Overall Survival In Breast Cancer Research Articles

The Clinicopathological and Prognostic Significance of the Expression of PD-L1 and MET Genes in Breast Cancer: Potential Therapeutic Targets.

The heterogeneity of breast cancer requires exploring novel prognostic biomarkers as well as therapeutic targets for the treatment of the disease. The METABRIC dataset was used to describe the gene expression of the programmed death-ligand 1 (PD-L1) and the hepatocyte growth factor receptor (MET) and their association with the tumor clinicopathologic characteristics and overall survival in breast cancer. The expression of the PD-L1 and MET genes correlated positively with the Nottingham Prognostic Index (NPI) (p=0.003 and p < 0.001, respectively). The expression of the two genes correlated inversely with luminal A and luminal B tumors (r= - 0.089, p= 0.021 and r= - 0.116, p= 0.013, respectively). The PD-L1 mRNA levels were significantly higher in hormone receptor-negative and HER2-positive tumors. MET mRNA expression levels were significantly higher in hormone receptor-negative, HER2-enriched, and non-luminal breast cancers. The PD-L1/MET double-high expression was associated with younger age of patients at diagnosis, higher NPI scores, larger tumors, advanced stage, high-grade, hormone receptor-negativity, HER2-positivity, and non-luminal tumors. None of the genes or their double expression status was significantly associated with overall survival in this analysis. The expression of the PD-L1 and MET genes is remarkably associated with worse tumor clinicopathologic features and poor prognosis in patients with breast cancer. Further investigations using combination drug regimens targeting PD-L1 and MET are important, particularly in breast tumors expressing high levels of both proteins.

Single-cell transcriptome analysis reveals immune microenvironment changes and insights into the transition from DCIS to IDC with associated prognostic genes

BackgroundDuctal carcinoma in situ (DCIS) of the breast is an early stage of breast cancer, and preventing its progression to invasive ductal carcinoma (IDC) is crucial for the early detection and treatment of breast cancer. Although single-cell transcriptome analysis technology has been widely used in breast cancer research, the biological mechanisms underlying the transition from DCIS to IDC remain poorly understood.ResultsWe identified eight cell types through cell annotation, finding significant differences in T cell proportions between DCIS and IDC. Using this as a basis, we performed pseudotime analysis on T cell subpopulations, revealing that differentially expressed genes primarily regulate immune cell migration and modulation. By intersecting WGCNA results of T cells highly correlated with the subtypes and the differentially expressed genes, we identified six key genes: FGFBP2, GNLY, KLRD1, TYROBP, PRF1, and NKG7. Excluding PRF1, the other five genes were significantly associated with overall survival in breast cancer, highlighting their potential as prognostic biomarkers.ConclusionsWe identified immune cells that may play a role in the progression from DCIS to IDC and uncovered five key genes that can serve as prognostic markers for breast cancer. These findings provide insights into the mechanisms underlying the transition from DCIS to IDC, offering valuable perspectives for future research. Additionally, our results contribute to a better understanding of the biological processes involved in breast cancer progression.

Impact of delays in neoadjuvant chemotherapy initiation on pathologic complete response among patients with HER2-positive or triple negative breast cancer.

102 Background: Pathologic complete response (pCR) is used as a surrogate endpoint for overall survival (OS) in high-risk early-stage breast cancer (BC). pCR rates vary according to BC molecular subtype and have the highest association with OS in triple negative BC (TNBC) and HER2-positive (HER2+) BC. In these subgroups, neoadjuvant chemotherapy (NACT) is often the standard of care. We evaluated the association of delays in NACT initiation (NACTI) with pCR. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis cT2+ or lymph node positive HER2+ or TNBC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of BC diagnosis. Time to chemotherapy (TTC) was recorded in days. Patients were categorized by receptor status. We used AJCC 7 th and 8 th edition T and N staging to define pCR (pT0 or pTis and pN0 or pN0I-). Delay was defined as TTC &gt; 60 days. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to calculate odds of pCR associated with delays. A sensitivity analysis defining delay &gt;30 and &gt;90 days was also conducted. Results: We identified 105,352 eligible patients, 73% were White, 19% were Black, 3% were Asian, and 4% were Other/Unknown. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180). There were 56,868 patients with HER2+ BC and 48,484 with TNBC; 9% of patients were delayed &gt; 60 days in each group. Among all HER2+ patients, 39.1% achieved a pCR: 35.0% with delay compared to 39.5% without delay. Among TNBC patients, 30% achieved a pCR: 25% with delay compared to 31% without delay (p &lt; 0.0001 for all). In multivariable analysis, patients with HER2+ disease (OR 0.85, 95%CI 0.79-0.92) and TNBC (OR 0.80, 95%CI 0.73-0.87) were less likely to achieve pCR if delayed &gt; 60 days. In a sensitivity analysis, delay &gt; 30 days was associated with lower likelihood of achieving pCR for all and delay &gt; 90 days was associated with lower likelihood for TNBC (Table). Conclusions: Delays in NACTI &gt;60 days among patients with HER2+ and TNBC BC was an independent predictor of not achieving pCR. Given the known association between socioeconomic factors and delays to initiation of treatment, interventions aimed at reducing delays may reduce disparities in BC outcomes. Future studies to identify causes of delays and the downstream impact are needed to ultimately develop interventions that mitigate these effects among patients with HER2+ or TNBC, where pCR rates are associated with OS. Association of pCR in patients who experience NACTI delay using multivariable logistic regression* n(complete case) = 77,690. Subgroup &gt;30-day Delay in NACTIOR (95% CI) &gt;60-day Delay in NACTIOR (95% CI) &gt;90-day Delay in NACTIOR (95% CI) HER2+n =41,672 0.91 (0.87-0.95) 0.85 (0.79-0.92) 0.93 (0.80-1.07) TNBCn = 36,018 0.87 (0.83-0.92) 0.80 (0.73-0.87) 0.78 (0.65-0.92) *Adjusted for demographic, socioeconomic and tumor characteristics.

