Preoperative lymphocyte count is an independent prognostic factor in node-negative non-small cell lung cancer

A number of prognostic factors have been reported in non-small cell lung cancer (NSCLC). Although lymph node metastasis is the most poorly predictive value in completely resected NSCLC, a significant number of patients have a fatal recurrence even in node-negative curative NSCLC. Recently inflammatory response has been shown as a predictive value in NSCLC. Neutrophils and lymphocytes play an important role in cancer immune response. In this study, we retrospectively examined the impact of preoperative peripheral neutrophil and lymphocyte counts on survival, and investigated the relationships of these factors to clinicopathological factors in node-negative NSCLC. A total 237 patients were evaluated. When the cut-off value of neutrophil count was 4500 mm⁻³ with a maximum log-rank statistical value, overall 5-year survival rates were 79.7% for the low-neutrophil-count group and 69.5% for the high-neutrophil-count group (P = 0.04). When the cut-off value of lymphocyte count was 1900 mm⁻³ with a maximum log-rank statistical value, overall survival rates were 67.9% for the low-lymphocyte group and 87.7% for the high-lymphocyte group (P < 0.001). High-neutrophil-counts were associated with tumor size (P = 0.002) and pleural invasion (P < 0.001). Low-lymphocyte-counts were correlated with vascular invasion (P = 0.018) and recurrence of NSCLC (P = 0.01). Multivariate analysis showed that the lymphocyte count was an independent prognostic factor (hazard ratio: 3.842; 95% confidence interval: 1.827-8.078; P < 0.001), but the neutrophil count was not (P = 0.185). We conclude that a peripheral lymphocyte count, which is associated with vascular invasion, is an independent prognostic factor in node-negative NCSLC.     

Effect of lymphoid volume irradiation on radiation-induced lymphopenia in head and neck cancers

PurposeRadiotherapy induces significant and prolonged lymphopenia in head and neck cancer patients with poorer outcomes and reduced survival. Irradiated volumes may be correlated with lymphopenia with a potential impact on immunotherapy efficacy. We assessed associations between volumes treated with radiotherapy and the nadir of the lymphocyte count in patients with head and neck cancer.Materials and methodsWe conducted a monocentric retrospective study in patients with head and neck cancer treated with radiation. Univariate analysis used regression analysis to model nadir lymphocyte count and radiotherapy volumes; multivariate analysis then modelled factors associated with nadir lymphocyte count.ResultsOf the 77 included patients, 97% presented lymphopenia during radiotherapy with an average nadir of 431 cells/mm³ at a median of 40 days after the beginning of treatment. The volume of high-risk radiotherapy and gross tumour volume were correlated with nadir lymphocyte count with a Spearman coefficient of −0.267 (P = 0.019) and −0.387 (P = 0.001), respectively. After multivariate linear regression, high-risk radiotherapy was significantly associated with nadir lymphocyte count with a regression coefficient of −0.32 (per cubic centimetre) [95% CI = −0.60; −0.03] (P = 0.028).ConclusionHigh-risk radiotherapy was significantly associated with nadir lymphocyte count in patients with head and neck cancer treated with radiation. Sparing lymphoid volumes from irradiation by elective nodal irradiation or proton therapy may limit lymphopenia and needs to be investigated in combination with immunotherapy.     

Analyses on clinical characteristic and prognoses of 41 patients with chronic myelomonocytic leukemia in China

PurposeTo investigate clinical characteristic and prognostic factors for chronic myelomonocytic leukemia (CMML).MethodsA retrospective cohort study was used in the research. We investigated clinical and laboratory characteristics of CMML patients and survival status. Patients were followed up regularly through out the course of the research.ResultsForty-one cases were diagnosed as CMML, including 27 male and 14 female patients. Median WBC was 13.7 × 10⁹/L. Five patients had leukocytopenia (1.92–3.46 × 10⁹/L). Median monocyte count in the peripheral blood was 2.13 × 10⁹/L. All patients presented with bone marrow dysplasia, and most showed hyperplasia, except 3 cases. Abnormal chromosome was detected in 34% cases. Median survival time for CMML-1 and CMML-2 was 20 and 12 months, respectively, but there were no statistical significance of survival duration between them. Univariable analysis showed that age (>60 years), neutrophil count (<2.0 × 10⁹/L), lymphocyte count (<1.0 × 10⁹/L), mature monocyte count (≥5 × 10⁹/L) and anemia (Hb < 60 g/L) were associated with poor prognosis for CMML. There was no statistical significance in LDH, gender, and abnormal chromosome for survival time. Only lymphocyte count and neutrophil count in peripheral blood were independent prognostic factors for CMML after multivariate analysis.ConclusionCMML mainly occurs in elderly patients. Although most patients have leukocytosis and monocytosis at diagnosis, few cases show leucopenia and monocytopenia. Age, neutrophil, lymphopenia, monocytosis, and severe anemia are associated with inferior prognosis of CMML. Lymphocyte < 1.0 × 10⁹/L and neutrophil count < 2.0 × 10⁹/L are adversely independent prognostic factors for CMML.     

