bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-02-08: Biomarker associated with response to CDK4/6 inhibitors in metastatic hormone receptor positive breast cancer
Authors: Witkiewicz Agnieszka
Published: March 2023

Background: In spite of widespread use and known mechanism of action, predictive biomarkers for the use of CDK4/6 inhibitors in conjunction with endocrine therapy have yet to emerge. Here a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS). Patients and Methods: In this cohort of 235 patients, >90% of patients were treated with Palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). The PFS mirrored that observed in randomized clinical trials. A total of 151 patient tumor tissues were used for targeted gene expression analyses with the HTG-Oncology Biomarker Panel. The association of disease state and gene expression analyses were interrogated for disease evolution and association with PFS. Results: HER2 immunohistochemistry (HER20, Her21+, Her22+) was not associated with PFS in full cohort, or AI and FUL subgroup analyses. The lack of progesterone receptor (PR+, PR-), was associated with shorter PFS in the full patient cohort (p=0.012) and selectively in patients treated with AI (p=0.005), but not FUL. Gene expression-based subtyping indicated that the majority of patients, as expected, had luminal breast cancer; however, the predominant subtypes changed with treatment and disease evolution. Primary tissue from tumor resection was dominated by luminal A subtype, which diminished in the context of metastatic disease, and was rare in post-progression specimens. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations (AI, p=0.01; FUL, p=0.03). Existing clinically developed breast cancer signatures (e.g. breast cancer index) had variable associations with PFS; however, high expression of gene signatures associated with cell cycle were broadly associated with short PFS. Concordantly, utilizing unbiased analyses, gene expression programs linked to cell cycle were associated with short PFS, while interferon response processes were associated with longer PFS. Algorithms that incorporated standard pathological and clinical variables with the gene expression data were developed that exhibited potent predictive power. Conclusions: Tumor evolution occurs on treatment with CDK4/6 inhibitors; however, analyses of pretreatment biopsies can inform the duration of PFS. These data support discrete biological processes associated with sensitivity/resistance. Predictive algorithms could be developed to inform features of treatment decision which will require prospective validation which is ongoing.

Citation Format: Agnieszka Witkiewicz. Biomarker associated with response to CDK4/6 inhibitors in metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-08.
Abstract P5-03-21: A COMPARISON OF BREAST CANCER SURVIVAL ACROSS DIFFERENT TUMOUR BIOLOGY IN YOUNG WOMEN: A MULTICENTRIC DATABASE STUDY IN KLANG VALLEY, MALAYSIA
Authors: See Mee Hoong , Rajehgopal Phrabakaran , Teh Mei Sze , Lai Lee Lee , Yahya Abqariyah
Published: March 2023

Background: OBJECTIVE: This study aims to determine the 5-year overall survival of young breast cancer according to tumour biology in Malaysia. METHODOLOGY: Multicenter retrospective study with convenience sampling method used to recruit the patients. All young women aged 50years and below with breast cancer who underwent surgery/under follow up from 1st January 2014 to 31st December 2017 in Hospital Tengku Ampuan Rahimah (HTAR), Klang, Hospital Selayang and Hospital Putrajaya were in included. Categorical data were analyzed using Chi-Square analysis and Fisher’s Exact Test. 5-year overall survival was calculated using Kaplan Meier. Cox Regression to estimate hazard ratio for mortality in patients with different tumour biology. Recurrence were analysed using Chi-Square analysis. RESULTS: A total of 360 patients were recruited predominantly within 41years to 50years of age (63.9%). The majority of the patients were Malays (66.4%). Most of the patients were in Stage II (39.4%) with a significant number of patients in Stage III and IV (25.0% & 26.4% respectively). 56.1% had tumour biology of Luminal A followed by Triple negative (21.7%), HER2 Enriched (12.2%) and Luminal B (10%). Kaplan Meier analysis showed that the 5-year overall survival was 58.3%. There were no statistical significance across the tumour biology subtypes. Among the tumour biology groups, Triple Negative had the highest probability of survival with 54.5%. CONCLUSION: We observed that Triple Negative had the highest probability of survival at 5years while Luminal B (HER 2 Positive) had the lowest probability. The 5-years overall survival was not statistically significant with accordance to locoregional recurrence rate and in different tumour biology. Keywords: Breast cancer, young women, tumour biology, overall survival, locoregional recurrence

Citation Format: Mee Hoong See, Phrabakaran Rajehgopal, Mei Sze Teh, Lee Lee Lai, Abqariyah Yahya. A COMPARISON OF BREAST CANCER SURVIVAL ACROSS DIFFERENT TUMOUR BIOLOGY IN YOUNG WOMEN: A MULTICENTRIC DATABASE STUDY IN KLANG VALLEY, MALAYSIA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-21.
Abstract P5-09-04: Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with hormone-responsive and HER2-negative, lymph node-negative breast cancer
Authors: gu chongshan , he yingjian , li jinfeng , wang tianfeng , Fan zhaoqing , ouyang tao
Published: March 2023

Background: Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive and her2-negative breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal patients with hormone-responsive, her2-negative and lymph node-negative breast cancer.

