bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-11-03: How to make decisions in ductal carcinoma in situ? The first study of clinical applicability of the MSKCC ductal carcinoma in situ nomogram in the prediction of local recurrence risk after breast conserving surgery in a Brazilian cohort
Authors: Marques Larissa , Carvalho Heloísa , Carvalho Filomena , Rodrigues Luciana , Aguiar Fernando , Barros Alfredo
Published: March 2023

Introduction: Radiation therapy (RT) plays an important role in the management of patients with ductal carcinoma in situ (DCIS) of the breast, treated by breast conserving surgery (BCS). RT reduces significantly the risk of local recurrences (LR). Efforts are being, currently, to de-escalate RT in this scenario with individualized decision-makings. Several biomarkers and clinical tools were developed to predict the probability of LR and aid a tailored clinical decision. The aim of this study is to assess the potential of the MSKCC DCIS Nomogram, which combines clinical, pathologic, and treatment features to forecast LR after BCS for DCIS patients and assist physicians to recommend RT. Methods: Were enrolled into the study women with DCIS undergoing BCS, with clear surgical margins, and external RT from 1993 to 2018 at a specialized breast cancer service in São Paulo, Brazil. The data were collected from medical records. The MSKCC DCIS Nomogram was applied to the study population. Receiver operating characteristic curve were drawn and the area under the curve (AUC) of 10-year risk of LR evaluation was calculated. Results: 110 women were eligible. Eight patients had LR (7,3%), being 5 invasives (62,5%) and 3 in situ (37,5%). The follow-up mean time was 4.8 years. Time to recurrence was 9.6 years with a 10 years risk of LR of 10,3%. The MSKCC DCIS Nomogram 10-year risk estimates showed satisfactory correlation as regard to LR with the AUC of 0.61. The nomogram is warranted for the 10-year risk LR prediction, and it may reinforce RT indication. Conclusions: The MSKCC DCIS Nomogram may identify patients with DCIS treated by BCS with high probability of LR, and therefore is a useful treatment decision aid for patients with DCIS and may assist the RT recommendation.

Citation Format: Larissa Marques, Heloísa Carvalho, Filomena Carvalho, Luciana Rodrigues, Fernando Aguiar, Alfredo Barros. How to make decisions in ductal carcinoma in situ? The first study of clinical applicability of the MSKCC ductal carcinoma in situ nomogram in the prediction of local recurrence risk after breast conserving surgery in a Brazilian cohort [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 P2-11-03.
Abstract P2-15-09: Impact of neoadjuvant chemotherapy on the short- and long-term outcomes in patients who underwent immediate breast reconstruction after mastectomy
Authors: Nogi Hiroko , ogiya Akiko , Kondo Naoto , Ishitobi Makoto , Yamauchi Chikako , Mori Hiroki , Shimo Ayaka , Narui Kazutaka , Nagura Naomi , Seki Hirohito , Sasada Shinsuke , Sakurai Teruhisa , Shien Tadahiko
Published: March 2023

Background and Purpose In breast cancer patients receiving neoadjuvant chemotherapy (NAC), the use of immediate breast reconstruction (IBR) as a breast cancer treatment option remains controversial. The Japanese breast cancer society conducted retrospective multicenter cohort study in the era of IBR, and we assessed the impact of NAC on surgical and oncological outcomes in patients underwent IBR. Methods Between January 2008 and December 2016, 473 (10.0%) breast cancer cases received NAC of 4726 cases underwent IBR after mastectomy. The clinicopathological and survival data of patients who received NAC (the NAC group) and those who did not receive NAC (the control group) were compared in terms of postoperative complications (infection, hemorrhage, seroma, dehiscence, tissue expander or implant loss, flap or skin necrosis) and oncologic safety. Results Eight-hundred forty cases had minor or major complications. NAC did not increase the risk of complications after IBR (OR 1.20; 95%CI 0.95 - 1.53; p = 0.13). Smoking (OR 1.35; 95%CI 1.14 - 1.62; p = 0.001), overweight (BMI25≤) (OR 1.94; 95%CI 1.61 - 2.35; p < 0.001), PMRT (OR 1.54; 95%CI 1.20 - 1.99; p = 0.01) increased risk of complications. At the median follow-up time of 76.5 months, 36 patient (7.6%) in the NAC group and 147 patients (3.5%) in the control group had local recurrence. 35 patient (7.4%) in the NAC group and 147 patients (2.0%) in the control group had reginal recurrence. Conclusion Immediate breast reconstruction after NAC is a safe procedure with post-operative complication profile. It can be performed safely and therefore should be considered as a strategy preferred for patients with local advanced breast cancer.

Citation Format: Hiroko Nogi, Akiko ogiya, Naoto Kondo, Makoto Ishitobi, Chikako Yamauchi, Hiroki Mori, Ayaka Shimo, Kazutaka Narui, Naomi Nagura, Hirohito Seki, Shinsuke Sasada, Teruhisa Sakurai, Tadahiko Shien. Impact of neoadjuvant chemotherapy on the short- and long-term outcomes in patients who underwent immediate breast reconstruction after mastectomy [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 P2-15-09.
Abstract P2-17-02: SMC6 down-regulation: marker of genetic instability and poor outcome in breast cancer
Authors: Mangone Flavia R. Rotea , Krepischi Ana Cristina V. , Carraro Dirce M. , Nagai Maria A.
Published: March 2023