Abstract A060: Breast cancer-associated leukocyte DNA methylation profile in obese African-American women

Abstract Background: DNA methylation (DNAme) is a stable epigenetic mark leading to reduced gene expression. However, genome-wide DNAme profile is susceptible to disease. Therefore, specific genetic DNAme profiles could potentially serve as biomarkers associated with breast cancer (BC) and obesity as its comorbidity. Incidentally, BC-related mortality is higher in African-American women, causing a significant health disparity. In this study, we profiled obesity and breast cancer-related leukocyte DNAme in African-American women to explore methylation- associated biomarkers in these women. Methods: We used 10 African-American women with confirmed breast cancer diagnosis and 10 otherwise healthy African-American women with known Body Mass Index (BMI) &amp;gt; 30 (Obese). DNA was extracted from the buffy coat of peripheral blood using Qiagen DNA extraction kits. We used the next-generation sequencing technology to perform reduced presentation bisulfite sequencing (RRBS) using the Tecan Ovation RRBS kit. We sequenced the libraries on a NextSeq 550 at our Precision Medicine Unit. Single-end 75bp reads were generated and processed using Bismark and mapped against the GRCh38 human genome, and differentially methylated regions (DMR) were derived using MethylKit using a 1 kb window. Gene Ontology and Disease association studies were conducted using DAVID and relapsed-free survival in Kmplot. Additionally, we compared the gene sets with obese and normal DMRs that had previously been obtained similarly. Results: We found that 83% of the DMRs were in the promoter/upstream regions of the nearest genes, and 96% of DMRs were part of CpG islands, indicating potential regulatory functions of these regions. Gene ontology analysis revealed that the DMR-associated genes were also overrepresented in breast carcinoma, Type 2 Diabetes, Obesity, and Tobacco usage, according to the DisGeNET and GAD disease associations databases. Genes with DMRs in their upstream or promoter regions - include PRDM16, PTBP1, RAB1A (lower methylation in cancer with obesity), and Multiple ribosomal genes along with RRAF, XKR4 (higher methylation in cancer with obesity). We observed lower methylation profiles in multiple genes in samples with cancer, which were higher in obese samples without cancer.Conclusion: Our study suggests that a distinct peripheral DNA methylation profile is associated with minority women suffering from both cancer and obesity. Our data show that showed that breast cancer modulates leucocyte DNA methylation profile in obese individuals towards that of a more normal BMI, causing a partial reversal. This potential reversal is primarily in the upstream regions of the genes detected for methylation. The DMR genes in cancer with obesity are significantly associated with overall survival in breast cancer, thus indicating a potential link in understanding the crosstalk between obesity and cancer. Citation Format: Pranabananda Dutta, Yanyuan Wu, Jaydutt V. Duta. Breast cancer-associated leukocyte DNA methylation profile in obese African-American women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A060.

Prognostic and clinicopathological significance of fibrinogen-to-albumin ratio (FAR) in patients with breast cancer: a meta-analysis

