Non-small Cell Lung Cancer Histological Subtypes Research Articles

Prognostic indices in stereotactic radiotherapy of brain metastases of non-small cell lung cancer.

BackgroundOur purpose was to analyze the long-term clinical outcome and to identify prognostic factors after Linac-based stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) on patients with brain metastases (BM) from non-small cell lung cancer (NSCLC).Materials and MethodsWe performed a retrospective analysis of survival on 90 patients who underwent SRS or FSRT of intracranial NSCLC metastases between 04/2004 and 05/2014 that had not undergone prior surgery or whole brain radiotherapy (WBRT) for BM. Follow-up data was analyzed until May 2015. Potential prognostic factors were examined in univariable and multivariable analyses. The Golden Grading System (GGS), the disease-specific graded prognostic assessment (DS-GPA), the RADES II prognostic index as well as the NSCLC-specific index proposed by Rades et al. in 2013 (NSCLC-RADES) were calculated and their predictive values were tested in univariable analysis.ResultsThe median follow-up time of the surviving patients was 14 months.The overall survival (OS) rate was 51 % after 6 months and 29.9 % after 12 months.Statistically significant factors of better OS after univariable analysis were lower International Union Against Cancer (UICC) stage at first diagnosis, histology of adenocarcinoma, prior surgery of the primary tumor and lower total BM volume. After multivariable analysis adenocarcinoma histology remained a significant factor; higher Karnofsky Performance Score (KPS) and the presence of extracranial metastases (ECM) were also significant.The RADES II and the NSCLC-RADES indices were significant predictors of OS. However, the NSCLC-RADES failed to differentiate between intermediate- and low-risk patients. The DS-GPA and GGS were not statistically significant predictors of survival in univariable analysis.ConclusionThe ideal prognostic index has not been defined yet. We believe that more specific indices will be developed in the future. Our results indicate that the histologic subtype of NSCLC could add to the prognostic value of specialized future indices. The RADES II index had the highest predictive value in the examined patient cohort.

Advances in molecular and immunologic targeted therapies for squamous cell carcinoma of the lung

While targeted therapy has revolutionized the treatment of some forms of non-small cell lung cancer (NSCLC) particularly adenocarcinoma of the lung, the standard treatments for advanced stage squamous cell carcinoma (SqCC) has remained platinum-doublet chemotherapy, and the prognosis remains poor. There remains a great need for breakthroughs in treatments for this common and deadly disease. Recently, a new understanding of the molecular and genetic makeup of SqCC, thanks to largescale genetic and molecular assays, has resulted in a number of targeted therapies entering clinical investigation for use in SqCC. Treatments targeting common mutations in SqCC have been studied in patient populations not preselected for mutations or overexpression and have had some early success. For example, the vascular endothelial growth factor receptor (VEFGR) inhibitor ramucirumab has been approved by the United States Food and Drug Administration (FDA) for use in certain settings for patients not selected for genetic mutations with NSCLC, including SqCC. Other agents are being investigated in selected populations with demonstrated genetic mutations or amplifications in the targeted pathway based on preclinical and early clinical data suggesting enhanced benefit in those groups. Early results in targeted immunotherapy have been particularly successful in SqCC compared to other histologic subtypes of NSCLC, and the programmed cell death 1 (PD-1) immune checkpoint inhibitor nivolumab has now been approved for second-line therapy in SqCC by the FDA. In this review, several oncogenic signaling pathways will be examined. The recent preclinical and clinical literature establishing those pathways as potential treatment targets, as well as ongoing clinical studies focused on those pathways, will be discussed. Recent and ongoing studies in targeted immune checkpoint inhibition and vaccine immunotherapy will also be reviewed.

"Blasts" from the Past: Lung Cancer in Cape Breton

Background: With the advent of molecular testing and its role in determining appropriate therapy for non small cell lung cancer (NSCLC), particularly adenocarcinoma, we reviewed charts from the Cape Breton Cancer Centre from 2011 to 2013, to determine availability of tissue for molecular testing. We were also interested in recording the distribution of histologic subtypes of NSCLC in this population. Methods: A detailed chart review was carried out exploring relative rates of various histologies, smoking history, type of diagnostic procedure carried out, availability of tissue for further testing, and need for re-biopsy. When necessary for diagnostic clarification, pathology review was done. Results: For convenience and to prevent selection bias, one hundred consecutive lung cancer cases coded as NSCLC by the provincial cancer registry were reviewed. The highest percentage was squamous cell (40%), followed by adenocarcinoma (29%), NSCLC not otherwise specified (18%), large cell (6%), neuroendocrine (4%), and adenosquamous (3%). These figures are out of line with typical North American figures and are similar to findings from the 1950s and 1960s. Conclusion: This study demonstrated more than expected squamous cell NSCLC and less adenocarcinoma. Environmental and lifestyle issues may be implicated. With recent environmental changes and the enactment of an anti-smoking bylaw in Cape Breton, we expect to see these figures change to those more typical for North America.

