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Aims: The recommended dosage of pegylated recombinant human granulocyte‐colony stimulating factor (PEG‐rhG‐CSF) for Western chemotherapy patients is 6 mg per cycle. However, for Eastern Asians, the optimal dose remains unknown. Methods: This open‐label, randomized, non‐inferiority trial (NCT05283616) enrolled Chinese female breast cancer patients receiving adjuvant chemotherapy. Participants were randomized to receive either 3 or 6 mg of PEG‐rhG‐CSF per cycle, stratified by body weight (BW; ≤60 kg vs. >60 kg). The primary endpoint was timely absolute neutrophil count (ANC) recovery before the second cycle of chemotherapy. Results: A total of 122 patients were randomized and 116 were included for efficacy analyses. The timely ANC recovery rate in the 3 mg arm was 89.8%, compared to 93.0% in the 6 mg arm (one‐sided 95% confidence interval [CI] lower limit for difference: −11.7%), meeting the prespecified non‐inferiority margin of 15%. The rate was 93.3% with PEG‐rhG‐CSF 3 mg and 96.6% with 6 mg in patients with BW ≤ 60 kg, and 86.2% and 89.3%, respectively, in those with BW > 60 kg. Although the incidence of severe neutropenia was similar across arms, the occurrence of excessively high ANC and white blood cell counts was higher in the 6 mg arm. No grade ≥3 adverse events related to PEG‐rhG‐CSF occurred. Conclusion: Three milligrams of PEG‐rhG‐CSF per cycle provided non‐inferior neutrophil protection and attenuated neutrophil overshoot compared to 6 mg doses. This low‐dose regimen could be a new supportive care option for Chinese breast cancer patients receiving anthracycline‐based adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The Nottingham prognostic index (NPI) has been shown to negatively impact survival in breast cancer (BC). However, its ability to predict the locoregional recurrence (LRR) of BC remains still unclear. This study aims to determine whether a higher NPI serves as a significant predictor of LRR in BC. Methods: In total, 238 patients with BC were included in this analysis, and relevant clinicopathological features were collected. Correlation analysis was performed between NPI scores and clinicopathological characteristics. The optimal nomogram model was determined by Akaike information criterion. The accuracy of the model's predictions was evaluated using receiver operating characteristic curves (ROC curves), calibration curves and goodness of fit tests. The clinical application value was assessed through decision curve analysis. Results: Six significant variables were identified, including age, body mass index (BMI), TNM stage, NPI, vascular invasion, perineural invasion (P<0.05). Two prediction models, namely a TNM-stage-based model and an NPI-based model, were constructed. The area under the curve (AUC) for the TNM-stageand NPI-based models were 0.843 (0.785,0.901) and 0.830 (0.766,0.893) in training set and 0.649 (0.520,0.778) and 0.728 (0.610,0.846) in validation set, respectively. Both models exhibited good calibration and goodness of fit. The Fmeasures were 0.761vs 0.756 and 0.556 vs 0.696, respectively. Clinical decision curve analysis showed that both models provided clinical benefits in evaluating risk judgments based on the nomogram model. Conclusions: a higher NPI is an independent risk factor for predicting LRR in BC. The nomogram model based on NPI demonstrates good discrimination and calibration, offering potential clinical benefits. Therefore, it merits widespread adoption and application. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between receptor heterogeneity and clinicopathological characteristics in 166 patients with invasive breast cancer during metastasis. Methods: We conducted a retrospective analysis of 166 patients diagnosed with metastatic breast cancer through biopsy, who were admitted to our hospital from January 2018 to December 2022. Statistical analysis was employed to assess the heterogeneity of receptors in both primary and metastatic lesions, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), Ki67, as well as their association with clinicopathological features such as tumor size, lymph node metastasis, treatment regimen, and disease-free survival. Results: The discordant expression rates of ER, PR, HER2, Ki-67 and Luminal classification between primary and metastatic lesions were 21.7%, 41.6%, 8.9%, 34.4% and 36.8%, respectively. There is a significant difference in disease-free survival between patients with consistent and inconsistent receptor status of primary and metastatic lesions, which is statistically significant. The median DFS for primary HER2(-) to metastatic HER2(+) was 84 months, which was relatively high. The Cox multivariate regression analysis revealed that the expression differences of ER, PR, HER2, and Ki67 were not influenced by endocrine therapy and chemotherapy. However, a statistically significant difference in HER2 expression was observed with targeted therapy. Tumor size was correlated with ER and Ki67 receptor status (P = 0.019, 0.016). Tumor size was not correlated with PR, and HER2 (P = 0.679, 0.440). Lymph node metastasis was not associated with changes in ER, PR, HER2, and Ki67. The discordant rates of ER, PR, HER2, and Ki-67 in patients with local recurrence were 22%, 23.7%, 5.1%, and 28.8% respectively, whereas those in patients with distant metastasis were 21.5%, 36.4%, 10.3%, and 31.8% respectively. Conclusions: The expression levels of ER, PR, HER2, and Ki-67 in primary and metastatic breast cancer exhibit heterogeneity, which is closely associated with the prognosis and treatment outcomes of patients. [ABSTRACT FROM AUTHOR]

Abstract Given the rarity of RAD51C mutations, the risk and treatment of metachronous breast cancer after the diagnosis of ovarian cancer in RAD51C mutation carriers is not clear, especially for those who have received PARPi treatment. We report the case of a 65-year-old woman diagnosed with stage IIIC high-grade serous primary fallopian tube cancer. The patient had no family history of breast or ovarian cancer. The patient received three cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin and achieved a complete response. After interval debulking surgery, the patient received three cycles of adjuvant chemotherapy. Collection and extraction of saliva DNA for next-generation sequencing identified a RAD51C mutation c.838-2 A > G. The patient received niraparib as front-line maintenance treatment. After 36 months of niraparib treatment, the patient had grade II invasive ductal carcinoma of the left breast that was positive for estrogen receptor (90%) and Ki-67 (30%) and negative for progesterone receptor and human epidermal growth factor receptor 2. Computed tomography revealed the absence of distant metastases. Modified radical mastectomy and axillary lymph node dissection were then performed. The final pathological report of the breast showed a 1.8 cm Bloom-Richardson grade II invasive ductal carcinoma in the left breast with axillary lymph node metastasis (1/21). Finally, the breast cancer was stage IIA, pT1cN1M0. The metachronous breast cancer in this case may be the first report of second primary cancer in fallopian tube cancer patient harboring a RAD51C mutation during niraparib treatment. Further studies are required to determine optimal treatment.

