Thymidine synthase,thymidine phosphorylase,and excision repair cross-complementation group 1 expression as predictive markers of capecitabine plus cisplatin chemotherapy as first-line treatment for patients with advanced oesophageal squamous cell carcinoma

Background:

Our purpose was to evaluate thymidine synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementation group 1 (ERCC1) expression as biomarkers for capecitabine and cisplatin (XP) combination chemotherapy in patients with metastatic oesophageal squamous cell cancer.

Method:

A total of 113 patients with metastatic oesophageal squamous cell cancer were treated with XP chemotherapy at the Samsung Medical Center between 2003 and 2007, of whom 72 had available clinical data and paraffin blocks for immunohistochemistry of TS, TP, and ERCC1.

Results:

The median age of the 72 patients was 62 years. The overall response rate (RR) was 51.4%. The median progression-free survival (PFS) and overall survival (OS) were 4.2 and 12.0 months, respectively. High expression of TS and TP was associated with a higher RR than was low expression of TS and TP (54.1 vs 40.5%, P=0.022). Strong ERCC1 expression and a low TS score were identified as unfavourable independent risk factors for PFS (HR 10.71, 95% confidence interval (CI) 2.1–54.7, P=0.004 for strong ERCC1 expression; and HR 2.9, 95% CI 1.0–7.9, P=0.044 for low TS score). Strong ERCC1 expression was identified as an unfavourable independent risk factor for OS (HR 3.73, 95% CI 1.39–10.0, P=0.009).

Conclusion:

These data indicate that expression of TS, TP, and ERCC1 may be predictive markers for response and survival in patients with metastatic oesophageal squamous cell cancer receiving XP chemotherapy.     

Influence of pre-diagnostic cigarette smoking on colorectal cancer survival: overall and by tumour molecular phenotype

Background:

Smoking is a risk factor for incident colorectal cancer (CRC); however, it is unclear about its influence on survival after CRC diagnosis.

Methods:

A cohort of 706 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and recurrence until April 2010. Smoking and other relevant data were collected by questionnaire after cancer diagnosis, using a referent period of ‘2 years before diagnosis'' to capture pre-diagnosis information. Molecular analyses of microsatellite instability (MSI) status and BRAF V600E mutation status were performed in tumour tissue using standard techniques. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards regression, controlling for major prognostic factors.

Results:

Compared with never smokers, all-cause mortality (overall survival, OS) was higher for current (HR: 1.78; 95% CI: 1.04–3.06), but not for former (HR: 1.06; 95% CI: 0.71–1.59) smokers. The associations of cigarette smoking with the study outcomes were higher among patients with ⩾40 pack-years of smoking (OS: HR: 1.72; 95% CI: 1.03–2.85; disease-free survival (DFS: HR: 1.99; 95% CI: 1.25–3.19), those who smoked ⩾30 cigarettes per day (DFS: HR: 1.80; 95% CI: 1.22–2.67), and those with microsatellite stable (MSS) or MSI-low tumours (OS: HR: 1.38; 95% CI: 1.04–1.82 and DFS: HR: 1.32; 95% CI: 1.01–1.72). Potential heterogeneity was noted for sex (DFS HR: 1.68 for men and 1.01 for women: P for heterogeneity=0.04), and age at diagnosis (OS: HR: 1.11 for patients aged <60 and 1.69 for patients aged ⩾60: P for heterogeneity=0.03).

Conclusions:

Pre-diagnosis cigarette smoking is associated with worsened prognosis among patients with CRC.     

Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer and the predictive role of endoluminal ultrasonography

Background:

The optimum multimodal treatment for oesophageal cancer, and the prognostic significance of histopathological tumour involvement of the circumferential resection margin (CRM+) are uncertain. The aims of this study were to determine the prognostic significance of CRM+ after oesophagectomy and to identify endosonographic (endoluminal ultrasonography (EUS)) features that predict a threatened CRM+.

Methods:

Two hundred and sixty-nine consecutive patients underwent potentially curative oesophagectomy (103 surgery alone, 124 neoadjuvant chemotherapy (CS) and 42 chemoradiotherapy (CRTS)). Primary outcome measures were disease-free survival (DFS) and overall survival (OS).

