Association between Genetic Variants and Peripheral Neuropathy in Patients with NSCLC Treated with First-Line Platinum-Based Therapy.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1−12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8−12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5−21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice.

Performance and Prospects of [68Ga]Ga-FAPI PET/CT Scans in Lung Cancer.

Fibroblast activation protein (FAP) could be a promising target for tumor imaging and therapy, as it is expressed in >90% of epithelial cancers. A high level of FAP-expression might be associated with worse prognosis in several cancer types, including lung cancer. FAPI binds this protein and allows for labelling to Gallium-68, as well as several therapeutic radiopharmaceuticals. As FAP is only expressed at insignificant levels in adult normal tissue, FAPI provides a highly specific tumor-marker for many epithelial cancers. In this review, current information on the use of [68Ga]Ga-FAPI PET/CT in lung cancer is presented. [68Ga]Ga-FAPI shows a high uptake (standardized uptake value = SUVmax) and tumor-to-background ratio (TBR) in primary lung cancer lesions, as well as in metastatic lesions of other tumor types located in the lung and in lung cancer metastases located throughout the body. Where a comparison was made to [18F]FDG PET/CT, [68Ga]Ga-FAPI showed a similar or higher SUVmax and TBR. In brain and bone metastases, [68Ga]Ga-FAPI PET/CT outperformed [18F]FDG PET/CT. In addition to this strong diagnostic performance, a possible prognostic value of [68Ga]Ga-FAPI PET/CT in lung cancer is proposed.

The association between skeletal muscle measures and chemotherapy-induced toxicity in non-small cell lung cancer patients.

BACKGROUND: Chemotherapy-induced toxicities frequently occur in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy-induced toxicity in a large cohort of NSCLC patients. METHODS: A multicentre prospective follow-up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m2 ) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy-induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non-haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose-limiting toxicity (DLT) (treatment switch, delay, de-escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI). RESULTS: In total, 297 patients (male n = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% (n = 108) of the patients, 24.6% (n = 73) experienced any non-haematological toxicity grade ≥2, and 55.6% (n = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31-4.45, P = 0.005) and age at diagnosis >65 years (ORadj 1.76, 95% CI 1.07-2.90, P = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non-haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23-4.04, P = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23-0.74, P = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT. CONCLUSIONS: Non-small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy.

Association of genetic variations in ACE2, TIRAP and factor X with outcomes in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. METHODS: We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. RESULTS: Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. CONCLUSION: This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.

Adjuvant Treatment Following Irradical Resection of Stage I-III Non-small Cell Lung Cancer: A Population-based Study.

Irradical (R1-2) resection for non-small cell lung cancer (NSCLC) is associated with a dismal prognosis. Adjuvant treatment attempts to improve survival outcomes, but evidence on the optimal strategy is limited. The purpose of this study was to compare overall survival (OS) between different adjuvant treatment strategies in these patients. Out of 8,528 patients with newly diagnosed NSCLC from 2015-2018, those with an R1-2 resection were identified from the Netherlands Cancer Registry. First, OS was compared between adjuvant treatment groups 'no therapy', 'radiotherapy (RT) only', 'chemotherapy only', and 'chemo- and radiotherapy (CRT)' using multinomial propensity score-weighted Cox regression analysis. Second, three 1:1 propensity score-matched sets were created for chemotherapy vs no chemotherapy, RT only vs no therapy, and CRT vs chemotherapy only. Kaplan-Meier and Cox regression analyses for OS were performed in each set. With a median follow-up of 23 months, 427 patients were selected. In the weighted regression analysis, compared to no adjuvant therapy, chemotherapy and CRT were associated with improved OS (HR 0.41, 95%CI: 0.22-0.76; and HR 0.55, 95%CI: 0.37-0.81, respectively), whereas RT was not (HR 1.04, 95%CI: 0.73-1.50). In the matched sets, OS was improved after chemotherapy (+/- RT) compared to no chemotherapy (HR 0.47, 95%CI: 0.32-0.69). No OS difference was observed between matched groups of RT only vs no adjuvant therapy (HR 1.13, 95%CI: 0.74-1.72), nor for CRT vs chemotherapy only (HR 1.37, 95%CI: 0.70-2.71). Adjuvant chemotherapy, but not radiotherapy, improves survival after an R1-2 resection in stage I-III NSCLC.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study.

