Prognosis In Early Breast Cancer Research Articles

A novel mitochondrial function-associated programmed cell death-related prognostic signature for predicting the prognosis of early breast cancer.

Purpose: To screen mitochondrial function-associated PCD-related biomarkers and construct a risk model for predicting the prognosis of early breast cancer. Methods: Data on gene expression levels and clinical information were obtained from the TCGA database, and GSE42568 and GSE58812 datasets were obtained from GEO database. The mitochondrial function-associated programmed cell death (PCD) related genes in early breast cancer were identified, then LASSO logistic regression, SVM-RFE, random forest (RF), and multiple Cox logistic regression analysis were employed to construct a prognostic risk model. Differences in immune infiltration, drug sensitivity, and immunotherapy response were evaluated between groups. Lastly, the qRT-PCR was employed to confirm the key genes. Results: Total 1,478 DEGs were screened between normal and early breast cancer groups, and these DEGs were involved in PI3K-Akt signaling pathway, focal adhesion, and ECM-receptor interaction pathways. Then total 178 mitochondrial function-associated PCD related genes were obtained, followed by a four mitochondrial function-associated PCD related genes prognostic model and nomogram were built. In addition, total 2 immune checkpoint genes were lowly expressed in the high-risk group, including CD47 and LAG3, and the fraction of some immune cells in high- and low-risk groups had significant difference, such as macrophage, eosinophil, mast cell, etc., and the Top3 chemotherapeutics with significant differences were included FH535, MK.2206, and bicalutamide. Finally, the qRT-qPCR results shown that the CREB3L1, CAPG, SPINT1 and GRK3 mRNA expression were in line with the bioinformatics analysis results. Conclusion: Four mitochondrial function-associated PCD-related genes were identified, including CREB3L1, CAPG, SPINT1, and GRK3, and the prognostic risk model and nomogram were established for predicting the survival of early breast cancer patient. The chemotherapeutics, containing FH535, MK.2206, and bicalutamide, might be used for early breast cancer.

Impact of race/ethnicity on the MammaPrint genomic assay risk and prognosis in early breast cancer (EBC): A National Cancer Database (NCDB) analysis.

564 Background: The 21-gene Oncotype DX Recurrence Score (RS) and 70-gene MammaPrint (MP) assays provide prognostic information for distant recurrence and are used to guide chemotherapy use in hormone receptor (HR)-positive, HER2-negative EBC. Previous reports have demonstrated that Black women with low genomic risk (RS 0-25) have a higher recurrence risk than White women in the TAILORx (PMID: 32986828) and RxPONDER trials (SABCS 2023, abstract GS1-01), and that Black race was associated with worse overall survival (OS) in multivariate models including RS in the NCDB registry (PMID: 33649322).The goal of this study was to evaluate the impact of race/ethnicity on MP risk distribution and prognostic information provided by the MP assay in the NCDB cohort. Methods: Women with HR-positive EBC with tumor size up to 5 centimeters (T1-T2), 0-3 involved lymph nodes (LNs, N0-N1), diagnosed between 2009-2018, and who had available information on MP testing and OS in the NCDB 2019 dataset were identified. Patients (pt) were stratified by MP result of high or low risk. T-tests and chi-square tests were used to compare pt characteristics, while log-rank tests assessed differences in OS between the high- and low-risk MP groups, as well as across different racial/ethnic categories. Results: 6096 eligible women were included of whom 41.0% (N=2502) were MP high-risk and 59.0% (N=3594) MP low-risk. Overall, 82.7% of pts were Non-Hispanic White (NHW), 8.7% Non-Hispanic Black (NHB), 4.7% Hispanic (H), and the remainder other/unknown (O). A higher proportion of H and NHB pts had high MP results, p<0.0001. The MP high-risk group had a greater proportion of pts </= 50 years (p=0.0013) and larger tumors (p<0.0001) and higher grade (p<0.0001), but not LN positive (p=0.7649). The 5-year OS rates (and 95% Confidence Intervals) for the MP high and low-risk groups were 92.6% (91.6% - 93.7%) and 96.6% (95.9% - 97.2%), respectively, p<0.0001. There were no differences in OS based on race/ethnicity in the low-risk group with 5-year OS rates of 98.4% (96.1%-100%), 95.9% (93.3% - 98.6%), 96.4% (95.7% - 97.1%), and 99.2% (97.7% - 100%) for H, NHB, NHW and O, respectively, p=0.34. Similarly, in MP high-risk, race/ethnicity did not impact prognosis with OS rates of 92.6% (88.2% - 97.1%), 90.8% (87.2% - 94.5%), 92.8% (91.7% - 94.1%), and 95.8% (91.2% - 100%) for H, NHB, NHW and O groups, respectively, p=0.45. There was no significant interaction between race and MP for OS when accounting for age, tumor grade, tumor size, and LN status, p=0.75. Conclusions: NHB and H women were more likely to have high-risk MP results compared with NHW women in this NCDB cohort, although race/ethnicity did not impact prognosis for 5-year OS in either MP risk group. Limitations of this analysis include absence of information on recurrence and short follow up, as about one-half of recurrences in HR-positive EBC occur after 5 years.

