Squamous cell lung cancer

Early detection

Liquid biopsy

Risk profile

Health Equity and Inclusiveness Junior Investigator Award

Stage I

Stage II

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Tumor draining lymph node immunomodulation to decrease recurrence in NSCLC

2022

Jonathan Villena-Vargas, MD

Weill Medical College of Cornell University

New York

Lymph nodes are small structures that work as filters for foreign substances, such as cancer cells and infections. These nodes contain infection-fighting immune cells that are carried in through the lymph fluid. This project will study the lymph node draining basin, which is involved in the spread of a tumor from the original location site to distant sites, and whether activating cancer-fighting T-cells can decrease recurrence in NSCLC. Dr. Villena-Vargas will use animal models to investigate whether immune checkpoint inhibitors enhance lymph node T-cells memory, which increases their ability to recognize cancer cells in the bod and can prevent metastatic recurrence.

Research Summary

Approximately 25% of the patients diagnosed with non-small cell lung cancer (NSCLC) exhibit early-stage disease. Patients with early-stage (I/II) NSCLC are routinely treated by surgery, which results in local control. However, systemic relapse (metastasis) occurs in 50% patients within 5 years of surgical intervention even with additional therapy such as chemotherapy and/or radiation. Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis have revolutionized the treatment landscape, generating therapeutic efficacy in approximately 25% of patients in early and advanced stages of lung cancer. However, there are currently inconclusive studies as to 1) timing of treatment 2) optimal combination therapy 3) prediction of patient response. In order, to recapitulate early-stage lung cancer treatment and metastatic recurrence, we have established a murine model of resection and recurrence. Our preliminary data has revealed a major immune response at the level of the tumor draining lymph node (TDLN) with PD-1 checkpoint blockade. In addition, this response is primarily responsible for T-cell memory differentiation, proliferation, and survival with subsequent decrease in metastatic recurrence in responding mice. Given these results, we hypothesize that optimal therapy against metastatic recurrence will be dependent on establishment of appropriate T-cell memory “immunosurveillance”. In addition, we have shown that the memory nodal response can be augmented by utilizing a cytokine immunomodulatory combination strategy with cure in over 70% of mice. Importantly, we have characterized that these specific T-cell memory population are uniquely found in the TDLN of early-stage patients (i.e. not in the primary tumor or peripheral blood that is commonly interrogated). In this proposal we will utilize a combination of both novel preclinical mouse models and patient-derived tumor draining lymph node T cells, to dissect molecular and cellular mechanisms of “immune-memory” response or resistance to immunotherapy, the key steps in establishing immunosurveillance for freedom from metastatic recurrence.

Technical Abstract

Anti–PD-1 therapy has transformed the management of NSCLC, but only a subset of patients respond to anti–PD-1 therapy, and responses are rarely curative. Understanding the effects of anti–PD-1 therapy on the composition and functional state of tumor-associated immune subsets can identify mechanisms of response and resistance to anti–PD-1 therapy and provide insights into rational combination strategies to improve upon response rates. Although the effects of anti–PD-1 therapy within the tumor immune microenvironment in preclinical and human subjects have been previously reported, we propose to broadly characterize the effects of anti–PD-1 therapy on the tumor draining lymph nodes (TDLN). Studying the TDLN is particularly valuable because it is the primary sites at which the tumor antigen exposure and the main site of immune T-cell differentiation. To determine the effect of ICI response in the lymph node, we have created an immunocompetent murine model that recapitulates early-stage treatment and outcomes in patients. Additionally, we have characterized TDLN T cells from early-stage cancer patients and have been able to recapitulate our preclinical findings of unique memory T-cell subsets. Our preliminary results of the immune cell type composition, checkpoint expression, and cytokine expression within TDLNs suggest that there are major remodeling events within the TDLN mediated by anti–PD-1 therapy that are critical for conferring effective antitumor long-term immune responses. We demonstrate that unique memory T cell subsets undergo significant activation, expansion, and maturation in response to anti–PD-1 therapy, to shape antitumor programming in TDLNs. Importantly, our proposed study will provide a methodological demonstration in both a murine model and human TDLN that simultaneous uses Flowcytometry, functional immune assays and single cell sequencing that will enable deep interrogation of the immune profile to PD-1 inhibition resistant and responsive patients.

