001-2013 time period(p<0.0001).The median survival in patients undergoing partial mastectomy was 42 months versus 48 months among patients undergoing mastectomy (p=0.0001).

Discussion: IBC continues to be an aggressive breast cancer subtype, but survival has improved over last decade. The utility of partial mastectomy has increased in the last decade compared to 1988-2000. Mastectomy still remains the standard surgical option, but with more effective systemic therapeutic agents, better tumor responses are noted especially in Her 2 positive and triple negative IBC. Partial Mastectomy may be a viable option for patients achieving complete clinical response.

Citation Format: Muzaffar M, Vohra N, Wong J. Primary surgery in inflammatory breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-21.
Abstract P3-13-26: Deep Infrared Imaging to identify venous impairment after breast cancer surgery
Authors: Belgrado J-P , Vandermeeren L , Vankerckhove S , Valsamis J-B , Feipel V , Rooze M , Moraine J-J , Hertens D , Carly B , Liebens F
Published: March 2017

This abstract was not presented at the symposium.
Abstract P3-13-27: Early detection of secondary lymphedema after cancer treatments
Authors: Belgrado J-P , Vandermeeren L , Vankerckhove S , Valsamis J-B , Carly B , Hertens D , Jeanjot I , Beier B , Etbaz S , De Coster C , Liebens F
Published: March 2017

This abstract was not presented at the symposium.
Abstract P3-17-05: Claudin-4 expression is associated with disease free survival in breast carcinoma in situ: Mean follow up of 8.2 years
Authors: Duarte GM , Almeida NR , Tocchet F , Espinola J , Pinto T , Barreto CT , Pinto GA , Soares FA , Marshall P , Paiva GR
Published: March 2017

Introduction: Claudins are tight junction molecules that have been associated with breast cancer prognosis. The claudin-low intrinsic subtype of invasive carcinoma was recently described and associated with high grade carcinoma, low junction molecules expression and worse response to chemotherapy. However, it is not known whether the expression of claudins may provide clues as to carcinoma in situ prognosis. The aim of study was evaluate the association between claudin–4 expression and disease-free survival and histologic type of local recurrence in carcinoma in situ after longer follow up.

Methods: A tissue microarray (TMA) block was constructed from 137 pure carcinoma in situ paraffin blocks sampled from patients treated from 1999 to 2009. The TMA was submitted to immunohistochemical staining for claudin-4. A claudin-4 score calculated based on percentage and intensity of expression, categorized samples as: claudin-4-low or claudin–4-high. Clinical data, treatment data, local recurrence data and survival of each patient were reanalyzed from medical records. Kaplan-Meier curves, log-rank and Wilcoxon tests were used to analyze disease-free survival; qui-square and Fisher test were employed to compare others variables; a significance level of 5 % was used.

Results: Claudin-4 expression was evaluated in 86 samples, 88.4% were claudin-4-high and 11.6% claudin-4-low. Mean follow up was 8.2 years ( and local recurrence rate was 10.5 %. There was significant difference in the disease-free survival between claudin-4-high and claudin-4-low (4.9 x 1.9 respectively, p= 0.02); however there was no difference between both in histologic type of recurrence, invasive or in situ (p=0.44).

Conclusion: In our samples, claudin-4-high expression in carcinoma in situ was more frequent than low expression. Our data showed that claudin-4-low expression had a worse prognosis in carcinomas in situ (inferior disease-free survival) but it was similar to claudin-4-high in histologic type of local recurrence.

Citation Format: Duarte GM, Almeida NR, Tocchet F, Espinola J, Pinto T, Barreto CT, Pinto GA, Soares FA, Marshall P, Paiva GR. Claudin-4 expression is associated with disease free survival in breast carcinoma in situ: Mean follow up of 8.2 years [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-05.
Abstract P4-01-05: In vivo, intraoperative margin detection utilizing the Lumicell margin assessment system
Authors: Rai U , Tang R , Plichta JK , Rice-Stitt T , Gadd MA , Specht MC , Strasfeld DS , Ferrer JM , Brachtel EF , Smith BL
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P4-02-06: Evaluation of contrast-enhanced ultrasonography for early prediction of response to neoadjuvant chemotherapy in triple negative breast cancer
Authors: Masumoto N , Kadoya T , Murakami C , Gouda N , Sasada S , Emi A , Haruta R , Kataoka T , Okada M
Published: March 2017

Objectives

We aimed to determine whether contrast-enhanced ultrasonography (CEUS) can predict the early effects of neoadjuvant chemotherapy on triple negative breast cancer.

