bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PO1-23-11: Differential m6A modification identified by direct RNA sequencing in endocrine- resistant and sensitive breast cancer cells
Authors: Petri Belinda , Valdes Bailey , Piell Kellianne , Rouchka Eric , Klinge Carolyn
Published: May 2024

A major limitation of current adjuvant treatments for the ~ 70% of breast cancer patients with estrogen receptor α–expressing (ER+) primary breast tumors is the development of acquired and adaptive endocrine therapy (ET) resistance and metastatic spread. Chemical modifications of transcribed RNAs alters their cellular location, stability, and, for mRNAs, translation into proteins. N-6 methyladenosine (m6A) is the most common modification of mRNA. We tested the hypothesis that m6A epitranscriptomic changes alters the transcriptome resulting in changes in targets in pathways contributing to the metastatic cascade in ET-resistant breast cancer cells. We used an unbiased approach of direct mRNA sequencing using the Oxford Nanopore MinION platform on polyA-selected mRNA from MCF-7 luminal A breast cancer cells and ER+, ET-resistant LCC9 breast cancer cells treated with vehicle control or 100 nM 4-hydroxytamoxifen (4-OHT) for 24 h. In addition, MCF-7 cells were treated with the METTL3 (the catalytic methyltransferase that adds the methyl group from S-adenosylmethionine (SAM) to the adenosine on the N6 position) inhibitor STM2457 to identify m6A positions and transcripts directly regulated by METTL3 activity. Computational analysis directly identified m6A locations in transcripts. We examined the differential modification rate (DMR) between MCF-7 cells +/STM2457 treatment, between MCF-7 and LCC9 cells with vehicle control treatment or with 4-OHT treatment and within each cell line with 4-OHT treatment. We identified 183 and 3,097 genes with m6A DMRs between vehicle-treated and 4-OHT-treated MCF-7 and LCC9 cells, respectively. For 4-OHT-treated cells, we identified 2,401 and 2,638 genes with m6A DMRs in MCF-7 and LCC9 cells respectively with 1,760 genes in common. We identified many genes with multiple m6A modifications, e.g., AMIGO2 appeared to have 14 m6A sites at DRACH motifs in MCF-7 cells, but none were m6A modified in LCC9 cells. Enrichment by Pathway Maps, Process Networks, and GO Processes were performed. Overall, our data suggest a role for altered m6A positions in transcripts and pathways involved in ET-resistance in breast cancer.

Citation Format: Belinda Petri, Bailey Valdes, Kellianne Piell, Eric Rouchka, Carolyn Klinge. Differential m6A modification identified by direct RNA sequencing in endocrine- resistant and sensitive breast cancer cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-23-11.
Abstract PO2-04-02: Trends in Disparities and Transitions of target therapy in Patients With ERBB2 Positive Early Breast Cancer in China and the US, 2011 to 2021
Authors: Li Jianbin , Zhou Jifang , Wang Haibo , liu Zhenzhen , Fan Zhimin , Liu Yinhua , Geng Cuizhi , Jiang Zefei
Published: May 2024

Background. Diagnosis and treatment of breast cancer have been profoundly improved in China recently. However, trends in disparities and transitions of target treatment in early stage with ERBB2 positive between China and United States are not well known. Methods. This cross-sectional study used Chinese Society of clinical oncology breast cancer (CSCO BC) database from hospitals in 13 provinces of China and Flatiron database from more than 280 US community oncology clinics. Patients with ERBB2 positive and diagnosed as stage I to III breast cancer from 2011 to 2021 were collected. The distribution of target therapy was examined overall and by years. Results. A total of 10245 early-stage breast cancer with ERBB2 positive diagnosed from 2011 to 2021 were screened from the CSCO BC database(n=8446) and the Flatiron Database(n=1799). The median age at diagnosis for Chinese and US was 47 years old and 63 years old. For neoadjuvant therapy, the annual rate of trastuzumab-therapy increased from 0.4% in 2011 to 33% in 2021 in CSCO BC database, while rate of trastuzumab and pertuzumab therapy increased from 0.6% in 2016 to 42% in 2021. The proportion of trastuzumab therapy in Flatiron database decreased from 50% in 2011 to 23% in 2021, while the proportion of dual target therapy increased from 11% in 2013 to 67% in 2021. In adjuvant setting, the trastuzumab therapy increased from 6.8% in 2011 to 37% in 2021 in CSCO BC database, with highest proportion of 65% in 2018. Only 0.1% of patients received dual target therapy in 2018, the proportion increased to 32% in 2021. In Flatiron database, the trastuzumab therapy decreased from 60% in 2011 to 50% in 2021, while rate of trastuzumab and pertuzumab therapy increased from 5% in 2015 to 10% in 2021. Further follow-up is needed for survival data from two databases. Conclusions. Although significant differences were found between the China and US in target therapy, the disparities have been gradually narrowed. Use of trastuzumab in China has overtaken that in US since 2017 attributed to the effort of China's health reform in medical insurance and the promotion of guidelines.

