bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-14-04: A Phase 0 Clinical trial of Sacituzumab Govitecan in Patients with Breast Cancer Brain Metastases and Recurrent Glioblastoma
Authors: Ghamasaee Pegah , Balinda Henriette , Brenner Andrew , Floyd John
Published: March 2023

Purpose: Sacituzumab govitecan has shown efficacy and acceptable tolerability in a multicenter phase I/II clinical trial (NCT01631552) in patients with advanced epithelial cancers. Our study was initiated to determine the bioavailability of Sacituzumab govitecan (SG) in breast brain metastasis and glioblastoma. The goals were to evaluate the extent by which SG can penetrate the blood brain barrier and access tumor tissues by testing free SN-38, SN-38G and total SN-38 concentrations in tumor tissue, serum, and CSF. Patients and methods: Patients diagnosed with brain metastatic breast cancer and recurrent glioblastoma were enrolled in a single-center clinical phase 0 study to receive a single intravenous dose of SG at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38 and its metabolites. Following recovery, patients resumed SG treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were assessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria. Total Sn-38 levels were quantified in tumor tissue and corresponding serum from the patients. Trop-2 and carbonic anhydrase IX (CAIX) expression was investigated by IHC. SG activity was tested in a breast cancer intracranial mouse model. Results: An average of 2365 ng/ml in serum and 132 ng/g in tissue of total SN-38 was quantified in our patient samples. Trop-2 expression was observed in 90% of patient tumors. 40% of the samples showed high expression of CAIX. SG significantly inhibited tumor growth in vivo and increased overall survival. 20% of patients in the breast cancer arm of the trial demonstrated a complete response by RANO criteria and the remaining 80% of patients demonstrated a partial response. Ultimately, 80% of the patients in the breast cancer metastasis arm survived. Conclusion: Sacituzumab govitecan is an effective drug that crosses the blood brain barrier to inhibit the growth of metastatic breast cancer to the brain after tumor resection surgery.

Citation Format: Pegah Ghamasaee, Henriette Balinda, Andrew Brenner, John Floyd. A Phase 0 Clinical trial of Sacituzumab Govitecan in Patients with Breast Cancer Brain Metastases and Recurrent Glioblastoma [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 P1-14-04.
Abstract P2-11-15: Focal ESR1 gene amplification is an independent prognostic marker in postmenopausal patients with endocrine-responsive early breast cancer
Authors: Singer Christian F. , Holst Frederik , Steurer Stefan , Burandt Eike , Lax Sigurd , Jakesz Raimund , Rudas Margaretha , Stöger Herbert , Greil Richard , Sauter Guido , Filipits Martin , Simon Ronald , Gnant Michael
Published: March 2023

Purpose: Estrogen receptor (ER) expression predicts response to endocrine therapy and is a prognostic biomarker. However, no ER-associated biomarker is able to identify patients with particularly favorable outcome among ER+ tumors. We investigated the value of ESR1 amplification in predicting long-term outcome in tamoxifen-treated postmenopausal women with early breast cancer with and without nodal involvement. Patients and Methods: 394 patients with ER+ breast cancer (235 node-negative, 159 patients node- positive), who had received adjuvant tamoxifen for 5 years in the prospective randomized ABCSG-06 trial, and in whom FFPE tumor tissue was available, were included in this analysis. ER alpha immunoreactivity was evaluated using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis. Results: Focal ESR1 amplification was detected in 187 (47%) tumors, and was associated with a favorable outcome. After a median follow-up of 10 years, women with focal ESR1 amplification had a significantly longer distant recurrence-free survival (DRFS; adjusted HR 0.48; 95% CI 0.26-0.91; p=0.02) and breast cancer-specific survival (BCSS; adjusted HR 0.47; CI 0.27-0.80; p=0.01) compared to women without ESR1 amplification. The association between ESR1 amplification and improved DRFS and BCSS was only found in node-positive tumors, but not in nodal-negative tumors. ER alpha immunoreactivity, evaluated by Allred score, correlated significantly with focal ESR1 amplification (p< 0∙0001; Chi-squared test), but without prognostic significance. Conclusion: We suggest focal ESR1 amplification as predictor of improved long-term outcome in postmenopausal women with node-positive ER+ early breast cancer.

Citation Format: Christian F. Singer, Frederik Holst, Stefan Steurer, Eike Burandt, Sigurd Lax, Raimund Jakesz, Margaretha Rudas, Herbert Stöger, Richard Greil, Guido Sauter, Martin Filipits, Ronald Simon, Michael Gnant. Focal ESR1 gene amplification is an independent prognostic marker in postmenopausal patients with endocrine-responsive early 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 P2-11-15.
Abstract P2-16-03: The Speckle-type POZ protein (SPOP) inhibits breast cancer malignancy by destabilizing oncogene TWIST1
Authors: Wei Chunli , Liu Yun , Liu Xiaoyan , Cheng Jingliang , Fu Jiewen , Xiao Xiuli , Moses Robb E , Li Xiaotao , Fu Junjiang
Published: March 2023

