The overall survival of lung cancer patients is disappointingly low. This is due to several factors, including the lack of an effective screening strategy to detect tumors at a potentially curable ...early stage, a marked resistance of lung cancer cells to drug treatment and a still superficial knowledge about the multifactorial cellular networks that are activated or suppressed during cancer progression. Furthermore, the armamentarium of clinicians and researchers in the field does not yet include reliable biomarkers to predict tumor response to treatment and foresee the natural history of the disease. In the present situation, a potential breakthrough is presented by proteomics technologies with the potential to discover relevant biomarkers which can be accurately quantified in multiplexed assays. Proteomics field can also contribute greatly in the understanding of mechanisms in tumor progression and treatment response.
In this review we will describe the work that is being done in the field of lung cancer proteomics, focusing on clinically relevant questions that need to be addressed and on the possible applications of novel technologies.
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Abstract
Background. The 7th TNM staging system for non-small cell lung cancer (NSCLC) developed by the International Association for the study of Lung Cancer (IASLC) has been applied in Sweden since ...the beginning of the year 2010. The aim of this retrospective study was to evaluate the prognostic role of the 7th TNM staging system in a surgical Swedish patient cohort with node-negative NSCLC. Material and methods. We collected data from stage I patients (pT1-2 pN0, 6th TNM system) who underwent surgery for NSCLC at Karolinska University Hospital from 1987 to 2002. Tumors were restaged according to the 7th TNM version. Cox multivariate survival analysis was implemented in order to determine the prognostic impact of pathological stage when classified according to either the 6th or the 7th TNM systems. Results. The patient population consisted of 452 subjects. Tumor size was ≤ 3 cm in 51% of cases. The predominant histology was adenocarcinoma (53%) and lobectomy was the most common surgical procedure (82% of patients). The five-year survival rate in patients with stage IA vs. IB (6th TNM) was 62% vs. 51%, respectively (log-rank p = 0.036). Corresponding figures for the 7th TNM system were 70% in stage IA-T1a, 51% in stage IA-T1b, 54% in stage IB, 51% in stage IIA and 35% in stage IIB (log-rank p = 0.002). On multivariate analysis, adjusted by age, gender, histology, kind of surgery, grade of differentiation and smoking status, pathological stage was an independent prognostic factor if classified according to the 7th TNM version (p = 0.001), but not if scored according to the 6th TNM edition (p = 0.090). Conclusion. The 7th TNM classification system is a more accurate predictor of prognosis in stage I operated patients than the old classification. The new system should be implemented even on retrospective cohorts especially when investigating the prognostic implication of the expression of molecular biomarkers.
Abstract Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, randomized trials have recently demonstrated the ...efficacy of several new drugs (pemetrexed, bevacizumab, cetuximab, erlotinib, gefitinib) in this setting. Hence, the choice of optimal treatment is no longer limited to the different platinum-based doublets. In order to guide clinical management of patients with advanced NSCLC, assess the strengths and limitations of available evidence, and to suggest priorities for clinical research, the Italian Association of Thoracic Oncology organized an International Expert Panel Meeting on the first-line treatment of advanced NSCLC, which took place in Sperlonga (Italy) in May 2009. Experts recommended that every effort should be made to obtain adequate tumor tissue before initiating treatment. Tumor histology/cytology subtyping is now important for the correct choice of treatment. In particular, considering efficacy data obtained with pemetrexed and safety concerns with bevacizumab, a division between squamous and non-squamous tumors is necessary. Epidermal growth factor receptor ( EGFR ) mutation analysis, at present, is not recommended in all patients, but should be performed in subgroups of patients characterized by higher prevalence of sensitizing mutations (Asians, never smokers, women, adenocarcinoma). When a mutation is present, first-line treatment with single-agent EGFR tyrosine-kinase inhibitor may be considered. Finally, the potential benefit of maintenance treatment for patients without progression at the end of first-line should be carefully discussed with each patient. Although the number of treatment options for patients with advanced NSCLC has increased recently, their results remain modest and further research is mandatory.
We analysed patients with advanced non–small cell lung cancer (NSCLC) who were treated with immune-checkpoint inhibitors (ICIs) to address the effect of the timeline and reason for corticosteroid ...administration on survival outcomes.