Citation Format: Jianbin Li, Jifang Zhou, Haibo Wang, Zhenzhen liu, Zhimin Fan, Yinhua Liu, Cuizhi Geng, Zefei Jiang. Trends in Disparities and Transitions of target therapy in Patients With ERBB2 Positive Early Breast Cancer in China and the US, 2011 to 2021 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-02.
Abstract PO2-05-09: Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer
Authors: Taya Marwa , Merenbakh-Lamin Keren , Zubkov Asia , Honig Zohar , Mayer Ori , Shomron Noam , Ido Wolf , Rubinek Tami
Published: May 2024

Purpose: All patients with metastatic breast cancer (MBC) expressing estrogen receptor-α (ESR1) will eventually develop resistance to endocrine therapies. In up to 40% of patients, this resistance is caused by activating mutations in the ligand-binding domain (LBD) of ESR1. Accumulating clinical evidence indicate adverse outcomes for these patients, beyond that expected by resistance to endocrine therapy. We hypothesized that ESR1 mutations may also confer resistance to chemotherapy. Experimental Design: MCF-7 cells harboring Y537S and D538G ESR1 mutations (mut-ER) were employed to study response to chemotherapy using viability and apoptotic assay in vitro, and tumor growth in vivo. JNK/c-Jun/MDR1 pathway was studied using qRT-PCR, western-blot, gene-reporter and ChIP assays. MDR1 expression was analyzed in clinical samples using IHC. Results: Cell harboring ESR1 mutations displayed relative chemoresistance, evidenced by higher viability and reduced apoptosis as well as resistance to paclitaxel in vivo. To elucidate the underlying mechanism, MDR1 expression was examined and elevated levels were observed in mut-ER cells, and in clinical BC samples. MDR1 is regulated by the JNK/cJun pathway, and indeed, we detected higher JNK/cJun expression and activity in mut-ER cells, as well as increased occupancy of c-Jun in MDR1 promoter. Importantly, JNK inhibition decreased MDR1 expression, particularly of D538G-cells, and reduced viability in response to chemotherapy. Conclusions: Taken together, these data indicate that ESR1 mutations confer chemoresistance in BC through activation of the JNK/MDR1 axis. Targeting this pathway may restore sensitivity to chemotherapy and serve as a novel treatment strategy for MBC patients carrying ESR1 mutations.

Citation Format: Marwa Taya, Keren Merenbakh-Lamin, Asia Zubkov, Zohar Honig, Ori Mayer, Noam Shomron, Wolf Ido, Tami Rubinek. Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-09.
Abstract PO2-06-14: Kynurenine induces senescence reprogramming to promote metastasis in young triple-negative breast cancer
Authors: Liu Cui-Cui , Yu Ke-da
Published: May 2024

Triple-negative breast cancer (TNBC), which has been associated with a high risk of relapse and poor prognosis, has an increasing incidence among young women and ongoing inferior long-term outcomes. Given TNBC arising at a young age are more likely to present at advanced stages and to have aggressive biology, it is necessary to investigate the underlying mechanism and develop multidisciplinary strategies for optimal therapy of young women with breast cancer. Here, we integrated the multiomics data of our large TNBC cohort (n=456) to investigate different molecular mechanism between younger and older patients in the context of genetic and transcriptional subtypes and immune cell infiltration. We discovered that young TNBC patients exhibited a poorer outcome of both 2-year relapse-free survival and 2-year distant disease-free survival. Multi-omics analysis revealed that kynurenine (KYN) was preferentially enriched in young TNBC and activated tumor cellular senescence pathway which was positively correlated with increased metastasis. Mechanistically, KYN activated the aryl hydrocarbon receptor (AHR) signaling pathway in an ARNT2-dependent manner which was critical for cellular senescence, to mediate senescence reprogramming and promote tumor metastasis in young TNBC. Our findings unveil a novel interplay between cancer cell metabolites and cell senescence, which provides valuable insights that can potentially enhance therapeutic strategies for young TNBC patients. Keywords: young TNBC, metastasis, kynurenine, cellular senescence, AHR pathway

Citation Format: Cui-Cui Liu, Ke-da Yu. Kynurenine induces senescence reprogramming to promote metastasis in young triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-14.
Abstract PO2-11-08: Divorce and marital dissolution after Breast Cancer diagnosis in young breast cancer survivors in Mexico
Authors: Campos-Gomez Saúl , Trujillo Andrea Ovando
Published: May 2024

