Poor Prognosis In Breast Cancer Research Articles

A real world study on the relationship between drug resistance of targeted therapy and prognosis of HER-2-positive advanced breast cancer

Objective: To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2 (HER-2) on the overall survival of patients with HER-2 positive advanced breast cancer. Methods: The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected, and their neoadjuvant/adjuvant and advanced three-line chemotherapy were summarized. Among them, targeted drugs for HER-2 included trastuzumab, pertuzumab, T-DM1, RC48-ADC, lapatinib, pyrotinib, allitinib, sipatinib, seratinib. Based on the duration of benefit from anti HER-2 treatment, the patients were divided into two groups: primary anti HER-2 resistance group and acquired anti HER-2 resistance group. In this study, the overall survival (OS) was used as the main end point. Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival. Results: The whole group of 284 patients were included. The median age of recurrence and metastasis was 48 years old, 155 (54.6%) were hormone receptor (HR) positive and 129 (45.4%) were HR negative, 128 cases (45.1%) were premenopausal and 156 cases (54.9%) were postmenopausal, 277 cases (97.5%) had a score of 0-1 in ECoG PS and 7 cases (2.5%) had a score of more than 2 in the first diagnosis of relapse and metastasis. There were 103 cases (36.3%) in the primary drug resistance group and 181 cases (63.7%) in the secondary drug resistance group. The median overall survival time of the two groups was 24.9 months and 40.4 months, respectively, with statistical significance (P<0.001). Conclusion: Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer, and its mechanism needs to be further explored.

Association of ZEB1 and Vimentin with poor prognosis in metaplastic breast cancer

Zinc finger E-box binding homeobox factor 1 (ZEB1) is a transcription factor involved in the epithelial to mesenchymal transition (EMT) process of metaplastic breast cancer (MBC). This study aimed to assess the expression of ZEB1 in MBC and explore its association with clinicopathological factors and prognosis. We analyzed the immunohistochemical expression of ZEB1 in 50 MBC tissue samples. ZEB1 was overexpressed in 36% (18/50) of cases. ZEB1 overexpression was significantly correlated to fibromatosis-like and spindle cell sarcoma subtypes (P < 0.001) and tended to be correlated to metastatic status (P = 0.069). Using the Kaplan-Meier method, ZEB1 expression was significantly associated with poor 5-years overall survival (OS) (P = 0.001) and relapse-free survival (RFS) (P = 0.0001). The multivariate Cox regression analysis showed that ZEB1 positive remained a significantly independent adverse prognostic factor for RFS and OS (HR = 4.9 [2.14–11.53]; P < 0.0001) and (HR = 4 [1.05–15.18]; P = 0.042), while Vimentin was an independent poor prognostic factor only for RFS (HR = 5.69 [1.79–18.11], P = 0.003). Our results indicated that ZEB1 and Vimentin overexpression might serve as adverse prognostic factors and potential therapeutic targets for MBC patients.

Recent Advances in IL-13Rα2-Directed Cancer Immunotherapy.

Interleukin-13 receptor subunit alpha-2 (IL-13Rα2, CD213A), a high-affinity membrane receptor of the anti-inflammatory Th2 cytokine IL-13, is overexpressed in a variety of solid tumors and is correlated with poor prognosis in glioblastoma, colorectal cancer, adrenocortical carcinoma, pancreatic cancer, and breast cancer. While initially hypothesized as a decoy receptor for IL-13-mediated signaling, recent evidence demonstrates IL-13 can signal through IL-13Rα2 in human cells. In addition, expression of IL-13Rα2 and IL-13Rα2-mediated signaling has been shown to promote tumor proliferation, cell survival, tumor progression, invasion, and metastasis. Given its differential expression in tumor versus normal tissue, IL-13Rα2 is an attractive immunotherapy target, as both a targetable receptor and an immunogenic antigen. Multiple promising strategies, including immunotoxins, cancer vaccines, and chimeric antigen receptor (CAR) T cells, have been developed to target IL-13Rα2. In this mini-review, we discuss recent developments surrounding IL-13Rα2-targeted therapies in pre-clinical and clinical study, including potential strategies to improve IL-13Rα2-directed cancer treatment efficacy.