Methods

The clinical responses of 20 consecutive patients with breast cancer (T1–2, N0–1, M0) to neoadjuvant chemotherapy between October 2012 and Feb 2016 were assessed using ultrasonography and contrast-enhanced ultrasonography before starting the therapy and after the treatment of 2 courses. Ascending slope (AS) of perfusion parameters for contrast-enhanced ultrasonography were created from time–intensity curves based on enhancement intensity and temporal changes to objectively evaluate contrast-enhanced ultrasonography findings.We investigated whether rate of change of ascending slope (ΔAS) and tumor size (Δ US) could predict pCR.

Results

Eight (40.0%) of the 20 patients achieved pathological complete response. ΔAS were significantly higher (-25.5 ± 35.5 vs. 14.7 ± 33.2; P < 0.02) in patients who achieved pCR than in those who did not. On the other hand, ΔUS of pCR and non-pCR did not significantly differ among tumors (-40.8 ± 22.4 vs. -21.4 ± 20.6; P = 0.06). The AUC values for ΔAS and ΔUS were 0.792 (95% CI, 0.579 -1.000, P = 0.03) and 0.729 (95% CI, 0.501 - 0.957;p = 0.09), respectively. We set ΔAS and Δ US cut-offs for predicting pCR at-20.08 and - 33.75 based on the ROC curves. Clinical and pathological characteristics of the 20 patients are summarized in Univariate (odds ratio, 2.71; p= 0.02) and multivariate (odds ratio, 2.88; p= 0.03) analysis showed that ΔAS was the sole independent predictor of pCR.

Clinical and pathological characteristics of patients with breast cancer.CharacteristicpCR (n)Non pCR (n)pClinical T status   T1110.71T2711 Clinical N status   Negative570.85Positive35 Nuclear Grade   1 or 2340.85358 ΔUS (%)   < -33.75390.09≥ -33.7553 ΔAS (%)   < -20.082100.009≥ -20.0862 

Univariate and multivariate logistic analysis of significant predictive factors for pCR in triple negative subtype Univariate analysisMultivariate analysis OR, 95% CI, pOR, 95% CI, pΔUS  > -33.751.61, 0.72-34.7, 0.101.85, 0.51-79.1, 0.15≤-33.75  ΔAS  > -20.082.71, 1.65-136.1, 0.022.88, 1.44-218.7, 0.03≤ -20.08  

Conclusion

ΔAS assessed with CEUS can help the physician to early predict the probability of achieving pCR or not.

Citation Format: Masumoto N, Kadoya T, Murakami C, Gouda N, Sasada S, Emi A, Haruta R, Kataoka T, Okada M. Evaluation of contrast-enhanced ultrasonography for early prediction of response to neoadjuvant chemotherapy in triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-06.
Abstract P4-02-08: Opto-acoustic imaging of the breast: Downclassification and upclassification of suspicious breast masses
Authors: Menezes GLG , Pijnappel RM , Meeuwis C , Bisschops B , Veltman J , Lavin PT , Mann RM
Published: March 2017

Background

Imagio® is an opto-acoustic (OA) breast imaging system designed to concomitantly collect OA images together with diagnostic ultrasound (CDU). The device is intended to improve distinction between benign and malignant masses. In this interim analysis of the post-market surveillance MAESTRO study we report the results of 75 patients who had breast masses classified as BI-RADS 4a and 4b by CDU.

Aim

We assessed OA's sensitivity, specificity, and its ability to downgrade benign masses and upgrade malignant masses based on the probability of malignancy (POM) and BI-RADS category.