Materials and Methods: In this prospective, randomised study, pre-menopausal patients with hormone-responsive, her2-negative and lymph node-negative breast cancer were recruited. Enrolled patients were randomly assigned (1:1) to receive either NCT or NET with goserelin and tamoxifen, followed by goserelin and anastrozole. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by ultrasound.

Results: A total of 68 patients were assigned to receive NCT (n = 31) or NET (n = 37). The clinical response rate was 16.1% for NCT and 35.1% for NET (estimated difference19%, 95%CI:-1.1%-39.1%, non-inferior p = 0.002). Rates of breast-conserving surgery were similar between NCT and NET (90.3% vs 83.8%, p=0.494).

Conclusions: The clinical response rate of NET is non-inferior to NCT in pre-menopausal patients with hormone-responsive, HER2-negative, lymph node-negative breast cancer.

Summary of ultrasound clinical response

The breast surgery and MP grading system

Citation Format: chongshan gu, yingjian he, jinfeng li, tianfeng wang, zhaoqing Fan, tao ouyang. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with hormone-responsive and HER2-negative, lymph node-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-04.
Abstract P5-13-05: Profiling of APOBEC3 dysregulation in breast cancer
Authors: Hamidi Hamid , Khosh Azad , Rahimi Hamzeh , Ebrahimi Diako
Published: March 2023

DNA of many breast tumors is barraged by C-to-T/G mutations within TCW (W:T,A). These mutations are attributed to the aberrant expression and activity of APOBEC3 enzymes. They have been shown to account for many driver mutations in genes such as PIK3CA, ERBB2, and PPP2R1A, however their precise source and also their roles in tumor development, evolution, and patient survival are debated. Currently, quantification of APOBEC3 expression changes in tumor cells is confounded by the ubiquitous expression of these enzymes in immune infiltrating cells. In this study, we used a novel quantitative biology approach to determine the expression profiles of APOBEC3 enzymes in breast tumor and tumor microenvironment cells from >1,000 patients. We combined diverse datasets including tumor/matched normal RNAseqs, tumor somatic mutations, cell line RNAseqs and mutations, estimates of tumor purities and immune cell compositions, and expression of purified cell populations to show that in breast cancer there is only a single APOBEC3 dysregulation process. This process is subtype-independent and is represented by APOBEC3B upregulation and and extreme APOBEC3C downregulation. Compared to all other tumor types, breast tumors are affected the most by this process.

Citation Format: Hamid Hamidi, Azad Khosh, Hamzeh Rahimi, Diako Ebrahimi. Profiling of APOBEC3 dysregulation in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-13-05.
Abstract P5-14-07: Somatic mutations of ER and HER2 subtypes exhibit divergent evolutionary trajectories determined by selective epistasis revealed in phylogenetic reconstruction and stage-specific analyses
Authors: Dasari Krishna , Fisk J. Nick , Townsend Jeffrey
Published: March 2023

Estrogen-receptor positive (ER+) and human epidermal growth factor receptor positive (HER2+) subtypes of breast cancers feature distinct histopathologies and prognoses. Their molecular profiles inform subtype-specific treatment combinations and possible therapeutic targets. However, the evolutionary trajectory of somatic mutations within each subtype has not been characterized, despite its utility in prioritizing drug development and therapeutic approaches. Quantifying the selective effects of somatic mutations on cancer conveys the likely efficacy of extant targeted therapies between subtypes. Furthermore, knowledge of epistatic interactions involving targetable mutations enables precision therapy at any stage of tumorigenesis. The strength of these interactions differ between receptor subtypes, mediated by differences in the adaptive landscape of each subtype. To investigate differences in subtype etiologies, we quantified selection on single-nucleotide mutations within ER and HER2 receptor subtypes using an aggregated multi-institutional cohort of tumor samples. We observed differential selection acting on mutations: PIK3CA H1047R is a strongly selected variant for which selection varied significantly based on the receptor subtype, experiencing maximal selection in ER+ HER2﹣ breast cancer. On a stage-specific basis, we show that adaptive landscapes change, altering optimal timings for treatment. We then infer epistasis by 1) stage-specific analysis that suggests likely orderings of mutations, 2) calculation of pairwise selective epistasis amongst mutations, which lends mechanistic explanations to these orderings, and 3) phylogenetic reconstruction of the evolution of ten breast cancers, revealing common orderings that further support inferred selective epistatic interactions. Our estimates of differential and stage-specific selection and epistasis between subtypes suggest distinct adaptive landscapes for breast cancer subtypes. These estimates should inform the development of targeted therapeutics and guide treatment schedules based on molecular profiling of the cancer.