SIA-IgG confers poor prognosis and represents a novel therapeutic target in breast cancer

ABSTRACT The incidence rate of breast cancer is the highest in the world, and major problem in the clinical treatment is the therapy resistance of breast cancer stem cells (CSCs). Thus, new therapeutic approaches targeting breast CSCs are needed. Our previous study demonstrated cancer-derived sialylated IgG (SIA-IgG) is highly expressed in cancer cells with stem/progenitor features. Furthermore, a high frequency of SIA-IgG in breast cancer tissue predicted metastasis and correlated with poor prognosis factors, and depletion of IgG in breast cancer leads to lower malignancy of cancer cells, suggesting SIA-IgG could be a potential therapeutic target in breast cancer. In this study, we first investigated the relationship of SIA-IgG expression with the clinicopathological characteristics and clinical prognosis of breast carcinoma patients, and the data confirmed that the expression of SIA-IgG confers poor prognosis in breast cancer. Successively, by using a monoclonal antibody specifically against SIA-IgG, we targeted SIA-IgG on the surface of MDA-MB-231 cells and detected their functional changes, and the results suggested SIA-IgG to be a promising antibody therapeutic target in breast cancer. In addition, we explored the mechanism of action at the molecular level of SIA-IgG on breast cancer cell, the findings suggest that SIA-IgG promotes proliferation, metastasis, and invasion of breast cancer cells through the Wnt/β-catenin signaling pathway. Developing therapeutic antibody needs effective therapeutic target, and the antibody should better be a monoclonal antibody with high affinity and high specificity. This study provides a potential prognostic marker and a novel therapeutic target for breast cancer.

Examining the miR-93-5p and miR-17-5p Expression in Plasma and Breast Cancer Tissue as Possible Markers in Breast Cancer Prognosis

Background and Aim MicroRNAs (miRNAs) are a class of small non-coding RNAs (17-25 nucleotides) that have been studied in many diseases. miRNAs studies in different cancers have shown that miRNAs may be considered oncogene or tumor suppressor. So far, many studies have shown that miR-17-5p and miR-93-5p are important regulatory molecules in some biological processes, such as cell proliferation, associated with cancer formation. This study aimed to investigate and compare the tissue and plasma expression levels of miR-17-5p and miR-93-5p in patients with ductal carcinoma breast cancer with the normal control group. Methods &amp; Materials The total RNA (including miRNA) was extracted from breast and plasma tissue samples of cancerous and normal samples. The RNA concentration and purity were confirmed using optical absorbance measurements. cDNA was synthesized, and the expression levels of miR-17-5p and miR-93-5p were assessed semi-quantitatively by SYBR Green-based real-time RT-PCR assay in plasma and breast tissues of ductal carcinoma breast cancer compared with the control normal samples with SNORD47 as internal normalizer. Data were statistically evaluated using GraphPad Prism 8.0.2. Ethical Considerations This study was approved by the Ethics Committee of the institute (IRAN 52d/4922, 6.10.2016). All study individuals signed a consent form to use their clinical samples and personal data under the physician’s supervision. Results The expression level of miR-17-5p showed significantly higher expression in tissues and plasma of the cancer group compared with the control group (P&lt;0.0001). It was also significantly associated with tumor stage and lymph node, and ER (estrogen receptor) and PR (progesterone receptor) status (P&lt;0.0001). While decreased expression of miR-93-5p in plasma and tumor tissues was shown to be significantly associated with tumor stage and lymph node involvement (P&lt;0.0001). Conclusion The data revealed that high expression of miR-17-5p and low expression of miR-93-5p in both plasma and breast tumor might be associated with poor prognosis in breast cancer. However, miR-17-5p, due to the greater change in expression and ease of plasma detection, may serve as a possible non-invasive biomarker for breast cancer’s poor prognosis. Further follow-up studies are required to confirm this finding.

Long non-coding RNA DEPDC1-AS1 promotes proliferation and migration of human gastric cancer cells HGC-27 via the human antigen R-F11R pathway.

ObjectiveLong non-coding (lnc) RNAs are critical regulators in carcinogenesis. The novel lncRNA DEPDC1 antisense RNA 1 (DEPDC1-AS1) was recently associated with poor prognosis in triple-negative breast cancer and lung adenocarcinoma. However, its role in regulating the malignant progression of gastric cancer (GC) and its molecular mechanism are unclear. We herein explored the functions of DEPDC1-AS1 in GC progression.MethodsDEPDC1-AS1 expression and prognosis in GC tissues were examined by bioinformatics analysis and quantitative reverse transcription polymerase chain reaction. The DEPDC1-AS1 function in GC cells was explored by the cell counting kit-8 assay, colony formation assay, Transwell assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, 5-ethynyl-2′-deoxyuridine-incorporation, and the xenograft tumor model. The DEPDC1-AS1 and human antigen (Hu)R interaction was determined by RNA pull-down and RNA immunoprecipitation.ResultsDEPDC1-AS1 was overexpressed in GC tissues and cell lines, and associated with a worse prognosis in GC patients. In vitro and in vivo assays showed that DEPDC1-AS1 promoted HGC-27 cell proliferation and migration. Mechanistically, DEPDC1-AS1 served as a scaffold by combining with HuR to target the specific mRNA F11R.ConclusionDEPDC1-AS1 plays a crucial role in GC development and progression and is a potential biomarker for the early detection or prognosis of GC.