Prognostic value of platelet-associated biomarkers in rectal cancer patients received neoadjuvant chemoradiation: A retrospective study

PurposePlatelet volume has been shown to prognostic value in patients with colorectal cancer. However, the changes of other platelet-associated biomarkers in rectal cancer patients, before and after the neoadjuvant chemoradiation therapy (NACRT), remain unclear. In this study, we investigated the prognostic value of platelet-associated biomarkers in rectal cancer patients with NACRT.Patients and methodsA total of 75 patients with locally advanced (T3–4 or N+) rectal cancer (LARC) cancer were selected and followed up from the Affiliated Cancer Hospital of Zhengzhou University between June 2013 and September 2016. The data of platelet-associated biomarkers, including the platelet count, platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), mean platelet volume (MPV), and platelet distribution width (PDW) both pre- and post- NACRT, were collected. The associations between these platelet-associated biomarkers and the overall survival (OS), as well as disease-free survival (DFS) of patients, were analysed. Patients were divided into groups with high or low values of the platelet-associated biomarkers, and the outcomes were compared by using Cox regression and Kaplan–Meier analysis.ResultsWe found that pre-PLR (HR: 4.104; 95%CI: 1.411–11.421; P = 0.009) and pre-LMR (HR: 0.384; 95%CI: 0.124–1.185; P = 0.066) could predict the OS in LARC patients after NACRT by multivariate Cox regression analysis, a cut-off value of pre-PLR > 7.02 and pre-LMR ≤ 7.10 could be used as independent prognostic factors for OS by Kaplan–Meier method. The pre-MPV value could be used as an independent prognostic factor for DFS by Kaplan–Meier analysis (P = 0.037). Moreover, post-CEA was correlated with OS and DFS in LARC patients with NACRT.ConclusionIn LARC patients with NACRT, the pre-PLR and pre-LMR are independent prognostic factors for OS, while pre-MPV has predictive value for DFS.     

Prognostic role of pretreatment blood neutrophil-to-lymphocyte ratio in advanced cancer survivors: A systematic review and meta-analysis of 66 cohort studies

BackgroundNeutrophil-to-lymphocyte ratio (NLR) is crucial for the incidence and mortality of various tumors. However, little is known on NLR and its association with prognosis in advanced tumors. Here we performed a meta-analysis to establish the prognostic significance of pretreatment blood NLR for advanced tumors.MethodsA systematic literature search through April 2016 was performed to evaluate the association between pretreatment blood NLR and overall survival (OS) or progression-free survival (PFS) in patients with advanced tumors. Data were extracted from studies reporting hazard ratios (HRs) and 95% confidence interval (CI) and pooled using the Mantel–Haenszel random-effect model.ResultsSixty-six studies with a total of 24536 individuals were included in the meta-analysis. Pooled analyses revealed that elevated pretreatment NLR was associated with worse OS (HR 1.70, 95% CI 1.57–1.84, P < 0.001) and PFS (HR 1.61, 95% CI 1.42–1.82, P < 0.001) in advanced tumors. Subgroup analysis stratified by tumor type demonstrated that pancreatic cancer patients with high pretreatment NLR had the worst OS (HR 1.94, 95% CI 1.55–2.54, P < 0.001) and colorectal cancer with the worst PFS (HR 1.74, 95% CI 1.04–2.90, P < 0.001). When stratified by cut-off value for NLR, we found that cut-off value being five indicated the worst PFS (HR 2.23, 95% CI 1.54–3.23, P = 0.019).ConclusionsOverall, high pretreatment blood NLR could be an adverse prognostic indicator for advanced tumor. Large-scale prospective studies investigating its survival outcomes in specific cancer type are strongly advocated.     

