Search

Background: Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-β (TGF-β), can be found free in circulation in the blood and packaged into extracellular vesicles (EVs), which have a specific delivery tropism and can affect in tumor/immune system interaction. TGF-β is an immunosuppressive cytokine that plays a crucial role in tumor immune escape, treatment resistance, and metastasis. Thus, we aimed to evaluate the predictive value of circulating and EV TGF-β in patients with non-small-cell lung cancer receiving ICIs., Methods: Plasma samples were collected in 33 patients with advanced non-small-cell lung cancer before and during treatment with ICIs. EV were isolated from plasma by serial ultracentrifugation methods and circulating and EV TGF-β expression levels were evaluated by enzyme-linked immunosorbent assay., Results: Baseline high expression of TGF-β in EVs was associated with nonresponse to ICIs as well as shorter progression-free survival and overall survival, outperforming circulating TGF-β levels and tissue PD-L1 as a predictive biomarker., Conclusion: If validated, EV TGF-β could be used to improve patient stratification, increasing the effectiveness of treatment with ICIs and potentially informing combinatory treatments with TGF-β blockade., Plain Language Summary: Treatment with immune-checkpoint inhibitors (ICIs) has improved the survival of some patients with lung cancer. However, the majority of patients do not benefit from this treatment, making it essential to develop more reliable biomarkers to identify patients most likely to benefit. In this pilot study, the expression of transforming growth factor-β (TGF-β) in blood circulation and in extracellular vesicles was analyzed. The levels of extracellular vesicle TGF-β before treatment were able to determine which patients would benefit from treatment with ICIs and have a longer survival with higher accuracy than circulating TGF-β and tissue PD-L1, which is the currently used biomarker in clinical practice., (© 2022 American Cancer Society.)

Background: This is the first report of long-term (>10 years) safety, tolerability, and survival data on patients with non-small cell lung cancer (NSCLC) who received treatment with gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor., Methods: Patients with advanced NSCLC (N = 191) who entered the IRESSA Clinical Access Program (ICAP) (June 2011 to January 2013) and had previously obtained a clinical benefit from gefitinib therapy (including patients who had received gefitinib since 2001) were analyzed for adverse events (AEs). A subset of patients (n = 79) underwent retrospective chart review to capture demographic, safety, and survival data., Results: Seventy-five of 191 patients (39%) remained on long-term gefitinib therapy as of September 2016. Overall, serious AEs (SAEs) were reported in 64 patients (34%), the majority of which were attributed to underlying disease or comorbidities; only 3 patients (1.6%) had SAEs that were considered as possibly gefitinib-related. In the retrospective chart review cohort, 70% of patients were women; 58% were former smokers, and 30% were never-smokers; 56% were diagnosed with adenocarcinoma, and 13% were diagnosed with squamous carcinoma. Although EGFR mutational status was tested in only 17 patients (22%), it was assumed that most tumors were EGFR-mutation-positive. The median duration of gefitinib therapy was 11.1 years (7.8 years before and 3.5 years during ICAP), with 10-year and 15-year survival rates of 86% and 59%, respectively, from the initiation of therapy., Conclusions: A subset of long-term NSCLC survivors who were receiving gefitinib had an excellent long-term safety profile. Although it is assumed that most of these patients' tumors harbor EGFR mutations, molecular studies of available tumor specimens are planned to uncover the features that predict long-term survival. Cancer 2018;124:2407-14. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Preclinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in combination as treatment for patients with non-small cell lung cancer (NSCLC)., Methods: Patients with chemotherapy-naïve, advanced NSCLC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m(2) intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease. The primary endpoint was progression-free survival (PFS). The study design required 180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison (arm A vs arm C or arm B vs arm C) using the log-rank test., Results: From September 2009 to December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively., Conclusions: On the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC., (© 2015 American Cancer Society.)

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have EGFR mutations. Recent studies have indicated that some patients with positive mutations were refractory to EGFR TKIs if they harbored a B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (Bim) deletion polymorphism. The objective of the current work was to retrospectively study the Bim deletion polymorphism in Chinese patients with NSCLC and its correlation with the efficacy of EGFR TKIs., Methods: Distribution of the Bim polymorphism was detected using polymerase chain reaction analysis and direct sequencing of DNA from peripheral neutrophils in samples from 352 patients with NSCLC. Of the 352 patients, 166 who received TKI therapy and had an activating mutation identified were involved in further analysis. Progression-free survival (PFS) was the primary endpoint of the subsequent analyses, and the incidence of the Bim polymorphism and its relation to clinical benefit from EGFR TKIs also were investigated., Results: In total, 45 of 352 patient samples (12.8%) had the Bim deletion polymorphism, which was distributed randomly with regard to various clinical characteristics. In patients with EGFR mutations who received treatment with TKIs, the median PFS and the median objective response rate were 4.7 months and 25%, respectively, for those with the Bim deletion polymorphism versus 11 months (P = .003) and 66% (P = .001), respectively, for those with wild-type Bim. Cox regression analysis identified Bim status (P = .016) and sex (P = .002) as independent factors predicting clinical benefit from EGFR TKIs in patients with EGFR-mutated NSCLC., Conclusions: The incidence of the Bim deletion polymorphism was approximately 13% in this study, and it was associated with a poor clinical response to EGFR TKIs in patients who had NSCLC with EGFR mutations., (© 2014 American Cancer Society.)