Analysis of Yes-Associated Protein-1 (YAP1) Target Gene Signature to Predict Progressive Breast Cancer.

Breast cancers are treated according to the ER/PR or HER2 expression and show better survival outcomes with targeted therapy. Triple-negative breast cancers (TNBCs) with a lack of expression of ER/PR and HER2 are treated with systemic therapy with unpredictable responses and outcomes. It is essential to investigate novel markers to identify targeted therapies for TNBC. One such marker is YAP1, a transcription co-activator protein that shows association with poor prognosis of breast cancer. YAP1 transcriptionally regulates the expression of genes that drive the oncogenic phenotypes. Here, we assess a potential YAP target gene signature to predict a progressive subset of breast tumors from METABRIC and TCGA datasets. YAP1 target genes were shortlisted based on expression correlation and concordance with YAP1 expression and significant association with survival outcomes of patients. Hierarchical clustering was performed for the shortlisted genes. The utility of the clustered genes was assessed by survival analysis to identify a recurring subset. Expression of the shortlisted target genes showed significant association with survival outcomes of HER2-positive and TNBC subset in both datasets. The shortlisted genes were verified using an independent dataset. Further validation using IHC can prove the utility of this potential prognostic signature to identify a recurrent subset of HER2-positive and TNBC subtypes.

Tubulin Carboxypeptidase Activity Promotes Focal Gelatin Degradation in Breast Tumor Cells and Induces Apoptosis in Breast Epithelial Cells That Is Overcome by Oncogenic Signaling.

Simple SummaryThe recent discovery of the genetic identity of the tubulin carboxypeptidase (TCP) provides a unique opportunity to study the role of the detyrosination of α-tubulin (deTyr-Tub), as performed by the TCP, in breast epithelial cells and breast cancer cells. Previous research has shown that elevated deTyr-Tub conveys a poor prognosis in breast cancer and is upregulated in a coordinated manner at the invasive margin of patient tumor samples. Using TCP expression constructs, we have shown that increased deTyr-Tub promotes apoptosis in normal breast epithelial cells, that does not occur in the same cells with an oncogenic KRas mutation or Bcl-2/Bcl-xL overexpression. Furthermore, the addition of the TCP to the breast cancer cell lines MDA-MB-231 and Hs578t, also harboring Ras mutations, leads to increased focal gelatin degradation.Post-translational modifications (PTMs) of the microtubule network impart differential functions across normal cell types and their cancerous counterparts. The removal of the C-terminal tyrosine of α-tubulin (deTyr-Tub) as performed by the tubulin carboxypeptidase (TCP) is of particular interest in breast epithelial and breast cancer cells. The recent discovery of the genetic identity of the TCP to be a vasohibin (VASH1/2) coupled with a small vasohibin-binding protein (SVBP) allows for the functional effect of this tubulin PTM to be directly tested for the first time. Our studies revealed the immortalized breast epithelial cell line MCF10A undergoes apoptosis following transfection with TCP constructs, but the addition of oncogenic KRas or Bcl-2/Bcl-xL overexpression prevents subsequent apoptotic induction in the MCF10A background. Functionally, an increase in deTyr-Tub via TCP transfection in MDA-MB-231 and Hs578t breast cancer cells leads to enhanced focal gelatin degradation. Given the elevated deTyr-Tub at invasive tumor fronts and the correlation with poor breast cancer survival, these new discoveries help clarify how the TCP synergizes with oncogene activation, increases focal gelatin degradation, and may correspond to increased tumor cell invasion. These connections could inform more specific microtubule-directed therapies to target deTyr-tubulin.

Histomorphology of immunomodulation and PD1 expression in breast cancer tumor draining lymph nodes