Genetic instability commonly found in tumors may be a consequence of imbalance in homologous recombination (HR), a mechanism of DNA double-strand break (DSB) repair dependent on the formation and resolution of Holliday junctions’ structures for genomic stability maintenance. The SMC6 is involved in DSB repair. The SMC6 gene is structurally located very close to the GEN1 gene in a head-to-head organization sharing a bi-directional promoter, and the encoded protein is also involved in HR. Herein, we explored the association between SMC6 expression, genomic instability, and prognosis of breast cancer (BC). SMC6 and GEN1 expression and Copy Number Variation (CNV) data measured by qRT-PCR and CGH array, respectively, were assessed in 33 BC of women non-carrier BRCA1/BRCA2-mutations. The SMC6 protein expression was evaluated on a Tissue Microarray containing 74 BC samples classified as low (negative/weak) or high (moderate/strong) according to SMC6 nuclear staining. SMC6 and GEN1 expressions were directly correlated (p=0.821). Moreover, SMC6-low tumors tend to show higher CNV. Yet, the SMC6-low group presented poorer disease-free survival (DFS) than the SMC6 high group (log-rank=0.008). Further, SMC6 expression broke the DFS ER+ cohort in groups of distinct prognoses (log-rank=0.029). By in silico data analysis, SMC6 downregulation was also associated with worse prognosis in some BC subtypes. Our findings point to a possible association between SMC6 down-regulation and BC poor outcomes, suggesting that SMC6 may serve as an indicator of tumor genetic instability for BC patients. Supported by Fapesp and CNPq.

Citation Format: Flavia R. Rotea Mangone, Ana Cristina V. Krepischi, Dirce M. Carraro, Maria A. Nagai. SMC6 down-regulation: marker of genetic instability and poor outcome 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 P2-17-02.
Abstract P2-23-09: Ultra-high Tumor Mutation Burden in Metastatic/Clinically Advanced Breast Cancer (MBC)
Authors: Fanucci Kristina , lustberg maryam , Fischbach Neal , Pelletier Maureen , Sivapiragasam Abirami , Kumar Prashanth Ashok , Kallem Mansi , Danziger Natalie A. , Sokol Ethan , Sivakumar Smruthy , Pavlick Dean , Ross Jeffrey S. , Pusztai Lajos
Published: March 2023

Background: High (HTMB) tumor mutation burden (TMB) defined as ≥10 mutations/megabase (Mb) identifies breast cancer patients who could benefit from pembrolizumab. The higher the TMB the greater the likelihood of benefit. The goal of this analysis was to determine the frequency and genomic landscape of MBC with ultra-high TMB (UHTMB) defined as a TMB > 20 mutations/Mb. Design 2,049 MBC patients (pts) underwent hybrid capture based comprehensive genomic profiling for genomic alterations (GA) in at least 324 genes including determination of TMB to guide therapy decisions using the FoundationOne®CDx assay. ER, PR and HER2 expression were abstracted from submitted pathology reports. Results: 165 of 2049 MBC (8.1%) had HTMB > 10 mutations/Mb, among these 45 (2.2% of all cases) had UHTMB. When compared with the 2,004 non-UHTMB MBC pts with TMB < 20 mutations/Mb, the 45 UHTMB pts were older (mean 64.6 yrs vs 58.2 yrs; p<.0001), more often had lobular histology (40.00% vs 14.5%; p<.0001) and ER+ disease (86.6% vs 70.0%), had higher average driver GA/tumor (9.84 vs 5.7; p<.0001), and less often had TNBC (13.3% vs 27.0%; p=.041) compared to non-UHTMB high cancers. There were no significant differences in ancestry. Mutation signature analysis revealed that APOBEC was predominant in UHTMB samples (82.5%) with a minor portion with an MMR signature (10%), however, MSI-H status was significantly higher in UHTMB high cases (11.6% vs 0.40%; p<.0001). GA more frequently identified in UHTMB cases included CDH1 (45.50% vs 14.32%; p<.0001), PIK3CA (81.80% vs 37.86%; p<.0001), CDKN2A (11.40% vs 3.19%; p=.017), ARID1A (25.00% vs 5.01%; p<.0001) and NF1 (20.50% vs 5.94%; p=.0014). PD-L1 (CD274) gene amplification (2.3% vs 1.3%) or protein expression by the Ventana SP142 assay (57.14% vs 51.10%) were not significantly different. Conclusions: UHTMB MBC is a rare but clinically important subset in breast cancer that could have high response rates to single agent pembrolizumab. This phenotype is driven by APOBEC mutagenesis, more often seen in ER+ lobular cancers, and have higher frequencies of MSI-high status and mutations in CDH1 and PIK3CA.

Citation Format: Kristina Fanucci, maryam lustberg, Neal Fischbach, Maureen Pelletier, Abirami Sivapiragasam, Prashanth Ashok Kumar, Mansi Kallem, Natalie A. Danziger, Ethan Sokol, Smruthy Sivakumar, Dean Pavlick, Jeffrey S. Ross, Lajos Pusztai. Ultra-high Tumor Mutation Burden in Metastatic/Clinically Advanced Breast Cancer (MBC) [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 P2-23-09.
Abstract P2-26-09: Synergistic activity of PI3K inhibitor in combination with AZD6738, ATR inhibitor in breast cancer preclinical model via DNA damage response pathway
Authors: Moon Yong Wha , Gosh Mithun , Park Nahee , Pandey Kamal , Katwal Nar Bahadur , Hong Sa Deok
Published: March 2023