Results:

CRM+ was reported in 98 (38.0%) of all, and in 90 (62.5%) of pT3 patients. Multivariate analysis of pathological factors revealed: lymphovascular invasion (HR 2.087, 95% CI 1.396–3.122, P<0.0001), CRM+ (HR 1.762, 95% CI 1.201–2.586, P=0.004) and lymph node metastasis count (HR 1.563, 95% CI 1.018–2.400, P=0.041) to be independently and significantly associated with DFS. Lymphovascular invasion (HR 2.160, 95% CI 1.432–3.259, P<0.001) and CRM+ (HR 1.514, 95% CI 1.000–2.292, P=0.050) were also independently and significantly associated with OS. Multivariate analysis revealed EUS T stage (T3 or T4, OR 24.313, 95% CI 7.438–79.476, P<0.0001) and use or not of CRTS (OR 0.116, 95% CI 0.035–0.382, P<0.0001) were independently and significantly associated with CRM+.

Conclusion:

A positive CRM was a better predictor of DFS and OS than standard pTNM stage.     

ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: results from a randomised,phase II trial

Background:

Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin-attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. The ERCC1-XPF nuclease is critical to DNA repair pathways resolving cisplatin-induced lesions.

Methods:

In a phase II trial, patients with untreated Stage III-IVb HNSCC were randomised to cisplatin-radiotherapy with/without erlotinib. Archived primary tumours were available from 90 of 204 patients for this planned substudy. Semi-quantitative ERCC1 protein expression (H-score) was determined using the FL297, 4F9, and 8F1 antibodies. The primary analysis evaluated the relationship between continuous ERCC1 protein expression and progression-free survival (PFS). Secondary analyses included two pre-specified ERCC1 cutpoints and performance in HPV-associated disease.

Results:

Higher ERCC1 expression was associated with inferior PFS, as measured by the specific antibodies FL297 (HR=2.5, 95% CI=1.1–5.9, P=0.03) and 4F9 (HR=3.0, 95% CI=1.2–7.8, P=0.02). Patients with increased vs decreased/normal ERCC1 expression experienced inferior PFS (HR=4.8 for FL297, P=0.003; HR=5.5 for 4F9, P=0.007). This threshold remained prognostic in HPV-associated disease.

Conclusion:

ERCC1-XPF protein expression by the specific FL297 and 4F9 antibodies is prognostic in patients undergoing definitive cisplatin-radiotherapy for HNSCC, irrespective of HPV status.     

Combined analysis of HLA class I,HLA-E and HLA-G predicts prognosis in colon cancer patients

Background:

Evasion of immune surveillance and suppression of the immune system are important hallmarks of tumour development in colon cancer. The goal of this study was to establish a tumour profile based on biomarkers that reflect a tumour''s immune susceptibility status and to determine their relation to patient outcome.

Methods:

The study population consisted of 285 stage I-IV colon cancer patients of which a tissue micro array (TMA) was available. Sections were immunohistochemically stained for the presence of Foxp3+ cells and tumour expression of HLA Class I (HLA-A, -B, -C) and non-classical HLA-E and HLA-G. All markers were combined for further analyses, resulting in three tumour immune phenotypes: strong immune system tumour recognition, intermediate immune system tumour recognition and poor immune system tumour recognition.

Results:

Loss of HLA class I expression was significantly related to a better OS (P-value 0.005) and DFS (P-value 0.008). Patients with tumours who showed neither HLA class I nor HLA-E or -G expression (phenotype a) had a significant better OS and DFS (P-value <0.001 and 0.001, respectively) compared with phenotype b (OS HR: 4.7, 95% CI: 1.2–19.0, P=0.001) or c (OS HR: 8.2, 95% CI: 2.0–34.2, P=0.0001). Further, the tumour immune phenotype was an independent predictor for OS and DFS (P-value 0.009 and 0.013, respectively).

Conclusion:

Tumours showing absence of HLA class I, HLA-E and HLA-G expressions were related to a better OS and DFS. By combining the expression status of several immune-related biomarkers, three tumour immune phenotypes were created that related to patient outcome. These immune phenotypes represented significant, independent, clinical prognostic profiles in colon cancer.     