Key words

Immune checkpoint inhibitors

Immunotherapy

Metastatic

Recurrent

Health Equity and Inclusiveness Junior Investigator Award

Stage III

Stage IV

Tumor microenvironment

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Lung cancer Equity Through Social needs Screening (LETS SCREEN)

2022

Ana Velazquez Manana, MD

University of California, San Francisco

San Francisco

Dr. Velasquez Manana will conduct an observational study in a multiethnic group of patients with unresectable lung cancer to determine the association between social needs, care utilization, and quality of life. The goal of this study is to fill a key knowledge gap in the care of patients with NSCLC and inform interventions to support patients at risk of social adversity during treatment to end disparities in lung cancer care.

Research Summary

Social circumstances in which we are born and live are some of the most important factors influencing our health. For people with cancer, these social circumstances (social determinants of health) drive differences in access to cancer screening and diagnostic tests, stage at diagnosis, and the types of treatments they are offered and receive. The treatment options for people living with lung cancer have changed drastically over the last decade with the addition of immunotherapies and targeted drugs. However, these treatments are not accessible to all. The high costs of cancer treatments and time lost from work make people with cancer more vulnerable to financial hardship, that could affect their ability to receive cancer treatments. In this study, we hope to understand how social needs (e.g., food access, ability to pay bills, access to transportation, housing stability, social isolation, and loneliness) relate to the use of healthcare, quality of care patients with lung cancer receive, and quality of life during their treatment. To do this, we will survey 150 patients with unresectable lung cancer within one month of start of systemic treatment and at 3 and 6-months during their treatment. We will measure how social needs change over time and relate to the use of healthcare for acute problems (i.e., emergency room visits, admissions to the hospital, and urgent care visits), quality of life, and quality of care received. To obtain an in-depth understanding of how social needs can affect patient care, we will interview 30 oncology providers. Providers will be asked if and how they consider the social needs of their patients when making treatment and clinical decisions. This study will give us essential information on how to better support patients with lung cancer who face social needs that impact their daily lives and cancer care.

Technical Abstract

Despite significant progress in the development of novel biomarkers and therapies for lung cancer, such progress has not equitably benefitted all population groups in the United States (US). Racial and ethnic minorities, low income, uninsured, and underinsured individuals with non-small cell lung cancer (NSCLC) continue to experience disparate access to diagnostics tests and treatments, and experience inferior outcomes. These disparities are, at least, partially driven by social context (i.e., social determinants of health). Patients with NSCLC experience high rates of financial hardship and unmet supportive needs, making them a population likely to have high rates of health-related social needs. The prevalence of social needs in patients with NSCLC and their impact on healthcare utilization, cancer outcomes, and quality of life (QOL) remains unknown. To fill this important knowledge gap, we propose an observational, prospective cohort study of 150 patients with unresectable lung cancer receiving first-line systemic therapy. Our study has two primary goals (Aims): 1) Prospectively quantify the prevalence of social needs and determine the associations between social needs, acute care utilization, and QOL; 2) investigate how patient’s social needs influence oncology providers’ clinical decisions for outpatient cancer care of adults with unresectable NSCLC. To achieve these goals, we will conduct serial survey assessments of 150 patients with unresectable NSCLC and conduct semi-structured interviews with 30 oncology providers. This study is significant as it is the first study longitudinally evaluating social needs during cancer therapy in patients with NSCLC. This study will fill a key knowledge gap and inform interventions focused on identifying and supporting patients at risk of social adversity during cancer treatment.

Key words

Health equity

Health Equity and Inclusiveness Junior Investigator Award

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Young lung cancer: psychosocial needs assessment

2022

Narjust Florez, MD

Dana-Farber Cancer Institute

Boston

Dr. Florez will study the psychosocial and financial impact of lung cancer in young patients (< 50 years of age). This patient population has seen an increase in incidence in recent years, but little is known about their specific needs. The study will include administration of a survey and focus groups to understand unmet needs of this group of patients. The information gathered from this study will be used to identify challenges unique to this population and develop the first clinical and research program of its kind for young lung cancer patients.