Background: The ISEL (Iressa Survival Evaluation in Lung Cancer) clinical trial evaluated the efficacy of gefitinib versus placebo in pretreated nonsmall-cell lung cancer patients. Two different antibodies, scoring systems, and cutoff points of epidermal growth factor receptor (EGFR) protein expression were compared to predict response and survival of enrolled patients., Methods: EGFR expression was assessed in tumor samples by immunohistochemistry using the Dako EGFR pharmDx kit (scoring percent of tumor cells with positive staining) and Zymed monoclonal antibody clone 31G7 (scoring staining index derived from proportion of positive cells times staining intensity)., Results: Data for EGFR expression were available for 379 patients for Dako and 357 patients for Zymed antibody (22% and 21%, respectively, of trial population). Objective response rates in gefitinib-treated EGFR-positive patients defined with various cutpoints with Dako antibody varied between 8% and 12%, and with Zymed antibody between 10% and 13%. Lower cutoff points with Dako antibody provided the best discrimination between EGFR-positive and EGFR-negative patients for survival hazard ratios comparing gefitinib to placebo, with a significant treatment/cutoff point interaction for 10% cutoff point (P = .049). A similar but less apparent trend was noted for Zymed antibody, although the discrimination between hazard ratios was not significant for any cutoff point analyzed., Conclusions: Assessment with the Dako PharmDx kit and percentage of cells with positive staining may provide more accurate prediction of differential effect on survival with gefitinib than assessment with Zymed antibody and staining index. Using higher cutpoints to define positivity does not improve test discrimination.

Background: The classification of lung tumors by the World Health Organization (WHO 1981) describes subtyping of adenocarcinoma of the lung (ACL) into acinar adenocarcinoma and papillary adenocarcinoma, bronchioloalveolar carcinoma, and solid carcinoma with mucus formation. Acinar and papillary adenocarcinoma may be graded as well-, moderately, or poorly differentiated. This study evaluated the interobserver variability in the subtyping and grading of ACL according to the WHO classification., Methods: Histologic specimens from 211 patients with disease of Stages IIIa-IV were classified in a blind manner by three panelists. All available paraffin-embedded tissue blocks, including metastatic tumors, were sampled, and new slides were made for the study., Results: Twenty-two ACL tumors could not be assigned a subtype by Panelist 1, which left 189 tumors as the basis for additional evaluation. Overall agreement for the three panelists regarding subtypes was 41%. Nonchance agreement was evaluated by kappa statistics, which may vary between -1 in the event of agreement that is less than that expected by chance and /1 in the event of full agreement. The kappa value regarding subtypes was 0.18 (95% confidence limits, 0.14-0.23). Overall observed agreement regarding degree of differentiation was 43%, with a kappa value of 0.12 (95% confidence limits, 0.06-0.17). Histologic material was obtained by thoracotomy in a subgroup of 53 patients, and in this patient group unanimity among two or more panelists was 88% for subtyping and 100% for degree of differentiation., Conclusions: The degree of agreement in subtying and grading of ACL in Stages IIIa-IV is low, suggesting that more objective criteria is needed before a prognostic impact of such variables can be assessed. The quality and quantity of material available for subtyping obviously influence the results, which is reflected in a better agreement when histologic material is obtained by thoracotomy.

Considerable attention has been devoted to the diagnosis of small cell lung carcinoma (SCLC) and its subtypes. In the literature contradictory opinions have been published concerning the clinical implications of subtyping, largely because of the different criteria used by different pathologists. This article is a consensus report by the Pathology Committee of the International Association for the Study of Lung Cancer. The following classification of SCLC is recommended: (1) Small cell carcinoma. This subtype includes most of the tumors previously included in the oat cell and intermediate subtypes. More than 90% of untreated SCLC fall into this category. (2) Mixed small cell/large cell carcinoma. This subtype, which may be associated with a poor prognosis and response to therapy, contains a spectrum of cell types ranging from typical SCLC to larger cells having prominent nucleoli and resembling large cell carcinoma. (3) Combined small cell carcinomas. Typical SCLC elements are intimately admixed with areas of differentiated squamous cell or adenocarcinoma. This simplified classification of SCLC will facilitate uniformity in the diagnosis and further our understanding of the clinical significance of the rarer SCLC with variant morphologies.