High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer

Background:

The Toll-like receptor (TLR) 4 signalling pathway has been shown to have oncogenic effects in vitro and in vivo. To demonstrate the role of TLR4 signalling in colon tumourigenesis, we examined the expression of TLR4 and myeloid differentiation factor 88 (MyD88) in colorectal cancer (CRC).

Methods:

The expression of TLR4 and MyD88 in 108 CRC samples, 15 adenomas, and 15 normal mucosae was evaluated by immunohistochemistry, and the correlations between their immunoscores and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analysed.

Results:

Compared with normal mucosae and adenomas, 20% cancers displayed high expression of TLR4, and 23% cancers showed high expression of MyD88. The high expression of TLR4 and MyD88 was significantly correlated with liver metastasis (P=0.0001, P=0.0054). In univariate analysis, the high expression of TLR4 was significantly associated with shorter OS (hazard ratio (HR): 2.17; 95% confidence interval (95% CI): 1.15–4.07; P=0.015). The high expression of MyD88 expression was significantly associated with poor DFS and OS (HR: 2.33; 95% CI: 1.31–4.13; P=0.0038 and HR: 3.03; 95% CI: 1.67–5.48; P=0.0002). The high combined expression of TLR4 and MyD88 was also significantly associated with poor DFS and OS (HR: 2.25; 95% CI: 1.27–3.99; P=0.0053 and HR: 2.97; 95% CI: 1.64–5.38; P=0.0003). Multivariate analysis showed that high expressions of TLR4 (OS: adjusted HR: 1.88; 95% CI: 0.99–3.55; P=0.0298) and MyD88 (DFS: adjusted HR: 1.93; 95% CI: 1.01–3.67; P=0.0441; OS: adjusted HR: 2.25; 95% CI: 1.17–4.33; P=0.0112) were independent prognostic factors of OS. Furthermore, high co-expression of TLR4/MyD88 was strongly associated with both poor DFS and OS.

Conclusion:

Our findings suggest that high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with CRC.     

The prognostic significance of tumour–stroma ratio in oestrogen receptor-positive breast cancer

Background:

A high percentage of stroma predicts poor survival in triple-negative breast cancers but is diminished in studies of unselected cases. We determined the prognostic significance of tumour–stroma ratio (TSR) in oestrogen receptor (ER)-positive male and female breast carcinomas.

Methods:

TSR was measured in haematoxylin and eosin-stained tissue sections (118 female and 62 male). Relationship of TSR (cutoff 49%) to overall survival (OS) and relapse-free survival (RFS) was analysed.

Results:

Tumours with ⩾49% stroma were associated with better survival in female (OS P=0.008, HR=0.2–0.7; RFS P=0.006, HR=0.1–0.6) and male breast cancer (OS P=0.005, HR=0.05–0.6; RFS P=0.01, HR=0.87–5.6), confirmed in multivariate analysis.

Conclusions:

High stromal content was related to better survival in ER-positive breast cancers across both genders, contrasting data in triple-negative breast cancer and highlighting the importance of considering ER status when interpreting the prognostic value of TSR.     

Prognostic effect of activated EGFR expression in human colon carcinomas: comparison with EGFR status

Background:

Evidence suggests that epidermal growth factor receptor (EGFR)-activation status may better predict the clinical behaviour of colon cancers than does EGFR expression. However, the prognostic effect of phospho-EGFR in primary colon cancer remains undefined.

Methods:

Phospho-EGFR (Tyr-1173) and EGFR expression were analysed by immunohistochemistry (IHC) in tissue microarrays of TNM stage II and III colon cancers from completed adjuvant therapy trials (n=388). Staining intensity was scored and correlated with clinicopathological variables, DNA mismatch repair (MMR) status, rates of cell proliferation (Ki-67), apoptosis (caspase-3), and patient survival.

Results:

Phospho-EGFR expression was detected in 157 of 388 (40%) tumours, whereas EGFR was found in 214 of 361 (59%). Although phospho-EGFR was unrelated to clinicopathological variables, strong EGFR intensity was associated with higher tumour stage (P=0.03). Tumours overexpressing EGFR (P=0.0002) or phospho-EGFR (P=0.015) showed increased Ki-67, but not caspase-3 expression. Phospho-EGFR was not prognostic. EGFR intensity was associated with worse disease-free survival (DFS) (hazard ratio (HR): 1.21 (1.03, 1.41); P=0.019) and overall survival (OS) (HR: 1.19 (1.02, 1.39); P=0.028). Tumours expressing both EGFR and phospho-EGFR had similar survival as EGFR alone. Stage and lymph node number were prognostic for DFS and OS, and histological grade for OS. EGFR was an independent predictor of DFS (P=0.042) after adjustment for stage, histological grade, age, and MMR status.