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO

BackgroundNeutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial.Patients and methodsPts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution.ResultsNLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05–1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25–1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14–1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95–1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64–1.08)] and high [HR 0.73 (95% CI 0.54–0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62–1.12) for low NLR; HR 0.82 (95% CI 0.59–1.12) for high NLR].ConclusionThis study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.     

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

BackgroundWe analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).Patients and methodsALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.ResultsAmong 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).ConclusionsIn ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.     

Patients with metastatic breast cancer leading to CD4+ T cell lymphopaenia have poor outcome

BackgroundLow lymphocyte count is a prognostic factor in cancer patients including metastatic breast cancer patients (MBC) but the relative role of each lymphocyte subtype is unclear in MBC.MethodsThe impact of lymphocyte subsets was analysed in two prospective MBC patients’ cohorts. Cohort A patients (n = 103) were included before the first line of chemotherapy and cohort B patients (n = 101) were included after at least one line of chemotherapy. Extensive phenotypic analyses were performed on fresh whole blood. Plasma cytokines levels were measured using commercially available Luminex-based multiplex kits. Prognostic value of lymphocyte subsets and circulating cytokines was analysed.ResultsIn both cohorts, severe lymphopaenia (<0.7 Giga/L) correlated with poor overall survival (OS) (median OS: 6.6 months versus 21.7 months in cohort A and 4.5 versus 9 months in cohort B). CD8⁺, CD19⁺ and CD56⁺ T cell counts had no significant prognostic value for OS. After stratification (?0.2, [0.20–0.45], >0.45 Giga/L), CD4 lymphopaenia appeared to be correlated with poor OS in both cohorts. Furthermore, severe CD4⁺ lymphopaenia (?0.2 Giga/L) was strongly correlated with poor OS in both cohorts (1.2 months versus 24.9 months in cohort A and 5.7 versus 13.1 months in cohort B). In multivariate analysis, after stratification CD4⁺ lymphopaenia appeared to be an independent prognostic factor for OS in both cohorts. CD4⁺ lymphopaenia correlated with low plasmatic levels of CCL22 that might directly contribute to CD4⁺ lymphopaenia.ConclusionsCD4⁺ lymphopaenia was associated with reduced OS in MBC patients regardless of the chemotherapy line. Decreased levels of plasmatic CCL22 may contribute to CD4⁺ lymphopaenia.     

Optimal duration of first-line chemotherapy for advanced non-small cell lung cancer: A systematic review with meta-analysis

BackgroundThe optimal duration of first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) has been a matter for debate for nearly 20 years. In order to elucidate this issue, a meta-analysis comparing the different durations of same treatments was performed.MethodsWe searched for all published randomised controlled trials (RCTs) comparing different durations of first-line treatment of advanced NSCLC. The MEDLINE, EMBASE, LILACS and CENTRAL databases were searched for RCTs comparing a defined number of cycles of chemotherapy versus continuing treatment until disease progression, or a defined number of cycles versus a higher number of cycles of the same chemotherapy. Trials including biological agents were excluded.ResultsSeven trials that included 1559 patients were analysed. Treatment for more than 4 cycles was associated with a non-statistically significant decrease in the hazard of mortality relative to shorter treatment (hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.84–1.11; P = .65). In those treated with third-generation chemotherapy through the whole study time, treatment for more than 4 cycles was associated with a non-statistically significant increase in mortality (HR = 1.08; 95% CI = 0.90–1.28; P = .28). Patients receiving more chemotherapy had significant longer progression-free survival (HR = .75; 95% CI = 0.60–0.85; P < 0.0001) than the group with shorter duration of treatment. In an intent-to-treat analysis, there was no difference in the overall response rate between the groups (odds ratio (OR) = 0.78; 95% CI = 0.60–1.01; P = .96). Longer treatment was associated with more severe leucopaenia but with no significant increase in non-haematological toxicities.ConclusionsIn patients with advanced NSCLC the use of more than 4 cycles of first-line chemotherapy with third-generation regimens significantly increases progression-free survival but not overall survival and is associated with higher incidence of adverse events. There is no evidence to support continuous chemotherapy until progression in patients with lung cancer.     

