PATHFINDER is a prospective, multi-center study in which approximately 6,200 participants will be enrolled. An investigational multi-cancer early detection test, developed by GRAIL, will be ordered by and results returned to a study investigator. In cases with a "signal detected" test result (with a predicted or indeterminate tissue of origin (TOO)), the diagnostic work-up will not be dictated by the protocol, but will instead be coordinated by the ordering and treating medical team at the enrolling sites based on the participant's clinical condition, recommendations by each institution's clinical practices, and in consultation with the study investigator and interdisciplinary care team, as necessary. Additionally, proposed clinical care pathways, developed based on a review of guidelines from the National Comprehensive Cancer Network (NCCN), American College of Radiology (ACR) and other professional organizations, should be referenced by the medical team to determine the diagnostic work-up. The number and types of diagnostic procedures required to achieve diagnostic resolution will be assessed. Performance of multi-cancer early detection test will be evaluated. Additionally, participant-reported outcomes will be collected at several time points to assess participants' perceptions about the multi-cancer early detection test. Participants will be followed for approximately 12 months from the time of enrollment. Cancer status will also be assessed at the 12 month time point.

Inclusion Criteria:

Cohort A: Elevated Risk Group (70% of cohort):

• Age: Participant must be 50 years of age or older at the time of signing the Informed Consent Form (ICF).
• Participants must meet at least one of the criteria below:
• History of smoking at least 100 cigarettes in his or her lifetime
• Documented genetic cancer predisposition, hereditary cancer syndrome, or meeting criteria for germline testing based on current NCCN guidelines
• Personal history of invasive or hematologic malignancy, with definitive treatment completed greater than 3 years prior to enrollment. Adjuvant hormone therapy for cancer is permissible (ie may be ongoing within 3 years or at the time of enrollment).

Cohort B: Non-Elevated Risk Group (30% of cohort):

• Age: Participant must be 50 years of age or older, at the time of signing the Informed Consent Form (ICF).
• None of the conditions described in Cohort A, criteria 2a-c
• For all participants, capable of giving signed and legally effective informed consent

Exclusion Criteria:

• Undergoing or referred for diagnostic evaluation due to clinical suspicion for cancer (e.g., referred to a medical or surgical oncologist, or scheduled for biopsy on the basis of a suspicious imaging abnormality).
• Personal history of invasive or hematologic malignancy, diagnosed within the 3 years prior to expected enrollment date, or diagnosed greater than 3 years prior to expected enrollment date and never treated.
• Definitive treatment for invasive or hematologic malignancy within the 3 years prior to expected enrollment date. Adjuvant hormone therapy for cancer is not an exclusion criterion.
• Individuals who will not be able to comply with the protocol procedures.
• Individuals who are not current patients at a participating center.
• Previous or current participation in another GRAIL-sponsored study.
• Previous or current employees or contractors of GRAIL.