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (ß = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10-8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10-7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: ß = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

Predicting Incomplete Resection in Non-Small Cell Lung Cancer Preoperatively: A Validated Nomogram.

BACKGROUND: Patients who are surgically treated for stage I to III non-small cell lung cancer (NSCLC) have dismal prognosis after incomplete (R1-R2) resection. Our study aimed to develop a prediction model to estimate the chance of incomplete resection based on preoperative patient-, tumor-, and treatment-related factors. METHODS: From a Dutch national cancer database, NSCLC patients who had surgical treatment without neoadjuvant therapy were selected. Thirteen possible predictors were analyzed. Multivariable logistic regression was used to create a prediction model. External validation was applied in the American National Cancer Database, whereupon the model was adjusted. Discriminatory ability and calibration of the model was determined after internal and external validation. The prediction model was presented as nomogram. RESULTS: Of 7156 patients, 511 had an incomplete resection (7.1%). Independent predictors were histology, cT stage, cN stage, extent of surgery, and open vs thoracoscopic approach. After internal validation, the corrected C statistic of the resulting nomogram was 0.72. Application of the nomogram to an external data set of 85,235 patients with incomplete resection in 2485 patients (2.9%) resulted in a C statistic of 0.71. Calibration revealed good overall fit of the nomogram in both cohorts. CONCLUSIONS: An internationally validated nomogram is presented providing the ability to predict the individual chance of incomplete resection in patients with stage I to III NSCLC planned for resection. In case of a high predicted risk of incomplete resection, alternative treatment strategies could be considered, whereas a low risk further supports the use of surgical procedures.

Genetic variants as predictors of toxicity and response in patients with non-small cell lung cancer undergoing first-line platinum-based chemotherapy: Design of the multicenter PGxLUNG study.

INTRODUCTION: Platinum-based chemotherapy is currently the most frequently applied first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) without targetable mutations or high PD-L1 expression. Unfortunately, chemotherapy-induced toxicity is prevalent and may affect patients' quality of life to a considerable extent. Presumably, genetic variants of genes, coding for proteins involved in the processes of the development of toxicity, may be of interest as predictors of benefits and harms of platinum-based chemotherapy. The primary objective of the study is to investigate the influence of genetic variants on the incidence of chemotherapy-induced toxicity in patients with NSCLC undergoing first-line platinum-based chemotherapy. The main secondary objectives are to study the association between genetic variants and treatment response and to study the association between skeletal muscle mass (SMM) as well as patient-reported health-related quality of life (HRQOL) and treatment response and toxicity. METHODS: In this multicenter prospective follow-up study, a total of 350 patients with NSCLC (stage II-IV) undergoing first-line platinum-based chemotherapy will be included. Blood samples for DNA isolation and genotyping, questionnaires and data on patients risk factors and disease stage will be recorded. The primary endpoint is chemotherapy-induced (non-)hematological toxicity, comprising; nephrotoxicity, neuropathy, esophagitis, ototoxicity, pneumonitis, gastrointestinal toxicity, anemia, leukocytopenia, neutropenia and thrombocytopenia. Secondary endpoints include dose-limiting toxicity, HRQOL, and treatment response (radiological response [RECIST 1.1] and overall survival [OS]). DISCUSSION: Results of the PGxLUNG study will be primarily used to determine the influence of genetic variants on the incidence of chemotherapy-induced toxicity in patients with NSCLC undergoing first-line platinum-based chemotherapy.

Association between serum biomarkers CEA and LDH and response in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.