BackgroundThe fibrinogen-to-albumin ratio (FAR) has been extensively studied for its role in predicting the prognosis of breast cancer (BC) patients; however, existing findings are conflicting. Therefore, this meta-analysis was conducted to identify the significance of FAR in predicting BC prognosis.MethodsWe searched PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases until May 25, 2024. The value of FAR for predicting overall survival (OS) and disease-free survival (DFS) in BC was examined by calculating the combined hazard ratios (HRs) and 95% confidence intervals (CIs). Correlations between FAR and clinicopathological factors were analyzed using combined odds ratios (ORs) and 95% CIs.ResultsEight studies involving 4094 patients were included in this work. As shown by our combined data, increased FAR significantly predicted poor OS (HR = 2.84, 95% CI = 1.83–4.39, p < 0.001) and poor DFS (HR = 2.43, 95% CI = 1.66–3.58, p < 0.001) of BC. Moreover, the combined data showed that increased FAR was significantly correlated with age ≥ 50 years (OR = 2.04, 95% CI = 1.37–3.04, p < 0.001), stage III cancer (OR = 1.53, 95% CI = 1.04–2.27, p = 0.033), and the presence of lymph node metastases (OR = 1.33, 95% CI = 1.11–1.61, p = 0.002). Nonetheless, FAR was not significantly associated with tumor size, ER/PR/HER-2 status, or lymphovascular invasion in patients with BC.ConclusionIn this meta-analysis, higher FAR was significantly associated with unfavorable OS and DFS in patients with BC and significantly correlated with several features predictive of cancer development in BC.

Relative efficacy of antibody-drug conjugates and other anti-HER2 treatments on survival in HER2-positive advanced breast cancer: a systematic review and meta-analysis

BackgroundNovel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain controversial. The aim of this meta-analysis was to evaluate the comparative effect of ADCs and other anti-HER2 therapy on progression-free survival (PFS) and overall survival (OS) for treatment of HER2-positive locally advanced or metastatic BC.MethodsRelevant randomized controlled trials (RCTs) were retrieved from five databases. The risk of bias was assessed with the Cochrane Collaboration’s tool for RCTs by RevMan5.4 software. The hazard ratio (HR) and 95% confidence intervals (CIs) were extracted to evaluate the benefit of ADCs on PFS and OS in HER2-positive advanced BC by meta-analysis.ResultsMeta-analysis of six RCTs with 3870 patients revealed that ADCs significantly improved PFS (HR: 0.63, 95% CI: 0.49–0.80, P = 0.0002) and OS (HR: 0.79, 95% CI: 0.72–0.86, P < 0.0001) of patients with HER2-positive locally advanced or metastatic BC. Subgroup analysis showed that PFS and OS were obviously prolonged for patients who previously received HER2-targeted therapy. Sensitivity analysis and publication bias suggested that the results were stable and reliable.ConclusionStatistically significant benefits for PFS and OS were observed with ADCs in HER2-positive locally advanced or metastatic BC, especially for those who received prior anti-HER2 treatment.

Recent trends in incidence, survival and mortality of female breast in the US: A Surveillance, Epidemiology, and End Results (SEER) database study 2010-2020.

e23078 Background: We examined epidemiological trends and patient characteristics including age, race, incidence and survival in female breast cancer (BC) using the updated largest population-based cancer registry in the US. Methods: Female patients diagnosed with breast cancer between 2010-2020 were identified in SEER registries. We incorporated SEER 22 registries to calculate incidence, race, disease characteristics and overall survival. Results: Incidence Rate (IR) for BC has been increasing by 0.4%/year and mortality rates (MR) have declined 1.3%/year during 2010-2020 for all patients. 5-&amp;10-year overall survival (OS) has increased by 0.1 and 0.2% respectively. For ages &lt; 50 years,IR increased by 0.9% vs 0.4% for those 65 and above. No statistically significant change in IR was noted for ages 50-64y. For ages &lt; 50 and between 50-64y, MR overall decreased by 1.4%/y each vs by 1.1%/y for those 65+. However, no statistically significant change in MR was noted for women &lt; 50y between 2016-2020. IR increased by 1.6%/year in Asian/Pacific Islanders (API), 1.1%/y in Hispanics (H),0.6% in Blacks (B) and 0.4% in Non-Hispanic White (NHW) and. MR declined 1.5%/y in B, 1.2%/y NHW, 1% H and by 0.3% in API.IR for HR+/HER2- BC increased by 1.9%. No statistically significant change in IR was noted for triple negative or HER2+ only BC. IR for HR+/HER2+ BC increased overall during this time period by 1.4%; however, IR increased by 3.6% between 2010-2016 and decreased by 2.9% after 2016. 5y-OS was 91% in 2015 (CI 90.7-91.3) for all women, improved from 89.7% in 2010 (CI 89.4-90.0). 5yOS was 90.7% vs 91.3% vs 91.0% for &lt; 50, 50-64 and 65+ age groups. When compared to 2010 and 2005, 5yOS was consistently improved across all age groups. 5yOS in B was 82.5% (CI 81.6-83.4) vs 92.1% (CI 91.8-92.5) in NHW. This discrepancy existed across all age groups: for &lt; 50, 50-64 and 65+y, 91.6 vs 92.5 vs 92.1% for W women vs 82.7 vs 82.9 vs 82.0% for their B counterparts. 5yOS for localized, regional and distant disease at diagnosis for all women was 99.2%, 86.7% and 31.5%. 5yOS for B vs W females was 95.9 vs 99.7% localized, 78.3 vs 88% regional and 23.4 vs 33.0% for distant disease. Conclusions: Epidemiological trends show improved OS in BC among all groups. B females and patients with advanced stage have worse outcomes. Greater increase in IR was noted for women &lt; 50 years of age. Greater IR increase was noted in H and API women but decline in MR was smallest in these women. IR for HR/HER2 + BC increased initially followed by a decline. 5r survival in B women was lower compared to NHW across all age groups. 5y survival for B women was worse, irrespective of stage at diagnosis. We hypothesize underlying disease biology may be a potential factor for worse outcome in B women.

