Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Nomogram Update to Predict the High Genomic Risk Breast Cancer by Different Races.

PURPOSE: To develop a nomogram to predict the high-risk recurrence score (RS) and to customize the nomogram for different races in early-stage hormone receptor (HoR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer. METHODS: Patients diagnosed between 2010 and 2015 were included from the surveillance, epidemiology, and end results oncotype DX database. The nomogram was assessed with a receiver operating characteristic curve to measure the area under the curve (AUC) with a 95% confidence interval (95% CI). The nomogram was developed and internally validated for discrimination and calibration, and then validated in different races. RESULTS: A total of 48,464 patients were included and randomly assigned to the training cohort (n = 36370, 75.0%) and validation cohort (n = 12,094, 25.0%). Patients in the training cohort were identified to develop the nomogram, including 32,683 (89.9%) White women, 3135 (8.6%) Black women, and 552 (1.5%) Chinese women. Five independent predictive factors for high-risk RS were included to develop the nomogram, including tumor grade, progesterone receptor status, histological subtype, race, and tumor stage. The AUC was 0.696 (95% CI, 0.682-0.710) in the training cohort and 0.700 (95% CI, 0.676-0.724) in the validation cohort. There was no significant difference between the training cohort and the validation cohort. When validating the nomogram classified by race, the AUC was 0.694 (95% CI, 0.682-0.706) for the White cohort, 0.708 (95% CI, 0.673-0.743) for the Black cohort, and 0.653 (95% CI, 0.565-0.741) for the Chinese cohort. CONCLUSION: The developed nomogram for predicting high-risk RS is available for different races in patients with HoR+/HER2- breast cancer, which could be used as qualified surrogates before ordering the 21-gene RS testing.

CircNCOR1 regulates breast cancer radiotherapy efficacy by regulating CDK2 via hsa-miR-638 binding.

BACKGROUND: Despite aggressive local and regional therapy, triple-negative breast cancer (TNBC) is characterized by an increased risk of locoregional recurrence. RNA-sequencing data has identified a large number of circRNAs in primary breast cancers, but the role of specific circRNAs in regulating the radiosensitivity of TNBC is not fully understood. This research aimed to investigate the function of circNCOR1 in the radiosensitivity of TNBC. METHODS: CircRNA high-throughput sequencing was conducted on two breast cancer MDA-MB-231 and BT549 cell lines after 6 Gy radiation. The relationship between circNCOR1, hsa-miR-638, and CDK2 was determined by RNA immunoprecipitation (RIP), FISH and luciferase assays. The proliferation and apoptosis of breast cancer cells were measured by CCK8, flow cytometry, colony formation assays, and western blot. RESULTS: Differential expression of circRNAs was closely related to the proliferation of breast cancer cells after irradiation. Overexpression of circNCOR1 facilitated the proliferation of MDA-MB-231 and BT549 cells and impaired the radiosensitivity of breast cancer cells. Additionally, circNCOR1 acted as a sponge for hsa-miR-638 to regulate the downstream target protein CDK2. Overexpression of hsa-miR-638 promoted apoptosis of breast cancer cells, while overexpression of CDK2 alleviated apoptosis and increased proliferation and clonogenicity. In vivo, overexpression of circNCOR1 partially reversed radiation-induced loosening of tumor structures and enhanced tumor cell proliferation. CONCLUSION: Our results demonstrated that circNCOR1 bounds to hsa-miR-638 and targets CDK2, thereby regulating the radiosensitivity of TNBC.

Impact of the 21-gene expression assay on treatment decisions and clinical outcomes in breast cancer with one to three positive lymph nodes.

