bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PS10-58: Cost effectiveness of routine cardiac imaging during adjuvant trastuzumab in HER2-positive breast cancer
Authors: Tatineni Vineeth , Redle Daniel , Singh Daljeet , Abid Arifa , Mahesh Sameer
Published: February 2021

Background: Guidelines recommend patients treated with trastuzumab (TRA) undergo a multiple gated-acquisition (MUGA) scan or echocardiogram (ECHO) at baseline and every 3 months thereafter. In this retrospective study, we evaluated the incidence of clinically significant cardiotoxicity and analyzed cost effectiveness of routine cardiac imaging during adjuvant TRA.

Methods: HER2-positive breast cancer patients treated with adjuvant TRA between 2015 and 2019 were investigated. Information regarding comorbidities, clinical diagnosis of cardiotoxicity, and alterations in therapy were collected. ECHO and MUGA scans were reviewed to monitor trends in ejection fractions (EF). Data was analyzed via the FREQ procedure. We defined clinically significant cardiotoxicity as holding or discontinuing TRA regimen.

Results: We found 108 patients. Median age was 57 years (interquartile range (IQR) of 47-68 years); 86% Caucasian and 12% African American. 3% had preexisting heart failure, 43% hypertension, 14% diabetes, 4% coronary artery diseases, 32% hyperlipidemia, 2% chronic kidney disease, 6% stroke, and 38% were smokers. No patients received anthracycline containing regimens. 30 patients (27.7%) had EF drop >10% from baseline. Six patients (5.5%) were identified with clinically significant cardiotoxicity; 4 (3.7%) had EF < 50% and 3 of those 4 were symptomatic (2.7% of total). Median time from initiation to decline in EF > 10% was 6 months (IQR of 4.5-7.5 months).

Conclusions: Current practice for TRA cardiotoxicity monitoring consists of cardiac imaging every 3 months. The average cost for a MUGA scan and ECHO is approximately $3700 and $2500, respectively. We determined that clinically significant cardiotoxicity, occurred in 5.5% of the patients approximately 6 months into treatment. With TRA causing reversible cardiotoxicity and 2.7% of the patients being symptomatic, cardiac imaging every 3 months appears excessive, especially in patients without comorbidities. Baseline cardiac imaging with repeat assessment in 6 months appears sufficient in non-anthracycline containing regimen. This strategy allows cost savings of approximately $6000 per patient.

Characteristics of patients with clinical cardiotoxicityClinically Significant Cardiotoxicity (N=6)StageChemotherapy RegimenHeart Failure SymptomsEF drop below 50%Initiation to Drop in EF >10% (months)Discontinuation to Recovery in EF (months)1IIBTCHPNoNo3.21.12IATCHPYesYes6.12.83IIATCHNoNo9.31.34IBTCHYesYes6.54.85IIATHYesYes6.12.66IIATCHPNoYes6.31.2

Citation Format: Vineeth Tatineni, Daniel Redle, Daljeet Singh, Arifa Abid, Sameer Mahesh. Cost effectiveness of routine cardiac imaging during adjuvant trastuzumab in HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-58.
Abstract PS11-34: Time to completion of breast cancer treatment and survival
Authors: Pratt Debra Ann , Burneikis Talia , Tu Chao , Grobmyer Stephen R.
Published: February 2021

Background:Modern breast cancer (BC) treatment involves the use of multimodality therapy. Treatment delays are common and can be multifactorial. There are few studies examining the association between the duration of the time from diagnosis to completion of all acute BC treatment modalities and survival. This study is designed to determine if there is an association between time to complete treatment and survival. Study Design:A retrospective analysis was performed using data from The National Cancer Database (NCDB) to determine whether an association exists between the duration of time from diagnosis to completing all acute BC treatment (surgery, chemotherapy and radiation therapy) and survival. A second analysis was performed to determine if the association between treatment duration and survival varies by receptor status. Results:The NCDB data from BC patients diagnosed in 2010 was analyzed. The inclusion criteria included less than 80 years of age with a single cancer diagnosis, Stage I through III invasive breast cancer who required treatment with surgery, chemotherapy and radiation therapy. A total of 28,284 patients were included in the analysis. Median follow-up was 5.8 years. The order of treatment included 20,772 patients had treatment in the order of surgery, chemotherapy and radiation therapy and 7,512 patients had treatment order chemotherapy, surgery and radiation therapy. A Cox proportional hazards model was developed and identified a cut off showing the risk of delaying completion of all treatment beyond 38 weeks was associated with decrease in overall survival. This was statistically significant with an adjusted hazard Ratio of 1.21. This cut off of 38 weeks was found to be significant regardless of receptors type. The statistically significant Hazard ratios for receptor subtypes include: Triple negative (HR: 1.188, 95%CI: 1.06-1.34), ER+PR+Her2- (HR: 1.22, 95%CI: 1.09-1.36), ER-PR-Her2+ (HR: 1.29, 95%CI: 1.004-1.67) and ER+PR+Her2+ (HR: 1.32, 95%CI: 1.01-1.72). The patients with treatment duration greater than 38 weeks were comprised of 4768(63.47%) neo-adjuvant chemotherapy patients and 8191 (39.43%) of the surgery first group. Conclusion: Efforts to improve the efficiency of multimodality BC treatment and reduce treatment delays should be a priority to optimize BC patient outcomes.