Citation Format: Krishna Dasari, J. Nick Fisk, Jeffrey Townsend. Somatic mutations of ER and HER2 subtypes exhibit divergent evolutionary trajectories determined by selective epistasis revealed in phylogenetic reconstruction and stage-specific analyses [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-07.
Abstract P6-01-12: Predictive value of immune genomic signatures from breast cancer cohorts containing data for both response to neoadjuvant chemotherapy and prognosis after surgery
Authors: Zhu Yidan
Published: March 2023

Abstract Background Previous studies of immune-related gene signatures (IGSs) in breast cancer have attempted to predict the response to chemotherapy or prognosis and were performed using different patient cohorts. The purpose of this study was to evaluate the predictive functions of various IGSs using the same patient cohort that included data for response to chemotherapy as well as the prognosis after surgery. Methods We applied five previously described IGS models in a public dataset of 508 breast cancer patients treated with neoadjuvant chemotherapy. The prognostic and predictive values of each model were evaluated, and their correlations were compared. Results We observed a high proportion of expression concordance among the IGS models (r: 0.56-1). Higher gene expression scores of IGSs were detected in aggressive breast cancer subtypes (basal and HER2-enriched) (P < 0.001). Four of the five IGSs could predict chemotherapy responses and two could predict 5-year relapse-free survival in cases with hormone receptor-positive (HR+) tumors. However, the models showed no significant differences in their predictive abilities for hormone receptor-negative (HR-) tumors. Conclusions IGSs are, to some extent, useful for predicting prognosis and chemotherapy response; moreover, they show substantial agreement for specific breast cancer subtypes. However, it is necessary to identify more compelling biomarkers for both prognosis and response to chemotherapy in HR- and HER2+ cases.

Citation Format: Yidan Zhu. Predictive value of immune genomic signatures from breast cancer cohorts containing data for both response to neoadjuvant chemotherapy and prognosis after surgery [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-12.
Abstract P6-03-08: Trained Artificial Intelligence (AI) for Predicting Treatment Termination Based on Patient Observations in Advanced Breast Cancer
Authors: Schinköthe Timo , Kates Ronald , Sprecher Benedikt , Meyer Silja , Tonk Christian Horst , Harbeck Nadia , Schmidt Annette
Published: March 2023

Background: In various fields outside of medicine, AI-supported systems have been established that can predict an undesirable event. The purpose of such systems is to detect events earlier and, if necessary, to be able to prevent them. In medicine, it would be particularly interesting to be able to make such predictions based solely on patient observations. Methods: The usage from 323 patients with advanced breast cancer with a total of 78542 documentation days was used. In addition, the premature termination of use was defined as an undesirable event. The data was then processed and annotated. A deep-learning neural network (NN) classifier was trained on this dataset independently on all documented days to predict this target endpoint. The patient classifier score was computed by averaging over daily scores. Overall classifier accuracy and binary cross entropy loss were computed as performance indicators on training and test data sets (2:1 split). Results: After tuning the hyperparameters, the best-performing NN comprised three hidden layers, each with 88 neurons, using ReLU (linear ramp) activation, and an output layer using sigmoid activation. In the test collective, this model achieved a prediction accuracy of 87%. Discussion: The present application shows for the first time that treatment discontinuation can be predicted with a very high degree of accuracy using patient data alone. This opens up new possibilities in the early detection of possible therapy failures and can represent an essential auxiliary tool in medical care in the future.

Citation Format: Timo Schinköthe, Ronald Kates, Benedikt Sprecher, Silja Meyer, Christian Horst Tonk, Nadia Harbeck, Annette Schmidt. Trained Artificial Intelligence (AI) for Predicting Treatment Termination Based on Patient Observations in Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-03-08.
Abstract P6-05-07: Oncologic outcomes of pregnancy after surgical treatment of breast cancer 35 years old or under
Authors: Kim Ji Hye , Woo Sang Uk , Lee Jae Bok , Kim Woo Young , Chung Jai Hyun , Kim Yong Yeup
Published: March 2023

Purpose: Recent advances in the treatment of breast cancer has led to the improvement of breast cancer patient’s survival. With prolonged survival of these patients, pregnancy became an important issue, especially in those of young cancer patients aged 35 or under. Increased hormone levels during pregnancy, however, raises concerns of elevating the risk of cancer recurrence. The aim of this study was to validate the notion of increased risk associated with pregnancy after breast cancer treatment in young patients. Methods: From January 2009 to December 2020, newly diagnosed breast cancer patients of 35 years old or under who underwent curative surgery in Korea University Guro Hospital were enrolled in this study. Patients were categorized into 3 groups: nulliparous, pregnancy prior to treatment of breast cancer, and patients with pregnancy after breast cancer treatment. Their overall survival and disease-free survival were evaluated. Results: A total of 126 patients was enrolled in this study. Seventeen patients (13.4%) conceived and successfully delivered. The mean age of enrolled patients was 32.0 years old (± 3.1), and the mean follow up period after surgery was 56.8 months (± 34.2). There was no significant difference in overall survival (p=0.490) and disease-free survival (p=0.740) among different groups. Among 22 patients with re-diagnosis of breast cancer, 2 of them (9%) had breast cancer on their contralateral breast. Conclusion: In young patients, pregnancy after treatment for breast cancer did not affect their overall survival or disease-free survival as compared to nullipara or previously delivered groups. Therefore, pregnancy counseling should not be prevented in young breast cancer patients of 35 years old or under.