Background: Metastasis in tumor draining lymph nodes (TDLNs) is correlated with poor prognosis in breast cancers. It is associated with local immune suppression, which can be partly due to the higher expression of check point inhibitors in immune cells. The morphological manifestation of the underlying immunomodulation of TDLNs has been less investigated. Here, we present the histomorphological changes and PD1 expression pattern in metastatic and non-metastatic TDLNs in breast cancer patients. Methods: A total of 248 metastatic or non-metastatic TDLNs from 50 breast carcinoma samples were examined histologically and for PD1 expression in the present study. We assessed the immune response in these TDLNs as per histomorphological patterns on H&amp;E stained slides, categorizing them into lymphocyte predominance, germinal center predominance and an un-stimulated pattern. Anti-PD1 immunohistochemistry was performed on all lymph nodes. The results were analyzed using SPSS version 23 and P value &lt;0.05 was considered to be significant. Results: The lymph node metastasis in breast carcinoma was significantly higher at younger age, patients with higher tumor grade and lympho-vascular invasion in the primary tumor. The metastatic lymph nodes showed significantly higher densities of germinal centers with abnormal shapes, as compared to non-metastatic ones. There was significantly higher expression of PD1 in the immune cells of metastatic TDLNs. Conclusion: The identification of PD1 immunohistochemical profile along with histological changes of TDLNs should therefore be considered as a possible prognostic and predictive marker for lymph node metastasis. The patients with higher densities of germinal center with abnormal shape and increased PD1 expression should benefit from immune-check point inhibitor therapy.

Stabilization of Notch1 and β-catenin in response to ER- breast cancer-specific up-regulation of PSAT1 mediates distant metastasis

Breast cancer has the highest incidence in women worldwide, with a mortality rate second only to lung cancer. Distant metastasis is the major cause of breast cancer-induced death. While upregulation of phosphoserine aminotransferase 1 (PSAT1) has been reported in several cancer types, its specific roles in breast cancer and potential involvement in distant metastasis remain unclear. In our study, PSAT1 was upregulated in metastatic breast cancer and promoted distant metastasis both in vitro and in vivo. Data obtained from transwell and wound healing, colony, sphere assays and detection of various malignant phenotypic markers showed that PSAT1 mediates distant metastasis by promoting invasion, migration, proliferation, anti-apoptosis, stemness and angiogenesis in breast cancer cells. Mechanistically, PSAT1 activated Notch and β-catenin signaling pathways, leading to enhanced distant metastasis. The clinical relevance of PSAT1 in breast cancer was additionally investigated, which revealed associations of poorer patient prognosis with high PSAT1 mRNA and protein expression. In summary, PSAT1 is a critical molecular regulator of distant metastasis that may effectively serve as a marker of poor prognosis in breast cancer.

Predictive value of topoisomerase II alpha protein for clinicopathological characteristics and prognosis in early breast cancer.

Topoisomerase II alpha (TOP2A) has been identified as a proliferation marker, of which the most common method for detection is immunohistochemistry (IHC). However, the optimal cut-off of TOP2A expression regarding prognostic value remains controversial. This study was to identify the optimal cut-off value of TOP2A expression and its correlation with clinicopathological variables and prognosis in early stage breast cancer in China. Between January 2013 and January 2015, a total of 1084 early breast cancer patients were enrolled. The optimal cut-off of TOP2A expression was assessed using the minimum P value approach. Correlations between TOP2A expression and clinicopathological characteristics were explored by the Spearman's correlation analysis, while the impact of TOP2A expression on disease-free survival (DFS) and overall survival (OS) was evaluated by the Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were executed to identify statistically significant prognostic factors. The optimal cut-off value of TOP2A was recommended as 15%. Overall, 603 (55.6%) patients were TOP2A over-expression and 481 (44.4%) patients were TOP2A low expression. TOP2A over-expression was in positive associations with a higher Ki67 index (r = 0.83, P < 0.001), HER2 positive (r = 0.26, P < 0.001), a larger tumor size (r = 0.14, P < 0.001), and a higher histologic grade (r = 0.59, P < 0.001), and in a significantly negative correlation with hormone receptor (HR) positive expression (r = - 0.40, P < 0.001) in early breast cancer. TOP2A over-expression significantly associated with worse DFS (P = 0.001) and OS (P < 0.001) and was an independent prognostic factor for both DFS (hazard ratio [HR] = 2.04; 95% confidence interval [95% CI] 1.30-3.18, P = 0.0018) and OS (HR = 3.54; 95%CI 1.53-8.23, P = 0.003) in stage I-II breast cancer patients. To our knowledge, this is the first study to recommend the optimal cut-off value of TOP2A expression in breast cancer. The TOP2A expression is significantly correlated with HER2 status, Ki67 index, tumor size, histologic grade and HR status, and could be a surrogate indicator for poor prognosis of early breast cancer.

High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer.