Citation Format: Debra Ann Pratt, Talia Burneikis, Chao Tu, Stephen R. Grobmyer. Time to completion of breast cancer treatment and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-34.
Abstract PS11-40: A novel and highly selective CDK9 inhibitor (D11) suppresses proliferation of triple negative breast cancer cells
Authors: Mustafa Ebtihal
Published: February 2021

Targeted treatment for triple-negative breast cancer (TNBC) remains an elusive clinical challenge. Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator shown to promote growth of multiple cancers, including TNBC, and represents a potential new therapeutic target. CDK9 increases RNA Polymerase II (RNAPII) activity, which facilitates sustained expression of normally short-lived oncogenic and anti-apoptotic proteins. However, preclinical evaluation of CDK9 as a therapeutic target has been hampered by the poor selectivity of existing CDK9 inhibitors (CDK9i). Herein, we evaluated the preclinical efficacy of a newly developed, highly selective CDK9i (D-11) across a panel of TNBC cell lines: MDA-MB-453, MDA-MB-468, MDA-MB-231 and MFM-223. Cells were treated with increasing concentrations of D-11 and effects on proliferation, apoptosis, cell cycle and expression of known CDK9 substrates were examined. Treatment with D-11 significantly reduced cell proliferation, induced G2/M cell cycle arrest and increased apoptosis in MDA-MB-453 and MDA-MB-468 cell lines (IC50s of 160 and 258 nM, respectively). Cell proliferation was also inhibited by D-11 in MDA-MB-231 and MFM-223 cells, but with IC50s of 400 and 468 nM, respectively, but without inducing apoptosis. Protein expression of known CDK9 targets, including phosphorylated-RNAPII, the proto-oncogene C-MYC, and the anti-apoptotic marker MCL-1, were examined by Western blot using the optimal D-11 dose determined for each cell line. As expected, D-11 suppressed phosphorylation of RNAPII (Ser2) without affecting total RNAPII expression in all cell lines, indicative of targeted CDK9 inhibition. C-MYC and MCL-1, which highly expressed in the TNBC models, were significantly decreased by treatment with D-11. To determine whether D-11 influenced normal breast epithelial cells, breast tissues were collected from women undergoing reduction mammoplasty and cultured ex vivo as explants treated with or without different doses of D-11 for 48h. A high dose of D-11 (2.7µM) elicited a 20% decrease in the proliferative index (Ki67 positivity) of epithelial cells within normal tissue explants but had no effect on their histology. Collectively, these data demonstrate that D-11 effectively inhibits CDK9 in TNBC cell lines, resulting in growth inhibition with non-toxic effects on histologically normal breast tissues.

Citation Format: Ebtihal Mustafa. A novel and highly selective CDK9 inhibitor (D11) suppresses proliferation of triple negative breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-40.
Abstract PS13-05: A phase 2 study of oral paclitaxel and encequidar (oPac+E) in the treatment of cutnaeous angiosarcoma: The breast angiosarcoma subgroup
Authors: Ravi Vinod , Wagner Michael , Chen Tom Wei-Wu , Loong Herbert H , Mennel Robert , Yen Cheuh-Chuan , Clack Glen , Cutler David , Kwan Rudolf , CHan Wing=Kai
Published: February 2021

Background Cutaneous angiosarcomas are highly aggressive malignant tumors with poor prognosis. Currently there is no FDA-approved treatment. oPac+E is a combination of oral paclitaxel and a novel oral P-glycoprotein inhibitor, Encequidar. Materials and Methods: This is a phase-2 study evaluating the activity, safety and tolerability of oPac 205mg/m2 + E 12.9 mg once daily for 3 consecutive days weekly for patients with unresectable cutaneous angiosarcoma. Tumour response was evaluated every 6 weeks using RECIST and photography. Results: From Aug-2018 to May-2020, 7 of 26 enrolled patients (pts) had breast cutaneous angiosarcoma. All had previous breast cancer, mastectomy and radiotherapy and/or adjuvant chemotherapy, no prior taxane for angiosacoma and no metastatic disease. Median age was 66 yrs (range 49-76). Best objective response rates were: complete response (CR) 43% (3/7 pts), partial response (PR) 14% (1/7 pts), stable disease (SD) 43% (3/7 pts), progressive disease (PD) 0%. Furthermore, 3 pts (43%) who had inoperable lesions were deemed operable after Oraxol treatment and received curative intent surgical resection. Median progression free survival (PFS) was 17 weeks. oPac+E was generally well tolerated. Grade-3 treatment related adverse events (AEs) occurred in 5 pts: diarrhea=1, fatigue=2, neutropenia =1, dyspnea=1, dehydration=1, pneumonitis=1. Grade-4 AE were neutropenia in 2 pts. Grade-2 paraesthesia=1. All pts fully recovered. Dose reductions were needed in 3 subjects. No patients discontinued treatment due to AEs. To date no patients died. Conclusions: oPac+E may provide an effective oral treatment for radiation-associated breast angiosarcoma, with a high clinical benefit rate (CR + PR+ SD=100%), durable response and enabled resection of unresectable tumors. It is generally well tolerated even in elderly patients; with low incidence of neuropathy. It may allow patients to avoid hospital IV chemotherapy visits and the option of home treatment.