Citation Format: Ji Hye Kim, Sang Uk Woo, Jae Bok Lee, Woo Young Kim, Jai Hyun Chung, Yong Yeup Kim. Oncologic outcomes of pregnancy after surgical treatment of breast cancer 35 years old or under [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-07.
Abstract P6-05-14: The association of sleep quality with anxiety, depression and social support in breast cancer patients with chemotherapy
Authors: Zhu Wenjuan , Li Wanling , Yang Hui , Wang Linying , Guo Jun , Gao Jinnan
Published: March 2023

Background:Chemotherapy has side effects on breast cancer patients, and sleep disturbance is one of the common psychological symptoms. Purpose: This study aimed to examine the incidence of sleep disorders and investigate the relationship between anxiety and depression, hope, social support and sleep disorders in breast cancer patients with chemotherapy in China.Results:Total 350 patients were administered questionnaires, and 329 patients completed the questionnaires. The recovery rate was 94%. The majority of participants reported clinically significant sleep disturbance prior to chemotherapy (67.8%), during chemotherapy (71.8%), and after chemotherapy (72.2%). Pearson correlation analysis showed that the higher the direct support, emotional support, social interaction support, informational support and total social support score, the lower the total PSQI score of breast cancer patients (r = -0.212, -0.292, -0.236, -0.271, and -0.195 p< 0.01, respectively). Multifactorial model analysis showed that direct support, anxiety and age were the three main factors that affected sleep quality in breast cancer patients. Conclusions:social support may provide a powerful tool to reduce anxiety and improve sleep quality in breast cancer patients with chemotherapy.

Citation Format: Wenjuan Zhu, Wanling Li, Hui Yang, Linying Wang, Jun Guo, Jinnan Gao. The association of sleep quality with anxiety, depression and social support in breast cancer patients with chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-14.
Abstract P6-05-24: Implementing System Solutions for Survivorship Care Plans
Authors: Alnabulsi Dina , Jackson Gloria L. , Lopez AnaMaria
Published: March 2023

Background: A survivorship care plan (SCP) is a detailed cancer care summary and future care plan that is generally given to a patient upon completion of adjuvant treatment for a cancer diagnosis. The initial goals of SCPs were to educate patients and other health care professionals about the treatments received, make them aware about potential long-term effects of therapy, and emphasize recommendations for future cancer screening and care (1). Due to numerous barriers—scheduling, staffing, and lack of awareness—SCPs are not delivered to all eligible patients. To address this unmet need our multidisciplinary breast clinic (MDBC) established an Advanced Practice Professional (APP) Survivorship Clinic. With the acute impact of the COVID-19 pandemic, survivorship referrals decreased. We, therefore, developed and implemented system solutions to address SCP access. Methods: System solutions include partnering with the Cancer Registry to provide the list of patients potentially in need of survivorship visits, partnering with pharmacy to confirm patient eligibility, creating specifically designated telemedicine survivorship visits in our electronic scheduling system, prospectively scheduling persons identified, engagement of APPs across the MDBC, and establishing a single coordinating point. Numbers of SCPs delivered are tracked monthly and patient satisfaction is assessed through data collected Press Ganey surveys. Results: This presentation will share our process interventions and outcomes as they mature. Our early data demonstrate the efficacy of the workflow and appear promising. Conclusion: We anticipate that system-based solutions will provide more patients with SCPs and demonstrate patient satisfaction. Blaes AH, Adamson PC, Foxhall L, Bhatia S. Survivorship Care Plans and the Commission on Cancer Standards: The Increasing Need for Better Strategies to Improve the Outcome for Survivors of Cancer. JCO Oncol Pract. 2020 Aug;16(8):447-450. doi: 10.1200/JOP.19.00801. Epub 2020 Apr 8. Erratum in: JCO Oncol Pract. 2020 Nov;16(11):774. PMID: 32267803. Gache, K., Leleu, H., Nitenberg, G. et al. Main barriers to effective implementation of stroke care pathways in France: a qualitative study. BMC Health Serv Res 14, 95 (2014). https://doi.org/10.1186/1472-6963-14-95

Citation Format: Dina Alnabulsi, Gloria L. Jackson, AnaMaria Lopez. Implementing System Solutions for Survivorship Care Plans [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-24.
Abstract P6-05-33: Distress Reduction and Physical Activity Enhancement by Mobile Support Group in Breast Cancer Survivors: a randomized controlled study
Authors: Chung Il-Yong , Jung Miyeon , Lee Sae Byul , Lee Jong Won , Ahn Sei Hyun , Chung Haekwon
Published: March 2023

Purpose Improving physical activity (PA) and reducing mental distress are important issues in the treatment of cancer survivors. This study aimed to investigate the effect of a mobile app-based community on enhancing PA and decreasing distress in breast cancer survivors. Methods We conducted a single-center, prospective, non-blinded, randomized controlled study. Subjects who got breast cancer surgery were allocated to a control group or a app-based community group (intervention) where members were able to share their daily physical activities. Daily walk steps and weekly distress scores using app-based Distress Thermometer (DT) questionnaires were collected from participants for 24 weeks. To examine the differences in levels of distress and weekly step counts for 6 months, we used a t-test method and multivariable regression modeling. Results From Jan 2019 to Apr 2020, a total of 202 participants were enrolled in this study. The intervention group showed a significant increase in weekly steps by 4,496 for 6 months (p < 0.001). The participants in the intervention group showed a significantly lower rate of above mild distress (DT≥3, beta[B] = -0.731, p < 0.001) and above moderate distress (DT≥5, B = -0.558, p < 0.001) compared to those in the control group for 6 months. Conclusions The mobile app-based community is an effective and less resource-intensive tool to increase PA and decrease distress in breast cancer survivors.