Research Summary

The number of lung cancer cases in young patients (<50 years of age) is increasing across the globe, from Asia to the United States. Young patients with lung cancer are more likely to be women, of Hispanic or Asian descent and be diagnosed with metastatic disease. In this patient population, a lung cancer diagnosis is not age normative and is profoundly disruptive. Young patients often receive more aggressive treatments and face long-term side effects. While we have seen substantial progress in mental health research in recent years, little is known about the psychological needs of young patients with lung cancer, including how they compare to those of older patients, the financial toxicity associated with their cancer treatments, and how their experiences with the healthcare system impact their wellbeing. Most survivorship studies in lung cancer have included small numbers of young patients with lung cancer, with many of these studies preceding newer cancer treatments like targeted therapy and immunotherapy.

We proposed a mixed-method study that will be designed in conjunction with an experienced research team and lung cancer patient advocates. The study will be divided into two phases 1) we plan to administer a survey that explores the psychosocial needs and the financial impact of cancer treatments to a group of young and old patients with lung cancer; this survey could be completed online, in person, or over the phone with trained personnel 2) following the survey completion, information from the survey will be used to create a guide for focus group discussions; we will conduct four focus groups with young patients with lung cancer to expand on the knowledge obtained from the survey. Focus groups are a powerful way to gain a comprehensive understanding of patient experiences by interacting on a personal, exploratory level to hear patient voices and understand their needs. We will also investigate the differences in these needs by gender and race/ethnicity in our two groups. The study results will be shared with the lung cancer patient community via a series of webinars.

The knowledge obtained from this study will be used to create the first clinical program dedicated to young patients with lung cancer in the nation and the creation of an international consortium that will focus on understanding why the number of lung cancer cases is increasing in patients <50 years of age. Most importantly, we will use the information to create interventions to improve this vulnerable population's clinical care and psychosocial support. Our study will be the first of its kind to critically evaluate the psychosocial needs of young patients with lung cancer in a diverse patient population with a secondary focus on their experiences with the healthcare system and the financial impact of a cancer diagnosis and treatments.

Technical Abstract

Background: In recent years, an increasing incidence of lung cancer among young patients (<50 years) has been reported in Europe, Asia, and the United States. Young patients with lung cancer are more likely to be women, of Asian or Hispanic descent, have adenocarcinoma histology, and are more likely to present with distant metastases at diagnosis. Although young patients with lung cancer are more likely to be diagnosed at a disruptive time in their lives and face greater mental health and financial challenges than older patients with lung cancer, we lack data regarding their specific psychosocial needs. The lack of inclusion of young patients in survivorship studies has created a knowledge gap that we propose to remedy with the proposed study.

Aim and Hypothesis: The overarching aim of this study is to define the psychosocial needs of young patients with lung cancer and evaluate important cancer care delivery factors, including financial toxicity, gender and racial differences and study participants’ experiences with the healthcare system. We hypothesize that young patients will have greater unmet psychosocial needs and financial toxicity than older patients with lung cancer.

Methods: This study will utilize an expert, multi-disciplinary research team aligned with patient advocates to deploy an explanatory sequential mixed methods design to understand the needs of young patients with lung cancer. We will conduct a cross-sectional two-arm survey regarding psychosocial distress and financial toxicity among a diverse patient population utilizing two validated questionnaires, the Psychosocial Screen for Cancer (PSSCAN-R) questionnaire and the COmprehensive Score for financial Toxicity (COST) assessment. After the quantitative data collection is completed, we will conduct a preliminary analysis that will guide the discussion in the next phase, where we will conduct four focus groups with young patients with lung cancer to expand and obtain in-depth answers about the issues discovered in the survey portion of the study. The study team will collaborate with experienced biostatisticians and qualitative data researchers to conduct the appropriate statistical analysis.

Results and Dissemination Plan: The study results will be submitted to an international conference and later be published in a high-impact journal. In addition, we will disseminate the study results to the lung cancer patient community via a series of webinars; these webinars will be recorded and later shared with patient advocacy groups and lung cancer organizations.

Long-term Outcomes: Our data will yield insights to inform the oncology community of the barriers encountered by young patients with lung cancer and will allow us to develop the first clinical and research program for young patients with lung cancer in the nation.