Citation Format: Vinod Ravi, Michael Wagner, Tom Wei-Wu Chen, Herbert H Loong, Robert Mennel, Cheuh-Chuan Yen, Glen Clack, David Cutler, Rudolf Kwan, Wing=Kai CHan. A phase 2 study of oral paclitaxel and encequidar (oPac+E) in the treatment of cutnaeous angiosarcoma: The breast angiosarcoma subgroup [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-05.
Abstract PS13-13: The value of shear-wave elastography for prediction of treatment response to neoadjuvant chemotherapy in patients with breast cancer
Authors: Bae Soong June , Kim Min Ji , Cha Yoon Jin , Eun Na Lae , Kim Dooreh , Lee Janghee , Ahn Sung Gwe , Son Eon Ju , Jeong Joon
Published: February 2021

Introduction Recently, Shear-wave elastography (SWE) has been known to be useful for the diagnosis of breast cancer and lymph node metastasis. However, little is known about whether SWE can predict the response to neoadjuvant chemotherapy in patients with breast cancer. This study aimed to investigate the relationship between treatment response and elasticity values. Method Pre-treatment shear-wave elastography was performed in 394 patients who underwent neoadjuvant chemotherapy followed by surgery at Gangnam Severance Hospital from January 2012 to May 2020. We evaluated the pathologic complete response (pCR, defined as ypTis/T0, No) according to elasticity values such as ‘Mean stiffness’, ‘Minimum stiffness’, ‘Maximum stiffness’, and ‘Ratio’. Results A total of 394 patients, 147 (37.3%) achieved pCR. All elasticity values were significantly lower in patients with pCR after neoadjuvant chemotherapy than those with the residual invasive tumor. In the multivariable analysis, the mean stiffness (OR 0.995; 95% CIs, 0.989-1.000; P=0.039) and the maximum stiffness (OR 0.995; 95% CIs, 0.990-0.999; P=0.024) were independent predictive factors for pCR after adjusting clinic-pathologic factors. Besides, the tumor-infiltrating lymphocytes (TILs) evaluated in biopsy samples were inversely correlated with pre-treatment mean stiffness (CC -0.053, P=0.044), and elasticity ratio (CC-0.288, P=0.033). Conclusion In this study, pre-treatment elasticity values measured by SWE were significantly associated with pCR in breast cancer. Our results suggest that SWE can be a useful diagnostic tool for predicting treatment response in patients with breast cancer who will receive neoadjuvant chemotherapy.

Citation Format: Soong June Bae, Min Ji Kim, Yoon Jin Cha, Na Lae Eun, Dooreh Kim, Janghee Lee, Sung Gwe Ahn, Eon Ju Son, Joon Jeong. The value of shear-wave elastography for prediction of treatment response to neoadjuvant chemotherapy in patients with breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-13.
Abstract PS13-15: Impact of neoadjuvant chemotherapy on breast reconstruction - systematic review and meta-analysis
Authors: Varghese Jajini Susan , Gohari Shireen , Shawky Michael , Hyun Faith , Johnson Laura , Schmid Peter
Published: February 2021

BackgroundImpact of neoadjuvant chemotherapy (NACT) on breast reconstruction outcomes remain unclear. We did a systematic review and meta-analysis to assess the effect of NACT on post-operative complications and delay to adjuvant therapy among women undergoing immediate breast reconstruction.

MethodsIn this systematic review and meta-analysis, we searched medical databases from inception of this technique to May 2, 2020 to identify articles that assessed the impact of NACT on separate techniques of immediate breast reconstruction. Studies reporting on at least one of our pre-defined major post-operative complications were included. Study authors were contacted for individual patient-level data which was not available. Study quality and risk of bias are reported through NOS Scores and GRADE table. PROSPERO registration CRD42020183761.

FindingsOf 477 identified articles, 17 studies (3249 patients) were eligible for inclusion. NACT did not increase the risk of overall complications after immediate breast reconstructions RR: 0.91(95% CI 0.74 to 1.11, p = 0.34). There was no large increase in flap losses (total and partial) in patients receiving NACT compared to control group (RR:1.23, 95% CI 0.70 to 2.18, p = 0.47; I2 = 0%). There was however, some evidence of increased risk of implant/expander loss after NACT treatment (RR:1.50, 95% CI 1.03 to 2.20, p = 0.04; I2 = 34%). NACT treatment was not associated with increase in haematomas, seromas or wound complications or significant delay to adjuvant therapy access; RR:1.59, 95% CI 0.66 to 3.87, p = 0.30

InterpretationImmediate breast reconstruction after treatment with NACT remains a safe procedure. Careful patient selection may play a bigger role when planning implant-based reconstructions after NACT.

FundingNone.

Citation Format: Jajini Susan Varghese, Shireen Gohari, Michael Shawky, Faith Hyun, Laura Johnson, Peter Schmid. Impact of neoadjuvant chemotherapy on breast reconstruction - systematic review and meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-15.
Abstract PS13-45: Radiological response pattern predicts disease-free survival in breast cancer patients undergoing neoadjuvant chemotherapy
Authors: Ahn Juneyoung , Yoo Tae-kyung , Paik Pill Sun , Cho Min Kyung , Yoon Chang Ik , Park Woo Chan
Published: February 2021

Purpose Pathological complete response (pCR) predicts improved survival in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). However, the prognosis of patients with non-pCR remains unclear. The aim of this study was to evaluate the effect of radiological response pattern on breast cancer patients’ outcome.

