Biomarkers for Risk Stratification in Lung Cancer

This is a prospective observational study that will follow patients who undergo lung cancer screening at the San Francisco VA Medical Center, University of California, San Francisco (UCSF) Medical Center, and the San Francisco General Hospital. The proposed study will comprise of two primary populations to determine the ctDNA assay performance in a variety of clinical settings.

Study objectives and statistical approaches to achieve those objectives are determined at the level of the populations described below:

Population 1: Sensitivity and Specificity Thresholding.

In this phase, the technical feasibility of the intended use case will be assessed in the intended use population relative to known cancer status as established by standard clinical methods. ctDNA samples from enrolled patients will be assessed in each of the following cohorts:

Cohort 1A: High-risk patients negative for lung cancer by CT screening and clinical follow-up.

Cohort 1B: Patients with lung nodules ≥6 mm by CT but negative for lung cancer by extended (3 years) CT screening follow-up.

Cohort 1C: Patients with lung cancer (histologically proven or by consensus tumor board opinion of ≥90% probability of cancer) prior to definitive therapy.

Population 2: Clinical Intended Use Performance. In this phase, the clinical performance of the ctDNA assay will be evaluated in patients with high clinical suspicion for lung cancer. ctDNA will be compared to the clinical diagnosis made according to the standard of care (e.g. biopsy, CT surveillance, etc.). ctDNA samples from enrolled patients will be assessed in each of the following cohorts:

Cohort 2A: High-risk patients newly positive (Lung imaging Reporting And Data System (Lung-RADS) \>=3) by CT screening.

Cohort 2B: Patients with \>= 6 mm lung nodules suspicious for lung cancer by treating physician judgment.

Cohort 2C: Patients with a personal history of lung cancer after completion of curative intent treatment but without evidence of recurrence.

Specific Aim 1: To estimate the ctDNA assay sensitivity and specificity requirements in the specific clinical use populations using patients with known non-small cell lung cancer status.

Specific Aim 2: To prospectively estimate the ctDNA assay clinical performance in the clinical application of interest.

ENDPOINTS

Primary Endpoints

Specific Aim 1: Estimation of the ctDNA assay's clinical sensitivity and specificity in patients with lung cancer as proven by histology or tumor board consensus opinion\* and in patients with lung nodule ≥6 mm but without cancer as proven by extended CT screening follow-up\*\*.

\*Patients may be treated with curative-intent Stereotactic Body Radiotherapy (SBRT) without tissue confirmation IF pretest probability for lung cancer by tumor board consensus opinion is ≥90% and the biopsy risk is high.

\*\*Extended CT screening follow-up defined by documentation of ≥3 years of radiographic stability and consensus clinical opinion.

Specific Aim 2: Estimation of the ctDNA assay's clinical predictive value relative to standard of care diagnostic work-up in suspicious nodule adjudication in both the high-risk and general populations (the clinical applications of interest).

Secondary Endpoints

* Correlation of the ctDNA assay performance with Lung-RADS radiographic criteria
* Correlation of Lung-RADS with disease truth defined by clinical follow up as the definite gold standard

Exploratory Endpoints

* Correlation of plasma and tissue genotyping results
* Correlation of the ctDNA assay with orthogonal reference technologies (e.g. ddPCR)
* Correlation of the ctDNA assay performance with histologic sub-type and clinical course (e.g. aggressive vs. indolent disease)
* Correlation of the ctDNA assay performance with clinical lung cancer risk factors
* Correlation of the ctDNA assay results pre-and post-resection
* Correlation of follow-up the ctDNA assay results and kinetics vs. clinical recurrence post-resection or radiotherapy
* Estimation of theoretical biopsy avoidance rate in clinical use population.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 40 years
* Ability to understand and provide written informed consent
* Willingness to comply with study protocols and provide blood samples.
* Willingness to complete 3-year clinical follow up

Exclusion Criteria:

* Active non-cutaneous malignancy within the past 5 years as per medical record or patient report.
* Exclusion criteria for possible follow-up visit blood draw:
* Anemia - measured by hematocrit level of less than 30%, measured after the first blood draw.
* Malnourishment - determined by BMI less than 19. If subject has BMI greater or equal to 19, but has a history of malnourishment, study staff will measure albumin level of subject's blood after initial blood draw. Albumin level must be greater than 2.5 mg per deciliter, or subject will be excluded.
* Severe Chronic Obstructive Pulmonary Disease (COPD) - defined by Gold Stage IV.
* Unstable heart conditions - defined by stable or unstable angina, recent myocardial infarction (within the last 2 years), active congestive heart failure, ischemic cardiomyopathy, or history of complications because of previous blood donation.
* Liver cirrhosis.