Prognostic factors and overall survival of breast cancer in Benin: a hospital-based study

BackgroundIn Benin, a country in West Africa, breast cancer is the leading cancer in women, both in terms of incidence and mortality. However, evidence on the mortality of breast cancer and its associated factors is lacking in this country. Our aim was to describe and analyze the clinical, histopathological, and prognostic aspects of breast cancer in Benin.MethodsA descriptive and analytical study was carried out at the CNHU-HKM and the CHU-MEL, two major tertiary referral hospitals for breast cancer management located in Cotonou, the capital city of Benin. All breast cancer medical records with histological evidence and immunohistochemistry studies were retrospectively collected between January 1, 2014, and September 30, 2020, in these two tertiary referral hospitals and analyzed in the current study.ResultsFinally, 319 medical records were included. The mean age at diagnosis was 48.74 years. The tumors were most frequently classified as T4 (47.6%) with lymph node involvement N2 (34.5%), and metastases were clinically noted in 21.9% of cases. Stage was reported in the medical records of 284 patients. Tumors were diagnosed at very late AJCC stages: stage III (47.5%) and stage IV (24.7%). Grades SBR 2 (49.2%) and SBR 3 (32.6%) were the most frequent grades. Triple-negative breast cancer (31.3%) was the most common molecular type. The overall 5-year survival was 48.49%. In multivariable analysis, the poor prognostic factors were lymph node invasion (HR = 2.63; p = 0.026; CI: [1.12, 6.17]), the presence of metastasis (HR = 3.64; p < 0.001); CI: [2.36, 5.62] and the immunohistochemical profile (HR = 1.29; p < 0.001; CI: [1.13, 1.48]).ConclusionsBreast cancer in Beninese is predominant in young adults and is often diagnosed at a late stage. The survival of breast cancer patients in Benin can be improved by enhancing early diagnosis and multidisciplinary management.

Abstract PO2-02-07: Clinicopathological Features and Prognostic Role of HER2 Low in Early Breast Cancer: A real world study

Abstract Background: The definition of human epidermal growth factor receptor-2(HER2) low was proposed with the development of T-DXd, a novel antibody-drug conjugate (ADCs) targeting HER2 in the field of breast cancer (BC) treatments. However, whether HER2 low is a distinct subgroup is still an ongoing debate with mixed results. Current retrospective studies focused on HER2 low concentrated more on metastatic BC, less was known in early BC. The retrospective study was conducted based on HER2 low early BC to comprehensively analyze its clinicopathological features and prognostic roles compared with HER2 IHC0. Methods: This single institution retrospective study enrolled 999 early stage (stage I through III) HER2 negative invasive BC patients diagnosed at Chinese PLA General Hospital from January 2010 to December 2015. Tumors with HER2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay were defined as HER2 low. Clinicopathological characteristics s and survival outcomes including disease-free survival (DFS) and overall survival (OS) were compared between HER2 IHC0 and HER2 low groups. The correlations between HER2 expression and estrogen receptor (ER) status were determined by Mantel-Haenszel χ2 test. Cohen’s kappa coefficient (k) was adopted to evaluate the concordance between HER2 expression on primary tumors and matched biopsies. Results: 999 patients were eligible for inclusion criteria, among which the percentages of HER2 low in the whole cohort, HR positive group and HR negative group were 83.6%, 86.54%, 72.14% respectively. It was observed the presence of a significant higher proportion of ER level &amp;gt; 10% (p &amp;lt; 0.001), PgR positive (p &amp;lt; 0.001) and more patients who received endocrine therapy (p = 0.002). In HR positive group, clinicopathological features were balanced between HER2 IHC0 and HER2 low. In HR negative group, HER2 low manifested a higher proportion of invasive ductal type (p = 0.016) compared with HER2 IHC0. Survival analysis showed a significantly longer OS in HER2 low BC than HER2 IHC0. (HR: 0.458, 95%CI: 0.262-0.800, p = 0.0005). Nevertheless, the independent role was not reached in DFS. When stratified by HR status, patients with HER2 low in HR positive group demonstrated a longer OS than HER2 IHC0 (HR: 0.55, 95%CI: 0.273-1.105, p = 0.0385). The same trend was observed in HR negative group (HR: 0.385, 95%CI: 0.158-0.939, p = 0.0132). Neither the HR positive group nor the HR negative group achieved significant DFS. Besides, a positive correlation was observed between ER status and the rate of HER2 low (Mantel-Haenszel c2 test, p &amp;lt; 0.001, Pearson’s R = 0.159, P &amp;lt; 0.001). No regularity of survival differences between HER2 IHC0 and HER2 low was found in each ER level in the exploratory study. Finally, 119 patients who developed relapsed or metastatic disease were identified, with the most prevalent metastatic site being bone (31.1%), following by lung (16.80%) and lymph node (13.44%). Among 52 patients with matched biopsy samples, dynamic changes of HER2 IHC status were confirmed in both primary and relapsed statuses, with an discordance rate of 28.84% (K = 0.194, 95%CI: 0.168-0.219). conclusion: HER2 low expression breast cancer may not be regarded as a unique BC group in this real-world population due to similar clinicopathological features and prognostic roles especially in hormone-receptor positive cases. ER level was positively correlated with the rate of HER2 low population. Overall, whether HER2 low is a distinct subgroup remains to be supported and validated by more data both in clinical and molecular levels. Key words: HER2 low; Breast cancer; Clinicopathological Features; Prognosis; Molecular type Clinicopathological Features and Prognostic Role of HER2 Low in Early Breast Cancer: A real world study Citation Format: Ziqing Kong, Weihong Zhao. Clinicopathological Features and Prognostic Role of HER2 Low in Early Breast Cancer: A real world 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 PO2-02-07.