Abstract PO4-22-10: Prognostic impact of preoperative lymph node diagnostic tools for patients with suspicious node positive breast cancer

Abstract (Abstract) Recently, the SOUND trial demonstrated the feasibility for omission of sentinel lymph node biopsy (SNB) in cases with negative ultrasound (US)-guided fine-needle aspiration cytology (FNA) of suspicious lymph nodes (LNs). An important consideration for omission of SNB depends on a highly accurate assessment of preoperative staging for axillary LNs. (Purpose) The purpose of this study was to investigate the impact of preoperative diagnostic tools for axillary lymph nodes (LNs) staging of early breast cancer. (Materials and Methods) A total of 3088 consecutive patients with operable breast cancer were retrospectively identified at our institution between April 2013 and March 2020. Patients with suspicious axillary LN of breast cancer were assessed using preoperative US and computed tomography (CT), underwent FNA or core needle biopsy (CNB). The inclusion criteria for both FNA and CNB were a cortical thickness [3 mm or abnormal morphological characteristics. Patients with biopsy-proven metastasis underwent axillary lymph node dissection (ALND), and those with a negative FNA or CNB underwent SNB. If the SNB was positive, ALND was performed. Diagnostic accuracy for SNB was calculated for both FNA and CNB. In addition, the patients in this study were divided into two groups as follows: the cN0-FNA negative group (suspicious LN but negative FNA) and the cN0-CNB group (suspicious LN but negative CNB). Overall survival (OS)and invasive disease survival(iDFS) was estimated by using the Kaplan-Meier method and compared by using the log-rank test. (Results) A number of patients with negative or suspicious metastasis US/CT findings of LNs were 3187, with 963 undergoing FNA and 395 undergoing CNB for suspicious LNs. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 63, 99, 99, 73, and 81% in FNA, and 87, 100, 100, 91 and 95% in CNB, respectively. SNB was performed in 207 (cN0-CNB group) of 395 CNB and 581 (cN0-FNA group) of 963 FNA patients. Two hundred and seven patients from the cN0-CNB group (T1ab; 42, T1c; 72, T2;84, T3;9 patients) treated with SNB were compared to 581 from the cN0-FNA group (T1ab;86, T1c;193, T2;278, T3;24 patients) in terms of number of LN metastasis. A number of patients with micrometastases, 1,2,3 or more than 4 positive LNs were 5(2%),7(3%),3(1%)9,3(1%) and 0 (0%) in cN0-CNB group, and 23(4%),67(12%),26(4%),12(2%) and 29 (5%) in cN0-FNA group, respectively. The significant difference in 5ys iDFS and OS was observed between CNB group and FNA group (94.2% vs.91.4%, p =0.04 and 99% vs. 95%, p=0.004, respectively). Conclusions The preoperative diagnosis of axillary LNs was influenced by the diagnostic tool used. CNB is a reliable method for the preoperative diagnosis of LN metastasis. The prognosis of early breast cancer with clinically metastasis-negative lymph nodes diagnosed by CNB is better than that by FNA. Table. Number of positive lymph nodes cN0-FNA (%) cN0-CNB (%) Total 207 100 581 100 0 189 91 424 73 micrometastasis 5 2 23 4 1 7 3 67 12 2 3 1 26 4 3 3 1 12 2 4 more than 0 0 29 5 Citation Format: Rikiya Nakamura, Shouko Hayama, Rikiya Nakamura, Naohito Yamamoto. Prognostic impact of preoperative lymph node diagnostic tools for patients with suspicious node positive 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 PO4-22-10.