Although the DNA repair mechanism is important in preventing carcinogenesis, its activation in established cancer cells may support their proliferation and aggravate cancer progression. RAD51 cooperates with BRCA2 and is essential in the homologous recombination of DNA repair. To this end, we hypothesized that RAD51 gene expression is associated with cancer cell proliferation and poor prognosis of breast cancer (BC) patients. A total of 8515 primary BC patients with transcriptome and clinical data from 17 independent cohorts were analyzed. The median value was used to divide each cohort into high and low RAD51 expression groups. High RAD51 expression enriched the DNA repair gene set and was correlated with DNA repair-related genes. Nottingham histological grade, Ki67 expression and cell proliferation-related gene sets (E2F Targets, G2M Checkpoint and Myc Targets) were all significantly associated with the high RAD51 BC group. RAD51 expression was positively correlated with Homologous Recombination Deficiency, as well as both mutational burden and neoantigens that accompanied a higher infiltration of immune cells. Primary BC with lymph node metastases was associated with high expression of RAD51 in two cohorts. There was no strong correlation between RAD51 expression and drug sensitivity in cell lines, and RAD51 expression was lower after the neoadjuvant chemotherapy compared to before the treatment. High RAD51 BC was associated with poor prognosis consistently in three independent cohorts. RAD51 gene expression is associated with aggressive cancer biology, cancer cell proliferation, and poor survival in breast cancer.

Functional Antagonism of Junctional Adhesion Molecule-A (JAM-A), Overexpressed in Breast Ductal Carcinoma In Situ (DCIS), Reduces HER2-Positive Tumor Progression.

Simple SummarySpecific drug targets for breast ductal carcinoma in situ (DCIS) remain elusive, despite increasing disease prevalence and burden to healthcare services. Estrogen receptor (ER)-negative HER2-positive DCIS, associated with the poorest patient prognosis, is in particular need of novel therapeutic avenues. This report provides the first evidence that a cell surface protein called JAM-A is upregulated on human DCIS patient tissues and can be readily targeted by a novel JAM-A-binding peptide inhibitor in separate in vivo models of DCIS. The anti-tumor efficacy and lack of systemic toxicity of this lead inhibitor, coupled with early indications of potential signaling pathways implicated, support the value of future studies investigating JAM-A as a novel drug target in DCIS patients.Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS.

MiRNA-186-5p Exerts an Anticancer Role in Breast Cancer by Downregulating CXCL13.

The aim of this study is to illustrate the biofunctions of miRNA-186-5p level in breast cancer (BCa) and to explore the underlying mechanisms. Levels of miRNA-186-5p in BCa tissues and adjacent normal ones were determined. Association of miRNA-186-5p with pathological parameters and prognosis in BCa patients was analyzed. Luciferase assay was conducted for the prediction of the interaction between miRNA-186-5p and CXCL13. Their mutual interaction in influencing the proliferative potential of BCa was finally explored. Results showed that miRNA-186-5p expression was downregulated in BCa cell lines and tissues. MiRNA-186-5p overexpression could attenuate proliferative ability in BCa cells. A direct and negative correlation was identified between miRNA-186-5p and CXCL13. In addition, their mutual interaction was coresponsible for the malignant development of BCa. In BCa patients, miRNA-186-5p level was remarkably associated with tumor size and tumor staging, rather than other pathological parameters. Low level of miRNA-186-5p predicted a poor prognosis in BCa. Downregulated miRNA-186-5p in BCa is linked to tumor size, tumor staging, and prognosis. miRNA-186-5p downregulates CXCL13 by binding CXCL13 3′UTR in BCa cells. Overexpression of CXCL13 can significantly neutralize the inhibitory effects of miRNA-186-5p on BCa proliferation.

Abstract P3-13-01: Association of polygenic risk score with 2 year risk of poor prognosis breast cancer