Given the rarity of RAD51C mutations, the risk and treatment of metachronous breast cancer after the diagnosis of ovarian cancer in RAD51C mutation carriers is not clear, especially for those who have received PARPi treatment. We report the case of a 65-year-old woman diagnosed with stage IIIC high-grade serous primary fallopian tube cancer. The patient had no family history of breast or ovarian cancer. The patient received three cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin and achieved a complete response. After interval debulking surgery, the patient received three cycles of adjuvant chemotherapy. Collection and extraction of saliva DNA for next-generation sequencing identified a RAD51C mutation c.838-2 A > G. The patient received niraparib as front-line maintenance treatment. After 36 months of niraparib treatment, the patient had grade II invasive ductal carcinoma of the left breast that was positive for estrogen receptor (90%) and Ki-67 (30%) and negative for progesterone receptor and human epidermal growth factor receptor 2. Computed tomography revealed the absence of distant metastases. Modified radical mastectomy and axillary lymph node dissection were then performed. The final pathological report of the breast showed a 1.8 cm Bloom-Richardson grade II invasive ductal carcinoma in the left breast with axillary lymph node metastasis (1/21). Finally, the breast cancer was stage IIA, pT1cN1M0. The metachronous breast cancer in this case may be the first report of second primary cancer in fallopian tube cancer patient harboring a RAD51C mutation during niraparib treatment. Further studies are required to determine optimal treatment. [ABSTRACT FROM AUTHOR]

Objective To explore the relationship between receptor heterogeneity and clinicopathological characteristics in 166 patients with invasive breast cancer during metastasis. Methods We conducted a retrospective analysis of 166 patients diagnosed with metastatic breast cancer through biopsy, who were admitted to our hospital from January 2018 to December 2022. Statistical analysis was employed to assess the heterogeneity of receptors in both primary and metastatic lesions, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), Ki67, as well as their association with clinicopathological features such as tumor size, lymph node metastasis, treatment regimen, and disease-free survival. Results The discordant expression rates of ER, PR, HER2, Ki-67 and Luminal classification between primary and metastatic lesions were 21.7%, 41.6%, 8.9%, 34.4% and 36.8%, respectively. There is a significant difference in disease-free survival between patients with consistent and inconsistent receptor status of primary and metastatic lesions, which is statistically significant. The median DFS for primary HER2(-) to metastatic HER2(+) was 84 months, which was relatively high. The Cox multivariate regression analysis revealed that the expression differences of ER, PR, HER2, and Ki67 were not influenced by endocrine therapy and chemotherapy. However, a statistically significant difference in HER2 expression was observed with targeted therapy. Tumor size was correlated with ER and Ki67 receptor status (P = 0.019, 0.016). Tumor size was not correlated with PR, and HER2 (P = 0.679, 0.440). Lymph node metastasis was not associated with changes in ER, PR, HER2, and Ki67. The discordant rates of ER, PR, HER2, and Ki-67 in patients with local recurrence were 22%, 23.7%, 5.1%, and 28.8% respectively, whereas those in patients with distant metastasis were 21.5%, 36.4%, 10.3%, and 31.8% respectively. Conclusions The expression levels of ER, PR, HER2, and Ki-67 in primary and metastatic breast cancer exhibit heterogeneity, which is closely associated with the prognosis and treatment outcomes of patients.

Limin Tang,1 Min Sha,2 Ting Guo,2 Huimin Lu,2 Jingyu Qian,2 Qixiang Shao,1 Jun Ye2 1Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China; 2Department of Central Laboratory, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, People’s Republic of ChinaCorrespondence: Jun Ye, Department of Central Laboratory, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 399 Hailing Road, Taizhou, Jiangsu, 225300, People’s Republic of China, Tel +86-13625171902, Email m13625171902@163.comPurpose: The roles of T cell immunoreceptor with Ig and ITIM domains (TIGIT) in the diagnosis of primary breast cancer (PBC) are still unclear. This study was designed to investigate the expression of TIGIT in PBC patients, with an aim to analyze its diagnostic value in PBC.Patients and Methods: We first explore the expression of TIGIT in cancer patients based on TCGA database, and then we analyzed its correlation with clinicopathological features. Afterwards, we compared the protein and mRNA expressions of TIGIT in two BC cell lines (MCF-7 and MDA-MB-231) and normal breast epithelial cell line (MCF-10A). Subsequently, 56 PBC female patients admitted to the Taizhou People’s Hospital from October 2018 to June 2021 were included in this study. Flow cytometry was used to detect TIGIT level on peripheral blood CD3+ T cells of PBC patients and healthy controls. TIGIT expression in PBC tissues was detected by immunohistochemistry (IHC) and immunofluorescence staining.Results: TCGA database showed that compared with adjacent tissues, TIGIT was significantly upregulated in tumor tissues. High TIGIT expression was positively correlated with tumor stage and negatively correlated with recurrence free survival (RFS) and overall survival (OS). TIGIT level in BC cell lines, peripheral blood and tumor tissues of PBC patients was significantly higher than that of control (P < 0.05). TIGIT level was correlated with age (P < 0.05), rather than tumor size, pathological type, lymph node metastasis, ER, PR, HER-2, and P53. ROC curve showed that the optimal critical value of peripheral blood TIGIT for BC screening was 23.38%. Postoperative TIGIT level in peripheral blood was significantly decreased compared to the preoperative TIGIT level (P < 0.05).Conclusion: TIGIT was upregulated in PBC and was correlated with age. It may be a potential target for the diagnosis and immunotherapy of PBC.Keywords: TIGIT, primary breast cancer, immune checkpoint, tumor immunity, bioinformatics analysis

Despite significant progress in early detection and treatment, a few aggressive breast cancers still exhibit resistance to therapy. This study aimed to identify a therapeutic target for radioresistant breast cancer (RRbc) through a protein network from breast cancer genes and to evaluate potent phytochemicals against the identified target. Our approach includes the integration of differential expression genes from expression datasets to create a protein network and to use survival analysis to identify the crucial RRbc protein in order to discover a therapeutic target. Next, the phytochemicals sourced from brown algae were screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation, MM-GBSA, and quantum mechanics against the identified target. As a result of our protein network investigation, the proto-oncogene c-KIT (KIT) protein was identified as a potent radioresistant breast cancer target. Further, phytochemical screening establishes that nahocol-A1 from brown algae has high binding characteristics (−8.56 kcal/mol) against the KIT protein. Then, quantum chemical analysis of nahocol-A1 provided insights into its electronic properties favorable for protein binding. Also, MD simulation comprehends the conformational stability of the KIT–nahocol-A1 complex. Overall, our findings suggest nahocol-A1 could serve as a promising therapeutic candidate for radioresistant breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer patients typically have decent prognoses, with a 5-year survival rate of more than 90%, but when the disease metastases to lymph node or distant, the prognosis drastically declines. Therefore, it is essential for future treatment and patient survival to quickly and accurately identify tumor metastasis in patients. An artificial intelligence system was developed to recognize lymph node and distant tumor metastases on whole-slide images (WSIs) of primary breast cancer. Methods: In this study, a total of 832 WSIs from 520 patients without tumor metastases and 312 patients with breast cancer metastases (including lymph node, bone, lung, liver, and other) were gathered. Based on the WSIs were randomly divided into the training and testing cohorts, a brand-new artificial intelligence system called MEAI was built to identify lymph node and distant metastases in primary breast cancer. Results: The final AI system attained an area under the receiver operating characteristic curve of 0.934 in a test set of 187 patients. In addition, the potential for AI system to increase the precision, consistency, and effectiveness of tumor metastasis detection in patients with breast cancer was highlighted by the AI's achievement of an AUROC higher than the average of six board-certified pathologists (AUROC 0.811) in a retrospective pathologist evaluation. Conclusion: The proposed MEAI system can provide a non-invasive approach to assess the metastatic probability of patients with primary breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Purpose Ki67 assessed at diagnosis (Ki67baseline) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki672week) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki672week) with recurrence-free survival. The aim was to define the association between Ki67baseline and after aromatase inhibitor (AI) exposure ∆Ki672week and Ki672week with key prognostic and biologic factors utilising data from the POETIC study. Patients and methods In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks’ presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression. Results Established associations of Ki67baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67baseline. In control group Ki672week was 18% lower than Ki67baseline (p

