"Moderate" adjuvant chemotherapy-induced leukopenia is beneficial for survival of patients with early breast cancer: a retrospective study.

BACKGROUND: The association between chemotherapy-induced leukopenia (CIL) and survival for patients with early breast cancer (EBC) is not known. We investigated the relationship between different grades of CIL and survival in patients with EBC receiving adjuvant chemotherapy. METHODS: A total of 442 patients with EBC receiving a regimen containing an anthracycline (A) and taxane (T) were included into our analysis. Survival analyses were undertaken using Kaplan-Meier curves. The P-value was calculated using the log rank test. Subgroup analysis was conducted to investigate the correlation of CIL grade and survival based on the clinicopathological characteristics of patients. Afterwards, univariate and multivariate analyses screened out independent prognostic factors to construct a prognostic model, the robustness of which was verified. RESULTS: Patients with EBC who experienced grade 2-4 ("moderate" and "severe") CIL were associated with longer overall survival (OS) than those with grade 0-1 (mild) CIL (P = 0.021). Compared with patients with mild CIL, OS was longer in patients with severe CIL (P = 0.029). Patients who suffered from moderate CIL tended to have longer OS than those with mild CIL (P = 0.082). Nevertheless, there was no distinguishable difference in OS between moderate- or severe-CIL groups. Subgroup analysis revealed that patients with moderate CIL had longer OS than those with mild CIL among patients who were premenstrual, or with human epidermal growth factor receptor 2-positive (HER2+), > 3 lymph nodes with metastases, a tumor diameter > 5 cm. A prognostic model based on menstrual status, N stage, and CIL grade showed satisfactory robustness. CONCLUSION: The grade of CIL was strongly associated with the prognosis among patients with EBC who received a regimen containing both anthracyclines and taxanes. Patients with a "moderate" CIL grade tended to have better survival outcomes.

The efficacy of human epidermal growth factor receptor 2 (HER2) blockade switching mode in refractory patients with HER2-positive metastatic breast cancer: a phase II, multicenter, single-arm study (SYSUCC-005).

BACKGROUND: Despite significant survival improvement in human epidermal growth factor receptor 2 (HER2) blockade for HER2-positive breast cancer, resistance to anti-HER2 remains inevitable. Subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable with limited efficacy when other anti-HER2 treatment is unavailable. This single-arm, phase II study (SYSUCC-005) aimed to explore the efficacy of switching mode for HER2-positive refractory metastatic breast cancer. METHODS: Patients with HER2-positive metastatic breast cancer rapidly progressing during pre-trastuzumab from six hospitals in China were designed to switch to lapatinib 1,250 mg orally once per day continuously plus capecitabine (1,000 mg/m2 orally twice per day on days 1-14) or vinorelbine (25 mg/m2 intravenously once per day on days 1 and 8) of each 21-day cycle. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 5, 2015 and May 31, 2020, 159 patients were eligible in this study. The median follow-up was 33.1 months, a median PFS of 8.5 months was achieved. Brain metastases (hazard ratio [HR] = 1.582, 95% confidence interval [CI] 1.019- 2.453, P = 0.041) and ≥ 2 metastatic sites (HR = 1.679, 95% CI 1.151-2.450, P = 0.007) were independent prognostic factors for PFS. The most common grade ≥ 3 adverse events were diarrhea (3.8%) and hand-foot syndrome (9.4%). CONCLUSION: The switching mode showed predominant efficacy, which might be a prior therapeutic option over continuing mode in subsequent anti-HER2 therapy for patients with HER2-positive refractory metastatic breast cancer. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov ( NCT02362958 ) on 13/02/2015.

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.

Efficacy of Moxifloxacin plus Treatment of Physician's Choice in Patients with Metastatic Breast Cancer.