Abstract Introduction: Mammography reduces breast cancer mortality, however, there is controversy surrounding when and how often women should undergo mammography screening. Knowledge of short-term risk of developing breast cancer, particularly poor prognosis breast cancer, would help direct more intensive screening to those at highest risk. Polygenic risk scores (PRS) are emerging as a powerful tool to predict breast cancer risk, however, few studies have evaluated the associations of breast cancer PRS with short-term risk or with risk of poor prognosis breast cancers specifically. Methods: Using a mammography screening cohort at Massachusetts General Hospital, we identified women who had a negative mammogram (BI-RADS assessment 1 or 2) from 2006 to 2015. We linked the cohort to a research biobank to obtain genetic information. In addition, we recruited 205 patients who developed breast cancer within 2 years of a negative mammogram to provide a DNA sample. Women with a prior history of breast cancer, with breast implants, and who were not residents of Massachusetts were excluded. Samples were genotyped using the Illumina Multi-Ethnic GWAS/Exome SNP (MEGA) array. Genotypes were imputed using TOPMed (Version r2 2020). Patients whose saliva DNA samples had low concentration or that failed quality control procedures were excluded. Ancestry specific principal components were generated and used as a covariate. We generated the 313-SNP breast cancer PRS, the estrogen receptor positive (ER+) PRS and the estrogen receptor negative (ER-) PRS using established methods. (PMID: 30554720) Breast cancers were defined as poor prognosis if they were metastatic, had positive lymph nodes, were ER/PR+HER2- and &amp;gt 2cm or ER/PR/HER2- or HER2+ and &amp;gt 1cm. (PMID: 33169794) Logistic regression was used to estimate the odds ratios for standardized PRS measures, adjusted for age, breast density, race/ethnicity, year of screening, and ancestry principal components. Results: After exclusions, 308 breast cancers and 3329 non-cases were analyzed. Of the breast cancers, 86% were ER/PR+ (264/308) and 14% were ER/PR- (42/308), and 137 (44%) were poor prognosis. The majority of patients were non-Hispanic White (87%) and the mean age was 57 years and was similar for cancers and non-cancers. Cancer cases were more likely than non-cases to have higher breast density and a family history of breast cancer. First, we examined the overall breast cancer PRS, and found the PRS was significantly associated with breast cancer diagnosed within two years of a negative mammogram (OR=1.39, 95% CI 1.23-1.57, p &amp;lt 0.001). The PRS was also significantly associated specifically with diagnosis of poor prognosis disease (OR=1.21, 95% CI 1.01-1.45, p=0.037). In addition, the ER+ PRS was significantly associated with ER/PR+ breast cancer (OR=1.41, 95% CI 1.24-1.61, p &amp;lt 0.001), and the ER- PRS was significantly associated with ER- breast cancer (OR=1.48, 95% CI 1.08-2.02, p=0.015). Conclusion: Even after adjusting for breast density and other risk factors, breast cancer PRS was significantly associated with diagnosis of both breast cancer overall and poor prognosis breast cancer within two years of a negative mammogram. Furthermore, the subtype specific PRS were significantly associated with short-term risk of ER+ and ER- disease. These results suggest that PRS may be useful in guiding decisions about screening interval and supplemental screening, given the association of PRS with risk of poor prognosis disease in the short term. Table 1.Logistic Regression of PRS and cancer diagnosis within 2 years of a negative mammogramOR95% CIp-valueAll Cancers (N=308), Overall PRS1.391.23-1.571.78x10-7Poor prognosis (N=147), Overall PRS1.211.01-1.450.037ER+ cancers (N=264), ER+ PRS1.421.24-1.621.87x10-7ER- cancers (N=42), ER- PRS1.521.11-2.090.008 Citation Format: Anne Marie McCarthy, Alisa K. Manning, Sarah Hsu, Beverly Moy, Constance D. Lehman, Katrina Armstrong. Association of polygenic risk score with 2 year risk of poor prognosis breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-01.

Abstract P2-12-23: Changes in 18F-FDG-PET uptake after the first course of DTX reflect response to preoperative chemotherapy and prognosis in breast cancer

