Portuguese Consensus Recommendations for Next-Generation Sequencing of Lung Cancer, Rare Tumors, and Cancers of Unknown Primary Origin in Clinical Practice.

Next-generation sequencing (NGS) has been implemented in clinical oncology for diagnosis, prognosis, and therapeutic guidance. Among the various NGS applications in molecular oncology, we focused on the following topics: laboratory standards for targeted gene panels (somatic mutations) and therapeutic guidance based on NGS of lung cancer and rare cancers, namely sarcomas and cancers of unknown primary. Multiple quality control checkpoints should be addressed in the pre-analytical phase for good quality and interpretation of the NGS results. It includes tumor size and cellularity, tissue processing and decalcification, tumor fraction, tumor viability, fixatives, and staining. Communication between clinicians and laboratory support is also essential. In lung cancer, all patients with non-squamous non-small cell lung cancer should be tested with a NGS panel, and it should include not only genes with approved targeted therapies (ALK, BRAF, EGFR, MET, NTRK, RET, and ROS1) but also genes with potentially actionable genomic alterations (HER2 and KRAS). Since there is a lack of extensive knowledge regarding the use of NGS in rare tumors performing comprehensive genomic profiling, NGS panels to better manage the disease are recommended. Moreover, other patients with other incurable solid tumors may benefit from being included in biomarker-driven clinical trials. Multidisciplinary tumor boards with the participation of experts with the ability to integrate genomic profiling data are essential to tailor the best strategy for each patient. Considering that there are no national guidelines, this article aims to guide laboratory and clinical practice for the use of NGS in the context of lung cancer, rare tumors, and cancer of unknown primary in Portugal.

Na área da oncologia clínica, a sequenciação de nova geração (NGS) foi implementada com o objetivo de contribuir para o diagnóstico, prognóstico e orientação terapêutica. A utilização de NGS em oncologia molecular é vasta, focalizando-se estas recomendações nas: normas laboratoriais para painéis genéticos direcionados (mutações somáticas) e na orientação terapêutica baseada em NGS de cancro do pulmão e cancros raros, nomeadamente sarcomas e cancros de origem desconhecida. Para que sejam obtidos resultados de NGS com a qualidade que permita a sua correta interpretação, devem ser abordados múltiplos controlos de qualidade na fase pré-analítica que disponibilizem informação sobre o tamanho e celularidade do tumor, processamento e descalcificação de tecidos, fração tumoral, viabilidade do tumor, fixadores e coloração utilizados. A comunicação entre os diferentes intervenientes no processo, em particular entre os clínicos e o laboratório também contribui, de forma inequívoca, para a interpretação dos resultados de NGS. Todos os doentes com cancro do pulmão de não pequenas células não escamoso devem ser testados com um painel de NGS, que deve incluir não só genes com terapias dirigidas aprovadas (ALK, BRAF, EGFR, MET, NTRK, RET e ROS1), mas também genes com alterações genómicas identificadas como potenciais alvos terapêuticos (HER2 e KRAS). Dada a escassez de evidência científica sobre a utilização de NGS em tumores raros, recomenda-se a realização de painéis genómicos abrangentes que poderão contribuir para uma melhor gestão da doença. Adicionalmente, outros doentes, com outros tumores sólidos incuráveis, podem beneficiar da inclusão em ensaios clínicos orientados por biomarcadores. A realização de reuniões multidisciplinares com a participação de diferentes especialistas capazes de integrar dados dos perfis genómicos são fundamentais para a escolha da melhor estratégia para cada doente. Considerando que não existem recomendações nacionais, este artigo visa orientar a prática laboratorial e clínica para a utilização de NGS em tumores do pulmão, raros e cancros de origem primária desconhecida em Portugal.

Detection and quantification of EGFR T790M mutation in liquid biopsies by droplet digital PCR.

