Stage II

Health equity

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Measuring provider engagement in lung cancer screening

2021

Veterans Affairs Research Scholar Award

Jennifer Lewis, MD, MS, MPH

Vanderbilt University Medical Center/VA-Tennessee Valley Healthcare System

Nashville

Research Summary

Fewer than 10% of eligible Veterans are screened for lung cancer with low-dose computed tomography (LDCT), and a lack of clinician engagement is one important reason for low screening rates. In this proposal, we will modify a survey tool that measures aspects of clinician engagement in lung cancer screening to better understand how to improve clinician engagement. We will perform experiments to evaluate if this measure is capturing the key concepts in engagement. We will evaluate if a provider who scores higher in certain engagement features orders more screening examinations. The results of this proposal will be used to develop an intervention to increase clinician engagement in lung cancer screening and evaluate if engagement changes before and after that intervention. Increasing clinician engagement can lead to improved screening rates and lung cancer outcomes.

Technical Abstract

Background: Provider engagement is key for successful implementation of evidence-based practices. Our prior work reported that providers’ guideline knowledge is strongly correlated to screening practices but other behavioral factors have not yet been measured in lung cancer screening.

Long-term Career Goal: To be a leader in implementation science with expertise in translating evidence-based lung cancer prevention and early detection into clinical practice through mixed-methods research (qualitative and quantitative) and pragmatic trials in the Veterans Affairs (VA). This award will advance the following career goals: To gain experience in: a) measurement science; b) quantitative analysis methods, and to transition to research independence.

Specific Aim: To measure and validate providers’ behavioral factors that influence lung cancer screening implementation.

Methodology: We will adapt the Determinants of Implementation Behavior Questionnaire (DIBQ) for lung cancer screening and leverage ongoing research infrastructure to survey primary care providers at 10 VA medical centers (VAMCs) participating in the Veterans Affairs Partnership to increase Access to Lung Screening (VA-PALS). The adapted questionnaire will be validated using factor analysis and association with prior screening practices. We will assess which behavioral factors are associated with screening using multivariable regression.

Future Directions: The data gathered will be used to design future interventions aimed at increasing provider engagement and measure how provider engagement changes before and after interventions. This proposal will advance the field of implementation science while also leading towards my independence as an implementation researcher.

Key words

Health equity

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Optimizing biomarker based strategies for lung cancer screening

2021

Early Detection Research Award

Anil Vachani, MD

University of Pennsylvania

Philadelphia

Currently, low-dose computed tomography (LDCT) is the only tool for the screening and early detection of lung cancer in individuals who meet screening criteria. LDCT is not very sensitive; often, abnormalities identified in an LDCT scan turn out to be benign. However, ruling out cancer requires an invasive biopsy. Dr. Vachani is testing whether a biomarker signature can be integrated into LDCT screening to improve the sensitivity of LDCT so that patients may be spared unnecessary biopsies.

Research Summary

Lung cancer remains the leading cause of cancer-related mortality in the US and globally accounting for 1.8 million deaths annually. Use of low-dose CT (LDCT) for lung cancer screening has been shown to save lives and is recommended for individuals at high-risk of lung cancer. However, LDCT has potential risks including a high rate of false positive findings, which may result in additional testing and potentially harmful invasive procedures. Several blood and imaging biomarkers have emerged as potentially useful complementary tools for lung cancer screening (LCS). Our proposed research will use a computational framework to estimate the population level impact of biomarker-based tests and identify the optimal strategy for integration of these emerging tools into LCS and pulmonary nodule evaluation.