The prognostic impact of subtyping pretreatment histologic material in adenocarcinoma of the lung (ACL) according to WHO was evaluated in 259 consecutive, inoperable, Stage III patients. One hundred thirty patients (50%) had acinar adenocarcinoma, 23 (9%) had papillary adenocarcinoma, 13 (5%) had bronchioloalveolar carcinoma, and 32 (12%) had solid carcinoma with mucus formation; five patients (2%) had other types of lung cancer. Subtyping was impossible due to cytology or insufficient histologic material in 56 patients (22%). Bronchioloalveolar carcinoma had the longest median duration of response to chemotherapy (47 weeks), time to progression (33 weeks), and median survival (40 weeks). Corresponding values for solid carcinoma with mucus formation were 8, 12, and 22 weeks. Acinar and papillary adenocarcinoma were intermediate. Survival curves and response rates were similar (P greater than 0.05). Bronchioloalveolar carcinoma had 46% 1-year survivors compared to 16% to 22% for other subtypes. The subtypes may have an impact on the prognosis of ACL, but further evaluation is required.

A consecutive series of 104 autopsies on patients treated in protocol for small cell carcinoma of the lung (SCCL) was studied with respect to metastatic pattern at autopsy in relation to pretreatment WHO 1981 classification, and extent and significance of non-SCCL tumor tissue at autopsy. The only significant difference in the metastatic pattern at autopsy between patients with pretreatment oat cell or intermediate subtype was metastases to the brain. Thus, the frequency of brain metastases was 17/35 (49%) in patients with oat cell type compared to 2/18 (11%) in patients with intermediate type (P less than 0.05). At autopsy 13 of 98 patients (13%) had non-SCCL tumor tissue in at least one site. These patients had a significantly shorter survival (P = 0.020) compared to patients with pure SCCL at autopsy. Furthermore, none of these 13 patients had obtained complete remission. Whether these morphologic variations had been present at the pretreatment stage of the disease or were due to the chemotherapeutic treatment could not be solved in the present study. However, the results might indicate that mixed SCCL/non-SCCL histology is a negative prognostic factor in the treatment of SCCL. Prospective studies including more extensive pretreatment tissue sampling seem to be required.

Two hundred-twelve consecutive patients with small cell carcinoma of the lung were studied in order to correlate the risk of developing intracranial metastases to the initial stage of the disease (locoregional versus extensive) and to evaluate the prognostic significance of developing intracranial dissemination of the disease. Clinically detected intracranial metastases were observed in four percent at the time of primary diagnosis, and an additional 18 percent developed metastases during treatment. As regards clinically observed metastases during treatment, no difference was found between the two initial staging groups. Intracranial metastases without clinical evidence of progressive disease elsewhere were demonstrated in 10 out of 205 patients (5%). The median survival time after clinical presentation of intracranial metastases was 85 days for patients with locoregional disease versus 60 days for patients with extensive disease. A significantly shorter survival time was observed for patients with intracranial metastases at 0, 100, 200 and 300 days after start of treatment compared to patients still alive without metastases at those times. Brain autopsy was performed in 82 patients and was positive in 42 (51%). No statistical difference in the frequency of brain metastases was demonstrated when compared to the initial stage of the disease. No difference was observed between the two initial staging groups of patients with regard to risk of developing brain metastases. Autopsy substantiated that there was no difference between patients with and without brain metastases as regards survival. However, clinical intracranial metastases were followed by a short survival time, and only a small fraction of the patients developed clinically isolated intracranial relapse.

A total of 114 patients with bronchogenic small cell anaplastic carcinoma and staged as having regional disease all underwent combination chemotherapy consisting of CCNU, cyclophosphamide, and methotrexate. They were randomized to receive either radiotherapy to the primary tumor and regional lymph nodes (4000 rad) or extensive radiotherapy, which included the brain, adrenals, and upper retroperitoneal lymph nodes. Fifteen patients were free of disease after 18 months of chemotherapy and the treatment was discontinued. Only 3 patients subsequently relapsed. No difference was observed between the two groups of patients in median survival time, response rate, duration of response or relapse pattern, including the frequency of brain metastasis.