Effects of erlotinib first-line maintenance therapy versus placebo on the health-related quality of life of patients with metastatic non-small-cell lung cancer

IntroductionMaintenance therapy can delay progression and prolong survival in metastatic non-small-cell lung cancer (mNSCLC). As treatment for mNSCLC is non-curative, its impact on patient health-related quality of life (HRQoL) is an important consideration. SATURN (Sequential Tarceva in Unresectable NSCLC) was a randomised, double-blind, placebo-controlled, multicentre study investigating the impact of erlotinib maintenance therapy on HRQoL in patients with locally advanced or recurrent NSCLC.Patients and MethodsEligible patients who had previously completed four cycles of platinum-based chemotherapy were randomised 1:1 to receive erlotinib 150 mg/day or placebo until disease progression, unacceptable toxicity or death. Patient HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung questionnaire, in terms of time to symptom progression (TSP), time to deterioration (TTD) in Trial Outcome Index (TOI) and TTD. Exploratory analysis was based on time to analgesia and appearance of key symptoms (pain, cough and dyspnoea).ResultsCompared with placebo, erlotinib maintenance therapy prolonged progression-free and overall survival by 41% and 23%, respectively. At baseline, HRQoL measures were comparable between the two treatment groups. Maintenance therapy with erlotinib did not impact on deterioration in HRQoL: TSP (hazard ratio [HR] = 0.91 [95% confidence interval (CI) 0.74–1.12]; n = 785), TTD in TOI (HR = 1.06 [95% CI 0.87–1.31]; n = 781) and TTD in HRQoL (HR = 0.96 [95% CI 0.79–1.16]; n = 776). Time to pain and time to analgesic use were significantly delayed in patients receiving erlotinib compared with placebo (HR = 0.61 [95% CI 0.42–0.88]; p = 0.0080 and HR = 0.66 [95% CI 0.46–0.94]; p = 0.0199, respectively). A non-significant trend towards delayed time to cough and time to dyspnoea (HR = 0.77 [95% CI 0.49–1.21] and HR = 0.75 [95% CI 0.48–1.17], respectively) was also observed.ConclusionsErlotinib maintenance therapy significantly extends progression-free survival without compromising patient HRQoL in comparison with placebo, with some improvement in symptoms.     

High pretreatment serum lactate dehydrogenase level correlates with disease relapse and predicts an inferior outcome in locally advanced nasopharyngeal carcinoma

PurposeHere, we evaluate the prognostic effect of pretreatment serum lactate dehydrogenase (LDH) in locally advanced nasopharyngeal carcinoma (NPC).Methods and materialsPretreatment serum samples from a randomized controlled trial, which contained 199 neoadjuvant chemoradiotherapy patients and 201 neoadjuvant-concurrent chemoradiotherapy cases with locally advanced NPC, were collected and examined for LDH. With 5-year follow-up, the prognostic effect of pretreatment serum LDH was analysed by Kaplan–Meier analysis and multivariate Cox regression model.ResultsThree hundred and sixty-seven patients (91.75%) had a normal (109.0–245.0 U/L) pretreatment LDH level, compared to 33 cases (8.25%) that had a higher (?245.0 U/L) LDH level. The mean and median pretreatment LDH levels of these 400 patients were 186.6 and 174.0 U/L (range, 83.0–751.0 U/L), respectively. Compared with the normal subset, elevated LDH level predicted an inferior 5-year overall survival (56.9% versus 76.8%, P = 0.004), disease-free survival (DFS, 45.4% versus 64.7%, P = 0.001), local relapse-free survival (76.1% versus 89.6%, P = 0.019) and distant metastasis-free survival (DMFS, 54.3% versus 72.2%, P = 0.001). Multivariate analysis confirmed that the LDH level was an independent prognostic factor to predict death, disease progression, local relapse and distant metastasis. For the subgroup with normal LDH (median point of 177.0 U/L), we detected an evident 5-year DFS (68.8% versus 59.5%, P = 0.047) and DMFS advantage (77.3% versus 65.3%, P = 0.016) in 109.0–177.0 U/L subset than that of 178.0–245.0 U/L subgroup.ConclusionsSerological LDH level was an independent prognostic factor for locally advanced NPC. Combining pretreatment LDH with TNM staging might lead to more accurate risk definition.     

Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients

BackgroundThe purpose of this study is to investigate the prognostic role of insulin-like growth factor receptor 1 (IGF1R) expression in surgically resected non-small-cell lung cancer (NSCLC).Patient characteristics and methodsThis retrospective study was conducted in 369 stage I–II–IIIA, surgically resected, NSCLC patients. Patients exposed to anti-epidermal growth factor receptor (EGFR) agents were excluded. IGF1R expression was evaluated by immunohistochemistry in tissue microarray sections.ResultsA positive IGF1R expression (score ≥ 100) was observed in 282 cases (76.4%) and was significantly associated with squamous cell histology (P = 0.04) and with grade III differentiation (P = 0.02). No difference in survival was observed between the positive and negative group when score 100 was used as cut-off for discriminating a positive versus a negative IGF1R result (52 versus 48 months, P = 0.99) or when median value of IGF1R expression was used (45 versus 55 months, P = 0.36). No difference in survival was observed between IGF1R-positive and -negative patients in a subgroup of stage I–II adenocarcinoma (n = 137) with known EGFR mutation and copy number status.ConclusionsIGF1R expression does not represent a prognostic factor in resected NSCLC patients. Patients with squamous cell carcinoma overexpress IGF1R more frequently than patients with nonsquamous histology, justifying the different sensitivity to anti-IGF1R agents observed in clinical trials.     

The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival

BackgroundThe aim of this study is to investigate the prognostic role of phosphorylated AMP-activated protein kinase (pAMPK) in surgically resected non-small-cell lung cancer (NSCLC).MethodsImmunohistochemical staining of pAMPK was carried out on tissue microarrays containing 463 samples obtained from patients with NSCLC and correlated with clinicopathological characteristics and survival.ResultspAMPK expression levels were significantly higher in never smokers versus former smokers versus current smokers (P = 0.045). A positive pAMPK expression was associated with increased overall survival (OS) and recurrence-free survival (RFS) (P = 0.0009 and P = 0.0007, respectively). OS and RFS were statistically superior in pAMPK-positive than in pAMPK-negative patients with adenocarcinoma (ADC; median OS: 5.6 and 4.2 years, respectively, P = 0.0001; median RFS: 5.0 and 2.4 years, respectively, P = 0.001), whereas they were similar in those patients with squamous cell carcinoma. Multivariate analysis confirmed that pAMPK positivity was associated with OS [hazard ratio (HR) = 0.574, 95% confidence interval (CI) 0.418–0.789, P = 0.0006) and RFS (HR = 0.608, 95% CI 0.459–0.807, and P = 0.0006), independent of clinical covariates.ConclusionsHigh pAMPK expression levels are associated with increased survival in patients with NSCLC, especially those with ADC. Our results support further evaluation of AMP-activated protein kinase as a potential prognostic and therapeutic target for lung cancer.     

Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer

BackgroundIn clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)—particularly near the cut-off defining positive status—and clinical outcomes have been limited by small sample sizes.Patients and methodsData were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively.ResultsOf 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%–19% ALK-positive cells; of ALK-negative patients, 2% had 10%–14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%–19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17).ConclusionsPatients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.     

Role of emphysema and airway obstruction in prognosis of lung cancer

Background and objectiveIt has been reported that the presence of COPD and emphysema is associated with an increased risk of lung cancer, but the prognosis significance of these two conditions is not well known. The aim of our study was to analyze the influence of COPD and emphysema in the prognosis of non-small cell lung cancer (NSCLC).MethodsThree hundred and fifty-three patients with cytohistologic diagnosis of NSCLC were prospectively collected. The relationship between survival at two years and the following variables: age, sex, smoking habit, comorbid diseases (cardiovascular diseases, previous tumour and COPD), weight loss, presence of emphysema on CT scan, performance status (PS) and treatment, was analyzed. The Kaplan–Meier method and log-rank test were used for survival analysis. A multivariate Cox proportional hazard model, stratified by TNM stage, was used to evaluate prognostic factors.ResultsEmphysema was present in 110 patients, associated with COPD in 78 (70.9%). In univariate analysis, survival decreased with age > 70 years (p = 0.01), presence of emphysema (p = 0.02), weight loss (p = 0.00001), PS ≥ 2 (p = 0.00001) and symptomatic treatment (p = 0.0001). Multivariate analyses identified emphysema (HR = 1.49 (95% CI 1.11–2.01)), PS ≥ 2 (HR = 2.12 (95% CI 1.31–3.38)) and treatment: surgery (HR = 0.3 (95% CI 0.15–0.56)) and chemotherapy (HR = 0.34 (95% CI 0.31–0.57)) as independent prognostic factors.ConclusionThe presence of emphysema affects the prognostic outcome of patients with non-small cell lung cancer. Emphysema should therefore be considered for prognostic studies on comorbidity.     