We retrospectively collected clinical data of non-oncogenic driven, advanced NSCLC patients treated with ICIs at Karolinska University Hospital, including the timeline and reason for steroid administration. Steroid administration was defined as > 10 mg prednisolone equivalent for ≥10 days. We subcategorized patients based on the aetiology of steroid administration into three subgroups: a) steroids for supportive reasons but not for cancer palliation; b) steroids for the palliation of cancer-related symptoms; c) steroids for the management of immune-related adverse events (irAEs). Furthermore, to analyse the timeline, patients were categorised into two groups; those who received corticosteroids within 2 weeks before until 2 days after ICI initiation and those who received steroids later during their treatment course.
Analysed data from 196 patients showed 46.3% of patients received corticosteroids. Steroid administration due to irAEs did not affect overall survival (OS) (p = 0.38) compared with the steroid naïve group. Only steroid administration for the palliation of cancer-related symptoms was an independent predictor for shorter OS (HR = 2.7; 95% CI, 1.5–4.9). The timeline of steroid administration did not affect OS (p = 0.456) in our cohort.
Steroids due to irAEs do not appear to hamper ICI efficacy. However, the administration of high-dose steroids to palliate malignancy-associated symptoms might reflect the dismal prognosis of this patient group.
•Steroid administration for cancer palliation was linked with poor patient outcomes.•Steroid administration due to immune-related adverse events did not affect patient survival outcomes.•Careful patient selection is warranted before immunotherapy initiation.
Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and ...NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors RECIST version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC.
After failure of first-line chemotherapy for advanced non-small cell lung cancer, many patients remain candidates to receive further antitumor treatment. To guide clinical management of these ...patients and to suggest priorities for clinical research, an International Panel of Experts met in Naples (Italy) in April 2007. Results and evidence-based conclusions are presented in this article. Single-agent chemotherapy with docetaxel or pemetrexed is the recommended option for unselected patients with performance status 0 to 2 who are candidates for second-line chemotherapy for advanced non-small cell lung cancer. Docetaxel has demonstrated superiority compared with best supportive care. Pemetrexed has been shown to be noninferior to docetaxel, with a more favorable toxicity profile. Erlotinib is effective in pretreated patients, and can be given second-line in patients not suitable or intolerant to chemotherapy, and in all patients as third-line treatment after failure of second-line chemotherapy. Gefitinib failed to show superiority to placebo as second- or third-line treatment, but it has been shown to be noninferior to docetaxel. In selected patients such as lifetime nonsmokers or those of East-Asian ethnicity, erlotinib, or gefitinib (where licensed) may be considered as second-line treatment even if they are fit for chemotherapy. Best supportive care in addition to active treatment remains important for all patients, but may be the exclusive option for patients unsuitable for more aggressive therapy. Further research is mandatory, to find better treatments, and to identify clinical and molecular predictive markers of efficacy, both for chemotherapy and for novel biologic agents.
•Investigate association between educational level and outcomes in SCLC patient.•The data was retrieved from the Lung Cancer Data Base in Sweden.•In patients with LD, the high education group had a ...favourable prognosis.•In men, a low level of education had a poorer prognosis compared to high education.
To examine if educational status is associated with outcome in patients with Small Cell Lung Cancer (SCLC). The study also investigated differences in patterns of management (lead times and treatment intensity) between educational levels.
This nationwide cohort study was based on data from Lung Cancer Data Base Sweden (LCBaSe) generated by record linkages between the Swedish National Lung Cancer Register and several other population-based registers. Educational level was categorized by number of years of schooling: low (≤ 9 years), medium (10–12 years) and high (≥ 13 years). Risk of death expressed as hazard ratios (HR) with 95 % confidence interval (CI) were estimated in multi-variable analyses adjusted for age, sex, disease stage at diagnosis, household size and performance status (PS). Analyses stratified by sex and stage were also performed.