Abstract [Purpose] It is important to make early decisions about treatment changes in treatment-resistant groups. The aim of this study is to extract non-responders among preoperative chemotherapy using 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) in primary breast cancer. We hypothesized that early evaluation of FDG PET after the first course of docetaxel (DTX) would predict treatment resistant group by the relationship between changes on FDG accumulation and tumor diameter on magnetic resonance imaging (MRI). [Patients and Methods] Thirty-seven of 41 patients were evaluated. Clinical stage was T1-4, N0-3, and M0 between August 2007 and December 2010. Four courses of DTX were administered followed by 4 courses of fluorouracil/epirubicin/cyclophosphamide (FEC) followed by surgery. FDG-PET evaluation was performed by the maximum standardized uptake value (SUVmax). FDG-PET scans were performed at baseline, at 15 days after the first course of DTX (C1D15), and at 15 days after 4 courses of DTX (C4D15). Tumor reduction rate was measured on MRI at baseline and at C4D15 according to Response Evaluation Criteria in Solid Tumors (RECIST). ROC analysis was performed by between SUVmax of C1D15 and MRI of C4D15. Changes of SUVmax C1D15 were divided into high and low group by ROC analysis. Core needle biopsy (CNB) was performed to evaluate the treatment effect pathologically after 4 courses of DTX (C4CNB). The pathological treatment effect of surgical specimens after 4 courses of FEC (C4FEC) was also examined. The difference in progression-free survival (PFS) rate or overall survival (OS) rate between the low and high SUVmax of C1D15 change rate was calculated using Kaplan-Meier survival curves and compared by log-rank test. The protocol of the study was approved by the Ethics Committee of the Gunma Prefectural Cancer Center (ECGPCC), and all patients gave their written informed consent before enrollment (No. 19011). The observational study was also approved by ECGPCC (No. 30087). [Results] There were ER+HER2-:17, ER+HER2+:4, ER-HER2-:11, and ER-HER2+:5 cases. SUVmax change rate C1D15 correlated with the SUVmax change rate C4D15 and tumor shrinkage rate on MRI C4D15 in univariate (SUVmax C4D15: γ=.567, p&amp;lt;.001, MRI C4D15: γ=.748, p&amp;lt;.001) and in multivariate analysis (SUVmax C4D15: γ=414, p=.002, MRI C4D15: γ=.616, p&amp;lt;.001). The SUVmax change rate C1D15 correlated with pathological effect of C4CNB (γ=.392, p=.032) and of surgical specimen C4FEC (γ=.440, p=.006) in univariate analysis. From ROC analysis based on SUVmax C1D15 and MRI C4D15 (AUC=.924, 95% CI: .828-1.000, p&amp;lt;.001), the SUVmax C1D15 were divided into two groups with high and low SUVmax changes. The mean SUVmax in the low group (&amp;lt;30%) (n=15) was 15.8% (±9.7). The mean SUVmax in the high group (≥30%) (n=22) was 50.8% (±11.7). The mean of MRI change rate of C4D15 was 20.4% (±5.4) in the low SUVmax change group and 69.2% (±5.8) in the high SUVmax change group, showing a significant difference between the two groups (p&amp;lt;.001). The low SUVmax change group showed shorter PFS than the high SUVmax group (median 80.9 vs 93.7 months, p=.050), but there was no difference in OS (p=.719). [Conclusion] Changes less than 30% of 18F-FDG uptake after the first course of DTX may reflect the treatment resistance and poor prognosis in primary breast cancer. Citation Format: Tomoko Hirakata, Yasuhiro Yanagita, Tomomi Fujisawa, Teruhiko Kinoshita, Hiroyuki Horikoshi, Nariyuki Oya, Tsukasa Akiyoshi, Misa Iijima, Takeshi Miyamoto, Keiko Yanai, Hiroshi Matsumoto, Kenichi Inoue, Rie Horii, Takaaki Fujii, Ken Shirabe. Changes in 18F-FDG-PET uptake after the first course of DTX reflect response to preoperative chemotherapy and prognosis in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-23.

Abstract PD1-06: Apobec mutagenesis is a pervasive feature of poor prognosis breast cancer associating with ESR1 wild type, endocrine resistant disease

Abstract Background: Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) enzymes drive genomic instability in breast cancer (BC) characterized by specific single base substitution mutation signatures (COSMIC S2 and S13). Computational algorithms have the potential to derive signatures from targeted sequencing assays with relatively small genomic footprints. We sought to develop a computational approach to identify APOBEC mutagenesis in samples subjected to targeted sequencing and to characterize the genomic and clinical features of APOBEC-positive BC. Methods: We retrieved clinical and genomic data from 4,595 consecutive BCs that had been subjected to targeted sequencing using the FDA-approved MSK-IMPACT assay. Additional whole exome sequencing (WES) data were retrieved from publicly available datasets, including TCGA (primary BC, n=1019) and Bertucci et al. cohorts (metastatic BC, n=617). APOBEC-related mutational signatures were computed by using the SigMA algorithm (Gulhan, Nat Genet 2019) for MSK-IMPACT samples with at least 5 single nucleotide variants (SNV) (n=2,983). Survival analyses were performed by using Kaplan Meier method with log-rank test and Cox proportional-hazards models. Results: A significant positive correlation between APOBEC exposure calculated by SigMA vs other computational tools (e.g., DeconstructSig, SigProfiler, MutationalPatterns) was found (r=0.99). After down-sampling the WES data from the TCGA BC dataset to the genomic footprint of MSK-IMPACT, SigMA showed high concordance in determining APOBEC exposures (r=0.78). BCs with high APOBEC exposure were enriched for pathogenic somatic mutations affecting several genes, including PIK3CA, CDH1 and GATA3 (q&amp;lt;0.05), as compared to tumors with no/low APOBEC. In the MSK-IMPACT cohort, median APOBEC mutational exposure was significantly higher in metastatic than primary samples (0.27 vs 0.19, p&amp;lt;0.001) and was the dominant mutational signature in 26% of primary and 34% of metastatic BC. A significant enrichment for APOBEC exposure in the metastatic setting was observed in both hormone receptor-positive (HR+) (p&amp;lt;0.001) and triple-negative (TN) (p&amp;lt;0.001) subtypes. Invasive lobular BCs displayed a higher proportion of cases with high APOBEC mutagenesis when compared to invasive ductal BCs in both primary and metastatic setting (p&amp;lt;0.001). Enrichment of APOBEC in metastatic samples could be due to signature acquisition or enrichment in poor prognosis tumors, to address this, we assessed the presence of APOBEC mutational exposure in patients with paired samples, which included 352 primary/metastasis (P/M) cases and 514 metastasis/metastasis (M/M) cases. Strikingly, no statistically significant increment of APOBEC exposure was found in the P/M nor in the M/M cohort (Wilcoxon signed-rank test p&amp;gt;0.05), overall and in different BC subtypes. We also assessed the association between APOBEC and response to endocrine therapy (ET). Patients with metastatic HR+ BC and APOBEC as dominant signature had a statistically significant lower progression-free survival (PFS) on first-line single-agent ET (aromatase inhibitors or SERDs; median PFS of 9.7 versus 14.7 months, p&amp;lt;0.001). This difference was more pronounced in patients treated with SERD with a median PFS of 4.7 and 14.3 months for APOBEC-dominant and APOBEC non-dominant tumors (p&amp;lt;0.001), respectively. Conclusions: Evidence for APOBEC mutagenesis is present in &amp;gt;30% of metastatic breast cancers and associated with resistance to ET. Unlike ESR1 mutations, which are acquired as a late event in metastatic HR+ BCs, APOBEC mutagenesis is commonly present in paired primary and metastatic BCs, indicating its relatively early onset and potential role in driving the poor prognosis of these cancers. Citation Format: Antonio Marra, Andrea Gazzo, Pier Selenica, Xin Pei, Avantika Gupta, Fresia Pareja, Giuseppe Curigliano, Reuben Harris, Nadeem Riaz, Jorge S. Reis-Filho, Sarat Chandarlapaty. Apobec mutagenesis is a pervasive feature of poor prognosis breast cancer associating with ESR1 wild type, endocrine resistant disease [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD1-06.