Epithelial-mesenchymal transition (EMT) inducing transcription factor TWIST1 plays a vital role in cancer metastasis. How the tumor-suppressive E3 ligase, Speckle-type POZ protein (SPOP), regulates TWIST1 in breast cancer remains unknown. In this study, we report that SPOP physically interacts with, ubiquitinates, and destabilizes TWIST1. SPOP promotes K63-and K48-linked ubiquitination of TWIST1, predominantly at K73, thereby suppressing cancer cell migration and invasion. Silencing SPOP significantly enhances EMT, which accelerates breast cancer cell migration and invasiveness in vitro and lung metastasis in vivo. Clinically, SPOP is negatively correlated with the levels of TWIST1 in highly invasive breast carcinomas. Reduced SPOP expression, along with elevated TWIST1 levels, is associated with poor prognosis in advanced breast cancer patients, particularly those with metastatic triple-negative breast cancer (TNBC). Taken together, we have disclosed a new mechanism linking SPOP to TWIST1 degradation. Thus SPOP may serve as a prognostic marker and a potential therapeutic target for advanced TNBC patients.

Citation Format: Chunli Wei, Yun Liu, Xiaoyan Liu, Jingliang Cheng, Jiewen Fu, Xiuli Xiao, Robb E Moses, Xiaotao Li, Junjiang Fu. The Speckle-type POZ protein (SPOP) inhibits breast cancer malignancy by destabilizing oncogene TWIST1 [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 P2-16-03.
Abstract P2-17-01: Targeted CRISPR screen to identify synthetic lethal combinations between APOBEC3B and DNA repair
Authors: Stefanovska Bojana , Lin Kevin , Troness Benjamin , Myers Chad , Harris Reuben
Published: March 2023

APOBEC-catalyzed deamination of cytosine bases is the largest enzymatic and second largest overall source of mutation in cancer. One member from the APOBEC family of enzymes, APOBEC3B (A3B) is overexpressed and dysregulated in many different cancer types. In addition to hallmark C-to-T transitions and C-to-G transversions, APOBEC-catalyzed uracil lesions can be processed into single- and double-strand DNA breaks. Therefore, A3B-positive tumors are under continual stress to repair DNA breaks and may be vulnerable to DNA repair inhibition. Previous results from the Harris lab have identified UNG2, DNA uracil glycosylase 2 (UNG2), initiator of the base excision repair pathway, as synthetic lethal pair with A3B. The genetic disruption of UNG2 combined with high expression of A3B, causes cell death. This provides the rational to hypothesize that also other DNA repair proteins could be putative synthetic lethal pairs with A3B, when its expression and activity are high. To test this hypothesis, CRISPR guide RNA library targeting 237 DNA damage repair and response genes was used in doxycycline-inducible TREX-293-A3Bi-eGFP cell line. Cells expressing or not A3B were harvested for DNA extraction and sequencing at different time points. Comparison of guide RNA abundance between doxycycline and H2O treated cells revealed the dropout guides that disrupt genes and create putative synthetic lethal combinations with A3B. The screen design and overall results will be presented

Citation Format: Bojana Stefanovska, Kevin Lin, Benjamin Troness, Chad Myers, Reuben Harris. Targeted CRISPR screen to identify synthetic lethal combinations between APOBEC3B and DNA repair [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 P2-17-01.
Abstract P2-24-01: The development of covalent microtubule stabilizers for drug-resistant cancers
Authors: Essif Jacob N. , Risinger April
Published: March 2023

Microtubule targeting agents (MTAs) are some of the most commonly used and effective chemotherapeutic agents used in the treatment of breast cancer and other solid tumors. Clinically approved MTAs include microtubule destabilizers, such as the vinca alkaloids or eribulin, as well as the taxane class of microtubule stabilizers, including paclitaxel. While MTAs are effective chemotherapeutics, the development of resistance due to drug efflux or changes in β-tubulin isotype expression are major clinical limitations to each the currently approved drugs of this class. One strategy for overcoming drug resistance is the development of drugs that covalently bind to their drug target, which has been validated in the clinic with the success of irreversible EGFR inhibitors in drug resistant non-small cell lung cancer. We have identified the C22,23-epoxytaccalonolides (taccas) as a class of plant-derived microtubule stabilizers that covalently bind to β-tubulin with a high degree of specificity and retain efficacy in drug-resistant models in vitro and in vivo. Although the taccas have potent and persistent antitumor efficacy in vivo, they suffer from a narrow therapeutic index and short serum half-life that provides optimal efficacy when targeted directly to the tumor site. We are undertaking a multipronged approach to generate synthetic tacca analogs (taccalogs) that retain the efficacy of the natural product with improved pharmacokinetic properties, including improved serum binding, to increase half-life and provide better in vivo tolerability. We are also identifying strategies to improve tumor targeting of the taccas, which is being guided by determining their in vivo distribution with radiolabeled analogs. In a complementary approach, we tested the hypothesis that non-covalent microtubule stabilizers that have increased binding affinity to tubulin share properties with the taccas, such as the ability to circumvent drug resistance and provide potent and persistent in vivo efficacy with a more tolerable therapeutic window. Our data suggest that while non-covalent microtubule stabilizers with improved binding compared to paclitaxel provide improved cellular persistence after drug washout and potent antitumor efficacy, they are not able to overcome drug resistance to some degree as covalent inhibitors, demonstrating the advantage of continuing to develop irreversible drugs such as the taccalonolides for the treatment of drug resistant disease.