Technical Abstract

Lung cancer remains the leading cause of cancer related mortality in the US and globally— responsible for ~1.8 million deaths annually. Randomized trials of low dose CT (LDCT) for lung cancer screening have demonstrated a clear mortality benefit and are recommended by the United States Preventive Services Task Force (USPSTF). However, most individuals currently eligible for screening do not have lung cancer and many at risk populations are not candidates for screening. Additionally, LDCT has a relatively high rate of false positives leading to potentially harmful tests and invasive procedures. Moreover, early experience suggests that LCS outcomes in clinical practice may differ from those observed in randomized trials. Given the concerns with the performance of LDCT, the use of blood and imaging biomarkers to complement the screening process has the potential to enhance its efficacy and effectiveness. Biomarkers could be employed at two different steps of the screening process – as the initial test for cancer screening, to better define the best candidates for screening, or following a positive LDCT scan, to inform lung nodule evaluation and management. While several screening and diagnostic biomarkers have been developed, they have not been formally evaluated in prospective comparative effectiveness trials, nor have they been subjected to cost-effectiveness analyses. More importantly, their impact on lung cancer burden at the population level is still unknown. Our proposed research will inform the following areas of LCS and biomarker discovery: 1) generate a computational framework to estimate and compare the population impact of emerging screening and diagnostic biomarkers, 2) identify the optimal strategy of integrating biomarker tests into LCS, and 3) highlight and identify the characteristics of biomarkers (sensitivity and specificity for histological subtypes, etc.) which are critical for cost-effective biomarker applications.

Key words

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Pilot study of SGLT2 in the characterization of early lung adenocarcinoma

2021

Early Detection Research Award

Claudio Scafoglio, MD, PhD

University of California, Los Angeles

Los Angeles

The protein SGL2 seems to be produced in higher quantities on abnormal lung cells than on normal lung cells. Dr. Scafoglio is testing whether SGL2 can be used to image lung cancer cells by using a new imaging technology.

Research Summary

Lung cancer claims around 140,000 lives in the United States every year; there is great need for early diagnosis strategies, and an attractive target is cancer metabolism. Cancer cells require more glucose than normal tissues for their unregulated growth; glucose cannot enter the cells freely, but needs to be transported by specific proteins called glucose transporters.

We have recently discovered that early-stage and pre-cancerous lesions rely on a specific glucose transporter to satisfy their metabolic needs: sodium-dependent glucose transporter 2 (SGLT2). We have introduced a new probe, Me4FDG, which can be used for positron emission tomography (PET) to detect accumulation of glucose in the patient’s tissues through a whole-body scan. We have started a pilot trial of Me4FDG PET in patients diagnosed with lung cancer as proof of principle that this diagnostic technique can be used for early lung cancer diagnosis. We propose to perform more thorough and systematic studies to evaluate the feasibility of Me4FDG PET as a novel diagnostic imaging technique for early stage lung cancer.

Technical Abstract

Lung cancer is the leading cause of cancer-related death in US, and lung adenocarcinoma (LUAD) is the most frequent histology. Early diagnosis is crucial. High-resolution CT has increased the discovery of solitary lung lesions, many of which are benign, whereas some progress to invasive cancer; the identification of novel biomarkers to predict the malignant potential of these lesions is of paramount importance. We found that sodium-dependent glucose transporter 2 (SGLT2) is expressed in human pre-malignant and early-stage LADC, and is required for progression of LUAD. SGLT activity can be measured by PET imaging with methyl-4-[18F] fluorodeoxyglucose (Me4FDG). Importantly, we identified SGLT2 activity in FDG-negative, early-stage lesions in mouse models and in human lung nodules.

Specific aims of the study are: 1. To assess the safety and efficacy of Me4FDG in patients with lung cancer, via a pilot study in 60 patients (30 with pathological diagnosis of LUAD, 30 with a clinical diagnosis of benign nodule); 2. To evaluate the prognostic significance of SGLT2 expression in early lung adenocarcinoma, through SGLT2 staining of 674 samples embedded in tissue microarrays.

The proposed research is likely to introduce a novel diagnostic tool for early diagnosis of lung adenocarcinoma, and further define the prognostic role of SGLT2 in lung cancer. If successful, this pilot trial will open the way for larger clinical studies where we will evaluate the ability of Me4FDG PET to predict the malignant behavior of indeterminate subsolid lung nodules. This will improve the early diagnosis of lung cancer.

Key words

Biomarker or biomarker testing

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Lung cancer detection by CRISPR-based detection of circulating tumor DNA

2018

Career Development Award

This grant was funded in part by Schmidt Legacy Foundation and Upstage Lung Cancer

Edwin Yau, MD, PhD

Roswell Park Cancer Institute

Buffalo

Currently, computed tomography (CT) is available as a tool for the early detection of lung cancer in high-risk individuals. Unfortunately, it has a high false-positive rate: less than 5% of people with nodules found through CT actually have lung cancer. Apart from the distress associated with false positives, individuals may have to undergo invasive procedures, such as a biopsy, to rule out lung cancer.