Background: To assess the practice patterns of the recurrence score (RS) based on the 21-gene expression assay on adjuvant chemotherapy recommendations and survival outcomes in estrogen receptor-positive (ER+)/HER2- breast cancer (BC) with one to three positive lymph nodes (N1). Methods: We included patients with T1-2N1M0 and ER+/HER2- BC diagnosed between 2010 and 2015 in the Surveillance, Epidemiology, and End Results Oncotype DX Database. Breast cancer-specific survival (BCSS) and overall survival (OS) were assessed. Results: We included 35,137 patients in this study. There were 21.2% of patients who had RS testing in 2010, which was significantly increased to 36.8% in 2015 (P < 0.001). Performance of the 21-gene testing was associated with older age, lower tumor grade, T1 stage, lower number of positive lymph nodes, and progesterone receptor-positive disease (all P < 0.05). In those without 21-gene testing, age was the main factor significantly related to the receipt of chemotherapy, whereas RS was the main factor significantly related to chemotherapy receipt in those with 21-gene testing. The probability of chemotherapy receipt in those without 21-gene testing was 64.1% and was decreased to 30.8% in those with 21-gene testing. On multivariate prognostic analysis, the performance of 21-gene testing was associated with better BCSS (P < 0.001) and OS (P < 0.001) compared with those without 21-gene testing. Similar results were found after propensity score matching. Conclusions: The 21-gene expression assay is frequently and increasingly used for chemotherapy decision-making in ER+/HER2- BC with N1 disease. Performance of the 21-gene testing is associated with improved survival outcomes. Our study supports the routine use of 21-gene testing in the clinical practice of this population.

The addition of radiotherapy to breast-conserving surgery improves survival for elderly patients with early breast cancer.

Purpose: To evaluate whether adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) was associated with better survival among elderly (≥70 years) breast cancer patients with T1-2N0 and estrogen receptor (ER) positive disease. Methods: We included patients who met the inclusion criteria between 2010 and 2014 from the Surveillance, Epidemiology, and End Results program. Patients were subdivided into three groups based on surgery and RT: BCS alone, BCS plus RT, and refusal of RT. The primary outcomes were breast cancer-specific survival (BCSS) and overall survival (OS). Chi-squared tests, Kaplan-Meier method, and Multivariate Cox regression analysis were used for statistical analysis. Propensity score matching (PSM) was performed to minimize the potential selection bias. Results: A total of 26586 patients were included in this analysis. The median follow-up was 66 months. Of these patients, 15591 (58.6%) patients received RT, RT was recommended but not performed due to patient refusal for 1270 (4.8%) patients, and RT was not recommended for 9725 (36.6%) patients. The 5-year BCSS was 98.3% for patients receiving RT, 97.1% for patients refusal of RT, and 96.4% for patients not recommended RT (P<0.001). The 5-year OS was 88.6% for patients receiving RT, 77.6% for patients who refused RT, and 72.1% for patients not recommended RT (P<0.001). Multivariate Cox regression analyses showed that patients who received adjuvant RT after BCS had significantly better BCSS (hazard ratio [HR] 0.523, 95%confidence interval [CI] 0.447-0.612, P<0.001) and OS (HR 0.589, 95%CI 0.558-0.622, P<0.001) compared to those without RT. A total of 7721 pairs of patients were matched successfully between those with and without RT using PSM. The results also showed that patients who received RT after BCS had significantly better BCSS (HR 562, 95%CI 0.467-0.676, P<0.001) and OS (HR 0.612, 95%CI 0.0.575-0.652, P<0.001) compared to those without RT. Conclusions: These data suggest that individual counseling is important for treatment decision-making in elderly breast cancer patients with T1-2N0 and ER-positive disease. Given the relatively lower toxicity of modern RT techniques, adjuvant RT should be recommended in patients with high life expectancy.

The Predictive Effect of the 8th AJCC Pathological Prognostic Staging on the Benefit of Postmastectomy Radiotherapy in N2/N3 Breast Cancer.