Simple Summary: ESR1 mutations in breast cancer are one of the mechanisms of resistance to aromatase inhibitors (AI). These mutations are common in metastatic breast cancer (MBC). In past reports, mutations in primary tumors were so rare that they were thought to occur de novo with AI therapy. Conversely, previous studies using droplet digital polymerase chain reaction (ddPCR) have suggested the existence of ESR1-mutant minor clones with low allele frequencies; however, no large-scale studies have been conducted. In this study, we attempted to detect ultra-rare ESR1 mutations in primary breast cancer tumors using locked nucleic acid (LNA)-clamp ddPCR, and 28 ESR1 mutations were found in 27 patients. Most of these mutations were minor clones with a variant allele frequency of <0.1% which may have been overlooked by conventional methods. LNA-clamp ddPCR can also be applied to detect other gene mutations, which would be very useful. ESR1 mutations in breast cancer are one of the mechanisms of resistance to aromatase inhibitors. These mutations are common in metastatic breast cancer; however, these are rare in primary breast cancer. However, these data have been analyzed mainly in formalin-fixed, paraffin-embedded tissue; thus, rare mutations that may be present in primary breast cancer may be overlooked. In this study, we developed a highly sensitive mutation detection method called locked nucleic acid (LNA)-clamp droplet digital PCR (ddPCR) and validated it. The mutation detection sensitivity was substantiated to 0.003%. Then, we used this method to analyze ESR1 mutations in fresh-frozen (FF) tissues of primary breast cancer. cDNA extracted from the FF tissues of 212 patients with primary breast cancers were measured. Twenty-eight ESR1 mutations were found in twenty-seven (12.7%) patients. Sixteen (7.5%) patients had Y537S mutations and twelve (5.7%) had D538G mutations. Two mutations with a variant allele frequency (VAF) of ≥0.1% and twenty-six mutations with a VAF of <0.1% were found. By using this LNA-clamp ddPCR, this study demonstrated the presence of minor clones with a VAF of <0.1% in primary breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Ki67 assessed at diagnosis (Ki67baseline) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki672week) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki672week) with recurrence-free survival. The aim was to define the association between Ki67baseline and after aromatase inhibitor (AI) exposure ∆Ki672week and Ki672week with key prognostic and biologic factors utilising data from the POETIC study. Patients and methods: In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression. Results: Established associations of Ki67baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67baseline. In control group Ki672week was 18% lower than Ki67baseline (p < 0.001) when Ki672week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki672week) was 79.3% (IQR: −89.9 to −54.6) and 53.7% (IQR: −78.9 to −21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type. Conclusions: The magnitude of this study allowed characterisation of relationships between Ki67baseline, ∆Ki672week and Ki672week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki672week or Ki672week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies. [ABSTRACT FROM AUTHOR]

Aims: In primary breast cancer, gene expression profiling tests can support adjuvant chemotherapy treatment decisions. Real-world test use in Germany was investigated in an online survey of female breast cancer patients (n = 475). Materials & methods: Relationships between three groups were examined for clinical and statistical relevance: no test indication (n = 353), test indication and tested (n = 65), and test indication but not tested (n = 57). Results: A total of 47% of participants with a test indication were not tested. Test rates increased by 23% from 2012–2018 (49%) to 2019–2021 (60%). A total of 65% of patients without testing received chemotherapy, whereas only 38% of tested patients received chemotherapy. Conclusion: The use of gene expression profiling tests correlates with a real-world chemotherapy reduction. Gene expression profiling testing may improve patient confidence in the decision for or against chemotherapy. In many cases, breast cancer can be removed by surgery. In addition to surgery, breast cancer patients may also receive chemotherapy; however, chemotherapy is not always useful. A gene expression profiling test can help physicians and patients decide if chemotherapy should be used. In a survey, 475 breast cancer patients in Germany were asked if they received such a test and chemotherapy. A total of 65% of patients who were not tested received chemotherapy compared with 38% of patients who were tested. Patients who received a test also felt more certain about their treatment decision. However, four of ten patients who were diagnosed between 2019 and 2021 and for whom a test would have helped in the treatment decision did not receive a test. Therefore, there is still room to increase the use of gene expression profiling tests for the benefit of breast cancer patients in Germany. [ABSTRACT FROM AUTHOR]

Abstract Objective To appraise the sources of evidence and methods to estimate input parameter values in decision-analytic model-based cost-effectiveness analyses of treatments for primary breast cancer (PBC) in older patients (≥ 70 years old). Methods Two electronic databases (Ovid Medline, Ovid EMBASE) were searched (inception until 5 September-2021) to identify model-based full economic evaluations of treatments for older women with PBC as part of their base-case target population or age-subgroup analysis. Data sources and methods to estimate four types of input parameters including health-related quality of life (HRQoL); natural history; treatment effect; resource use were extracted and appraised. Quality assessment was completed by reference to the Consolidated Health Economic Evaluation Reporting Standards. Results Seven model-based economic evaluations were included (older patients as part of their base-case (n = 3) or subgroup (n = 4) analysis). Data from younger patients (

Despite significant progress in early detection and treatment, a few aggressive breast cancers still exhibit resistance to therapy. This study aimed to identify a therapeutic target for radioresistant breast cancer (RRbc) through a protein network from breast cancer genes and to evaluate potent phytochemicals against the identified target. Our approach includes the integration of differential expression genes from expression datasets to create a protein network and to use survival analysis to identify the crucial RRbc protein in order to discover a therapeutic target. Next, the phytochemicals sourced from brown algae were screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation, MM-GBSA, and quantum mechanics against the identified target. As a result of our protein network investigation, the proto-oncogene c-KIT (KIT) protein was identified as a potent radioresistant breast cancer target. Further, phytochemical screening establishes that nahocol-A1 from brown algae has high binding characteristics (−8.56 kcal/mol) against the KIT protein. Then, quantum chemical analysis of nahocol-A1 provided insights into its electronic properties favorable for protein binding. Also, MD simulation comprehends the conformational stability of the KIT–nahocol-A1 complex. Overall, our findings suggest nahocol-A1 could serve as a promising therapeutic candidate for radioresistant breast cancer.

Background: Circulating tumor cells (CTCs) contribute to the metastatic cascade and represent an independent survival predictor in breast cancer (BC) patients. Vitamin D has pleiotropic effects, and its low concentrations are associated with breast cancer and metastasis. The aim of this study was to assess plasma vitamin D in primary BC patients in relation to CTCs. Methods: This study included 91 non-metastatic BC patients (stage I-III) and 24 healthy donors. Blood samples for the analyses were drawn at the time of surgery. CTCs were assessed using a quantitative RT-PCR assay for expression of epithelial (CK19) or epithelial-to-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, and ZEB1). Total 25-OH vitamin D was measured in plasma using ELISA. Plasma cytokines and angiogenic factors were measured by enzyme-linked immunoassay. Results: CTCs were detected in 30 (33%) patients. Patients with detectable CTCs in peripheral blood had significantly lower vitamin D concentrations in comparison to patients without detectable CTCs ((mean ± SD) 8.50 ± 3.89 µg/L for CTCpositive vs 9.69 ± 3.49 µg/L for CTC-negative patients, p = 0.03). The mean (± SD) vitamin D plasma level was 9.3 ± 3.65 µg/L for breast cancer patients compared to 18.6 ± 6.8 for healthy donors (p < 0.000001). There was no association between plasma vitamin D and other patient/tumor characteristics. Plasma vitamin D levels are inversely correlatedwith plasma TGF-b1, TGF-b2, IL b, IL-5, and eotaxin (all p < 0.05). Patients with vitamin D above the median had a better overall survival (hazard ratio (HR) = 0.36, 95% CI 0.16-0.80, p = 0.017), and combined analysis showed the best survival for CTC-negative patients with vitamin D levels above the median as compared to patients with opposite characteristics (HR = 0.18, 95% CI 0.05-0.63, p = 0.004). Conclusions: Low vitamin D could be a consequence and hence a biomarker of amore invasive disease. Alternatively, vitamin D could be associated with survival because of its role in tumor dissemination. Whether its supplementation affects the metastatic cascade should be tested in animal experiments and interventional studies. [ABSTRACT FROM AUTHOR]

Background: The Nottingham prognostic index (NPI) has been shown to negatively impact survival in breast cancer (BC). However, its ability to predict the locoregional recurrence (LRR) of BC remains still unclear. This study aims to determine whether a higher NPI serves as a significant predictor of LRR in BC., Methods: In total, 238 patients with BC were included in this analysis, and relevant clinicopathological features were collected. Correlation analysis was performed between NPI scores and clinicopathological characteristics. The optimal nomogram model was determined by Akaike information criterion. The accuracy of the model's predictions was evaluated using receiver operating characteristic curves (ROC curves), calibration curves and goodness of fit tests. The clinical application value was assessed through decision curve analysis., Results: Six significant variables were identified, including age, body mass index (BMI), TNM stage, NPI, vascular invasion, perineural invasion ( P <0.05). Two prediction models, namely a TNM-stage-based model and an NPI-based model, were constructed. The area under the curve (AUC) for the TNM-stage- and NPI-based models were 0.843 (0.785,0.901) and 0.830 (0.766,0.893) in training set and 0.649 (0.520,0.778) and 0.728 (0.610,0.846) in validation set, respectively. Both models exhibited good calibration and goodness of fit. The F-measures were 0.761vs 0.756 and 0.556 vs 0.696, respectively. Clinical decision curve analysis showed that both models provided clinical benefits in evaluating risk judgments based on the nomogram model., Conclusions: a higher NPI is an independent risk factor for predicting LRR in BC. The nomogram model based on NPI demonstrates good discrimination and calibration, offering potential clinical benefits. Therefore, it merits widespread adoption and application., Competing Interests: The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zheng, Zeng, Huang, Wu, Xiao and Li.)

BackgroundCirculating tumor cells (CTCs) contribute to the metastatic cascade and represent an independent survival predictor in breast cancer (BC) patients. Vitamin D has pleiotropic effects, and its low concentrations are associated with breast cancer and metastasis. The aim of this study was to assess plasma vitamin D in primary BC patients in relation to CTCs.MethodsThis study included 91 non-metastatic BC patients (stage I–III) and 24 healthy donors. Blood samples for the analyses were drawn at the time of surgery. CTCs were assessed using a quantitative RT-PCR assay for expression of epithelial (CK19) or epithelial-to-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, and ZEB1). Total 25-OH vitamin D was measured in plasma using ELISA. Plasma cytokines and angiogenic factors were measured by enzyme-linked immunoassay.ResultsCTCs were detected in 30 (33%) patients. Patients with detectable CTCs in peripheral blood had significantly lower vitamin D concentrations in comparison to patients without detectable CTCs ((mean ± SD) 8.50 ± 3.89 µg/L for CTC-positive vs 9.69 ± 3.49 µg/L for CTC-negative patients, p = 0.03). The mean ( ± SD) vitamin D plasma level was 9.3 ± 3.65 µg/L for breast cancer patients compared to 18.6 ± 6.8 for healthy donors (p < 0.000001). There was no association between plasma vitamin D and other patient/tumor characteristics. Plasma vitamin D levels are inversely correlated with plasma TGF-β1, TGF-β2, IL β, IL-5, and eotaxin (all p < 0.05). Patients with vitamin D above the median had a better overall survival (hazard ratio (HR) = 0.36, 95% CI 0.16–0.80, p = 0.017), and combined analysis showed the best survival for CTC-negative patients with vitamin D levels above the median as compared to patients with opposite characteristics (HR = 0.18, 95% CI 0.05–0.63, p = 0.004).ConclusionsLow vitamin D could be a consequence and hence a biomarker of a more invasive disease. Alternatively, vitamin D could be associated with survival because of its role in tumor dissemination. Whether its supplementation affects the metastatic cascade should be tested in animal experiments and interventional studies.

Simple Summary: Breast cancer is a heterogeneous disease, and numerous associated genetic alterations have been identified. Knowledge of driver and other associated mutations has progressed significantly in recent years, secondarily to advances in gene sequencing. This manuscript provides an overview of genetic alterations in both primary and metastatic breast cancer. Specific genomic alterations have been found in primary breast cancer involving driver mutations that result in tumorigenesis. Metastatic breast cancer, which is uncommon at the time of disease onset, variably impacts patients throughout the course of their disease. Both the molecular profiles and diverse genomic pathways vary in the development and progression of metastatic breast cancer. From the most common metastatic site (bone), to the rare sites such as orbital, gynecologic, or pancreatic metastases, different levels of gene expression indicate the potential involvement of numerous genes in the development and spread of breast cancer. Knowledge of these alterations can, not only help predict future disease, but also lead to advancement in breast cancer treatments. This review discusses the somatic landscape of breast primary and metastatic tumors. [ABSTRACT FROM AUTHOR]

Objective: To appraise the sources of evidence and methods to estimate input parameter values in decision-analytic model-based cost-effectiveness analyses of treatments for primary breast cancer (PBC) in older patients (≥ 70 years old). Methods: Two electronic databases (Ovid Medline, Ovid EMBASE) were searched (inception until 5 September-2021) to identify model-based full economic evaluations of treatments for older women with PBC as part of their base-case target population or age-subgroup analysis. Data sources and methods to estimate four types of input parameters including health-related quality of life (HRQoL); natural history; treatment effect; resource use were extracted and appraised. Quality assessment was completed by reference to the Consolidated Health Economic Evaluation Reporting Standards. Results: Seven model-based economic evaluations were included (older patients as part of their base-case (n = 3) or subgroup (n = 4) analysis). Data from younger patients (< 70 years) were used frequently to estimate input parameters. Different methods were adopted to adjust these estimates for an older population (HRQoL: disutility multipliers, additive utility decrements; Natural history: calibration of absolute values, one-way sensitivity analyses; Treatment effect: observational data analysis, age-specific behavioural parameters, plausible scenario analyses; Resource use: matched control observational data analysis, age-dependent follow-up costs). Conclusion: Improving estimated input parameters for older PBC patients will improve estimates of cost-effectiveness, decision uncertainty, and the value of further research. The methods reported in this review can inform future cost-effectiveness analyses to overcome data challenges for this population. A better understanding of the value of treatments for these patients will improve population health outcomes, clinical decision-making, and resource allocation decisions. [ABSTRACT FROM AUTHOR]

Introduction: Most common metastasis site for breast carcinoma in axillary lymph nodes. Lymph nodes of the axilla metastasis are one of the reliable and vital prognostic factors in subjects with breast cancer. Early and accurate differentiation of benign axillary lymph nodes from malignant lymph nodes is vital to prevent the conversion of treatable lesions to an incurable one and for improved survival and outcomes. Aims: The present study was conducted to assess axillary lymph nodes in subjects with breast carcinoma on strain wave elastography, color doppler, and greyscale ultrasound and to correlate them histopathologically. Also, the present study compared the negative and positive predictive values, specificity, and sensitivity of combined greyscale ultrasound and elastography findings to findings of greyscale ultrasound. Materials and Methods: In 68 subjects with a confirmed diagnosis of carcinoma breast on histopathology were evaluated for axillary lymph nodes assessed for cortical thickness/fatty hilum thickness ratio (C/F ratio), cortical thickness, long/short axis ratio (L/S ratio), presence/absence of hilum, shape, and size on color doppler for vascularity, greyscale ultrasound, and elastography. The diagnosis was made and was confirmed on histopathology. Results: It was seen that malignancy was favored by increased C/F ratio, decreased L/S ratio, increased cortical thickness, eccentric/compressed or absent hilum, irregular nodular margins, and round shape in morphology. Differentiation from benign to malignant lymph nodes was done based on peak systolic velocity/end-diastolic velocity ratio, resistivity index, and vascular flow pattern type. In malignant lymph nodes, the mean strain ratio was higher than benign lymph nodes. Conclusions: The present study concludes that ultrasound including strain elastography, color Doppler, and greyscale ultrasound should be routinely included in the initial screening of subjects with breast carcinoma owing to its advantages of being accurate, easy accessibility, radiation-free nature, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background: Supplier-induced demand (SID) refers to the concept that healthcare providers may deliver services to patients that are not medically necessary. An estimation of the extent to which this event has occurred can be insightful for policymaking and guiding health systems. This study aimed to investigate the extent to which SID presents itself during diagnostic MRI (magnetic resonance imaging) for primary breast cancer. Methods: In this cross-sectional study, data were obtained using questionnaires from a random sample of 310 cases. To identify patients who were candidates for undergoing a necessary diagnostic MRI, we employed the international clinical guidelines with the confirmation of our expert panelists. With their assistance, a comprehensive index was created to screen those who were affected by SID. Results: Of the respondents, 94.1% had undergone an unnecessary diagnostic MRI and, thus, were likely affected by SID, which indicated the lack of sovereignty of clinical guidelines in the prescription of MRI diagnosis imaging. Conclusion: This study supported the SID hypothesis and the unnecessary demand for diagnostic MRI in primary breast cancer. In addition, our evidence indicated that excessive costs were imposed; these can positively influence policymakers’ decisions regarding healthcare management.

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Thus, combined results of breast-related and extramammary organ/tumor-specific markers can be helpful to distinguish between primary and metastatic tumors and to indicate the possible primary site or tumor type of metastatic tumors. The prior/concomitant cancer history, histology, I in situ i carcinoma component, and immunophenotype constitute four diagnostic clues to suspect and diagnose metastatic tumors. Regarding the I in situ i carcinoma component, pathologists should be aware of I in situ i -mimicking structures in metastatic tumors and should not exclude the possibility of metastatic tumors. [Extracted from the article]

Primary breast cancer is the most common malignant tumor in women worldwide, and axillary lymph node metastasis (ALNM) is an important marker of disease progression in patients with breast cancer. The objective of the present study was to analyze the association between contrast-enhanced ultrasound (CEUS) features and ALNM in primary breast cancer and its predictive value. A total of 120 patients with breast cancer were assigned to the non-metastatic group (n=70) and metastatic group (n=50). The factors influencing ALNM were explored by multivariate logistic regression analysis. The consistency of CEUS, ordinary ultrasonography and pathological examination in the diagnosis of the ALNM of breast cancer was evaluated by consistency testing. The sensitivity, specificity and consistency rate of CEUS features and ordinary ultrasonography were analyzed by receiver operating characteristic curve and four-fold table analyses. High enhancement amplitude, centripetal enhancement sequence, increased maximum cortical thickness, high peak intensity and a larger area under the curve of lymph nodes were more commonly found in the metastatic group than in the non-metastatic group. The lymph node aspect ratio and time to peak were lower in the metastatic group than the non-metastatic group. The time to peak was a protective factor for ALNM in patients with breast cancer. The sensitivity, specificity and coincidence rate with pathological examination of CEUS in the diagnosis of ALNM were 92.00, 90.00 and 90.83%, while these of ordinary ultrasonography were 76.00, 80.00 and 78.33%, respectively. The consistency test indicated that CEUS and pathological examination were consistent in the diagnosis of ALNM in patients with breast cancer, with a κ value of 0.816, indicating a good consistency. The κ value of ordinary ultrasonography and pathological examination was 0.763, also indicating a good consistency. However, these results indicate that CEUS is more valuable than ordinary ultrasonography in the diagnosis of ALNM in cases of breast cancer. In conclusion, the present study indicates that CEUS features were influencing factors associated with ALNM in patients with breast cancer and may serve as an important reference for the preoperative prediction of ALNM in breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background To evaluate the clinicopathological and prognostic significance of the percentage change between maximum standardized uptake value (SUVmax) at 60 min (SUVmax1) and SUVmax at 120 min (SUVmax2) (ΔSUVmax%) using dual time point 18F-fluorodeoxyglucose emission tomography/computed tomography (18F-FDG PET/CT) in breast cancer. Methods Four hundred and sixty-four patients with primary breast cancer underwent 18F-FDG PET/CT for preoperative staging. ΔSUVmax% was defined as (SUVmax2 − SUVmax1) / SUVmax1 × 100. We explored the optimal cutoff value of SUVmax parameters (SUVmax1 and ΔSUVmax%) referring to the event of relapse by using receiver operator characteristic curves. The clinicopathological and prognostic significances of the SUVmax1 and ΔSUVmax% were analyzed by Cox’s univariate and multivariate analyses. Results The optimal cutoff values of SUVmax1 and ΔSUVmax% were 3.4 and 12.5, respectively. Relapse-free survival (RFS) curves were significantly different between high and low SUVmax1 groups (P = 0.0003) and also between high and low ΔSUVmax% groups (P = 0.0151). In Cox multivariate analysis for RFS, SUVmax1 was an independent prognostic factor (P = 0.0267) but ΔSUVmax% was not (P = 0.152). There was a weak correlation between SUVmax1 and ΔSUVmax% (P

Noninvasive circulating tumor DNA (ctDNA) can be used to predict breast cancer recurrence and prognosis. In this study, we detected 226 and 114 somatic variants in tumor DNA from 70 primary breast cancer (PBC) patients (98.59%) and ctDNA from 48 patients (67.61%), respectively. Gene frequencies of tumor DNA and ctDNA significantly correlated (R2 = 0.9532, P

Background The Ki‐67 labeling index (LI) is a well‐known prognostic factor for primary breast cancer, but its clinical significance for metachronous axillary lymph node (ALN) recurrence has not been well documented. Methods Ki‐67 expression in primary tumors (PTs) and ALN metastases (ALNMs) was evaluated in 21 patients and quantified to investigate the relationship between Ki‐67 LIs in PTs and metachronous ALNMs. Results The median Ki‐67 LIs in the PTs and ALNMs were 25.2% (range: 2.3–80.2%) and 70% (range: 10.4–97.4%), respectively. A majority of patients had higher Ki‐67 LIs in ALNMs than in PTs (76.2%, 16/21). Disease‐specific survival was significantly better in patients with a lower‐than‐median ALNM Ki‐67 LI (P = 0.019, log‐rank test). Receiver operating characteristic curves showed a PT Ki‐67 LI of 62.8% as the optimal cutoff value and an ALNM Ki‐67 LI of 65.1%. Accordingly, we divided the patients into four groups: PT Ki‐67 LI lower than 62.8%/ALNM Ki‐67 LI lower than 65.1%, PT Ki‐67 LI lower/ALNM Ki‐67 LI higher, PT Ki‐67 LI higher/ALNM Ki‐67 LI higher, and PT Ki‐67 LI higher/ALNM Ki‐67 LI lower. Disease‐specific survival was significantly better in patients with Ki‐67 LI lower/ALNM Ki‐67 LI lower than in the other groups. Conclusion This is the first study to show that the Ki‐67 LI in metachronous ALNM is a prognostic factor for patients with metachronous ALN recurrence of breast cancer.

Background: : There is an unmet need to identify biomarkers that directly reflect response to adjuvant radiotherapy (RT). Circulating epithelial tumor cells (CETCs) represent the liquid component of solid tumors and are responsible for metastatic relapse. CETC subsets with cancer stem cell characteristics, circulating cancer stem cells (cCSCs), play a pivotal role in the metastatic cascade. Monitoring the most aggressive subpopulation of CETCs could reflect the aggressiveness of the remaining tumor burden. There is limited data on the detection and monitoring changes in CETC and cCSC numbers during RT in early breast cancer. Methods: : CETC numbers were analyzed prior to, at midterm and at the end of RT in 52 primary non-metastatic breast cancer patients. Hormone receptor status was determined in CETCs prior to and at the end of RT. For the identification of cCSCs cell suspensions from the peripheral blood of patients were cultured in vitro under conditions favoring growth of tumorspheres. Results: : Hormone receptor status in CETCs before RT was comparable to that in primary tumor tissue. Prior to RT numbers of CETCs correlated with aggressiveness of primary tumors. cCSCs could be successfully identified and monitored during RT. Prior to RT patients treated with neoadjuvant chemotherapy had significantly higher numbers of CETCs and tumorspheres compared to patients after adjuvant chemotherapy. During RT, the number of CETCs decreased continuously in patients after neoadjuvant chemotherapy but not after adjuvant chemotherapy. Conclusion: : Monitoring the number of CETCs and the CETC subset with cancer stem cell properties during RT may provide additional clinically useful prognostic information.

Breast cancer (BC) is the most common cause of cancer-related deaths among women in Europe and worldwide. Adherent (2D) cell cultures have been the routine in vitro model system employed in preclinical BC research for the last half-century. Over the past decade, new protocols have been developed allowing patient-derived three-dimensional organoid (3D) cell culture development from a range of solid tumours, including BC. These 3D models offer a promise of closer resemblance to the native tumour than the 2D cultures. To test the assumption that an in vitro 3D BC model system provides increased faithfulness to the molecular processes happening in vivo, as compared to 2D BC cultures, post-operational material from three BC patients was used to simultaneously develop 2D and 3D cultures in vitro. When analysed by quantitative polymerase chain reaction (PCR), the gene expression patterns of the cells from 3D cultures resembled the original tissues, while the gene expression patterns of the conventional 2D cultures were more distant. [ABSTRACT FROM AUTHOR]

Purpose: Prediction of response to primary endocrine therapy (PET) in older women is based on measurement of oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor (HER)-2. This study uses a unique method for construction of core needle biopsy (CNB) tissue microarray (TMA), to correlate expression of a panel of 17 biomarkers with clinical outcome, in patients receiving PET. Methods: Over 37 years (1973–2010), 1758 older (≥ 70 years) women with operable primary breast cancer were managed in a single institution. Of these, 693 had sufficient good-quality CNB to construct TMA, of which 334 had ER-positive tumours treated by PET with a minimum of 6-month follow-up. A panel of biomarkers was measured by immunohistochemistry (ER, PgR, HER2, Ki-67, p53, CK5/6, CK 7/8, EGFR, BCL-2, MUC1, VEGF, LKB1, BRCA1, HER3, HER4, PTEN and AIB1). Expression of each biomarker was dichotomised into 'low' or 'high' based on breast cancer-specific survival (BCSS). Results: From the panel of biomarkers, multivariate analysis showed: High ER (p = 0.003) and PgR (p = 0.002) were associated with clinical benefit of PET at 6 months, as opposed to progressive disease. High ER (p = 0.0023), PgR (p < 0.001) and BCL-2 (p = 0.043) and low LKB1 (p = 0.022) were associated with longer time to progression. High PgR (p < 0.001) and low MUC1 (p = 0.021) were associated with better BCSS. Expression of other biomarkers did not show any significant correlation. Conclusions: In addition to ER and PgR; MUC1, BCL-2 and LKB1 are important in determining the outcome of PET in this cohort. [ABSTRACT FROM AUTHOR]

Background: Completion axillary lymph node dissection is overtreatment for patients with sentinel lymph node (SLN) metastasis in whom the metastatic risk of residual non-SLN (NSLN) is low. However, the National Comprehensive Cancer Network panel posits that none of the previous studies has successfully identified such subset patients. Here, we develop a multicentre deep learning radiomics of ultrasonography model (DLRU) to predict the risk of SLN and NSLN metastasis. Methods: In total, 937 eligible breast cancer patients with ultrasound images were enrolled from two hospitals as the training set (n = 542) and independent test set (n = 395) respectively. Using the images, we developed and validated a prediction model combined with deep learning radiomics and axillary ultrasound to sequentially identify the metastatic risk of SLN and NSLN, thereby, classifying patients to relevant axillary management groups. Findings: In the test set, the DLRU yields the best performance in identifying patients with metastatic disease in SLNs (sensitivity=98.4%, 95% CI 96.6–100) and NSLNs (sensitivity=98.4%, 95% CI 95.6–99.9). The DLRU also accurately stratifies patients without metastasis in SLN or NSLN into the corresponding low-risk (LR)-SLN and high-risk (HR)-SLN&LR-NSLN category with the negative predictive value of 97% (95% CI 94.2–100) and 91.7% (95% CI 88.8–97.9), respectively. Moreover, compared with the current clinical management, DLRU appropriately assigned 51% (39.6%/77.4%) of overtreated patients in the entire study cohort into the LR group, perhaps avoiding overtreatment. Interpretation: The performance of the DLRU indicates that it may offer a simple preoperative tool to promote personalized axillary management of breast cancer. Funding: The National Nature Science Foundation of China; The National Outstanding Youth Science Fund Project of National Natural Science Foundation of China; The Scientific research project of Heilongjiang Health Committee; The Postgraduate Research &Practice Innovation Program of Harbin Medical University.