Quality of Life Outcomes Associated With Optimization of Treatment by Omitting Radiotherapy in Early Breast Cancer

PurposeImproved prognosis of early breast cancer (EBC) has created opportunities for treatment optimization but reducing morbidity should not inadvertently compromise quality of life (QoL). PROSPECT1 used pre-operative MRI and pathology findings to identify women suitable for radiotherapy (RT) omission following breast conserving surgery. We retrospectively explored the association between de-escalation by omission of RT and QoL in women with EBC. Materials and methodsThree groups were recruited: PROSPECT participants who omitted RT following preoperative MRI (A); participants who received RT following preoperative MRI (B); and women who received usual care - No MRI, received RT (C). Measures included the EORTC QLQ-C30 and BR23, BCTOS, DASS-21 and a measure of decision regret. Between group differences were assessed using ANOVA or nonparametric equivalents. Semi-structured interviews were analyzed with qualitative description (n = 44). ResultsData from 400 women were analyzed (125A, 102B, 173C). Group A had fewer symptoms and better body image (breast symptoms: A-B P = .003, A-C P = <.001; arm symptoms: A-B P = .004, A-C P = .011; body image: A-C P = .041) and fewer differences between the treated and untreated breasts (cosmetic: A-B P < .001, A-C P < .001; functional: A-C P = .011; breast specific pain: A-B P < .001, A-C P < .001). Two qualitative themes were found: Treatment with the biggest impact on QoL, and Specific impact of RT on QoL. ConclusionsOmission of RT was associated with better QoL and functional and cosmetic outcomes. It was highly acceptable to patients. Clinicians should consider the potential for preserved QoL associated with treatment optimization via omission of RT in treatment planning for patients with EBC.

Predictive factors of axillary lymph node involvement in Tunisian women with early breast cancer.

Axillary lymph node involvement (ALNI) is associated with an increased risk of local recurrence and poor prognosis in early breast cancer. The determination of the risk of positive axillary lymph node contributes to therapeutic decisions. The aim of this study was to identify clinicopathological predictive factors of axillary lymph node metastases in patients with early breast cancer. We included patients with clinical T0, T1 andT2 invasive breast carcinoma who underwent resection of the primary tumor and axillary staging by sentinel lymph node biopsy and/or axillar lymph node dissection between 2012 and 2018. Of the 135patients included, 41.5% had ALNI. Regarding univariate analysis, clinical factors correlated with positive ALNM were clinical tumour size>30mm, clinical tumour stage, clinical number of tumours, clinical axillary nodal status and nodal status on ultrasound. Pathologic factors associated with nodal involvement were pathologic tumour stage, tumour grade SBR, number of foci, lymphovascular invasion, perineural invasion and Ki67>20%.In multivariate logistic regression, clinical axillary nodal status, pathologic tumour stage and lymphovascular invasion (LVI) remained as independent predictors of ALNI. Based on these results, we suggest that clinical axillary nodal status, pathologic tumour stage and LVI are predictive factors for ALNM in Tunisian women with early breast cancer.

Differences of prediction performances by multigene assays in patients with breast cancer with distinct genetic backgrounds.