Circulating tumor DNA (ctDNA) is DNA released from dying cancer cells into the bloodstream. Individuals with early-stage lung cancer may have ctDNA in their blood, even when the cancer is localized. CRISPR-Cas technology is a novel DNA modifying tool that can be used to develop sensitive, specific, and economic ctDNA assays. Dr. Edwin Yau will develop a CRISPR-Cas-based blood test to detect ctDNA in the blood of individuals suspected of having lung cancer. While the immediate goal of the project is to evaluate this blood test in individuals who have already undergone a CT scan, the ultimate goal of the project is to develop a blood test for screening all individuals.

Research Summary

Lung cancer remains the leading cause of death related to cancer and the majority of lung cancer patients present with advanced disease that is for the most part incurable. Efforts to improve the early detection of lung cancer are crucial to help decrease the number of people who die from lung cancer. It has long been known that genetic information specific to cancer cells can be detected in the blood of cancer patients. Current technologies are enabling us to identify this cancer-specific genetic information directly from blood samples allowing for “liquid biopsies” that offer the potential of making cancer diagnoses directly from blood tests. However, the amount of cancer specific genetic information in the blood of patients with smaller tumors in early stages is often only present in very minute amounts that are difficult to detect. The development of new liquid biopsy technologies that can identify smaller amounts of genetic information more economically could potentially lead to blood tests that are able to detect smaller, more curable tumors and could be used for lung cancer screening. The recent identification of CRISPR-Cas systems, bacterial immune systems adapted to recognize specific genetic sequences, that can accurately detect very small quantities of specific genetic sequences are an attractive platform to develop liquid biopsy tests. The goal of the proposed project is to develop a CRISPR based blood test that can accurately identify genetic sequences specific to lung cancer and can accurately identify patients with early stage lung cancer.

Technical Abstract

The majority of lung cancer patients present with advanced disease that is largely incurable. Efforts to improve the early detection of this disease are critical to decrease lung cancer-related mortality. Low-dose computed tomography (CT) screening in high risk patients has demonstrated reduction in lung cancer related mortality through diagnosis of earlier stage disease at the cost of high false-positive rates and the frequent need for invasive diagnostic testing when indeterminate lung nodules are identified. Detecting tumor specific somatic mutations and/or epigenetic signatures in circulating tumor DNA (ctDNA) represents an attractive non-invasive method for identifying early stage lung cancer. However, to realize this promise for lung cancer screening, where ctDNA from small tumors is miniscule, the development of sensitive, specific, and economical ctDNA based assays is critical.
The bacterial innate immune system consisting of clustered regularly interspaced short palindromic repeats (CRISPR) and their associated endonucleases (CRISPR-Cas) are specifically adapted to recognize foreign nucleic acids. The recent identification and diagnostic adaptation of certain classes of CRISPR-Cas systems, such as CRISPR-Cas12a and -Cas13a, offer unique platforms on which to develop sensitive, specific, and economical assays for the detection of ctDNA. The goal of the current project is to develop CRISPR-Cas12a and -Cas13a based ctDNA assays that can sensitively detect somatic cancer mutations and aberrant promoter hypermethylation often found in lung cancer patients and to validate these assays in plasma samples of patients with early stage NSCLC and in discriminating between benign and malignant nodules identified by low-dose CT screening studies.

Key words

Circulating tumor DNA

Molecular profile or molecular testing

Liquid biopsy

Mutation profile

Read more about Lung cancer detection by CRISPR-based detection of circulating tumor DNA

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

Biomarker or biomarker testing

Adjuvant or neoadjuvant

Immune checkpoint inhibitors

Immunotherapy

Interception

Liquid biopsy

Squamous cell lung cancer

Screening

Stage I

Stage II

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

Integrated Blood-Based and Radiographic Interception of Lung Cancer

2017

SU2C-LUNGevity-ALA LC Interception Award

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

Squamous cell lung cancer

Recurrent

Screening

Read more about Integrated Blood-Based and Radiographic Interception of Lung Cancer

Optical Imaging for Early Lung Cancer Diagnosis

2016

Career Development Award

Lida Hariri, MD, PhD

Massachusetts General Hospital/Harvard University

Boston

A tissue biopsy is often required to make a definitive diagnosis of lung cancer. However, because of small size and inadequate biopsy yield, early-stage lung cancer is often difficult to diagnose. Dr. Hariri is using a novel imaging technique called optical coherence tomography (OCT) to develop tools to guide tissue biopsy sampling to improve tissue yield. These tools will also provide additional diagnostic information.