Outcomes and resource use of non-small cell lung cancer (NSCLC) patients treated with first-line platinum-based chemotherapy across Europe: FRAME prospective observational study.

FRAME was a prospective observational study that captured real-world data on patients with advanced or metastatic non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapies as first-line treatment (FLT) across Europe. As previously reported, most patients observed in the study had initiated FLT with either pemetrexed, gemcitabine, vinorelbine or taxanes in combination with a platinum. Baseline patient and disease characteristics including age, performance status, and histology varied (all p<0.01) across cohorts. Consenting adult patients initiating FLT for advanced or metastatic NSCLC with platinum-based chemotherapy, with or without a targeted agent, entered the study between April 2009 and February 2011. The choice of FLT was left to physicians' discretion per routine clinical practice. The primary objective was to evaluate overall survival (OS) across platinum-based doublet chemotherapy cohorts and key secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented. Median OS in months was 10.3 across cohorts (n=1524), 10.7 for pemetrexed (n=569), 10.0 for gemcitabine (n=360), 9.1 for taxanes (n=295), and 10.7 for vinorelbine (n=300). For patients with non-squamous NSCLC who received cisplatin (n=616, 40% of total), median OS in months was 10.6 across the cohorts, 11.6 for pemetrexed, 8.4 for gemcitabine, 9.6 for taxanes, and 9.9 for vinorelbine. FRAME describes real-world treatment patterns and survival for patients initiating FLT for advanced or metastatic NSCLC between 2009 and 2011 across Europe.

Abstract 1684: Histone deacetylase inhibition enhances Pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer models

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed (PEM), a multi-target folate antagonist, has demonstrated targeted efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS, one of PEM's molecular targets) expression. Histone deacetylase inhibitors (HDACi) modulate the expression of multiple genes, including thymidylate synthase (TS), one of the main targets of Pemetrexed. Since high levels of TS have been linked to clinical resistance to Pemetrexed in non-small cell lung cancer (NSCLC), we investigated the molecular and functional effects of combined Pemetrexed and ITF2357, a class I/II HDACi currently in clinical trials as anti-cancer agents .ITF2357 reduced TS mRNA and protein expression, potentially affecting sensitivity to Pemetrexed. When the two drugs were used in combiation, their sequence of administration was critical in determining the pharmacologic response: in both NSCLC cell lines and LCSC, a strikingly synergistic reduction in cell viability was observed with the sequence Pemetrexed followed by ITF2357, in both adenocarcinoma and squamous cell carcinoma models. Cell death induced by the combination involved both apoptosis and autophagy. Genetic and pharmacological approaches provided an interesting link between these two pathways and showed that sequential Pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential Pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival. Overall, this data provide a strong rationale for the clinical development of sequential schedules employing Pemetrexed followed by HDAC inhibition in NSCLC. Citation Format: Daniela Trisciuoglio, Marianna Desideri, Teresa De Luca, Marta Di Martile, Chiara Gabellini, Adriana Eramo, Ruggero De Maria, Michele Milella, Donatella Del Bufalo. Histone deacetylase inhibition enhances Pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1684. doi:10.1158/1538-7445.AM2014-1684

Circulating endothelial cells as a biomarker in non-small cell lung cancer patients: correlation with clinical outcome.