A comprehensive analysis of the prognostic characteristics of microRNAs in breast cancer.

Both overall survival (OS) and disease-specific survival (DSS) are significant when determining a patient's prognosis for breast cancer (BC). The effect of DSS-related microRNAs on BC susrvival, however, is not well understood. Here, we spotted differentially expressed miRNAs (DEMs) in the TCGA database of BC DSS, identified eight DSS-related miRNAs, and constructed a risk model. AUC values at 1, 3, and 5years were 0.852, 0.861, and 0.868, respectively, indicating a risk model's excellent prognostic prediction ability. Then, we validated miRNA roles in BC OS and finally defined miR-551b as an independently prognostic miRNA in BC. According to function analysis, miR-551b is strongly linked with the emergence and spread of cancer, including protein ubiquitination, intracellular protein transport, metabolic pathways, and cancer pathways. Moreover, we confirmed the low expression of miR-551b in BC tissue and cells. After miR-551b inhibition or overexpression, cell function was either dramatically increased or diminished, respectively, indicating that miR-551b could regulate BC proliferation, invasion, and migration. In conclusion, we thoroughly clarified BC-related miRNAs on DSS and OS and verified miR-551b as a crucial regulator in the development and prognosis of cancer. These results can offer fresh ideas for BC therapy.

SIRT3 Expression Predicts Overall Survival and Neoadjuvant Chemosensitivity in Triple-Negative Breast Cancer.

The Sirtuin (SIRT) family consists of seven evolutionary conserved NAD-dependent deacetylases that play important roles in various cancers, including breast cancer (BC). SIRTs expression has been reported to have prognostic value in BC, but these studies used limited sample size and yielded inconsistent conclusions. This study evaluated the association of SIRT3 and other SIRT family members with survival and neoadjuvant chemotherapy outcomes. BC patients' data was obtained from the TCGA-BRCA, METABRIC and GEO databases, comprising 4336 samples. SIRTs expression and overall survival (OS) were analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. SIRT3 expression levels were compared between pathologic complete response (pCR) and non-pCR groups after neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Protein-protein interaction networks were constructed using the STRING database. Gene set enrichment analysis (GSEA) was performed to explore potential functions of SIRT3. Through systematic analysis of SIRTs expression and OS of BC using three independent cohorts: TCGA-BRCA, METABRIC and GSE16446, we found that high SIRT3 expression was significantly associated with worse OS in TNBC in the TCGA-BRCA cohort, which was validated in the METABRIC and GSE16446 cohorts. SIRT3 expression was correlated with BC subtypes and American Joint Committee on Cancer (AJCC) T stage, but not with age-at-diagnosis, race, or tumor stage. Moreover, TNBC patients with higher SIRT3 expression had lower pCR rates after neoadjuvant chemotherapy (p = 6.40e-03) and SIRT3 expression was significantly lower in the pCR group than in the non-pCR group in TNBC (p = 4.2e-03). GSEA indicated that SIRT3 was involved in drug-related pathways such as oxidative phosphorylation, metabolism of xenobiotics by cytochrome P450, and drug metabolism. Our study suggests that SIRT3 is a potential biomarker for both OS and neoadjuvant chemosensitivity in TNBC. It may also assist in selecting suitable candidates and treatment options for TNBC patients.

The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer

BackgroundThe androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employ an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease.ResultsThe DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.ConclusionsAR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in breast cancer regardless of ER status. This interaction facilitates the tumor suppressor function of AR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer.

