Breast cancer (BC) is a leading cause of cancer-related death in females worldwide. Previous studies have demonstrated that matrix metalloproteinases (MMPs) play key roles in metastasis and are ...associated with survival in various cancers. The prognostic values of MMP2 and MMP9 expression in BC have been investigated, but the results remain controversial. Thus, we performed the present meta-analysis to investigate the associations between MMP2/9 expressions in tumor cells with clinicopathologic features and survival outcome in BC patients.
Eligible studies were searched in PubMed, Web of Science, EMBASE, CNKI and Wanfang databases. The associations of MMP2/9 overexpression in tumor cells with overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) were assessed by hazard ratio (HR) and 95% confidence interval (CI). The associations of MMP2/9 overexpression with clinicopathological features were investigated by calculating odds ratio (OR) and 95% CI. Subgroup analysis, sensitivity analysis, meta-regression, and analysis for publication bias were performed.
A total of 41 studies comprising 6517 patients with primary BC were finally included. MMP2 overexpression was associated with an unfavorable OS (HR = 1.60, 95% CI 1.33 -1.94, P < 0.001) while MMP9 overexpression predicted a shorter OS (HR = 1.52, 95% CI 1.30 -1.77, P < 0.001). MMP2 overexpression conferred a higher risk to distant metastasis (OR = 2.69, 95% CI 1.35-5.39, P = 0.005) and MMP9 overexpression correlated with lymph node metastasis (OR = 2.90, 95% CI 1.86 - 4.53, P < 0.001). Moreover, MMP2 and MMP9 overexpression were both associated with higher clinical stage and histological grade in BC patients. MMP9 overexpression was more frequent in patients with larger tumor sizes.
Tumoral MMP2 and MMP9 are promising markers for predicting the prognosis in patients with BC.
Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity ...is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma.
Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis.
A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses).
Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)
Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study ...aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.
ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008–31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor–positive and HER2-negative (HR+/HER2–, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR–/HER2–, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.
Median OS of the whole cohort was 37.22 months (95% confidence interval CI, 36.3–38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 95% CI, 0.97–1.00, P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2–, HER2+ and HR–/HER2– subcohorts was, respectively, 42.12 (95% CI, 40.90–43.10), 44.91 (95% CI, 42.51–47.90) and 14.52 (95% CI, 13.70–15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 95% CI, 0.88–0.94, P < .001), but not in HR+/HER2– nor HR–/HER2– subcohorts (hazard ratio 1.00 95% CI, 0.98–1.01, P = .80 and 1.00 95% CI, 0.97–1.02, P = .90, respectively).
The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.
•Overall survival (OS) of metastatic breast cancer patients has slightly improved over the past decade.•OS improvement was confined to Epidermal Growth Factor (HER)-2-overexpressing metastatic breast cancer patients.•The uptake of therapeutic innovations was lower than expected.
Summary Background The antibody–drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a ...taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. Methods EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m2 self-administered orally twice daily on days 1–14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1–21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov , number NCT00829166. Findings Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months 95% CI 26·3–34·1 vs 25·9 months 95% CI 22·7–28·3; hazard ratio 0·75 95% CI 0·64–0·88). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months IQR 19·5–26·1). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 49% of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 48% of 490) than with capecitabine plus lapatinib control treatment (291 60% of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 21% of 488 patients) followed by palmar–plantar erythrodysaesthesia syndrome (87 18%), and vomiting (24 5%). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 14% of 490), increased aspartate aminotransferase levels (22 5%), and anaemia (19 4%). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group coronary artery disease and multiorgan failure and three in the trastuzumab emtansine group metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia). Interpretation This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population. Funding F Hoffmann-La Roche/Genentech.
Background
Radiation Therapy Oncology Group (RTOG)‐0129 recursive partitioning analysis was the basis for risk‐based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors’ ...knowledge, the question of whether RTOG‐0129 overall survival (OS) estimates for low‐risk, intermediate‐risk, and high‐risk groups are similar in other data sets or applicable to progression‐free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG‐0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups.
Methods
Prospective randomized clinical trials were analyzed retrospectively. RTOG‐0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG‐0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible.
Results
There was a total of 260 patients and 287 patients, respectively, from RTOG‐0129 and RTOG‐0522, with median follow‐ups for surviving patients of 7.9 years (range, 1.7‐9.9 years) and 4.7 years (range, 0.1‐7.0 years), respectively. Previous OS differences in RTOG‐0129 persisted at 5 years. In RTOG‐0522, the 5‐year OS rates for the low‐risk, intermediate‐risk, and high‐risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5‐year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG‐0522 among a subgroup of patients considered to be at very good risk (p16‐positive disease, smoking history of ≤10 pack‐years, and classified with T1‐T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5‐year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group.
Conclusions
RTOG‐0129 risk groups persisted at 5 years and were reproducible in RTOG‐0522. However, there was variability in the estimates. These data underscore the importance of long‐term follow‐up and appropriate patient selection in therapeutic deintensification trials.