Background: The current literature suggests that facing breast cancer can have significant effects on the relationship, for the better or for the worse. The needs of younger women with breast cancer are receiving increased attention, as 23.1% of all newly diagnosed invasive cancer occur in women age 50 or younger. Marital relationships, in particular, may be strained for younger cancer patients as they face health, emotional, and financial stressors from their cancer. The few studies that are available to date have examined the effect of breast cancer diagnosis on marital and relationship Purpose: We examined marital outcomes among young locally advanced breast cancer patients in our institution Methods: Eligible participants were women with diagnosis of breast cancer stage I–III, were at least 6 months post diagnosis, and age 50 or younger at the time of diagnosis. Demographic data collected. Participants reported their marital o relationship status at time of breast cancer diagnosis and after at least 6 moth post diagnosis, whether they were currently married or a member of an unmarried couple, divorced, widowed or separated Other variables examined regarding a possible separation, the reasons for separation, the influence of the cancer on the relationship, the positive or negative perception of the impact of cancer on the relationship, the highest educational attainment and employment status. Descriptive statistics, percentages, frequencies, mean values and standard deviations were calculated. Results: In total, 75 patients were eligible for inclusion with a total of 250 patient with diagnosis of locally advanced breast cancer. The median age was 44 (range 30–48). Most of the patients, stage I or II tumors (55%). The divorce or separation rate was 36%, higher than reported in the literature (14.5%). Among those who were separated, 77% reported that cancer contributed to the separation or divorce. Also, for those who stayed together, 81% reported an impact of the cancer on the relationship, of which 50% reported a negative impact. Of those who had separated, none were in a new relationship. Conclusions: The emotional burdens of cancer may lead to marital stress for younger cancer survivors.; support systems are needed to assist them in the years following diagnosis. Because the marital relationship has multiple dimensions, it is also important to explore and identify those areas of the couple's life that are affected by the experience

Citation Format: Saúl Campos-Gomez, Andrea Ovando Trujillo. Divorce and marital dissolution after Breast Cancer diagnosis in young breast cancer survivors in Mexico [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-08.
Abstract PO2-22-09: The impact of blood loss and blood pressure management in DIEP flap surgery– a retrospective analysis of 206 patients
Authors: Fritsch Hanna , Schreiber Cosima , Malter Wolfram , Warm Matthias , Zinser Max , Bach Alexander , Eichler Christian
Published: May 2024

Introduction:

Autologous breast reconstruction using the deep inferior epigastric perforator flap has excellent success rates and a natural aesthetic result. Therefore, this method and its management are of great importance in modern oncoplastic surgery. In particular, women who have undergone radiation therapy after mastectomy benefit from this satisfactory and usually uncomplicated method of breast reconstruction. To achieve a desirable outcome, the effects of blood loss and blood pressure management may play an important role. In this analysis, we hypothesize that neither postoperative blood pressure management (using catecholamines) nor the amount of blood loss (defined by the median hemoglobin level difference) will worsen the surgical outcome or increase the complication rate.

Patients and Methods:

We performed a multicenter, multisurgeon retrospective analysis with the following primary end points: intraoperative blood loss and postoperative blood pressure management. Secondary endpoints included serious complications including flap loss and minor complications. Patients (n=194) were included from 2014-2018 at St. Antonius Hospital in Eschweiler and from 2016 to July 2018 at the Cologne Municipal Breast Cancer Center in Holweide. Patients underwent either unilateral (n=180) or bilateral (n=13) breast reconstructions with DIEP flaps, resulting in a total of n=206 cases. The subgroup regarding blood pressure management was defined by cohorts with or without catecholamine administration and included all n=206 cases. Blood loss was defined by median hemoglobin level difference and could be calculated in n=199 cases. The cohorts of the two subgroups were comparable.

Results:

Six flap losses were detected in a total of 206 cases (2.9%). The distribution of flap losses in the blood pressure management subgroup was not statistically significant (p=.67), while the test was not available for the blood loss subgroup.

Furthermore, the analysis showed that there were no significant differences in the rates of overall complications related to the amount of blood loss intraoperatively (p= .06) or blood pressure management postoperatively (p= .19).

Conclusion:

DIEP flap surgery is a safe method for autologous breast reconstruction, independent of blood loss and blood pressure management.

Citation Format: Hanna Fritsch, Cosima Schreiber, Wolfram Malter, Matthias Warm, Max Zinser, Alexander Bach, Christian Eichler. The impact of blood loss and blood pressure management in DIEP flap surgery– a retrospective analysis of 206 patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-09.
Abstract PO2-23-11: SMAD4 depletion contributes to endocrine therapy resistance by ERBB signaling in HR+HER2- breast cancer
Authors: Li Kang , Shu Dan , Li Han
Published: May 2024

