The goal of this dissertation was to examine the realized value of targeted therapies in routine care and to identify opportunities for improving the return on medical spending for these technologies. Chapter 1 investigated the value of targeted therapies in lung cancer patients who were treated in routine care. This observational, claims-based analysis used propensity score, and instrumental variable methods, combined with a Kaplan Meier Sample Average estimator to calculate lifetime costs and life expectancy. An incremental comparison showed that the realized value of targeted therapies in routine care was unfavorable relative to chemotherapy treatment. Subgroup analyses revealed that initial erlotinib therapy yielded effectiveness results that are substantially lower than efficacy survival outcomes in molecularly guided trials. Our results indicated that in routine care, chemotherapy was the most cost effective strategy. The unexpectedly low outcomes with first-line erlotinib suggested that some of the value of this treatment was not being realized in practice. Chapter 2 examined the practice patterns of targeted therapies and utilization of predictive biomarker testing in routine care to better understand the observed gaps between trial-based and `real-world' outcomes with these agents. In our nationally representative cohort of lung cancer patients, we found that the vast majority of patients did not undergo molecular testing to inform first-line therapy. Our prediction models for biomarker screening and first-line treatment suggested that phenotypic enrichment criteria guided selection for testing and initiation of erlotinib therapy. Since clinical characteristics do not adequately discriminate between mutation positive and wild type tumors, these practices signal the need for wider dissemination of biomarker screening to accurately target patients towards improving therapeutic gains with erlotinib. Chapter 3 assessed the cost-effectiveness of multiplexed predictive biomarker screening to inform treatment decisions in lung cancer patients. Using a micro-simulation model to evaluate the incremental value of molecularly guided therapy compared to chemotherapy in unselected patients, we found that personalized therapy is a cost effective strategy. Our results indicated that better value of targeted therapies in lung cancer is achievable through molecularly guided treatment.

This thesis examined associations between ecological indicators of residential radon and fine particulate matter air pollution (PM2.5) and lung cancer mortality using data from the American Cancer Society Cancer Prevention Study-II (CPS-II) prospective cohort. Nearly 1.2 million CPS-II participants were recruited in 1982. Mean county-level residential radon concentrations were linked to study participants according to ZIP code information at enrollment (mean (SD) = 53.5 (38.0) Bq/m3). Cox proportional hazards regression models were used to obtain adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer mortality associated with radon. After necessary exclusions, a total of 811,961 participants in 2,754 counties were retained for analysis. A significant positive linear trend was observed between categories of radon concentrations and lung cancer mortality (p = 0.02). A 15% (95% CI 1 - 31%) increase in the risk of lung cancer mortality was observed per each 100 Bq/m3 radon. Radon was also positively associated with chronic obstructive pulmonary disease mortality (HR per each 100 Bq/m3 = 1.13, 95% CI 1.05 - 1.21). No clear associations were observed between radon and non-respiratory mortality. In lifelong never smokers (n = 188,699), each 10 µg/m3 increase in mean metropolitan statistical area PM2.5 concentrations was associated with a 15-27% increase in the risk of lung cancer death which strengthened among individuals with a history of asthma or any prevalent chronic lung disease at enrollment (p for interaction < 0.05). There was no association between PM2.5 and mortality from non-malignant respiratory disease. In conclusion, this thesis observed significant positive associations between ecological indicators of residential radon and PM2.5 concentrations and lung cancer mortality. These findings further support efforts to reduce radon concentrations in homes to the lowest possible level and strengthens the evidence that ambient concentrations of PM2.5 measured in recent decades are associated with small but measurable increases in lung cancer mortality. Further research is needed to better understand possible complex inter-relationships between environmental risk factors, chronic lung disease, and lung cancer.