Method A total of 396 breast cancer patients who underwent neoadjuvant chemotherapy between 2010-2017 at Seoul St. Mary’s Hospital were retrospectively reviewed. Among them, patients who underwent 4-6 cycles of neoadjuvant chemotherapy and underwent response evaluation every 2 cycles using breast MRI were included for analysis. Early and late response ratio was calculated from breast MR images using the longest diameter of the main tumor. Early response ratio was calculated as post-2 cycle NAC / pre-NAC ratio. Late response ratio was calculated as post-4 cycle NC / post-2 cycle NAC ratio. Radiological response pattern was divided into three groups; fast-slow responder meaning early response ratio > late response ratio + 20%, slow-fast responder meaning late response ratio > early response ratio + 20% and constant responder meaning the difference between initial response ratio and later response ratio is lower than 20%. Survival analysis was done using the Kaplan-Meier method and multivariate analysis by Cox regression. Disease-free survival (DFS) was defined as locoregional recurrence, contralateral breast recurrence and distant metastasis.

Result A total of 177 patients were included for analysis. Among them 19 (10.7%) patients were pCR, 122 (68.9%) patients had partial response, 29 (16.4%) patients had stable disease and 7 (4.0%) patients had progressive disease. Median follow-up period was 50 months (range, 3-112 months). Radiological response pattern was significantly associated with disease-free survival in univariate analysis (p=0.042). Fast-slow responders had significantly worse disease-free survival (DFS) in univariate analysis compared to slow-fast responders and constant responders (p=0.042, 5-year DFS 67.6%, 88.3% 67.6%). Radiological response pattern continued to be statistically significant by multivariable analysis (p=0.037).

Conclusion Our results showed that fast-slow responders have worse survival compared to constant or slow-fast responders. Radiological response patterns may be useful to more accurately assess prognosis, especially when considering adjuvant chemotherapy.

Citation Format: Juneyoung Ahn, Tae-kyung Yoo, Pill Sun Paik, Min Kyung Cho, Chang Ik Yoon, Woo Chan Park. Radiological response pattern predicts disease-free survival in breast cancer patients undergoing neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-45.
Abstract PS14-24: Multi-center trial in the treatment of ductal carcinoma in situ of breast using intra-operative electronic brachytherapy technique, results
Authors: Syed Alam M.Nisar
Published: February 2021

Purpose: To report on the technique of intra-operative electronic brachytherapy, local control, side effects and complications after a single fraction of 2000 cGy at the time of partial mastectomy.

Material & Methods: 1200 patients with early stage invasive ductal carcinoma and carcinoma in situ were enrolled in the Multi-Center Trial. 246 (20.5%) patients among these 1200 patients had carcinoma in situ and were treated by a single fraction of 2000 cGy dose by intra-operative irradiation to the lumpectomy cavity using Xoft system of electronic brachytherapy at the time of partial mastectomy. 80% of the patients were Caucasian, 7% African American, 7% Hispanic and 6% others. Estrogen receptor was positive in 211 patients, negative in 28 patients and unknown/not assessed in 7 patients. Progesterone receptor was positive in 190 patients, negative in 45 patients and unknown/not assessed in 11 patients. All patients were BRCA negative. 34 (14%) patients had low grade tumors, 109 (44%) intermediate grade tumors, and 103 (42%) high grade tumors. Seroma occurred in 9.8%, induration in 7.6%, and significant fibrosis in 3.5% of the patients. 2/246 (1%) developed ipsilateral recurrence and one patient developed a gastrointestinal cancer. 118 (48%) patients had characteristics of ASTRO criteria being suitable, 108 (44%) cautionary and 20 (8%) unsuitable.

Conclusion: The relatively early 2.3 year results of a single fraction of 2000 cGy by IORT to the lumpectomy cavity at the time of partial mastectomy using Xoft Axxent electronic brachytherapy in the treatment of carcinoma in situ of the breast is safe and associated with low morbidity and local recurrence with good to excellent cosmesis in 80% of the patients.

Citation Format: Alam M.Nisar Syed. Multi-center trial in the treatment of ductal carcinoma in situ of breast using intra-operative electronic brachytherapy technique, results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-24.
Abstract PS15-06: The distribution of radiosensitivity index differs by PAM50 subtype in primary breast tumors
Authors: Fahey Matthew , Russo Nicholas , Liveringhouse Casey , Mills Matthew , Ahmed Kamran , Diaz Roberto
Published: February 2021

Background: Prior studies identified radiosensitive and radioresistant breast tumor phenotypes and demonstrated that gene-expression signatures such as the radiosensitivity index (RSI) can be used to derive biologically rational radiation dose selection. In this study, we assessed the RSI of primary breast tumor samples and its association with PAM50 subtype.Materials/Methods: Primary breast tumor samples were identified from a multi-institutional tissue biorepository. Tumors were excluded if they were treated with neoadjuvant therapy or had distant metastatic disease at the time of sample collection. The RSI gene signature and PAM50 subtype were assessed through transcriptomic profiling performed on Affymetrix microarray chips. Distribution of RSI values across PAM50 subtypes was assessed with the Kruskal-Wallis test. Differences in proportions of radioresistant and radiosensitive tumors among PAM50 subtypes were assessed with the Chi-squared test, where radioresistant was defined as RSI>0.3745 based on prior studies. Clinicopathologic characteristics were obtained through clinical chart review. Results: A total of 637 primary breast tumors with available genomic profiling and clinical information were included for analysis. HIstologies were predominantly invasive ductal carcinoma (81.5%) and invasive lobular (11.6%). Most tumors were T1-T2 (91.7%) while 35.9% had pathologically positive lymph nodes. The distribution of RSI significantly differed by PAM50 classification (Kruskal-Wallis p < 0.001). Proportions of radioresistant vs radiosensitive tumors varied significantly according to PAM50 subtype and are included in the accompanying table (Chi-squared p < 0.001). Median follow-up was 89 months.