Key words

Health equity

VA Research Scholar Award

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Predicting clinical benefit of immunotherapy in veterans

2022

Alex Bryant, MD

University of Michigan/VA Ann Arbor Healthcare System

Ann Arbor

This study will use data from the Veterans Affairs system to develop statistical models to predict response to immunotherapy in patients with lung cancer. While immunotherapy has improved outcomes for many patients, it is still not well understood why some respond well and others do not. If successful, this work will produce a comprehensive prediction model of immunotherapy benefit in lung cancer that could be used to counsel patients, inform patient-physician decision making, and identify patients who need more- or less-aggressive treatment.

Research Summary

Immunotherapy is a new type of cancer treatment that has revolutionized lung cancer care and improved cancer outcomes for many patients. While immunotherapy is an exciting advance, some patients do not respond to immunotherapy, and we do not fully understand why some patients respond well and others do not. Immunotherapy can also cause serious and unpredictable side effects. In addition, some patients are so sick from other non-cancer medical conditions that they may not benefit from immunotherapy at all. The purpose of this study is to use large-scale data on lung cancer patients from the Veterans Affairs system to understand why some patients benefit from immunotherapy while other experience severe side effects. If successful, this work will produce a comprehensive prediction model of immunotherapy benefit in lung cancer which could be used to counsel patients, inform physician decision-making, and identify patients who need more- or less-aggressive treatment.

Technical Abstract

Though the introduction of immune checkpoint inhibitors (ICI) has improved outcomes for patients with stage III non-small-cell lung cancer, most patients do not have robust tumor responses to ICI and real-world patients discontinue ICI due to toxicity at a higher rate than clinical trial populations. There is an unmet need to develop predictive models to identify patients at risk of poor ICI response, high risk of ICI toxicity, and high risk of non-cancer mortality, as these patients are unlikely to benefit from ICI and may require treatment intensification or de-intensification, selection of alternative therapies, or enrollment on clinical trials. In this proposal we seek to leverage the richness and national scale of Veterans Affairs (VA) clinical data to develop statistical models to predict ICI efficacy, toxicity, and non-cancer mortality. We will evaluate specific hypotheses generated from preclinical research and use machine-learning approaches to identify new predictors from high-dimensional VA healthcare data. These models will be integrated into a unified multistate model, allowing prediction of the individualized overall survival benefit of ICI for each patient. Clinical decision-making based on model predictions will be compared to other decision making strategies using decision-curve analysis. This work will identify novel biomarkers of ICI efficacy and toxicity, validate putative ICI effect modifiers from the preclinical literature, and develop the first unified model for ICI clinical benefit. If successful, this tool can be used for patient counseling, physician decision-making, and identification of patients likely to benefit from alternative therapies, treatment de-escalation, or clinical trial enrollment.

Key words

Immune checkpoint inhibitors

Immunotherapy

EGFR Resisters / LUNGevity Research Award

Stage III

Stage IV

Veterans Affairs

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Molecular Characterization of Lineage Plasticity

2021

Helena Yu, MD

Memorial Sloan Kettering Cancer Center

New York

As a mechanism of resistance to EGFR inhibitors, cancers can change histology from adenocarcinoma to small cell or squamous cell lung cancer. Once this happens, EGFR inhibitors are no longer effective treatment; there are no strategies currently available to prevent or reverse transformation after it has occurred. Dr. Yu will use advanced molecular techniques to identify genetic changes that contribute to transformation. Understanding these genetic changes will identify biomarkers that can be utilized to develop treatments to prevent and reverse transformation.

Research Summary

Metastatic EGFR-mutant lung cancer remains an incurable disease despite significant advances in cancer therapeutics. With better EGFR inhibitors, we have identified new mechanisms of resistance that are independent of EGFR signaling, notably small cell and squamous cell histologic transformation. Targeted therapies are ineffective and survival is shortened once transformation has occurred, and no strategies are available to prevent or reverse transformation after it has occurred.

Mutations in EGFR, TP53, and RB1 are associated with transformation, but additional genetic or epigenetic changes must occur for transformation to happen. We will use advanced molecular techniques to identify the mutations and cell signaling pathways that drive transformation in order to identify biomarkers that can be utilized to develop treatments to prevent and reverse transformation. Treatments will then be validated in our unique pre-clinical models which can be rapidly translated into clinical trials, providing treatments for these aggressive cancers.