Conclusion:

Phospho-EGFR and EGFR expression were associated with tumour cell hyperproliferation. Phospho-EGFR was not prognostic, whereas increased EGFR intensity was independently associated with poor DFS.     

Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases

Background:

Identifying patients who will experience lung cancer recurrence after surgery remains a challenge. We aimed to evaluate whether mutant forms of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (mEGFR and mKRAS) are useful biomarkers in resected non-small cell lung cancer (NSCLC).

Methods:

We retrospectively reviewed data from 841 patients who underwent surgery and molecular testing for NSCLC between 2007 and 2012.

Results:

mEGFR was observed in 103 patients (12.2%), and mKRAS in 265 (31.5%). The median overall survival (OS) and time to recurrence (TTR) were significantly lower for mKRAS (OS: 43 months; TTR: 19 months) compared with mEGFR (OS: 67 months; TTR: 24 months) and wild-type patients (OS: 55 months; disease-free survival (DFS): 24 months). Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort (OS: KRAS G12V: 26 months vs Cohort: 60 months; DFS: KRAS G12V: 15 months vs Cohort: 24 months). These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28–0.65), P<0.0001 for OS; HR: 0.67 (0.48–0.92), P=0.01 for TTR). Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001–0.08), P<0.0001).

Conclusions:

mKRAS and mEGFR may predict survival and recurrence in early stages of NSCLC. Patients with KRAS G12V exhibited worse OS and higher recurrence incidences.     

Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer

Background:

The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model.

Methods:

Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models.

Results:

The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215–0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370–0.891), progression-free survival after first-line CT ⩾6 months (P=0.027; HR, 0.633; 95% CI 0.422–0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392–0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001).

Conclusions:

Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.     

Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer

Background:

Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects.

Methods:

We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population.

Results:

Patients with low expression of VEGF-D (0, 1+) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CB+CBM), 0.21; 95% CI, 0.08–0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13–0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2+ PFS HR, 0.67; 95% CI, 0.45–1.00; OS HR, 0.82; 95% CI, 0.52–1.30; VEGF-D 3+ PFS HR, 0.77; 95% CI, 0.50–1.17; OS HR, 1.28; 95% CI, 0.79–2.09) (P interaction <0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression.

Conclusions:

The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.     

The impact of plasma epstein–barr virus DNA and fibrinogen on nasopharyngeal carcinoma prognosis: an observational study

Background:

The impact of combining plasma fibrinogen levels with Epstein–Barr Virus DNA (EBV DNA) levels on the prognosis for patients with nasopharyngeal carcinoma (NPC) was evaluated.

Methods:

In this observational study, 2563 patients with non-metastatic NPC were evaluated for the effects of circulating plasma fibrinogen and EBV DNA levels on disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS).

Results:

Compared with the bottom biomarker tertiles, TNM stage-adjusted hazard ratios (HR, 95% confidence intervals (CIs)) for predicting DFS in fibrinogen tertiles 2 to 3 were 1.26 (1.00 to 1.60) and 1.81 (1.45 to 2.26), respectively; HR for EBV DNA tertiles 2 to 3 were 1.49 (1.12 to 1.98) and 4.24 (3.27 to 5.49), respectively. After additional adjustment for established risk factors, both biomarkers were still associated (P for trend <0.001) with reduced DFS (HR: 1.79, 95% CI, 1.43 to 2.25 for top fibrinogen tertiles; HR: 4.04, 95% CI: 3.10 to 5.27 for top EBV DNA tertiles compared with the bottom tertiles). For patients with advanced-stage disease, those with high fibrinogen levels (⩾3.34 g l⁻¹) presented with worse DFS, regardless of EBV DNA ⩾4000 or <4000 copies ml⁻¹ subgroup. Similar findings were observed for DMFS and OS.