Conclusion: Breast tumor PAM50 subtypes demonstrate significant variation in radiosensitivity. Further studies are needed to determine if genomic subtyping can refine the ability to predict clinical radiation response and further optimize individual therapy.

PAM50TotalBasalHer2LumALumBNormalRSI PhenotypeRadioresistantn (%)50 (60.2%)32 (42.1%)146 (54.4%)82 (45.3%)24 (82.8%)334 (52.4%)Radiosensitive n (%)33 (39.8%)44 (57.9%)122 (45.6%)99 (54.7%)5 (17.2%)303 (47.5%)Total837626818129637

Citation Format: Matthew Fahey, Nicholas Russo, Casey Liveringhouse, Matthew Mills, Kamran Ahmed, Roberto Diaz. The distribution of radiosensitivity index differs by PAM50 subtype in primary breast tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-06.
Abstract PS16-21: Apc control of taxane resistance in breast cancer
Authors: Prosperi Jeni , Astarita Emily , Hoover Camden , Maloney Sara
Published: February 2021

Adenomatous Polyposis Coli (APC) is a multi-domain tumor suppressor with multiple binding partners, including β-catenin, axin, and microtubules. APC is lost in many epithelial cancers, including up to 70% of sporadic breast cancers, with a tendency towards triple negative breast cancers (TNBCs). We previously demonstrated that APC knockdown in the human TNBC cell line, MDA-MB-157, resulted in resistance to Paclitaxel (PTX), a chemotherapeutic agent of the Taxane family that inhibits mitotic progression. Further studies have confirmed this finding in the MDA-MB-231 cells with CRISPR-mediated APC knockout. To understand the mechanism(s) by which APC controls response to PTX, we have taken two approaches. We first performed an unbiased analysis of transcriptomic changes downstream of APC loss to identify potential therapeutic targets to overcome PTX resistance. In this, a group of transcripts involved in regulation of the cell cycle were identified, including LBH, GLI1, RGS4, and NUPR1. These results have been validated by qRT-PCR and western blot, leading to studies in the laboratory to investigate their specific effects on the response to PTX in breast cancer. Along with the broad exploration studies, molecular studies have focused on whether APC controls expression of cell cycle proteins, leading to PTX resistance. While we observed changes in multiple cell cycle proteins, our focus was on the G2/M transition, given that both PTX and APC impact microtubule dynamics and the G2/M phase of the cell cycle. We examined the effect of APC loss on expression of G2/M proteins, identifying a significant upregulation of CDK1 in APCKD cells. Despite no changes in phosphorylation status of CDK1, we found that Cyclin B1 and CDK1 are only complexed in the APCKD cells, suggesting increased activation. Further studies showed that while the majority of CDK1 and Cyclin B1 are localized to the cytoplasm, there is a small amount in the nucleus. Based on these findings, we sought to investigate whether PTX sensitivity would be altered in response to CDK1 inhibitor, RO-3306. We have shown that PTX resistant APCKD cells are more sensitive (IC50 = 25.5uM) to RO-3306 compared the parental control (IC50 = 78uM). Future studies will use combination and sequential treatments to monitor PTX response in vitro and in vivo. Combined, these studies are elucidating the mechanisms by which loss of APC controls sensitivity to PTX in TNBC, with the long-term goal of designing treatment regimens to improve patient health and survival.

Citation Format: Jeni Prosperi, Emily Astarita, Camden Hoover, Sara Maloney. Apc control of taxane resistance in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-21.
Abstract PS16-23: Elucidating the role of APC resulting in doxorubicin resistance in breast cancer
Authors: Prosperi Jeni , Stefanski Casey
Published: February 2021

Chemoresistance is a leading cause of breast cancer related deaths. Therefore, understanding the molecularbasis for chemoresistance is essential for novel therapeutic advancement improving patient outcome. TheAdenomatous Polyposis Coli (APC) tumor suppressor is lost in up to 70% of sporadic breast cancer; however,little is known about how APC loss contributes to chemoresistance. Using mammary tumor cells isolated fromthe Apc Min/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we werethe first to show that APC loss decreased doxorubicin (DOX) induced apoptosis. Therefore, we investigatedthe mechanisms contributing to DOX resistance with APC loss to identify combination therapy options. DOX, acommonly used chemotherapeutic in breast cancer, inhibits topoisomerase IIa (Topo IIa), causing doublestranded breaks (DSBs), the most lethal form of DNA damage, and APC has been shown to affect Topo IIaactivity. DSB repair is mediated through HRR (homologous recombination repair) or NHEJ (nonhomologousend joining), which are regulated by the repair serine/threonine kinases: ataxia telangiectasia mutated (ATM)or ataxia telangiectasia and Rad3 related (ATR), but only NHEJ activates DNA-dependent protein kinase(DNA-PK). We hypothesized that APC loss prevents DOX-mediated apoptosis through alterations in HRR andNHEJ. To investigate the effect of APC loss on DNA damage repair pathways, we monitored damagerecognition pathways after 24-hour DOX treatment. The MMTV-PyMT;Apc Min/+ cells exhibited decreaseddamage as measured by γH2AX expression and comet assay. We also observed decreased ATMphosphorylation in MMTV-PyMT;Apc Min/+ following DOX treatment compared to control. Decreasedphosphorylation of Chk1 and Chk2 was also observed in DOX-treated MMTV-PyMT;Apc Min/+ cells. Using theATM inhibitor (KU55933) or the DNA-PK inhibitor (NU7441), we observed increased DOX-induced apoptosis inMMTV-PyMT;Apc Min/+ cells. These data suggest enhanced DNA repair in MMTV-PyMT;Apc Min/+ cells and will beconfirmed by measuring repair efficiency via reporter plasmids. In addition, knowing that APC affects activitiesby Topo IIa, we measured the amount of Topo IIa: DNA cleavage complexes following DOX treatment.Taken together, APC loss mediates DOX resistance via increasing DNA repair demonstrating the potential useof combination therapy to overcome chemoresistance.