526 Background: The 21-gene (Oncotype Dx), PAM50 (Prosigna) and Chinese-based 28-gene (RecurIndex) are validated genomic assays that provide prognostic information for distant recurrence risk in patients with hormone receptor (HR)-positive, HER2-negative early breast cancer (EBC). In this study, we aim to compare the differences in prediction performance by different multigene assays and gene expression profiles between the Eastern and the Western. Methods: Under the Affymetrix U133 platforms, the differences in gene expressions and risk scores from the Eastern population comprised of GSE20685 (n = 327) and part of GSE45255 (n = 95), and the Western population GSE25066 (n = 508) and the European in GSE45255(n = 44) were analyzed respectively. Patients were stratified by 21-gene Recurrence Scores (RS) of low (0-10), intermediate (11-25) and high (26-100) and categorized by ROR-S score of PAM50 of low (0-40), intermediate (41-60) and high (61-100). For 28-gene, a recurrence index for distant recurrence (RI-DR) cutoff of 33 was used to classify patients into high- and low-risk groups. Wilcoxon rank test was used to test for continuous variables and the chi-square test was used for categorical variables. Results: The Western population has significantly higher RS (85.9 vs. 65.5, p &lt; 0.001) and ROR-S (57.4 vs.53.7, p = 0.034) scores than the Eastern population. The distribution of 28-gene risk groups was significantly different between races with a higher proportion of high-risk in the Western (10.5% vs. 6.6%, p = 0.035). The low-risk patients in the Eastern stratified by 28-gene assay had significantly higher distant metastasis-free survival (DMFS) rates than high-risk (80% vs. 52%, p &lt; 0.001), which compared with Oncotype Dx RS (96% vs. 76%, p &lt; 0.001) and PAM50 ROR-S (93% vs. 72%, p &lt; 0.001). At the same time, the analysis of gene expressions revealed significantly high expressions of YWHAB, SF3B5, CKAP5, and DDX39A in the Eastern than that in the Western. However, most genes from 21-gene and ROR-S were more highly expressed in the Western than that in the Eastern. Conclusions: 21-gene and PAM50 provide the good performance and show similar patterns in the prognosis of EBC; However, the DMFS rate of the high-risk in the Eastern population determined by 28-gene was much lower than 21-gene and PAM50, which means there are bigger chemo-benefit in the high-risk from 28-gene. In conclusion, 28-gene has better performance in the prognosis of the Eastern population and is a more suitable tool for Eastern breast cancer patients.

140P HER2-low status and response to neoadjuvant chemotherapy and prognosis in early breast cancer

140P HER2-low status and response to neoadjuvant chemotherapy and prognosis in early breast cancer

Research Status of Systemic Adjuvant Therapy for Early Breast Cancer.

Breast cancer has surpassed lung cancer as the most common cause of cancer deaths, worldwide. Early breast cancers are treatment sensitive and patients under standardized treatment have prolonged. Breast cancer treatment has significantly evolved from the conventional surgical approach and radiotherapy to local and systemic adjuvant therapies. Though localized breast cancers are clinically manageable, distant recurrence is a cause of morbid concern. Adjuvant systemic therapy is effective in both distant and local recurrences and hence gained significant attention. Early breast cancer prognosis has greatly improved in the past 3 decades with reduced mortality rates due to the widespread use of adjuvant therapy. It can markedly increase the cure rate of breast cancers, and postoperative adjuvant therapy became a part of comprehensive breast cancer treatment. Further research to understand the early breast cancer characteristics could expand the treatment modalities that can improve the outcomes and survival benefits of breast cancer patients.

Abstract P3-05-12: A matched cohort study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome

Abstract Background: Patients with germline TP53 pathogenic variants (Li-Fraumeni syndrome - LFS) have an increased risk of breast cancer, which is the most common type of cancer in premenopausal women with LFS. These women are also at risk of other second malignancies, including radiotherapy-induced malignancies. On the other hand, little is known about the prognosis of breast cancer in patients with LFS or if the disease behavior differs from non-hereditary BC. The objective of this study was to characterize the phenotype and prognosis of early BC in patients with LFS compared to a matched cohort of patients without germline pathogenic variants (PV) related to BC. Methods: This retrospective study evaluated patients with early BC treated in an academic cancer center from Dec 1999 to Mar 2022. The LFS cohort included consecutive patients with BC who harbored a PV or likely PV of TP53. The matched control cohort (2:1) included patients with BC with no germline PV in a panel test. Primary endpoint was disease-free survival (DFS). Since LFS is associated with an increased risk of new primary malignancies, only locoregional and distant BC recurrence were considered as events in the DFS analysis. Secondary endpoints included response to systemic therapy, sites of recurrence, and breast cancer-related deaths. Results: Forty-six patients with LFS were evaluated; the control cohort included 91 matched patients. In the LFS cohort, 14 different PV or likely PV were identified, with TP53 p.R337H being the most common (n=32). Median age was 40 years in both groups. In the LFS cohort, 35% of the pts had HER2-positive BC compared to 21% in the control cohort. Primary tumors greater than 5 cm were observed in 15% of pts in the LFS cohort and 25% of pts in the control cohort. Positive lymph nodes were observed in 11% and 14%, respectively. Among 15 pts with LFS who received neoadjuvant chemotherapy, all (100%) had a response, with 5 (33%) complete responses. Thirty-five patients in the control group received neoadjuvant chemotherapy: 83% responded, with 11 (31%) presenting a complete response. With a median follow-up of 43 months, 5-year DFS rates were 82.6% (95% CI 65.1 – 91.9%) in the LFS cohort and 91.5% (95% CI 79.1 – 96.6%) in the control cohort (P=0.427). Rates and sites of recurrence, new primary BC, and deaths are detailed in the table. Conclusions: In addition to a higher risk of new primary breast cancer, LFS patients with early breast cancer had numerically higher rates of locoregional and distant recurrence in comparison with a matched cohort. Nevertheless, further studies are required to understand if these differences are due to tumor behavior particularities or to differences in therapeutic management. Recurrence and death events Citation Format: Vanessa Petry, Renata Colombo Bonadio, Daniela Jafet, Roberta Campos, Luiz Senna, Allyne Cagnacci, Laura Testa, Maria Candida Villares Fragoso, Maria del Pilar Estevez Diz. A matched cohort study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-12.