Background: The PI3K inhibition has been an appealing approach for anticancer therapy due to its crucial role in cell growth, proliferation, and survival in various cancers. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. Here, to enhance the efficacy of PI3K inhibitors, we investigated the novel approach combining PI3K inhibitors (alpelisib, AZD8835, AZD8186, NVP-BKM120) with DDR blockade using ATR inhibitor (AZD6738) in breast cancer preclinical models. Methods: Hormone receptor-positive breast cancer cells, MCF7 (PIK3CA E545K mutation) and T47D (PIK3CA H1047R mutation) were used. First, cell viability and the synergistic effect of combination drug was carried out by MTT assy. Next, western blot, cell cycle analysis, apoptosis assay, and immunocytochemistry were conducted to validate the hypothesis. Finally, tumor xenograft experiments were conducted using BALB/c nude mice to validate the in vitro data. Results: A synergistic antiproliferative effect was observed over a wide range of combination (PI3K inhibitor + ATR inhibitor) concentrations (even in a lower concentration as 1/10 x IC50) in vitro, suggesting that when alpelisib is combined with an ATR inhibitor, there may be possibility of lowering the effective dosage of alpelisib. After confirmation of the strong synergistic effect in sub-G1/G0-G1 arrest-mediated apoptosis by the combination treatment, we demonstrated that expressions of phospho ATR, ATM, and CHK1 were suppressed but -H2AX markedly increased by combination treatment as compared to PI3K inhibitors and ATR inhibitor alone. This suggests that combination treatment activates apoptotic pathway through enhanced DNA double strand breaks. Finally, the in vivo study showed that the combination treatment group tended to show a greater tumor growth inhibition compared with PI3K inhibitor or ATR inhibitor alone. Conclusion: The combined inhibition of PI3K and ATR showed a synergistic anticancer effect in vitro and in vivo. ATR inhibitor in combination with PI3K inhibitor merits further clinical investigation to enhance the activity of PI3K inhibitor for the treatment of PIK3CA mutated breast cancer patients.

Citation Format: Yong Wha Moon, Mithun Gosh, Nahee Park, Kamal Pandey, Nar Bahadur Katwal, Sa Deok Hong. Synergistic activity of PI3K inhibitor in combination with AZD6738, ATR inhibitor in breast cancer preclinical model via DNA damage response pathway [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 P2-26-09.
Abstract P2-26-15: CCR7 expression in Inflammatory breast cancer
Authors: Balema Wintana , Krishnamurthy Savitri , Lawrence Alison , Rodriguez Megan , Larson Richard , Fowlkes Natalie , Ueno Naoto T. , Woodward Wendy
Published: March 2023

Background: Inflammatory breast cancer is an aggressive breast cancer characterized by florid congestion of lymphovascular spaces by tumor emboli. CCR7 is an immune cell receptor that mediates traffic of immune cells into lymphatics that can be expressed on tumor cells. An RNA-seq screen of tumor promoting mammary glands in mice identified CCR7 as an upregulated signal in mammary glands that promoted IBC-like skin invasion. We examined the expression of CCR7 in IBC cell lines and patients to determine the prevalence of this receptor in IBC. Methods: Protein lysates from IBC and non-IBC cell lines were subjected to immunoblotting using anti CCR7 (R&D systems). An IBC tissue microarray from post-chemotherapy mastectomy specimens of 39 patients, each with three replicates was subjected to immunohistochemical staining for CCR7 (Invitrogen, catalog number MA5-31992) performed using a Leica Bond RX autostainer with an incubation time of 60 minutes at 1:15,000 after 20 minutes of heat-induced antigen retrieval at pH 6.0. In 15 cases there were no tumor cells observed in the cores. Staining was scored by an expert breast pathologist for intensity and percent tumor stained. Staining patterns were scored. Descriptive statistics were examined for representation by receptor subtype. Results: CCR7 staining was strong in all lines examined including MCF7, SUM149, SUM190, MDA-IBC, and SUM159. Among 24 IBC patient cores with tumor in the tissue, 23 (96%) expressed CCR7 in tumor, 15 with complete membranous staining and 9 with incomplete membranous staining. In one case with LVSI the emboli were CCR7 positive. Among the 24 positive cases, 22 were 3+ intensity while two were 2+. Nine CCR7+ cases were estrogen receptor (ER) ER+, 8 ER-, and 6 unknown. HER2 status is pending. Conclusions: CCR7 expression is present across tumor subtypes in IBC cell lines and in both ER+ and ER- patient tumors. Given developing novel pharmacologic targeting of CCR7, this target warrants further investigation in IBC and other breast cancers.

Citation Format: Wintana Balema, Savitri Krishnamurthy, Alison Lawrence, Megan Rodriguez, Richard Larson, Natalie Fowlkes, Naoto T. Ueno, Wendy Woodward. CCR7 expression in Inflammatory 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 P2-26-15.
Abstract P4-03-10: BREAST DENSITY AND RISK OF BREAST CANCER
Authors: Lynge Elsebeth , Vejborg Ilse , Lillholm Martin , Nielsen Mads , Napolitano George , von Euler-Chelpin My
Published: March 2023