Objectives: Endocrine therapy resistance is a significant clinical challenge for patients with estrogen receptor (ER)-positive breast cancer. Dysregulation of the ER and ERBB signaling pathways plays a key role in endocrine therapy resistance. However, it is unclear how these pathways are integrated during resistance development. SMAD4 is involved in multiple stages of tumorigenesis, but its role in endocrine resistance development remains elusive. Here, we aimed to investigate the role of SMAD4 in the development of acquired endocrine therapy resistance in ER-positive breast cancer. Methods: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) screening was conducted to identify genes involved in regulating the sensitivity of T47D cells to 4-hydroxytamoxifen (OHT). Bioinformatics analysis was performed to explore the clinical significance of SMAD4. The differential expression of SMAD4 in cells before and after endocrine treatment was assessed by RT-qPCR and immunoblotting. Loss-/gain-of-function assays were conducted to validate the phenotype. RNA-seq and phenotype rescue experiments were used to explore the underlying mechanisms. Drug combination experiments were performed to assess the therapeutic effect on SMAD4-depleted cells. Results: CRISPR screening identified SMAD4 as a key determinant of endocrine therapy resistance. Bioinformatic analysis showed that SMAD4 expression was downregulated in breast cancer tissues and that low expression was associated with poor patient prognosis. Differential expression analysis after endocrine therapy treatment showed that endocrine therapy downregulated the expression of SMAD4. In vitro and in vivo models further demonstrated that SMAD4 downregulation leads to endocrine therapy resistance. Transcriptome sequencing analysis identified that the ER, ERBB and PI3K/Akt/mTOR signaling pathways were aberrantly activated upon SMAD4 depletion. Further analysis revealed that the PI3K/Akt/mTOR pathway may contribute to the regulation of ERBB on ER signaling to some extent. The aberrant activation of autophagy in phenotype rescue experiments was found to reduce the rescue effect of the combination of 4-hydroxytamoxifen (OHT) and lapatinib (LAPA). Finally, drug combination experiments verified that the combined use of OHT, LAPA and hydroxychloroquine (CQ) produced a synergistic effect in SMAD4-depleted cells. Conclusions: Taken together, our findings demonstrate that SMAD4 plays a crucial role in endocrine therapy resistance and suggest a reasonable treatment strategy for ER-positive breast cancer patients who are resistant to endocrine therapy.

Citation Format: Kang Li, Dan Shu, Han Li. SMAD4 depletion contributes to endocrine therapy resistance by ERBB signaling in HR+HER2- breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-11.
Abstract PO2-24-07: Investigation into potential Estrogen Receptor (ER)-mediated regulation of Phosphoserine Aminotransferase (PSAT1)
Authors: Sumlut Mary , Wittliff James , Clem Brian
Published: May 2024

Breast cancer is one of the leading causes of death among women. Expression of different proteins, such as hormone receptors (HR), are used to classify different types of breast cancer (i.e., HR+BC or triple negative breast cancer (TNBC)). While activation of the estrogen receptor (ER) in HR+BC is known to regulate a vast number of downstream targets in promoting breast cancer, there may be additional ER-regulated processes that are still unknown. The serine synthetic pathway has been demonstrated to be crucial in the proliferation and survival of select subtypes of breast cancer and phosphoserine aminotransferase 1 (PSAT1) is a key regulatory step. Previous studies have demonstrated higher PSAT1 levels in cells lacking ER and we now show a negative correlation between ERα protein levels and PSAT1 transcripts in human patient samples. This indicates that ER may potentially regulate PSAT1 expression. To initially investigate this potential relationship, either WT or constitutively active mutant ERα was expressed in TNBC cells (MDA-MB-231), which have high endogenous PSAT1 expression and no ER. Immunoblot was used to verify ERα levels and to assess effects on PSAT1. We observed a qualitative trend in decreasing PSAT1 levels with re-expression of ERα in the TNBC cells. While the variabilities in these results preclude any conclusion of a ERα:PSAT1 regulatory axis, the lack of a quantifiable effect on PSAT1 levels is postulated to be due to the transient nature of ERα expression/suppression in these systems. A more profound effect would be expected under durable changes in ERα levels and is a focus on-going studies.

Citation Format: Mary Sumlut, James Wittliff, Brian Clem. Investigation into potential Estrogen Receptor (ER)-mediated regulation of Phosphoserine Aminotransferase (PSAT1) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-24-07.
Abstract PO2-28-03: E-Cigarette Aerosol Exposure: Unraveling the Nexus of Autophagy, Cancer Stem Cells, and EMT in Breast Cancer Metastasis
Authors: Thota Shilpa , Begum Rizwana , Chintalaramulu Naveen , Sapkota Biplov , Pandit Abhishek
Published: May 2024

Electronic cigarettes (E-cigs) have emerged as a significant public health concern due to their increasing popularity. These products have been associated with various harmful effects on human health. In the United States, breast cancer is the most diagnosed cancer among women, and its recurrence and metastasis are primary contributors to morbidity and mortality. Two critical factors in cancer progression are Epithelial-mesenchymal transition (EMT) and Cancer stem-like cells (CSCs), both of which play pivotal roles in metastasis. As a result, targeting the signaling pathways involved in these processes has become a promising avenue for cancer therapy. Autophagy, a cellular process, has dual roles in cancer development depending on the cancer type and stage. Given these considerations, our hypothesis centers on disrupting the EMT-mediated metastatic cascade in breast cancer by targeting autophagy in Cancer Stem Cells (CSCs). To investigate this hypothesis, we conducted experiments using mouse breast epithelial cells (HC11) and Triple-negative mouse breast cancer cells (4T1) exposed to E-cig aerosol at the air-liquid interphase (ALI) for 1 hr followed by a 24 hr recovery period. Our findings indicate that exposure to E-cig aerosols led to a decrease in epithelial markers (E-Cadherin and β-catenin) and an increase in mesenchymal markers (N-Cadherin and Vimentin) in HC11 cells. This suggests that normal cells may acquire characteristics associated with solitary migration. Furthermore, we observed significant changes in the levels of autophagy-related proteins (LC3B, Beclin-1, ATG12, and ATG16) and upregulation of stem cell markers (OCT4, SOX2, NANOG, KLF4, and c-MYC) in response to E-cig aerosol exposure, both in HC11 and 4T1 cells. Additionally, these alterations extended to changes in the expression of genes associated with the Transforming Growth Factor-beta (TGF-β) signaling pathway, known to play a potential role in promoting EMT. Our results provide a deeper understanding of the interplay between EMT, CSCs, and the autophagy process in the context of ALI exposure in normal and cancer cells. This underscores the need for further research into the shared molecular mechanisms of these three processes to identify common therapeutic targets that can simultaneously affect them.