A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53)

IntroductionBreast cancer (BC) is the most common type of cancer in premenopausal women with germline TP53 pathogenic variants (mTP53) (Li Fraumeni syndrome - LFS). However, little is known about the BC prognosis in these patients. This study analyzed the BC-related oncologic outcomes of patients with LFS. MethodsWe evaluated a cohort of LFS patients with BC in comparison with a control cohort of BC patients with no pathogenic variant in a hereditary cancer panel. The primary endpoint was recurrence-free survival (RFS). Due to the risk of second malignancies in LFS, only locoregional and distant recurrences were considered events for RFS. Secondary endpoints included rates of contralateral BC, overall survival (OS), and breast cancer-specific survival (BCSS). ResultsForty-one patients were evaluated in the mTP53 group and 82 in the control group. Median age at BC diagnosis was 40 and 41 years, respectively. The mTP53 group received less adjuvant radiotherapy than the control group (63.4% vs 93.9%, P < 0.001). Other relevant baseline characteristics and treatment received were similar between groups. 5y-RFS rates were 79.4% in the mTP53 versus 93.6% in the control group (HR 2.43, 95%CI 0.74–8.01, P = 0.143); and were not impacted by the use of adjuvant radiotherapy. 5y-BCSS rates were 92.2% and 98.6%, respectively (HR 1.87, IC95% 0.25–13.48, P = 0.534). ConclusionsOur results showed no statistically significant difference in BC-related RFS and BCSS between patients with mTP53 and a control group with no pathogenic variant. Larger multicentric studies are warranted to confirm these results.

Comparison of changes in lipid profiles of premenopausal women with early-stage breast cancer treated with different endocrine therapies

Adjuvant endocrine therapy improves the prognosis of early breast cancer with hormone receptor positivity. However, there is no systematic report on the effect of endocrine therapy (particularly ovarian function suppression, OFS) on serum lipids in premenopausal women. This retrospective cohort study aimed to determine whether various endocrine treatments had different effects on blood lipids. This study enrolled 160 premenopausal patients with stage I–III breast cancer in eastern China. The initial diagnostic information was retrieved from patient's medical records, including age at the time of diagnosis, tumor characteristics, anticancer treatment and past medical history. The changes in blood lipids in patients receiving different types of endocrine therapy were compared at the 3rd, 6th, 12th, and 24th months after initiating endocrine therapy. Generalized linear mixed model was used in our analyses. Our data revealed that low-density lipoprotein cholesterol (LDL-C) levels in patients with tamoxifen (TAM) were significantly lower in the 6th, 12th, and 24th months than that in the 3rd month, while high-density lipoprotein cholesterol (HDL-C) levels in the 6th, 12th, and 24th months were significantly higher than that in the 3rd month, indicating that blood lipid levels generally improved with time. While in TAM plus OFS group, HDL-C levels were significantly higher in the 24th month than in the 3rd month, total cholesterol (TC) levels were significantly higher in the 24th month than in the 6th month. The lipid profiles of OFS plus aromatase inhibitor (AI) group did not show significant differences at any time point but were significantly higher than those of the other two groups especially in LDL and TC. TAM group tended to have lower serum lipid levels. With longer follow-up, no statistically significant difference in values was observed between TAM and TAM plus OFS groups at various time points. Compared with the other two groups, OFS plus AI group presented an increasing trend toward LDL-C and TC. The risk of dyslipidemia requires further investigation using a large sample size.

