Combination of preoperative tumour markers and lymphovascular invasion with TNM staging as a cost and labour efficient subtyping of colorectal cancer.
ABSTRACT: Tumour-Node-Metastasis (TNM) staging of colorectal cancer (CRC) needs further classification for better treatment because of disease heterogeneity. Although molecular classifications which are expensive and laborious are under study, cost and labour efficient subtyping is desirable. We assessed the combinations of preoperative tumour marker (TM) elevation and tumour lymphovascular invasion (LVI) as a solution. We used the pooled data of 7151 colon cancer (CC) patients and 4620 rectal cancer (RC) patients who received curative surgery between 2004 and 2008 in Japan. The best-matched subtyping for predicting relapse-free survival (RFS) was statistically selected using the c-index and Akaike's information criterion. This subtyping (TM-LVI), which consisted of three categories by TM elevation status and severity of LVI status, was an independent prognostic factor for RFS of CC (stage IIa, IIIb, and IIIc) and RC (stage I, IIa, IIb, IIIa, and IIIb) and also for disease specific survival of CC (stage IIa, IIb, IIIb, and IIIc) and RC (all stage except for IIc). Although TM-LVI classified CRC patients into low and high recurrence risk groups, the application of adjuvant therapy was not accordance with the TM-LVI status. TM-LVI may be a cost and labour efficient subtyping of colorectal cancer for better treatment strategy.
Project description:<h4>Background</h4>Cure proportion represents the proportion of patients who experience the same mortality rate as the general population and can be estimated together with the survival of the proportion experiencing excess mortality (the uncured). The aim was to estimate the cure proportions and survival among uncured stage II-III cutaneous melanoma (CM) patients.<h4>Methods</h4>1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II-III CM patients in Sweden (<i>n</i> = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005-2013 with a follow-up through 2018.<h4>Results</h4>Stages IIB and IIC showed significant differences in standardized cure proportions vs. stage IIA CM (0.80 (95% CI 0.77-0.83) stage IIA; 0.62 (95% CI 0.59-0.66) stage IIB; 0.42 (95% CI 0.37-0.46) for stage IIC). Significant differences in standardized cure proportions were found for stages IIIB and IIIC-D CM vs. stage IIIA (0.76 (95% CI 0.68-0.84) stage IIIA; 0.52 (95% CI 0.45-0.59) stage IIIB; 0.35 (95% CI 0.30-0.39) for stage IIIC-D).<h4>Conclusions</h4>The results are emphasizing the poor prognosis with low proportions cured by surgery only for sub-groups of stage II-III CM, specifically within stages IIB-C CM.
Project description:<h4>Bakcground</h4>The recently proposed 8th American Joint Committee on Cancer (AJCC) staging for gastric cancer (GC) did not include the evaluated lymph node (ELN) count as a prognostic indicator. In this study, we performed recursive partitioning analysis (RPA) to objectively combine the 15-ELN threshold and 8th AJCC stage to refine the staging for GC.<h4>Methods</h4>We analyzed 19,018 patients with non-metastatic GC from the Surveillance, Epidemiology, and End Results database. The dataset was randomly divided into training and validation sets.<h4>Results</h4>For each 8th AJCC stage, survival was significantly better for patients with ?15 ELNs versus those with <15 ELNs (P < 0.001 for all). RPA divided non-metastatic GC into seven stages: RPA-IA (8th AJCC IA with ?15 ELNs), RPA-IB (IA with <15 ELNs and IB/IIA with ?15 ELNs), RPA-IIA (IB with <15 ELNs and IIB with ?15 ELNs), RPA-IIB (IIA with <15 ELNs and IIIA with ?15 ELNs), RPA-IIIA (IIB with <15 ELNs), RPA-IIIB (IIIA with <15 ELNs and IIIB ?15 ELNs), and RPA-IIIC (IIIB with <15 ELNs and IIIC). The corresponding 5-year survival rates were 84.1, 70.3, 52.8, 41.4, 32.9, 21.7, and 10.2%, respectively (P < 0.001 for all pairwise comparisons). The RPA staging outperformed the 8th AJCC staging in terms of discrimination and homogeneity among the SEER training and validation sets, as well as an independent Chinese cohort.<h4>Conclusion</h4>By equipping the 8th AJCC stage with the 15-ELN threshold, the proposed RPA staging is superior to the 8th AJCC staging without overcomplicating.