Research Summary

Early, accurate diagnosis of lung cancer is fundamental to improving patient survival. Tissue biopsy is key to early diagnosis in order to determine if a lung nodule is malignant or benign. Unfortunately, low-risk methods of biopsy, such as bronchoscopy, are often not able to adequately sample targeted nodules when they are small and/or difficult to navigate to. If a diagnosis cannot be made, patients must undergo repeat biopsy or even surgery, which increases risk and delays diagnosis and therapy. This project aims to dramatically improve lung cancer diagnosis on low-risk biopsy using cutting-edge optical imaging tools in combination with navigation techniques to provide (1) real-time, intra-procedural assessment of biopsy site locations to ensure adequate tissue sampling and (2) large-volume “virtual optical biopsy” of nodules for diagnosis as a complement to tissue biopsy. This project will result in a powerful new bronchoscopy tool that could reduce unnecessary risky procedures, eliminate delays in diagnosis, and allow earlier therapy initiation.

Technical Abstract

Inadequate biopsy yield is a significant limitation to early lung cancer diagnosis and is a two-pronged problem: (1) Early-stage lung cancers are not adequately targeted during biopsy due to their small size and (2) even if a nodule is adequately targeted, often there is insufficient tumor in the biopsy to make a definitive diagnosis and/or accomplish all diagnostic testing for patient care. Optical coherence tomography (OCT) is a high-resolution imaging modality that provides virtual visualization of tissue volumes orders of magnitude larger than biopsy without tissue removal. Dr. Hariri’s group has developed OCT catheters compatible with standard bronchoscopes and demonstrated that OCT can identify lung nodules and assess pathologic features of lung cancer with high sensitivity/specificity. This project’s aims are to dramatically improve diagnostic capability in lung cancer using large volume OCT to provide (1) virtual intra-procedural evaluation in real-time (VIPER) of biopsy site location and 2) large volume virtual optical biopsy for subsequent pathology diagnosis as a complement to tissue biopsy. In Aim 1, they will assess if in vivo OCT VIPER biopsy assessment increases tumor yield on bronchoscopic biopsy in a powered, blinded clinical study. In Aim 2, they will use the data obtained in Aim 1 to determine the diagnostic accuracy of large volume OCT optical biopsy with tissue biopsy as compared to tissue biopsy alone. This project will result in clinical translation of a powerful, robust new optical bronchoscopy tool that could reduce unnecessary diagnostic procedures, eliminate delayed diagnoses, provide earlier intervention, and improve patient morbidity/mortality.

Key words

Stage - all

Stage I

Stage II

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The Occurrence of Lung Cancer After Surgical Resection: Impact of New Staging System, Use of Adjuvant Chemotherapy and Value of Chest CT Versus Chest Radiograph

2002

Targeted Therapeutics Research Award

Funded by LUNGevity Foundation in collaboration with The CHEST Foundation, the philanthropic arm of the American College of Chest Physicians

Alexei V. Bogolioubov, MD

Memorial Sloan Kettering Cancer Center

New York

Surgery is often recommended for patients who have localized lung cancer. Dr. Bogolioubov is analyzing how fast lung cancer comes back after surgery to remove the primary tumor. He is also evaluating the role of chest CT radiography for post-operative follow-up.

Key words

Chemotherapy

Biomarker or biomarker testing

Read more about The Occurrence of Lung Cancer After Surgical Resection: Impact of New Staging System, Use of Adjuvant Chemotherapy and Value of Chest CT Versus Chest Radiograph

Autoantibody biomarkers for the detection of lung cancer

2008

Early Detection Research Award

Funded equally by LUNGevity Foundation and the American Lung Association

Michael Tainsky, PhD

Wayne State University, Karmanos Cancer Institute

Detroit

Dr. Tainsky has developed a technology that takes advantage of the responses of the human immune system to identify cancer-associated proteins that bind to antibodies present in the blood of cancer patients but not in the blood of healthy subjects or those with benign diseases. Dr. Tainsky is working to develop a non-invasive screening test for the early detection of lung cancer by using cancer-associated antigens as biomarkers.

Key words