Background: The 8th edition American Joint Committee on Cancer (AJCC) proposed a prognostic stage (PS), which included not only anatomical factors, but also biological factors. We aimed to investigate the clinicopathological significance of the PS and to compare PS and anatomical stage (AS) that has been established by the Union for International Cancer Control (UICC). Methods: Between 2002 and 2017, 800 patients were included in the study. Patients were classified using pathological UICC AS and pathological AJCC PS. The usefulness of PS in comparison with AS was validated using the Akaike information criterion (AIC) and Harrell concordance index (C-index). Results: A total of 401 (50.1%) patients had pathological AS I, 324 (40.5%) had AS II, and 75 (9.4%) had AS III. Meanwhile, 535 (66.8%) had pathological PS I, 163 (20.4%) had PS II, and 102 (12.8%) had PS III. The number of AS II cases was 1.99-fold higher than that of PS II cases. For each stage, these survival curves were almost similar between AS and PS classification. Therefore, many patients to be classified into stage I and stage III were included in AS II group, while many patients to be classified into stage II were included in AS I group. To trichotomize the survival groups, PS appeared to be more specific than AS, and AIC and C-index confirmed the speculation. Conclusion: For the prognostication of primary breast cancer patients, AJCC PS appeared to be able to stratify the cases more appropriately than UICC AS. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) play a pivotal role in tumor dissemination and progression, and are considered to be a critical part of the metastatic cascade. The aim of the present research article was to examine breast cancer-specific mutations in primary breast cancer (PBC) using targeted resequencing. A total of 78 patients with PBC were enrolled into this translational study. Reverse transcription-quantitative PCR assay for the expression of epithelial markers (CK19) or epithelial-to-mesenchymal transition (EMT)-related genes (TWIST1, SNAIL1, SLUG and ZEB1) was applied for identification of CTCs prior to surgery. Total DNA was isolated from fresh frozen primary tumors. Sequencing was performed by Agilent SureSelect target enrichment and Illumina paired-end sequencing on the MiSeq platform. The most commonly affected genes were TP53 (mutated in 21 tumors; 26.9%), followed by PIK3CA (mutated in 16 tumors; 20.5%) and BRCA1/2 (mutated in 7 tumors, BRCA1 n=2 and BRCA2 n=5; 9.0%). In our cohort, a significantly higher proportion of patients with epithelial CTCs harbored mutations in the BRCA1/2 genes in the tumor tissue. There were no mutations in specific genes associated with CTCs with the EMT phenotype. To the best of our knowledge, this study is the first to report a correlation between the presence of epithelial CTCs in the peripheral blood and mutations of the BRCA1/2 genes in primary tumor tissue. [ABSTRACT FROM AUTHOR]

Background: The chemokine receptor CXCR4 and the transcription factor JUNB, expressed on a variety of tumor cells, seem to play an important role in the metastatic process. Since disseminated tumor cells (DTCs) in the bone marrow (BM) have been associated with worse outcomes, we evaluated the expression of CXCR4 and JUNB in DTCs of primary, nonmetastatic breast cancer (BC) patients before the onset of any systemic treatment. Methods: Bilateral BM (10 ml) aspirations of 39 hormone receptor (HR)-positive, HER2-negative BC patients were assessed for the presence of DTCs using the following combination of antibodies: pan-cytokeratin (A45-B/B3)/CXCR4/JUNB. An expression pattern of the examined proteins was created using confocal laser scanning microscopy, Image J software and BC cell lines. Results: CXCR4 was overexpressed in cancer cells and DTCs, with the following hierarchy of expression: SKBR3 > MCF7 > DTCs > MDA-MB231. Accordingly, the expression pattern of JUNB was: DTCs > MDA-MB231 > SKBR3 > MCF7. The mean intensity of CXCR4 (6411 ± 334) and JUNB (27725.64 ± 470) in DTCs was statistically higher compared with BM hematopoietic cells (2009 ± 456, p = 0.001; and 11112.89 ± 545, p = 0.001, respectively). The (CXCR4+JUNB+CK+) phenotype was the most frequently detected [90% (35/39)], followed by the (CXCR4–JUNB+CK+) phenotype [36% (14/39)]. However, (CXCR4+JUNB–CK+) tumor cells were found in only 5% (3/39) of patients. Those patients harboring DTCs with the (CXCR4+JUNB+CK+) phenotype revealed lower overall survival (Cox regression: p = 0.023). Conclusions: (CXCR4+JUNB+CK+)-expressing DTCs, detected frequently in the BM of BC patients, seem to identify a subgroup of patients at higher risk for relapse that may be considered for close follow up. [ABSTRACT FROM AUTHOR]

Background: To evaluate the clinicopathological and prognostic significance of the percentage change between maximum standardized uptake value (SUVmax) at 60 min (SUVmax1) and SUVmax at 120 min (SUVmax2) (ΔSUVmax%) using dual time point 18F-fluorodeoxyglucose emission tomography/computed tomography (18F-FDG PET/CT) in breast cancer.Methods: Four hundred and sixty-four patients with primary breast cancer underwent 18F-FDG PET/CT for preoperative staging. ΔSUVmax% was defined as (SUVmax2 - SUVmax1) / SUVmax1 × 100. We explored the optimal cutoff value of SUVmax parameters (SUVmax1 and ΔSUVmax%) referring to the event of relapse by using receiver operator characteristic curves. The clinicopathological and prognostic significances of the SUVmax1 and ΔSUVmax% were analyzed by Cox's univariate and multivariate analyses.Results: The optimal cutoff values of SUVmax1 and ΔSUVmax% were 3.4 and 12.5, respectively. Relapse-free survival (RFS) curves were significantly different between high and low SUVmax1 groups (P = 0.0003) and also between high and low ΔSUVmax% groups (P = 0.0151). In Cox multivariate analysis for RFS, SUVmax1 was an independent prognostic factor (P = 0.0267) but ΔSUVmax% was not (P = 0.152). There was a weak correlation between SUVmax1 and ΔSUVmax% (P < 0.0001, R2 = 0.166). On combining SUVmax1 and ΔSUVmax%, the subgroups of high SUVmax1 and high ΔSUVmax% showed significantly worse prognosis than the other groups in terms of RFS (P = 0.0002).Conclusion: Dual time point 18F-FDG PET/CT evaluation can be a useful method for predicting relapse in patients with breast cancer. The combination of SUVmax1 and ΔSUVmax% was able to identify subgroups with worse prognosis more accurately than SUVmax1 alone. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association between PD-L1 expression (PD-L1+) and clinicopathological characteristics and effect on prognosis in primary breast cancer (PBC). Methods: A systematic search of the PubMed, Web of Science, and Embase databases was conducted in November 2018. Studies detecting PD-L1 using immunohistochemistry, and concerning its prognostic or clinicopathological significance in PBC were included. The HR with 95% CI for survival, and the events for clinicopathological features were pooled. Results: Forty-seven studies were included, with a total of 14,367 PBC patients. PD-L1+ tumor cells (TCs) were associated with ductal carcinomas, large tumor size, histological Grade 3 tumors, high Ki-67, ER and PR negative, and triple-negative breast cancer; and also, related to high tumor-infiltrating lymphocytes (TILs) and PD-1 expression. PD-L1+ TCs were significantly associated with shorter disease-free survival (DFS, HR = 1.43, 95% CI 1.21–1.70, P < 0.0001) and overall survival (OS, HR = 1.58, 95% CI 1.14–2.20, P = 0.006). And the HRs of PD-L1+ TCs on DFS and OS were higher (1.48 and 1.70, respectively) and homogeneous when using whole tissue section, compared with tumor microarrays. However, PD-L1+ TILs related to better DFS (HR = 0.45, 95% CI 0.28–0.73, P = 0.001) and OS (HR = 0.41, 95% CI 0.27–0.63, P < 0.0001). Conclusion: PD-L1 expression on TCs associates with high-risk clinicopathological parameters and poor prognosis in PBC patients, while PD-L1+ TILs may relate to a better survival. Comprehensive assessment of TCs and TILs is required when evaluating the clinical relevance of PD-L1 expression in future studies. [ABSTRACT FROM AUTHOR]