Background: The role of the 8th American Joint Committee on Cancer (AJCC) pathological prognostic staging (PPS) on treatment-decision making of breast cancer (BC) remains unclear. This study aimed to investigate the predictive effect of the 8th AJCC PPS on the benefit of postmastectomy radiotherapy (PMRT) in N2/N3 BC. Methods: We included women with stage N2/3 BC diagnosed between 2010 and 2018 from the Surveillance, Epidemiology, and End Results database. The effect of PMRT on breast cancer-specific survival (BCSS) was evaluated using the multivariate Cox proportional-hazards models. Results: A total of 13,445 patients were identified, including 10,547 (78.4%) patients treated with PMRT. All patients had reassigned stages based on the 8th AJCC PPS. There were 7102 patients (52.8%) that had stage changed, including 1160 patients (8.6%) were upstaged and 5942 patients (44.2%) were downstaged from the 7th AJCC anatomical staging (AS) to the 8th AJCC PPS. Regarding the 7th AJCC AS, 7603 (56.5%), 948 (7.1%), and 4895 (36.4%) were stage IIIA, IIIB, and IIIC diseases, respectively. Using the 8th AJCC PPS, 3525 (26.2%), 460 (3.4%), 1335 (9.9%), 3457 (25.7%), 2169 (19.1%), and 2100 (15.6%) patients were restaged as IB, IIA, IIB, IIIA, IIIB, and IIIC diseases, respectively. The PPS displayed increased prognostic accuracy and improved model fit with respect to BCSS compared to the 7th AS (C-index, 0.731 vs 0.605, P < 0.001; Akaike Information Criterion, 42141 vs 43118). Regarding the AS, the receipt of PMRT was associated with a better BCSS in those with stage IIIA (P = 0.004), IIIB (P = 0.003), and IIIC (P < 0.001) diseases. Using the PPS, the receipt of PMRT was not associated with a better BCSS among patients with stage IB (P = 0.446), IIA (P = 0.140), and IIB (P = 0.248) disease, while the receipt of PMRT was associated with a better BCSS for those with stage IIIA (P = 0.009), IIIB (P < 0.001), and IIIC (P < 0.001) disease. Conclusion: The 8th AJCC staging provides superior risk stratification and a better tool to predict the benefit of PMRT in N2/3 BC.

Impact of AJCC prognostic staging on prognosis and postmastectomy radiotherapy decision-making in hormone receptor-positive and HER2-positive breast cancer.

BACKGROUND: The role of postmastectomy radiotherapy (PMRT) in patients with node-positive hormone receptor-positive (HoR) and HER2-positive breast cancer (BC) regarding AJCC pathological prognostic staging (PPS) has not been fully determined. This study aimed to validate PPS in patients with node-positive HoR+/HER2+ BC after mastectomy and to investigate the role of PPS on PMRT decision-making in this patient subset. METHODS: Patients diagnosed with BC from the Surveillance, Epidemiology, and End Results database were included. Patients were classified based on the anatomical staging (AS) and PPS. Breast cancer-specific survival (BCSS) was calculated. RESULTS: In total, 6862 patients were included: 4306 (62.8 per cent) patients received PMRT and 2556 (37.2 per cent) patients had not. Compared to AS, PPS downstaged 5260 patients (76.7 per cent) and no patients were upstaged. The C-index was similar between PPS and AS (0.690 versus 0.682; P = 0.346). Regarding AS, patients who received PMRT had significantly better BCSS than those who had not in stage IIIA (P = 0.017) and stage IIIC (P < 0.001) disease, but not in stage IB (P = 0.675), IIA (P = 0.677), IIB (P = 0.100), and IIIB (P = 0.747) disease. Regarding PPS, patients who received PMRT had significantly better BCSS than those who had not in stage IIIA (P = 0.038) and stage IIIB (P = 0.017) disease, but not in stage IA (P = 0.336), IB (P = 0.893), IIA (P = 0.815), and IIB (P = 0.120) disease. PPS might allow approximately 1390 stage III patients (45.0 per cent) in the AS criterion to avoid PMRT. CONCLUSION: PPS does not provide better risk discriminatory ability in predicting prognosis than AS in patients with node-positive HoR+/HER2+ BC after mastectomy. However, PPS is valuable in providing prognostic counselling to patients and may also guide PMRT decision-making.

Prognostic significance of the skeletal muscle index and systemic inflammatory index in patients with lymph node-positive breast cancer after radical mastectomy.

BACKGROUND: The role of skeletal muscle index (SMI) and systemic inflammation index (SII) for patients with lymph node-positive breast cancer remain controversial. This retrospective study aims to evaluate the individual and synergistic value of SMI and SII in outcomes prediction in this population. METHODS: Lymph node-positive breast cancer patients who received mastectomy between January 2011 and February 2013 were included in this retrospective study. We used abdominal computed tomography (CT) to measure skeletal muscle mass at the third lumbar (L3) level. The optimal cut-off values of SMI and SII were determined through maximizing the Youden index on the receiver operating characteristic (ROC) curves. Kaplan-Meier method was used to assess the correlation between SMI, SII, and overall survival (OS). The prognostic value of SMI and SII were analyzed with the multivariable Cox proportional hazards model. RESULTS: Of 97 patients included in our study (mean age: 46 [range: 27-73] years; median follow-up: 62.5 months), 71 had low SMI (sarcopenia), 59 had low SII, and 56 had low SMI + SII. Kaplan-Meier survival curves showed that both high SMI (P = 0.021, 5-year OS: 84.0% vs. 94.1%) and high SII (P = 0.043, 5-year OS: 81.0% vs. 97.3%) were associated with worse OS. Additionally, patients with either low SMI or low SII had significantly better OS (P = 0.0059, 5-year OS: 100.0% vs. 84.6%) than those with high SMI + SII. Multivariable analysis confirmed the predictive values of high SMI (P = 0.024, hazard ratio [HR]: 9.87) and high SII (P = 0.048, HR: 6.87) for poor OS. Moreover, high SMI + SII was significantly associated with poor survival (P = 0.016, HR: 16.36). CONCLUSIONS: In this retrospective analysis, both SMI and SII independently predicted the prognosis of patients with lymph node-positive breast cancer. SMI + SII might be a stronger prognostic factor than either alone based on our findings, but should be further verified in a larger study.

A case of giant Ewing's sarcoma (EES)/primitive neuroectodermal tumor (PNET) of the cervicothoracic junction in children with incomplete paralysis of both lower limbs: Case report and literature review.

Background: Extraosseous Ewing's sarcoma/primary neuroectodermal tumor (EES/PNET) is a rare, malignant, small round blue cell tumor, which usually involves the larynx, kidneys, and esophagus. The most common metastatic sites are lung and bone. The incidence of epidural EES/PNET was 0.9%, and a detailed search of the PubMed literature found only 7 case reports of epidural ESS/PNET at the cervicothoracic junction in children. Case description: We report a case of epidural ESS/PNET at the cervicothoracic junction in a child with chest and back pain as the first symptom, which worsened after half a year and developed incomplete paralysis of both lower extremities and urinary incontinence. She underwent emergency surgery, chemotherapy and radiotherapy, and died of lung metastases 8 months after surgery. Conclusion: Primary epidural tumors are mostly benign, such as spinal meningiomas and neuromas. Contrary to what has been previously thought, we report a case of malignant epidural EES/PNET at the cervicothoracic junction without bone destruction; The rarity of epidural EES/PNET at the cervicothoracic junction in children has led to a lack of data, particularly on prognostic factors and recurrence patterns. Due to the difficulty of early diagnosis and high mortality, spine surgeons must explore and increase their awareness of this disease.

Flexible boron nitride-based memristor for in situ digital and analogue neuromorphic computing applications.

The data processing efficiency of traditional computers is suffering from the intrinsic limitation of physically separated processing and memory units. Logic-in-memory and brain-inspired neuromorphic computing are promising in-memory computing paradigms for improving the computing efficiency and avoiding high power consumption caused by extra data movement. However, memristors that can conduct digital memcomputing and neuromorphic computing simultaneously are limited by the difference in the information form between digital data and analogue data. In order to solve this problem, this paper proposes a flexible low-dimensional memristor based on boron nitride (BN), which has ultralow-power non-volatile memory characteristic, reliable digital memcomputing capabilities, and integrated ultrafast neuromorphic computing capabilities in a single in situ computing system. The logic-in-memory basis, including FALSE, material implication (IMP), and NAND, are implemented successfully. The power consumption of the proposed memristor per synaptic event (198 fJ) can be as low as biology (fJ level) and the response time (1 µs) of the neuromorphic computing is four orders of magnitude shorter than that of the human brain (10 ms), paving the way for wearable ultrahigh efficient next-generation in-memory computing architectures.

CMOS back-end compatible memristors for in situ digital and neuromorphic computing applications.