Citation Format: Il-Yong Chung, Miyeon Jung, Sae Byul Lee, Jong Won Lee, Sei Hyun Ahn, Haekwon Chung. Distress Reduction and Physical Activity Enhancement by Mobile Support Group in Breast Cancer Survivors: a randomized controlled study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-33.
Abstract P6-07-01: Costs of breast cancer recurrence after initial treatment for high risk early breast cancer using SEER-Medicare linked data
Authors: Vitko Alexandra S. , Martin Pamela A. , Zhang Sheng , Johnston Adam F. , Ohsfeldt Robert L. , Zheng Shen , Liepa Astra M.
Published: March 2023

Background: Despite the good prognosis with treatment for most patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) early breast cancer (EBC), ~ 20–30% of patients experience locoregional or distant disease recurrence. To assist in value assessments of novel therapies in the adjuvant setting, this study aimed to determine the costs of treated breast cancer recurrence following treated EBC.

Methods: This retrospective study analyzed linked patient data from the US Surveillance Epidemiology and End Results (SEER) registry (2010-2014) and Medicare claims (2009 to 2019, which included data from Part A, B, and Prescription Drug Events [Part D]). Data were analyzed for patients aged ≥65 years with HR+, HER2-, node-positive EBC at high risk of recurrence (consistent with monarchE trial high risk criteria). Treated recurrences were defined based on treatment events/procedure codes, including surgery, radiation and systemic therapy, after a 90-day gap following the last treatment for initial EBC. Recurrences were classified based on Medicare claim diagnosis codes or SEER registry data. Extra cost was defined as cost attributable to treated recurrence. Cumulative extra costs were estimated by calculating cost differences between patients with treated vs non/untreated recurrence. Cumulative extra costs were analyzed over the first 6 years following first treated recurrence, a duration which ensured adequate sample size. Costs were inflated to 2021-US$.

Results: We identified 3081 eligible patients (mean age at diagnosis 74.5±7.1 years, 97.4% female, 87.8% White). We identified 964 patients with treated recurrence (distant=432, locoregional=128, contralateral=9, unclassified=347) and 2117 patients with non/untreated recurrence. Six-year cumulative extra costs were higher for patients with distant recurrences ($168,656) than for patients with locoregional recurrences ($96,465) (Table 1).

Conclusions: Cost of recurrence in patients with high risk EBC is considerable, particularly in patients with distant recurrences. Most patients who recurred in this population experienced distant recurrence. Delaying or preventing recurrence may reduce long term costs in these high risk EBC patients.

Table 1. Mean cumulative extra costs attributable to treated recurrence.

Citation Format: Alexandra S. Vitko, Pamela A. Martin, Sheng Zhang, Adam F. Johnston, Robert L. Ohsfeldt, Shen Zheng, Astra M. Liepa. Costs of breast cancer recurrence after initial treatment for high risk early breast cancer using SEER-Medicare linked data [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-07-01.
Abstract P6-10-02: Self-assembled nano drugs of pyrotinib and indocyanine green based on photothermal photodynamic therapy
Authors: Xuhong Juncheng , Deng Jun , Jiang Jun , Qi Xiaowei
Published: March 2023

Background: Photothermal and photodynamic therapy is a new tumor treatment strategy, which can kill tumor cells and reduce the damage to surrounding normal tissues, but the lack of targeting limits its efficacy. In this study, the targeted photothermal and photodynamic nanodrug P/ICG was synthesized by self-assembly of the targeted drug pyrotinib and photosensitizer indocyanine green (ICG), and its application in the photothermal and photodynamic therapy of HER2 positive breast cancer was explored. Method: In this study, the nano drug P/ICG was self-assembly synthesized of pyrotinib and ICG, and its physical parameters and stability were tested. We used 808nm near-infrared light and infrared thermal imager to verify the photothermal effect of nano drugs. Then we used DCFH-DA probe to detect the level of ROS in cells by laser confocal and flow cytometry to verify the photodynamic effect of the nano drug, and verified the antitumor effect of P/ICG combined with near-infrared light irradiation in vitro. We established a PDX mouse breast cancer model and verified the efficacy and safety of P/ICG in the treatment of HER2-positive breast cancer in vitro. Finally, the effect of P/ICG on ferroptosis was verified by MDA, CCK8 and WB experiments. Result: We mixed pyrotinib and ICG in a certain proportion, and purified them by high-speed centrifugation and ultrafiltration to synthesize nano drug P/ICG. P/ICG has good stability and can be effectively ingested by HER2-positive breast cancer cells. Subsequently, we proved through in vitro and in vivo experiments that P/ICG combined with near-infrared light irradiation can significantly inhibit the growth of tumor cells and improve the survival rate of mice. At the same time, P/ICG combined with near-infrared light irradiation increased the phosphorylation of Nrf2 protein, increased the level of free KEAP1 protein, and decreased the levels of SLC7A11, GPX4 and FTH1 protein, significantly increased the lipid peroxidation of tumor cells, and promoted the ferroptosis of tumor cells. Conclusion: Pyrotinib and ICG self-assembled nano drug P/ICG can significantly promote the ferroptosis of HER2-positive breast cancer cells and inhibit the growth of cancer cells, which can be used as a new strategy for the treatment of HER2-positive breast cancer. Key words: pyrotinib; HER2-positive breast cancer; Photothermal therapy; photodynamic therapy

