Molecular profile of driver genes in lung adenocarcinomas of Brazilian patients who have never smoked: implications for targeted therapies.

INTRODUCTION: Lung cancer in never-smoker (LCINS) patients accounts for 20% of lung cancer cases, and its biology remains poorly understood, particularly in genetically admixed populations. We elucidated the molecular profile of driver genes in Brazilian LCINS. METHODS: The mutational and gene fusion status of 119 lung adenocarcinomas from self-reported never-smoker patients, was assessed using targeted sequencing (NGS), nCounter, and immunohistochemistry. A panel of 46 ancestry-informative markers determined patients' genetic ancestry. RESULTS: The most frequently mutated gene was EGFR (49.6%), followed by TP53 (39.5%), ALK (12.6%), ERBB2 (7.6%), KRAS (5.9%), PIK3CA (1.7%), and less than 1% alterations in RET, NTRK1, MET∆ex14, PDGFRA, and BRAF. Except for TP53 and PIK3CA, all other alterations were mutually exclusive. Genetic ancestry analysis revealed a predominance of European (71.1%), and a higher African ancestry was associated with TP53 mutations. CONCLUSION: Brazilian LCINS exhibited a similar molecular profile to other populations, except the increased ALK and TP53 alterations. Importantly, 73% of these patients have actionable alterations that are suitable for targeted treatments.

Disruptive and Truncating TP53 Mutations Are Associated with African-Ancestry and Worse Prognosis in Brazilian Patients with Lung Adenocarcinoma.

INTRODUCTION: TP53 is the most frequently mutated gene in lung tumors, but its prognostic role in admixed populations, such as Brazilians, remains unclear. In this study, we aimed to evaluate the frequency and clinicopathological impact of TP53 mutations in non-small cell lung cancer (NSCLC) patients in Brazil. METHODS: We analyzed 446 NSCLC patients from Barretos Cancer Hospital. TP53 mutational status was evaluated through targeted next-generation sequencing (NGS) and the variants were biologically classified as disruptive/nondisruptive and as truncating/nontruncating. We also assessed genetic ancestry using 46 ancestry-informative markers. Analysis of lung adenocarcinomas from the cBioportal dataset was performed. We further examined associations of TP53 mutations with patients' clinicopathological features. RESULTS: TP53 mutations were detected in 64.3% (n = 287/446) of NSCLC cases, with a prevalence of 60.4% (n = 221/366) in lung adenocarcinomas. TP53 mutations were associated with brain metastasis at diagnosis, tobacco consumption, and higher African ancestry. Disruptive and truncating mutations were associated with a younger age at diagnosis. Additionally, cBioportal dataset revealed that TP53 mutations were associated with younger age and Black skin color. Patients harboring disruptive/truncating TP53 mutations had worse overall survival than nondisruptive/nontruncating and wild-type patients. CONCLUSION: TP53 mutations are common in Brazilian lung adenocarcinomas, and their biological characterization as disruptive and truncating mutations is associated with African ancestry and shorter overall survival.

Implementation of an Integrated Lung Cancer Prevention and Screening Program Using a Mobile Computed Tomography (CT) Unit in Brazil.

INTRODUCTION: Lung cancer is the deadliest cancer worldwide and in Brazil. Despite strong evidence, lung cancer screening by low-dose computed tomography (LDCT) in high-risk individuals is far from a reality in many countries, particularly in Brazil. Brazil has a universal public health system marked with important inequalities. One affordable strategy to increase the coverage of resources is to use mobile units. OBJECTIVES: To describe the implementation and results of an innovative lung cancer prevention program that integrates tobacco cessation and lung cancer screening using a mobile CT unit. METHODOLOGY: From May 2019 to Dec 2020, health professionals from 18 public primary health care units in Barretos, Brazil, were trained to offer smoking cessation counseling and treatment. Eligible high-risk participants of this program were also invited to perform lung cancer screening in a mobile LDCT unit that was specially conceived to be dispatched to the community. A detailed epidemiological questionnaire was administered to the LDCT participants. RESULTS: Among the 233 screened participants, the majority were women (54.9%), and the average age was 62 years old. A total of 52.8% of participants showed high or very high nicotine dependence. After 1 year, 27.8% of participants who were involved in smoking cessation groups had quit smoking. The first LDCT round revealed that the majority of participants (83.7%) exhibited lung-Rads 1 or 2; 7.3% exhibited lung-Rads 3; 7.7% exhibited lung-Rads 4a; and 3% exhibited lung-Rads 4b or 4x. The three participants with lung-Rads 4b were further confirmed, and their surgery led to the diagnosis of early-stage cancer (1 case of adenocarcinoma and two cases of squamous cell carcinoma), leading to a cancer diagnosis rate of 12.8/1000. CONCLUSION: Our results indicate promising outcomes for an onsite integrative program enrolling high-risk individuals in a middle-income country. Evidence barriers and challenges remain to be overcome.

Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations.

Lung cancer is the deadliest cancer worldwide. The mutational frequency of EGFR and KRAS genes in lung adenocarcinoma varies worldwide per ethnicity and smoking. The impact of EGFR and KRAS mutations in Brazilian lung cancer remains poorly explored. Thus, we investigated the frequency of EGFR and KRAS mutations in a large Brazilian series of lung adenocarcinoma together with patients' genetic ancestry, clinicopathological and sociodemographic characteristics. The mutational frequency of EGFR was 22.7% and KRAS was 20.4%. The average ancestry proportions were 73.1% for EUR, 13.1% for AFR, 6.5% for AME and 7.3% for ASN. EGFR mutations were independently associated with never-smokers, high-Asian ancestry, and better performance status. KRAS mutations were independently associated with tobacco exposure and non-Asian ancestry. EGFR-exon 20 mutations were associated with worse outcome. The Cox regression model indicated a worse outcome for patients whose were older at diagnosis (>61 y), solid histological subtype, loss of weight (>10%), worse performance status (≥2), and presence of KRAS mutations and EGFR mutational status in TKi non-treated patients. In conclusion, we assessed the clinicopathological and ethnic impact of EGFR and KRAS mutations in the largest series reported of Brazilian lung adenocarcinomas. These findings can support future clinical strategies for Brazilian lung cancer patients.

EGF+61 A>G polymorphism is not associated with lung cancer risk in the Brazilian population.

Epidermal growth factor (EGF) and its receptor (EGFR) play an important role in lung carcinogenesis. A functional single nucleotide polymorphism (SNP) in EGF promoter region (EGF+61 A>G-rs4444903) has been associated with cancer susceptibility. Yet, in lung cancer, the EGF+61 A>G role is unclear. The aim of this study was to evaluate the risk of lung cancer associated with EGF+61 A>G SNP in the Brazilian population. For that, 669 lung cancer patients and 1104 controls were analyzed. EGF+61 A>G genotype was assessed by PCR-RFLP and TaqMan genotyping assay. Both patients and controls were in Hardy-Weinberg equilibrium. As expected, uni- and multivariate analyses showed that tobacco consumption and age were significant risk factors for lung cancer. The genotype frequencies in lung cancer patients were 27.3% of AA, 47.4% of AG and 25.3% of GG, and for controls were 25.3% of AA, 51.6% of AG and 23.1% of GG. The allele frequencies were 51.1% of A and 48.9% of G for both cases and controls. No significant differences for the three genotypes (AA, AG and GG-codominant model) were observed between cases and controls. We then grouped AG and GG (recessive model) genotypes, as well as AA and AG (dominant model), and again, no significant differences were also found. This is the largest study to explore EGF+61 A>G polymorphism association with lung cancer risk and suggests that this SNP is not a risk factor for lung cancer in the Brazilian population.

Detection of ALK fusion transcripts in FFPE lung cancer samples by NanoString technology.

BACKGROUND: ALK-rearranged lung cancers exhibit specific pathologic and clinical features and are responsive to anti-ALK therapies. Therefore, the detection of ALK-rearrangement is fundamental for personalized lung cancer therapy. Recently, new molecular techniques, such as NanoString nCounter, have been developed to detect ALK fusions with more accuracy and sensitivity. METHODS: In the present study, we intended to validate a NanoString nCounter ALK-fusion panel in routine biopsies of FFPE lung cancer patients. A total of 43 samples were analyzed, 13 ALK-positive and 30 ALK-negative, as previously detected by FISH and/or immunohistochemistry. RESULTS: The NanoString panel detected the presence of the EML4-ALK, KIF5B-ALK and TFG-ALK fusion variants. We observed that all the 13 ALK-positive cases exhibited genetic aberrations by the NanoString methodology. Namely, six cases (46.15%) presented EML-ALK variant 1, two (15.38%) presented EML-ALK variant 2, two (15.38%) presented EML-ALK variant 3a, and three (23.07%) exhibited no variant but presented unbalanced expression between 5'/3' exons, similar to other positive samples. Importantly, for all these analyses, the initial input of RNA was 100 ng, and some cases displayed poor RNA quality measurements. CONCLUSIONS: In this study, we reported the great utility of NanoString technology in the assessment of ALK fusions in routine lung biopsies of FFPE specimens.

Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study.

BACKGROUND: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). METHODS: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. FINDINGS: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. INTERPRETATION: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. FUNDING: Eli Lilly and Company.

Preoperative nodal staging of non-small cell lung cancer using 99mTc-sestamibi spect/ct imaging.

OBJECTIVES: The proper nodal staging of non-small cell lung cancer is important for choosing the best treatment modality. Although computed tomography remains the first-line imaging test for the primary staging of lung cancer, its limitations for mediastinum nodal staging are well known. The aim of this study is to evaluate the accuracy of hybrid single-photon emission computed tomography and computed tomography using 99mTc-sestamibi in the nodal staging of patients with non-small cell lung cancer and to identify potential candidates for surgical treatment. METHODS: Prospective data were collected for 41 patients from December 2006 to February 2009. The patients underwent chest computed tomography and single-photon emission computed tomography/computed tomography examinations with 99mTc-sestamibi within a 30-day time period before surgery. Single-photon emission computed tomography/computed tomography was considered positive when there was focal uptake of sestamibi in the mediastinum, and computed tomography scan when there was lymph nodes larger than 10 mm in short axis. The results of single-photon emission computed tomography and computed tomography were correlated with pathology findings after surgery. RESULTS: Single-photon emission computed tomography/computed tomography correctly identified six out of 19 cases involving hilar lymph nodes and one out of seven cases involving nodal metastases in the mediastinum. The sensitivity, specificity, positive predictive value, and negative predictive value for 99mTc-sestamibi single-photon emission computed tomography/computed tomography in the hilum assessment were 31.6%, 95.5%, 85.7%, and 61.8%, respectively. The same values for the mediastinum were 14.3%, 97.1%, 50%, and 84.6%, respectively. For the hilar and mediastinal lymph nodes, chest tomography showed sensitivity values of 47.4% and 57.1%, specificity values of 95.5% and 91.2%, positive predictive values of 90% and 57.1% and negative predictive values of 67.7% and 91.2%, respectively. CONCLUSION: Single-photon emission computed tomography/computed tomography with 99mTc-sestamibi showed very low sensitivity and accuracy for the nodal staging of patients with non-small cell lung cancer, despite its high level of specificity. In addition, the performance of single-photon emission computed tomography/computed tomography added no relevant information compared to computed tomography that would justify its use in the routine preoperative staging of non-small cell lung carcinoma.

Preoperative nodal staging of non-small cell lung cancer using 99mTc-sestamibi spect/ct imaging

OBJECTIVES: The proper nodal staging of non-small cell lung cancer is important for choosing the best treatment modality. Although computed tomography remains the first-line imaging test for the primary staging of lung cancer, its limitations for mediastinum nodal staging are well known. The aim of this study is to evaluate the accuracy of hybrid single-photon emission computed tomography and computed tomography using 99mTc-sestamibi in the nodal staging of patients with non-small cell lung cancer and to identify potential candidates for surgical treatment. METHODS: Prospective data were collected for 41 patients from December 2006 to February 2009. The patients underwent chest computed tomography and single-photon emission computed tomography/computed tomography examinations with 99mTc-sestamibi within a 30-day time period before surgery. Single-photon emission computed tomography/computed tomography was considered positive when there was focal uptake of sestamibi in the mediastinum, and computed tomography scan when there was lymph nodes larger than 10 mm in short axis. The results of single-photon emission computed tomography and computed tomography were correlated with pathology findings after surgery. RESULTS: Single-photon emission computed tomography/computed tomography correctly identified six out of 19 cases involving hilar lymph nodes and one out of seven cases involving nodal metastases in the mediastinum. The sensitivity, specificity, positive predictive value, and negative predictive value for 99mTc-sestamibi single-photon emission computed tomography/computed tomography in the hilum assessment were 31.6 percent, 95.5 percent, 85.7 percent, and 61.8 percent, respectively. The same values for the mediastinum were 14.3 percent, 97.1 percent, 50 percent, and 84.6 percent, respectively. For the hilar and mediastinal lymph nodes, chest tomography showed sensitivity values of 47.4 percent and 57.1 percent, specificity values of 95.5 percent and 91.2 percent, positive predictive values of 90 percent and 57.1 percent and negative predictive values of 67.7 percent and 91.2 percent, respectively. CONCLUSION: Single-photon emission computed tomography/computed tomography with 99mTc-sestamibi showed very low sensitivity and accuracy for the nodal staging of patients with non-small cell lung cancer, despite its high level of specificity. In addition, the performance of single-photon emission computed tomography/computed tomography added no relevant information compared to computed tomography that would justify its use in the routine preoperative staging of non-small cell lung carcinoma.