Citation Format: Shilpa Thota, Rizwana Begum, Naveen Chintalaramulu, Biplov Sapkota, Abhishek Pandit. E-Cigarette Aerosol Exposure: Unraveling the Nexus of Autophagy, Cancer Stem Cells, and EMT in Breast Cancer Metastasis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-28-03.
Abstract PO3-01-11: Clinical Significance of HER2-low Breast Cancer
Authors: Zaiem Fadi , AbuJamea Asem , Kheil Mira , Numi Anna , Abbas Omar , Awada Sanaa , Almsaddi Ragad , Al-Juburi Saleh , Larson Lauren , Jain Deepti , AlSaghir Maya , Jang Hyejeong , Kim Seongho , Bandyopadhyay Sudeshna , Jaiman Sunil , Ali-Fehmi Rouba
Published: May 2024

Context: Breast cancers with a HER2 immunohistochemistry (IHC) result of 1+ or 2+ and a negative amplification test (FISH), previously treated as HER2 negative, are now termed HER2-low and are being targeted for treatment. We aim to explore the clinical significance of this group. Design: 394 breast cancer cases were included from our institution from 2010. Demographic and clinicopathological data on receptors status, recurrence/metastasis, treatment, and survival was collected. HER2 was re-evaluated according to the 2018 CAP ASCO guidelines and patients were treated according to standardized protocol. HER2 +2 with positive FISH and HER2 +3 were excluded. HER2-low was compared to HER2-0. Appropriate statistical analysis was performed. Results: 394 patients (76% IDC; 8% ILC; 16% others) were included, such that 91 (23%) were HER2-0 and 303 (77%) HER2-low. Median age was 58 years (range: 25-95). Median follow-up was 54 months (range: 0.5-259). Grade 3 tumors were significantly more frequent in HER2-0 than HER-2 low (52% vs. 33%; p=0.010). Grade 3 or ILC patients had higher risk of recurrence than Grade 1 (HR 2.55; p< 0.001) or IDC (HR 2.03; p=0.033). After adjusting for grade, HER2-low had a significantly worse RFS than HER2-0 (HR 1.58; p=0.043). In the ER negative subgroup, HER2-low had significantly worse RFS than HER2-0 (HR 2.02; p=0.023). No differences in overall survival were seen. Conclusions: Our data showed higher recurrence in HER2-low group compared to HER2-0. This suggests that breast cancer patients with HER2- low are a separate entity and might benefit from additional targeted therapy.

Table 1 Hazard regression analysis of risk factors associated with recurrence

Citation Format: Fadi Zaiem, Asem AbuJamea, Mira Kheil, Anna Numi, Omar Abbas, Sanaa Awada, Ragad Almsaddi, Saleh Al-Juburi, Lauren Larson, Deepti Jain, Maya AlSaghir, Hyejeong Jang, Seongho Kim, Sudeshna Bandyopadhyay, Sunil Jaiman, Rouba Ali-Fehmi. Clinical Significance of HER2-low Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-11.
Abstract PO3-04-09: Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis
Authors: Zhang Jin , Liu Yan , Zhang Shichao
Published: May 2024

Abstract: Purpose: To evaluate the clinical characteristics, pathological response, and prognostic significance of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC) after neoadjuvant chemotherapy (NAC). Methods: A survival analysis was performed to detect the factors related to recurrence and death in 3070 consecutive patients with HR+/HER2− BC who received NAC from 2011 to 2022. All patients received current “standard of care” following neoadjuvant therapy based on guidelines, including surgery and adjuvant endocrine therapy. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC 2+ and fluorescence in-situ hybridization-negative. Results: The complete pathological response (pCR) (ypT0/is ypN0) rate was 14.5%. The clinical tumor size (cT), ER scores, PR status, and Ki67 levels were related to pCR. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 82.6% and 90.4%, respectively. PR, Ki67 levels, and postmastectomy radiotherapy were independent factors for DFS and OS, and the extranodal extension (ENE) correlated with DFS. However, pCR and HER2 status were related to OS. The pCR rate in PR negativity BC was significantly higher than that in PR positivity BC (21.1% vs. 12.2%, p = 0.000), but PR negativity BC had a poorer prognosis than PR positivity BC. HER2-low BC showed high ER scores (over 50%), PR positivity, large ypT, ENE, and lymphovascular invasion but a lower pCR rate than HER2-zero BC. Patients with HER2-low BC had shorter OS than those with HER2-zero BC (p = 0.037). However, there was no difference in DFS. Conclusions: Depending on PR status and HER2 status, patients with ER positivity and HER2 negativity exhibit different pathologic complete response rates to neoadjuvant chemotherapy and long-term outcomes, especially patients with PR negativity or HER2-low status. Keywords: breast cancer; neoadjuvant chemotherapy; survival; prognosis; PR; HER2-low