Circulating endothelial cells (CECs) have been proposed as a biomarker for the assessment of patients with solid tumors. However, few data are available in non-small cell lung cancer (NSCLC). We therefore analyzed the clinical significance of CECs in newly diagnosed NSCLC patients. In addition, we tried to determine the prognostic value of CECs in NSCLC. In this prospective study, 151 newly diagnosed NSCLC patients and 25 healthy volunteers were included. Furthermore, 25 patients with a partial response (n=15) or stable disease (n=10) after treatment were evaluated at recurrence with a mean follow-up of 117 days (range: 47-364 days). CECs were counted using magnetic beads coupled to a specific antibody against CD146. The pre-treatment CEC count was significantly higher in patients with all histological subtypes of NSCLC than in healthy volunteers (p&lt;0.0001). High baseline CEC counts were significantly correlated with advanced clinical stages (p=0.026), weight loss (p=0.03), and poorly differentiated NSCLC (p=0.02). The amount of CECs increased significantly at recurrence compared with their amount after treatment in 20/21 assessable patients (p=0.0001). Nevertheless, there was no significant correlation between baseline CEC count and median duration of progression-free survival (p=0.402). Increased CEC counts were present in patients with newly diagnosed NSCLC compared with healthy subjects. Elevated levels of baseline CECs correlated with high-risk factors in NSCLC. In addition, increased CEC count during follow-up seems to be correlated with recurrence in NSCLC patients.

Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype.

The vascular endothelial growth factor (VEGF) pathway is a clinically validated antiangiogenic target for non-small cell lung cancer (NSCLC). However, some contradictory results have been reported on the biological effects of antiangiogenic drugs. In order to evaluate the efficacy of these drugs in NSCLC histological subtypes, we analyzed the anticancer effect of two anti-VEGFR2 therapies (sunitinib and DC101) in chemically induced mouse models and tumorgrafts of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Antiangiogenic treatments induced vascular trimming in both histological subtypes. In ADC tumors, vascular trimming was accompanied by tumor stabilization. In contrast, in SCC tumors, antiangiogenic therapy was associated with disease progression and induction of tumor proliferation. Moreover, in SCC, anti-VEGFR2 therapies increased the expression of stem cell markers such as aldehyde dehydrogenase 1A1, CD133, and CD15, independently of intratumoral hypoxia. In vitro studies with ADC cell lines revealed that antiangiogenic treatments reduced pAKT and pERK signaling and inhibited proliferation, while in SCC-derived cell lines the same treatments increased pAKT and pERK, and induced survival. In conclusion, this study evaluates for the first time the effect of antiangiogenic drugs in lung SCC murine models in vivo and sheds light on the contradictory results of antiangiogenic therapies in NSCLC.

Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer.

BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed, a multi-target folate antagonist, has demonstrated efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS) expression. Among many other potential targets, histone deacetylase inhibitors (HDACi) modulate TS expression, potentially sensitizing to the cytotoxic action of anti-cancer drugs that target the folate pathway, such as pemetrexed. Since high levels of TS have been linked to clinical resistance to pemetrexed in NSCLC, herein we investigated the molecular and functional effects of combined pemetrexed and ITF2357, a pan-HDACi currently in clinical trials as an anti-cancer agent.ResultsIn NSCLC cell lines, HDAC inhibition by ITF2357 induced histone and tubulin acetylation and downregulated TS expression at the mRNA and protein level. In combination experiments in vitro ITF2357 and pemetrexed demonstrated sequence-dependent synergistic growth-inhibitory effects, with the sequence pemetrexed followed by ITF2357 inducing a strikingly synergistic reduction in cell viability and induction of both apoptosis and autophagy in all cell line models tested, encompassing both adenocarcinoma and squamous cell carcinoma. Conversely, simultaneous administration of both drugs achieved frankly antagonistic effects, while the sequence of ITF2357 followed by pemetrexed had additive to slightly synergistic growth-inhibitory effects only in certain cell lines. Similarly, highly synergistic growth inhibition was also observed in patient-derived lung cancer stem cells (LCSC) exposed to pemetrexed followed by ITF2357. In terms of molecular mechanisms of interaction, the synergistic growth-inhibitory effects observed were only partially related to TS modulation by ITF2357, as genetic silencing of TS expression potentiated growth inhibition by either pemetrexed or ITF2357 and, to a lesser extent, by their sequential combination. Genetic and pharmacological approaches provided an interesting link between the autophagic and apoptotic pathways, and showed that sequential pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival.ConclusionsOverall, these data provide a strong rationale for the clinical development of sequential schedules employing pemetrexed followed by HDACi in NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-230) contains supplementary material, which is available to authorized users.

FDG PET/CT for the preoperative nodal staging of non-small cell lung cancer in a tuberculosis-endemic country: Are maximum standardized uptake values useful?