BACKGROUND: In addition to radiological evaluation, biomarkers may be useful in providing early information on the response to treatment, and supporting clinical decision-making. The objective of this study was to investigate carcinoembryonic antigen (CEA) and lactate dehydrogenase (LDH) as biomarkers for early assessment of response in patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. METHODS: A retrospective follow-up study was conducted from 2012 to 2017 among 593 consecutive patients with advanced NSCLC treated with first-line platinum-based chemotherapy in a large teaching hospital in the Netherlands. Pretreatment biomarker levels and changes from pretreatment levels were studied for association with radiologic response (partial response [PR] or complete response [CR], according to RECIST 1.1) using multivariate logistic regression, and with overall survival using COX proportional hazard modeling. Patient and disease characteristics such as age and disease stage were taken into account as potential confounding factors. RESULTS: Decreases in CEA and LDH (≥ 20%), particularly early in treatment, were significantly associated with better radiological response. Increases in these biomarkers (≥ 20%) and high pretreatment LDH levels (≥ 247 U/L) were significantly associated with lower overall survival. CONCLUSIONS: Our results support determination of CEA and LDH levels for earlier assessment of response to platinum-based chemotherapy in patients with advanced NSCLC. Hence, routine determination and evaluation of CEA and LDH levels, prior to each cycle of platinum-based chemotherapy in advanced NSCLC, should be considered as part of daily clinical practice. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Serum biomarkers in monitoring of treatment in advanced NSCLC would be useful. CEA and LDH decrease (≥ 20%) is favorable for achieving radiological response. High LDH levels and CEA/LDH increase (≥ 20%) is associated with reduced survival. WHAT THIS STUDY ADDS: Monitoring of CEA seems to be particularly relevant in early stage of treatment. CEA and LDH determination should be considered as part of daily clinical practice.

Added Value of 50-Gene Panel Sequencing to Distinguish Multiple Primary Lung Cancers from Pulmonary Metastases: A Systematic Investigation.

Differentiation between multiple primary lung cancers and pulmonary metastases (PM) has important implications in staging, prognosis, and treatment strategies. Clinical and immunohistopathologic criteria have been standardized; however, a substantial number of cases remain difficult to classify. Using next-generation sequencing, it is now possible to improve the classification of multiple lung cancer lesions. This study systematically investigated the value of routine morphologic and IHC characteristics, p53 protein expression, TP53 mutation analysis, and 50-gene panel sequencing (GPS) in 111 lesions from 50 patients with multiple lung lesions. Based on immunohistopathologic criteria, 32 paired lesions were classified as multiple primary lung cancer (MPLC) and 21 as PM. TP53 mutation analysis indicated MPLC in 23 and PM in 6 pairs, but in the majority of cases (n = 28, 49%) no mutation was observed and no conclusion could be drawn. In contrast, only 2 pairs were not conclusive using GPS. In a significant number of matching tumor samples (n = 19, 39%), sequencing results were contradictory to the initial immunohistopathology diagnosis. No separation in overall survival for classifications based on immunohistopathology was observed, while a clear but nonsignificant trend was observed concerning survival in MPLC patients (hazard ratio = 3.98) using 50-gene GPS. In about one-third of the patients, GPS provided additional information to improve the differentiation between MPLC and PM.

Comparison of clinical outcome after first-line platinum-based chemotherapy in different types of KRAS mutated advanced non-small-cell lung cancer.

OBJECTIVES: As suggested by in-vitro data, we hypothesize that subtypes of KRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens. METHODS: Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinum-based chemotherapy, were retrieved from hospital databases. PRIMARY OBJECTIVE: to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation. RESULTS: 464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of KRAS mutation were G12C (46%), G12V (20%) and G12D (10%). Platinum was combined with pemetrexed (n=334), taxanes (n=68) or gemcitabine (n=62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p<0.01). Patients treated with bevacizumab in addition to taxanes (n=38) had the highest ORR (62%). The PFS was significantly improved in patients treated with taxanes compared to pemetrexed (HR=0.72, p=0.02), but not OS (HR=0.87, p=0.41). In patients with G12V, significantly improved ORR (p<0.01) was observed for taxanes, but not PFS or OS. Patients with G12C or G12D mutation had comparable ORR, PFS and OS in all treatment groups. CONCLUSION: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR. Response to chemotherapy regimens was different in types of KRAS mutation. Especially patients with G12V had better response to taxane treatment.

Different cutoff values for thyroid transcription factor-1 antibodies in the diagnosis of lung adenocarcinoma.