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment

BackgroundThe efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.Patients and methodsWe identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).ResultsIn cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8⁺ TIL density and nonsynonymous mutation burden.ConclusionT790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.     

Local recurrence following breast-conserving treatment in women aged 40 years or younger: Trends in risk and the impact on prognosis in a population-based cohort of 1143 patients

AimTo evaluate trends in the risk of local recurrences after breast-conserving treatment (BCT) and to examine the impact of local recurrence (LR) on distant relapse-free survival in a large, population-based cohort of women aged ?40 years with early-stage breast cancer.MethodsAll women (n = 1143) aged ?40 years with early-stage (pT1-2/cT1-2, N0-2, M0) breast cancer who underwent BCT in the south of the Netherlands between 1988 and 2010 were included. BCT consisted of local excision of the tumour followed by irradiation of the breast.ResultsAfter a median follow-up of 8.5 (0.1–24.6) years, 176 patients had developed an isolated LR. The 5-year LR-rate for the subgroups treated in the periods 1988–1998, 1999–2005 and 2006–2010 were 9.8% (95% confidence interval (CI) 7.1–12.5), 5.9% (95% CI 3.2–8.6) and 3.3% (95% CI 0.6–6.0), respectively (p = 0.006). In a multivariate analysis, adjuvant systemic treatment was associated with a reduced risk of LR of almost 60% (hazard ratio (HR) 0.42; 95% CI 0.28–0.60; p < 0.0001). Patients who experienced an early isolated LR (?5 years after BCT) had a worse distant relapse-free survival compared to patients without an early LR (HR 1.83; 95% CI 1.27–2.64; p = 0.001). Late local recurrences did not negatively affect distant relapse-free survival (HR 1.24; 95% CI 0.74–2.08; p = 0.407).ConclusionLocal control after BCT improved significantly over time and appeared to be closely related to the increased use and effectiveness of systemic therapy. These recent results underline the safety of BCT for young women with early-stage breast cancer.     

High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients

BackgroundInsulin-like growth factor receptor-1 (IGFR-1) represents a novel molecular target in non-small-cell lung cancer (NSCLC). IGFR-1 and epidermal growth factor receptor (EGFR) activation is essential to mediate tumor cell survival, proliferation and invasion. We explored the correlation between IGFR-1 and EGFR, their relationship with clinicopathological parameters and their impact on outcome in resected stage I–III NSCLC patients.Patients and methodsTumors from 125 surgical NSCLC patients were evaluated for IGFR-1 and EGFR expression by immunohistochemistry. Kaplan–Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis.ResultsIGFR-1 protein overexpression was detected in 36.0% of NSCLC patients and was associated with larger tumor size (P = 0.04) but not with other clinical or biological characteristics. EGFR protein overexpression was observed in 55.2% of NSCLC, more frequently in squamous cell carcinoma (SCC) than non-SCC (63.7% versus 36.3%, χ² = 9.8, P = 0.001). IGFR-1 protein expression was associated with EGFR protein expression (P = 0.03). At the multivariate analysis, high coexpression of both IGFR-1 and EGFR was a significant prognostic factor of worse disease-free survival (DFS) (hazard ratio 2.51, P = 0.01).ConclusionA statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.     

Serum inflammatory miRNAs predict radiation esophagitis in patients receiving definitive radiochemotherapy for non-small cell lung cancer

Background and purposeMicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC).Material and methodsWe measured serum miR-155, miR-221 and miR-21, before and during week 1–2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression.ResultsWe found that patients with stage IIIB–IV disease, higher mean esophagus dose or esophageal V₅₀ had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1–2 of CRT were also risk factors for severe RIET (miR-155: OR = 1.53, 95% CI: 1.04–2.25, P = 0.03; miR-221: OR = 2.07, 95% CI: 1.17–3.64, P = 0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR = 1.18, 95% CI: 1.02–1.37, P = 0.026). However, pretreatment miRNAs was not predictive of severe RIET.ConclusionsHigh serum miR-155 and miR-221 during the first 2 weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity.