Comparative efficacy and safety of different combinations of three CDK4/6 inhibitors with endocrine therapies in HR+/HER-2 - metastatic or advanced breast cancer patients: a network meta-analysis.

BACKGROUND: This network meta-analysis aimed to assess the comparative efficacy and safety of combinations involving three cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapies (ETs) in patients with metastatic or advanced breast cancer (BC) who are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-). METHODS: We initially identified relevant studies from previous meta-analyses and then conducted a comprehensive search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases to locate additional studies published between February 2020 and September 2021. Essential data were extracted, and a network meta-analysis was performed using R 4.1.1 software with a random-effects model. Furthermore, we assigned rankings to all available treatment combinations by calculating their cumulative probability. RESULTS: Data analysis included ten reports from nine studies. Pooled results demonstrated that each treatment combination significantly reduced the hazard risk of progression-free survival (PFS) compared to treatment with an aromatase inhibitor (AI) or fulvestrant alone. However, there were no differences observed in PFS or overall survival (OS) among the different treatment combinations. Additionally, patients receiving palbociclib plus AI and abemaciclib plus AI or fulvestrant experienced more severe adverse events (AEs), with hazard ratios (HRs) of 10.83 (95% confidence interval [CI] = 2.3 to 52.51) and 4.8 (95%CI = 1.41 to 16.21), respectively. The HR for ribociclib plus AI was 9.45 (95%CI = 2.02 to 43.61), and the HR for palbociclib plus fulvestrant was 6.33 (95%CI = 1.03 to 39.86). Based on the ranking probabilities, palbociclib plus fulvestrant had the highest probability of achieving superior PFS (37.65%), followed by abemaciclib plus fulvestrant (28.76%). For OS, ribociclib plus fulvestrant ranked first (34.11%), with abemaciclib plus fulvestrant in second place (25.75%). In terms of safety, palbociclib plus AI (53.98%) or fulvestrant (51.37%) had the highest probabilities of being associated with adverse events. CONCLUSIONS: Abemaciclib plus fulvestrant or ribociclib plus AI appear to be effective and relatively safe for the treatment of HR+/HER2- metastatic or advanced BC patients. However, given the reliance on limited evidence, our findings require further validation through additional studies.

Nomogram for predicting overall survival in Chinese triple-negative breast cancer patients after surgery.

BACKGROUND: There are few nomograms for the prognosis of Chinese patients with triple-negative breast cancer (TNBC). AIM: To construct and validate a nomogram for overall survival (OS) of Chinese TNBC patients after surgery. METHODS: This study used the data of SEER*stat 8.3.5 and selected Chinese patients with TNBC operated on between 2010 and 2015. Univariate and multivariate Cox proportional hazard regression models were used. The identified variables were integrated to form a predictive nomogram and risk stratification model; it was assessed with C-indexes and calibration curves. RESULTS: The median and maximal OS of the 336 patients was 39 and 83 mo, respectively. The multivariate analysis showed that age (P = 0.043), marital status (P = 0.040), tumor localization (P = 0.030), grade (P = 0.035), T classification (P = 0.012), and N classification (P = 0.002) were independent prognostic factors. The six variables were combined to construct a 1-, 3- and 5-year OS nomogram. The C-indexes of the nomogram to predict OS were 0.766 and compared to the seventh edition staging system, which was higher (0.766 vs 0.707, P < 0.001). In order to categorize patients into different prognostic groups, a risk stratification model was created. There was a significant difference between the Kaplan-Meier curves of the entire cohort and each disease stage according to the nomogram. CONCLUSION: The nomogram provided prognostic superiority over the traditional tumor, node and metastasis system. It could help clinicians make individual OS or risk predictions for Chinese TNBC patients after surgery.

Effect of Previous Cancer History on Survival of Patients with Different Subtypes of Breast Cancer.

Patients with a previous cancer history (PCA) are routinely excluded from most clinical trials, which may limit the accuracy and universality of clinical trials. We aimed to explore the association between PCA and survival of patients with different molecular subtypes of breast cancer. Patients diagnosed with breast cancer from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 were included in this retrospective cohort study. The primary outcome was overall survival (OS), which was calculated from date of diagnosis to date of death or censor date during this period. The relationship between PCA and OS of patients with different molecular subtypes of breast cancer was analyzed by the Kaplan-Meier curves and multivariate Cox proportional-hazards model. A total of 35,640 primary breast cancer patients were included, and 2,038 (5.72%) patients had a PCA. Female genital system cancer (491 cases, 24.09%) was the largest proportion type of previous cancer, and HER2-positive (24,754 cases, 69.46%) breast cancer was the most common subtype. Patients with previous female genital/endocrine system cancer history and other cancers history were associated with a poorer OS in overall patients, and in patients with triple-negative and HER2-positive subtypes (P < 0.05). In patients with Luminal A and Luminal B subtypes, previous other cancers history was related to poor OS (P < 0.05), while female genital/endocrine system cancer history may not influence the OS (P > 0.05). Subgroup analyses presented that PCA was related to poor OS in patients aged 40-64 years and ≥65 years (P <0.05), while prognosis in patients aged 18-40 years may not be influenced by PCA (P > 0.05). The impact of PCA on the prognosis of breast cancer patients was related to molecular type, patient age, and type of PCA. In clinical trials of breast cancer, the exclusion criteria for PCA patients may be modified according to the above variables.

Follicular carcinoma of the thyroid with a single metastatic lesion in the lumbar spine: A case report.

BACKGROUND: The bone is the second most common site of thyroid cancer metastasis, after the lung. Treatment options for bone metastasis of thyroid cancer include surgery, radioiodine therapy (RAIT), external radiation therapy, thyroid-stimulating hormone (TSH) inhibition, bisphosphonates, and small-molecule targeted therapies. In most cases, thyroid carcinoma is found in the thyroid tissue; reports of follicular thyroid carcinoma with a single metastasis to the lumbar spine are rare. CASE SUMMARY: We report a case of bone metastasis as the only clinical manifestation of thyroid cancer. The patient was a 67-year-old woman with lumbar pain for 7 years and aggravation with intermittent claudication who had previously undergone partial thyroidectomy of a benign thyroid lesion. No abnormal nodules were found in the bilateral thyroid glands. However, imaging studies were consistent with a spinal tumor, and the lesion was diagnosed as a metastatic follicular carcinoma of thyroid origin. We adopted a multidisciplinary collaboration and comprehensive treatment approach. The patient underwent lumbar spine surgery, total resection of the thyroid, postoperative TSH suppression therapy, and RAIT. There were no complications associated with the operation, and the patient had good postoperative recovery. She has experienced no recurrence. CONCLUSION: Follicular thyroid carcinoma is associated with early hematogenous metastasis, and the bone is a typical site of metastasis. Single bone metastasis is not a contraindication to medical procedures, and providing the appropriate therapy can result in better outcomes and quality of life for these patients.

Development and validation of a novel endoplasmic reticulum stress-related lncRNA prognostic signature and candidate drugs in breast cancer.

Breast cancer (BC), the most common malignancy in women, has a high cancer-related mortality. Endoplasmic reticulum stress (ERS), a response to the accumulation of unfolded proteins, has emerging roles in tumorigenesis, including invasion, metastasis, immune escape, etc. However, few studies have focused on the correlation between ERS with long non-coding RNAs (lncRNAs) in BC. We attempted to construct an ERS-related lncRNA prognostic signature and study its value in BC from tumor mutational burden (TMB), tumor immune microenvironment (TIME), cluster, clinical treatment, and so on. In the present study, transcriptomic and clinical data of BC patients were extracted from The Cancer Genome Atlas (TCGA) database. Correlation test, Cox regression analysis, least absolute shrinkage, and selection operator (LASSO) method were performed to determine an ERS-related lncRNA prognostic signature. Survival and predictive performance were analyzed according to Kaplan-Meier curves and receiver operating characteristic (ROC) curves, while nomograms and calibration curves were established. Then, an enrichment analysis was performed to study the functions and biological processes of ERS-related lncRNAs. TMB and TIME were also analyzed to assess the mutational status and immune status. Additionally, by using consensus cluster analysis, we compared differences among tumor subtypes. Drug sensitivity analysis and immunologic efficacy evaluations were performed together for further exploration. We identified a novel prognostic signature consisting of 9 ERS-related lncRNAs. High-risk patients had worse prognoses. The signature had a good predictive performance as an independent prognostic indicator and was significantly associated with clinicopathological characteristics. Enrichment analysis showed that metabolic pathways were enriched in high-risk patients, while immune pathways were more active in low-risk patients. Low-risk patients had lower TMB, higher immune scores, and stronger immune functions. Cluster analysis clarified that cluster 2 had the most active immune functions and was sensitive to more drugs, which may have the best clinical immunological efficacy. A clinical efficacy evaluation revealed that patients in the low-risk group may benefit more from chemotherapy, targeted therapy, and immunotherapy. The novel signature has significant clinical implications in prognosis prediction for BC. Our study clarifies that there is a potential connection between the ERS-related lncRNAs and BC, which may provide new treatment guidelines for BC.

Addition of Capecitabine to Adjuvant Chemotherapy May be the Most Effective Strategy for Patients With Early-Stage Triple-Negative Breast Cancer: A Network Meta-Analysis of 9 Randomized Controlled Trials.

Background and Objective: Previous studies determined the therapeutic effects of capecitabine-based chemotherapy regimens on early-stage triple-negative breast cancer (TNBC). However, the optimal strategy of capecitabine-based chemotherapy remains uncertain. We conducted this network meta-analysis to address this issue. Methods: We systematically searched PubMed, Embase, and the Cochrane Registry of Controlled Trials (CENTRAL) to retrieve eligible studies published before September 2021. Two independent reviewers extracted information from eligible studies using a pre-designed data extraction sheet. The primary outcome included disease-free survival, and the second outcome showed overall survival and adverse events. Direct meta-analysis was performed using RevMan 5.4, and Bayesian network analysis was performed using R version 3.6.1 with the "gemtc" and "rjags" packages. Results: Nine studies involving 3661 TNBC patients met the selection criteria. The network meta-analysis suggested that the addition of capecitabine to adjuvant chemotherapy achieved a significantly longer disease-free (HR = 0.66, 95% CrI = 0.49 to 0.86) and overall survival time (HR = 0.60, 95% CrI = 0.43 to 0.83) than standard chemotherapy. All comparisons did not achieve statistical significance. The addition of capecitabine to adjuvant chemotherapy was the most effective treatment for improving disease-free (81.24%) and overall survival (78.46%) times, and the replacement of capecitabine to adjuvant chemotherapy was the safest regime. Conclusions: Based on available evidence, capecitabine-based chemotherapy benefits TNBC patients, and the addition of capecitabine with adjuvant chemotherapy was the most effective regime. In contrast, the replacement of capecitabine to adjuvant chemotherapy was the safest regime. More studies of high quality and large scale are needed to confirm our findings.

Identification of a 5-gene-risk score model for predicting luminal A-invasive lobular breast cancer survival.

Breast cancer is a devastating malignancy, among which the luminal A (LumA) breast cancer is the most common subtype. In the present study, we used a comprehensive bioinformatics approach in the hope of identifying novel prognostic biomarkers for LumA breast cancer patients. Transcriptomic profiling of 611 LumA breast cancer patients was downloaded from TCGA database. Differentially expressed genes (DEGs) between tumor samples and controls were first identified by differential expression analysis, before being used for the weighted gene co-expression network analysis. The subsequent univariate Cox regression and LASSO algorithm were used to uncover key prognostic genes for constructing multivariate Cox regression model. Patients were stratified into high-risk and low-risk groups according to the risk score, and subjected to multiple downstream analyses including survival analysis, gene set enrichment analysis (GSEA), inference on immune cell infiltration and analysis of mutation burden. Receiving operator curve analysis was also performed. A total of 7071 DEGs were first identified by edgeR package, pink module was found significantly associated with invasive lobular carcinoma (ILC). 105 prognostic genes and 9 predictors were identified, allowing the identification of a 5-key prognostic genes (LRRC77P, CA3, BAMBI, CABP1, ATP8A2) after intersection. These 5 genes, and the resulting Cox model, displayed good prognostic performance. Furthermore, distinct differences existed between two risk-score stratified groups at various levels. The identified 5-gene prognostic model will help deepen the understanding of the molecular and immunological mechanisms that affect the survival of LumA-ILC patients and guide and proper monitoring of these patients.

Individualized treatment of breast cancer with chronic renal failure: A case report and review of literature.