Citation Format: Jin Zhang, Yan Liu, Shichao Zhang. Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-09.
Abstract PO3-09-12: Exploring Gender-Specific Patterns of Breast Cancer in Brazil: A Comparative Epidemiological Study
Authors: Antonini Marcelo , Pannain Gabriel , Buttenbender Steffi , Mattar Andre , Lopes Reginaldo Coelho , Ferraro Odair
Published: May 2024

Introduction: Male breast cancer constitutes approximately 1% of all breast cancer cases, and limited studies have focused on this population, resulting in a lack of understanding of the disease in men. This study aims to describe the epidemiological profile of male breast cancer in Brazil and compare it with female breast cancer. Methods: A comprehensive observational cross-sectional study was conducted using retrospective data from the DATASUS database (SISCAN/Cancer Information System) spanning the period from 2017 to 2021. Male and female patients diagnosed with breast cancer (ICD C50) during this period were included. Statistical analysis involved absolute values, percentages, and a 95% confidence interval (p < 0.05). Results: Analysis of the study period revealed 4,326 cases (1.8%) of male breast cancer and 236,597 cases (98.2%) of female breast cancer in Brazil. The southeast region had the highest concentration of cases for both sexes, while the northeast region showed a higher prevalence in males (p < 0.0004). Noteworthy findings include a higher mean age among males (59.5 years) compared to females (55.7 years) and a higher prevalence of advanced stages at diagnosis in males (72.8% vs. 59.3%). Diagnostic approaches, subtype distribution, and treatment modalities also differed between the genders. Conclusions: Male breast cancer presents with more advanced stages at diagnosis compared to females, necessitating more aggressive surgical interventions. However, males benefit from earlier initiation of treatment. These findings contribute to a better understanding of male breast cancer, enabling the development of tailored management strategies for this unique patient population.

Comparison between male and female MC

XX XX Source: Panel-Oncology Brazil (accessed 15/04/2023)

Citation Format: Marcelo Antonini, Gabriel Pannain, Steffi Buttenbender, Andre Mattar, Reginaldo Coelho Lopes, Odair Ferraro. Exploring Gender-Specific Patterns of Breast Cancer in Brazil: A Comparative Epidemiological Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-12.
Abstract PO3-12-02: SAFETY AND TOLERANCE OF THE USE OF SHOCK WAVE THERAPY IN LYMPHEDEMA SECONDARY TO THE TREATMENT OF BREAST CANCER
Authors: Ventura Patricia Lima , Haddad Cinira , Sanvido Vanessa , Nazário Afonso , Facina Gil , Estevao Amanda , Rizzi Samantha Lopes de Almeida
Published: May 2024

Introduction: Lymphedema is a very common complication of breast cancer treatment. The first-line therapeutic method for lymphedema is Complex Physical Therapy. An option currently mentioned as an adjuvant and non-invasive treatment for lymphedema secondary to breast cancer is Shockwave Therapy. Objectives: To evaluate the safety and tolerance of shockwave therapy for the treatment of upper limb lymphedema secondary to breast cancer treatment. Methods: This is a quasi-experimental study carried out with 17 women who underwent breast surgery associated with axillary lymphadenectomy or Sentinel Lymph Node Biopsy and who had upper limb lymphedema secondary to the treatment of breast cancer. All were treated with complex physical therapy prior to the study. Four sessions of Shockwave Therapy were applied, 4000 shocks at 0.06 mJ/mm2, 1 time per week for 4 consecutive weeks. For that, the participants were evaluated through the application of questionnaires and physical examination and underwent shock wave therapy for the upper limb ipsilateral to the surgery. Results: After the intervention, none of the participants had skin lesions, blisters, desquamation or hyperthermia of the limbs, and 17.65% had skin redness. Most patients reported no change in their social life and that they felt safer in daily activities and very satisfied with the treatment. The patients showed improvement in upper limb functionality after the intervention versus baseline (p=0.02). No difference in limb volume and shoulder range of motion over time for all movements performed was found after the intervention and at the evaluated intervals. In addition, improvements were observed in some domains of the quality-of-life questionnaires. Conclusion: Shockwave Therapy proved to be safe and tolerable in patients with lymphedema, with improved functionality and no significant change in the volume of the affected limb. Keywords: Extracorporeal shock wave therapy; Lymphedema; Breast cancer.