Citation Format: Jacob N. Essif, April Risinger. The development of covalent microtubule stabilizers for drug-resistant cancers [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 P2-24-01.
Abstract P2-26-12: Interaction between CTCs and platelets complicate their detection by masking surface epitopes
Authors: Schott Dorothea , PIZON Monika , Pachmann Katharina
Published: March 2023

1) Background: It is well known that solid tumors have the ability to form metastases. The development of distant metastases is due to the primary tumor shedding cells that travel to distant sites via the blood vessels. Platelets specifically promote tumor cells survival in the bloodstream. To investigate the interplay between platelets and circulating tumor cells, we implemented our approach to label simultaneously circulating epithelial tumor cells and platelets. 2) Methods: 40 breast cancer patients were enrolled into the study. Blood samples were collected in EDTA tubes without fixatives and processed at 3 timepoints (0h, 24h and 48h) using the maintrac® approach. In order to visualize platelets we used anti-CD36 antibody staining. 3) Results: We observed at 0h post-blood draw platelet aggregates strictly attached to single cells that did not stain with anti-EpCAM antibody. After keeping blood samples at room temperature for 24h platelet aggregates could still be detected, but the anti-EpCAM antibody became accessible to the underlying cells. CTCs were detected in 94% of patients on day 1 post-blood draw. At 48h following initial blood drawing, platelets had almost completely disappeared from the cell surface and the number of detected CTCs remains stable between 24h and 48h. Furthermore, the number of CTCs correlates with clinical stage of disease. Patients with stage I/II have significantly less CTCs as compared to patients with stage III/IV (median 5 vs. 19 CTCs/100µl cell suspension, p< 0.05). 4) Conclusion: Our results suggest that platelets play a key role in masking circulating tumor cells. Masking may explain the difficulties in detection of these cells and prevention of their elimination by the immune system.

Citation Format: Dorothea Schott, Monika PIZON, Katharina Pachmann. Interaction between CTCs and platelets complicate their detection by masking surface epitopes [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 P2-26-12.
Abstract P3-02-01: Chemotherapy plus immunotherapy in stage IV triple-negative breast cancer patient during pregnancy: a case report
Authors: Lima Candice , Apolinario Thiago L.
Published: March 2023

Introduction Cancer during pregnancy is uncommon but the incidence is increasing, particularly in breast cancer, the most common tumor diagnosed in this scenario. The treatment decision in pregnant patients with triple-negative breast cancer is challenging, even more so in cases with advanced disease. Clinical case A 36-year-old woman was referred to our hospital in January, 2020 with the diagnosis of an early (T2N0M0, stage IIA) invasive carcinoma of no special type triple-negative tumor on the left breast and germinative CHEK2 mutation. She received neoadjuvant treatment with four cycles of ACdd followed by nine weeks of paclitaxel and carboplatin, interrupted for local disease progression. The patient underwent a nipple-sparing mastectomy plus sentinel lymph node biopsy without complications. The pathology report showed gross residual disease, so we decided on adjuvant treatment with radiotherapy followed by capecitabine. Twelve months after the end of the treatment, she received the diagnosis of second-trimester pregnancy but also presented suspicion of pulmonary, nodal, and liver relapse. The liver biopsy confirmed triple-negative histology with CPS > 10. The first-line chemotherapy was liposomal doxorubicin, which showed hepatic disease progression after two cycles. As second-line, we started carboplatin, gemcitabine, and pembrolizumab. The radiologic evaluation after two cycles showed a partial response in the lung and liver, with the patient presenting excellent tolerability without fetal complications. The treatment plan is to wait until the term for delivery and continue treatment until progression or toxicity. Conclusion We report the first stage IV triple-negative breast cancer case in a pregnant patient treated with chemotherapy plus immunotherapy. This case indicates that the treatment is feasible and should be considered in this scenario.

Citation Format: Candice Lima, Thiago L. Apolinario. Chemotherapy plus immunotherapy in stage IV triple-negative breast cancer patient during pregnancy: a case report [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 P3-02-01.
Abstract P3-04-06: Artificial intelligence-based triaging of breast cancer screening mammograms and radiologist workload reduction: a systematic review and meta-analysis
Authors: Xavier Debora , Miyawaki Isabele A. , Jorge Carlos Alberto Campello , Moreira Matheus Jose Barbosa , Carvalho Bruno M. , Batalini Felipe
Published: March 2023

Introduction: Deep learning (DL) has shown promising results for mammographic breast cancer diagnosis. However, the impact of artificial intelligence (AI) in the screening process have not yet been fully addressed in terms of workload reduction, which has potential to decrease healthcare disparities. Radiologists are tasked with overwhelming volumes of screening mammograms, particularly in medically underserved areas. Therefore, when applied to workflow improvement, AI might be a tool to reduce healthcare disparities. The purpose of this systematic review and meta-analysis was to assess if AI-based triaging of breast cancer screening mammograms could reduce the radiologist’s workload with non-inferior sensitivity. Methods: PubMed, EMBASE, Cochrane Central and Web of Science databases were systematically searched for studies that evaluated AI algorithms on computer-aided triage of breast cancer screening mammograms. We extracted data from homogenous studies and performed a proportion meta-analysis with random-effects model to verify the radiologist’s workload reduction and the software’s sensitivity. Results: A total of 14 studies were systematically selected. Three studies using the same commercially available DL algorithm were included in the meta-analysis, with 156852 examinations evaluated at the threshold of 8. The radiologist’s workload decreased by 68.3% (95%CI 0.655-0.711, I² = 98.76%, p < 0.001), with a sensitivity of 93.1% (95%CI 0.882-0.979, I² = 83.86%, p = 0.002). Conclusion: Our findings suggest that DL computer-aided triage of breast cancer screening mammograms significantly reduces the radiologist’s workload with high sensitivity. Although AI’s implementation remains complex and heterogeneous, it is a promising tool to optimize healthcare resources with a potential large impact in low resource settings that struggle with workforce shortage.

Citation Format: Debora Xavier, Isabele A. Miyawaki, Carlos Alberto Campello Jorge, Matheus Jose Barbosa Moreira, Bruno M. Carvalho, Felipe Batalini. Artificial intelligence-based triaging of breast cancer screening mammograms and radiologist workload reduction: a systematic review and meta-analysis [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 P3-04-06.
Abstract P3-05-30: Survival after Development of Contralateral Breast Cancer
Authors: Kim Hakyoung , Kim Hee Jeong , In Yoon Tae , Kim Seonok , Lee Sae Byul , Kim Jisun , Chung Il-Yong , Ko Beom Seok , Lee Jong Won , Son Byung Ho , Ahn Sei Hyun
Published: March 2023

Purpose There are many studies reporting survival after development of contralateral breast cancer(CBC) but with inconsistent results. Also, many studies were based on European or North American population and few on Asian population. However, Korean breast cancer patients have different characteristics such as age distribution. Therefore, purpose of this study is to investigate whether development of CBC has influence on survival in Korean breast cancer population. Methods In this retrospective study, we included patients who were diagnosed with a first primary unilateral non-metastatic breast cancer at Asan Medical Center, Korea, between 1999-2013 followed through 2018. In this population, patients who delveloped CBC during the follow-up period were divided into the CBC cohort, and who did not into the non-CBC cohort. Survival of CBC cohort and non-CBC cohort was compared in the whole study population and in subgroup analysis by interval of CBC development, and breast cancer subtype. Results Over median follow-up of 107 months, 418 patients developed CBC out of 16,251 patients. Development of CBC did not influence overall survival or breast cancer-specific survival. In subgroup analysis by interval of CBC development, patients who developed CBC within one year after diagnosis of the first breast cancer had higher risk for overall death in CBC cohort (hazard ratio 2.58; 95% CI 1.28-5.18), and patients who developed CBC after one year showed no significant difference in survival compared with non-CBC cohort. In subgroup analysis by the subtype, patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative subtype for the first breast cancer showed higher risk for overall death in CBC cohort (hazard ratio 1.88; 95% CI 1.14-3.10) whereas patients with triple negative subtype for the first breast cancer showed lower risk for overall survival in CBC cohort (hazard ratio 0.42; 95% CI 0.19-0.95). Conclusion Development of CBC in Korean breast cancer patients did not have significant impact on survival. However, development of CBC early after diagnosis of first breast or having certain subtype of breast cancer may have affect on survival. Such information can be important information when counseling patients who are considering contralateral prophylactic mastectomy.

Citation Format: Hakyoung Kim, Hee Jeong Kim, Yoon Tae In, Seonok Kim, Sae Byul Lee, Jisun Kim, Il-Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn. Survival after Development of Contralateral 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 P3-05-30.
Abstract P4-01-34: Benefits Provided by Antibody Drug Conjugates in Overall Survival Outweighs those in Progression-free Survival for Metastatic Breast Cancer: A Class Effect
Authors: Chen I-Chun , Lin Ching-Hung , Lu Yen-Shen
Published: March 2023

Background: In metastatic breast cancer (MBC), the benefits of progression-free survival (PFS) and overall survival (OS) is not always proportional. This dissociation is related to the multiple other treatment options such as chemotherapy after disease progression and these treatments would contribute to the long post-progression survival. A constant improvement of PFS that translates into OS has been reported in anti-HER2 antibody containing treatments. In the era of antibody drug conjugates (ADC), we aim to examine the relationship between the increments of PFS and OS in MBC.

Methods: We have used “ metastatic breast cancer” and “antibody drug conjugate” to search for clinical trials that report both PFS and OS. Hazard ratios (HR) and median survival were analyzed. Increments in PFS (delta PFS) and increments in OS (delta OS) were compared between studies.