Radon is a human carcinogen and is an important occupational and public health concern. Radiation protection programs, implemented since the 1950s and 1960s, have significantly reduced radon levels in uranium mines and improved the quality of exposure information. Precise quantification of the risk of lung cancer at low levels of radon exposure and the factors that confound and modify this risk are important for occupational radiation protection. This is a joint cohort study of 408 lung cancer deaths and 394,236 person-years of risk from the Czech, French and Canadian male uranium miners, employed in 1953 or later, with cumulative radon exposures < 100 working level months (WLM). Internal Poisson regression models, stratified by cohort, age at risk and calendar year period at risk were used to calculate the linear excess relative risk (ERR) per unit cumulative radon exposure (lagged five-years). The impact of effect modifiers: time since exposure, attained age, and exposure rate were assessed using an exposure-age-concentration model. Finally, sensitivity analyses assessed the confounding effect of unmeasured tobacco smoking on the radon-lung cancer mortality risk estimate. A statistically significant linear relationship between radon and lung cancer mortality was found, with ERR/WLM = 0.017 (95% confidence intervals (CI): 0.009–0.028) at < 100 WLM cumulative radon exposures. In trend analyses, statistically significant risk was observed at cumulative exposures as low as 10–19 WLM, with RR = 1.64 (95% CI: 1.03–2.65, N = 48 deaths). Radon exposures received in more recent periods (5–14 years previously) had the greatest risk of lung cancer mortality. These risks decreased with increasing time since exposure and attained age. No effect of exposure rate, separate from measures of cumulative exposure, was observed at low radon levels. The confounding effect of unmeasured tobacco smoking was small and did not substantially change the radon-lung cancer mortality risk estimates found. These findings provide strong evidence for an increased risk of lung cancer mortality after long-term low radon exposure among Czech, French and Canadian uranium miners. The results are compatible with other studies of miners restricted to low radon levels and residential radon studies. The results suggest radiation protection measures are of significant importance among modern uranium miners with low radon exposure levels.

Objetivo: O câncer de pulmão é a primeira causa de morte relacionada ao câncer quando considerados ambos os sexos. Os grandes esforços para a redução do tabagismo e para a introdução do filtro de cigarro mudaram a epidemiologia do câncer de pulmão. Em países desenvolvidos, a ascensão do adenocarcinoma e o declínio do epidermoide são de notório conhecimento. Outra característica é o aumento da incidência da doença entre mulheres. Um entendimento melhor da atual epidemiologia do câncer de pulmão é necessário para o desenvolvimento de estratégias de saúde pública de prevenção, diagnóstico e tratamento. Métodos: Análise retrospectiva de todos os pacientes com CPNPC tratados com ressecção pulmonar entre 1986 e 2010 em um hospital universitário do Sul do Brasil. As análises foram divididas em três períodos: 1986-1990, 1991-2000 e 2001-2010. O mesmo grupo de patologistas realizou o diagnóstico, e os estágios foram atualizados para a nova classificação da IASLC, 7ª edição. Todas as análises foram realizadas utilizando o programa SAS, versão 13. Resultados: Foram estudados 817 pacientes submetidos à ressecção pulmonar por CPNPC entre 1986 e 2010. Setenta por cento eram homens, média de idade de 61,4 anos, 44,2% carcinoma epidermoide e 40% adenocarcinoma, 26,7% estágio IIIA. A proporção de mulheres apresentou um aumento de 22% no primeiro período para 36% na última década. A idade média no momento da cirurgia era de 52,7 anos para mulheres e 57,3 para homens no primeiro período, e 60,1 para mulheres e 63,9 para homens no último período (p<0.001). A proporção de carcinoma epidermoide modificou de 49,1% inicialmente para 38,7% no último período (p=0.017). Em comparação, a prevalência do adenocarcinoma cresceu de 35,4% para 39,6% e, mais recentemente, para 41,2%. Em relação ao número total de pessoas acometidas pela doença, mulheres com adenocarcinoma representavam 9,4% no primeiro período, 12,5% no segundo e 16,8% no último período. Pacientes com estágio IIIA representavam 27,9% na última década. O tipo de cirurgia predominante foi a lobectomia. A pneumonectomia foi o procedimento cirúrgico em 21,9%, 18,8% e 16,8% dos casos em cada período, em ordem crescente, respectivamente (p<0.03). Conclusão: Neste estudo de pacientes no Sul do Brasil, a análise de gênero demonstrou que a taxa de câncer de pulmão entre as mulheres está aumentando nas últimas três décadas, mas ainda não chegou a ultrapassar a taxa masculina. A proporção de adenocarcinoma em mulheres aumentou. O significativo declínio da quantidade proporcional de pneumonectomia provavelmente reflete a mudança da indicação e técnica cirúrgica. A idade média de pacientes submetidos a tratamento cirúrgico aumentou tanto para homens