LESSONS LEARNED: Moxifloxacin plus continuation of the previous treatment of physician's choice shows promising efficacy in patients with metastatic breast cancer. The addition of moxifloxacin shows well-tolerated toxicities. BACKGROUND: Recent studies have confirmed bacterial infection as an important contributor in cancer. Elimination of tumor-associated microbes may lead to a reduction in tumors and improved survival. Moxifloxacin is an orally administrated fourth-generation quinolone with broad-spectrum coverage against tumor-associated bacteria. METHODS: In this study, we assessed the efficacy and safety of moxifloxacin in combination with treatment of physician's choice (TPC) in patients with metastatic breast cancer (MBC). In this single-arm, phase II study, we recruited 30 patients with MBC who had a trend toward disease progression (stable disease [SD] with increased tumor size) during TPC before enrollment at Sun Yat-sen University Cancer Center between January 1 and July 30, 2018. Eligible patients were given moxifloxacin once daily at a dose of 400 mg from days 1 to 7 of a 28-day cycle, in addition to continuing to receive the therapy previously selected by their physicians. Tumor response was determined according to RECIST (version 1.1). Progression-free survival (PFS) was calculated using the Kaplan-Meier method. RESULTS: The concomitant use of moxifloxacin and previous TPC yielded a median PFS of 6.6 months (95% confidence interval [CI]: 4.0-9.1) and a 1-year PFS of 25.9% (95% CI: 10.0%-41.9%). Objective responses were achieved in seven (23.3%, 95% CI: 7.3%-39.4%) patients. The clinical benefit rate was 46.7% (95% CI: 27.7%-65.6%). No grade 4 adverse events (AEs) and four grade 3 AEs were observed, none of which were considered to have definite relation to moxifloxacin. CONCLUSION: The combination of moxifloxacin with previous TPC shows promising efficacy and well-tolerated toxicities in patients with MBC.

Effect of rituximab on adult Burkitt's lymphoma: a systematic review and meta-analysis.

The treatment of Burkitt's lymphoma with rituximab is controversial, and studies that compared the efficacy of chemotherapy alone with chemotherapy plus rituximab have not been powered to test differences in overall survival (OS). We conducted this systematic review and meta-analysis to identify the value of rituximab for the treatment of BL to guide treatment decisions. Based on the PubMed, Web of Science, and Cochrane library online electronic databases, all retrospective and randomized clinical trial studies that compared the aforementioned two regimens were included. The pooled hazard ratio and odds ratio were analyzed using Review Manager 5.3. The primary outcome was the 2-year OS. A total of 581 publications were identified using a predetermined search strategy. One randomized controlled trial (RCT) and five retrospective studies, which included 646 cases (351 cases for the chemotherapy with rituximab group and 295 cases for the chemotherapy alone group), fulfilled the selection criteria and were included in the meta-analysis. The chemotherapy with rituximab group was associated with a higher 2-year OS (hazard ratio 0.62, 95 % CI 0.45-0.85, P = 0.003), 2-year progression-free survival (hazard ratio 0.46, 95 % CI 0.43-0.50, P < 0. 001), and complete remission rate (odds ratios 3.26, 95 % CI 1.22-8.66, P = 0.02). In addition, the treatment-related mortality did not significantly differ between the two treatment regimens (odds ratio 1.16, 95 % CI 0.55-2.45, P = 0.69). The meta-analysis indicates that the addition of rituximab to the treatment regimen for Burkitt's lymphoma may be associated with a significant survival benefit and did not increase the mortality compared with chemotherapy alone.

Radiotherapy and PGEMOX/GELOX regimen improved prognosis in elderly patients with early-stage extranodal NK/T-cell lymphoma.

The optimal treatment strategy for elderly patients with natural killer/T-cell lymphoma (NKTCL) remains to be established. A total of 63 elderly patients with newly diagnosed NKTCL were retrospectively reviewed. Among the patients with stage I-II disease, 58.3 % received radiotherapy (RT) ± chemotherapy, and 41.7 % received chemotherapy alone. Compared with chemotherapy alone, RT ± chemotherapy elicited a significantly higher overall response rate (ORR) (100 vs. 57.1 %, P < 0.001) and substantially prolonged 5-year overall survival (OS) (55.3 vs. 18.0 %, P < 0.001) in patients with stage I-II disease. Compared with other chemotherapeutic regimens, pegaspargase plus gemcitabine and oxaliplatin (PGEMOX)/L-asparaginase plus gemcitabine and oxaliplatin (GELOX) was associated with a significantly higher ORR (92.9 vs. 51.6 %, P = 0.009) and a significantly improved 5-year OS (78.6 vs. 23.9 %, P = 0.010) in patients with stage I-II disease. Nine patients with stage I-II disease who were treated with PGEMOX/GELOX followed by RT had an encouraging outcome (5-year OS 100 %, 5-year progression-free survival (PFS) 85.7 %), which was superior to that of patients receiving other regimens followed by RT. In conclusion, RT played an important role for elderly patients with early-stage NKTCL, and the PGEMOX/GELOX regimen was superior to other regimens. The combination of them may be a promising treatment option.