Results: A total of 5 trials were identified and summarized in table 1. The target of ADC is HER2 (N=4) or Trop2 (N=1). In DESTINY-Breast 03 trial, the control arm is another ADC (T-DM1). The control arms in all the other 4 trials are chemotherapy. The HR of PFS ranged from 0.28 to 0.65 and the HR of OS ranged from 0.48 to 0.68. The HR of PFS is smaller than HR of OS in all of the 5 trials. The median OS was not reached in 1 of the trials (DB-03) and was thus removed from the analysis for delta PFS and delta OS. In the comparison of delta PFS, the increments of median PFS fell between 2.9 and 4.8 months. The increments of median OS were between 5.4 and 6.6 months. All the delta OS are larger than the delta PFS in the four trials.Conclusion: Regardless of the antibody drug targets, ADC provides consistent improvements in median OS that surpasses the improvements in median PFS in metastatic breast cancer. The mechanism warrants further investigation.

Citation Format: I-Chun Chen, Ching-Hung Lin, Yen-Shen Lu. Benefits Provided by Antibody Drug Conjugates in Overall Survival Outweighs those in Progression-free Survival for Metastatic Breast Cancer: A Class Effect [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 P4-01-34.
Abstract P4-02-08: Towards Precision Radiation Oncology: Endocrine Therapy Resistance as a Biomarker for Radiation Resistance in ER-Positive Breast Cancer
Authors: Udden SM Nashir , Rahimi Asal , Kim Dong W. Nathan , Alluri Prasanna
Published: March 2023

Pre-operative endocrine therapy use in post-menopausal women with localized, ER-positive breast cancer affords comparable rates of response and breast preservation, but lower toxicity relative to chemotherapy. Pre-operative endocrine therapy exerts selective pressure on cancer cells and promote evolution and/or enrichment of pathogenic alternations such as ESR1 mutations and other cellular adaptations. How such endocrine therapy-induced adaptations alter response to radiation therapy remains poorly defined. In this study, we show that diverse mechanisms that confer endocrine therapy resistance also drive radiation resistance by reprogramming of DNA repair pathways. We also show that BRD4, a member of bromodomain and extraterminal domain (BET) family of proteins, mediates such DNA repair reprogramming. BRD4 also plays a key role in trascriptional reprogramming in ER-positive breast cancer cells that confers endocrine therapy resistance. Thus, OTX015, a BET inhibitor with a favorable safety profile in early stage clinical trials, reverses both endocrine therapy resistance and radiation resistance in ER-positive breast cancer cells and tumors. Our findings are also consistent with reports that tamoxifen-resistant breast cancer cells are resistant to DNA damaging chemotherapeutic agents such as adriamycin and cisplatin. Overall, our findings suggest that endocrine therapy resistance in the pre-operative setting serves as a biomarker for reduced response to adjuvant radiation therapy, and that pharmacological BET inhibition reverses radiation resistance in such patients. The increasing use of “window of opportunity” studies to assess response to endocrine therapy in the pre-operative setting will further facilitate personalization of radiation treatments in these patients based on their response to endocrine therapy. Thus, we provides a therapeutic rationale for personalization of radiation treatments in breast cancer patients based on their response to endocrine therapy. We also provide a molecularly targeted approach for reversing radiation resistance in such patients. Thus, our study provides a framework for advancing Precision Radiation Oncology in breast cancer patients.

Citation Format: SM Nashir Udden, Asal Rahimi, Dong W. Nathan Kim, Prasanna Alluri. Towards Precision Radiation Oncology: Endocrine Therapy Resistance as a Biomarker for Radiation Resistance in ER-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 P4-02-08.
Abstract P4-03-09: Risk of breast cancer after false-positive mammography recalls: a matched cohort study
Authors: Mao Xinhe , He Wei , Humphreys Keith , Yang Haomin , Czene Kamila
Published: March 2023

Background: False-positive mammography recalls are common and associated with an increased risk of subsequent breast cancer. But the long-term risk and whether the risk restricts to the breast cancer detected on the false-positive recalled side remain unclear. Objective: To examine long-term risk of breast cancer after false-positive recalls by side of breasts, mode of detection and tumor characteristics. Design: Matched cohort. Setting: The mammography screening program in Stockholm, Sweden. Participants: We included 45,588 women who received false-positive recalls (1991-2017) and 455,880 matched women who were not recalled, and then followed them until March 31st, 2020. Measurement: Breast cancer incidence; mode of breast cancer detection; tumor characteristics; re-attendance at mammography screening. Results: With Kaplan-Meier curves, we showed that women with false-positive recalls were more likely than those without to have breast cancers, on not only the previously recalled (false-positive) side but also the unrecalled side, up to at least 20 years since the next scheduled screen. We further found that risks were particular higher for breast cancer diagnosed on the false-positive side within first four years of follow-up (hazard ratio [HR]: 2.40; 95% confidence interval [CI]: 2.17-2.65), by the use of stratified Cox model while allowing for time-varying effects. In addition, when stratifying by age at matched mammograms, we found the association was stronger among old women (60-74) than young women (40-59). This was consistent with the result that the risk of breast cancer was higher among women with low density than those with high density. Of note, within the first four years, women with false-positive recalls were at an increased risk of clinical detected cancers (cancer detected among women who did not attend last scheduled screen or were at an age out of screening age ranges) on the false-positive side compared with those who were not recalled. In addition, we found that women with false-positive recalls had statistically significantly lower re-attendance rates at every of next five scheduled screenings. Conclusion: Women with false-positive recalls are at an increased risk of breast cancer for at least two decades, while these women are less likely to adhere to subsequent mammography screens comparing to women who were not recalled. Thus, women with false-positive recalls, especially older women, should be encouraged to re-attend the mammography screening program.