A nomogram for predicting overall survival of breast cancer with regional lymph node metastasis in young women.

Young breast cancer (YBC) patients demonstrate a heightened propensity for regional lymph node metastasis (RLNM) in contrast to cohorts across varying age demographics. The aim of our study was to identify clinicopathologic prognostic variables in YBC patients with RLNM and construct a practical and reliable nomogram for the prediction of overall survival (OS) using the Surveillance, Epidemiology, and End Results (SEER) database. Young individuals (≤40 years) with a diagnosis of breast cancer with RLNM were recognized from the SEER database between 2010 and 2015, and further randomly split into two cohorts: the training set (n=4,497) and the validation set (n=1,927). We first performed univariate and multivariate Cox regression analyses to confirm independent survival predictors of OS. A novel prognostic nomogram was developed and evaluated using Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). To make a clear distinction between high- and low-risk patients in terms of patient survival, Kaplan-Meier survival curves were assessed using the log-rank test. Nine risk factors were found as independent prognostic variables in predicting OS, including race, grade, histology, surgery, radiation, molecular subtype, American Joint Committee on Cancer (AJCC) stage 7th edition, T stage, and N stage. The C-index values of our nomogram were 0.786 [95% confidence interval (CI): 0.767-0.805] and 0.791 (95% CI: 0.760-0.822) in our training and validation groups, respectively. The ROC curves demonstrated sufficient discriminating ability, while the predicted and real survival rates were fairly consistent, as shown by the calibration plots. The prediction model had a higher net benefit and acceptable clinical value, as shown by the DCA curves. In YBC patients with RLNM, we successfully established a unique nomogram to forecast the 2-, 3-, and 5-year OS. Clinicians may utilize this nomogram to pinpoint patients at higher risk and provide them with appropriate customized therapies.

Molecular subtype identification and prognosis stratification based on lysosome-related genes in breast cancer

BackgroundLysosomes are known to have a significant impact on the development and recurrence of breast cancer. However, the association between lysosome-related genes (LRGs) and breast cancer remains unclear. This study aims to explore the potential role of LRGs in predicting the prognosis and treatment response of breast cancer. MethodsBreast cancer gene expression profile data and clinical information were downloaded from TCGA and GEO databases, and prognosis-related LRGs were screened for consensus clustering analysis. Lasso Cox regression analysis was used to construct risk features derived from LRGs, and immune cell infiltration, immune therapy response, drug sensitivity, and clinical pathological feature differences were evaluated for different molecular subtypes and risk groups. A nomogram based on risk features derived from LRGs was constructed and evaluated. ResultsOur study identified 176 differentially expressed LRGs that are associated with breast cancer prognosis. Based on these genes, we divided breast cancer into two molecular subtypes with significant prognostic differences. We also found significant differences in immune cell infiltration between these subtypes. Furthermore, we constructed a prognostic risk model consisting of 7 LRGs, which effectively divides breast cancer patients into high-risk and low-risk groups. Patients in the low-risk group have better prognostic characteristics, respond better to immunotherapy, and have lower sensitivity to chemotherapy drugs, indicating that the low-risk group is more likely to benefit from immunotherapy and chemotherapy. Additionally, the risk score based on LRGs is significantly correlated with immune cell infiltration, including CD8 T cells and macrophages. This risk score model, along with age, chemotherapy, clinical stage, and N stage, is an independent prognostic factor for breast cancer. Finally, the nomogram composed of these factors has excellent performance in predicting overall survival of breast cancer. ConclusionsIn conclusion, this study has constructed a novel LRG-derived breast cancer risk feature, which performs well in prognostic prediction when combined with clinical pathological features.

Transforming growth factor-induced gene TGFBI is correlated with the prognosis and immune infiltrations of breast cancer

BackgroundTransforming growth factor β (TGFβ) is a critical regulator of lung metastasis of breast cancer and is correlated with the prognosis of breast cancer. However, not all TGFβ stimulated genes were functional and prognostic in breast cancer lung metastatic progress. In this study, we tried to determine the prognosis of TGFβ stimulated genes in breast cancer.MethodsTGFβ stimulated genes in MDA-MB-231 cells and lung metastasis-associated genes in LM2-4175 cells were identified through gene expression microarray. The prognosis of the induced gene (TGFBI) in breast cancer was determined through bioinformatics analysis and validated using tissue microarray. The immune infiltrations of breast cancer were determined through “ESTIMATE” and “TIMER”.ResultsTGFBI was up-regulated by TGFβ treatment and over-expressed in LM2-4175 cells. Through bioinformatics analysis, we found that higher expression of TGFBI was associated with shorted lung metastasis-free survival, relapse-free survival, disease-free survival, and overall survival of breast cancer. Moreover, the prognosis of TGFBI was validated in 139 Chinese breast cancer patients. Chinese breast cancer patients with higher TGFBI expression had lower overall survival. Correspondingly, breast cancer patients with higher TGFBI methylation had higher overall survival. TGFBI was correlated with the score of the TGFβ signaling pathway and multiple immune-related signaling pathways in breast cancer. The stromal score, immune score, and the infiltrations of immune cells were also correlated with TGFBI expression in breast cancer.ConclusionsTGFβ-induced gene TGFBI was correlated with the prognosis and immune infiltrations of breast cancer.

Preoperative systemic inflammation response index: Clinicopathologic predictor of pathological complete response in HER2-positive breast cancer patients receiving neoadjuvant systemic therapy.

Multiple pretreatment systemic inflammatory markers (SIMs) have been reported as predictors of pathological complete response (pCR) after neoadjuvant systemic therapy (NST) in patients with breast cancer (BC). However, the most significant SIM remains to be conclusively identified, and variations among different molecular subtypes remain unknown. The objective of the study was to identify the most significant SIM in patients with human epidermal growth factor receptor 2 (HER2) positive BC, to construct a pCR-predictive nomogram combining it with other clinicopathologic factors, and to evaluate its prognostic value on survival. We retrospectively reviewed the findings for 240 patients with stage I-III HER2-positive BC who underwent NST and subsequent surgery at Kaohsiung and Taichung Veterans General Hospital from 2011 to 2021. Clinicopathologic factors were analyzed by stepwise logistic regression with backward selection. The data were used to construct a nomogram plot for determining the pCR probability. Kaplan-Meier curves and log-rank test were used to evaluate disease-free survival (DFS) and overall survival (OS). Among the pretreatment SIMs, only the systemic inflammation response index (SIRI) was significantly related to pCR, with an optimal cutoff value of 1.27 × 10 9 /L. Stepwise logistic analyses indicated that clinical N stage, HER2 immunohistochemistry score, hormone receptor status, targeted therapy regimen, and SIRI were independent predictors of pCR, with an area under the curve of 0.722. The Hosmer-Lemeshow test and calibration curve revealed that the predictive ability was a good fit to actual observations. A nomogram was constructed based on the logistic model. The external validation of the model also revealed satisfactory discrimination and calibration. Kaplan-Meier analysis showed that patients with SIRI <1.27 had longer DFS and OS. Pretreatment SIRI <1.27 is predictive of pCR, DFS, and OS in HER2-positive BC. Our nomogram could efficiently predict pCR and facilitate clinical decision-making before neoadjuvant treatment.

Treatment of Internal Mammary Nodes is Associated With Improved Overall Survival in Breast Cancer: A Meta-Analysis.

The role of internal mammary nodal irradiation (IMNI) as a component of regional nodal radiotherapy is a controversial issue in breast radiation oncology with conflicting results presented in recent landmark trials. We thus created a meta-analysis of available data to better ascertain the potential benefit of IMNI. We hypothesize that with the increased power available within a meta-analysis, IMNI will prove to improve overall survival (OS) in breast cancer. Literature search was conducted for prospective studies comparing IMNI to no IMNI. Primary endpoint was OS and secondary endpoints included local recurrence, regional recurrence, disease-free survival (DFS), breast cancer mortality (BCM), distant metastasis-free survival (DMFS), grade 2+ skin toxicity, cardiac events, and pneumonitis events. Subgroup analyses were performed for tumor location (medial/central vs. lateral), and nodal status (pN+ vs. pN0). Fixed-effect model was used if there was no heterogeneity, random-effects model otherwise. Four studies with a total of 5258 patients (IMNI: n=2592; control: n=2666) were included in the study. Pooled results showed IMNI significantly improved OS for all-comers (hazard ratio [HR]=0.89; 95% CI 0.81-0.97; P =0.008), as well as subgroups of pN+ with medial/central tumor location (HR=0.84; 95% CI 0.73-0.96; P =0.01) and pN+ with lateral tumor location (HR=0.87; 95% CI 0.77-0.99; P =0.04). There was no significant difference in OS for subgroups of pN0 and medial/central tumor location. There was no difference in local recurrence, but regional recurrence was significantly improved ( P =0.04). Endpoints of DFS (HR 0.91, 95% CI 0.84-0.99 P =0.03), BCM (HR 0.87, 95% CI 0.77-0.98, P =0.03), and DMFS (HR=0.87; 95% CI, 0.78-0.98; P =0.02) were all improved with IMNI. Grade 2+ skin toxicity, cardiac events and pneumonitis events were not significantly different between patient in the IMNI and no IMNI groups. Inclusion of IMN irradiation improves OS, DFS, BCM, and DMFS in breast cancer. Largest effect on OS was noted in the subgroup of patients with pN+ and medial/central tumor location.