BACKGROUND: Studies have shown that patients with chronic renal failure (CRF) are more likely to suffer from breast cancer and other malignant tumors. To our knowledge, CRF can reduce drug excretion, thereby increase drug exposure and lead to increased toxicity, which will limit drug treatment and lead to tumor progression. Currently, there are few successful reports on the combination of docetaxel, trastuzumab, and pertuzumab (THP) as a neoadjuvant treatment regimen for breast cancer patients with CRF. CASE SUMMARY: We report a breast cancer (cT2N2M0, Her-2+/HR-) patient with CRF. It was a clinical stage IIIA tumor on the left breast. The patient had suffered from uremia for 2 years, and her heart function was normal. Based on the pathological type, molecular type, and clinical stage of breast cancer, and the patient's renal function, the clinician analyzed the pharmacological and pharmacokinetic characteristics of the antitumor drugs after consulting the relevant literature, and prescribed the neoadjuvant regimen of THP (docetaxel 80 mg/m², trastuzumab 8 mg/kg for the first dose, and 6 mg/kg for the maintenance dose with pertuzumab 840 mg for the first dose and 420 mg for the maintenance dose), once every 3 wk, for a total of 6 courses. The neoadjuvant treatment had a good effect, and the patient then underwent surgery which was uneventful. CONCLUSION: CRF is not a contraindication for systemic treatment and surgery of breast cancer. The THP regimen without dose adjustment may be a safe and effective neoadjuvant treatment for HER-2 positive breast cancer patients with CRF.

Prognostic and Immune-Infiltrate Significance of miR-222-3p and Its Target Genes in Thyroid Cancer.

Thyroid cancer (THCA) is a common endocrine malignancy. With increasing incidence and low mortality, balancing the therapeutic approach is an inevitable issue. This study aimed to confirm the role of miR-222-3p and its target genes in THCA survival and immune infiltration. From different expression analyses based on the GEO and TCGA databases, we predicted and subsequently identified the key target genes of miR-222-3p. We then explored the expression, enrichment, pairwise correlation, protein expression, survival analysis, principal component analysis, and immune significance of the critical genes using bioinformatics analysis. The present study demonstrated that NEGR1, NTNG1, XPNPEP2, NTNG2, CD109, OPCML, and PRND are critical genes. The miR-222-3p was highly expressed, probably leading to low NEGR1 and high PRND expression in THCA tissues. Low NEGR1 expression indicated favorable prognosis in THCA patients, and high PRND expression indicated poor prognosis. Seven critical genes were significantly related to gender, age, race, tumor stage, and lymph node metastasis. In addition, the seven-gene biomarker exhibited a certain diagnostic value. Finally, CD109 expression was closely correlated with immune cells, especially B cells and CD4+ T cells. The miR-222-3p and its critical target genes could be promising biomarkers for the prognosis of THCA and may emerge as key regulators of immune infiltration in THCA.

The Global, Regional, and National Burden and Trends of Breast Cancer From 1990 to 2019: Results From the Global Burden of Disease Study 2019.

BACKGROUND: The burden of breast cancer has been increasing globally. The epidemiology burden and trends need to be updated. This study aimed to update the burden and trends of breast cancer incidences, deaths, and disability-adjusted life-years (DALYs) from 1990 to 2019, using the Global Burden of Disease 2019 study. METHODS: The data of incidences, deaths, DALYs, and age-standardized rates were extracted. Estimated annual percentage changes were used to quantify the trends of age-standardized rates. Besides, the population attributable fractions of the risk factors of breast cancer were also estimated. RESULTS: Globally, the incidences of breast cancer increased to 2,002,354 in 2019. High social-development index (SDI) quintiles had the highest incidence cases with a declining trend in age-standardized incidence rate. In 2019, the global deaths and DALYs of breast cancer increased to 700,660 and 20,625,313, respectively. From 1990 to 2019, the age-standardized mortality rates and age-standardized DALY rates declined globally, especially in high and high-middle SDI quintiles. Besides, the trends varied from different regions and countries. The proportion of the patients in the 70+ years age group increased globally. Deaths of breast cancer attributable to high fasting plasma glucose and high body mass index increased globally, and high fasting plasma glucose was the greatest contributor to the global breast cancer deaths. CONCLUSION: The burden of breast cancer in higher SDI quintiles had gone down while the burden was still on the rise in lower SDI quintiles. It is necessary to appeal to the public to decrease the exposure of the risk factors.

Identification of immune-related lncRNAs to improve the prognosis prediction for patients with papillary thyroid cancer.

OBJECTIVE: To identify immune-related long non-coding RNAs (lncRNAs) in papillary thyroid cancer (PTC). METHODS: The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to obtain the gene expression profile. Immune-related lncRNAs were screened from the Molecular Signatures Database v4.0 (MsigDB). We performed a survival analysis of critical lncRNAs. Further, the function of prognostic lncRNAs was inferred using the Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) to clarify the possible mechanisms underlying their predictive ability. The assessment was performed in clinical samples and PTC cells. RESULTS: We obtained 4 immune-related lncRNAs, 15 microRNAs (miRNAs), and 375 mRNAs as the key mediators in the pathophysiological processes of PTC from the GEO database. Further, Lasso regression analysis identified seven prognostic markers (LINC02550, SLC26A4-AS1, ACVR2B-AS1, AC005479.2, LINC02454, and AL136366.1), most of which were related to tumor development. The KEGG pathway enrichment analysis showed different, changed genes mainly enriched in the cancer-related pathways, PI3K-Akt signaling pathway, and focal adhesion. Only SLC26A4-AS1 had an intersection in the results of the two databases. CONCLUSION: LncRNA SLC26A4-AS1, which is the most associated with prognosis, may play an oncogenic role in the development of PTC.