Citation Format: Jeni Prosperi, Casey Stefanski. Elucidating the role of APC resulting in doxorubicin resistance in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-23.
Abstract PS16-24: Mechanisms underlying obesity-induced enrichment of stem-like breast cancer cells
Authors: Mayberry Shannon , Harlow Brittany , Eichman Elizabeth , Hsu Christopher , deGraffenried Linda
Published: February 2021

Background: Breast cancer represents the most common nonskin malignancy in women worldwide, and most deaths result from metastatic dissemination of the disease. At the same time, studies indicate that obesity induces a stem cell-like phenotype, required for tumor metastases and associated with cancer progression and mortality. Although the precise mechanism behind this reprogramming event remains to be elucidated, preliminary data from our lab demonstrate that the epithelial-mesenchymal transition (EMT) associated with obese conditions is linked to IL-6 mechanistically. Because IL-6 cannot be targeted clinically, it will be of the utmost importance to identify downstream effectors of this IL-6-mediated response. This said, we hypothesize that increased levels of IL-6 in obese conditions are at least partially responsible for inducing a stem cell-like phenotype in breast cancer cells through activation of the Akt-mTOR pathway.Methods: MCF-7 and T47D breast cancer cells will be exposed to sera pooled from normoweight (BMI<25 kg/m2) or obese (BMI≥30 kg/m2) women as an in vitro model of the systemic inflammation present in obesity. The cells will then be assessed for changes in expression of genes and proteins involved in induction of EMT using qPCR and western immunoblotting, respectively. Finally, flow cytometry will be used to confirm establishment of an EMT phenotype with measurement of the stem cell markers CD24 and CD44.Results: Our gene expression analyses confirm that obese conditions increase expression of EMT-related genes, including those encoding the transcription factors Snail and Twist. Our flow cytometric analyses also indicate an increase in the stem cell population following a 10-day IL-6 exposure. Additionally, supplementation of IL-6 to non-obese sera increased expression of Twist and Snail in breast cancer cells, while inhibition of IL-6 in obese sera reduced expression of these transcription factors. Finally, western blot analyses demonstrate mechanistic involvement of the Akt-mTOR pathway.Conclusions: These data contribute to our understanding of the means by which obesity induces a stem-like phenotype in breast cancer cells and will ultimately bring light to a therapeutic target that can be used to modulate IL-6-induced activation of the Akt-mTOR signaling pathway leading to an EMT phenotype in obese conditions.

Citation Format: Shannon Mayberry, Brittany Harlow, Elizabeth Eichman, Christopher Hsu, Linda deGraffenried. Mechanisms underlying obesity-induced enrichment of stem-like breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-24.
Abstract PS16-28: Runx3 regulates emt during development lapatinib resistance
Authors: Kim So Hyeon , Min Ahrum , Kim Seongyeong , Park Yoonjung , Kim Yu Jin , Im Seock-Ah
Published: February 2021

RUNX3 regulates EMT during development lapatinib resistanceBackground: Lapatinib is a small molecular inhibitor of HER2 and EGFR tyrosine kinase, which is used for HER2 positive metastatic breast cancer patients. However, significant proportion of patients relapse due to acquired resistance. The epithelial to mesenchymal transition (EMT), which induces cell migration, invasion and cancer stem cell progression, was one of the mechanism that confers to drug resistance. We determined the correlation of lapatinib resistance and EMT, and identified a regulatory factor of EMT which associated with the development process of acquired lapatinib resistance.Methods: Acquired lapatinib resistant SK-BR-3 (SK-BR-3 LR) cells were established by continuously exposing to lapatinib for 7 months. The sensitivity of lapatinib was confirmed by MTT assay. Cell cycle progression was verified using flow cytometry analysis. Expression of signal transduction molecules were determined using quantitative PCR, western blotting and transcriptome data analysis. Cell migration and invasion ability were verified using wound healing assay and Boyden chamber assay. siRNA knock-down system were used for further analysis. Results: Lapatinib resistant (SK-BR-3 LR) cells showed aggressive morphology compared with parental cells. The growth rate and cell cycle progression were increased in SK-BR-3 LR cells. Expression of Snail, Vimentin, SOX2, Nanog, TGF-b1 and Smad proteins increased in SK-BR-3 LR cells. In SK-BR-3 LR cells, cell migration and invasion were significantly increased. Correlated with a promoter methylation of RUNX3, expression of RUNX3 was down-regulated in SK-BR-3 LR cells. In Runx3 knock-down cells TGF-b1, SOX2, smad molecules were up-regulated. Conclusion: SK-BR-3 LR cells showed aggressive phenotype. Expression of EMT markers, cancer stem cell markers, TGF-β pathway associated molecules and Smad proteins were increased in SK-BR-3 LR cells. Also, the increase of cell migration and invasion was observed in LR cells. RUNX3 affected to cell migration and invasion through regulation of EMT associated molecules. Therefore, RUNX3 might be a specified molecule, which partially contributes resistance to lapatinib through regulates EMT.

Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Yoonjung Park, Yu Jin Kim, Seock-Ah Im. Runx3 regulates emt during development lapatinib resistance [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-28.
Abstract PS16-34: Phenotype and prognosis of patients with breast cancer and pathogenic TP53 variants
Authors: Petry Vanessa
Published: February 2021

Background: The lifetime risk of cancer in individuals with Li Fraumeni syndrome (LFS) is more than 70% for men and more than 90% for women. Breast cancer (BC) is the most common type of cancer in premenopause women with pathogenic allelic TP53 variants (PVs). However, little is known about the BC response to systemic therapy and the prognosis in these patients. We aim to analyze the phenotype and the outcomes of patients with LFS and BC. Methods: We evaluated a cohort of patients with PVs or likely PVs of TP53 with BC diagnosis treated from December 1999 to June 2020 from a single tertiary cancer center. Our primary objective is to evaluate the outcomes of these patients. Secondary objective is to describe the BC phenotype, characterizing the clinical and the pathological features.Results: Among 56 patients with PVs or likely PVs of TP53, 25 were diagnosed with BC. Median age at BC diagnosis was 39.2 years (range 23.4-57.4 years). The majority (N= 18, 72%) harbored a germline PV TP53 p.R337H in heterozygosity status. The most common histology type was an invasive carcinoma of no special subtype, 73% were hormone receptor-positive, and 32% were HER2-positive. Three (12%) patients were metastatic at diagnosis. Seven (28%) of the patients with localized disease at diagnosis received neoadjuvant chemotherapy, and other 7 (28%) received adjuvant chemotherapy. Among patients treated with neoadjuvant chemotherapy, 5 (71%) had a tumor response, while 2 (29%) presented with disease progression. No pathologic complete response was achieved. After a median follow-up of 52.6 months, no deaths secondary to breast cancer occurred. Only 1 patient died due to another neoplasm (jaw osteosarcoma), and 3 (12%) patients developed radiotherapy-induced malignancies in the irradiated field. Conclusions: BC in patients with LFS is mainly the invasive carcinoma of no special subtype, enriched in hormone receptor and HER2 positivity. Although response to neoadjuvant chemotherapy is high, no pathologic complete response occurred in this cohort. Favorable outcomes were observed, with a high BC specific survival. Secondary malignancies remain a major concern. Larger cohorts should test whether new genes act as modifiers of p53 function and breast cancer susceptibility.

Citation Format: Vanessa Petry. Phenotype and prognosis of patients with breast cancer and pathogenic TP53 variants [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-34.
Abstract PS17-25: Repurposing anti-depressant imipramine for treating breast cancers
Authors: Timilsina Santosh , Rajamanickam Subapriya , Rao Arhan , Subbarayalu Panneerdoss , Jatoi Ismail , Chen Yidong , Vadlamudi Ratna , Kaklamani Virginia G , Rao Manjeet
Published: February 2021

About 1 in 8 women will develop invasive breast cancer during their life time and more than 41,000 women die every year in the United States alone. Most of these deaths are attributed to relapse, distant metastasis and therapy resistance. For example, despite initial response to therapy, a significant proportion of ER+ BCs become therapy resistant and progress to incurable metastases. Similarly, TNBCs, which is highly aggressive and are more likely to occur in Hispanic and black women, have higher propensity to relapse and contribute to disproportionate number of deaths. Unfortunately, the patients who do survive, have reduced quality of life due to the chemotherapy-associated toxicity. One mechanism that helps BCs to survive and become therapy-resistant is their unique ability to keep repairing their DNA. The aim of this study was to identify and test whether any FDA-approved non-cancer drug/s can block DNA repair ability and consequently growth of BC cells. Treatment of BC cells with a set of FDA approved drugs showed that antidepressants imipramine can inhibit the BC cell growth. Imipramine treatment significantly reduced the short and long-term viability of TNBC and ER+ breast cancer cells. Further, imipramine treatment inhibited the migration and invasion of breast cancer cells. Systemic delivery of imipramine suppressed the breast cancer cells growth in orthotopic mouse xenograft model. Our results revealed that imipramine treatment induced G1/S cell cycle arrest and apoptosis in breast cancer cells. Importantly, imipramine blocked the DNA repair capacity of BC cells by inhibiting the expression of DNA repair proteins including FOXM1 and RAAD51. Notably, imipramine treatment improved the efficacy of the PARP inhibitor “olapraib” in TNBC and sensitized the tamoxifen response in tamoxifen resistant ER+ breast cancer cells. Our results suggest that imipramine can be used as a single or therapeutic adjuvant for treating therapy sensitive and therapy resistant breast cancers. Based on these results, we are currently conducting a clinical trial to test the therapeutic efficacy of imipramine for treating breast cancer patients (https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2017 01937&r=1).

