bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-04-04: Identification and development of oral estrogen receptor PROTAC degraders for breast cancer
Authors: Flanagan JJ , Qian Y , Gough SM , Andreoli M , Bookbinder M , Bradley J , Rousseau E , Willard R , Crews CM , Crew AP , Taylor I , Houston J 
Published: February 2018

Abstract
ER-positive breast cancers comprise approximately 70-80% of all newly diagnosed cases. Downregulation or degradation of ER is a treatment approach currently used in the clinic to target estrogen receptor signaling. Faslodex, the only clinically-approved ER-downregulator, is administered as a monthly intramuscular injection with limiting pharmaceutical properties. Reasoning that an orally-available estrogen receptor degrader would be beneficial to patients, we have leveraged our experience in targeted protein degradation to generate and characterize novel proteolysis targeting chimeras (PROTACs) against estrogen receptor alpha. PROTACs are heterobifunctional molecules that facilitate the formation of a “trimer complex” comprised of the PROTAC, a pathogenic target protein of interest and an E3 ligase, which catalyzes the ubiquitylation and subsequent degradation of the target protein via the proteasome. To identify novel ER degraders (ER PROTACs), we have used several in vitro assays to characterize the extent of target engagement and receptor degradation. Potent ER PROTACs with good oral exposure and other pharmaceutical properties in multiple pre-clinical species were further evaluated in breast cancer xenograft models. Orally-administered ER PROTACs achieved &gt;80% degradation of estrogen receptor alpha and demonstrated single agent tumor growth inhibition in these disease models. Further, combination with a CDK4/6 inhibitor resulted in the expected improvement in anti-proliferative activity.
Citation Format: Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, Bradley J, Rousseau E, Willard R, Crews CM, Crew AP, Taylor I, Houston J. Identification and development of oral estrogen receptor PROTAC degraders for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-04.
Abstract P4-04-08: Therapeutic strategy for ERα mutation driven-endocrine resistance in ER-positive breast cancers
Authors: Kim J-A , Fuqua SAW 
Published: February 2018

Abstract
Background: Although estrogen receptor (ER)-positive breast cancers are treated with endocrine therapy, 25% of these patients are at risk of relapse and the development of acquired endocrine resistance. Recently mutations in the ER gene (ESR1) have been identified which induce resistance to endocrine therapy. The most frequent ESR1 mutation, Y537S, promotes ligand-independent ER activity. It is known that ER regulates the cell cycle in a ligand-dependent manner. In this study, we examined the effects of the Y537S ESR1 mutation on cell cycle signaling and therapeutic response to checkpoint inhibitor.
Material and Methods: MCF-7 cells expressing the Y537S ESR1 mutation were generated by CRISPR-Cas9 knock-in techniques. Cells were incubated in phenol red minus medium containing 5% charcoal-dextran treated serum for 5 days to remove exogenous hormones. Cell cycle and apoptosis were examined by Flow cytometry and Annexin-V assays. Proliferation was analyzed by BrdU incorporation. Cell senescence was determined using beta-galactosidase assays. Cell cycle checkpoint kinases were examined by western blot analysis. Cell growth was analyzed using soft agar or MTT assays.
Results: Levels of p53 and apoptosis pathway proteins were significantly elevated in Y537S ESR1 mutant cells using RNA expression and reverse-phase protein microarrays. The ATM/ATR and Chk1/Chk2 mediated checkpoint signaling, the upstream pathway of p53, was activated in ESR1 Y537S mutation, which was repressed with fulvestrant treatment. ESR1 Y537 mutant cells accumulated about 5 fold in S phase and 1.7 fold in G2/M phase compared to control cells in estrogen deprived (ED) condition. BrdU incorporation was also increased about 2.5 fold compared with parental cells in estrogen-free medium. In addition, ESR1 Y537 mutant cells expressed a DNA double-strand break marker, gamma-H2AX protein in ED condition. Apoptosis and senescence were observed in ESR1 Y537S mutant cells in regular medium, however, apoptosis was not shown in ED medium. Chk1 inhibitor, PF477736 sensitized MCF-7 expressing ESR1 Y537S mutation to endocrine treatments such as fulvestrant, tamoxifen and AZD9496.
Conclusion: Combination therapy with cell cycle checkpoint kinase inhibitor may lead better prognosis in ER mutation driven-endocrine resistance in postmenopausal breast cancers.
Citation Format: Kim J-A, Fuqua SAW. Therapeutic strategy for ERα mutation driven-endocrine resistance in ER-positive breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-08.
Abstract P4-09-09: Correlation of breast cancer index (BCI) predictive (HoxB13/IL17BR) results to nodal status and hormone receptor expression in early stage HR+ breast cancer
Authors: Elias A , Israel MA , Zhang Y , Schnabel CA , Mayordomo J 
Published: February 2018