Methods

Seventy-five patients with 78 breast masses were evaluated with OA prior to biopsy. For each mass, the radiologist scored 5 OA features, assigned a POM and BI-RADS category. OA sensitivity, specificity, and BI-RADS downgrade and upgrade percentages were assessed with and without contribution from a previously derived nomogram.

Results

The mean POM difference between malignant and benign masses was higher for OA (37%) than for CDU (27%). OA specificity was 43% without the nomogram and 68% with the nomogram. OA sensitivity was 97% with and without the nomogram. With OA 43% of benign masses could be downgraded and 47% of malignant masses could be upgraded in BIRADS category.

Conclusion

These results appear to confirm the previously reported ability of OA to improve the differentiation between benign and malignant masses compared to CDU alone, to potentially decrease negative biopsies, and to upgrade BI-RADS category in malignant masses. The MAESTRO study (n=200) may further confirm these results.

Citation Format: Menezes GLG, Pijnappel RM, Meeuwis C, Bisschops B, Veltman J, Lavin PT, Mann RM. Opto-acoustic imaging of the breast: Downclassification and upclassification of suspicious breast masses [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-08.
Abstract P4-02-13: Breast ultrasound surveillance with image fusion technique in a short-interval follow-up for BI-RADS category 3 mass lesions
Authors: Nakano S , Fujii K , Kousaka J , Mouri Y , Ando T
Published: March 2017

PURPOSE: Breast ultrasound (US) is a diagnostic imaging modality that is now widely used as an adjunct to mammography for evaluation of breast abnormalities. In the Breast Imaging-Reporting and Data System (BI-RADS) lexicon, a solid mass with an oval shape, well-circumscribed margins and parallel orientation is classified as category 3 (BI-RADS category 3 mass lesions) . This mass should have a risk of malignancy of < 2%. Surveillance breast US in short-interval follow-up for BI-RADS category 3 mass lesions is an acceptable alternative to biopsy. The surveillance US is recommended 6 month after initial lesion identification and then every year for at least 2 y. However, inconsistent reproducibility for US due to operator dependence is still a clinical issue. The aim of our study was to verify the utility of US using real-time virtual sonography (RVS) - to coordinate present US images with past US images reconstructed from previously acquired US volume data using magnetic tracking system – in a short-interval follow--up for BI-RADS category 3 mass lesions.

METHOD AND MATERIALS: We enrolled 20 women (23 lesions) with more than 24 months of follow-up after classification as BI-RADS category 3 during initial US. US surveillance was scheduled at 6, 12 and 24 months. Three-dimensional assessment of morphologic features was performed while serially checking past US volume data corresponding to the present US probe position. Measurement of the target lesion diameter was performed after the probe was adjusted to include the maximum diameter of a past US image at each visit.

RESULTS: RVS was technically successful in 100% of patients. All target lesions were detected, including two iso-echoic lesions. The mean target lesion diameters at baseline and at 6, 12 and 24 months were 8.2+4.2, 8.4+4.5, 8.1+4.5 and 8.3+5.0 mm, respectively . Statistical analysis using a Friedman test with multiple comparisons revealed no significant difference between the diameters at each time point (p = 0.785). RVS was used to directly compare the US morphologic characteristics and sized of lesions. Furthermore, the RVS data can be reproduced in their entirety for independent review at a later date by using stored US volume data.

CONCLUSION:Our results suggest that RVS is reproducible, operator-independent technique for comparison of US images of BI-RADS category 3 mass lesions obtained at different time points.

Citation Format: Nakano S, Fujii K, Kousaka J, Mouri Y, Ando T. Breast ultrasound surveillance with image fusion technique in a short-interval follow-up for BI-RADS category 3 mass lesions [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-13.
Abstract P4-03-06: Microenvironmental control of breast cancer subtype elicited by paracrine growth factors signaling
Authors: Bocci M , Bartoschek M , Pietras K
Published: March 2017

During cancer progression from an indolent stage to a clinically manifested disease, the surrounding microenvironment co-evolves into an activated state through continuous and dynamic paracrine communication between all constituent cell types that collectively sustain malignant growth. Hence, from a therapeutic perspective, tumors must be regarded as multi-cellular organs. Mesenchymal cells are highly plastic entities. Normal fibroblasts are described to counteract tumorigenesis by repressing cancer initiation. However, co-evolution of the malignant epithelium and its underlying stroma instigates activation of cancer-associated fibroblasts (CAFs) into a phenotype endorsing most, if not all, hallmarks of cancer progression.