With the use of more specific treatments and targeted therapies for non-small cell lung carcinoma, distinction between adenocarcinoma (ADC) or squamous cell carcinoma (SCC) becomes increasingly important. For this, the key technique is an immunohistochemical panel in which a thyroid transcription factor-1 (TTF-1) antibody is often used. Two different TTF-1 clones (8G7G3/1 and SPT24) are used in daily practice, which appear to have different sensitivities and specificities. The aim of this study was to assess the differences between these clones and to identify the optimal cutoff value for correctly diagnosing primary or metastatic lung ADC. 182 pulmonary (109 lung ADCs, 62 lung SCCs, 11 lung metastases) and 115 extrapulmonary (36 metastatic lung ADCs, 79 nonpulmonary tumors) samples were stained with both TTF-1 antibodies. The percentage of tumor cells with nuclear staining was scored in categories of <1%, 1% to 5%, 6% to 25%, 26% to 50%, 51% to 75%, and 76% to 100%. The staining was further assessed as weak or strong. The sensitivity and specificity were calculated at different cutoff values. Applying the same cutoff value for positivity to both clones resulted in a significant difference between the clones at all cutoff values, with a lower sensitivity of 8G7G3/1 at high cutoff values and a lower specificity of SPT24 at low cutoff values. However, when the optimal cutoff value was used for each clone (>5% staining for 8G7G3/1 and >50% strong staining for SPT24), no significant difference in sensitivity (0.79 vs. 0.82) or specificity (0.98 vs. 0.98) was detected, making the clones equally useful for reliably diagnosing lung ADC.

EGFR mutation analysis in sputum of lung cancer patients: a multitechnique study.

OBJECTIVES: Epidermal growth factor receptor (EGFR) mutations have been identified in lung adenocarcinomas and are associated with high response chance to EGFR tyrosine kinase inhibitors. EGFR mutations can be detected in tumour tissue, cytology specimens and blood from lung cancer patients. Thus far, EGFR mutation analysis has not been systematically demonstrated for sputum samples. The aim of the present study was to determine whether EGFR mutation analysis is attainable on sputum samples, employing different assays in a multicenter study. MATERIALS AND METHODS: Sputum DNA from 10 lung cancer patients with confirmed EGFR mutation in their tumour tissue, 10 lung cancer patients without evidence of an EGFR mutation, and 10 patients with chronic obstructive pulmonary disease (COPD) was used for mutation analysis by Cycleave PCR, COLD-PCR, PangaeaBiotech SL Technology (PST), and High Resolution Melting, respectively. Targeted resequencing (TruSeq Amplicon Cancer Panel) and droplet digital PCR were additionally performed on the 10 samples with EGFR mutation. RESULTS: Dependent on the assay, EGFR mutations could be detected in 30-50% of the sputum samples of patients with EGFR mutations. The different techniques revealed consistent results, with slightly higher sensitivity for PST. Neither the lung cancer patients without EGFR mutation nor the COPD controls tested positive for EGFR mutations in their sputum samples, indicating high clinical specificity of all assays. CONCLUSION: EGFR mutations can be detected in sputum samples from patients with EGFR-mutated non-small cell lung cancer, which may replace biopsy procedure for some patients.

Health-related quality of life and utility in patients with advanced non-small-cell lung cancer: a prospective cross-sectional patient survey in a real-world setting.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has a significant impact on patients' health-related quality of life (HRQOL). This study aimed to measure health state utility values representing the individual's preferences for specific health-related outcomes in advanced NSCLC patients and to assess predictive parameters. METHODS: We conducted a prospective quality-of-life survey on advanced NSCLC patients in 25 hospitals in Europe, Canada, Australia, and Turkey. HRQOL was assessed using the EuroQol (EQ-5D) questionnaire and EQ-5D utility and EQ-visual analog (EQ-VAS) scores were estimated. RESULTS: Three hundred nineteen patients were recruited of which 263 had evaluable data. Mean utility for progression-free (PF) patients on first-, second-, and third-/fourth-line treatment was 0.71 (SD = 0.24), 0.74 (SD = 0.18), and 0.62 (SD = 0.29), respectively. Mean utility for patients with progressive disease (PD) while on first-, second- and third-/fourth-line treatment was 0.67 (SD = 0.2), 0.59 (SD = 0.34), and 0.46 (SD = 0.38), respectively. Overall, patients with PD had lower mean utility scores than PF patients (0.58 versus 0.70). The results of the EQ-VAS showed that the score decreased with later treatment lines. Patients with PD had a 10-point decrease in VAS scores compared with PF patients (53.7 versus 66.6). The regression analysis revealed that stage IV disease, higher lines of treatment, and health state were significant predictors of utility at the 10% level. CONCLUSION: The results presented indicate a substantial impact of lung cancer on patients' HRQOL, with stage IV disease, line of treatment, and PD, resulting in considerable deterioration of utility. The values obtained here will inform evaluations of cost-utility for NSCLC therapies.