Citation Format: Xinhe Mao, Wei He, Keith Humphreys, Haomin Yang, Kamila Czene. Risk of breast cancer after false-positive mammography recalls: a matched cohort 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 P4-03-09.
Abstract P5-02-10: In-silico approaches that detect immune contexture to trastuzumab response in neo-adjuvant studies
Authors: AlSultan Dalal , Eustace Alex J. , Madden Stephen F. , Crown John
Published: March 2023

Introduction: Computational approaches have aided in estimating cellular composition of the tumour microenvironment. The evaluation of immune composition in tumours before treatment may predict pathologic complete response (pCR). The aim of the study was to perform a meta-analysis of HER2-positive breast cancer subjects who received neoadjuvant trastuzumab to detect associations between immune cells measured by CIBERSORT and ESTIMATE and pCR. Methods: PubMed was used to identify transcriptomic data of HER2-positive breast cancer patients who received neoadjuvant trastuzumab. Baseline data from eight neoadjuvant studies (N=338) was downloaded from GEO. Data from each study was background corrected and quantile normalised using ‘limma’ or ‘oligo’ packages in R. Immune profiles per sample was generated using computational softwares CIBERSORT and ESTIMATE, and were then linked to pCR status. Correlations between immune contexture and pCR for each study were interpreted using statistical testing. Meta-analysis by a logistic regression model was conducted on studies which passed assumptions to identify CIBERSORT immune subsets robust to pCR. Results: CIBERSORT results showed that three studies had reduced T follicular helper cells (Tfh) (Brodsky p=0.38, CHER-LOB p=0.17, TransNOAH p=0.25) and two studies had reduced plasma cells (CHER-LOB p=0.15, Brodsky p=0.38) in the pCR group, but was not significant after multiple correction. ESTIMATE analysis showed that data from two studies had elevated immune infiltration in pCR (Brodsky p=0.19, CHER-LOB p=0.10) but was not significant. A meta-analysis of pooled data from four studies (TRIO-US B07, 03-311, TransNOAH, CHER-LOB) showed that low Tfh (p=0.053, OR=0.04, CI [0.0012-0.99]) and high memory B-cells (p=0.008, OR=2126.9, CI [8.12-7.65 × 10+5]) prior to trastuzumab treatment may be associated with a better chance of achieving pCR. Conclusion: Results from our meta-analysis proposed that memory B- and T follicular helper subsets may predict a role in achieving pCR. Incorporating studies with larger sample cohorts such as the CALGB-40601 (N=265) study can achieve statistical power of this analysis.

Citation Format: Dalal AlSultan, Alex J. Eustace, Stephen F. Madden, John Crown. In-silico approaches that detect immune contexture to trastuzumab response in neo-adjuvant studies [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 P5-02-10.
Abstract P5-02-12: Prognostic relevance of PD-L1 expression on circulating tumor cells in metastatic breast cancer patients treated with anti-PD-1 immunotherapy
Authors: Zhou Ying , Zhou Jinmei , Shi Haoyuan , Hu Zhiyuan , Yang Yanlian , Jiang Zefei , Wang Tao
Published: March 2023

Rationale: Breast cancer has become the leading cause of cancer mortality in women. Although immune checkpoint inhibitors targeting programmed death-1 (PD-1) are promising, it remains unclear whether PD-L1 expression on circulating tumor cells (CTCs) has predictive and prognostic values in predict and stratify metastatic breast cancer (MBC) patients who can benefit from anti-PD-1 immunotherapy. Methods: Twenty six MBC patients that received anti-PD-1 immunotherapy were enrolled in this study. The peptide-based Pep@MNPs method was used to isolate and enumerate CTCs from 2.0 ml of peripheral venous blood. The expression of PD-L1 on CTCs was evaluated by an established immunoscoring system categorizing into four classes (negative, low, medium, and high). Results: Our data showed that 92.3% (24/26) of patients had CTCs, 83.3% (20/26) of patients had PD-L1-positive CTCs, and 65.4% (17/26) of patients had PD-L1-high CTCs. We revealed that the clinical benefit rate (CBR) of patients with a cut-off value of ≥ 35% PD-L1-high CTCs (66.6%) was higher than the others (29.4%). We indicated that PD-L1 expression on CTCs from MBC patients treated with anti-PD-1 monotherapy was dynamic. We demonstrated that MBC patients with a cut-off value of ≥ 35% PD-L1-high CTCs had longer PFS (P< 0.05) and OS (P< 0.01) compared with patients with a cut-off value of < 35% PD-L1-high CTCs. Conclusion: Our findings suggested that PD-L1 expression on CTCs could predict the therapeutic response and clinical outcomes, providing a valuable predictive and prognostic biomarker for patients treated with anti-PD-1 immunotherapy.