Technical Abstract

EGFR-mutant lung cancers (LC) serve as the prototype oncogene-driven cancer and mechanisms of resistance to EGFR therapy are well-established. Selective pressure of EGFR inhibitors can induce lineage plasticity to escape oncogene-dependence. While we have shown EGFR/TP53/RB1-mutations are necessary but insufficient to induce small cell transformation, no other genomic signatures and transcriptomic/epigenomic effectors that induce transformation have been identified.

Using parallel exome sequencing, bulk RNA sequencing, and bisulfite sequencing, we will characterize the biomarkers of transformation in EGFR/TP53/RB1-mutant LC and mixed adenocarcinoma/squamous cell tumors. We will also utilize single-cell RNA sequencing to identify the transcriptional changes associated with transformation and to identify distinct cell types within a heterogenous tumor. We will reconstruct a phenotypic landscape to identify subclones in a transitional state between histologies. The information obtained from these studies will nominate novel biomarkers of lineage plasticity that will be validated and proposed for study in clinical trials.

Key words

Acquired resistance

Epidermal growth factor receptor (EGFR)

Metastatic

Molecular profile or molecular testing

Mutation profile

Tyrosine kinase inhibitors (TKIs)

Stage III

Stage IV

Targeted therapy

Tumor microenvironment

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Intercept Lung Cancer Through Immune, Imaging & Molecular Evaluation-InTIME

2017

SU2C-LUNGevity-ALA LC Interception Award

Grant title (if any)

SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Dream Team

This grant was co-funded by Stand Up to Cancer, LUNGevity, and the American Lung Association

Avrum Spira, MD, MSc

Boston University

Boston

Steven Dubinett, MD

UCLA

Los Angeles

Julie Brahmer, MD

Johns Hopkins Kimmel Cancer Center

Baltimore

Sam Gambhir, MD, PhD

Stanford University

Palo Alto

Matthew Meyerson, MD, PhD

Harvard/Dana-Farber Cancer Institute

Boston

Charles Swanton, PhD

Francis Crick Institute

London, England

The SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Dream Team, led by LUNGevity SAB member Dr. Avrum Spira, is developing a combination of diagnostic tools, such as non-invasive nasal swabs, blood tests, and radiological imaging, to confirm whether lung abnormalities found on chest imaging are benign lung disease or lung cancer.

Technical Abstract

Statement of the Problem: Cancer develops in a sequenced manner. Patches of lung cells gain the ability to multiply faster than their neighboring normal cells by acquiring mutations. These patches of cells are called “premalignant lesions" (PMLs). Some of these lesions may eventually become cancer. Knowledge about how some PMLs may develop into lung cancer is central to developing tools for Cancer Interception—interrupting the cancer development process and blocking progression to advanced metastatic disease. However, we lack effective lung cancer interception approaches due to our incomplete understanding of the earliest molecular events associated with the development of lung cancer, as well as the challenge in developing personalized tools for early detection and prevention.

Proposed Solution: The Dream Team will use a holistic approach to understand the genetics, immunology, radiological (imaging) profile, and treatment response of patients who show evidence of abnormal lung tissue that puts them at high risk to develop lung cancer. The Team has access to unique groups of patient populations (adenocarcinoma—ADC and squamous cell carcinoma—SCC) with signs of lung cancer risk, and has assembled a collection of blood and tissue specimens from these individuals. The main objective of the Team is to understand how lung cancer develops and test methods that will block the development of cancer. Their three-pronged approach to solve this problem will include:

Creation of a molecular pre-cancer genome atlas (PCGA) of the lung with the goal of identifying which types of precancerous lung tissue require aggressive treatment and which treatments will block the development of these abnormal lesions to invasive lung cancer.
Development of two diagnostic tools that can be directly applied in the clinic for simple, yet accurate, detection of early lung cancer: 1) the use of nasal swabs, blood tests, and imaging to confirm whether lung abnormalities found on chest imaging are lung cancer or benign lung disease. 2) blood tests that can identify patients at the earliest stages of lung cancer recurrence, thus enabling their timely and effective intervention with therapies such as those that boost the immune system.
Development of tests to identify which individuals are most likely to benefit from a number of treatment strategies to intercept lung cancer, including emerging immunotherapies.