quanto para mulheres, mas não alcançou a média de países desenvolvidos de 71 anos. A mudança da proporção do tipo histológico e de mulheres está de acordo com os dados de países desenvolvidos. / Objective: Lung cancer is the leading cause of cancer-related death worldwide when considering both genders. The great effort to reduce smoking and to introduce the usage of cigarette filter has changed lung cancer epidemiology. In developed countries, the increasing incidence of adenocarcinoma and the decrease of squamous cell carcinoma are well known. Other characteristic reported is the rising number of women with the disease. Better understanding of current lung cancer epidemiology is necessary for the appropriate design of public health strategies for prevention, diagnosis and treatment. Methods: Retrospective analysis of all patients with non-small cell lung cancer (NSCLC) treated with lung resection between 1986 and 2010 in a university hospital of Southern Brazil. Analysis was divided in three periods: 1986-1990, 1991-2000 and 2001-2010. The same pathology group performed histological diagnosis and all staging was updated according to the new IASLC, 7th edition. All analyses were performed using the SAS program, version 13. Results: We studied 817 patients who underwent lung resection for NSCLC from 1986 to 2010. Seventy percent were males, average age 61.4 years old, 44.2% squamous cell carcinoma and 40% adenocarcinoma, 26.7% stage IIIA. The female proportion increased from 22% in the first period to 36% in the last decade. Mean age at surgery treatment was 52.7 years old for women and 57.3 years old for men in the first period, and 60.1 for women and 63.9 for men in the last period (p<0.001). The proportion of squamous cell changed from 49.1% initially to 38.7% in the last period (p=0.017). In comparison, the adenocarcinoma prevalence increased from 35.4% to 39.6% and, most recently, to 41.21%. Of the total NSCLC patients, females with adenocarcinoma represented 9.4% in the first period, 12.5% in the second and 16.8% in last period. Patients with stage IIIA represented 27.9% in the last decade. Lobectomy was the predominant type of surgery. Pneumonectomy was the surgical procedure in 21.9%, 18.8% and 16.8% of the cases in each period, respectively (p<0.03). Conclusions: In this cohort of patients in Southern Brazil, gender analysis shows that rates of lung cancer in females are rising over the last three decades, but have not surpassed men rates. The proportion of adenocarcinoma in females has increased. The significant decrease of pneumonectomy rates probably reflects changes on surgical management techniques and indication. The mean age of patients undergoing surgical treatment has increased for both men and women, but has not reached the average age reported in developed countries, 71 years old. The histological and gender findings for lung cancer are in accordance with the data of developed countries.

Respiratory gating in lung PET imaging to compensate for respiratory motion artifacts is a current research issue with broad potential impact on quantitation, diagnosis and clinical management of lung tumors. However, PET images collected at discrete bins can be significantly affected by noise as there are lower activity counts in each gated bin unless the total PET acquisition time is prolonged, so that gating methods should be combined with imaging-based motion correction and registration methods. The aim of this study was to develop and validate a fast and practical solution to the problem of respiratory motion for the detection and accurate quantitation of lung tumors in PET images. This included: (1) developing a computer-assisted algorithm for PET/CT images that automatically segments lung regions in CT images, identifies and localizes lung tumors of PET images; (2) developing and comparing different registration algorithms which processes all the information within the entire respiratory cycle and integrate all the tumor in different gated bins into a single reference bin. Four registration/integration algorithms: Centroid Based, Intensity Based, Rigid Body and Optical Flow registration were compared as well as two registration schemes: Direct Scheme and Successive Scheme. Validation was demonstrated by conducting experiments with the computerized 4D NCAT phantom and with a dynamic lung-chest phantom imaged using a GE PET/CT System. Iterations were conducted on different size simulated tumors and different noise levels. Static tumors without respiratory motion were used as gold standard; quantitative results were compared with respect to tumor activity concentration, cross-correlation coefficient, relative noise level and computation time. Comparing the results of the tumors before and after correction, the tumor activity values and tumor volumes were closer to the static tumors (gold standard). Higher correlation values and lower noise were also achieved after applying the correction algorithms. With this method the compromise between short PET scan time and reduced image noise can be achieved, while quantification and clinical analysis become fast and precise.