The study population encompassed 4256 patients with an SCLC diagnosis between 2002 and 2011. Higher education was associated with a significantly lower risk of death in univariable and multivariable models. The univariable HR comparing high to low level of education was 0.84 (95 % CI: 0.75–0.93), an estimate that was attenuated following adjustments (HR 0.88; 95 % CI: 0.80–0.98). Compared to men with a low level of education, the risk of death was significantly lower in men with a high education; HR 0.84 (95 % CI: 0.73–0.98). In Limited Disease (LD), the prognosis was significantly better in both men and women with high compared low education (HR 0.76; 95 % CI: 0.58–0.98).
In Swedish men with SCLC, and among patients with LD-SCLC, a low level of education was associated with a poorer prognosis compared to patients with high education.
In-depth proteomics analyses of tumors are frequently biased by the presence of blood components and stromal contamination, which leads to large experimental variation and decreases the proteome ...coverage. We have established a reproducible method to prepare freshly collected lung tumors for proteomics analysis, aiming at tumor cell enrichment and reduction of plasma protein contamination. We obtained enriched tumor-cell suspensions (ETS) from six lung cancer cases (two adenocarcinomas, two squamous-cell carcinomas, two large-cell carcinomas) and from two normal lung samples. The cell content of resulting ETS was evaluated with immunocytological stainings and compared with the histologic pattern of the original specimens. By means of a quantitative mass spectrometry-based method we evaluated the reproducibility of the sample preparation protocol and we assessed the proteome coverage by comparing lysates from ETS samples with the direct lysate of corresponding fresh-frozen samples.
Cytological analyses on cytospin specimens showed that the percentage of tumoral cells in the ETS samples ranged from 20% to 70%. In the normal lung samples the percentage of epithelial cells was less then 10%. The reproducibility of the sample preparation protocol was very good, with coefficient of variation at the peptide level and at the protein level of 13% and 7%, respectively. Proteomics analysis led to the identification of a significantly higher number of proteins in the ETS samples than in the FF samples (244 vs 109, respectively). Albumin and hemoglobin were among the top 5 most abundant proteins identified in the FF samples, showing a high contamination with blood and plasma proteins, whereas ubiquitin and the mitochondrial ATP synthase 5A1 where among the top 5 most abundant proteins in the ETS samples.
The method is feasible and reproducible. We could obtain a fair enrichment of cells but the major benefit of the method was an effective removal of contaminants from red blood cells and plasma proteins resulting in larger proteome coverage compared to the direct lysis of frozen samples. This sample preparation method may be successfully implemented for the discovery of lung cancer biomarkers on tissue samples using mass spectrometry-based proteomics.
Objectives: This real-world study on small-cell lung cancer (SCLC) patients aimed to investigate treatment patterns, outcome of re-challenge with platinum doublet chemotherapy (PDCT), and ...associations between clinical characteristics and survival outcomes.
Material and methods: This retrospective single center cohort study was based on patients diagnosed with SCLC between 2008 and 2016 at the Karolinska University Hospital, Stockholm, Sweden. Patients were divided into two subgroups; limited disease (LD), receiving concomitant chemo- and radiotherapy and extensive disease (ED), receiving palliative PDCT. The progression-free survival (PFS) was defined as the interval between the start of CT and the earliest date of documented progression. 'Refractory relapse' (Rr) and 'Sensitive relapse' (Sr) were defined as relapse occurring < or ≥180 days after start of PDCT, respectively. The results for treatment patterns were reported as numbers and percentages of patients, and descriptive analyses including medians and 95% confidence intervals (CIs). The Cox proportional hazards regression model was applied to assess the relationship between clinical characteristics and overall survival (OS).
Results: The study included 544 patients; 408 with ED and 136 patients had LD. The median PFS and OS for ED patients were 5.1 and 7.0, respectively. In the ED subgroup, Sr occurred in 169 patients (41%), with a longer median OS when compared to Rr patients (10.8 vs. 3.6 months). Patients with LD had a median PFS and OS of 12 and 24 months, respectively. Some LD patients did not show a sign of relapse (22%). The majority of LD patients who relapsed had Sr (66%), with a longer median OS when compared to patients with Rr (20.9 vs. 7.8 mo).
Conclusions: The survival outcomes for ED and LD SCLC patients correspond to historical data. Patients with Sr after 1st line therapy might benefit from re-challenge with PDCT in the 2nd line setting.
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