Key words

Adjuvant or neoadjuvant

Immune checkpoint inhibitors

Immunotherapy

Interception

Liquid biopsy

SU2C-LUNGevity-ALA LC Interception Award

Stage I

Stage II

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Integrated Blood-Based and Radiographic Interception of Lung Cancer

2017

Grant title (if any)

SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Translational Research Team

This grant was co-funded by Stand Up to Cancer, LUNGevity, and the American Lung Association

Lecia Sequist, MD

Massachusetts General Hospital

Boston

Max Diehn, MD

Stanford University

Palo Alto

Tilak Sundaresan, MD

Kaiser Permanente San Francisco

San Francisco

Gad Getz, PhD

Broad Institute

Cambridge

The SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Translational Research Team, headed by LUNGevity Scientific Advisory Board (SAB) member Dr. Lecia Sequist, is developing a lung cancer interception assay (LCIA) that can be used in conjunction with low-dose CT scans. This assay will be based on an integration of several blood-based assays that examine circulating tumor cells and circulating tumor DNA.

Technical Abstract

Statement of the Problem: Currently, low dose CT (LDCT) screening for lung cancer is recommended for high-risk individuals, defined as current or former smokers (quit within the past 15 years) with a 30-or-more pack-year smoking history, 55 to 74 years of age, and with no evidence of lung cancer. However, uptake of LDCT screening has been impeded by high rates of false-positive results, which in turn add significant physical and emotional stress to patients as well as additional healthcare costs. Since LDCT is now commonly available, lung nodules detected in LDCT scans are plentiful, but imprecise guidelines for care make it a challenge to ensure quality follow-up and expedited diagnoses for those with lung cancer. Furthermore, screening is not available for those who don’t meet the screening criteria (younger age or low smoking history) when they are the exact population among whom lung cancer rates are rising.

Proposed Solution: Leveraging expertise of academic research centers (Massachusetts General Hospital, Broad Institute, and Stanford University) and a non-profit managed-care consortium (Kaiser Permanente), the Dream Team will develop a test called the Lung Cancer Interception Assay (LCIA) to complement LDCT screening.

The proposal is novel in that it will develop complex computational algorithms to combine high-sensitivity/high-accuracy blood-based molecular biomarkers with image-based biomarkers to create the LCIA assay. At the end of the award period, a streamlined product, the LCIA, will be ready to use in population-level definitive trials for the early detection of lung cancer.

Key words

Circulating tumor cells

Circulating tumor DNA

Recurrent

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Genome Alterations Associated With Airway Premalignant Lesion Progression

2016

Career Development Award

Joshua Campbell, PhD

Boston University

Boston

One of the challenges for early detection and prevention of squamous cell lung cancer, a type of non-small cell lung cancer (NSCLC), is the lack of understanding of how premalignant lesions develop and progress to lung cancer. Dr. Campbell is studying how normal lung cells acquire changes in their DNA to form premalignant lesions. His ultimate goal is to develop a biomarker to predict development of squamous cell lung cancer.

Research Summary

Lung cancer remains the leading cause of death from cancer in the US, and lung squamous cell carcinoma is the second most common type of lung cancer. Many regions of abnormal cell growth can be identified via autofluorescence bronchoscopy in the airway of high-risk smokers. Many of these abnormal regions, which are called premalignant lesions, will resolve without any clinical intervention. However, a small subset will turn into lung squamous cell carcinoma. An ability to identify the lesions that are going to progress before they grow to invasive cancer would allow clinicians to intervene earlier and should reduce the number of deaths from this type of lung cancer. Over the past several years, DNA sequencing of tumors has revealed many mutations in important genes that cause cells to grow and proliferate uncontrollably. In this study, DNA sequencing will be used to identify mutations in premalignant lesions from the airways of high-risk smokers that have been sampled over time. It will be determined whether the presence or types of mutations can predict progression or regression of these lesions and use this knowledge to build a test to rapidly identify the mutations associated with progression. This test could have utility in the setting of lung cancer screening to stratify patients into chemoprevention trials.