Project description:Multiple clinical trials have shown that neoadjuvant systemic therapy has a benefit in women who are borderline lumpectomy candidates and in those with locally advanced breast cancers by reducing the mastectomy rate and making inoperable tumors operable. The study aim was to examine the patterns of neoadjuvant chemotherapy and endocrine therapy use among younger women in the United States treated at different types of cancer centers.Data from the National Cancer Data Base for 118,086 women younger than 65 years with clinical stage IIA (T2N0 only) to IIIC breast cancer. Following the National Comprehensive Cancer Network guideline categorization, patients were grouped into those who were borderline lumpectomy candidates (clinical stage IIA [T2N0 only], IIB, or IIIA [T3N1 only]) or those with locally advanced disease (clinical stage IIIA [T0-3N2 only], IIIB, or IIIC). The main outcome was the proportion of women who received neoadjuvant systemic therapy.Use of neoadjuvant chemotherapy ranged from 17% (stage IIA) to 79% (stage IIIB). Across almost all stage and receptor subtypes, the use was lower in community vs academic centers. On multivariable analysis, use of neoadjuvant chemotherapy was decreased in community vs academic centers (borderline lumpectomy candidates: adjusted risk ratio = 0.73; 95% CI, 0.69-0.77; locally advanced disease: adjusted risk ratio = 0.78; 95% CI, 0.74-0.83).Use of guideline-concordant neoadjuvant chemotherapy is significantly higher among women treated at academic vs community centers in young and healthy women who do not commonly have contraindications to this treatment. Our study identified a potential disparity in cancer care by type of center where patients receive treatment.
Project description:<h4>Purpose</h4>The present study aimed to evaluate the clinicopathologic characteristics of patients with extranodal extension (ENE) and the prognostic implications of ENE in stage III colorectal cancer (CRC).<h4>Results</h4>ENE was more frequent in younger patients and those with rectal cancer, higher T stage, higher N stage, lymphovascular invasion (LVI), and perineural invasion (PNI). Five-year disease-free survival (DFS) and overall survival (OS) were lower in patients with ENE-positive than in those with ENE-negative tumors (DFS, 66.4% vs. 80.1%; and OS, 74.8% vs. 85.6%, respectively; <i>P</i> < 0.001 both). In multivariate analysis, pathologic stage, the presence of ENE, LVI, PNI, and no adjuvant chemotherapy were significant independent prognostic factors for DFS and OS. There were no statistically significant differences in DFS and OS between ENE-positive stage IIIB tumors and ENE-negative stage IIIC tumors.<h4>Materials and methods</h4>The records of 1,948 stage III CRC patients who underwent curative surgery between January 2003 and December 2010 were retrospectively reviewed.<h4>Conclusions</h4>The presence of ENE is independently and significantly associated with lower DFS and OS rates after curative resection for stage III CRC. ENE status should be considered in both the pathologic report and CRC staging system.
Project description:<h4>Background</h4>Deregulation of fibroblast growth factor receptor 3 (FGFR3) is involved in several malignancies. Its role in colorectal cancer has not been assessed before.<h4>Methods</h4>Expression of FGFR3 in human colorectal tumour specimens was analysed using splice variant-specific real-time reverse transcriptase PCR assays. To analyse the impact of FGFR3-IIIc expression on tumour cell biology, colon cancer cell models overexpressing wild-type (WT-3b and WT3c) or dominant-negative FGFR3 variants (KD3c and KD3b) were generated by either plasmid transfection or adenoviral transduction.<h4>Results</h4>Although FGFR3 mRNA expression is downregulated in colorectal cancer, alterations mainly affected the FGFR3-IIIb splice variant, resulting in an increased IIIc/IIIb ratio predominantly in a subgroup of advanced tumours. Overexpression of WT3c increased proliferation, survival and colony formation in all colon cancer cell models tested, whereas WT3b had little activity. In addition, it conferred sensitivity to autocrine FGF18-mediated growth and migration signals in SW480 cells with low endogenous FGFR3-IIIc expression. Disruption of FGFR3-IIIc-dependent signalling by dominant-negative FGFR3-IIIc or small interfering RNA-mediated FGFR3-IIIc knockdown resulted in inhibition of cell growth and induction of apoptosis, which could not be observed when FGFR3-IIIb was blocked. In addition, KD3c expression blocked colony formation and migration and distinctly attenuated tumour growth in SCID mouse xenograft models.<h4>Conclusion</h4>Our data show that FGFR3-IIIc exerts oncogenic functions by mediating FGF18 effects in colorectal cancer and may constitute a promising new target for therapeutic interventions.