Through translational studies using breast cancer patient cohorts, genetically engineered mouse models (including patient derived xenografts), and single-cell RNA sequencing, we delineate a previously unappreciated role for CAFs as determinants of breast cancer prognosis and treatment response through specification of the molecular subtype of breast cancer.

Expression of paracrine growth factors mediating malignant cell-CAF crosstalk in breast cancer was found to be associated with a hormone receptor-negative state. Genetic targeting of the signaling networks governing the interactions between tumor cells and CAFs confirmed their functional importance by prompting a delay in tumor growth, impaired extra-cellular matrix deposition and reduced angiogenesis. Importantly, our work holds therapeutic implications, as genetic or therapeutic targeting of CAF subsets resulted in conversion of basal-like/triple-negative breast tumors into a luminal state that conferred sensitivity to endocrine therapy in previously impervious tumors. Additionally, to mechanistically explore the heterogeneity of mesenchymal cells in breast tumors, we have made use of single cell RNA sequencing of isolated CAFs as a guide to divide cells into transcriptionally similar groups. Distinct clusters of different CAF subtypes were identified and found to denote diverse functions in the tumor microenvironment.

In conclusion, therapeutic targeting of functional subsets of CAFs may be exploited as a refined strategy to improve patient benefit from established treatments by impinging on the stimulatory crosstalk between CAFs and their surrounding malignant microenvironment.

Citation Format: Bocci M, Bartoschek M, Pietras K. Microenvironmental control of breast cancer subtype elicited by paracrine growth factors signaling [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-06.
Abstract P4-06-02: The mammary ducts create a favourable microenvironment for xenografting of luminal and molecular apocrine breast tumours
Authors: Bonnefoi H , Richard E , Grellety T , Velasco V , MacGrogan G , Iggo R
Published: March 2017

This abstract was not presented at the symposium.
Abstract P4-06-04: Triple negative breast cancer patient-derived xenografts: Molecular characteristics and sensitivity to emerging therapies
Authors: Evans KW , Yuca E , Akcakanat A , Scott SM , Paez Arango N , Zheng X , Chen K , Tapia C , Tarco E , Eterovic AK , Black DM , Jennifer LK , Tripathy D , Mills GB , Meric-Bernstam F
Published: March 2017

Background: Patients with triple negative breast cancer (TNBC) that have significant residual disease following neoadjuvant therapy have a poorer prognosis. The difficulty in developing improved treatment strategies for these patients is compounded by the molecular diversity of this pathology. Thus, preclinical efficacy testing with models representing the molecular heterogeneity of TNBC may not only improve efficacy testing but also has the potential to facilitate biomarker discovery to inform patient selection.

Methods: We generated 28 hormone receptor-low/HER2- patient-derived xenografts (PDXs) from 26 patients; the majority from residual disease following neoadjuvant chemotherapy. We characterized the tumors from the patients and the matched PDXs by targeted exome sequencing, RNA sequencing, and Reverse Phase Protein Arrays. We established single agent sensitivity for a set of PDXs to standard TNBC therapies as well as emerging targeted therapies targeting PARP, mTOR, PI3K and MEK1/2.

Results: PDXs maintained DNA/RNA profiles similar to the patients' tumors. Our PDX set exhibits a diverse set of potential driver alterations and is comprised of PDXs representative of all TNBC molecular subtypes. The PDXs varied in their sensitivity to standard chemotherapeutics. PI3K, mTOR and MEK inhibition caused tumor growth inhibition in several PDX models but were unable to cause tumor regression as single agent. In contrast, talazoparib caused dramatic regression in 5 out of 12 PDXs tested, including 3 PDXs from patients whose tumors had progressed on neoadjuvant anthracyclines and/or paclitaxel. Four of these talazoparib sensitive PDXs were derived from patients not harboring BRCA1/2 germline alterations; three had somatic alterations in genes linked to DNA damage repair (ATM, BRCA2, PTEN). The comparison of PARP sensitivity with molecular profiles will be presented.