Technical Abstract

One of the challenges for early detection and prevention of lung squamous cell carcinoma is the lack of understanding of the molecular and cellular changes that cause initiation and progression of this disease. Airway premalignant lesions are the precursors of lung squamous cell carcinoma and can be detected and monitored by autofluorescence bronchoscopy. However, many of these lesions will regress without clinical intervention, and only a subset will progress to invasive carcinoma. The goal of this study is to characterize the landscape of somatic mutations in airway premalignant lesions and to develop an early detection biomarker using targeted DNA sequencing that can predict risk of lesion progression. Ultra-deep whole-exome sequencing will be performed on a previously collected cohort of airway premalignant lesions from high-risk smokers that have been sampled over time, characterized histologically, and classified into those that are stable, regress, or progress. Significantly mutated genes, recurrent copy number changes, and mutational signatures will be identified, and a determination will be made whether they are associated with lesion histology or progression or regression status. Finally, the findings from this study will be combined with the driver genes from The Cancer Genome Atlas (TCGA) to build a targeted DNA sequencing panel. This panel will serve as a rapid and relatively inexpensive method for monitoring premalignant lesions from patients over time and can be used in a clinical trial to assess the ability of autofluorescence bronchoscopy in combination with molecular profiling to stratify patients and serve as a companion diagnostic in chemoprevention trials.

Key words

Molecular profile or molecular testing

Early detection

Mutation profile

Risk profile

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Lung screening via biophotonic analysis of nanoarchitecture of buccal cells

2015

Early Detection Award

This grant was funded in part by Upstage Lung Cancer

Vadim Backman, PhD

Northwestern University

Evanston

Ankit Bharat, MBBS

Northwestern University

Evanston

Cells in the respiratory tract are usually stacked in an orderly fashion. As lung cancer develops, the cells get “un-stacked” and their shapes change, giving them the ability to grow and spread to other parts of the body. Dr. Vadim Backman from Northwestern University is utilizing a new technology called Partial Wave Spectroscopy for seeing those cells. With the LUNGevity Early Detection Award, he will check how cells taken from the cheeks of stage I lung cancer patients reflect these early changes with the ultimate goal of using partial wave spectroscopy technology for early detection of lung cancer.

Research Summary

The goal of this project is to translate a state-of-the-art nanoscale imaging technology, nanocytology, into an inexpensive and accurate lung cancer screening method among current/past smokers via an automated analysis of nanoscale morphology of buccal (cheek) cells obtained by a simple check swab. Dr. Backman and his group envision buccal nanocytology becoming a prescreen for lung cancer that is simple and reliable enough to be performed by a primary care physician or dentist as part of an annual exam of current or past smokers. If the buccal PWS is positive, a patient can be offered more expensive/invasive diagnostic tests such as low dose CT.

This is analogous to the other two-tier screening approach: Pap smear --> colposcopy paradigm, where the initial low-cost, patient-compliant screening test is applied on the entire screening population and used to identify a small subset of these patients who would actually benefit from more extensive examination. This two-tier screening strategy has been highly successful in reducing cervical cancer mortality by 90%. Their goal is to develop a similar approach for lung cancer screening.

Technical Abstract

The overarching goal of the project is to develop a new technology for accurate and cost-effective lung cancer screening in current/former smokers. Lung cancer is curable if detected early. However, there are no robust screening techniques with options such as CT scans fraught with cost, harms, and a high false positive rate. Dr. Backman and his group hope to transform the clinical practice of lung cancer screening by exploiting field carcinogenesis, the concept that the genetic/environmental milieu that results in lung tumor impacts upon the entire aerodigestive mucosa including the buccal mucosa, which was referred to as a “molecular mirror” of lung carcinogenesis.

Their data show that the alteration of nanoscale architecture of buccal cells is exquisitely sensitive to lung field carcinogenesis and may serve as a robust biomarker for lung cancer. These nanoarchitectural changes can be detected in a practical and highly accurate fashion via a new technology, partial wave spectroscopic (PWS) microscopy (‘nanocytology’).

In the proposed study, they will conduct a blinded validation case-control trial to determine the sensitivity and specificity of buccal nanocytology for lung cancer. They will evaluate the ability of the test to identify patients who have lung cancer and how many patients with lung cancer would be missed using this technique. They will perform a subgroup analysis for Stage I lung cancers. They will assess the potential confounding effects of smoking frequency and time of cessation and other aerodigestive malignancies.

This project will provide the requisite data for the future definitive multicenter validation trial followed by FDA submission.

Key words

Early detection