The extent of local tumor invasion predicts prognosis in stage IE nasal natural killer/T-cell lymphoma: a novel T staging system for risk stratification.

A heterogeneous treatment response and prognosis exists among patients with Ann Arbor stage IE natural killer/T-cell lymphoma (NKTCL), and further risk stratification is required to identify high-risk patients. Here, we assessed the extent of local tumor invasion (LTI) in 185 patients with Ann Arbor stage IE primary nasal NKTCL and proposed a novel four-level T staging system. We found that a more advanced T stage was associated with a significantly lower rate of complete remission (CR) after chemotherapy and a marginally lower rate of CR after radiotherapy. While patients with no LTI (T1) or mild LTI (T2) presented with similar 5-year overall survival (OS; 83.6 % vs. 86.0 %, P = 0.990), those with moderately or highly advanced local disease (T3 or T4) had significantly worse survival (5-year OS was 63.3 % and 35.1 %, respectively). A more advanced T stage (T3 or T4) was an independent prognostic factor for both OS and progression-free survival (PFS) in the Cox regression model. In addition, patients with T3 or T4 disease experienced locoregional failure more frequently than those with T1 or T2 disease, and patients with T4 disease had a significantly higher risk of distant failure. Our data demonstrated that the T staging system, based on the extent of LTI, could serve as an effective clinical parameter for further risk stratification among patients with primary nasal Ann Arbor stage IE NKTCL.

Treatment outcome of patients with advanced stage natural killer/T-cell lymphoma: elucidating the effects of asparaginase and postchemotherapeutic radiotherapy.

The prognosis of advanced stage natural killer/T-cell lymphoma (NKTCL) remains relatively disappointing, and the optimal treatment strategy for this disease has yet to be discovered. Seventy-three patients with Ann Arbor stage III or IV NKTCL were retrospectively reviewed. The treatment efficacies of asparaginase-containing and asparaginase-absent chemotherapy regimens were compared, and the effects of postchemotherapeutic radiotherapy were explored. The overall response rate (ORR) of the asparaginase-containing regimens was marginally higher than that of the asparaginase-absent regimens (56.5 vs 32.6 %, P = 0.057). However, no significant difference was observed in 2-year overall survival (OS) (38.3 vs 22.7 %, P = 0.418) or 2-year progression-free survival (PFS) (25.4 vs 14.9 %, P = 0.134) between the asparaginase-containing and asparaginase-absent groups. Postchemotherapeutic radiotherapy was associated with a significantly prolonged survival (2-year OS 57.5 vs 14.5 %, P < 0.001; 2-year PFS 46.3 vs 8.4 %, P < 0.001) and was an independent predictor of both OS and PFS. Radiotherapy significantly improved the prognosis among the patients who exhibited complete or partial remission after initial chemotherapy (2-year OS 81.5 vs 40.2 %, P = 0.002; 2-year PFS 65.6 vs 23.4 %, P = 0.008) but failed to provide a significant survival advantage among those who experienced stable or progressive disease after initial chemotherapy. In conclusion, the use of asparaginase did not significantly improve survival for the treatment of patients with stage III/IV NKTCL. Postchemotherapeutic radiotherapy provided additional prognostic benefits to patients who responded well to the initial chemotherapy, which requires further validation in future prospective studies using larger sample sizes.

Expression of BAFF-R, but not BAFF, is an independent prognostic factor in diffuse large B-cell lymphoma patients treated with R-CHOP.