Project description:The 8th edition of the TNM was released in 2016 and included major revisions, especially for stage III. We aimed to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Clinical data from 1557 patients operated on for stage III gastric cancer according to the 7th edition between 2007 and 2014 were analyzed and compared using the 7th and 8th TNM classifications. A proposed staging system was established, and the three systems were compared in terms of prognostic performance. The stage shifted for 669 (42.96%) patients. It shifted from IIIA to IIIB (one patient, 0.06%), IIIB to IIIA (230 patients, 14.8%), IIIB to IIIC (94 patients, 6.0%), and IIIC to IIIB (344 patients, 22.1%). However, the new AJCC subgroupings did not prove distinctive for survival levels between T3N3aM0 (stage IIIB) and T3N3bM0 (stage IIIC) or between T4aN3aM0 (stage IIIB) and T4aN3bM0 (stage IIIC) when <30 lymph nodes (LNs) were resected. The performance of the 8th edition (c-index, 0.614; 95% confidence interval [CI], 0.596-0.633) revealed no relevant improvement compared to the 7th edition (c-index, 0.624; 95% CI, 0.605-0.643). The proposed staging system generated the best prognostic stratification. The 8th TNM edition may not provide better accuracy in predicting the prognosis of stage III gastric cancer. The proposed staging system, comprised of a combination of the number of LNs harvested and the 7th and 8th AJCC classifications, may improve predictive capacities for stage III gastric cancer.
Project description:<h4>Objectives</h4>To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post hoc analysis of a prospective clinical trial. To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumours exhibited LVI.<h4>Patients and methods</h4>Surgical and tumour factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1-T2 N0 UCB in the p53-MVAC trial (Southwest Oncology Group 4B951/NCT00005047). The presence or absence of LVI was determined by pathological examination of transurethral resection or RC specimens. Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS).<h4>Results</h4>Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20%) had LVI-positive tumours. Of these, 34 patients had pT1 and 68 had pT2 disease. LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.15-2.77; number of events (EV) 95; P = 0.01) and with OS with a HR of 2.02 (95% CI 1.31-3.11; EV 98; P = 0.001) after adjustment for pathological stage. Among 27 patients with LVI-positive tumours who were randomised to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70, 95% CI 0.16-3.17; EV 7; P = 0.65) or with OS (HR 0.45, 95% CI 0.11-1.83; EV 9; P = 0.26).<h4>Conclusions</h4>Our post hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1-T2N0 disease. The analysis did not show a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not excluded.
Project description:PURPOSE:To use pathologic indicators to determine which patients benefit from postmastectomy radiation therapy (PMRT) for breast cancer after neoadjuvant chemotherapy (NACT) and total mastectomy (TM). PATIENTS AND METHODS:We enrolled 4236 patients with breast invasive ductal carcinoma who received NACT followed by TM. Cox regression analysis was used to calculate hazard ratios (HRs) and confidence intervals; independent predictors were controlled for or stratified in the analysis. RESULTS:After multivariate Cox regression analyses, the adjusted HRs derived for PMRT for all-cause mortality were 0.65 (0.52-0.81, P < 0.0001) and 0.58 (0.47-0.71, P < 0.0001) in postchemotherapy pathologic tumor stages T2-4 (ypT3-4) and postchemotherapy pathologic nodal stages N2-3 (ypN2-3), respectively. Moreover, adjusted HRs derived for PMRT with all-cause mortality were 0.51 (0.38-0.69, P < 0.0001), 0.60 (0.40-0.88, P = 0.0096), and 0.64 (0.48-0.86, P = 0.0024) in pathological stages IIIA, IIIB, and IIIC, respectively. Additionally, the PMRT group showed significant locoregional control irrespective of the pathologic response, even ypT0, ypN0, or pathological complete response (pCR), compared with the No-PMRT group. The multivariate analysis showed no statistical differences between the PMRT and No-PMRT groups for distant metastasis-free survival in any pathologic response of ypT0-4, ypN0-3, and pathologic American Joint Committee on Cancer stages pCR to IIIC. CONCLUSION:For patients with breast cancer ypT3-4, ypN2-3, or pathologic stages IIIA-IIIC receiving NACT and TM, benefit from PMRT if it is associated with OS benefits, regardless of the clinical stage of the disease. Compared with No-PMRT, PMRT improved locoregional recurrence-free survival, even pCR, in patients with breast cancer receiving NACT and TM.