BACKGROUND: Liquid biopsy allows the identification of targetable cancer mutations in a minimally invasive manner. In patients with advanced non-small cell lung cancer (NSCLC), droplet digital PCR (ddPCR) is increasingly used to genotype the epidermal growth factor receptor (EGFR) gene in circulating cell-free DNA (cfDNA). However, the sensitivity of this method is still under debate. The aim of this study was to implement and assess the performance of a ddPCR assay for detecting the EGFR T790M mutation in liquid biopsies. METHODS: A ddPCR assay was optimized to detect the EGFR T790M mutation in plasma samples from 77 patients with NSCLC in progression. RESULTS: Our ddPCR assay enabled the detection and quantification of the EGFR T790M mutation at cfDNA allele frequency as low as 0.5%. The mutation was detected in 40 plasma samples, corresponding to a positivity rate of 52%. The number of mutant molecules per mL of plasma ranged from 1 to 6,000. A re-biopsy was analyzed for 12 patients that had a negative plasma test and the mutation was detected in 2 cases. A second liquid biopsy was performed for 6 patients and the mutation was detected in 3 cases. CONCLUSIONS: This study highlights the value of ddPCR to detect and quantify the EGFR T790M mutation in liquid biopsies in a real-world clinical setting. Our results suggest that repeated ddPCR tests in cfDNA may obviate tissue re-biopsy in patients unable to provide a tumor tissue sample suitable for molecular analysis.

Characterization and management of elderly and very elderly patients with non-small cell lung cancer.

OBJECTIVES: Despite non-small cell lung cancer (NSCLC) high prevalence and increasing incidence, evidence specific to the elderly and very elderly is sparse. To retrospectively compare characterization and approach of NSCLC patients (pts) aged 70-79 and ≥80 years. METHODS: We performed a retrospective analysis of 297 adult NSCLC pts who registered and initiated NSCLC management in our Pulmonology Oncology Unit from January 2013 to December 2016 corresponding to 38.2% of all NSCLC patients (n = 778). Demographic data and lung cancer management were analysed. RESULTS: Pts were categorized as elderly (n = 211, 71.0%) and very elderly (n = 86, 29.0%). Very elderly pts had worse Eastern Cooperative Oncology Group performance status (P = 0.047), higher Charlson age comorbidity index (P < 0.001) and the majority had stage IV cancer (66.3%, P = 0.04). The first management option in very elderly pts was chemotherapy (CTX) (30.2%, P = 0.37) and in elderly pts was multimodal therapy (30.3%, P ≤ 0.001). Support therapy and first-line targeted (EGFR or ALK-positive) were more common in the very elderly (23.6%, P = 0.01; 17.4% P = 0.002, respectively). Curative radiation or surgery rates did not differ between groups. Reasons for premature first-line CTX stop, toxicity and hospitalization did not differ. Death rate (69.7% vs 63.5% for very elderly and elderly, respectively) and mean survival since diagnosis (11.5 vs 11.6 months for very elderly and elderly, respectively) did not differ. CONCLUSIONS: There were significant differences in pts characteristics having the very elderly more multimorbidity and advanced state of disease. First management options were significantly different with respect to multimodal, targeted and support therapy.

Angiosarcoma of the lung.

Angiosarcoma is a rare malignant vascular tumor. Pulmonary involvement is usually attributable to metastasis from other primary sites, primary pulmonary angiosarcoma therefore being quite uncommon. We report a case of angiosarcoma with pulmonary involvement, probably primary to the lung, which had gone untreated for more than two years. We describe this rare neoplasm and its growth, as well as the extensive local invasion and hematogenous metastasis at presentation. We also discuss its poor prognosis.

Angiosarcoma of the lung / Angiossarcoma pulmonar

Angiosarcoma is a rare malignant vascular tumor. Pulmonary involvement is usually attributable to metastasis from other primary sites, primary pulmonary angiosarcoma therefore being quite uncommon. We report a case of angiosarcoma with pulmonary involvement, probably primary to the lung, which had gone untreated for more than two years. We describe this rare neoplasm and its growth, as well as the extensive local invasion and hematogenous metastasis at presentation. We also discuss its poor prognosis.