Identification of prognostic biomarkers of invasive ductal carcinoma by an integrated bioinformatics approach

Background: Invasive ductal carcinoma (IDC) is the most common type of breast cancer (BC) worldwide. Nowadays, due to its heterogeneity and high capacity for metastasis, it is necessary to discover novel diagnostic and prognostic biomarkers. Therefore, this study aimed to identify novel candidate prognostic genes for IDC using an integrated bioinformatics approach. Methods: Three expression profile data sets were obtained from GEO (GSE29044, GSE3229, and GSE21422), from which differentially expressed genes (DEGs) were extracted for comparative transcriptome analysis of experimental groups (IDC versus control). Next, STRING was utilized to construct a protein interaction network with the shared DEGs, and MCODE and cytoHubba were used to identify the hub genes, which were then characterized using functional enrichment analysis in DAVID and KEGG. Finally, using the Kaplan-Meier tracer database, we determined the correlation between the expression of hub genes and overall survival in BC. Results: We identified seven hub genes (Kinesin-like protein KIF23 [KIF23], abnormal spindle-like microcephaly [ASPM]-associated protein [ASPMAP], Aurora kinase A [AURKA], Rac GTPase-activating protein 1 [RACGAP1], centromere protein F [CENPF], hyaluronan-mediated motility receptor [HMMR], and protein regulator of cytokinesis 1 [PRC1]), which were abundant in microtubule binding and tubulin binding, pathways linked to fundamental cellular structures including the mitotic spindle, spindle, microtubule, and spindle pole. The role of these genes in the pathophysiology of IDC is not yet well characterized; however, they have been associated with other common types of BC, modulating pathways such as Wnt/β-catenin, the epithelial-to-mesenchymal transition (EMT) process, chromosomal instability (CIN), PI3K/AKT/mTOR, and BRCA1 and BRCA2, playing an important role in its progression and being associated with a poor prognosis, thus representing a way to improve our understanding of the process of tumorigenesis and the underlying molecular events of IDC. Conclusions: Genes identified may lead to the discovery of new prognostic targets for IDC.

Expression and prognostic role of STAT5a across cancer types.

Studies examining the role of signal transducer and activator of transcription 5 (STAT5) in various cancers have produced controversial results. To address this controversy, we examined the prognostic role of STAT5a in cancer patients across multiple cancers. Transcription levels of STAT5a between tumors and normal tissues, obtained from public databases, were analyzed for statistical differences using Cox regression analysis with the outcome as overall survival and covariate of interest as high STAT5a expression. Meta-analysis was then conducted to summarize the hazard ratio estimate from the Cox regression analyses. We found that STAT5a was significantly under-expressed in breast, lung, and ovarian cancers, while STAT5a was significantly overexpressed in lymphoid neoplasm diffuse large B-cell lymphoma, glioblastoma, and glioma. High STAT5a expression was significantly associated with favorable survival in bladder cancer (lnHR = -0.8689 [-1.4087, -0.3292], P-value = 0.0016), breast cancer (lnHR = -0.7805 [-1.1394, -0.4215], P-value < 0.0001) and lung cancer (lnHR = -0.3255 [-0.6427, -0.0083], P-value = 0.0443). After adjusting for clinicopathological factors, high STAT5a expression remained significantly associated with favorable survival in breast cancer (lnHR = -0.6091 [-1.0810, -0.1372], P-value = 0.0114). These results suggest that higher STAT5a expression is associated with favorable overall survival in breast cancer, and therefore might have protective effects, and that STAT5a expression could be a potential prognostic biomarker, especially in breast cancer. However, the prognostic role of STAT5a is dependent on cancer type.

Risk-adjusted benchmarking of long-term overall survival in patients with HER2-positive early-stage Breast cancer: A Swedish retrospective cohort study.

The main objective of the current study was to explore the value of risk-adjustment when comparing (i.e. benchmarking) long-term overall survival (OS) in breast cancer (BC) between Swedish regions. We performed risk-adjusted benchmarking of 5- and 10-year OS after HER2-positive early BC diagnosis between Sweden's two largest healthcare regions, constituting approximately a third of the total population in Sweden. All patients diagnosed with HER2-positive early-stage BC between 01-01-2009 and 31-12-2016 in healthcare regions Stockholm-Gotland and Skane were included in the study. Cox proportional hazards model was used for risk-adjustment. Unadjusted (i.e. crude) and adjusted 5- and 10-year OS was benchmarked between the two regions. The crude 5-year OS was 90.3% in the Stockholm-Gotland region and 87.8% in the Skane region. The crude 10-year OS was 81.7% in the Stockholm-Gotland region and 77.3% in the Skane region. However, when adjusted for age, menopausal status and tumour biology, there was no significant OS disparity between the regions, neither at the 5-year nor 10-year follow-up. This study showed that risk-adjustment is relevant when benchmarking OS in BC, even when comparing regions from the same country that share the same national treatment guidelines. This is, to our knowledge, the first published risk-adjusted benchmarking of OS in HER2-positive BC.