B-cell activating factor (BAFF) and BAFF-receptor (BAFF-R) play crucial roles in the progression of malignant B-cells. The aim of the present study was to evaluate the expression profiles and the clinical significance of BAFF and BAFF-R in diffuse large B-cell lymphoma (DLBCL). Paraffin-embedded specimens from 136 patients with newly diagnosed DLBCL, treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP), were examined for BAFF and BAFF-R expression by immunohistochemistry. BAFF and BAFF-R were expressed in 72.1 % (98/136) and 47.1 % (64/136) of the DLBCL tissues, respectively. Negative BAFF-R expression was significantly correlated with elevated serum lactate dehydrogenase (LDH) levels (P = 0.036), an International Prognostic Index (IPI) score of 2 or higher (P < 0.001), and a poor revised IPI (R-IPI) risk score (P = 0.043). The complete response rate after R-CHOP was higher in patients with positive BAFF-R expression than in those with negative BAFF-R expression (73.4 vs. 56.9 %, P = 0.045). Negative expression of BAFF-R, but not of BAFF, was significantly associated with inferior progression-free survival (PFS; P = 0.020) and overall survival (OS; P = 0.028). Only negative BAFF-R expression was correlated with inferior PFS and OS in multivariate analysis (P = 0.049 and 0.040, respectively). Taken together, our results showed that the majority and approximate one-half of patients with DLBCL were positive for BAFF and BAFF-R, respectively. Negative expression of BAFF-R, but not of BAFF, could be an independent risk factor for PFS and OS in patients with DLBCL treated with standard R-CHOP.

Screening optimal candidates with operable, early-stage triple-negative breast cancer benefitting from capecitabine maintenance: A post-hoc analysis of the SYSUCC-001 study.

BACKGROUND: To explore whether specific clinicopathological covariates are predictive for a benefit from capecitabine maintenance in early-stage triple-negative breast cancer (TNBC) in the SYSUCC-001 phase III clinical trial. METHODS: Candidate covariates included age, menstrual status, type of surgery, postoperative chemotherapy regimen, Ki-67 percentage, histologic grade, primary tumor size, lymphovascular invasion, node status, and capecitabine medication. Their nonlinear effects were modeled by restricted cubic spline. The primary endpoint was disease-free survival (DFS). A survival prediction model was constructed using Cox proportional hazards regression analysis. RESULTS: All 434 participants (306 in development cohort and 128 in validation cohort) were analyzed. The estimated 5-year DFS in development and validation cohorts were 77.8 % (95 % CI, 72.9%-82.7 %) and 78.2 % (95 % CI, 70.9%-85.5 %), respectively. Age and node status had significant nonlinear effects on DFS. The prediction model constructed using four covariates (node status, lymphovascular invasion, capecitabine maintenance, and age) demonstrated satisfactory calibration and fair discrimination ability, with C-index of 0.722 (95 % CI, 0.662-0.781) and 0.764 (95 % CI, 0.668-0.859) in development and validation cohorts, respectively. Moreover, patient classification was conducted according to their risk scores calculated using our model, in which, notable survival benefits were reported in low-risk subpopulations. An easy-to-use online calculator for predicting benefit of capecitabine maintenance was also designed. CONCLUSIONS: The evidence-based prediction model can be readily assessed at baseline, which might help decision making in clinical practice and optimize patient stratification, especially for those with low-risk, capecitabine maintenance might be a potential strategy in the early-disease setting.

Pyrotinib Combined with Vinorelbine in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Single-Arm, Prospective Study.

PURPOSE: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. MATERIALS AND METHODS: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. RESULTS: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). CONCLUSION: Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.

Pyrotinib and trastuzumab plus palbociclib and fulvestrant in HR+/HER2+ breast cancer patients with brain metastasis.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients are at a high risk of developing metastases in the brain. However, research focusing on treatment strategies for hormonal receptor positive (HR+), HER2+ BC patients with brain metastases (BM) remains limited. Thus, a multi-center, prospective trial was conducted in China. Women over the age of 18 who were naive to whole brain radiotherapy and had estrogen receptor (ER)/progesterone-receptor (PgR) positive, HER2+ BM were treated with palbociclib, fulvestrant, trastuzumab and pyrotinib, until disease progression or the development of intolerable side effects. The primary endpoint was objective response rate (ORR) in the central nervous system (CNS). This ongoing study is still recruiting participants and is registered with ClinicalTrials.gov (NCT04334330). This report presents the findings from an interim analysis. From December 4, 2020, to November 2, 2022, 15 patients were enrolled. Among the 14 patients who were evaluable for clinical response, the ORR was 35.7% (95% CI: 12.8-64.9%), with a CNS-ORR of 28.6% (95% CI: 8.4-58.1%). The median follow-up period was 6.3 months (range, 2.1-14.3 months), during which the median progression-free survival (PFS) was 10.6 months (95% CI: 4.3-16.9 months), and the median time to CNS progression was 8.5 months (95% CI: 5.9-11.1 months). The most common adverse event was diarrhea (93%), with 33% having grade 3 and 6.7% having grade 4. The study suggests that the combination of palbociclib, trastuzumab, pyrotinib and fulvestrant offers a promising chemo-free treatment strategy for HR+, HER2+ BC patients with BM.