O angiosarcoma é um tumor vascular maligno. O envolvimento pulmonar é geralmente atribuído à metástase de outros sítios primários, sendo o angiossarcoma pulmonar primário extremamente raro. Relatamos um caso de angiossarcoma com envolvimento pulmonar, provavelmente primário no pulmão com mais de dois anos de evolução. Descrevemos seu crescimento e sua extensa invasão local e hematogênica na apresentação. Documentamos ainda seu mau prognóstico.

Bevacizumab for the treatment of nonsquamous non-small-cell lung cancer in Portugal: a retrospective, multicenter study.

INTRODUCTION: Lung cancer is the leading cause of cancer-related mortality. In patients with nonsquamous non-small-cell lung cancer (NSCLC) stage IIIB/IV treatment with chemotherapy plus bevacizumab led to significant improvements in progression-free and median overall survival (OS). AIM: To report the experience of five Portuguese centers in treating patients with nonsquamous NSCLC in stage IIIB or IV with bevacizumab and chemotherapy regarding survival and toxicity outcomes. MATERIALS AND METHODS: This was a retrospective, multicenter study on patients with nonsquamous stage IIIB/IV NSCLC treated with bevacizumab and chemotherapy from November 2007 to August 2010 through special use permits. We reviewed the medical records, registry of demographic characteristics, treatments provided, treatment responses, adverse events, and dates of death. Statistical analysis was performed with SPSS statistics software. Median OS and event-free survival (EFS) were calculated using the Kaplan-Meier method. RESULTS: From an eligible population of 41 patients, 37 participants were registered. Study participants were predominantly male (78.4%) with a median age of 53 years (29-75 years). In total, 83.8% patients had stage IV disease (TNM, 6th Ed.). The OS was 21.5 months (95% confidence interval [CI]: 12.6-30.5] and median EFS was 9.4 months (95% CI9: 7.1-11.7). Hematologic toxicity grade 3/4 occurred in 35.1% of patients, and nonhematologic toxicity in 24.3% patients. One fatal thromboembolic event was recorded (2.7%). CONCLUSIONS: The results of chemotherapy plus bevacizumab treatment for nonsquamous NSCLC obtained from the daily clinical practice of the centers involved in this study were similar to those of published clinical trials. Collaboration between the different Portuguese centers is crucial for this kind of study.

Clinical characteristics of patients with lung cancer and metachronous or synchronous tumours with other locations.

Lung cancer is the leading form of cancer death worldwide. Cancer patients are at a high risk of developing a second cancer. The present study attempts to determine the characteristics of a population with lung cancer diagnosed with another cancer. We analysed records of patients from the Department of Lung Oncology of our hospital from 2000 to 2007 who were identified as having two or more tumours. We found 4.2% (n=44) multiple cancers among the registered cases (n=1046), 88.6% males, (high) mean age 70.1+/-10 years old. About 86% (n=38) of the patients were smokers or ex -smokers. From the patients with record of family history, 65.4% (n=17) had relevant family history of cancer. The majority of the first malignancy diagnosed was prostate, colon, head and neck and bladder. Lung cancer was essentially the second malignancy. The mean time lag between the two diagnoses was 62.9+/-64.9 months (max. 240, min. 0), with the second cancer usually detected at an advanced stage. The mean survival of patients who had a second primary lung cancer was 8.6+/-8.24 months (max. 32, min. 1), with four patients still surviving. Our results suggest that extended follow -up is needed in these patients, using screening strategies which follow international recommendations, and with control of carcinogenic risk factors such as smoking. We suggest a tailored risk algorithm and a further study to assess if there are particular molecular markers in these patients.

[Cost of cancer care in Portugal]. / Custo do tratamento do cancro em Portugal.