Cover Image, Volume 61, Issue 3

The cover image is based on the Research Article Neoadjuvant endocrine therapy expands stromal populations that predict poor prognosis in estrogen receptor-positive breast cancer by Heather M. Brechbuhl et al., https://doi.org/10.1002/mc.23377.

Selective serotonin reuptake inhibitors associated with increased mortality risk in breast cancer patients in Northern Israel.

Approximately one in six women in the USA takes antidepressants and a third use selective serotonin reuptake inhibitors (SSRIs) after breast cancer diagnosis. Recent investigation demonstrated serotonin receptor (5-HTR2B) expression in the breast and serotonin production as an indicator of poor breast cancer prognosis. This study investigates the association between SSRI use at different time intervals relative to breast cancer diagnosis on survival. A population-based sample of 6959 consecutive, newly diagnosed breast cancer cases in Northern Israel was included. Patients were recruited from January 2000 and followed up through March 2020. Participants completed risk factor questionnaires regarding medical, reproductive and family history, medication use and health habits. Full prescription data were available through the Israeli national Clalit medical database. Multivariate Cox proportional hazard models were used to determine survival based on time of SSRI use. Use of SSRIs in the 5 years prior to breast cancer diagnosis was associated with a 66% increase in overall mortality (HRadj = 1.66; CI: 1.05-2.63). SSRI use that initiated after breast cancer diagnosis was associated with an 81% increase in mortality (HRadj = 1.81; CI: 1.58-2.06). Use of SSRIs in the 5 years post-diagnosis was associated with a dose-response increase (P < 0.001) in long-term mortality (>5 years). Heavy SSRI use (≥24 prescription fills) after diagnosis was associated with nearly doubling in mortality (HR = 1.99; CI: 1.39-2.83). SSRI use prior to and after breast cancer diagnosis is associated with increased mortality in breast cancer patients. Additional research is needed to better understand mechanisms mediating this association.

Cxcl10 Chemokine Induces Migration of ING4-Deficient Breast Cancer Cells via a Novel Cross Talk Mechanism between the Cxcr3 and Egfr Receptors

The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study has shown that CXCL10 was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression data sets and found that patients with CXCL10-high/ING4-low expressing tumors had significantly reduced disease-free survival in breast cancer. In vitro, Cxcl10 induced migration of ING4-deleted breast cancer cells but not of ING4-intact cells. Using inhibitors, we found that Cxcl10-induced migration of ING4-deleted cells required Cxcr3, Egfr, and the Gβγ subunits downstream of Cxcr3 but not Gαi. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both ING4-intact and ING4-deleted cells, which recurred only in ING4-deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of ING4-deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gβγ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.