Pemetrexed induced thymidylate synthase inhibition in non-small cell lung cancer patients: a pilot study with 3'-deoxy-3'-[¹8F]fluorothymidine positron emission tomography.

OBJECTIVES: Pemetrexed is a thymidylate synthase (TS) inhibitor and is effective in non-small cell lung cancer (NSCLC). 3'-deoxy-3'-[¹8F]fluorothymidine (¹8F-FLT), a proliferation marker, could potentially identify tumor specific TS-inhibition. The aim of this study was to investigate the effect of pemetrexed-induced TS-inhibition on ¹8F-FLT uptake 4 hours after pemetrexed administration in metastatic NSCLC patients. METHODS: Fourteen NSCLC patients underwent dynamic ¹8F-FLT positron emission tomography (PET) scans at baseline and 4 hours after the first dose of pemetrexed. Volumes of interest were defined with a 41%, 50% and 70% threshold of the maximum pixel. Kinetic analysis and simplified measures were performed. At one, two, four and six hours after pemetrexed, plasma deoxyuridine was measured as systemic indicator of TS-inhibition. Tumor response measured with response evaluation criteria in solid tumors (RECIST), time to progression (TTP) and overall survival (OS) were determined. RESULTS: Eleven patients had evaluable ¹8F-FLT PET scans at baseline and 4 hours after pemetrexed. Two patients had increased ¹8F-FLT uptake of 35% and 31% after pemetrexed, whereas two other patients had decreased uptake of 31%. In the remaining seven patients ¹8F-FLT uptake did not change beyond test-retest borders. In all patients deoxyuridine levels raised after administration of pemetrexed, implicating pemetrexed-induced TS-inhibition. ¹8F-FLT uptake in bone marrow was significantly increased 4 hours after pemetrexed administration. Six weeks after the start of treatment 5 patients had partial response, 4 stable disease and 2 progressive disease. Median TTP was 4.2 months (range 3.0-7.4 months); median OS was 13.0 months (range 5.1-30.8 months). Changes in ¹8F-FLT uptake were not predictive for tumor response, TTP or OS. CONCLUSIONS: Measuring TS-inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in ¹8F-FLT uptake within the tumor. No significant association with tumor response, TTP or OS was observed.

Toward prediction of efficacy of chemotherapy: a proof of concept study in lung cancer patients using [¹¹C]docetaxel and positron emission tomography.

PURPOSE: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([(11)C]docetaxel). The objective of this study was to investigate whether a [(11)C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel. EXPERIMENTAL DESIGN: Docetaxel-naïve lung cancer patients underwent 2 [(11)C]docetaxel PET scans; one after bolus injection of [(11)C]docetaxel and another during combined infusion of [(11)C]docetaxel and a therapeutic dose of docetaxel (75 mg·m(-2)). Compartmental and spectral analyses were used to quantify [(11)C]docetaxel tumor kinetics. [(11)C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans. RESULTS: Net rates of influx (Ki) of [(11)C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [(11)C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [(11)C]docetaxel during the therapeutic scan. At 90 minutes, the accumulated amount of docetaxel in tumors was less than 1% of the total infused dose of docetaxel. [(11)C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman ρ = 0.715; P = 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman ρ = -0.800; P = 0.010). CONCLUSIONS: Microdosing data of [(11)C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients.

EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma.

BACKGROUND: Frequencies of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) have predominantly been determined in East Asian and North American populations, showing large differences between these populations. The aim of the present study was to determine the frequency of EGFR and KRAS mutations in NSCLC in the West European Dutch population in primary carcinomas and different metastatic locations. METHODS: EGFR (exons 19, 20 and 21) and KRAS (exons 2 and 3) mutation test results of NSCLC samples of patients in 13 hospitals were collected. The tests were performed on paraffin-embedded tissue or cytological material of primary and metastatic lung carcinomas. RESULTS: EGFR mutations were detected in 71/778 (9.1 %) tested patients; in 66/620 (10.6 %) adenocarcinomas. EGFR mutations were significantly more often detected in female than in male patients (13.4 % vs. 5.5 %, p < 0.001). KRAS mutations were found in 277 out of 832 (33.3 %) tested patients; in 244/662 (36.9 %) adenocarcinomas. A significantly increased frequency of EGFR mutations was observed in patients with malignant pleural/pericardial effusions (26.5 %; odds ratio (OR) 2.80, 95 % confidence interval (CI) 1.22-6.41), whereas the frequency of KRAS mutations was significantly decreased (18.8 %; OR 0.35, 95 % CI 0.14-0.86). CONCLUSIONS: In the investigated Dutch cohort, patients with malignant pleural/pericardial effusion of lung adenocarcinoma have an increased frequency of EGFR mutations. The overall frequency of EGFR mutations in lung adenocarcinomas in this West European population is within the frequency range of North American and South European populations, whereas KRAS mutation frequency is higher than in any population described to date.