Conclusions: TNBC PDXs represent molecular tumor heterogeneity as well as heterogeneity in response to targeted therapeutics. PDXs represent an opportunity for biomarker discovery as well as for rationale combination therapies to enhance the efficacy targeted therapies.

Citation Format: Evans KW, Yuca E, Akcakanat A, Scott SM, Paez Arango N, Zheng X, Chen K, Tapia C, Tarco E, Eterovic AK, Black DM, Jennifer LK, Tripathy D, Mills GB, Meric-Bernstam F. Triple negative breast cancer patient-derived xenografts: Molecular characteristics and sensitivity to emerging therapies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-06-04.
Abstract P4-07-06: MicroRNAs associated with acquired taxane resistance in a breast cancer cell line model
Authors: Taylor KJ , Chong T , D'Costa A , Yao C , Gourley C , Cameron DA , Bartlett JMS , Spears M
Published: March 2017

Background: Acquired chemoresistance remains the major cause of therapeutic failure in the treatment of breast cancer. Improved knowledge of the transition from drug sensitive to resistant breast cancer will pave the way for novel preventative and therapeutic strategies. MicroRNAs (miRNA) are endogenous, small non-coding RNAs that regulate gene expression by targeting the 3'UTR region of messenger RNAs. There is a growing body of evidence to suggest miRNAs may be involved in the development of chemoresistance and may play a role in the regulation of drug resistance pathways.

Methods: An in vitro model of paclitaxel resistance was developed through the generation of resistant MDA-MB-231 cell lines by serial culture in escalating doses of taxane until resistance was achieved. The chemoresistant model was used to compare differential miRNA expression with the sensitive, parental line using the Nanostring® platform, analysing 800 human miRNAs. Confirmation of differential expression was performed by QRT-PCR.

Results: This analysis resulted in 30 significantly altered miRNA (1.5 fold, p value < 0.05) at 25nM paclitaxel and 48 significantly altered miRNA at 50nM paclitaxel. The top up-regulated miRNA cluster in MDA-MB-231 25PACR is hsa-miR-548l (fold change: 2.89, p value: 0.016) and top down-regulated was hsa-miR-449a (fold change: -4.1. p value: 0.001). In MDA-MB-231 50PACR the top up-regulated miRNA cluster is hsa-miR-193a-5p (fold change: 3.746, p value: 0.008) and the top down-regulated miRNA cluster is hsa-miR-135a (fold change: -4.085, p value: 0.001). To explore the molecular mechanisms of the differentially expressed miRNAs in paclitaxel resistance, targets were predicted by in silico analysis. Pathways and networks designated by miRNA targets included the cell cycle, PI3K/Akt pathways and focal adhesion.

Conclusion: In this study we identified candidate resistance-associated miRNAs which were differentially expressed between in vitro derived paclitaxel resistant MDA-MB-231 and the sensitive parental line. Further validation to ascertain their role in the transition to a chemoresistant phenotype is currently ongoing.

Citation Format: Taylor KJ, Chong T, D'Costa A, Yao C, Gourley C, Cameron DA, Bartlett JMS, Spears M. MicroRNAs associated with acquired taxane resistance in a breast cancer cell line model [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-07-06.
Abstract P4-08-01: IsomiRs and tRNA fragments are race-dependent regulators in breast cancer
Authors: Rigoutsos I , Telonis AG , Loher P , Jing Y , Londin E
Published: March 2017

This abstract was not presented at the symposium.
Abstract P4-11-01: A genetic model of mammary gland fibrosis and cancer risk
Authors: Wu J , Crowe D
Published: March 2017