The aim of this study was to determine an optimum standardized uptake value threshold for identifying nodal metastasis in non-small cell lung cancer (NSCLC) patients using Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) in Taiwan, a tuberculosis-endemic country. The variation in standardized uptake values of nodal metastasis among different NSCLC histological subtypes was also evaluated. We retrospectively reviewed 75 NSCLC patients who had received FDG PET/CT before surgery. The diagnostic accuracy of FDG PET/CT for the preoperative nodal staging was evaluated by histopathologic findings. A total of 316 nodal stations were evaluated. The sensitivity and specificity of FDG PET/CT for nodal staging were 58.6% and 81.8%, respectively, using an SUV cut-off of 2.6. With regard to the levels of mean SUVmax in true-positive and false-positive groups, there was no significant difference among different histological subtypes. The present study demonstrated that FDG PET/CT for pre-operative nodal staging using SUVmax > 2.6 is a useful tool (with a higher specificity and a higher negative predictive value) to rule out the possibility of metastatic lymphadenopathy in operable patients with NSCLC.

Identification of microRNAs differentially expressed between lung squamous cell carcinoma and lung adenocarcinoma

Recent advances in the treatment of non-small cell lung cancer (NSCLC) with new agents require accurate histological subtyping at diagnosis to avoid the higher risk of an adverse response and to obtain the maximum therapeutic response. However, interobserver variability, tumor heterogeneity and the degree of differentiation may affect the decision concerning a pathological diagnosis of NSCLC. Therefore, the aim of this study was to identify specific microRNAs (miRNAs) as standardized biomarkers with high sensitivity and specificity in order to distinguish between squamous cell carcinoma (SCC) and adenocarcinoma (AC). Quantitative polymerase chain reaction (qPCR)‑based miRNA array analysis was performed to identify microRNAs differentially expressed between SCC and AC using 86 resected NSCLC samples in addition to adjacent normal tissues. The results were confirmed by independent qRT-PCR assays with the same test samples and 88 additional validation samples, and from this we evaluated the usefulness of the identified miRNAs as biomarkers to distinguish between SCC and AC. Three miRNAs (hsa-miR-196b, hsa-miR-205 and hsa-miR-375) were identified. Discriminant analysis combining the three miRNAs appeared to distinguish SCC from AC accurately in the test and validation samples, demonstrating a sensitivity and specificity of 76 and 80%, and 85 and 83%, respectively. hsa-miR-196b, hsa-miR-205 and hsa-miR-375 were identified as biomarkers capable of distinguishing between lung SCC and lung AC. These newly identified miRNAs may prove to be highly valuable molecular markers for the classification of NSCLC histological subtypes and may contribute to the pathogenesis of each subtype of NSCLC.

Evaluation of 2-Year Experience With EGFR Mutation Analysis of Small Diagnostic Samples

Mutation analysis of the epidermal growth factor receptor (EGFR) gene is an essential part of the diagnostic algorithm in patients with metastatic or recurrent non-small cell lung cancer (NSCLC). Small biopsies or cytology specimens represent >80% of the available diagnostic material. EGFR mutation analyses were realized on 835 samples (675 cytology specimens, 151 formalin-fixed paraffin-embedded blocks, 5 tumors, and 4 pleural effusions). EGFR mutation analysis was performed by high-resolution melting analysis in combination with mutant-enriched polymerase chain reaction and sequencing analysis. Because of increased risk of inaccuracy in histology diagnosis of small specimens, all subtypes of NSCLC were analyzed. EGFR mutations were detected in 83 cases (10%). EGFR mutation testing failed in 5% (42/835) and was associated with poor cellularity, low percentage of tumor cells, and bad quality of DNA. Although 281 samples were evaluated as insufficient material (poor cellularity and/or unrepresentative tumor content), mutation rates were 7%. Although only adenocarcinomas or NSCLC-not otherwise specified are recommended for EGFR mutation testing, EGFR mutations in 11% of the large cell carcinomas and 4% of the squamous cell carcinomas were observed. Our results indicate that defined algorithm for EGFR testing of small diagnostic samples is sensitive, fast, and suitable even for samples with poor cellularity. The results of this testing should be evaluated depending on tumor content and DNA quality for each sample individually. At the conclusion of our results, we recommend to realize EGFR mutation analysis of small diagnostic samples regardless of the histologic subtypes of NSCLC.