Circular RNA hsa_circ_0001785 inhibits the proliferation, migration and invasion of breast cancer cells in vitro and in vivo by sponging miR-942 to upregulate SOCS3.

Circular RNAs (circRNAs) are a class of widely expressed noncoding RNA with significant regulatory potential discovered in recent years. The purpose of this study was to investigate the effects of hsa_circ_0001785 on the proliferation, migration and invasion of breast cancer (BC) cells in vivo and in vitro and the potential underlying molecular mechanism. In the present study, the expressions of hsa_circ_0001785 in five BC cells (T47D, MCF-7, MDA-MB-453, MDA-MB-231 and BT-549) and one normal breast cell (MCF-10A) were the first to examined by qRT-PCR. Then, we studied the biological function of hsa_circ_0001785 in BC by in vivo and in vitro experiments. CCK-8, clone formation, wound-healing and Transwell assays were performed to analyze the cellular proliferation, migration and invasion in vitro. The subcutaneous tumor model of nude mice was used for in vivo experiment. In addition, we determined that hsa_circ_0001785 acted as competing endogenous RNAs (ceRNAs) in BC by RNA immunoprecipitation (RIP) and dual-luciferase reporter assays. Results showed that the expressions of hsa_circ_0001785 were decreased in BC cells. Hsa_circ_0001785 overexpression inhibited the proliferation, migration, invasion of BC cells and tumor growth in nude mice. RIP and dual-luciferase reporter assay demonstrated that hsa_circ_0001785 could regulate the SOCS3 by sponging miR-942. In general, circular RNA hsa_circ_0001785 inhibits the proliferation, migration and invasion of BC cells by modulating the miR-942/SOCS3 signaling axis.

Diffusion Kurtosis at 3.0T as an in vivo Imaging Marker for Breast Cancer Characterization: Correlation With Prognostic Factors.

BACKGROUND: Diffusion-kurtosis imaging (DKI) has preliminarily shown promise as a relatively new MRI technique to provide useful information regarding breast lesions, but the diagnostic performance of DKI has not been fully evaluated. PURPOSE: To compare the diagnostic accuracy of DKI, diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE)-MRI) and proton MR spectroscopy (1 H-MRS) in differentiating malignant from benign breast lesions independently or jointly, and explore the correlation between DKI-derived parameters and prognostic factors. STUDY TYPE: Prospective. SUBJECTS: Seventy-one patients with breast lesions (50 malignant, 26 benign). SEQUENCE: DKI, DWI, DCE-MRI, and 1 H-MRS were performed at 3.0T. ASSESSMENT: Mean kurtosis (MK), mean diffusivity (MD), apparent diffusion coefficient (ADC), BI-RADS category, and choline peaks were analyzed by two experienced radiologists. STATISTICAL TESTS: Student's t-test was used for continuous variables; receiver operating characteristic (ROC) analysis for assessing the diagnostic accuracy of imaging parameters; Spearman or Pearson correlations for assessing the associations between imaging parameters and prognostic factors. RESULTS: MK exhibited higher area under the curves (AUCs) for differentiating malignant from benign lesions than did MD, ADC, DCE, and tCho (0.979 vs. 0.928, 0.911, 0.777, and 0.833, respectively, P < 0.05). MK showed a positive association with Ki-67 expression (r = 0.508) and histologic grades (r = 0.551), whereas MD and ADC were negatively correlated with Ki-67 expression (r = -0.416 and r = -0.458) and histologic grades (r = -0.411 and r = -0.319). Moreover, MK showed relatively higher AUCs compared with MD and ADC in detecting breast cancers with lymph nodal involvement, histologic grades, and Ki-67 expression. DATA CONCLUSION: MK has higher diagnostic accuracy compared with ADC, DCE, and tCho regarding detection of breast cancer. Moreover, DKI shows promise as a quantitative imaging technique for characterizing breast lesions, highlighting the potential utility of MK as a promising imaging marker for predicting tumor aggressiveness. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:845-856.