Project description:This study focused on improving the American Joint Committee on Cancer TNM staging system and demonstrated an improvement in prognostic accuracy and clinical management of colon cancer using the P-TNM staging system.Eligible patients (N=56,800) were identified from the Surveillance, Epidemiology, and End Results database between January 1, 2010, and December 31, 2014. The P-stage (P0 or P1) was assigned to each patient based on age at diagnosis, tumor grade, and tumor size. The outcome of interest was cancer-specific survival (CSS). The Cox proportional hazards regression analyses were used to identify independent prognostic factors and analyze the CSS probabilities of patients with colon cancer having different P-TNM stages, respectively.A total of 29,627 patients were assigned to P0-stage and 27,173 patients were assigned to P1-stage. The P1-stage was associated with a 98.1% increased risk of cancer-specific mortality (hazard ratio =1.981, 95% confidence interval =1.891-2.076, P<0.001), which was higher in patients with nonmetastatic colon cancer. The P1-stage patients had improvement in CSS compared with those in P0-stage in respective stages (P<0.001). Moreover, CSS decreased in stage I-P1 compared with stage IIA-P0 or IIIA-P0 (P<0.001), stage IIIA-P1 compared with stage IIA-P0 (P<0.001), stage IIB-P1 compared with stage IIIB-P0 or IIC-P0 (P<0.001), stage IIIB-P1 compared with stage IIC-P0 (P<0.001), and stage IIC-P1 compared with stage IIIC-P0 (P<0.001).P-stage was an independent prognostic factor for colon cancer. This study strongly supported the incorporation of P-stage into the American Joint Committee on Cancer TNM staging system for a better approach to prognostication and, thus, more individualized risk-adaptive therapies in colon cancer.
Project description:BACKGROUND:The aim of this study was to investigate the potential of cell-free DNA (cfDNA) as a disease biomarker in oesophageal squamous cell carcinoma (ESCC) that can be used for treatment response evaluation and early detection of tumour recurrence. METHODS:Matched tumour tissue, pre- and post-surgery plasma and WBCs obtained from 17 ESCC patients were sequenced using a panel of 483 cancer-related genes. RESULTS:Somatic mutations were detected in 14 of 17 tumour tissues. Putative harmful mutations were observed in genes involved in well-known cancer-related pathways, including PI3K-Akt/mTOR signalling, Proteoglycans in cancer, FoxO signalling, Jak-STAT signalling, Chemokine signalling and Focal adhesion. Forty-six somatic mutations were found in pre-surgery cfDNA in 8 of 12 patients, with mutant allele frequencies (MAF) ranging from 0.24 to 4.91%. Three of the 8 patients with detectable circulating tumour DNA (ctDNA) had stage IIA disease, whereas the others had stage IIB-IIIB disease. Post-surgery cfDNA somatic mutations were detected in only 2 of 14 patients, with mutant allele frequencies of 0.28 and 0.36%. All other somatic mutations were undetectable in post-surgery cfDNA, even in samples collected within 3-4?h after surgery. CONCLUSION:Our study shows that somatic mutations can be detected in pre-surgery cfDNA in stage IIA to IIIB patients, and at a lower frequency in post-surgery cfDNA. This indicates that cfDNA could potentially be used to monitor disease load, even in low disease-stage patients.