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.

NAD induces astrocyte calcium flux and cell death by ART2 and P2X7 pathway.

Mono-ADP-ribosyltransferase 2 (ART2) is found in mouse T cells and has mediated NAD-induced cell death (NICD) alongside the P2X7 pathway. We determined whether ART2 was expressed in mouse brain astrocytes and the possible function of the NAD-ART2-P2X7 pathway in astrocytes. Our results demonstrate that ART2 existed both in cultured mouse astrocytes and mouse brain slices. Exposure of astrocytes to the ART2 substrate, NAD, induced calcium elevation, which was blocked by ART2 and P2X7 inhibitors. ATP and NAD had an additive effect on calcium elevation. NICD in low-calcium conditions was blocked by ART2 and P2X7 inhibitors. The harmful effect of ATP on astrocytes was inhibited by P2X7 and ART2 inhibitors, meaning that endogenous NAD release may occur. Both NICD function and oxygen-glucose deprivation injury in mouse brain slices were also involved in the ART2-P2X7 pathway. Collectively, to our knowledge, our study provides the first evidence that ART2 exists in mouse brain astrocytes and NAD induces calcium elevation and astrocyte death by an ART2 and P2X7-mediated mechanism. The results suggest a novel approach for manipulating astrocyte death.

Survival advantage of locoregional and systemic therapy in oligometastatic breast cancer: an international retrospective cohort study (OLIGO-BC1).

BACKGROUND: An international retrospective cohort study was conducted to clarify the survival advantage of combination therapy with locoregional and systemic therapy (ST) in oligometastatic breast cancer (BC). METHODS: Patients with oligometastatic BC diagnosed from 2007 to 2012 were enrolled in center hospitals in China, Korea and Japan. It was defined as a low-volume metastatic disease at up to five sites and not necessarily in the same organ. Cases with brain, pleural, peritoneal and pericardial metastases were excluded. The primary endpoint was overall survival (OS) from the initial diagnosis of oligometastases. OS was summarized using the Kaplan-Meier method. A multivariable Cox regression model was used to estimate the hazard ratio (HR) for clinicopathological factors. RESULTS: Among 1,295 cases registered from February 2018 to May 2019, 932 remained for analysis after the exclusion of unavailable cases and locoregional recurrence. One metastatic site was found in 400 cases, 2 in 243, 3 in 130, 4 in 86 and 5 in 73. At the median follow-up of 4.5 years, 5-year OS was 54.7% and 39.7% for 321 cases in the combination therapy group and 611 cases in the ST group, respectively. An adjusted HR was 0.66 (95% confidence interval: 0.55, 0.79). Some types of ST without chemotherapy alone, younger age, ECOG performance status 0, early-stage BC, non-triple negative subtype, fewer metastatic sites and longer duration of surgery to relapse were significantly favorable prognostic factors. CONCLUSION: Combination therapy may be considered for longer survival under some conditions in oligometastatic BC.

What is the appropriate genetic testing criteria for breast cancer in the Chinese population?-Analysis of genetic and clinical features from a single cancer center database.

BACKGROUND: Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large-scale Chinese BC patients. METHODS: BC patients who had undergone genetic testing at the Sun Yat-sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. RESULTS: A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high-risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high-risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non-BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non-BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. CONCLUSIONS: Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non-BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.

The Iron-Inflammation Axis in Early-Stage Triple-Negative Breast Cancer.