Conclusions:

Circulating fibrinogen and EBV DNA significantly correlate with NPC patients survival. Combined fibrinogen and EBV DNA data lead to improved prognostic prediction in advanced-stage disease.     

Tumour-infiltrating inflammation and prognosis in colorectal cancer: systematic review and meta-analysis

Background:

The role of tumour-infiltrating inflammation in the prognosis of patients with colorectal cancer (CRC) has not been fully evaluated. The primary objective of our meta-analysis was to determine the impact of tumour-infiltrating inflammation on survival outcomes.

Methods:

Ovid MEDLINE and EMBASE were searched to identify studies reporting the prognostic significance of tumour-infiltrating inflammation for patients with CRC. The primary outcome measures were overall survival (OS), cancer-specific survival (CS) and disease-free survival (DFS).

Results:

A total of 30 studies involving 2988 patients were identified. Studies were subdivided into those considering the associations between CRC survival and generalised tumour inflammatory infiltrate (n=12) and T lymphocyte subsets (n=18). Pooled analyses revealed that high generalised tumour inflammatory infiltrate was associated with good OS (HR, 0.59; 95% CI, 0.48–0.72), CS (HR, 0.40; 95% CI, 0.27–0.61) and DFS (HR, 0.72; 95% CI, 0.57–0.91). Stratification by location and T lymphocyte subset indicated that in the tumour centre, CD3⁺, CD8⁺ and FoxP3⁺ infiltrates were not statistically significant prognostic markers for OS or CS. In the tumour stroma, high CD8⁺, but not CD3⁺ or FoxP3⁺ cell infiltrates indicated increased OS. Furthermore, high CD3⁺ cell infiltrate was detected at the invasive tumour margin in patients with good OS and DFS; and high CCR7⁺ infiltrate was also indicated increased OS.

Conclusion:

Overall, high generalised tumour inflammatory infiltrate could be a good prognostic marker for CRC. However, significant heterogeneity and an insufficient number of studies underscore the need for further prospective studies on subsets of T lymphocytes to increase the robustness of the analyses.     

Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in testicular germ cell tumours

Background:

Cisplatin cures over 80% of testicular germ cell tumours (TGCTs), and nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. We explored the association between NER proteins and their polymorphisms with cisplatin sensitivity (CPS) and overall survival (OS) of patients with non-seminomatous (ns)-TGCTs.

Methods:

The expression of ERCC1 and XPA and the presence of γH2AX were evaluated in cancer cell lines and in fresh ns-TGCTs. The ERCC1 protein was also determined in ns-TGCTs. The differences between CPS and non-CPS cell lines and patients were analysed by Student''s t- or χ²-tests. The differences in OS were analysed using the log-rank test, and the hazard ratios (HRs) were calculated using the Cox model.

Results:

High ERCC1 expression was observed in the non-CPS cells, and both ERCC1 and γH2AX expressions were augmented after cisplatin treatment. Increased ERCC1 expression was also identified in non-CPS patients. Neither polymorphism was associated with either CPS or OS. The presence of ERCC1 was associated with non-CPS (P=0.05) and adjusted in the prognosis groups. The HR in ERCC1-negative and non-CPS patients was >14.43, and in ERCC1-positive and non-CPS patients the HR was >11.86 (P<0.001).

Conclusions:

High levels of ERCC1 were associated with non-CPS, suggesting that ERCC1 could be used as a potential indicator of the response to cisplatin and prognosis in ns-TGCTs.     

Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer

Background:

Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study.

Methods:

DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM.

Results:

Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71–1.17)) or OS (HR 0.95 (0.71–1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37–0.85) for RAS MT and HR 0.69 (0.5–0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic.

Conclusion:

Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.     

Small bowel adenocarcinoma phenotyping,a clinicobiological prognostic study

Background:

Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking.

Methods:

Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated.

Results:

We obtained samples from 63 SBA patients (tumour stages: I–II: 30% III: 35% IV: 32% locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P<0.001), WHO PS 0–1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0–1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0–1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS.

Conclusion:

This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.     

Prognostic factors in elderly patients with malignant pleural mesothelioma: results of a multicenter survey

Background:

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. There are no specific guidelines for their management.

