Is the SPOT‑MAS (Screening for the Presence Of Tumor – Multi‑Analyte Sequencing) blood‑based genetic test appropriate for routine cancer screening, or should it be limited to high‑risk individuals such as those with hereditary cancer syndromes, strong family history, or significant carcinogen exposure?

SPOT-MAS Genetic Testing Should Be Limited to High-Risk Individuals, Not Used for Routine Population Screening

Blood-based multi-cancer early detection tests like SPOT-MAS are not recommended for routine cancer screening in the general population and should be reserved for individuals meeting established high-risk criteria for hereditary cancer syndromes, including strong family history, known pathogenic variants in relatives, or specific clinical features suggesting inherited susceptibility. 1

Why SPOT-MAS Is Not Appropriate for General Population Screening

Absence of Guideline Endorsement

• No major guideline organization—including NCCN, USPSTF, American Cancer Society, American Academy of Family Physicians, or American College of Physicians—recommends blood-based multi-cancer early detection assays for cancer screening in any population 1
• The systematic literature review of multi-cancer early detection tests found no completed randomized controlled trials demonstrating mortality benefit, and most studies had high risk of bias due to limited follow-up of participants with negative test results 2

Limited Evidence for Clinical Utility

• While SPOT-MAS demonstrates sensitivity of 72.4-100% and specificity of 97.0-99.9% in case-control studies, these performance characteristics were derived from studies with significant methodological limitations 2
• Sensitivity for early-stage cancers (stages I-II) is substantially lower than for later-stage disease, undermining the primary rationale for screening asymptomatic individuals 2
• No meaningful data exist on patient-relevant outcomes including mortality reduction, health-related quality of life, or long-term harms from false-positive results 2

Prioritization of Established Screening

• Complete all age-appropriate, guideline-endorsed screening modalities (colonoscopy, low-dose CT for lung cancer in smokers, mammography, PSA with shared decision-making) before considering any multi-cancer early detection test, as these established methods have higher sensitivity, specificity, and proven mortality benefit 1

Appropriate Use: High-Risk Individuals Meeting Genetic Testing Criteria

When Multigene Panel Testing Is Indicated

Genetic testing should be offered to individuals meeting specific clinical criteria that suggest hereditary cancer susceptibility, not as a general screening tool. 3

Breast and Ovarian Cancer Risk Criteria

• Personal history of breast cancer diagnosed at age ≤45 years 4
• Breast cancer diagnosed at age ≤50 years with one or more close blood relatives with breast cancer at age ≤50 years 4
• Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer at any age 4
• Male breast cancer in the patient or close male blood relative 4
• Family member with known BRCA1/BRCA2 or other breast cancer susceptibility gene mutation 4
• Ashkenazi Jewish ancestry with breast, ovarian, or pancreatic cancer at any age 4

Colorectal Cancer Risk Criteria

• Personal or family history suggesting Lynch syndrome, including CRC diagnosed before age 50, multiple Lynch-associated cancers, or meeting Amsterdam/Bethesda criteria 3
• Multiple adenomatous polyps (≥10 cumulative) suggesting polyposis syndromes like FAP, attenuated FAP, or MUTYH-associated polyposis 3
• Personal history of endometrial cancer, particularly if diagnosed before age 50 or with synchronous Lynch-associated tumors 3

Rationale for Phenotype-Directed Testing

• Multigene panel testing is most useful when pathogenic variants in more than one gene could explain the patient's clinical and family history, making phenotype-directed testing based on personal and family history more efficient and cost-effective 3
• Testing should focus on identifying pathogenic or likely pathogenic variants that are clinically actionable—meaning the treatment or surveillance of the patient would be altered based on the presence of such a variant 3

Critical Distinction: Germline vs. Tumor Testing

Confirmatory Germline Testing Required

• Changes to a patient's medical management based solely on direct-to-consumer testing or tumor profiling results are not recommended 3
• Confirmatory germline testing by a certified laboratory is required, as tumor testing has lower sensitivity (particularly for intermediate-sized deletions and duplications) and may filter out germline findings 3
• The absence of a pathogenic variant from tumor profiling does not rule out the possibility of a germline pathogenic variant in that gene 3

Pre-Test Counseling Mandatory

• Genetic testing should only be performed with appropriate pre-test and post-test counseling by a professional with expertise in cancer genetics 3
• Pre-test counseling must include discussion of why the test is offered, how results may impact medical management, cancer risks associated with identified variants, significance of possible results, technical accuracy, cost considerations, risks of genetic discrimination under GINA, psychosocial aspects, and implications for family members 3

Management Based on Test Results

Positive Result (Pathogenic/Likely Pathogenic Variant)

• Implement enhanced screening protocols specific to the identified syndrome (e.g., annual colonoscopy starting at age 20-25 for Lynch syndrome, risk-reducing mastectomy/oophorectomy consideration for BRCA1/2) 4
• Cascade testing should be offered to at-risk family members 4

Variant of Uncertain Significance (VUS)

• Manage based on personal and family history, not the VUS itself 3
• Offer participation in research studies and periodic reclassification as databases expand 3
• Multigene tests increase the likelihood of detecting VUS, though this frequency is expected to decrease as testing becomes more widespread 3

Negative Result

• If a known familial mutation exists and the patient tests negative, follow general population screening guidelines 4
• If no known familial mutation exists, manage based on personal and family history risk assessment, as a negative test does not rule out hereditary cancer risk when family history remains suggestive 4

Common Pitfalls to Avoid

Do Not Use SPOT-MAS as First-Line Screening

• The proper sequence is to complete guideline-endorsed, cancer-specific screening first (colonoscopy for CRC, LDCT for lung cancer in high-risk smokers, mammography for breast cancer) before considering any multi-cancer early detection test 1
• These established modalities have Level I evidence for mortality reduction, whereas SPOT-MAS does not 1

Do Not Skip Genetic Counseling

• Ordering multigene panels without proper genetic counseling leads to misinterpretation of results, inappropriate management of VUS, and missed opportunities for family cascade testing 3
• Commercially available tests differ significantly in genes analyzed, laboratory expertise, and variant reclassification protocols, requiring careful selection 3

Do Not Assume Negative Results Rule Out Risk

• Limited data exist regarding degree of cancer risk associated with many genes on multigene panels, particularly low-to-moderate penetrance genes 3
• Gene-gene and gene-environment interactions may influence risk beyond the identified variant alone 3
• Family history should be periodically reassessed as new cancer events may occur over time 4

Do Not Delay Cancer Treatment for Testing

• Primary cancer treatment should not be delayed for genetic counseling referral or test results 4
• Genetic testing can be performed after treatment initiation if clinically indicated 4