Background: Early studies reported a 4-6-fold risk of breast cancer between women with extremely dense and fatty breasts. As most early studies were case-control studies, we took advantage of a population-based screening program to study density and breast cancer incidence in a cohort design. Methods: In the Capital Region, Denmark, woman aged 50-69 are invited to screening biennially. Women screened November 2012 - December 2017 were included, and classified by BI-RADS density code, version 4, at first screen after recruitment. Women were followed up for incident breast cancer, including ductal carcinoma in situ (DCIS), to 2020 in nationwide pathology data. Rate ratios (RR) and 95% confidence intervals (CI) were compared across density groups using Poisson-regression. Results: We included 189,609 women; 1,067,293 person-years; and 4110 incident breast cancers/DCIS. Thirty-three percent of women had BI-RADS density code 1; 38% code 2; 24% code 3; 4.7% code 4; and missing 0.3%. Using women with BI-RADS density code 1 as baseline; women with code 2 had RR 1.69 (95% CI 1.56-1.84); women with code 3, RR 2.06 (95% CI 1.89-2.25); and women with code 4, RR 2.37 (95% CI 1.05-2.74). Results differed between observations accumulated during screening and above screening age. Conclusions: This cohort study showed a 2.37-fold difference in breast cancer risk between women with highest and lowest breast density. Translated into absolute risk of breast cancer after age 50, this was a 6.2% risk for the one-third of women with lowest density, and 14.7% for the five percent of women highest density.

Citation Format: Elsebeth Lynge, Ilse Vejborg, Martin Lillholm, Mads Nielsen, George Napolitano, My von Euler-Chelpin. BREAST DENSITY AND RISK OF 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 P4-03-10.
Abstract P4-07-19: Eribulin enhances STING-dependent induction of type I interferons in immune and triple-negative breast cancer cells
Authors: Takahashi-Ruiz Leila , Fermaintt Charles , Wilkinson Nancy , Mooberry Susan , Risinger April
Published: March 2023

Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that lacks effective targeted treatment options. However, TNBC typically has a higher mutational burden and greater degree of immunogenicity than other breast tumors, making immunotherapy a viable strategy for effective treatment of this disease. Strategies to improve the response of TNBC patients to immunotherapy include the upregulation of the cGAS-STING innate immune sensing pathway and STING agonists are in clinical development for the treatment of TNBC. We demonstrate that eribulin, a microtubule destabilizer currently used in the treatment of TNBC, functions as an indirect STING agonist because it promotes the release of mitochondrial DNA into the cytoplasm. Eribulin also enhances type I interferon expression induced by STING agonists through a second TBK1-dependent mechanism downstream of STING activation that is shared by the RIG/MAVS RNA sensing pathway. Both mechanisms of eribulin-mediated activation of interferon expression occur in immune and TNBC cells and are shared with other microtubule destabilizers, including vinorelbine, but not with the microtubule stabilizing agent paclitaxel. These effects of eribulin on innate immune sensing pathways in vitro prompted further evaluations of the impact of eribulin on the in vivo immunological response to mammary tumors. We found that eribulin, but not paclitaxel, promotes the activation of CD4+ T-cells in the spleens and draining lymph nodes of tumored animals. This activation required tumor priming but was independent of any direct effect on tumor growth inhibition, demonstrating a specific role of eribulin as a tumor immune modulator. These data contribute to accumulating evidence that there are important mechanistic differences between the microtubule targeted chemotherapeutics currently used in the treatment of TNBC and suggest that eribulin elicits a more favorable innate immunological signature than paclitaxel. Research supported by Eisai Inc.

Citation Format: Leila Takahashi-Ruiz, Charles Fermaintt, Nancy Wilkinson, Susan Mooberry, April Risinger. Eribulin enhances STING-dependent induction of type I interferons in immune and triple-negative breast cancer cells [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 P4-07-19.
Abstract P4-07-63: Local delivery of immunotherapeutics as an in situ vaccine in triple negative breast cancer
Authors: Mantooth Siena , Zaharoff David
Published: March 2023

Introduction. Breast cancer (BC) is among the most common types of cancer among women, with an estimated 287,850 new cases and 43,250 deaths in 2022 [1]. Triple negative breast cancer (TNBC), characterized by lack of ER/PR/HER2 receptors, constitutes 10-15% of diagnosed BC and correlates with the worst prognosis and most aggressive form of the disease [2]. Additionally, compared to the other BC subtypes, TNBC have higher rates of recurrence and highest therapy resistance [2]. Because TNBC lacks a clearly defined target, in situ vaccination may pose a viable therapy option, to locally stimulate an immune response and thereby reduce the tumor burden and prevent recurrence and metastasis. To this end, we developed an injectable delivery medium to effectively localize immune agonists at the site of the tumor. Materials and methods. Hydrogel delivery medium: Low-viscosity, high-deacetylated chitosan was crosslinked with 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide at room temperature overnight. The mixture was dialyzed and freeze-dried. A hydrogel was formed by dissolving the chitosan in deionized water at concentrations from 25-50 mg/mL. In vivo tumor treatment: 1e5 E0771 breast cancer cells were implanted subcutaneously in the right flank of C57BL/6 mice. When tumors were 50-100mm3, mice were treated intratumorally with 50ug Poly(I:C) + 50ug CpG in 30 mg/mL chitosan gel, with 50ug Poly(I:C) + 50ug CpG in saline, or with gel alone. In the second experiment, to enhance the anti-tumor effect of the immunotherapeutic, 2ug of the cytokine interleukin-12 in the chitosan gel will be delivered intratumorally. All experiments involving laboratory animals were approved by the Institutional Animal Care and Use Committee at North Carolina State University. Results and Discussion. The gel was effectively localized within the tumor environment upon injection. The localized Poly(I:C) + CpG in the gel demonstrated an enhanced anti-tumor effect, compared to gel alone. Ongoing work will determine the efficacy of administering the cytokine IL-12. Acknowledgements. This work is supported by an NSF Graduate Research Fellowship. References. [1] Siegel R, et al. CA A Cancer J Clin (2022) 72(1):7-33. [2] Retecki K, et al. Cancers (2021) 13(23):6012