Abstract
Background: The HoxB13/IL17BR (H/I) ratio, the endocrine response component of the Breast Cancer Index (BCI), was initially discovered in patients with LN- breast cancer, and validated as a predictive biomarker of benefit from extended endocrine therapy (EET) in a cohort from MA.17 that included both LN- and LN+ patients. Here, correlative analyses were performed to further characterize BCI Predictive (H/I) results with nodal status and quantitative hormone receptor expression.
Methods: Analyses were performed using data from the BCI Clinical Database for Correlative Studies, an IRB-approved de-identified database that contains &gt;50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice (N=19,126). Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of these cases. Cases from patients with confirmed nodal status were analyzed. Chi-squared tests and ANOVA were used to compare results between subgroups.
Results: Analyses included 13,114 patients (median age 58.9y; range 23-92y); 9562 were LN- and 3552 LN+. The distribution of individual H/I scores and proportion of patients classified as High H/I were generally similar in LN- and LN+ patients, though a modestly greater proportion of LN+ patients (46.2%) were classified as High H/I compared to LN- patients (42.0%; P&lt;0.01). In both LN- and LN+ patients, median quantitative ER (qER) expression was slightly higher in patients with Low H/I than with High H/I; qPR showed the same trend but with a larger magnitude (P&lt;0.0001 for both). Similar results were observed for percent positive staining by IHC (P&lt;0.0001). In both LN- and LN+ patients, H/I showed a weak negative correlation with qER (LN-, 0.227; LN+, 0.192) and qPR expression (LN-, 0.311; LN+, 0.311).
Conclusion: In this study to evaluate potential biological correlates of BCI, results showed that H/I biomarker activity did not appear to be dependent on nodal status. Secondly, although ER expression is an established biomarker for endocrine sensitivity, High H/I status did not correlate with increased quantitative ER and PR expression. The H/I ratio may be an independent new marker for endocrine sensitivity independent of the strength of ER expression.
Citation Format: Elias A, Israel MA, Zhang Y, Schnabel CA, Mayordomo J. Correlation of breast cancer index (BCI) predictive (HoxB13/IL17BR) results to nodal status and hormone receptor expression in early stage HR+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-09-09.
Abstract P4-10-11: An active approach to genetic counseling in Trinidadian women with breast cancer
Authors: George SH , Bravo GL , Sandoval AC , Palacio S , Ali J , Donenberg TR , Akbari MR , Narod S , Hurley J 
Published: February 2018

Abstract
Introduction
Breast cancer (BC) is the leading cause of cancer death in Caribbean women. The prevalence of deleterious mutations in BRCA1/2, PALB2 and RAD51C among unselected BC patients in the Caribbean is 5-25%. We previously reported data on low usage of genetic counseling services by Bahamian women. In order to improve the dissemination of genetic testing results to Caribbean probands and their families we developed a structured approach to genetic test result dissemination and family counseling.
Methods
After approval by the University of Miami IRB and the Ethics Committee of the Ministry of Health of Trinidad & Tobago, we prospectively evaluated the active approach to genetic counseling in 32 BC mutation carriers in Trinidad & Tobago in 2015. The intervention consisted of: 1) initial appointment with referring oncologist for results discussion; 2) review of family tree with proband to identify all relatives at 25% or 50% risk (ARR) who should attend the genetic counseling session; 3) preschedule a counseling appointment for ARR within 2 weeks; 4) written invitation to genetic counseling session; 5) handouts of genetic information given to proband to distribute to family members; 6) offer assistance with contacting family members; 7) free genetic testing to ARR who attended the family counseling session.
Results
Twenty-five carriers (78%) consented to enroll in the study. At initial counseling, probands identified 158 ARR, however full family pedigree review at post-result counseling/consultation identified 225 ARR. 101 ARR (64%) attended the information sessions and 76 participants (75.2%) consented to be tested for BC gene mutations. Genetic sequencing revealed 35 ARR (46%) were carriers of at least one mutation. The most frequent reasons for ARR not attending the meetings were: living abroad (18%), unable to be contacted (17%), refusing to participate (17%), not showing up (17%), probands being estranged from ARR (12%) or being afraid to know the results (7%).
Conclusions
In Trinidad & Tobago, a structured approach to the dissemination of genetic test results leads to a significant improvement in the rate of family participation compared to previous efforts (64% in Trinidad & Tobago vs. 9% in the Bahamas).
Citation Format: George SH, Bravo GL, Sandoval AC, Palacio S, Ali J, Donenberg TR, Akbari MR, Narod S, Hurley J. An active approach to genetic counseling in Trinidadian women with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-11.
Abstract P4-13-04: Robotic nipple-sparing mastectomy with immediate prosthetic breast reconstruction : A preliminary study
Authors: Sarfati B , Struk S , Leymarie N , Honart JF , Rimareix F , Delaloge S , Saghatchian M , Ghouadni A , Alkhashnam H , Mazouni C , Kolb F 
Published: February 2018