279 (PB-103) Poster - Mammographic breast density correlated with worse prognosis of early breast cancer regardless of menopausal status

Background: Breast density (BD) is known to affect breast cancer risk, but it may be associated with breast cancer survival. The underlined mechanism remains unclear. Aldehyde dehydrogenase 1 (ALDH-1) and CD44+CD24− are the most consistently used biomarkers to identify and characterize breast cancer stem cells (CSCs). However, correlation between expression of CSCs and BD remains unclear. The interpretation of results from previous studies on mammographic BD and survival is complicated by the association between confounding factors and survival.

(Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study.

Adherence to treatment and use of co-medication, but also molecular factors such as CYP2D6 genotype, affect tamoxifen metabolism, with consequences for early breast cancer prognosis. In a prospective study of 149 tamoxifen-treated early-stage breast cancer patients from Brazil followed up for 5 years, we investigated the association between the active tamoxifen metabolite (Z)-endoxifen at 3 months and event-free survival (EFS) adjusted for clinico-pathological factors. Twenty-five patients (16.8%) had recurred or died at a median follow-up of 52.3 months. When we applied a putative 15 nM threshold used in previous independent studies, (Z)-endoxifen levels below the threshold showed an association with shorter EFS in univariate analysis (p = 0.045) and after adjustment for stage (HR 2.52; 95% CI 1.13–5.65; p = 0.024). However, modeling of plasma concentrations with splines instead of dichotomization did not verify a significant association with EFS (univariate analysis: p = 0.158; adjusted for stage: p = 0.117). Hence, in our small exploratory study, the link between impaired tamoxifen metabolism and early breast cancer recurrence could not be unanimously demonstrated. This inconsistency justifies larger modeling studies backed up by mechanistic pharmacodynamic analyses to shed new light on this suspected association and the stipulation of an appropriate predictive (Z)-endoxifen threshold.

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.

The Role of C-Reactive Protein as a Prognostic Biomarker in Patients with Early Breast Cancer Treated with Neoadjuvant Chemotherapy

Background: C-reactive protein (CRP) is an acute phase reactant influenced by inflammation and tissue damage. Elevated CRP levels have been associated with poor outcome of various cancers including breast cancer. However, evidence regarding a potential impact of CRP levels on outcome of neoadjuvant chemotherapy (NACT) in patients with early breast cancer (EBC) is insufficient. Methods: Patients who had received NACT for EBC and had available data regarding CRP levels before therapy, pathologic complete remission (pCR), and follow-up were included. The association between CRP at baseline and outcome parameters was analyzed. Results: 152 women were included in this analysis; median follow-up was 5.8 years. No association between CRP at baseline and pCR rates could be detected. 6.6% of the patients developed a local recurrence, 10.5% developed a distant recurrence, and 5.2% died from breast cancer. A negative correlation (Spearman-Rho) between CRP at baseline and overall survival (OS) (correlation coefficient (CC) −0.255; p = 0.45), disease-free survival (DFS) (CC −0.348; p = 0.075), local recurrence-free survival (LRFS) (CC −0.245; p = 0.327), and distant DFS (DDFS) (CC −0.422; p = 0.057) was not statistically significant, although especially in DFS and DDFS a strong trend was detected. The probability of death from breast cancer was 2% if the CRP was <0.08 mg/dL and 40% if the CRP was >2.08 mg/dL; this association was highly statistically significant (χ2; p < 0.001). These results were independent from age, estrogen and progesterone receptor status, HER2 status, nodal status, and grading. The hazard ratio for OS was 5.75 (p = 0.004) for CRP <0.08 mg/dL versus CRP >2.08 mg/dL. Discussion/Conclusion: CRP at baseline is not predictive for pCR in EBC after NACT in our patient dataset. However, an association of parameters of long-term prognosis with CRP could be demonstrated. Although the correlations of higher CRP levels at baseline and shorter OS, DFS, LRFS, and DDFS were not significant, a strong trend could be detected that was reproduced in the analysis of different groups of CRP levels and the probability of breast cancer mortality. Higher CRP levels are indicating a worse prognosis in EBC after NACT in this retrospective analysis. These results justify further investigation of CRP not as a predictive parameter for pCR but as a biomarker of long-term prognosis in EBC in prospective trials and may lead to therapeutic approaches with the aim of lowering CRP levels.