INTRODUCTION: Cancer is the second most important cause of death in Portugal, following cardiovascular diseases (CVD), and shows a constant progressive increase in the proportional share of total deaths. In Portugal, as in most countries, the health care budget is under constant cost-containment pressures. In this context it is necessary to verify if enough resources have been allocated to the disease in terms of health care expenditure. The main objective of this study is to estimate the cost of cancer care in Portugal and to compare it to similar data in Europe and the United States of America (USA), to the cost of CVD. The secondary objective is to evaluate the cost of pharmaceuticals used in the treatment of cancer in Portugal, both in relation to total pharmaceutical expenditure and to other therapeutic areas. METHODS: Three main sources of information were used: comprehensive literature review, primary and secondary data sources, and a modified Delphi Panel, which was used to fill in gaps in the information derived from the data sources and the literatura review. The burden of cancer was measured through the Disability-adjusted life-year (DALY) and, in order to determine the costs of cancer, detailed information on the costs of medical visits and of inpatient episodes based on Diagnosis Related Groups (DRG), in 2006, was used. To estimate the total cost of cancer, we used a combination of top down (breaking global expenditure data to specific levels) and bottom up methodology (based on the sum of different components). RESULTS: Based on 2006 data on direct medical care expenditures in Portugal, we found that 565 million euro were spent on cancer in comparison to 1 320 million on CVD representing 3.91% and 9.14% of total cost on health respectively. When we break down total expenditure on drugs by therapeutic area we find that CVD drugs represent about 21.6% of total drug costs in Portugal and cancer drugs represent about 5.6% of the total. Oncology drugs represent 32% of the total expenditure on cancer, while CVD drugs represent 54% of the total expenditure on CVD. In comparison, in terms of BoD in Portugal, 18.6% of DALY's were associated with CVD and 15.3% with cancer. CONCLUSION: Considering the burden of disease (BoD) of CVD and cancer in Portugal, we can state that the expenditure allocated to cancer is significantly lower than expected. Using the criterion of expenditure according to need, we observed that there is an imbalance of expense/BoD in oncology indicating that cancer seems to be underfunded in Portugal. Even considering that this shouldn't be the only criterion to determine the volume of expense in a certain therapeutic area, the differential observed in this study is sufficiently high to deserve attention from the decision-makers.

Treatment of non-small cell lung cancer, advanced disease, with erlotinib in 2(nd) and 3(rd) lines. Two cases report. / Tratamento do carcinoma pulmonar de não pequenas células, doença avançada, com erlotinib em segunda e terceira linhas. A propósito de dois casos clínicos.

Agents that inhibit the activity of cell membrane receptor tyrosine kinases, such as the human epidermal growth factor receptor (EGFR) have been an attractive target because EGFR is expressed by 80% of NSCLC. Erlotinib as monotherapy in the treatment of NSCLC after failure of at least one prior chemotherapy regimen, prolonged survival and improved quality of life, although modest response rate. Women, Asiens, patients with Adenocarcinoma and never smokers, were more likely than other patients to have a response to erlotinib. This is the group of patients that most commonly have an EGFR mutation. The authors describe two cases, with important control of symptoms and increased time to progression, independently o response rate (stable disease or partial response). Rev Port Pneumol 2008; XIV (Supl 3): S53-S60.

[Idiophatic mediastinal fibrosis: a case report]. / Fibrose idiopática do mediastino: A propósito de um caso clínico.

We herein report a case of a male patient, who presented a mediastinal mass that had a slow growth over the years. After surgery, that made the diagnosis of idiopathic mediastinal fibrosis, the growth stabilized. Four years latter it was observed a substantial increase which lead to the inevitable compression of vital structures which, in turn, led to pulmonary hypertension. Idiopathic mediastinal fibrosis is an extremely rare pathology. There are same cases in which it is associated with other pathologies but has always a fatal prognosis when surgery is not an option.