Prolonged sampling of spontaneous sputum improves sensitivity of hypermethylation analysis for lung cancer.

AIMS: The adequacy of lung cancer diagnosis with sputum cytology depends on duration of sputum sampling. The aim of this methodological study was to determine whether the hypermethylation detection rate of RASSF1A, adenomatous polyposis coli (APC) and cytoglobin (CYGB) is influenced by the duration of sputum collection. METHODS: Prospective sputum samples were collected from 53 lung cancer patients and 47 chronic obstructive pulmonary disease patients as controls. Subjects collected spontaneous sputum at home during nine consecutive days in three canisters I, II and III (ie, days 1-3, days 4-6, days 7-9, respectively). Quantitative methylation-specific PCR was performed to assess gene promoter methylation status of RASSF1A, APC and CYGB. RESULTS: Analysis of each canister separately showed hypermethylation of RASSF1A, APC and/or CYGB in samples I, II and III, in 43%, 40% and 47% of cases, respectively. In control samples, these numbers were 4%, 2% and 4%, respectively. Cumulative analysis for days 1-6 and days 1-9 revealed an increase in sensitivity to 53% and 64%, and specificity of 94% and 91%, respectively. CONCLUSION: Sputum collected over multiple successive days results in a gain in sensitivity for the detection of lung cancer, at the expense of a small loss in specificity. Condensed abstract Assessment of hypermethylation sensitivity of biomarkers in sputum collected over a prolonged period for the detection of lung cancer resulted in a promising gain in sensitivity, at the expense of a small loss in specificity.

Pulmonary masses: initial results of cone-beam CT guidance with needle planning software for percutaneous lung biopsy.

PURPOSE: To evaluate the outcome of percutaneous lung biopsy (PLB) findings using cone-beam computed tomographic (CT) guidance (CBCT guidance) and compared to conventional biopsy guidance techniques. METHODS: CBCT guidance is a stereotactic technique for needle interventions, combining 3D soft-tissue cone-beam CT, needle planning software, and real-time fluoroscopy. Between March 2007 and August 2010, we performed 84 Tru-Cut PLBs, where bronchoscopy did not provide histopathologic diagnosis. Mean patient age was 64.6 (range 24-85) years; 57 patients were men, and 25 were women. Records were prospectively collected for calculating sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. We also registered fluoroscopy time, room time, interventional time, dose-area product (DAP), and complications. Procedures were divided into subgroups (e.g., location, size, operator). RESULTS: Mean lesion diameter was 32.5 (range 3.0-93.0) mm, and the mean number of samples per biopsy procedure was 3.2 (range 1-7). Mean fluoroscopy time was 161 (range 104-551) s, room time was 34 (range 15-79) min, mean DAP value was 25.9 (range 3.9-80.5) Gy·cm(-2), and interventional time was 18 (range 5-65) min. Of 84 lesions, 70 were malignant (83.3%) and 14 were benign (16.7%). Seven (8.3%) of the biopsy samples were nondiagnostic. All nondiagnostic biopsied lesions proved to be malignant during surgical resection. The outcome for sensitivity, specificity, positive predictive value, negative predictive value, and accuracy was 90% (95% confidence interval [CI] 86-96), 100% (95% CI 82-100), 100% (95% CI 96-100), 66.7% (95% CI 55-83), and 91.7% (95% CI 86-96), respectively. Sixteen patients (19%) had minor and 2 (2.4%) had major complications. CONCLUSION: CBCT guidance is an effective method for PLB, with results comparable to CT/CT fluoroscopy guidance.