Ductal cells of the mammary gland arise from mammary stem cells (MSC) and consist of estrogen receptor a negative (ER-) luminal cells and a small ER+ luminal population. Luminal cells are maintained by the proliferation of ER- luminal progenitor (LP) cells, which are expanded in basal subtype breast cancer. Human breast LP cells exhibit telomere DNA damage, which is associated with mammographic density and increased cancer risk. Short telomeres resulting from the DNA damage response correlate with aggressive breast cancer phenotypes. Telomeric repeat factor 2 (TRF2) binds to telomeres and protects them from the DNA damage response. TRF2 expression is reduced in most human breast cancers but the phenotypic advantages of this genetic alteration are unknown. To determine the effects of telomere DNA damage on mammary gland function and tumor phenotype, we deleted TRF2 expression in mammary gland epithelium. Mammary glands lacking TRF2 expression exhibited increased telomere DNA damage response, histopathological and functional degeneration, and prominent ductal fibrosis. MSC from TRF2 deficient glands were unable to completely regenerate mammary glands following transplantation to cleared fat pads. TRF2 deficient mammary tumors also demonstrated telomere DNA damage response but exhibited rapid onset and increased proliferation. Tumor derived LP cells underwent expansion but exhibited high telomere DNA response and failed to form tumors following transplantation. In contrast, the severely depleted MSC population was highly tumorigenic and maintained telomeres via the ALT mechanism. Telomere DNA damage response in mammary tumors resulted in p53 dependent ER+ cellular differentiation and sensitivity to anti-estrogen therapy. Our results provide a new in vivo model for exploring mechanisms of mammographic density, stem cell differentiation, cancer risk, and therapeutic sensitivity.

Citation Format: Wu J, Crowe D. A genetic model of mammary gland fibrosis and cancer risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-11-01.
Abstract P4-12-03: Estrogen receptor-positive breast cancer in BRCA1 mutation carriers shows a BRCAness profile, suggesting sensitivity to drugs targeting homologous recombination deficiency
Authors: Lips EH , Debipersad R , Scheerman E , Mulder L , Sonke GS , van der Kolk LE , Wessling J , Hogervorst FBL , Nederlof PM
Published: March 2017

Background

As estrogen receptor (ER)-positive breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER negative BRCA1 mutated breast cancer, it has been suggested that these tumors are 'sporadic' and not BRCA1-driven. With the introduction of targeted treatments specific for tumors with a non-functioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor, is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors.

Methods

Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity (LOH) analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER- tumors, 36 BRCA2-mutated ER+ associated tumors, and 182 sporadic ER+ tumors.

Results

The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER- breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wildtype BRCA1 allele was observed. Clinico-pathological variables in BRCA1-mutated ER+ cancer were more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1 mutated ER- cancers.

Conclusions

As BRCA1-mutated ER+ tumors showed a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect.

Citation Format: Lips EH, Debipersad R, Scheerman E, Mulder L, Sonke GS, van der Kolk LE, Wessling J, Hogervorst FBL, Nederlof PM. Estrogen receptor-positive breast cancer in BRCA1 mutation carriers shows a BRCAness profile, suggesting sensitivity to drugs targeting homologous recombination deficiency [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-03.
Abstract P4-12-10: Prognostic relevance of caspase 8 polymorphisms for breast cancer
Authors: Wimberger P , Jan Dominik K , Agnes B , Kurt S , Rainer C , Rainer K , Winfried S , Hagen B
Published: March 2017

Background: The minor allele of two caspase 8 polymorphisms, namely CASP8 -652 6N InsDel (rs3834129) and CASP8 Asp302His (rs1045485), were repeatedly associated with reduced breast cancer susceptibility. Contrarily, the presence of the -652 6N Del or the CASP8 302His variant was reported to be an unfavorable prognostic factor in colorectal cancer or neuroblastoma. However, prognostic relevance of these genetic variants for breast cancer is completely unknown and is therefore adressed by the current study.

Methods: Genotyping was performed by pyrosequencing. Caspase 8 mRNA expression was quantified by comparative RT-qPCR.