Abstract
Background: Robotic nipple-sparing mastectomy (RNSM) could be a significant advancement in the treatment of selected breast cancers and prophylaxis. The aim of this prospective study was to assess feasibility of the RNSM with immediate prosthetic breast reconstruction (IPBR) on the first 50 consecutive cases performed in Gustave Roussy.
Methods: RNSM with IPBR was offered to patients with breast cup size A, B or C and ptosis grade ≤ 2. In case of oncologic surgery, RNSM was offered only if the patient fulfilled oncological indications for NSM (NAC). In case of prophylactic surgery, RNSM was offered only if a high-risk genetic mutation had been identified or if the patient was at high risk of breast cancer. The primary endpoint was the conversation rate to open technique. The duration of the surgery, the rate of postoperative complications, the length of the scar, the duration of drainage and hospital stay, the rate and duration of rehospitalization were also analyzed.
Results: Of 50 RNSM with IPBR from December 2015 to April 2017, 1 case of conversion to open technique occurred (2%) because of an uncontrolled bleeding from an internal mammary perforator. Two infections occurred (4%) : one led to implant loss. There were no cases of mastectomy skin flap or NAC necrosis. No other major complications were observed. The duration of the whole procedure was reduced gradually from 214 min to 86 min. Length of scar was between 2.5 and 5 cm. Patients were discharged home between the 4th and the 10th postoperative day after the removal of the drain.
Conclusion: Preliminary data attest to the feasibility, the reproducibility and the safety of this approach. However, long-term data are needed to confirm the reduced rate of skin and NAC necrosis compared to the open technique, the oncological safety and the aesthetic stability of the result.
Citation Format: Sarfati B, Struk S, Leymarie N, Honart JF, Rimareix F, Delaloge S, Saghatchian M, Ghouadni A, Alkhashnam H, Mazouni C, Kolb F. Robotic nipple-sparing mastectomy with immediate prosthetic breast reconstruction : A preliminary study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-13-04.
Abstract P4-13-05: Detection of local recurrence in premenopausal patients treated with neoadjuvant chemotherapy and mastectomy with or without breast reconstruction
Authors: Jacobson CE , Kozak M , Walck E , Hawley E , Horst K 
Published: February 2018

Abstract
Background: Women who undergo mastectomy for breast cancer treatment often undergo implant based or autologous reconstruction. There are limited data, however, as to whether reconstruction may interfere with detection of a locoregional recurrence. The goal of this study was to assess whether women who undergo reconstruction after mastectomy have an increased risk of local recurrence and/or longer time to local recurrence detection.
Methods: One hundred and fifty-four premenopausal patients who underwent neoadjuvant chemotherapy followed by mastectomy were identified between 2005 and 2015. Patients with de novo Stage IV disease or insufficient medical records were excluded from analysis. Patient and treatment variables were collected, including clinical stage, type of chemotherapy, type of surgery and reconstruction, use of postmastectomy radiotherapy, and use of endocrine therapy. Local recurrence (LR) was defined as a chest wall or skin recurrence. Regional failure (RF) was defined as recurrence in the axilla, supraclavicular fossa, or internal mammary nodes.
Results:
The median follow up for this cohort was 49.9 months. Of the 154 patients, 71 (46%) underwent unilateral mastectomy and 83 (54%) underwent bilateral mastectomies. Thirty patients (19%) elected to forgo reconstruction while 78 (51%) received tissue expander/implant based reconstruction, 29 (19%) received autologous reconstruction, and 17 (11%) had unknown reconstruction histories. Patients who had reconstruction had an increased time to detection of a LR compared to those without reconstruction (p=0.048). However, controlling for the T and N stage of disease, Cox regression demonstrated no observable difference in risk for LR between patients who underwent reconstruction compared to those who didn't. There was no difference in detection of RF between those with and without reconstruction (p=0.092).
Conclusions: Premenopausal patients treated with neoadjuvant chemotherapy followed by mastectomy with any type of reconstructive surgery had an increased time to local recurrence detection compared to those without reconstruction. There was no difference in the risk for local recurrence between those who underwent reconstruction compared to those who didn't.
Citation Format: Jacobson CE, Kozak M, Walck E, Hawley E, Horst K. Detection of local recurrence in premenopausal patients treated with neoadjuvant chemotherapy and mastectomy with or without breast reconstruction [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-13-05.
Abstract P4-13-16: Impact of immediate breast reconstruction after mastectomy on the outcome of patients receiving neoadjuvant chemotherapy
Authors: Nogi H , Tomita S , Kamio M , Shioya H , Toriumi Y , Takeyama H 
Published: February 2018