Citation Format: Siena Mantooth, David Zaharoff. Local delivery of immunotherapeutics as an in situ vaccine 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 P4-07-63.
Abstract P5-01-09: Evaluation of the efficacy of using fluorescence-associated indocyanine green in sentinel lymph node biopsies from breast cancer patients
Authors: Sá Rafael , Nazário Afonso , Sanvido Vanessa M. , Giordano Roberto , Rodrigues Raquel , Bugalho Luiz , Silva Suelen
Published: March 2023

Introduction: Sentinel lymph node biopsy is the technique of choice for axillary staging in patients with breast cancer. Although it is already a widespread technique, its history is relatively recent. Three techniques are globally used to detect sentinel lymph nodes: the patent blue, described by Giuliano et al. (1994); the technetium-99 radiopharmaceutical with gamma probe, published by Krag et al. (1993); and the combination of these two techniques. Objective: This study aims to evaluate sentinel lymph node detection rate using the innovative fluorescence-associated indocyanine green technique in breast cancer patients, and to compare it with that of patent blue and with a combination of the two dyes. Method: A randomized trial was conducted on 99 patients who were equally divided into three arms, each one undergoing sentinel lymph node detection using either patent blue, indocyanine green, or a combination of the two dyes. The study was conducted at Hospital de Esperança, Presidente Prudente, SP, Brazil, in partnership with the Breast Department of Paulista School of Medicine, Federal University of São Paulo. Results: The accuracy rate in identifying sentinel lymph nodes was 78.8% with patent blue, 93.9% with indocyanine green, and 100% with patent blue + indocyanine green. Two sentinel nodes (48.5%) were mostly identified in the combined group; however, only one sentinel node was identified in the other groups. The mean time for sentinel lymph node identification was 20.6 minutes with the traditional dye, 8.6 minutes with indocyanine green, and 10 minutes with the combination of the two methods (p < 0.001). The mean surgical time was 69.4 minutes with patent blue, 55.1 minutes with indocyanine green, and 69.4 minutes with their combination (p < 0.001). Conclusion: Sentinel lymph node detection rate by fluorescence-associated indocyanine green was considered effective. The comparison of sentinel lymph node detection rates between patent blue, indocyanine green, and a combination of patent blue + indocyanine green revealed statistically significant differences (p = 0.030), with the combined method being the most effective. Keywords: breast neoplasm, sentinel lymph node biopsy, fluorescence, indocyanine green

Citation Format: Rafael Sá, Afonso Nazário, Vanessa M. Sanvido, Roberto Giordano, Raquel Rodrigues, Luiz Bugalho, Suelen Silva. Evaluation of the efficacy of using fluorescence-associated indocyanine green in sentinel lymph node biopsies from breast cancer patients [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 P5-01-09.
Abstract P5-03-11: The impact of single nucleotide polymorphisms on return-to-work after taxane-based chemotherapy in breast cancer
Authors: Hjorth Cathrine , Damkier Per , Stage Tore B. , Feddersen Søren , Hamilton-Dutoit Stephen , Ejlertsen Bent , Lash Timothy L. , Bøggild Henrik , Sørensen Henrik , Cronin-Fenton Deirdre
Published: March 2023

Background Return-to-work (RTW) after breast cancer may be challenging for breast cancer survivors, especially those who experience adverse effects. Neuropathies are common adverse effect of taxane-based chemotherapy. Single nucleotide polymorphisms (SNPs) in genes related to taxane metabolism and transport, neural function, and neural- or DNA-repair may influence the risk of taxane-induced adverse effects, potentially impacting patient recovery and RTW. We examined the association of such SNPs with RTW in premenopausal breast cancer survivors. Methods We used Denmark’s nationwide population-based health registries to ascertain data on premenopausal women aged 18‒55 years diagnosed with non‒distant metastatic breast cancer during 2007‒2011, who were candidates for adjuvant combination chemotherapy including cyclophosphamide and docetaxel. Only women employed at diagnosis were included. We collected archived tumor tissue from nationwide pathology departments and genotyped 26 SNPs in 20 genes using TaqMan assays. For each SNP, we categorized the women as wildtype, homozygote or heterozygote. Follow-up continued from the date of primary surgery to the first of RTW (defined as 4 consecutive weeks of work), recurrence, maternity leave/childbirth, other malignancy, retirement, death, emigration or 25th September 2017. We computed the cumulative incidence of RTW and used Cox regression models to calculate unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of RTW. Results We included 1,963 women. Women who were homozygotes for the phase 1 metabolizer CYP3A5 rs776746 (n=15) had lower cumulative incidence of RTW than wildtypes (n=1,600) and heterozygotes (n=249), 7%, 25% and 17% at six months, 57%, 87% and 88% at two years, and 82%, 94% and 94% at end of follow-up, respectively. Compared with wildtypes, CYP3A5 rs776746 homozygotes had delayed RTW throughout follow-up (HR 0-10 years: 0.48, 95% CI: 0.26, 0.86). No other SNPs were associated with RTW. Conclusions Among 26 SNPs, CYP3A5 rs776746 was associated with delayed RTW after breast cancer among premenopausal women. Our findings may help identify women at risk of a poor clinical course, who may benefit from enhanced supportive care during treatment and follow-up.