Results: We observed an allele-dose dependent association between CASP8 -652 6N InsDel and caspase 8 mRNA expression in breast cancer tissue, with homozygous deletion carriers showing lowest relative caspase 8 expression (p=0.0131). Intriguingly, the presence of the -652 6N Del or the 302His variant was shown to be a negative prognostic factor for breast cancer in terms of an allele-dose dependent influence on overall survival (OS, p=0.0018, p=0.0150, respectively). Moreover, both polymorphisms were independent predictors of OS after adjusting for co-variats (p=0.007, p=0.037, respectively). Prognostic relevance of both polymorphisms was independent from ER or Her2/Neu receptor status and a combined analysis of diplotypes revealed an additive influence on OS (p=0.0002).

Conclusion: This is the first report, showing negative and independent prognostic impact of the CASP8 -652 6N Del and the 302His variant for breast cancer. Our data provide rationale to further validate clinical utility of these polymorphisms for breast cancer and to extend this investigation to a broad scope of other malignancies.

Citation Format: Wimberger P, Jan Dominik K, Agnes B, Kurt S, Rainer C, Rainer K, Winfried S, Hagen B. Prognostic relevance of caspase 8 polymorphisms for breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-10.
Abstract P4-12-11: Up-regulation of SPARC is associated with breast tumor progression and epithelial SPARC expression is correlated with poor survival and MMP-2 expression in patients with breast carcinoma
Authors: Lee JS , Kim G-E , Park MH , Yoon JH
Published: March 2017

Background: Secreted protein acidic and rich in cysteine (SPARC) plays a crucial role in the process of tumor invasion and metastasis in many cancers. Matrix metalloproteinases (MMPs) degrade the extracellular matrix and participate in several key processes of invasion and metastasis. The aims of this study were to evaluate the potential involvement of SPARC in the progression of breast tumor and to determine its association with outcome variables and MMPs expression in patients with breast carcinoma (BC).

Materials and Methods: SPARC expression was examined in 8 pairs of BC tissues and surrounding normal tissues at mRNA and protein levels by quantitative real-time PCR (qRT-PCR), RNAscope in situ hybridization (ISH), Western blotting, and immunohistochemistry techniques. Immunohistochemical staining of SPARC on tissue microarray was done in 26 normal breasts, 76 ductal carcinoma in situ (DCIS), and 198 BC samples. In addition, we performed immunohistochemical staining for MMP-2 and MMP-9 in BC.

Results: SPARC expression at mRNA and protein levels by qRT-PCR and Western blotting was significantly increased in BC tissues compared to the surrounding normal tissues (p < 0.05 and p < 0.01, respectively). RNAscope ISH and immunohistochemistry of SPARC confirmed that SPARC expression was increased in BC tissues compared with their normal tissues and its expression was more pronounced in the stromal compartment than in epithelial compartment. SPARC expression was different among the normal, DCIS and BC groups and epithelial SPARC expression increased progressively from normal breast through DCIS to BC (p < 0.001). In patients with BC, high epithelial SPARC expression was associated with worse disease-free and overall survival (p = 0.002 and p = 0.048, respectively) and independently predicted worse disease-free survival (p = 0.002). Epithelial SPARC expression was significantly correlated with MMP-2 expression (p < 0.05).

Conclusion: Our results suggest that up-regulation of SPARC contributes to breast tumor progression. SPARC expression may be a useful biomarker for the prognostic prediction in patients with BC. SPARC can control extracellular matrix degradation through up-regulation of MMP-2.

Citation Format: Lee JS, Kim G-E, Park MH, Yoon JH. Up-regulation of SPARC is associated with breast tumor progression and epithelial SPARC expression is correlated with poor survival and MMP-2 expression in patients with breast carcinoma [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-11.
Abstract P4-12-14: Folate receptor alpha (FOLR1) expression in triple-negative breast cancer (TNBC)
Authors: Cui X , McIntire PJ , Ginter PS , Irshaid L , Chen Z , Shin SJ
Published: March 2017