Citation Format: Patricia Lima Ventura, Cinira Haddad, Vanessa Sanvido, Afonso Nazário, Gil Facina, Amanda Estevao, Samantha Lopes de Almeida Rizzi. SAFETY AND TOLERANCE OF THE USE OF SHOCK WAVE THERAPY IN LYMPHEDEMA SECONDARY TO THE TREATMENT OF BREAST CANCER [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-02.
Abstract PO3-15-06: Identification of a Novel Five Ferroptosis-Related Gene Signature as a Promising Prognostic Model for Breast Cancer
Authors: Cheng Tian-cheng , Wu Jia-hao , Zhu Bei , Zheng Lin , Chen Wei-xian
Published: May 2024

Background: Breast cancer (BCa) is a major challenge for women's health worldwide. Ferroptosis is closely related to tumorigenesis and cancer progression. However, the prognostic value of ferroptosis-related genes in BCa remains unclear, and more accurate prognostic models are urgently needed. Methods: Gene expression profiles and clinical information of BCa patients were collected from public databases. LASSO and multivariate Cox regression analysis were utilized to construct the prognostic gene signature. Kaplan-Meier plotter, Receiver Operating Characteristic (ROC) curves, and nomogram were used to validate the prognostic value of the gene signature. Gene set enrichment analysis was performed to explore the molecular functions and signaling pathways. Results: Differentially expressed ferroptosis-related genes between BCa samples and normal tissues were obtained. A novel five-gene signature including BCL2, SLC40A1, TFF1, APOOL, and PRAME was established for prognosis prediction. Patients stratified into high-risk or low-risk group displayed significantly different survival. Kaplan-Meier and ROC curves showed a good performance for survival prediction in different cohorts. Biological function analysis revealed that the five-gene signature was associated with cancer progression, immune infiltration, immune response, and drug resistance. Nomogram including the five-gene signature was established. Conclusions: A novel five ferroptosis-related gene signature and nomogram could be used for prognostic prediction in BCa. Key words: breast cancer, ferroptosis, gene signature, overall survival, prognosis

Citation Format: Tian-cheng Cheng, Jia-hao Wu, Bei Zhu, Lin Zheng, Wei-xian Chen. Identification of a Novel Five Ferroptosis-Related Gene Signature as a Promising Prognostic Model for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-06.
Abstract PO3-16-04: Distribution of intrinsic subtypes in endocrine-resistant and endocrine-sensitive breast cancer
Authors: Schagerholm Caroline , Robertson Stephanie , Karlsson Emelie , Sifakis Emmanouil , Hartman Johan
Published: May 2024

Background

Breast cancer (BC) is a heterogeneous disease that can be divided into intrinsic molecular subtypes. Among the four intrinsic subtypes, Luminal A and Luminal B are the most common and associated with the best outcome, whereas HER2-enriched and basal-like are less frequent. Tumors that are estrogen receptor α (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) are mostly found among the luminal subtypes. Despite that patients with ER+/HER2- tumors are offered adjuvant endocrine therapy, around one-third eventually develop endocrine resistance. The aim of this study was to explore the distribution of intrinsic subtypes in endocrine-resistant primary and relapse tumors, comparing these to endocrine-sensitive controls.

Materials and methods

Verified endocrine-resistant BC patients diagnosed in 2008-2012 were retrospectively collected at the Karolinska University Hospital, Stockholm, Sweden. Cases (N=70) were identified as patients with ER+/HER2- primary tumors and subsequent ER+/HER2- relapse tumors within 5 years and during endocrine therapy. Patients with primary ER+/HER2- tumors without progression or relapse at 10 years of follow-up were defined as controls (N=78), diagnosed in 2005-2006. Extracted RNA from formalin-fixed paraffin-embedded tumor tissue was analyzed by Affymetrix Clariom D Microarray and assessed by Transcriptome Analysis Console and R software.

Results

Among the controls, the distribution of Luminal A, Luminal B, and HER2-enriched subtypes was 65.4%, 34.6%, and 0%, respectively. In primary tumors, the distribution was in turn 55.4%, 43.1%, and 1.5%, and among relapse tumors 57.6%, 37.9%, and 4.5%, respectively. A total of 19 cases, accounting for 27.1%, switched intrinsic subtypes between the paired primary and relapse tumors. No tumors exhibited the basal-like subtype.

Conclusion

In this unique cohort, Luminal B and HER2-enriched subtypes were more common in primary and relapse tumors of verified endocrine-resistant patients than in primary tumors of endocrine-sensitive controls. Further, the HER2-enriched subtype, although sparse, was more frequently found in patients’ relapse tumors than in their corresponding primary tumors, and over one-fourth of cases switched subtypes during progression. These findings support the presence of subtype shifting in endocrine-resistant relapses and that endocrine-resistant tumors are more prone to be of Luminal B or HER2-enriched subtypes than endocrine-sensitive tumors.