The iron-related homeostasis and inflammatory biomarker have been identified as prognostic factors for cancers. We aimed to explore the prognostic value of a novel comprehensive biomarker, the iron-monocyte-to-lymphocyte ratio (IronMLR) score, in patients with early-stage triple-negative breast cancer (TNBC) in this study. We retrospectively analysed a total of 257 early-stage TNBC patients treated at Sun Yat-sen University Cancer Center (SYSUCC) between March 2006 and October 2016. Their clinicopathological information and haematological data tested within 1 week of the diagnosis were collected. According to the IronMLR score cutoff value of 6.07 µmol/L determined by maximally selected rank statistics, patients were stratified into the low- and high-IronMLR groups, after a median follow-up of 92.3 months (95% confidence interval [CI] 76.0-119.3 months), significant differences in 5-years disease-free survival (DFS) rate (81.2%, 95% CI 76.2%-86.5% vs. 65.5%, 95% CI 50.3%-85.3%, p = 0.012) and 5-years overall survival (OS) rate (86.0%, 95% CI 81.6%-90.7% vs. 65.5%, 95% CI 50.3%-85.3%, p = 0.011) were seen between two groups. Further multivariate Cox regression analysis revealed the IronMLR score as an independent predictor for DFS and OS, respectively, we then established a prognostic nomogram integrating the IronMLR score, T stage and N stage for individualized survival predictions. The prognostic model showed good predictive performance with a C-index of DFS 0.725 (95% CI 0.662-0.788) and OS 0.758 (95% CI 0.689-0.826), respectively. Besides, calibration curves for 1-, 3-, 5-DFS, and OS represented satisfactory consistency between actual and nomogram predicted survival. In conclusion, the Iron-inflammation axis might be a potential prognostic biomarker of survival outcomes for patients with early-stage TNBC, prognostic nomograms based on it with good predictive performance might improve individualized survival predictions.

Novel Signatures Based on the Lymphocyte-to-C-Reactive Protein Ratio Predict the Prognosis of Patients with Early Breast Cancer: A Retrospective Study.

Background: The value of the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) in early breast cancer (BC) is unclear. We explored the correlation between the LCR and survival of patients with early BC and established effective LCR-based prognostic signatures for predicting prognosis. Methods: In this retrospective study, we randomized 623 patients with early-stage BC diagnosed in December 2010 to October 2012 at the Sun Yat-sen University Cancer Center to training and verification datasets. The median follow-up of all patients was 109 months. The survival differences were calculated by Kaplan-Meier method using the Log rank test. For overall survival (OS) and disease-free survival (DFS), the independent factors in the training dataset were identified using univariate and multivariate Cox analyses, in which two-tailed P-values < 0.05 were considered statistically significant. Based on this, we respectively constructed novel signatures for survival prediction and validated the efficiency of signatures through the concordance index (C-index), calibration and receiver operating characteristic (ROC) curves in both datasets. Results: The LCR, lymphatic vessel invasion (LVI), progesterone receptor (PR) status, and Ki67 index were independent prognostic factors of OS. And the LCR and LVI are associated to DFS too. High LCR was associated with better OS and DFS. We constructed the prediction signatures based on those independent prognostic factors and calculated the risk scores. Patients in the training dataset with higher risk scores had significantly worse prognosis (P < 0.001). The signature had excellent discrimination capacity, with an OS C-index of 0.785 [95% confidence interval (CI): 0.713-0.857] and 0.750 (95% CI: 0.669-0.832) in the training and verification datasets, respectively. The time-ROC curves also suggest accurate prediction by the signature. Conclusion: The LCR was a significant prognostic predictor of OS and DFS in early BC. The LCR-based prognostic signatures could be a useful tool for individualized therapeutic guidance.

Systemic Therapy Combined with Locoregional Therapy Improved Survival in Oligometastatic Breast Cancer: A Single-Center Retrospective Cohort Study.

The optimal therapeutic options, adding locoregional therapy (LRT) to systemic therapy (ST) or not, for patients with oligometastatic breast cancer (OMBC) have not been fully elucidated. Hence, we designed a retrospective observational study which enrolled patients with measurable extracranial OMBC having less than 5 metastatic lesions not necessarily in the same organ. We retrospectively reviewed a total of 199 patients diagnosed with extracranial OMBC, including 28 receiving ST followed by LRT (ST to LRT group), 44 receiving LRT followed by ST (LRT to ST group), and 127 receiving ST alone (ST alone group). After a median follow-up of 28.7 months, patients receiving both ST and LRT had a significantly better prognosis than those receiving ST alone: the median progression-free survival (PFS) was 16.3, 14.0, and 9.3 months (P < 0.001) and the median overall survival (OS) was 39.8, 70.5, and 26.7 months (P < 0.001) in the ST to LRT, LRT to ST, and ST alone groups, respectively. Sequence of ST and LRT had no significant impact on survival among patients receiving both. Further exploratory analysis identified ST plus LRT as an independent predictor for longer PFS. In conclusion, we demonstrated that adding LRT to ST was associated with survival benefits for patients with OMBC, and further prospective studies were warranted.