Giant cell tumor of the sternum.

We report the case of a 74-year-old female patient diagnosed with a giant cell tumor of the sternum. The clinical and radiological presentation was indicative of a primary tumor of the sternum. The patient underwent complementary tests and surgery. The pathological examination confirmed the diagnosis. Commonly observed in the long bones of the appendicular skeleton, this type of tumor is characterized by its local aggressiveness and metastatic potential. We also review the literature on the topic.

Tumor de células gigantes do esterno / Giant cell tumor of the sternum

Relatamos o caso de uma paciente de 74 anos portadora de tumor de células gigantes em osso esterno. A apresentação clínica e radiológica indicava neoplasia primária de osso esterno. A paciente realizou exames complementares e cirurgia. O exame patológico confirmou o diagnóstico. Comumente observado em ossos longos no esqueleto apendicular, esse tipo de tumor caracteriza-se por sua agressividade local e pelo potencial metastático. Também fazemos uma revisão sobre o tema.

We report the case of a 74-year-old female patient diagnosed with a giant cell tumor of the sternum. The clinical and radiological presentation was indicative of a primary tumor of the sternum. The patient underwent complementary tests and surgery. The pathological examination confirmed the diagnosis. Commonly observed in the long bones of the appendicular skeleton, this type of tumor is characterized by its local aggressiveness and metastatic potential. We also review the literature on the topic.

Gastos näo médicos de pacientes com câncer / Non-medical expenses with cancer pacients

Os autores, preocupados com gastos näo médicos como transporte, alimentaçäo, hospedagem, etc., de pacientes com câncer nos seus deslocamentos até o Hospital Säo Judas Tadeu, Barretos, SP, resolveram fazer um estudo deste problema. Um questionário foi aplicado a 114 pacientes que faziam quimioterapia ambulatorialmente, no período de janeiro a maio de 1985. A análise mostrou que os gastos relativos com transporte, alimentaçäo e perda do dia de trabalho foram respectivamente de 80%, 11% e 9%. Os fatores que mais influenciaram estes resultados foram diferentes distâncias da residência do paciente ao Hospital e diferentes meios de transporte. Concluiu-se, também, que os pacientes com baixa renda mensal apresentavam despesas aproximadamente iguais aos de alta renda. Considerando os sofrimentos do paciente com câncer e de seus familiares, além da alta significância dos gastos encontrados, a situaçäo requer maior atençäo dos Orgäos governamentais competentes

Ensaio terapêutico controlado no carcinoma primitivo avançado de pulmäo / Controlled clinical trial in the advanced primary lung cancer

Os AA. apresentam os resultados de ensaio terapêutico controlado no carcinoma primitivo de pulmäo avançado, em que foram incluidos 39 pacientes atendidos no Departamento de Cirurgia torácica do Hospital A. C. Camargo da Fundaçäo Antonio Prudente, Säo Paulo. Brasil. Os grupos foram: 1) Telecobaltoterapia + Quimioterapia e 2) Quimioterapia. A técncia usada no tratamento pelas irradiaçöes foi "split dose" (6.000 rads, em 3 séries de 2.000 rads cada uma). A terapêutica pelas drgas antitumorais constou de 16 séries (5 Fluoro-uracil, Metilhidrazina, Matotrexate, Actinomicina D, Vincristina, Ciclofosfamida), visando um bloqueio sucessivo, sincrônico e funcional da populaçäo celular neoplásica (base citodinâmica). Näo houve diferenças significativas, do ponto de vista estatístico, na comparaçäo das sobrevidas dos pacientes submetidos aos tratamentos propostos: TECO + Qt = 19,3 semanas e Qt = 14,6 semanas