Citation Format: Juncheng Xuhong, Jun Deng, Jun Jiang, Xiaowei Qi. Self-assembled nano drugs of pyrotinib and indocyanine green based on photothermal photodynamic therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-02.
Abstract P6-10-18: Developing novel lysyl oxidase (LOX) inhibitors to overcome chemotherapy resistance in triple negative breast cancer
Authors: Cetin Metin , Saatci Ozge , Akbulut Ozge , Beneker Chad , Rezaeian Abdol-Hossein , Chernov Mikhail , McInnes Campbell , Sahin Ozgur
Published: March 2023

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of all breast cancer patients yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily with conventional chemotherapy; however, resistance to therapy is common, leading to high mortality rates. Importantly, the benefit of current therapeutic strategies used in chemoresistant TNBC, i.e., immunotherapy and antibody-drug conjugates, is confined to only a fraction of patients, and survival benefit is limited. Therefore, there is an urgent need to identify novel and effective treatment strategies to overcome chemoresistance. Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX), a member of LOX family, as a key mediator of chemoresistance in TNBC. However, currently available LOX inhibitors are either non-selective and/or show toxicity. Here, we performed a high-throughput cell-based LOX activity screen (HTS) with more than 5,000 molecules selected from a diversified compound library and identified the bi-thiazole derivatives as novel potent LOX inhibitors. Our structure activity relationship (SAR) analysis resulted in two lead compounds 6403, a relatively LOX-specific inhibitor, and 6415, a more LOX/LOXL2 inhibitor. Both compounds reduced collagen cross-linking (canonical function of LOX) and led to chemosensitization in TNBC cell lines and in chemoresistant TNBC PDX organoids. In addition, 6403 and 6415 reduced the TGF-beta induced fibrosis and inhibited migration capacity of the breast cancer cell lines. Importantly, 6403 showed excellent pharmacokinetic profile and did not lead to any observable toxicity in mice. Notably, 6403 overcame doxorubicin resistance in LOX-expressing 4T1 syngeneic model with no apparent toxicity. Furthermore, our novel LOX and LOX/LOXL2 dual inhibitors show superior inhibition of LOX activity compared to the recently developed and clinically tested LOX family or LOXL2/LOXL3 inhibitors. Overall, we identified novel potent LOX inhibitors with no observable toxicity for further preclinical development and future clinical testing to overcome chemoresistance in TNBC.

Citation Format: Metin Cetin, Ozge Saatci, Ozge Akbulut, Chad Beneker, Abdol-Hossein Rezaeian, Mikhail Chernov, Campbell McInnes, Ozgur Sahin. Developing novel lysyl oxidase (LOX) inhibitors to overcome chemotherapy resistance in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-18.
Abstract P6-10-19: Screening of GPCR-targeting drugs for repositioning in breast cancer
Authors: Abdulkareem Noor , Bhat Raksha , Powell Reid , Chikermane Soumya , Yande Soham , Trinh Lisa , Abdelnasser Hala , Ruiz Alexis , Sobieski Mary , Nguyen Nghi , Johnson Camille , Johnson Michael , Stephan Clifford , Trivedi Meghana
Published: March 2023

Drug repositioning can overcome both substantial costs and the long process of new drug discovery and development in cancer treatment. Some FDA-approved drugs have been found to have the potential to be repositioned as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repositioning potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repositioning potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of anti-HER2 therapies. We identified 7 drugs/compounds as potential hits, out of which 4 were FDA-approved drugs. We focused on beta-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide (NO) production. Nebivolol reduced invasion and migration potentials which may suggest its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset found a reduced but not statistically significant risk of all-cause mortality in the nebivolol group. In-depth future analyses including detailed in vivo studies and real-world data analysis with more patients are needed to investigate further the potential of nebivolol as a repositioned therapy for BC.