Citation Format: Ying Zhou, Jinmei Zhou, Haoyuan Shi, Zhiyuan Hu, Yanlian Yang, Zefei Jiang, Tao Wang. Prognostic relevance of PD-L1 expression on circulating tumor cells in metastatic breast cancer patients treated with anti-PD-1 immunotherapy [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 P5-02-12.
Abstract P5-03-17: BRCA1/2 gene mutations in patients with high-risk breast cancer in a tertiary-level hospital in Guatemala
Authors: Alvarado-Muñoz Juan , Reyes-Morales Agatha , Chivalan Marco , Torselli Silvana , Valenzuela Hector , Yalibat Gozalo , Ordoñez Mario , León Rosa , Alvarez Egly
Published: March 2023

Objectives, to stablish the frequency of BRCA1/2 mutation rate in high-penetrance breast cancer susceptibility population Methods Based on NCCN guidelines for testing criteria for high-penetrance breast cancer susceptibility genes genetic counseling was offered to 140 breast cancer patients in the hemato-oncology unit of Roosevelt Hospital at Guatemala City performing test with NGS and MLPA technology from 2019 to 2021. Results The overall BRCA1/2 mutation rate high-risk patients were 23% (33/140). Of the patients with mutations, 66.6% (22/33) had BRCA1 mutation, 33.3% (11/33) had BRCA2 mutation, of the mutated population the median age was 45 years. Regarding the phenotype in the mutated population, 75% were triple negative, 16% luminal and 9% with Her2 overexpression. Of the patients carrying the BRCA1 mutation, we identified the c.212+1G>A mutation in 40% of the patients, possibly a founder mutation. In the triple negative population and under 45 years of age, the percentage of patients with BRCA 1/2 mutation is 40.9 (88.8% BRCA1 and 11.1% BRCA2). Conclusions: we found a percentage of BRCA 1/2 mutations in the selected population (NCCN criteria) similar to that reported in other Latin American countries, highlighting the high percentage of BRCA mutations in women under 45 years with triple negative phenotype, previous reports have highlighted the frequency of the c.212+1G>A mutation of BRCA1 in breats cancer patient in Guatemala, in this study 40% of the BRCA1 mutations correspond to said mutation, considering it as a probable founder mutation.

Citation Format: Juan Alvarado-Muñoz, Agatha Reyes-Morales, Marco Chivalan, Silvana Torselli, Hector Valenzuela, Gozalo Yalibat, Mario Ordoñez, Rosa León, Egly Alvarez. BRCA1/2 gene mutations in patients with high-risk breast cancer in a tertiary-level hospital in Guatemala [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 P5-03-17.
Abstract P5-07-01: Outcomes of multidisciplinary team approach and intensive patient education in young women with breast cancer to improve the rate of fertility preservation
Authors: Lee Young Joo , Han Hayan , Kim Hee Jeong
Published: March 2023

Background Young breast cancer patients of childbearing age often had to give up their opportunity as women or mothers for cancer treatment. As the survival rate of young breast cancer patients increases with advances in early detection and treatment of breast cancer, interest in issues such as fertility preservation, which have not been satisfied so far, is increasing. This study aims to report the experience of improvement of the fertility preservation rate through a multidisciplinary team approach and systematic patient education for young breast cancer patients. Methods Patients treated with multidisciplinary team approach including surgical, medical oncologist and fertility specialist were included for analysis. Patient were divided into two periods: before and after intensive patient education. Patient education included in-person counseling, hand-out materials, and audiovisual education about ovarian dysfunctions related to cancer treatment and fertility preservation methods. We compared the rate of fertility counseling, preservation between two periods. Also, effect of hormonal receptor status on fertility outcome with pregnancy and birth were analyzed. Results The rates of fertility counseling (39.4% to 58.1%), ovarian function preservation with gonadotropin releasing hormone antagonists (37.8% to 49.7%), and either embryo (0.9% to 5.6%) or oocyte preservation (0 to 7.5%) were significantly increased (all, p< 0.001) after intensive patient education. Pregnancy (9.5% vs 14.2%, p=0.034) and birth rate (7.7% vs 12.2%, p=0.043) were significantly higher with women with negative hormone receptor status. In hormone receptor positive patients, similar pregnancy rates were observed (13.3 ~ 15.4%) in patients who complete 5yearsd of endocrine therapy, stopped endocrine therapy due to side effects, and received no endocrine therapy. Patients with any type of recurrence were not pregnant during follow up period. Patients who stopped endocrine therapy for child plan showed highest rate of pregnancy (56.0%). Multivariable analysis revealed intensive education were highly associated with improved fertility outcomes (OR 3.843 95% CI 2.781–5.311, p=< 0.001) after adjusted for different stage and treatment modality. Conclusion Multidisciplinary team approach with intensive patient education of fertility preservation in young women breast cancer significantly improved fertility preservation attempt. Hormonal receptor status and recurrence were associated with impaired fertility outcomes