Citation Format: Cathrine Hjorth, Per Damkier, Tore B. Stage, Søren Feddersen, Stephen Hamilton-Dutoit, Bent Ejlertsen, Timothy L. Lash, Henrik Bøggild, Henrik Sørensen, Deirdre Cronin-Fenton. The impact of single nucleotide polymorphisms on return-to-work after taxane-based chemotherapy 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 P5-03-11.
Abstract P5-15-01: Rediscovering IRF5: A prognostic indicator with novel roles in mammary gland development, ribosome biogenesis, tumor initiation, and metastasis
Authors: Barnes Betsy , Brune Zarina , Rice Matthew , Somerville Carter
Published: March 2023

Breast cancer is the second leading cause of death for women in the United States. However, only 10% of breast cancers have been linked to inherited genomic mutations. Thus, identifying biomarkers to predict cancer progression and metastasis remains a clear need in the research and medical world. Here, we report a novel role for Interferon Regulatory Factor 5 (IRF5) in mammary gland development, tumorigenesis, and metastasis. Historically, IRF5 has been studied as a transcription factor in the context of genetic risk for autoimmune diseases. However, mining of The Cancer Genome Atlas revealed that loss of IRF5 expression in human breast cancer is significantly linked with progression to high grade carcinoma, increased metastasis, and decreased overall and recurrence-free survival. Supporting these analyses, we demonstrated that female Irf5-/- BALB/c mice have higher incidence of spontaneous atypical ductal hyperplasia (ADH), increased progression to DCIS, and ultimately, increased incidence of IDC. Using qPCR, FISH and IHC, we confirmed that IRF5 is expressed in both luminal and basal myoepithelial cells, but expression is higher in basal cells. Histologic analysis of whole mount preparations of Irf5-/- mammary glands revealed aberrant ductal morphogenesis, characterized by expansion of luminal and basal myoepithelial cells with a loss of organized glandular structure. RNAseq of primary mammary epithelial cells from wild type and Irf5-/- littermate mice showed Irf5-/- mammary epithelial cells to be enriched in ribosome biogenesis pathways, the physiologic consequences of which were demonstrated through increased rates of protein synthesis. Transferring our studies in vivo, we demonstrated that loss of tumor IRF5 expression resulted in decreased tumor-infiltrating lymphocytes and increased pulmonary metastasis in the murine orthotopic 4T1 implantation model. Mechanistically, we found that—as in our studies utilizing primary mammary epithelial cells—IRF5 expression in tumors regulated protein translation and ribosome biogenesis. In light of these findings, we propose IRF5 as a novel prognostic biomarker, loss of which alters mammary gland development, drives tumor initiation and metastasis, and dysregulates mammary epithelial cell protein synthesis.

Citation Format: Betsy Barnes, Zarina Brune, Matthew Rice, Carter Somerville. Rediscovering IRF5: A prognostic indicator with novel roles in mammary gland development, ribosome biogenesis, tumor initiation, and metastasis [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 P5-15-01.
Abstract P6-02-16: Breast cancer prognosis of germline BRCA1/BRCA2 mutation carriers of young women: a retrospective hospital-based cohort
Authors: HEGO Florent , BARTHOULOT Maël , PIERARD Charles , Mailliez Audrey
Published: March 2023

Background Studies evaluating prognostic impact of germline BRCA1/2 mutations (gBRCAm) on breast cancer patients reported controversial results. The primary aim of this study was to investigate outcomes of young gBRCAm patients with very early onset of breast cancer (< 30 years) compared with noncarriers. Methods In this retrospective study, 149 patients 30 years aged or younger at early breast cancer diagnosis between 2005 and 2019 were included in Oscar Lambret Center. Outcomes were overall survival (OS) and disease-free survival (DFS), defined as time from first diagnosis to first recurrence, second cancer or death from any cause, at 2 years, 5 years, and 10 years. Key patient data, kaplan-meier plots and outcomes were described by BRCA mutation status. Hazard ratios (HR) were calculated using Cox proportional-hazards models. Results Twenty-eight (18.8%) patients were gBRCAm carriers. The median follow-up was 6.5 years (IQR 0.25-16.5). Twenty-three deaths, 41 recurrences and 2 second cancers were reported. OS was 89.3% [70.4–96.4] in gBRCAm patients vs 99.1% [95% CI 93.9–99.9] in non-carriers patients at 2 years; 85.0% [64.7–94.1] vs 92.3% [85.1–96.1] at 5 years and 75.3% [52.5–88.3] vs 80.2% [66.6–88.7] at 10 years. There was no difference in OS between groups in multivariable analysis (HR=1.63 [0.55–4.77], p=0.37). Similar results were noted when comparing disease-free survival (HR=1.42 [0.64–3.11], p=0.38). Conclusions In this cohort of 149 patients with very early onset breast cancer, outcomes of gBRCAm mutation carriers did not differ from non-carriers when adjusted for others prognostic factors.

Citation Format: Florent HEGO, Maël BARTHOULOT, Charles PIERARD, Audrey Mailliez. Breast cancer prognosis of germline BRCA1/BRCA2 mutation carriers of young women: a retrospective hospital-based cohort [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 P6-02-16.
Abstract P6-05-32: Does Aggregation Hide Place of Death Disparities for Asians with Breast Cancer?
Authors: Lall Naveena , Noveihed Alexandra , Hussaini Qasim S. , Blackford Amanda L. , Gupta Arjun , Sedhom Ramy
Published: March 2023

Introduction: Place of death (PoD) studies are often used to motivate and monitor progress on health inequities for persons with cancer. It remains unclear whether aggregation of Asian race masks disparities in health equity for care at the end of life.