In-memory logic calculations and brain-inspired artificial synaptic neuromorphic computing are expected to solve the limitations of the traditional von Neumann computing architecture. The data processing efficiency of the traditional von Neumann architecture is inherently limited by its physically separated processing and storage units, and thus data transmission besides calculation leads to a limited calculation speed and additional high-power consumption. In addition, traditional digital logic calculations and analog calculations have greater limitations in conversion. Herein, we report a flexible two-terminal memristor based on SiCO:H, which is a porous low-k back-end complementary metal-oxide-semiconductor (CMOS)-compatible material. Due to its low operating voltage (200 mV) and fast response speed (100 ns), it could perform digital memory calculation and neuromorphic calculation simultaneously. The memristor could realize a transition from short-term to long-term plasticity in the process of enhancement and inhibition during neuromorphic calculation, with high biological reality. In digital logic calculations, IMP-based and MAGIC-based logic calculations were verified. In neuromorphic computing, an Ag ion-based conductive filament was introduced. The relationship between the temporal dynamics of the conductance evolution and the diffusive dynamics of the Ag active metal could be modulated by the external programming electric field strength. The synapses and neuron dynamics in biology were faithfully simulated, realizing a transition from short-term to long-term plasticity in the process of enhancement and inhibition, which has high compatibility and scalability, proposing a novel solution for the next generation of computer architectures.

Triple-negative breast cancer outcomes: Does AJCC 8th staging improve chemotherapy decision-making.

PURPOSE: To investigate the effect of the 8th American Joint Committee on Cancer (AJCC) pathological prognostic staging on chemotherapy decision-making for triple-negative breast cancer (TNBC) patients with T1-2N0M0 disease. METHODS: Patients diagnosed with T1-2N0M0 TNBC were retrieved from the Surveillance, Epidemiology, and End Results program. Statistical methods including Kaplan-Meier survival curve, receiver operating characteristics curve, and Cox proportional hazard model. RESULTS: We identified 12,156 patients, including 9371 (77.1%) patients who received chemotherapy. Overall, 57.4% of patients (n = 6975) were upstaged after being reassigned by the 8th AJCC staging. However, the 8th staging of AJCC did not have a greater prognostic value compared to the 7th staging (P = 0.064). The receipt of chemotherapy significantly improved the breast cancer-specific survival for stage T1c and T2 tumors (P < 0.001), but not for stage T1a (P = 0.188) and T1b (P = 0.376) tumors. Using AJCC 8th staging, chemotherapy benefit was only found in stage IIA patients (P = 0.002), but not for stage IA (P = 0.653) and IB (P = 0.492) patients. There were 9564 patients with stage T1c and T2 diseases and 4979 patients with 8th AJCC stage IIA disease. Therefore, approximately half of patients (47.9%, n = 4585) may be safe to omit chemotherapy using the AJCC 8th staging compared to the current chemotherapy recommendation for T1-2N0M0 TNBC. CONCLUSION: The 8th AJCC staging system did not demonstrate the superior discriminatory ability of prognostic stratification than the 7th AJCC staging system in T1-2N0M0 TNBC. However, this new AJCC staging could more accurately predict the chemotherapy benefit, thereby enabling more patients to avoid unnecessary chemotherapy.

Identification of MEG8/miR-378d/SOBP axis as a novel regulatory network and associated with immune infiltrates in ovarian carcinoma by integrated bioinformatics analysis.