Citation Format: Young Joo Lee, Hayan Han, Hee Jeong Kim. Outcomes of multidisciplinary team approach and intensive patient education in young women with breast cancer to improve the rate of fertility preservation [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 P5-07-01.
Abstract P5-08-15: Reducing Rates of Chronic Breast Cancer Related Lymphedema with Screening & Early Intervention: An Update of Recent Data
Authors: Whitworth Pat , Vicini Frank , Valente Stephanie , Brownson Kirstyn , Dupree Beth , Kohli Manpreet , Lawson Laura , Shah Chirag
Published: March 2023

Background: Breast cancer related lymphedema (BCRL) represents a dreaded complication of breast cancer treatment that can lead to morbidity, diminished quality of life, and psychosocial harm and is associated with increased costs. Increasingly, data has supported the concept of prospective BCRL surveillance coupled with early intervention to mitigate these effects. Methods: We performed a systematic review of the literature searching for published randomized and prospective data evaluating prospective BCRL surveillance with early intervention. Results: We identified 12 studies (2,907 patients) including 4 randomized trials (1,203 patients) and 8 prospective studies (1,704 patients). Randomized data consistently demonstrate that early intervention reduces rates of progression to chronic BCRL with multiple paradigms and diagnostic modalities utilized; the strongest data in the review comes from the randomized PREVENT trial which demonstrated early detection with bioimpedance spectroscopy (BIS), coupled with a compression garment applied for 12 hours a day over 4 weeks, significantly reduced the rate of chronic BCRL compared to tape measurement. Conclusions: Current data support the role of prospective BCRL surveillance with early detection and intervention to reduce rates of chronic BCRL. Breast cancer patients at risk for BCRL should undergo prospective surveillance as part of survivorship. Given the level 1 data demonstrating that BIS is superior to conventional tape measure, it should be included as the standard BCRL diagnostic modality unless an equally effective modality is employed.

Citation Format: Pat Whitworth, Frank Vicini, Stephanie Valente, Kirstyn Brownson, Beth Dupree, Manpreet Kohli, Laura Lawson, Chirag Shah. Reducing Rates of Chronic Breast Cancer Related Lymphedema with Screening & Early Intervention: An Update of Recent 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 P5-08-15.
Abstract P6-01-30: PgR levels and Ki67 expression of Lobular Carcinomas of the Breast might indicate OncotypeDX testing to evaluate Chemotherapy benefit
Authors: Markopoulos Christos , Sariyanni Mahi , Karamargiou Asimina , Antonopoulou Zoi , Tsoulos Nikolaos
Published: March 2023

AIM: The majority of invasive lobular carcinomas (ILC) of the breast are luminal A tumors of good prognosis, having a low or intermediate OncotypeDX Recurrence Score (RS). They are usually treated with hormonal therapy only and some have doubted the relevance of the RS for patients with ILC. However, in a number of ILC cases a high RS can be found, indicating chemotherapy benefit. The aim of the present analysis was to explore in our database of lobular carcinomas analyzed with OncotypeDX, the percentage of tumors with a RS >25 and test the hypothesis if Progesterone Receptor (PgR) and/or Ki-67 expression could be an indicator to have patients evaluated with OncotypeDX. PATIENTS AND METHODS: Among 2.946 patients analyzed with Oncotype DX, we found 397 patients with pure lobular carcinomas (13.47%). Ki-67 expression was obtained from 315 patients and 13 of them (4%) had a high Ki-67 value of >30%. PgR expression was negative in 56 out of 397 patients (14%). We analyzed the possible relationship of RS values with PgR levels and Ki-67 expression. RESULTS: Overall, 94% of patients with ILC had a Recurrence Score ≤25 and only 6% (24/397) had a RS ≥26. There was a wide distribution of RS among patients with different values of PgR; however, there was a negative trend of Recurrence Score values and PgR expression levels. This trend was more obvious in the 56 patients with negative PgR expression. Although there were high RS values across all levels of Ki-67 expression, there was a trend towards high RS with higher Ki-67 expression; 5 out of 13 patients (38%) with ki-67 >30% had a RS ≥26. CONCLUSION: Our analysis shows that the majority of lobular carcinomas of the breast have a low OncotypeDX RS, suggesting that can be treated only with hormonal therapy. However, negative or low PgR levels and high Ki-67 expression might predict a high RS and thus chemotherapy benefit and those two parameters could be used as indicators for OncotypeDX evaluation of lobular carcinomas of the breast.

Citation Format: Christos Markopoulos, Mahi Sariyanni, Asimina Karamargiou, Zoi Antonopoulou, Nikolaos Tsoulos. PgR levels and Ki67 expression of Lobular Carcinomas of the Breast might indicate OncotypeDX testing to evaluate Chemotherapy benefit [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 P6-01-30.