Methods: De-identified death certificate data were obtained via the National Center for Health Statistics. All adult (>18 years of age) breast cancer deaths from 2018 to 2019 were included. Multinomial logistic regression was used to test for differences in place of death associated with sociodemographic variables.

Results: From 2018 through 2019, 81,772 died from breast cancer in the United States. Overall, persons of Asian descent were less likely to die at home compared to White patients. Disaggregation noted significant differences in likelihood of hospice facility use. For example, Filipino race was approximately 5 times more likely to utilize hospice facilities (CI 3.764, 8.718; p< 0.001) compared to Whites, whereas Chinese race was significantly less likely (OR 0.49, 95% CI 0.307 to 0.627, p< 0.001). American Indian (OR 0.006), Asian Indian (OR 0.016), and Samoan (0.011) were the least likely to die in a nursing facility. While trends were overall similar when compared to White, Black and Hispanics, the likelihood of PoD among Asian subgroups were significantly different.

Conclusion: Our data highlights notable differences in PoD only apparent with disaggregation of Asian race. While this study remains exploratory in nature, and reasons to explain these disparities are necessary, disaggregation of the Asian Pacific Island category is imperative to unmask disparities to improve health equity among all indigenous populations.

Association Between Race and Place of Death for Patients with Breast Cancer

Table 1. Number of deaths due to breast cancer in 2018 and 2019, by race. Odds ratios for the association between race and place of death from multinomial regression.

Citation Format: Naveena Lall, Alexandra Noveihed, Qasim S. Hussaini, Amanda L. Blackford, Arjun Gupta, Ramy Sedhom. Does Aggregation Hide Place of Death Disparities for Asians 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 P6-05-32.
Abstract P6-05-59: Clinical Characteristics and Prognosis of Postpartum Breast Cancer
Authors: Bae Soo Youn , Paik Pill Sun , Lee Young Joo , Kang Young-Joon
Published: March 2023

Background: Postpartum breast cancer (PPBC) is a not well-established subset of breast cancer, and only few studies address its poorer prognosis. However, there are previous studies that PPBC is associated with worse outcome with higher rates of metastasis than in young women’s breast cancer (YWBC). The purpose of this study was to analyze the clinical characteristics and prognosis according to the onset period of PPBC, Materials and methods: 208,780 breast cancer patients from the online Korean Breast Cancer Society (KBCS) registry database between January 2000 and December 2014 were reviewed retrospectively. Premenopausal women aged 20 to 50 years who underwent breast cancer surgery were included. According to the diagnosis period of breast cancer, it was classified into groups diagnosed within 5 years (PPBC< 5) after delivery, between 5-10 years((5≤PPBC< 10), and after 10 years(PPBC≥10). Results: The patients in PPBC < 5 group showed a younger and more advanced stage compared to other groups, and the expression of estrogen receptor (ER) and progesterone receptor (PR) was lower and the HER2 positive rate was higher. PPBC< 5 group had worse survival rate compared to nulliparous and other group (5-year cumulative survival; PPBC< 5 group, 89% vs. nulliparous group, 97.3% vs. 5≤ PPBC< 10 group 93%). In multivariate analysis, PPBC< 5 group was associated with worse survival rate (Hazard ratio 1.55, 95% CI 1.148-2.094, p=0.004) after adjustment for age at diagnosis, breast cancer stage, ER and HER2 status, Ki-67 level, and chemotherapy. Conclusion: We demonstrated that patients with breast cancer diagnosed within first five years after delivery had aggressive characteristics and a worse survival rate. In order to improve the survival rate of PPBC, the cause should be identified and new therapeutic strategy should be established.

Citation Format: Soo Youn Bae, Pill Sun Paik, Young Joo Lee, Young-Joon Kang. Clinical Characteristics and Prognosis of Postpartum 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 P6-05-59.
Abstract P6-12-03: Proinflammatory and estrogen signaling modulates the chemoresistance and metastasis of breast cancer cells through post-translational modifications of pioneering factor FOXA1
Authors: Li Shen , Franco Hector L. , Kim Hyunsoo , Plagens Rosemary N. , Mendez-Giraldez Raul , Tubbs Colby , Malladi Venkat , Garay Joseph
Published: March 2023

ER-positive breast cancers compose most breast cancers at the time of diagnosis and are primarily driven by mitogenic estrogen signaling. In ER-positive breast cancers, the pioneer transcription factor FOXA1 plays a critical role in the estrogen receptor (ER) function. It binds to condensed chromatin and promotes chromatin accessibility for subsequent ER binding upon estrogen stimulation. We have reported that TNFa-stimulated proinflammatory signaling relocates FOXA1 to a new set of latent enhancers, which initiates the binding of estrogen liganded ER and subsequent expression of a unique transcriptome with clinical significance. The redistribution of FOXA1 occurs within 40 mins of the TNFa treatment, which implies a rapid signaling cascade that arises from changes to either FOXA1’s post-translational modifications (PTMs) or its binding partners. To understand this genomic redistribution of FOXA1, we compared the post-translational modifications (PTMs) of FOXA1 from Vehicle, E2, TNFa, and E2+TNFa treated MCF-7 breast cancer cells. More than five acetylation and phosphorylation events have been identified around the DNA binding domain of FOXA1 by semi-quantitative and quantitative mass spectrometry approaches, and their abundance varies across treatments. To study these PTMs of FOXA1, we used CRISPR/Cas9 to create specific knock-in mutations to mimic or prevent acetylation events in MCF-7 cells. Specifically, we engineered MCF-7 cell lines where K270 was mutated to glutamine (K270Q) to mimic acetylation. And for comparison, we also created cell lines where K270 was mutated to arginine (K270R) to prevent acetylation of FOXA1. Our data, including FOXA1 ChIP-seq and RNA-seq, revealed the genomic redistribution of FOXA1 with these PTMs, which subsequently alters gene expression programs and promotes cell growth, migration, or chemoresistance. These results were confirmed in other ER+ cell lines (such as T47D cells) providing evidence for the generalizability of our findings. Taken together, our data suggest that inflammatory signaling signaling can reshape the enhancer landscape of FOXA1 through post-translational modifications, resulting in changes to estrogen signaling that have profound effects on breast cancer biology.