Discordance between anaplastic lymphoma kinase status in primary non‐small‐cell lung cancers and their corresponding metastases

The anaplastic lymphoma kinase gene (ALK) has attracted considerable attention as a potential molecular target in non-small-cell lung cancer (NSCLC). However, it is unclear whether ALK alterations are acquired during the metastatic progression of NSCLC. ALK status and ALK expression were evaluated in a series of 67 primary NSCLCs and their corresponding metastatic lesions using fluorescence in-situ hybridization and immunohistochemistry. ALK rearrangement was detected in 7.5% (5/67) of the primary tumours and in 9.0% (6/67) of the metastases (P < 0.001). ALK copy number gain (CNG) was detected in 1.5% (1/67) of the primary tumours and in 35.8% (24/67) of the metastases. Whereas ALK rearrangement was detected only in adenocarcinomas, CNG was identified in various histological subtypes of NSCLC. ALK expression was detected in 11.9% (8/67) of the primary tumours and in 25.4% (17/67) of the metastatic lesions. ALK alteration and ALK expression can be acquired during metastatic progression in NSCLC, and ALK CNG is associated with ALK expression.

The influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival

Most studies exploring ethnic/racial disparities in nonsmall cell lung cancer (NSCLC) compare black patients with whites. Currently, the effect of Hispanic ethnicity on the overall survival of NSCLC is poorly understood. Therefore, the authors carried out a large-scale, population-based analysis using the Surveillance, Epidemiology, and End Results (SEER) data base to determine the impact of Hispanic ethnicity the survival of patients with NSCLC. The authors identified 172,398 adult patients with pathologically confirmed NSCLC from the SEER data base who were diagnosed between 1988 and 2007. A multivariate Cox proportional hazards regression analysis was used to determine the impact of race/ethnicity on overall survival. Pair-wise comparisons were used to determine whether Hispanic ethnicity influenced NSCLC histology or stage at diagnosis. Compared with non-Hispanic white patients, Hispanic white patients had a statistically significant better overall survival (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.83-0.87), and black patients had worse survival (HR, 1.091; 95% CI, 1.072-1.109). Within the bronchioalveolar carcinoma (BAC) subtype, Hispanic-white patients tend to be over represented (8.1% Hispanic whites vs 5.5% non-Hispanic whites vs 3.7% blacks; P < .001). The current study demonstrated that Hispanic-white patients with NSCLC had a decreased risk for overall mortality compared with non-Hispanic whites and blacks. Moreover, Hispanic patients were over represented within the BAC histologic subtype. Thus, the overall survival advantage of Hispanic NSCLC patients may be because of their predilection toward developing certain histologic subtypes of NSCLC. Further studies are warranted to determine the etiologies of such predilections and may reveal certain genetic, environmental, and/or epigenetic factors associated with Hispanic ethnicity.

Abstract IA15: Bringing personalized therapy into the clinic: Can pathology deliver?

Abstract IA15: Bringing personalized therapy into the clinic: Can pathology deliver?

Abstract 2251: High VEGFA pathway expression predicts good prognosis in stage I squamous cell carcinoma of the lung

Abstract Vascular endothelial growth factor A (VEGFA) mediates its effects through VEGFR1 and VEGFR2, regulating angiogenesis in healthy and tumor tissues. Hence, an anti-VEGFA therapy has been approved, in combination with platinum-based chemotherapy, as first line treatment in unresectable advanced non-small cell lung cancer (NSCLC). This antiangiogenic therapy is based on the inactivation of the VEGFA pathway in endothelial cells. However, tumor cells also express VEGFA and its receptors. In fact, the relationship between NSCLC prognosis and the expression of VEGFA and its receptors has been widely studied. However, the results are controversial. The lack of agreement may be due to variations in gene expression, response to therapy or outcome between the different NSCLC histological subtypes. Moreover, different oxygen requirements in early versus late stages of the disease may profoundly influence the relevance of the VEGFA pathway in NSCLC. The aim of this study was to analyze the prognostic significance of the activation of the VEGFA pathway in early NSCLC by means of the development of a VEGFA signaling score that reflects the activation of VEGFA pathway in tumor cells. A second objective was to clarify the prognostic relevance of this pathway in the two main histological subtypes, adenocarcinoma (ADC) and squamous cell carcinoma (SCC), separately. To this purpose, we analyzed the VEGFA signaling score in three series of NSCLC patients: 1) a series of 298 stage I-IIIA NSCLC patients recruited in the context of the European Early Lung Cancer (EUELC) project; 2) a first validation series of 173 stage I-IIIA NSCLC patients from the MD Anderson Cancer Center; and 3) a second validation series of 50 patients stage I SCC from the CHU Hospital. Immunohistochemistry was used to detect VEGFA, VEGFR1, VEGFR2, and results were analyzed by semiquantitative methods. The VEGFA signaling score was calculated as the sum of VEGFA, VEGFR1 and VEGFR2 scores. In the EUELC series, the multivariate analysis, using the Fine &amp; Gray adaptation of Cox proportional hazard model, revealed that high VEGFA signaling score is an independent good prognostic factor for progression-free survival (HR=0.61 [0.41-0.91], p=0.01). Sub-group analysis revealed that the favorable prognostic value of VEGFA signaling score was restricted to SCC patients (HR=0.40 [0.20-0.78], p=0.007). Conversely, this association was not observed in ADC cases (HR=0.83 [0.48-1.45], p=0.52). The strong association between high VEGFA signaling score and longer recurrence-free survival among stage I SCC patients was validated in the MD Anderson series (HR=0.05 [0.004-0.62], p=0.02). In the stage I SCC series of the CHU Hospital the same tendency was found (p=0.08). In conclusion, these data point to different roles of VEGFA and its receptors in the biology of the two main histological types of lung cancer, and suggests a paradigm shift in the role of the VEGFA pathway in SCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2251. doi:10.1158/1538-7445.AM2011-2251