Citation Format: Caroline Schagerholm, Stephanie Robertson, Emelie Karlsson, Emmanouil Sifakis, Johan Hartman. Distribution of intrinsic subtypes in endocrine-resistant and endocrine-sensitive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-04.
Abstract PO3-25-01: CTLA4 expression profiles and their association with clinical outcomes of breast cancer
Authors: Noh Woo Chul , Yoo Young Bum , Park Kyoung Sik , Nam Sang Eun , Lim Seung Hwan
Published: May 2024

The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is involved in the progression of various cancers, but its biological roles in breast cancer (BRCA) remain unclear. Therefore, we performed a systematic multiomic analysis to expound on the prognostic value and underlying mechanism of CTLA4 in BRCA. First, the expression of CTLA4 in pan-cancer was evaluated using the platforms of Oncomine. Afterward, the web-based bioinformatics platforms of GEPIA and UCLAN were used to compare the expression of CTLA4 in breast cancer and normal tissues. Next, we assessed the relationship between CTLA4 mRNA expression and prognosis in breast cancer patients using the PrognoScan Database, Kaplan-Meier Plotter, and R2: Kaplan-Meier Scanner. Additionally, the correlation between CTLA4 expression and immune cell infiltration in breast cancer and functional enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was performed to elucidate the potential biological functions of CTLA4. Finally, we used the STRINGdb and cytoHubba plugin Cytoscape to create a PPI network and identify known and predicted structural essentials for CTLA4 functions and the top five hub genes. CTLA4 was highly expressed in BRCA tumor tissue compared to normal tissue (p< 0.01). The CTLA4 mRNA levels in BRCA based on breast cancer subtypes of luminal, Human epidermal growth factor receptor 2 (HER-2), and Triple-negative breast cancer (TNBC) were considerably higher than in normal tissues (p< 0.001). However, the overexpression of CTLA4 was associated with a better prognosis in BRCA (P< 0.001), and was correlated with clinicopathological characteristics including age, T-stage, estrogen receptors (ER), progesterone receptors (PR), and PAM50 (P< 0.01). The infiltration of multiple immune cells was associated with increased CTLA4 expression in BRCA (P< 0.001). CTLA4 was highly enriched in antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. This study provides suggestive evidence of the prognostic role of CTLA4 in breast cancer, which may be a therapeutic target for breast cancer. Furthermore, CTLA4 may influence breast cancer prognosis through antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. These findings help us understand how CTLA4 plays a role in breast cancer and set the stage for more research.

Citation Format: Woo Chul Noh, Young Bum Yoo, Kyoung Sik Park, Sang Eun Nam, Seung Hwan Lim. CTLA4 expression profiles and their association with clinical outcomes of breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-01.
Abstract PO3-25-06: Expression of CD28, Fas, PD1, and CTLA4 molecules on cellular immune response in the blood peripheral of patients with locally advanced triple-negative breast cancer
Authors: Salgado Marcelo , Soares Fernando , Viana Denise , Salgado Amanda , Vasconcelos Carolina , Anunciação Carlos Eduardo , Salgado Eduardo , Torres Leuridan
Published: May 2024

Background: Locally advanced triple-negative breast cancer (TNBC) represents a public health problem in Brazil; its standard treatment consists of neoadjuvant chemotherapy followed by surgical and radiotherapy, with highly variable success rates are depended on access to appropriate cancer treatment, and the type of pathological response. In the last decade, the immune system's role in breast cancer has gained space by demonstrating the favorable impact of lymphocyte tumor infiltrate (TILs) and gene expression of the immune response, especially in tumors with high proliferation rates and negative estrogen receptors. The cellular immune response is regulated by co-stimulatory and co-inhibitory proteins such as CD28, Fas, PD1, and CTLA4 molecules. Methods: This was a longitudinal study with follow-up performed between 2015 and 2017. The study was conducted at the Hospital de Cancer de Pernambuco and Translational Research Laboratory of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP). Thirty women (18 to 60 years) diagnosed with locally advanced TNBC submitted to neoadjuvant chemotherapy (NAC), and 30 healthy women as a control group were included. The co-stimulatory and co-inhibitory proteins analyses were performed in the peripheral blood of TNBC women before (Pre-NAC) and after NAC (Post-NAC) Results: High levels of CD28+CD3+ T, CD28+CD4+ T, PD1+CD3+ T, and CTLA4+CD3+ T cells in the pathological complete response (pCR) and non-pCR groups compared to the control group (p < 0.05). High levels of Fas+CD4+T cells and PD1+CD8+T cells in the non-pCR compared to the pCR group (p < 0.05). In the paired analysis, significant differences were observed in CD3+T and CD4+T levels with CD28, Fas, and PD1 expression between pre- and post-NAC. Conclusion: Fas+CD4+T and PD1+CD8+T levels in peripheral blood in TNBC are associated with pCR, suggesting potential predictive biomarkers of NAC response. Preliminary results allow us to infer that neoadjuvant chemotherapy modulates the cellular immune response in TNBC women.

Citation Format: Marcelo Salgado, Fernando Soares, Denise Viana, Amanda Salgado, Carolina Vasconcelos, Carlos Eduardo Anunciação, Eduardo Salgado, Leuridan Torres. Expression of CD28, Fas, PD1, and CTLA4 molecules on cellular immune response in the blood peripheral of patients with locally advanced triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-06.