BACKGROUND: To investigate the potential molecular mechanism of ovarian cancer (OC) evolution and immunological correlation using the integrated bioinformatics analysis. METHODS: Data from the Gene Expression Omnibus was used to gain differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway analysis were completed by utilizing the Database for Annotation, Visualization, and Integrated Discovery. After multiple validations via The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) projects, the Human Protein Atlas, Kaplan-Meier (KM) plotter, and immune logical relationships of the key gene SOBP were evaluated based on Tumor Immune Estimation Resource, and Gene Set Enrichment Analysis (GSEA) software. Finally, the lncRNAs-miRNAs-mRNAs subnetwork was predicted by starBase, TargetScan, miRBD, and LncBase, individually. Correlation of expression and prognosis for mRNAs, miRNAs, and lncRNAs were confirmed by TCGA, Gene Expression Profiling Interactive Analysis 2 (GEPIA 2), starBase, and KM. RESULTS: A total of 192 shared DEGs were discovered from the four data sets, including 125 upregulated and 67 downregulated genes. Functional enrichment analysis presented that they were mainly enriched in cartilage development, pathway in PI3 K-Akt signaling pathway. Lower expression of SOBP was the independent prognostic factor for inferior prognosis in OC patients. The downregulation of SOBP enhanced the infiltration levels of B cells, CD8+ T cells, Macrophage, Neutrophil, and Dendritic cells. GSEA also disclosed low SOBP showed a significantly associated with the activation of various immune-related pathways. Finally, we first reported that the MEG8/miR-378d/SOBP axis was linked to the development and prognosis of OC through regulating the cytokines pathway. CONCLUSIONS: Our study establishes a novel MEG8/miR-378d/SOBP axis in the development and prognosis of OC, and the triple subnetwork probably affects the progression of the OC by regulating the cytokines pathway.

Additional radiotherapy to breast-conserving surgery is an optional treatment for de novo stage IV breast cancer: A population-based analysis.

BACKGROUND: We aim to assess the value of locoregional treatment (LRT) including breast-conserving surgery (BCS), mastectomy (MAST), and radiotherapy (RT) in patients with de novo stage IV breast cancer. METHODS: Patients with de novo stage IV breast cancer were retrospectively identified from the Surveillance, Epidemiology, and End Results database between 2004 and 2014. Kaplan-Meier analysis, log-rank tests, propensity score matching (PSM), and the multivariate Cox proportional model were used for statistical analysis. RESULTS: A total of 5798 patients were identified including 849 (14.6%), 763 (13.2%), 2338 (40.3%), and 1848 (31.9%) who received BCS alone, BCS+RT, MAST alone, and MAST+RT, respectively. The proportions of receiving BCS decreased from 35.9% in 2004 to 26.2% in 2014 (p = 0.002), and the probability of patients receiving MAST increased from 64.1% in 2004 to 74.8% in 2014 (p = 0.002). Before PSM, there was a significant difference in breast cancer-specific survival (BCSS) among the treatment arms. Patients who received RT had better BCSS, the 5-year BCSS was 40.5%, 52.3%, 41.5%, and 47.7% in patients treated with BCS alone, BCS+RT, MAST alone, and MAST+RT, respectively (p < 0.001). In the PSM cohort, patients treated with BCS alone had lower 5-year BCSS compared to those treated with BCS+RT (43.9% and 52.1%, p = 0.002). However, there were comparable 5-year BCSS between BCS+RT and MAST alone groups (51.3% and 50.1%, p = 0.872), and BCS+RT and MAST+RT cohorts (51.5% and 55.7%, p = 0.333). Similar results were confirmed in multivariate analysis. CONCLUSIONS: Postoperative RT improves BCSS in patients with de novo stage IV breast cancer, and BCS+RT shows a non-inferior outcome compared to MAST+RT. BCS+RT may be the optimal local management of de novo stage IV breast cancer.

The prognostic and predictive value of the 8th American Joint Committee on Cancer (AJCC) staging system among early breast cancer patients aged <50 years.

BACKGROUND: This study respectively analyzed the prognostic value and the role in treatment decision-making [breast-conserving surgery (BCS) + radiotherapy (RT) or mastectomy (MAST)] of the 8th American Joint Committee on Cancer (AJCC) pathological prognostic staging system compared with the 7th AJCC anatomical staging system among early breast cancer patients aged <50 years. METHODS: Patients with T1-2N0M0 breast cancer aged <50 years were extracted from the Surveillance, Epidemiology, and End Results database between 2010 and 2014. Breast cancer-specific survival (BCSS) was used as the primary endpoint. Chi-squared test, receiver operating characteristics analysis, Kaplan-Meier method, and multivariate Cox proportional models were used to conduct statistical analysis. RESULTS: A total of 22,640 female patients were identified, and 24.4% of them reallocated to new stage groups from the 7th to the 8th AJCC staging. Among them, 46.2% (n=10,450) and 53.8% (n=12,190) of patients received BCS + RT and MAST, respectively. The 8th AJCC staging system was an independent prognostic factor for BCSS. Patients treated with BCS + RT had better BCSS compared to those treated with MAST (P<0.001). According to the 8th AJCC staging, BCS + RT could improve 5-year BCSS compared with MAST in patients with stage IA (P=0.006) and stage IB (P=0.001) diseases, while comparable BCSS was found between the two treatment arms in patients' stage IIA disease (P=0.366). Multivariate analyses replicated similar findings after stratification by the 8th AJCC stages. CONCLUSIONS: In patients with T1-2N0 breast cancer and aged <50 years, the 8th AJCC pathological staging system provides accurate prognostic information than the 7th anatomical staging. BCS + RT is the optimal local management for stage IA and IB diseases, while it is the optional management in stage IIA disease according to the 8th AJCC staging.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