Purpose: Locoregional control is a prerequisite to cure primary breast cancer but the prediction of locoregional recurrence to guide further local therapy following neoadjuvant chemotherapy remains a challenge. The CPS + EG score was designed to predict distant recurrences. Here we examine its ability to predict both not only distant but also locoregional recurrences with respect to accuracy and clinical applicability. Methods: Clinical data from 432 patients with primary breast cancer treated with neoadjuvant chemotherapy between 2003 and 2011 were prospectively collected. Using the Kaplan–Meier method we analyzed the risk of local and distant recurrences according to individual CPS + EG scores, stratified by type of surgery. Possible confounding of the relationship between recurrence risk and CPS + EG score by established risk factors was accounted for in multiple survival regression models. Additionally, we analyzed the performance of the CPS + EG score to predict isolated locoregional recurrence by censoring patients with prior or simultaneous distant metastases. Results: 5-year locoregional recurrence-free survival was 90%, and 5-year distant metastases-free survival was 82%. The CPS + EG score stratified patients into six prognostic groups with distinct 5-year locoregional recurrence-free survival, ranging from 100 to 41% (p = 0.02) and 5-year distant metastases-free survival, ranging from 96 to 35% (p < 0.0001). 8 patients (17%) with CPS + EG scores ≥ 4 experienced locoregional recurrence—5 of them presented with simultaneous distant disease. Conclusion: The CPS + EG score, originally designed to predict distant relapse, is also valuable for assessing local recurrence risks. Our data demonstrate that distant and locoregional recurrence risks are closely related. As prognosis of patients with high risk of locoregional failure based on CPS + EG is dominated by distant recurrences, escalating local therapies may have limited impact on overall prognosis. [ABSTRACT FROM AUTHOR]

Noninvasive circulating tumor DNA (ctDNA) can be used to predict breast cancer recurrence and prognosis. In this study, we detected 226 and 114 somatic variants in tumor DNA from 70 primary breast cancer (PBC) patients (98.59%) and ctDNA from 48 patients (67.61%), respectively. Gene frequencies of tumor DNA and ctDNA significantly correlated (R2 = 0.9532, P < 0.0001), and tumor‐derived variants were detectable in the blood of 43 patients. ctDNA was more often detected in locally advanced/metastatic and nonluminal patients. Multivariate analysis revealed that individual N stage (P < 0.001) and hormone receptor (HR) status (P = 0.001) could independently predict the detectability of tumor‐derived mutations in blood. The maximal variant allele frequency of ctDNA was significantly higher in patients with stage IV/M1 (P = 0.0136) and stage T3/T4 (P = 0.0085) cancers. Finally, clonal variants in tumor DNA were more easily traced in ctDNA than subclonal variants (84.62% vs 48.75%). In conclusion, ctDNA fragments concordant with tumor DNA can be consistently detected in the majority of tested PBC patients, which may enable noninvasive genomic profiling of PBC, particularly for patients with advanced‐stage tumors and positive HR status. [ABSTRACT FROM AUTHOR]

Background: Carcinoma of the breast is the most common of non-skin malignancies in women and is second to lung cancer is a cause of cancer deaths. A woman who lives to age 90 has a one in eight chance of developing breast cancer. It is as ironic and tragic that a neoplasm arising in an exposed organ, readily accessible to self-examination and clinical surveillance, continues to exact such a heavy toll. The aim of the study: To determine, if differences in the extent of axillary node dissection would alter the number of reported positive nodes, to emphasize the presence and importance of dissecting the inter pectoral node (Rotter's Node) in Modified Radical Mastectomy. Materials and methods: This study was conducted in the Department of General Surgery, Government Stanley Medical College, Chennai in 2018. Patients were evaluated according to NCCN guidelines and were subjected to Modified Radical Mastectomy for whomsoever it was needed. 32 cases underwent Modified Radical Mastectomy with complete axillary dissection (level I/II/III and inter pectoral node) according to the identical procedure. The dissection was carried out in all patients, irrespective of whether they had palpable nodes or not clinically. Results: An average of 13 lymph nodes was examined per case (range: 8-20). Axillary lymph node involvement was found in 56% of the cases (18/32). Of the 18 cases, 83% (n = 15) had involvement of level I/II nodes only, and 16% (n = 3) had positive ALN in levels III and, or, inter pectoral nodes, in addition to the level I/II. Involvement of lymph nodes in level III and inter pectoral nodes without a level I metastasis was not found. By the inclusion of level III to a level I/II dissection, two cases (11%) was converted from one to three positive nodes (pN1) to ≥4 positive nodes (pN2). Involvement of lymph nodes in level III was found in 3 cases (16%) 10/32 cases (31%) had ≥4 positive nodes who required adjuvant therapy. Conclusion: Variations in the level of axillary node dissection for breast cancer which includes the inter pectoral and level III nodes can result in significant changes in the number of positive axillary nodes stepping up the pathologic nodal status from pN1 to pN2. This can potentially bias adjuvant therapy recommendations if treatment decisions are based on this prognostic factor. [ABSTRACT FROM AUTHOR]

Background: The Ki‐67 labeling index (LI) is a well‐known prognostic factor for primary breast cancer, but its clinical significance for metachronous axillary lymph node (ALN) recurrence has not been well documented. Methods: Ki‐67 expression in primary tumors (PTs) and ALN metastases (ALNMs) was evaluated in 21 patients and quantified to investigate the relationship between Ki‐67 LIs in PTs and metachronous ALNMs. Results: The median Ki‐67 LIs in the PTs and ALNMs were 25.2% (range: 2.3–80.2%) and 70% (range: 10.4–97.4%), respectively. A majority of patients had higher Ki‐67 LIs in ALNMs than in PTs (76.2%, 16/21). Disease‐specific survival was significantly better in patients with a lower‐than‐median ALNM Ki‐67 LI (P = 0.019, log‐rank test). Receiver operating characteristic curves showed a PT Ki‐67 LI of 62.8% as the optimal cutoff value and an ALNM Ki‐67 LI of 65.1%. Accordingly, we divided the patients into four groups: PT Ki‐67 LI lower than 62.8%/ALNM Ki‐67 LI lower than 65.1%, PT Ki‐67 LI lower/ALNM Ki‐67 LI higher, PT Ki‐67 LI higher/ALNM Ki‐67 LI higher, and PT Ki‐67 LI higher/ALNM Ki‐67 LI lower. Disease‐specific survival was significantly better in patients with Ki‐67 LI lower/ALNM Ki‐67 LI lower than in the other groups. Conclusion: This is the first study to show that the Ki‐67 LI in metachronous ALNM is a prognostic factor for patients with metachronous ALN recurrence of breast cancer. [ABSTRACT FROM AUTHOR]