Citation Format: Santosh Timilsina, Subapriya Rajamanickam, Arhan Rao, Panneerdoss Subbarayalu, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia G Kaklamani, Manjeet Rao. Repurposing anti-depressant imipramine for treating breast cancers [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-25.
Abstract PS17-33: Sumo-modified androgen receptors support the metastatic phenotype of endocrine-resistant hormone receptor-positive breast cancer
Authors: Bawa-Khalfe Tasneem , Bahnassy Shaymaa , Thangavel Hariprasad , Quttina Maram , Khan Ashfia Fatima , Dhanyalayam Dhanya , Ritho Joan , Karami Samaneh , Ren Jing
Published: February 2021

Background: Conventional endocrine therapy is the first-line treatment for hormone receptor positive (HR+) breast cancer (BCa) subtype. Frequently, intrinsic and acquired ET resistance (ET-R) persists to support a disease with poor prognosis and limited therapy than the ET-sensitive carcinoma. High levels of androgen receptors (AR) in HR+ BCa correlate with insensitivity to ET tamoxifen and greater susceptibility to cancer metastasis. However, targeting AR with antagonist enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. In the current report, we present novel findings of a constitutively active modified AR population that accumulates in the ET-R HR+ BCa cells to drive cell migration and metastatic phenotype.

Methods: Cell-free protein modification tests, in-house SUMOylation assays, and PLA imaging were used to determine the AR protein profile in multiple ET-sensitive, intrinsic-, and acquired-ET HR+-BCa lines. Reporter assay and targeted transcriptome studies evaluate the genomic activity of native and modified-AR mimetic. Finally, the inhibitory effect of Enz with or without combination therapy was determined using migration and spheroid growth studies.

Results: In acquired and intrinsic ET-R BCa cell lines, a constitutively active, higher molecular weight SUMO-modified AR (SUMO-AR) persists at the chromatin. The SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation. We now report that the canonical AR chaperone protein HSPB1/Hsp27 functions as a novel SUMO-E3 ligase for AR. SUMO-AR interacts with a unique repertoire of biomolecules as compared to unmodified AR in the same cell lines. An increase in the SUMO protein and global SUMO-modified proteome supports this multimeric complex. The ligand-independent SUMO-AR activity promotes a gene-expression profile that favors epithelial-mesenchymal transition. Treatment with Enz alone or in combination with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa.

Conclusion: SUMO-AR dictates metastatic susceptibility and Enz responsiveness of ET-R HR+ BCa. Consistently, targeting both unmodified and SUMO-modified AR serves as a better therapeutic strategy for advanced HR+ BCa.

Citation Format: Tasneem Bawa-Khalfe, Shaymaa Bahnassy, Hariprasad Thangavel, Maram Quttina, Ashfia Fatima Khan, Dhanya Dhanyalayam, Joan Ritho, Samaneh Karami, Jing Ren. Sumo-modified androgen receptors support the metastatic phenotype of endocrine-resistant hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-33.
Abstract PS17-49: Investigating CDK4/6 inhibition in triple negative breast cancer
Authors: Guo Qiuchen , Goreczny Gregory J , Spasic Milos , Maynard Adam , McAllister Sandra S
Published: February 2021

The purpose of our study is to evaluate the immunological effects of CDK4/6 inhibitors in pre-clinical models of triple negative breast cancer (TNBC). CDK4/6 inhibitors, including abemaciclib, are currently approved to treat patients with metastatic hormone receptor-positive (HR+), Her2-negative breast cancer. We previously reported in our Her2+ model that CDK4/6 inhibitors promote anti-tumor immunity through inducing tumor cell antigen presentation via activating tumor endogenous retroviral elements, which induce type III interferon production and MHC-I upregulation (Goel, DeCristo, et al., Nature, 2017). We also uncovered important anti-tumor effects on the immune system: CDK4/6 inhibitors decrease T regulatory cell proliferation without affecting cytotoxic CD8 T cell numbers. TNBC has been considered a poor candidate for CDK4/6 inhibitor therapy, as tumors often lose retinoblastoma (Rb) protein expression/function, which is critical for CDK4/6 inhibitor-induced cell cycle arrest. However, Rb mutation or loss occurs in only ~20% of TNBC cases and we found Rb expressing murine and human TNBC cell lines decreased proliferation in vitro in response to abemaciclib. In our preclinical model of TNBC, abemaciclib induced tumor regression. Consistent with previous findings, TNBC tumor cells upregulated MHC-I upon abemaciclib treatment, suggesting increased antigen presentation. Tumor cell-surface PD-L1 was also increased with abemaciclib both in vitro and in vivo, as assessed by flow cytometry and RT-qPCR. These results are encouraging, given that αPD-L1 therapy (Atezolizumab) in combination with chemotherapy (nab-paclitaxel) has recently been approved as standard care for metastatic TNBC and the IMpassion130 trial reported enhanced progression-free and overall survival in patients with PD-L1+ tumors. We also found that abemaciclib increased CD8+ and CD4+ T cells and decreased PD1+ CD8 and CD4 cells in the spleen. Furthermore, total numbers of naïve CD8+ and CD4+ T cells increased with abemaciclib treatment, suggesting a favorable anti-tumor systemic immunological effect. Our data suggest the potential efficacy of CDK4/6 inhibitors in combination with αPD-L1 in the treatment of Rb+ TNBC. Deeper analysis of the mechanisms involved in regulating PD-L1 and enhancing naïve T cells should enable us to evaluate combination therapies using CDK4/6 inhibitors for this particularly deadly breast cancer subtype.

Citation Format: Qiuchen Guo, Gregory J Goreczny, Milos Spasic, Adam Maynard, Sandra S McAllister. Investigating CDK4/6 inhibition in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-49.