Lung cancer is the second most prevalent cancer in men and women in the United States and the overall leading cause of cancer-related deaths. Due to this high prevalence, lung cancer screening is a critical procedure in all Family Medicine practices. However, screening is particularly important in rural Appalachian clinics, as this area experiences especially high rates of mortality due to lung cancer. The United States Preventive Services Task Force recommends annual low-dose computed tomography (LDCT) lung cancer screening in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. The goal of this project is assess readiness of clinical providers of the risks and benefits of lung cancer screening, to encourage screening when appropriate, and ultimately increase then number of LDCT annual screenings. Provider knowledge was assessing using a lung cancer screening knowledge and practice survey. Participants then attended an educational sessions that provided information on the importance of screening and when it is appropriate to administer LDCT. Finally, a second survey was administered, again to assess knowledge and practice. Data analysis is currently in process. A t-test will be executed to determine if there is a statistically significant difference between survey scores before and after the educational session. It is expected that the educational program will lead to increases in provider knowledge and more appropriate screenings. The results of this study have important ramifications for this area; because Appalachia has disproportionately high mortality due to lung cancer, it is imperative that the disease be identified as early as possible to ensure the most effective treatment. This project illustrates a method to increase screenings.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22729号 / 医博第4647号 / 新制||医||1046(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 伊達 洋至, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are highly effective therapies for sub-populations of non-small cell lung cancers. Specific mutations have been identified in the EGFR gene such as L858R which overstimulate cell pathways that lead to tumor growth. All tumors eventually develop resistance to this treatment, rendering them useless, and tumor growth progresses. Escape mutations in the EGFR gene were first seen in patients undergoing treatment with first-generation TKI erlotinib and gefitinib. T790M is a widely seen gate-keeping mutation which overcomes inhibition from erlotinib and gefitinib. Third-generation irreversible TKI, osimertinib, can inhibit tumor cells with this gate-keeping mutation thus overcoming a major hurdle in containment of tumor growth. Unfortunately, patients eventually develop resistance to osimertinib, exhausting options for managing non-small cell lung cancer. Here we analyzed H1975 cells which harbor L858R + T790M mutations. We aimed to track genomic, transcriptomic, and proteomic changes to uncover mechanisms cells use to develop resistance to osimertinib. We established cell colonies which were able to survive high dose treatment up to 2 µM osimertinib. We also saved cells with IC50 of 30 nM to represent drug-tolerant cells. We conducted single-cell sequencing of mRNA transcription and performed hierarchal gene analysis which identified CD74 as a novel factor which was upregulated in drug-tolerant cells. Further we showed CD74 gene was accessible as open chromatin for easy upregulation. Western blot analysis showed increased expression of CD74 after 24 hours of osimertinib treatment. Using siRNA in H1975 cells, we conducted knockdown experiments of CD74 during osimertinib treatment and showed reduced viability. Next, H1975 cells lines were engineered with deletions in CD74 to knockout its expression. These cells also showed reduced viability in the presence of osimertinib. Quantification of apoptosis using caspase-glo assays showed greater activation of apoptosis in cell populations without CD74 compared to normal H1975 cells. H1975-CD74 knockout cells also took longer to become resistant to osimertinib when compared with control. These results show the role of CD74 in helping tumor cells survive EGFR TKI treatment. / 2023-12-05T00:00:00Z

Lung cancer is the leading cause of cancer death worldwide with 2.2 million new cases diagnosed and 1.8 million deaths per year. Lung squamous cell carcinoma (LSCC) is an aggressive histological subtype of non-small cell lung cancers (NSCLC), which is strongly associated with cigarette smoking and exposure to environmental pollutants. In collaboration with the Computational Biomedicine group at Boston University, we identified several putative cancer driver mutations in benign premalignant lung tumors, extracted from upper bronchial airway epithelium. The gene mutations from premalignant tumors are thought to initiate neoplasia but cannot promote malignancy independently. It is hypothesized that additional cooperating mutations will have a compounding effect on tumorigenesis if co-expressed in the same tumor cell. We used cancer genomics data from LSCC primary tumors in the Cancer Genome Atlas (TCGA) database to identify lung pre-malignancy associated genes that are significantly co-mutated. Two of the identified mutant genes, PIK3CA and NFE2L2, were shown to co-occur at a statistically significant rate in LSCC primary tumors. The PIK3CA gene encodes the PI3K lipid kinase, which regulates the AKT and mTOR kinase signaling pathways, thus promoting cell proliferation and survival. NRF2, the product of NFE2L2 gene, is a transcription factor that regulates the antioxidant response, playing a protective role against oxidizing cellular damage. NRF2 promotes the transcription of key proteins in the antioxidant response such as glutathione S transferase