Methods:

The clinical records of elderly patients (⩾70 years old) with MPM referred from January 2005 to November 2011 to six Italian Centres were reviewed. Age, gender, histology, International Mesothelioma Interest Group (IMIG) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were analysed and correlated to overall survival (OS).

Results:

In total, 241 patients were identified. Charlson Comorbidity Index was ⩾1 in 92 patients (38%). Treatment was multimodality therapy including surgery in 18, chemotherapy alone in 180 (75%) and best supportive care in 43 cases (18%). Chemotherapy was mainly pemetrexed based. Median OS was 11.4 months. Non-epithelioid histology (HR 2.32; 95% CI 1.66–3.23, P<0.001), age ⩾75 years (HR 1.44; 95% CI 1.08–1.93, P=0.014), advanced (III–IV) stage (HR 1.47; 95% CI 1.09–1.98, P=0.011) and CCI⩾1 (HR 1.38; 95% CI 1.02–1.85, P=0.034) were associated to a shorter OS. Treatment with pemetrexed was associated with improved OS (HR 0.40; 95% CI 0.28–0.56, P<0.001).

Conclusions:

Non-epithelioid histology, age ⩾75 years, advanced IMIG stage and presence of comorbidities according to CCI were significant prognostic factors in elderly patients with MPM. Treatment with pemetrexed-based chemotherapy was feasible in this setting. Prospective dedicated trials in MPM elderly patients selected according to prognostic factors including comorbidity scales are warranted.     

The derived neutrophil to lymphocyte ratio is an independent prognostic factor in patients with diffuse large B-cell lymphoma

Background:

With growing evidence on the role of inflammation in cancer biology, the systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. Recently, the derived neutrophil to lymphocyte ratio (dNLR) has been proposed as an easily determinable prognostic factor in cancer patients. Nevertheless, its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients has never been explored.

Methods:

Data from 290 consecutive DLBCL patients, diagnosed between 2004 and 2013 at a single Austrian centre, were evaluated retrospectively. The prognostic influence of the dNLR and other clinico-pathological factors including age, lactate dehydrogenase, cell of origin category and Ann Arbor stage on 5-year overall- (OS) and disease-free (DFS) survival was studied by Kaplan–Meier curves. To evaluate the independent prognostic relevance of dNLR, univariate and multivariate Cox regression models were applied.

Results:

An independent significant association between high dNLR and poor clinical outcome in multivariate analysis for OS (HR=2.02, confidence interval (CI) 95%=1.17–3.50, P=0.011), as well as DFS (HR=2.15, CI 95%=1.04–4.47, P=0.038), was identified.

Conclusion:

In the present study, we showed that a high dNLR at diagnosis of DLBCL represents an independent poor prognostic factor for clinical outcome. Our data encourage the further validation of this easily available parameter in prospective studies and as a potential stratification tool in clinical trials.     

Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma

Background:

We retrospectively analyzed sunitinib outcome as a function of age in metastatic renal cell carcinoma (mRCC) patients.

Methods:

Data were pooled from 1059 patients in six trials. Kaplan–Meier estimates of progression-free survival (PFS) and overall survival (OS) were compared by log-rank test between patients aged <70 (n=857; 81%) and ⩾70 (n=202; 19%) years.

Results:

In first-line patients, median PFS was comparable in younger and older patients, 9.9 vs 11.0 months, respectively (HR, 0.89; 95% CI: 0.73–1.09; P=0.2629), as was median OS, 23.6 vs 25.6 months (HR, 0.93; 95% CI: 0.74–1.18; P=0.5442). Similarly, in cytokine-refractory patients, median PFS was 8.1 vs 8.4 months (HR, 0.79; 95% CI: 0.49–1.28; P=0.3350), while median OS was 20.2 vs 15.8 months (HR, 1.14; 95% CI: 0.73–1.79; P=0.5657). Some treatment-emergent adverse events were significantly less common in younger vs older patients, including fatigue (60% vs 69%), cough (20% vs 29%), peripheral edema (17% vs 27%), anemia (18% vs 25%), decreased appetite (13% vs 29%), and thrombocytopenia (16% vs 25% all P<0.05). Hand–foot syndrome was more common in younger patients (32% vs 24%).

Conclusions:

Advanced age should not be a deterrent to sunitinib therapy and elderly patients may achieve additional clinical benefit.