Two hundred-twelve consecutive patients with small cell carcinoma of the lung were included in an evaluation of clinical and diagnostic neurologic findings of intracranial metastases. A correlation of premortem findings to postmortem examination of the brain was obtained in 87 of the patients. Clinical intracranial metastases were diagnosed in 21.2% on the basis of symptoms and signs. At autopsy 44 of the 87 patients (50%) had metastases. Lesions located to the posterior cranial fossa were demonstrated in 53% of the positive autopsies. A correlation of 96% existed between significant premortem clinical findings and positive autopsy, while 33% had clinically "silent" metastases at autopsy. A neuro-oncologic examination was performed in 49 patients at the time of presentation of neurologic symptoms. Twenty-eight patients were considered to have intracranial metastases. Gait disturbances were the presenting signs in more than 50% of the patients. Brain metastases were demonstrated at autopsy in 14 of 15 patients considered to have intracranial metastases by the neuro-oncologist, and clinically "silent" metastases were observed in one out of 10 patients. Radionuclide brain scan was negative in seven of 13 patients in spite of "positive" neuro-oncological examination had a subsequent positive autopsy. Cerebrospinal fluid examination was of no value in the diagnosis of brain metastases. It is concluded that a careful clinical examination by a neuro-oncologist is of great value in early detection of brain metastases, especially in diagnosing metastases to the posterior cranial fossa.

In order to evaluate the consistency in diagnosing the morphologic subtypes of small cell carcinoma of the lung (SCCL), 93 microscopic slides were blindly classified by three panelists according to the World Health Organization's (WHO) Lung Tumor Classifications of 1967 and 1981. Unanimity in the diagnosis of SCCL as the main cell type was obtained in 91 and 94% respectively. With regard to the diagnosis of the various morphologic subtypes unanimity among the three panelists was achieved in 38% according to the WHO 1967 classification and in 54% using the 1981 classification. It is concluded that the criteria used for SCCL as a distinct histopathologic entity were reproducible among the different panelists. However, different criteria were applied in the diagnosis of the morphologic subtypes of SCCL. This fact could explain the contradictory results of clinical studies reported in the literature concerning subtyping of SCCL.

One hundred ninety-three patients with untreated advanced small cell anaplastic carcinoma of the lung were divided into two groups on the basis of whether or not the pretreatment bone marrow examination revealed tumor. The groups were analyzed with regard to survival, treatment response, tolerated amount of chemotherapy, hematologic toxicity including necessity for blood transfusions, and episodes of clinical sepsis. The median survival time was significantly lower for patients with a positive bone marrow examination (149 days vs. 231 days) (P less than 0.01). Short survival times were especially observed for patients with bone marrow metastases and initial thrombocytopenia as compared to those with bone marrow metastases but normal platelet counts (68 days vs. 176 days) (P less than 0.05). The median duration of remission was 86 days for the groups with positive bone marrow examinations vs 182 days for the negative group (P less than 0.05). No difference was observed with regard to other parameters studied. It is concluded that a positive pretreatment bone marrow examination is an unfavorable prognostic indicator, especially for patients with additional thrombocytopenia, but it does not seem to be a restrictive factor for effective use of intensive chemotherapy in the treatment of small cell anaplastic carcinoma of the lung.

Three hundred seventy-five consecutive patients treated with intensive chemotherapy in the same institution are included in this study in order to evaluate the prognostic significance of the World Health Organization's (WHO) subclassification of small cell lung cancer. Morphologic subtyping, based on primary biopsy specimens, was obtained in 200 patients. Oat cell type was diagnosed in 106 patients (53%), while intermediate subtype was diagnosed in 93 patients (47%), including 27 patients (14%) with small cell/large cell morphologic features. One patient had combined oat cell type. No difference in survival period was observed between the group of patients classified as oat cell versus the group with intermediate subtype. However, a significantly shorter survival period was demonstrated for patients with small cell/large cell features compared with patients with pure small cell carcinoma (median 168 days versus 280 days, P less than 0.01). It is concluded that there is no difference in survival period between patients with oat cell and intermediate subtype of small cell lung cancer using the criteria of the WHO. However, it might be of prognostic importance to identify patients with tumors demonstrating small cell/large cell features.

To elucidate the ectopic hormonal pattern in patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, serum gastrin, plasma glucagon, serum insulin, plasma secretin, plasma VIP, serum growth hormone, serum hCG/LH, the total of serum hCG and hCG-beta-subunit,serum alpha-subunit, serum human placental lactogen, urine ADH, urine 5-HIAA, urine VMA, urine HVA, and urine hCG-LH were measured prior to therapy in 75 patients. Twenty-two patients (29%) had elevated plasma ACTH, and 18 of these had concomitant increased values of corticosteroid in a 24-hour urine sample. Forty-eight patients (64%) were found to have elevated serum calcitonin, and one-third of the patients were diagnosed as having the ectopic ADH syndrome. Serum gastrin concentrations were increased in 20% of the patients, but the elevations were marginal in almost all cases. None of the remaining substances was found to be significantly elevated. Concentrations of plasma ACTH, serum calcitonin, and urine ADH were not found to be correlated with the stage of the disease, and no correlation of these substances with the histological subtypes of small cell carcinoma was disclosed.