Aggressive Local Treatment Improves Survival in Stage IV Breast Cancer With Synchronous Metastasis.

INTRODUCTION: To investigate the effect of local treatment strategy on survival outcome in de novo stage IV breast cancer patients who received chemotherapy. METHODS: We identified stage IV breast cancers that presented with synchronous metastasis from the Surveillance, Epidemiology, and End Results database. Binomial logistic regression, Kaplan-Meier survival curves, propensity score matching (PSM), and multivariate Cox regression model were used for statistical analyses. RESULTS: We identified 5,374 patients in total, including 2,319 (43.2%), 2,137 (39.8%), and 918 (17.1%) patients who received surgery alone, surgery+radiotherapy, and radiotherapy alone, respectively. The probability of patients receiving surgery alone decreased over time, and the probability of patients receiving radiotherapy alone increased over time. However, no significant difference was observed in the probability of patients receiving postoperative radiotherapy (P = 0.291). The 3-year breast cancer-specific survival (BCSS) in patients treated with surgery alone, radiotherapy alone, and surgery+radiotherapy was 57.1, 35.9, and 63.9%, respectively (P < 0.001). The local treatment strategy was the independent prognostic factor related to BCSS. Using surgery alone as the reference, radiotherapy alone was related to lower BCSS (P < 0.001), while additional radiotherapy after surgery improved BCSS (P < 0.001). Similar results were observed using PSM. CONCLUSIONS: Compared to radiotherapy alone, surgery to the primary site may confer a survival benefit in stage IV breast cancer with synchronous metastasis, and additional postoperative radiotherapy further improves outcome after primary tumor removal. Local treatment can only be an option in highly selected patients with de novo stage IV disease in the treatment guidelines. More prospective studies are needed to investigate the role of local management for this patient subset.

The longitudinal risk of mortality between invasive ductal carcinoma and metaplastic breast carcinoma.

The management of metaplastic breast carcinoma (MBC) has largely paralleled the paradigms used for invasive ductal carcinoma (IDC) in the current National Comprehensive Cancer Network guidelines of breast cancer. However, patients with IDC and MBC have been shown to have a different prognosis, and there are significant differences in risk and failure patterns after treatment. The purpose of this study was to compare breast cancer specific survival (BCSS) and hazard function between IDC and MBC. We included patients from the Surveillance, Epidemiology, and End Results program with stage I-III IDC and MBC between 2000 and 2012. Statistical analyses were including chi-square analysis, life-table methods, multivariate Cox proportional hazards models, and propensity score matching (PSM). We identified 294,719 patients; 293,199 patients with IDC and 1520 patients with MBC. Multivariate analyses showed that the MBC subtype had significantly lower BCSS than the IDC subtype before and after PSM (p < 0.001). There were significant differences in the hazard curve between IDC and MBC. The hazard curve for breast cancer mortality in the IDC cohort peaked at 3 years (2%), and then changed to a slowly decreasing plateau after prolonged follow up. However, the hazard curve for breast cancer mortality in the MBC cohort peaked at 2 years (7%), then declined sharply between 3 and 6 years, and changed to a low death rate after a follow-up time exceeding 6 years. Subgroup analyses revealed that the hazard curves significantly differed between IDC and MBC after stratifying by tumor stage and hormone receptor status. Our study suggests that patients with MBC should receive more effective systemic agents and intensive follow-up because of their significantly augmented risk of death compared to IDC patients.