Background Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in breast cancer. The limited studies evaluating the role of FOLR1 in breast cancer have shown that FOLR1 protein expression is enriched in triple-negative breast cancer (TNBC). Newly developed anti-FOLR1 therapy could potentially be used for patients with TNBC for whom few therapeutic options exist. We sought to evaluate FOLR1 protein expression in a cohort of patients with TNBC to determine its prevalence and prognostic value. Design Immunohistochemistry was performed for FOLR1 (26B3.F2, Biocare, RTU) on tissue microarray (TMA) slides consisting of 62 primary TNBC. Membranous staining in ≥5% of cells was deemed positive in a given case. Statistical analyses correlating FOLR1 protein expression with clinicopathologic parameters and clinical outcome [disease-free survival (DSF) and overall survival (OS) (range: 16 to 196 months, mean: 111 months)] were performed. Results 62 cases of primary TNBC from 61 patients were studied. All patients were female and the mean age was 55 years (range 30 to 91 years). Histologically, almost all tumors were invasive ductal carcinoma (94%; 58/62) and grade 3 (89%; 55/62). Most were pT1 tumors (71%; 44/62) or pT2 (27%; 17/62). For the majority of patients, the nodal status was N0 (61%; 38/62) or N1 (24%; 15/62) and the stage was 1 (53%; 33/62) or 2 (32%; 20/62). Most cases were negative for FOLR1 (84%; 52/62). FOLR1 expression did not correlate with any clinicopathologic parameters, DFS or OS (P>0.05). Conclusion Similar to other studies, we found no correlation with FOLR1 expression and common clinicopathologic parameters and clinical outcome in TNBC. While FOLR1 expression has been previously reported to confer poor prognosis in breast cancer (all types), our findings suggest that in TNBC specifically, FOLR1 expression is not prognostically significant.

Citation Format: Cui X, McIntire PJ, Ginter PS, Irshaid L, Chen Z, Shin SJ. Folate receptor alpha (FOLR1) expression in triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-14.
Abstract P4-13-04: Efficacy of dipsacus asperoides (DA) in a model for triple negative breast cancer
Authors: Telang NT , Nair HB , Wong GYC
Published: March 2017

Background: The triple negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α (ER-α), Progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2). This molecular subtype responds only to conventional cytotoxic chemotherapy and to small molecule based targeted therapy. These therapeutic options are associated with long-term systemic toxicity and acquired tumor resistance leading to compromised efficacy. These limitations emphasize identification of efficacious non-toxic agents for secondary prevention/therapy of TNBC. Dipsacus asperoides (DA) is a Chinese herb of a nutritional nature. The root of this herb represents an ingredient that is commonly included in the traditional Chinese herbal formulations for health management purposes. The present study examines the growth inhibitory effects of DA and identifies possible mechanistic leads for their efficacy in a preclinical cell culture model for TNBC.

Experimental Model, Herbal Extract and Biomarkers: The human mammary carcinoma derived ER-α -, PR - and HER-2 - MDA-MB-231 cell linerepresents the model for TNBC. Non-fractionated aqueous extract from DA represents the test agent. Anchorage dependent growth, anchorage independent (AI) colony formation, cell cycle progression and relevant pathway specific mechanistic assays represent the quantitative biomarkers for efficacy.

Results: Treatment of MDA-MB-231 cells with DA extract induces a dose dependent cytostatic growth arrest (IC50: 0.0015%, IC90: 0.0030%), and strongly inhibits AI colony formation. Within the cytostatic concentration range, DA treatment inhibits cell cycle progression via progressive G2/M arrest, suggesting abrogation of the G2/M checkpoint affecting DNA damage repair pathway. The induction of cellular apoptosis by DA is indicated by a dose dependent up-regulation of pro-apoptotic Caspase 3/7 activity.

Conclusion: These data identify potential mechanistic leads for the efficacy of DA in the present model. The present study validates a mechanism based approach to prioritize efficacious non-toxic herbal extracts for secondary prevention/therapy of the TNBC molecular subtype of clinical breast cancer.

Citation Format: Telang NT, Nair HB, Wong GYC. Efficacy of dipsacus asperoides (DA) in a model for triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-13-04.
Abstract P4-16-02: An open labelled longitudinal evaluation of a subcutaneous combination of testosterone and anastrozole in pre-menopausal women with high volumetric mammographic breast density
Authors: Birrell SN , Birrell ND
Published: March 2017

This abstract was withdrawn by the authors.