and NADPH oxidase. NRF2 is normally subject to ubiquitin-mediated degradation, which is regulated by the KEAP1 protein. Loss of function KEAP1 gene mutations are common in lung cancer. When cells are exposed to oxidizing agents, KEAP1 is modified by these agents, resulting in release and stabilization of NRF2, and the subsequent transcription of antioxidant response genes. Studies of PI3K and NRF2, and their downstream effectors have shown that both the PI3K/AKT/mTOR and NRF2/KEAP1 signaling pathways control autophagy, which is a catabolic process that regulates the recycling of macromolecules under conditions of nutrient deprivation. PI3K and NRF2 both control the activity of the SQSTM1/p62 protein, which plays a major role in autophagic degradation of cargo proteins. Autophagy has been implicated as a tumor suppressive mechanism. Both PI3K and NRF2 are known to inhibit autophagy in lung cancer cells. Based on the significant frequency of co-occurrence of PIK3CA and NFE2L2 gene mutations in pre-malignant LSCC lesions, we hypothesize that PI3K and NRF2 cooperate to inhibit autophagy to promote LSCC progression. To test our hypothesis, we co-expressed mutant forms of PIK3CA (E545K) and NFE2L2 (T80K) into a non-transformed Human Bronchial Epithelial Cell line (HBEC-3KT). We performed a series of Western Blots to verify PI3K and NRF2 protein expression as well as downstream AKT activation and markers of autophagy pathway activation. mTORC1 is an effector of PI3K and plays a central role in the inhibition of autophagy through the PI3K/AKT/mTOR signaling network. Therefore, we performed Western Blot analysis of samples treated with the mTORC1 inhibitor Everolimus to compare the effects of mTORC1 inhibition on autophagy activation in control, single PIK3CA, NFE2L2 and double mutant HBEC3-KT cells. We observed significant suppression of autophagy in the PI3K/NRF2 double mutant cells. Moreover, the studies also showed that the double mutant cells are more sensitive to anti-proliferative effects of Everolimus compared to control and single mutant cells. Taken together, our studies show that PIK3CA and NFE2L2 mutations cooperate to hyperactivate the AKT kinase and to suppress autophagy pathway activation. This represents a key mechanism of the malignant transformation of benign premalignant LSCC lesions. This warrants further research into the cooperation between PI3K and NRF2 in lung cancer pathogenesis. Our results have important implications both for diagnosis and treatment of LSCC. Though many important advances in the treatment of lung cancer have been made over the past few decades including the use of tyrosine kinase inhibitors (TKIs) such as Erlotinib, there is still much to understand about the biology and mechanisms of the disease.1 Blockers of the T-cell checkpoint, such as anti-PD-1 drugs are currently FDA-approved first lines of therapy for NSCLC. In addition, immunotherapy has shown some efficacy in lung cancer patients.2 Our studies provide rationale for the development of therapeutics that suppress NRF2 and PI3K activity in the treatment of LSCC.3 Since mTORC1 inhibitors cause robust inhibition of PIK3CA/NFE2L2 double mutant cell proliferation, future studies will be aimed at testing combinations of mTORC1, PI3K and NRF2 pathway inhibitors to treat LSCC.

Les cancers du poumon non à petites cellules (CPNPC) restent une cause majeure de mortalité par cancer, malgré l’apport de thérapies moléculaires ciblées et des immunothérapies. La survie des patients aux stades avancés reste limitée et la mise au point de biomarqueurs pronostiques permettant de stratifier les patients ou prédictifs de réponse à différents types de traitement constitue un enjeu important pour la prise en charge des patients.La mise au point de biomarqueurs obéit à des enjeux spécifiques tenant à la connaissance de la biologie tumorale dans des domaines complexes tels que celui de la réparation de l’ADN, aux caractéristiques des outils disponibles pour créer ces biomarqueurs et à leur applicabilité dans le contexte clinique.Dans le cadre de cette thèse, il a été étudié la manière dont l’expression de la protéine PARP1 peut s’intégrer aux biomarqueurs pronostiques de réparation de l’ADN dans les CPNPC. Il a par ailleurs été étudié le rôle de la protéine MMS19, identifiée à partir d’études d’expression génique, comme biomarqueur prédictif potentiel de réponse au cisplatine dans les CPNPC. Enfin, l’utilisation des cellules tumorales circulantes pour le développement de biomarqueurs a été étudiée dans le cadre de la détection des remaniements du gène ALK, une altération oncogénique constituant une cible thérapeutique dans les CPNPC. / Non-small cell lung cancers (NSCLC) remain a leading cause of cancer-related death despite the advent of targeted therapies and immunotherapies. At advanced stages, patient survival remains limited and establishment of new biomarkers, either prognostic for patient stratification or predictive of response to various therapies, is an important goal for patient’s treatment.Development of biomarkers is dependent on many components among which: knowledge of cancer cell biology in complex cellular processes such as DNA repair, characteristics of tools available to create biomarkers and applicability in daily medical practice.In this thesis, expression of PARP1 has been evaluated as a prognostic biomarker in NSCLC, in the broader context of DNA repair biomarkers. The biological and clinical relevance of MMS19 protein, identified in gene expression analysis , as a biomarker for cisplatin sensitivity in NSCLC has also been studied. Finally, the use of circulating tumor cells for biomarker development has been studied through the detection of ALK gene rearrangment, an oncogenic targetable alteration in NSCLC.