Detection of circulating tumour cells before and following adjuvant chemotherapy and long-term prognosis of early breast cancer

BackgroundThe detection of circulating tumour cells (CTC) is prognostic for disease recurrence in early breast cancer (BC). This study aims to investigate whether this prognostic effect persists or varies over time.MethodsThe study population consisted of prospectively included stage I–III BC patients. The presence of CK19 mRNA-positive CTC in the peripheral blood was evaluated before and after adjuvant chemotherapy, using a real-time RT–PCR assay. Longitudinal samples were collected for a subset of patients.ResultsBaseline CTC data were available from 1220 patients, while 1132 had both pre- and post-therapy data. After a median follow-up of 134.1 months, CTC positivity at baseline was associated with shorter overall survival (OS; HRadj = 1.72, 95% CI 1.34–2.21, p < 0.001). For disease-free survival, an interaction with time (p = 0.045) was observed. CTC positivity predicted early (within 5 years; HRadj = 1.76, 95% CI 1.33–2.32, p < 0.001) but not late recurrence (HRadj = 1.10, 95% CI 0.79–1.53, p = 0.577). Following adjuvant chemotherapy, more patients converted from CTC-positive to CTC-negative than vice versa (p < 0.001). Ten-year OS was 68.6% for + /+ and 86.7% for −/− group (p < 0.001). CTC status at follow-up predicted disease recurrence.ConclusionCTC detection pre- and post-adjuvant chemotherapy is prognostic for early relapse, supporting investigations for novel adjuvant therapeutic approaches.

Epigenetic study of early breast cancer (EBC) based on DNA methylation and gene integration analysis

Breast cancer (BC) is one of the leading causes of cancer-related deaths in women. The purpose of this study is to identify key molecular markers related to the diagnosis and prognosis of early breast cancer (EBC). The data of mRNA, lncRNA and DNA methylation were downloaded from The Cancer Genome Atlas (TCGA) dataset for identification of differentially expressed mRNAs (DEmRNAs), differentially expressed lncRNAs (DElncRNAs) and DNA methylation analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzes were used to identify the biological functions of DEmRNAs. The correlation analysis between DNA methylation and DEmRNAs was carried out. Then, diagnostic analysis and prognostic analysis of identified DEmRNAs and DElncRNAs were also performed in the TCGA database. Subsequently, methylation state verification for identified DEmRNAs was performed in the GSE32393 dataset. In addition, real-time polymerase chain reaction (RT-PCR) in vitro verification of genes was performed. Finally, AC093110.1 was overexpressed in human BC cell line MCF-7 to verify cell proliferation and migration. In this study, a total of 1633 DEmRNAs, 750 DElncRNAs and 8042 differentially methylated sites were obtained, respectively. In the Venn analysis, 11 keys DEmRNAs (ALDH1L1, SPTBN1, MRGPRF, CAV2, HSPB6, PITX1, WDR86, PENK, CACNA1H, ALDH1A2 and MME) were we found. ALDH1A2, ALDH1L1, HSPB6, MME, MRGPRF, PENK, PITX1, SPTBN1, WDR86 and CAV2 may be considered as potential diagnostic gene biomarkers in EBC. Strikingly, CAV2, MME, AC093110.1 and AC120498.6 were significantly actively correlated with survival. Methylation state of identified DEmRNAs in GSE32393 dataset was consistent with the result in TCGA. AC093110.1 can affect the proliferation and migration of MCF-7. ALDH1A2, ALDH1L1, HSPB6, MME, MRGPRF, PENK, PITX1, SPTBN1, WDR86 and CAV2 may be potential diagnostic gene biomarkers of EBC. Strikingly, CAV2, MME, AC093110.1 and AC120498.6 were significantly actively correlated with survival. The identification of these genes can help in the early diagnosis and treatment of EBC. In addition, AC093110.1 can regulate SPTBN1 expression and play an important role in cell proliferation and migration, which provides clues to clarify the regulatory mechanism of EBC.