Citation Format: Noor Abdulkareem, Raksha Bhat, Reid Powell, Soumya Chikermane, Soham Yande, Lisa Trinh, Hala Abdelnasser, Alexis Ruiz, Mary Sobieski, Nghi Nguyen, Camille Johnson, Michael Johnson, Clifford Stephan, Meghana Trivedi. Screening of GPCR-targeting drugs for repositioning in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-19.
Abstract P6-11-05: Carnitine palmitoyltransferase 1A (CPT1A) mediates therapeutic response to endocrine therapy in estrogen receptor positive breast cancer
Authors: Hussein Shaimaa , Gatza Michael L. , Ganesan Shridar
Published: March 2023

Breast cancer (BC) is the most commonly diagnosed cancer and second leading cause of cancer-related deaths in women in the United States, with more than 70% of the cases are hormone receptor positive (HR+) disease. Endocrine based therapies (ET) are successfully used, however, 30-50% will acquire ET resistance leading to tumor progression. Since the mechanism of acquired resistance remains unknown for ~60% of patients, identifying novel mechanisms of resistance is essential. We recently reported that carnitine palmitoyltransferase 1A (CPT1A), the rate limiting enzyme in fatty acid oxidation, is overexpressed in aggressive HR+ tumors, including ET resistant patients. We propose that CPT1A level and activity changes the tumor microenvironment to enhance tumorigenesis and contribute to ET resistance. To determine the mechanism by which CPT1A is promoting cell proliferation, tumor microenvironment, cellular signaling and ET resistance, we used a series of in vitro studies incorporating a panel of either endogenously or experimentally derived CPT1A-low and CPT1A-high controls, HR+ breast cancer cell lines as well as their ET resistant counterparts. We determined that CPT1A is upregulated in cell lines that acquire ET resistance. Our analyses demonstrated that levels of CPT1A can affect tumor formation ability in both CPT1A-high and adjacent CPT1A-low tumor cells with concurrent changes in both intra- and inter-cellular signaling which may be essential to promote tumor progression and mediate therapeutic response. This represents a promising step in understanding the mechanisms that promote tumorigenesis and ET resistance in HR+ breast cancer.

Citation Format: Shaimaa Hussein, Michael L. Gatza, Shridar Ganesan. Carnitine palmitoyltransferase 1A (CPT1A) mediates therapeutic response to endocrine therapy in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-05.
Abstract P6-11-11: Breast cancer stem cell marker, CD24 regulates metabolic reprogramming in triple negative breast cancer
Authors: Murthy Divya , Dutta Debasmita , Yang Sukjin , Park Junhyoung , Kaipparettu Benny
Published: March 2023

Breast cancer stem cell (BCSC) is a subset of cancer cells that can dictate the tumor initiation, metastatic progression, and therapeutic resistance in BC. The eradication of this unusual population is emerging as a new paradigm in cancer treatment. Molecularly, CD24 negativity in conjunction with high expression of CD44 is considered a hallmark for the BCSCs. While extensive studies have been performed to delineate the role of CD44 in BCSCs, the regulation of CD24 and its functional role have not been fully understood. In this study, we investigated the regulatory mechanisms responsible for low CD24 expression in BCSCs and their functional relevance in BCSCs. Analysis of DNA from tumor tissues and blood from BC patients as well as BCSCs sorted from BC cell lines suggest that CD24 is epigenetically regulated via DNMT-1/HDAC1-dependent increased methylation of CpG islands in the CD24 proximal promoter region. To understand the role of CD24 in triple-negative BC (TNBC), an aggressive subgroup of BC, we knocked down (CD24-KD) and overexpressed (CD24-OE) CD24 in metastatic TNBC cells. While CD24-KD resulted in increased proliferation and stemness, CD24-OE diminished the proliferative and stem-like potential. To further identify the signaling cascade underpinning these effects, we performed phospho-proteome analysis using Reverse Phase Protein Array (RPPA). Remarkably, we observed an enhanced activation of AMPK and NF-kB signaling cascades, and reduced PDGFRβ signaling upon depletion of CD24. As signaling cascades are intricately linked to cellular metabolism, we performed a metabolomic analysis of CD24-KD and CD24-OE cells. Our comprehensive analysis revealed heightened activation of mitochondrial fatty acid β-oxidation (FAO) in CD24-KD and increased glutamine metabolism in CD24-OE cells. In coherence with these findings, we observed significant regulation of genes related to fatty acid metabolism in the TNBC patient cohort expressing low levels of CD24. Consistently, the CD24-KD cells demonstrated increased sensitivity towards FAO inhibitors while CD24-OE cells were more sensitive to glutamine metabolism inhibitors. In vivo studies to further understand the translational significance of this metabolic axis is underway. Taken together, our study demonstrates, for the first time, that CD24 presents a novel metabolic vulnerability that can target BCSCs to gain a therapeutic advantage in the treatment of drug-resistant TNBC patients.