Customising chemotherapy in advanced nonsmall cell lung cancer: daily practice and perspectives

Treating patients with advanced nonsmall cell lung cancer (NSCLC) is a daunting task but during recent years new options have emerged. By tailoring treatment using either information on histological subtypes of NSCLC or biomarkers it is now possible to improve outcome and maintain stable quality of life. We conducted a literature search of tailored treatment already implemented in advanced NSCLC in order to highlight the information required to decide on the optimal oncological treatment for individual patients. 16 studies were identified by literature review. Significantly improved outcome was demonstrated in patients with nonsquamous NSCLC treated with cisplatin/pemetrexed in pre-planned, exploratory and retrospective analysis from large-scale, randomised trials. Level 1 evidence showed significantly better progression-free survival when patients carrying an epidermal growth factor receptor (EGFR) mutation were treated with gefitinib compared to standard chemotherapy. Retrospective, unplanned analysis of excision repair cross complementation group 1 (ERCC1) and betatubulin III upregulation demonstrated poorer outcome in NSCLC patients treated with platinum-doublets and vinorelbine-based chemotherapy, respectively. In conclusion, tailoring treatment according to either histological subtype or EGFR mutation status in advanced NSCLC should today be part of daily practice based on current evidence. Future biomarkers need optimisation of methodology and prospective validation before clinical implementation.

What’s new in non-small cell lung cancer for pathologists the importance of accurate subtyping, EGFR mutations and ALK rearrangements

In the past, the only critical point of distinction in the pathological diagnosis of lung cancer was between small cell and non-small cell lung cancer (NSCLC). The emergence of new targeted therapies and clinical trials demonstrating differing efficacy and toxicity of treatments according to specific histological subtypes of NSCLC, has resulted in an increasing need for improvements in pathological diagnosis. Accurate distinction between adenocarcinoma and squamous cell carcinoma is now critical as histological subtyping has the potential to influence clinical decision making and impact on patient outcome. While morphological criteria remain the most important feature to distinguish NSCLC subtypes, use of mucin and immunohistochemical stains (TTF-1, p63 and CK5/6) can be of assistance in difficult small biopsy cases. With the emergence of selective kinase inhibitors targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), there is a corresponding need to identify the subset of NSCLCs harbouring specific genetic mutations associated with sensitivity to these agents, almost all of which are found in adenocarcinomas. In this review, the importance of accurately subtyping NSCLC is discussed, along with a suggested approach for distinguishing histological subtypes in small biopsy specimens. The significance of EGFR and ALK mutations in NSCLC and the impact of these genotypes on pathology and clinical practice are also reviewed.