Effect of Estrogen Receptor Expression Level and Hormonal Therapy on Prognosis of Early Breast Cancer.

PurposeEstrogen receptor (ER) expression in breast cancer plays an essential role in carcinogenesis and disease progression. Recently, tumors with low level (1%–10%) of ER expression have been separately defined as ER low positive (ERlow). It is suggested that ERlow tumors might be morphologically and behaviorally different from tumors with high ER expression (ERhigh).Materials and MethodsRetrospective analysis of a prospective cohort database was performed. Patients who underwent curative surgery for early breast cancer and had available medical records were included for analysis. Difference in clinicopathological characteristics, endocrine responsiveness and five-year recurrence-free survival was evaluated between different ER subgroups (ERhigh, ERlow, and ER-negative [ER−]).ResultsA total of 2,162 breast cancer patients were included in the analysis, Tis and T1 stage. Among them, 1,654 (76.5%) were ERhigh, 54 (2.5%) were ERlow, and 454 (21.0%) were ER− patients. ERlow cases were associated with smaller size, higher histologic grade, positive human epidermal growth factor receptor 2, negative progesterone receptor, and higher Ki-67 expression. Recurrence rate was highest in ER− tumors and was inversely proportional to ER expression. Recurrence-free survival was not affected by hormonal therapy in the ERlow group (p=0.418).ConclusionERlow breast cancer showed distinct clinicopathological features. ERlow tumors seemed to have higher recurrence rates compared to ERhigh tumors, and they showed no significant benefit from hormonal therapy. Future large scale prospective studies are necessary to validate the treatment options for ERlow breast cancer.

Lanthanide Nanoprobes for the Multiplex Evaluation of Breast Cancer Biomarkers.

Metal stable isotope tagging has demonstrated great and unique success in the multiplex and ratiometry-based accurate detection of biomolecules and single cells, while its sensitivity is regarded as an Achilles' heel. Although lanthanide nanoparticles remain the most promising tags for elemental mass spectrometry, there is no report on the lanthanide nanoparticle-based multiplex immunoassay of disease markers in clinical serum samples because of their tough synthesis and bioconjugation and a complex physiological sample matrix. Herein, to fill this gap, multiple lanthanide nanoparticle tags (NaEuF4, NaTbF4, and NaHoF4) were delicately designed and facilely synthesized with a one-pot solvothermal method for the multiplex evaluation of breast cancer biomarkers carcinoembryonic antigen (CEA), CA153, and CA125 in human serum samples. The proposed method exhibited wide linear ranges and low levels of the detection limit for all biomarkers. The test results were consistent with the routine electrochemiluminescence results in clinical serum samples, which proved the possibility of the early prognosis of breast cancer as well as improving the surgical outcome prediction.

Using Breast Cancer Gene Expression Signatures in Clinical Practice: Unsolved Issues, Ongoing Trials and Future Perspectives.

Simple SummaryGene expression signatures were initially developed to take into account tumor biology for adjuvant chemotherapy decision and have become a standard option in hormone receptors-positive/HER2-negative early breast cancer. While recent randomized phase III studies have provided high level evidence to support their use, much more remains to be explored. This prospective review highlights the unsolved issues regarding targeted populations, delineates the best clinical indications and addresses questions that ongoing and future trials will have to meet. Apart from adjuvant chemotherapy indications, we review their potential interest to tailor neoadjuvant systemic treatments, adjuvant radiation therapy, extended adjuvant hormone therapy and CDK4/6 inhibitor adjuvant treatment.The development of gene expression signatures since the early 2000′s has offered standardized assays to evaluate the prognosis of early breast cancer. Five signatures are currently commercially available and recommended by several international guidelines to individualize adjuvant chemotherapy decisions in hormone receptors-positive/HER2-negative early breast cancer. However, many questions remain unanswered about their predictive ability, reproducibility and external validity in specific populations. They also represent a new hope to tailor (neo)adjuvant systemic treatment, adjuvant radiation therapy, hormone therapy duration and to identify a subset of patients who might benefit from CDK4/6 inhibitor adjuvant treatment. This review will highlight these particular issues, address the remaining questions and discuss the ongoing and future trials.