Citation Format: Shen Li, Hector L. Franco, Hyunsoo Kim, Rosemary N. Plagens, Raul Mendez-Giraldez, Colby Tubbs, Venkat Malladi, Joseph Garay. Proinflammatory and estrogen signaling modulates the chemoresistance and metastasis of breast cancer cells through post-translational modifications of pioneering factor FOXA1 [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 P6-12-03.
Abstract PD14-02: PD14-02 Ten-year follow-up of an image-based AI risk model for breast cancer
Authors: Eriksson Mikael , Czene Kamila , Conant Emily F. , Hall Per
Published: March 2023

Background: Artificial intelligence based, image-derived short-term risk models for breast cancer have shown high discriminatory performance compared to traditional lifestyle familial-based risk models. However, the long-term performance has not yet been investigated. Methds: In this study, we investigated the long-term performance for predicting breast cancer throughout 10 years using an image-based risk model and compared the results to a traditional lifestyle familial-based risk model. We performed a nested case-control study based on a mammography screening cohort conducted since 2010 in Sweden for women aged 40-74. Mammograms, age, lifestyle and familial risk factors were collected at study entry. In the breast cancer register update in 2022; 2,028 incident breast cancers were included together with 8,398 controls that were matched to the cases on year of prior baseline mammogram. The image-based model extracted mammographic features (density, microcalcifications, masses, left-right breast asymmetries of these features) and age from the baseline mammograms. Tyrer-Cuzick risk model used self-reported lifestyle and familial risk factors to estimate risk at study-entry. Absolute risks were estimated using the risk models. We estimated model performances using Area Under the receiver operating characteristic Curves (AUC) statistics of the absolute risks and, risk ratios of women classified as high-risk and low risk using NICE and USPSTF guidelines. Results: The AUCs of the image-derived risk model ranged from 0.76 (95%CI 0.72-0.81) to 0.66 (95%CI 0.65-0.67) for breast cancers developed 1-10 years after study-entry. The corresponding Tyrer-Cuzick AUCs were 0.68 (95%CI 0.63-0.73) to 0.62 (95%CI 0.60-0.63). For estrogen negative and symptomatic cancers, the AUCs for the image-derived model were ≥0.75 during the first 2 years. Women with high and low mammographic density showed similar AUCs. Throughout the 10-years of follow-up, 20% of all women with cancers were deemed high risk at study-entry by the image-derived risk model compared to 6% of all women with cancers identified as high risk by the lifestyle familial-based model (p< 0.01). Conclusion: The image-derived model outperformed the lifestyle familial-based model both for short-term and long-term risk assessment and, could be used for identifying women who possibly could benefit from additional examinations and primary prevention.

Citation Format: Mikael Eriksson, Kamila Czene, Emily F. Conant, Per Hall. PD14-02 Ten-year follow-up of an image-based AI risk model for 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 PD14-02.
Abstract WS2-4: Clinical implications of tumor heterogeneity single cell genomics
Authors: Kanu Nnennaya
Published: March 2023

An understanding of how and why somatic mutations accumulate is required to shed light on cancer evolution. DNA replication during each cell cycle is an essential and highly regulated process that ensures the correct duplication of the entire genome. The timing of DNA replication has been indirectly linked to mutation acquisition and genome instability. However, the extent and the importance of altered replication timing (ART) from normal to cancer cells, and whether this process directly influences mutation acquisition during cancer evolution, have not been explored. Here we evaluated the impact of ART by analysing data from 1271 whole-genome sequenced lung (100,000 Genomes Project 1) and breast (560 breast cancer genomes from Nik-Zainal et al. 2) tumours, together with replication-timing sequencing data of multiple cancer and normal cell lines. We find that 6%-18% of the genome is subject to ART in cancer cells. Genomic regions subject to a shift from early to late replication in cancer cells exhibit an increased mutation rate in tumours and are associated with distinct mutational signatures compared to unaltered early replicated regions. In particular, we identify APOBEC3-mediated mutation clusters (omikli events) in unaltered early and late-to-early ART regions, associated with the acquisition of driver mutations. We demonstrate that ART is a relatively early event during the evolution of breast cancer and lung adenocarcinomas. Finally, genes replicated early in cancer but late in normal cells exhibit an up-regulated expression in tumour samples. The incorporation of single-cell DNA sequencing further enables accurate identification of proliferation rates. Taken together, replication timing alterations during malignant transformation are prevalent in cancer and significantly impact the genomic and transcriptomic landscape during tumour evolution.

Citation Format: Nnennaya Kanu. Clinical implications of tumor heterogeneity single cell genomics [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 WS2-4.