Abstract
Background and purpose
In breast cancer patients receiving neoadjuvant chemotherapy (NAC), immediate breast reconstruction (IBR) is controversial. IBR might favor recurrences and metastases due to delayed adjuvant radiation therapy.
We retrospectively investigated whether IBR after mastectomy influenced the outcome of patients receiving neoadjuvant chemotherapy.
Patients and methods
Between 2006 and 2016, 243 breast cancer patients received total mastectomy after NAC, 48 of whom underwent IBR. Patients receiving IBR (IBR group) were compared to patients who did not receive IBR (no-IBR group) over a prolonged median follow-up time (72.3 moths).
The regimen was 4 cycles of epirubicin (100 or 75 mg/m2), 5-fluorouracil (500 mg/m2), and cyclophosphamide (500 mg/m2) followed by 4 cycles of docetaxel (75 mg/m2). Post-mastectomy radiation was applied in cases treated by IBR following the same selection criteria as for standard mastectomy regardless of the reconstruction approach.
Results
Patients in the IBR group were on average younger than patients in no-IBR
group (p&lt;0.001). The percentage of patients with clinical T1/2 tumor was 81.2% in the IBR group and 58.4% in no-IBR group (p=0.0042). 2 patients (4.2%) in the IBR group and 9 patients (4.6%) in no-IBR group showed the locoregional recurrences. 2 patients (4.2%) in the IBR group and 20 patients (10.3%) showed distant metastases. There were no significant differences.
Conclusions
IBR after total mastectomy was not associated with worse rate of locoregional recurrences in patients receiving NAC.
Citation Format: Nogi H, Tomita S, Kamio M, Shioya H, Toriumi Y, Takeyama H. Impact of immediate breast reconstruction after mastectomy on the outcome of patients receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-13-16.
Abstract P5-01-02: Quantitative assessment of tumor response to neoadjuvant chemotherapy in women with locoregional invasive breast cancer using Tc99m sestamibi molecular breast imaging - preliminary results
Authors: Rauch GM , Adrada BE , Kappadath C , Candelaria RP , Huang ML , Santiago L , Moseley T , Scoggins ME , Knudtson JD , Lopez BP , Hess KR , Krishnamurthy S , Moulder S , Valero V , Yang W 
Published: February 2018

Abstract
Purpose: To report preliminary data in a pilot study evaluating the ability of Tc99m sestamibi Molecular Breast Imaging (MBI) to predict response and assess residual disease at the completion of neoadjuvant chemotherapy (NAC) in breast cancer patients.
Materials and Methods: Patients with localized, invasive breast cancer (T1-T4, N0-N3, M0) planned for NAC were enrolled in this prospective IRB approved clinical trial. All patients had digital mammography (DM), ultrasound (US), and MBI at baseline (T0), after 2 NAC cycles (T1), and at after NAC completion (T2). Tumor size and volume changes were compared with residual disease at surgery. MBI images were corrected for scatter and attenuation using a novel approach and regions of interest (ROI) were drawn over tumors to compute three quantitative MBI uptake metrics for correlation with pathologic response: tumor to background ratio (TBR), fractional activity uptake (FAU), and MBI-specific standardized uptake value (SUV). ROC analysis was performed.
Results: Patients (n=25) who completed NAC, had 75 imaging time points and had surgery, were included in this analysis. Median age was 49 years (range 31 -77). Eleven patients (11/25, 44%) had complete pathologic response (pCR). Absolute TBR values after 2 cycles (T1) and before surgery (T2) had highest correlation with pCR (AUC 0.81; 95% CI 0.63 to 0.99, p=0.01, and AUC 0.78; 95% CI 0.59 to 0.97, p=0.015, respectively). Change in SUV after 2 cycles, Δ SUV1 (T1-T0), (AUC 0.84; 95% CI 0.66 to 1.00, p=0.01) and change in SUV prior to surgery, Δ SUV2 (T2-T0) (AUC 0.80; 95% CI 0.60 to 1.00, p=0.02), were most predictive of pCR. Tumor size and volume showed modest specificity for detecting residual disease, and was highest for MBI (79%), followed by MMG (64%), and lowest for US (55%).
Conclusion: Quantitative MBI metrics show promise for the prediction of pCR in breast cancer patients undergoing NAC. Establishment of quantitative metrics for the early prediction of tumor response during NAC of breast cancer patients may provide an alternate to influencing NAC choice early in the management algorithm. Further investigation with a larger sample size is warranted.
Citation Format: Rauch GM, Adrada BE, Kappadath C, Candelaria RP, Huang ML, Santiago L, Moseley T, Scoggins ME, Knudtson JD, Lopez BP, Hess KR, Krishnamurthy S, Moulder S, Valero V, Yang W. Quantitative assessment of tumor response to neoadjuvant chemotherapy in women with locoregional invasive breast cancer using Tc99m sestamibi molecular breast imaging - preliminary results [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-01-02.