The Evolving Role of Histology in the Management of Advanced Non–Small-Cell Lung Cancer

Until recently, non-small-cell lung cancer (NSCLC) was treated as a single disease despite recognition of its histologic and molecular heterogeneity. Recent clinical trials, however, demonstrate that histology is an important factor for individualizing treatment, based on either safety or efficacy outcomes. For example, the labeling of the licensed agents bevacizumab and pemetrexed is restricted to patients with nonsquamous cell NSCLC. For bevacizumab, this restriction is due to an apparent association between squamous cell histology and severe pulmonary hemorrhage, whereas for pemetrexed, superior treatment effects have been observed in patients with nonsquamous cell histology. Given fewer agents are both active and tolerable in patients with squamous cell carcinoma compared with adenocarcinoma, and the nature of this particular phenotype of NSCLC, new drugs are needed for this histology. In this new histology-based treatment era, questions persist. Can pathology accurately distinguish the histologic subtypes of NSCLC? Can we use cytologic diagnosis? In the future, will molecular profiling of tumors trump histologic analysis? Herein we describe how therapy for NSCLC is evolving on the basis of a better understanding of molecular mechanisms underlying NSCLC histologic heterogeneity and tumorigenesis.

EphA2 Mutation in Lung Squamous Cell Carcinoma Promotes Increased Cell Survival, Cell Invasion, Focal Adhesions, and Mammalian Target of Rapamycin Activation

Non-small cell lung cancer (NSCLC) has a poor prognosis and improved therapies are needed. Expression of EphA2 is increased in NSCLC metastases. In this study, we investigated EphA2 mutations in NSCLC and examined molecular pathways involved in NSCLC. Tumor and cell line DNA was sequenced. One EphA2 mutation was modeled by expression in BEAS2B cells, and functional and biochemical studies were conducted. A G391R mutation was detected in H2170 and 2/28 squamous cell carcinoma patient samples. EphA2 G391R caused constitutive activation of EphA2 with increased phosphorylation of Src, cortactin, and p130(Cas). Wild-type (WT) and G391R cells had 20 and 40% increased invasiveness; this was attenuated with knockdown of Src, cortactin, or p130(Cas). WT and G391R cells demonstrated a 70% increase in focal adhesion area. Mammalian target of rapamycin (mTOR) phosphorylation was increased in G391R cells with increased survival (55%) compared with WT (30%) and had increased sensitivity to rapamycin. A recurrent EphA2 mutation is present in lung squamous cell carcinoma and increases tumor invasion and survival through activation of focal adhesions and actin cytoskeletal regulatory proteins as well as mTOR. Further study of EphA2 as a therapeutic target is warranted.

Thymidylate synthase polymorphisms and immunohistochemistry in non-small cell lung cancer

11101 Background: Recently, pemetrexed has been introduced into the treatment of non-small cell lung cancer (NSCLC). There's evidence that pemetrexed appears to be more efficient in non squamous NSCLC including adenocarcinoma (AC) and large cell carcinoma (LCC). TS represents a major target enzyme of pemetrexed. We evaluated the expression of TS among different histological types of NSCLC and its association with functional genetic polymorphisms of the TS gene. Methods: Archived tumor samples from 312 individuals with NSCLC were analyzed. Immunohistochemistry (IHC) was performed using a mouse monoclonal antibody to TS. TS stained sections were scored for cytoplasmic and nuclear localization. For each compartment, the tumor was evaluated for the estimated percentage of positive cells with the greatest intensity within the tumor. Intensity was scored on a scale of 0–4. A score of 3–4 was classified as high expression. Genotyping of TS-VNTR including the G/C SNP and TS1394del6 was performed by PCR based RFLP techniques. Genotypes supposed to be associated with low expression were grouped (group A: 2R/2R or 2R/3RC or 3RC/3RC + -6/-6) and compared to genotype groups associated with high expression (group B: 2R/3RG or 3RC/3RG or 3RG/3RG + -6/+6 or +6/+6). Results: IHC and polymorphisms could be performed successfully in 312 (100%) and 287 (92%), respectively. Distribution of histology was as follows: 50% AC, 42% squamous cell carcinoma (SCC), 3% LCC and 5% mixed or other histological subtypes. Group B genotypes were significantly more present in SCC than in AC (49% vs 23%, p=.002). Tumors with group B genotypes were more likely to display high nuclear staining intensity than group A tumors (30% vs. 17%, p=.077). A similar but not significant trend was seen for cytoplasmic staining intensity. There was no significant difference between histological subtypes of NSCLC with respect to TS protein expression. AC were more common than SCC to show a G1 differentiated tumors (8% vs 1%, p&lt;.001). No difference between genotype groups were observed with respect to grading. Conclusions: TS polymorphisms are significantly associated with histology subtypes in NSCLC. These results represent a potential explanation for efficacy differences of pemetrexed in NSCLC and warrants further investigations. [Table: see text]