To the authors’ knowledge, the issue of whether Radiation Therapy Oncology Group (RTOG)‐0129 overall survival estimates for low‐risk, intermediate‐risk, and high‐risk groups are similar in other data sets or applicable to progression‐free survival is unknown. In the current study, RTOG‐0129 risk groups appear to persist at 5 years, are reproducible in RTOG‐0522, and can be applied to progression‐free survival. However, there is variability in the estimates, which underscores the importance of long‐term follow‐up in therapeutic deintensification.
We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer ...Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application.
We assessed a retrospective cohort of women from the Tübingen University Women’s Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features.
Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB 89 (19.7%), stage II 26 (5.8%), and stage III/IV 61 (13.5%). ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P=0.001) and disease-specific (P=0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88.
We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.
Survival analysis is a subfield of statistics where the goal is to analyze and model data where the outcome is the time until an event of interest occurs. One of the main challenges in this context ...is the presence of instances whose event outcomes become unobservable after a certain time point or when some instances do not experience any event during the monitoring period. This so-called censoring can be handled most effectively using survival analysis techniques. Traditionally, statistical approaches have been widely developed in the literature to overcome the issue of censoring. In addition, many machine learning algorithms have been adapted to deal with such censored data and tackle other challenging problems that arise in real-world data. In this survey, we provide a comprehensive and structured review of the statistical methods typically used and the machine learning techniques developed for survival analysis, along with a detailed taxonomy of the existing methods. We also discuss several topics that are closely related to survival analysis and describe several successful applications in a variety of real-world application domains. We hope that this article will give readers a more comprehensive understanding of recent advances in survival analysis and offer some guidelines for applying these approaches to solve new problems arising in applications involving censored data.
Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial to mesenchymal transition (EMT) but remains highly controversial ...since--depending on the cell-line studied--either epithelial (E) or mesenchymal (M) markers, alone or together have been associated with stemness. Using distinct transcript expression signatures characterizing the three different E, M and hybrid E/M cell-types, our data support a novel model that links a mixed EM signature with stemness in 1) individual cells, 2) luminal and basal cell lines, 3) in vivo xenograft mouse models, and 4) in all breast cancer subtypes. In particular, we found that co-expression of E and M signatures was associated with poorest outcome in luminal and basal breast cancer patients as well as with enrichment for stem-like cells in both E and M breast cell-lines. This link between a mixed EM expression signature and stemness was explained by two findings: first, mixed cultures of E and M cells showed increased cooperation in mammosphere formation (indicative of stemness) compared to the more differentiated E and M cell-types. Second, single-cell qPCR analysis revealed that E and M genes could be co-expressed in the same cell. These hybrid E/M cells were generated by both E or M cells and had a combination of several stem-like traits since they displayed increased plasticity, self-renewal, mammosphere formation, and produced ALDH1+ progenies, while more differentiated M cells showed less plasticity and E cells showed less self-renewal. Thus, the hybrid E/M state reflecting stemness and its promotion by E-M cooperation offers a dual biological rationale for the robust association of the mixed EM signature with poor prognosis, independent of cellular origin. Together, our model explains previous paradoxical findings that breast CSCs appear to be M in luminal cell-lines but E in basal breast cancer cell-lines. Our results suggest that targeting E/M heterogeneity by eliminating hybrid E/M cells and cooperation between E and M cell-types could improve breast cancer patient survival independent of breast cancer-subtype.
Background
Laparoscopy-assisted gastrectomy (LG) is rapidly gaining popularity owing to its minimal invasiveness. Previous studies have found that compared with two-dimensional (2D)-LG, ...three-dimensional (3D)-LG showed better short-term outcomes. However, the long-term oncological outcomes in patients with locally resectable gastric cancer (GC) remain controversial.
Methods
In this noninferiority, open-label, randomized clinical trial, a total of 438 eligible GC participants were randomly assigned in a 1:1 ratio to either 3D-LG or 2D-LG from January 2015 to April 2016. The primary endpoint was operating time, while the secondary endpoints included 5-year overall survival (OS), disease-free survival (DFS), and recurrence pattern.
Results
Data from 401 participants were included in the per-protocol analysis, with 204 patients in the 3D group and 197 patients in the 2D group. The 5-year OS and DFS rates were comparable between the 3D and 2D groups (5-year OS: 70.6% vs. 71.1%, Log-rank
P
= 0.743; 5-year DFS: 68.1% vs. 69.0%, log-rank
P
= 0.712). No significant differences were observed between the 3D and 2D groups in the 5-year recurrence rate (28.9% vs. 28.9%,
P
= 0.958) or recurrence time (mean time, 22.6 vs. 20.5 months,
P
= 0.412). Further stratified analysis based on the type of gastrectomy, postoperative pathological staging, and preoperative BMI showed that the 5-year OS, DFS, and recurrence rates of the 3D group in each subgroup were similar to those of the 2D group (all
P
> 0.05).
Conclusions
For patients with locally resectable GC, 3D-LG performed by experienced surgeons in high-volume professional institutions can achieve long-term oncological outcomes comparable to those of 2D-LG.
Registration number
NCT02327481 (
http://clinicaltrials.gov
).
Graphical abstract
PDF