Citation Format: Divya Murthy, Debasmita Dutta, Sukjin Yang, Junhyoung Park, Benny Kaipparettu. Breast cancer stem cell marker, CD24 regulates metabolic reprogramming in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-11.
Abstract P6-14-15: PD-L1 expression regulated by JAK/STAT signaling pathway contributes to cell migration and invasion in breast cancer
Authors: Chen Junqing
Published: March 2023

Background: Programmed death-ligand 1 (PD-L1) implicated in tumor immune evasion and predictive biomarker in immunotherapy is widely recognized, however, the role of PD-L1 in modulating tumor invasion remains largely unexplored. PD-L1 expression on tumor tissue is usually limited by the invasiveness, tumor heterogeneity as well as insufficient tumor tissue samples, while PD-L1 expression on circulating tumor cells (CTCs) might overcome the limitation. In the present study, we aimed to investigate the role and mechanism of PD-L1 in regulating the migration and invasion of breast cancer cells and to evaluate PD-L1 expression on CTCs in metastatic breast cancer patients. Methods: The expression level of PD-L1 in MCF-7 cells and MDA-MB-231 cells was assessed by quantitative real-time RT-PCR and Western Blot. Gain-of-function and loss-of-function study on cell migration and invasion abilities were carried out by overexpression of PD-L1 or silencing PD-L1. PD-L1 expression on CTCs in thirty-six metastatic breast cancer patients were detected. A novel staining procedure which included fluorescent glucose analog staining for CTC enumeration and immunostaining targeting CD45, vimentin and PD-L1 were analyzed. Survival curves were estimated by the Kaplan-Meier method and the log-rank test was used to compare between groups. All tests were two-sided, and p values were considered significant at the 0.05 level. Results: Compared with MCF-7 cells, PD-L1 mRNA and PD-L1 protein expression were significantly increased in MDA-MB-231 cells. Down-regulation of PD-L1 expression in MDA-MB-231 cells inhibited the migration and invasion of MDA-MB-231 cells, while overexpression of PD-L1 in MCF-7 cells increased the migration and invasion of MCF-7 cells. In addition, we found that PD-L1 expression was regulated by JAK/STAT signaling pathway. PD-L1 expression on CTCs in metastatic breast cancer patients was associated with triple negative breast cancers subtype (P=0.013). High expression of PD-L1 on CTCs in metastatic breast cancer patients was correlated to poor overall survival (HR=3.165, 95%CI: 1.121-8.938, P=0.029). Conclusion: Our results indicate that high expression of PD-L1 contributes to cell migration and invasion in breast cancer cell possibly partially through JAK/STAT signaling pathway. The PD-L1 expression on CTCs might serve as a promising non-invasive prognostic biomarker in patients with metastatic breast cancer.

Citation Format: Junqing Chen. PD-L1 expression regulated by JAK/STAT signaling pathway contributes to cell migration and invasion in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-15.
Abstract PD1-08: PAM50 and 21-gene recurrence scores in younger and Black women with breast cancer
Authors: Vohra Sanah , Van Alsten Sarah , Ivory Joannie M. , Hamilton Alina , Gao Xiaohua , Kirk Erin , Nsonwu-Farley Joseph , Butler Ebonee , Taffe Brianna , Perou Charles M. , Carey Lisa , Troester Melissa
Published: March 2023

Background: Black and younger women have poorer breast cancer outcomes. Using a diverse population-based study, we examined the role of biology as measured by genomic assays in outcome disparity among clinically HR+/HER2- women. Methods: Data and biospecimens from the Carolina Breast Cancer Study (CBCS, including 2,103 non-metastatic, invasive breast cancers) were used to perform RNA-based classification according to molecular subtype and research versions of known prognostic assays, the 21-gene Recurrence Score (RS) and the PAM50-based Risk of Recurrence (ROR-PT) score. Prevalence odds ratios (PORs) and 95% confidence intervals (CIs) for subtype by race and age were estimated. Results: Black women had higher frequency of Luminal B [POR (95% CI): 2.08 (1.60, 2.71)], HER2-enriched [POR (95% CI): 2.01 (1.45, 2.79)], and Basal-like tumors [POR (95% CI): 3.51 (2.81, 4.40)] compared to non-Black women. Similarly, younger (< 50 years) women had higher frequency of Luminal B [POR (95% CI): 1.57 (1.21, 2.04)], HER2-enriched [POR (95% CI): 2.03 (1.46, 2.82)], and Basal-like tumors [POR (95% CI): 2.40 (1.92, 3.01)]. Additionally, within clinically-defined HR+/HER2- tumors, Black women had higher frequency of high ROR-PT among younger women [POR (95% CI): 2.88 (1.19, 6.97)], but this association was attenuated among older women [POR (95% CI): 1.99 (0.84, 4.71)]. Race was not significantly associated with the 21-gene RS among younger or older women. Conclusion: While Black and younger women with clinically-defined HR+/HER2- often have higher burden of non-Luminal/high genomic risk tumors, PAM50 and 21-gene assays show different demographic patterns and heterogeneity within age- and race-defined groups, underscoring the value of genomic testing in understanding outcome disparities.

Citation Format: Sanah Vohra, Sarah Van Alsten, Joannie M. Ivory, Alina Hamilton, Xiaohua Gao, Erin Kirk, Joseph Nsonwu-Farley, Ebonee Butler, Brianna Taffe, Charles M. Perou, Lisa Carey, Melissa Troester. PAM50 and 21-gene recurrence scores in younger and Black women with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD1-08.