What are the approved diagnostic and prognostic tests for cancer?

Approved Diagnostic and Prognostic Tests for Cancer

The approved diagnostic and prognostic tests for cancer are highly cancer-specific and include immunohistochemistry panels, molecular biomarker testing (EGFR, ALK, KRAS, NRAS, BRAF, HER2, ER/PR), next-generation sequencing, and tissue-agnostic markers (MSI, TMB, PD-L1, NTRK), all of which must be performed in CLIA-certified laboratories. 1

Cancer-Specific Molecular Testing Requirements

Lung Cancer

• All patients with lung adenocarcinoma require molecular testing for EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, PD-L1 expression, and NRAS mutations to guide targeted therapy selection 1
• Next-generation sequencing techniques are increasingly used as more biomarkers are identified and validated 2
• Blood-based tumor mutation burden (TMB) shows association with improved atezolizumab clinical benefit, though unique assays and cut-offs are not yet standardized 2

Colorectal Cancer

• All colorectal adenocarcinomas must be tested for KRAS, NRAS, and BRAF mutations to predict response to anti-EGFR antibody therapy 1

Breast Cancer

• All invasive breast cancers require testing for estrogen receptor (ER), progesterone receptor (PR), and HER2 status by immunohistochemistry and/or FISH 1

Prostate Cancer

• Tumor-based molecular assays provide prognostic information independent of NCCN risk groups, including likelihood of biochemical recurrence after surgery or radiotherapy and likelihood of developing metastasis 2
• Several tissue-based molecular assays have received positive reviews by the Molecular Diagnostic Services Program (MolDX) and are likely covered by CMS, though no randomized controlled trials have studied their utility 2
• Routine use of serum markers such as CEA is not recommended 2

Cancer of Unknown Primary (CUP) Diagnostic Algorithm

Initial Immunohistochemistry Panel

• Broad-spectrum cytokeratin (AE1/AE3, OSCAR) to confirm epithelial origin 1
• CD45 to exclude hematologic malignancy 1
• SOX10 and/or S100 to exclude melanoma 1
• CK7 and CK20 staining patterns provide clues to primary site 2, 1

Sex-Specific Testing

• Males with adenocarcinoma bone metastases: PSA testing mandatory 2
• Males with adenocarcinoma bone metastases: PSMA and/or NKX3.1 immunohistochemistry to rule out prostate cancer 1
• Females with axillary adenopathy: Estrogen and progesterone receptor testing, GATA3 immunohistochemistry 2, 1
• Females with peritoneal carcinomatosis: Consider serous histologic type adenocarcinoma workup 2

Specialized Testing for Specific Presentations

• Patients with midline metastatic disease: Serum α-fetoprotein and β-human chorionic gonadotropin to exclude extragonadal germ-cell tumors 2
• Poorly differentiated cases: Immunohistochemistry to exclude lymphomas and germ-cell tumors 2
• Neuroendocrine differentiation: Synaptophysin and/or INSM1 immunohistochemistry, plasma chromogranin A 2, 1

Tissue-Agnostic Predictive Biomarkers

Immunotherapy Response Markers

• MSI (microsatellite instability), PD-L1, and TMB (tumor mutation burden) determination is generally recommended when immune checkpoint inhibitor treatment is considered 2
• Higher PD-L1 expression and higher TMB are associated with better response rates and longer survival in previously treated CUP patients receiving nivolumab 2

Targeted Therapy Markers

• NTRK rearrangements predict response to NTRK inhibitors irrespective of tissue of origin 2

Prognostic Laboratory Parameters

Adverse Prognostic Factors

• Elevated lactate dehydrogenase (LDH) is an independent adverse prognostic factor across multiple cancer types 2
• Elevated alkaline phosphatase (ALP) indicates worse prognosis 2
• Low serum albumin and lymphopenia or elevated neutrophil-to-lymphocyte ratio (NLR) reflect inflammatory state and worse outcomes 2

Risk Stratification for CUP

• The recommended two-factor prognostic score combines ECOG performance status with LDH levels: good prognosis (ECOG PS 0-1 and normal LDH) versus poor prognosis (ECOG PS >1 or elevated LDH) 2

Molecular Prognostic Markers

• KRAS or NRAS activation and CDKN2A deletion confer independent adverse prognosis 2
• TP53 mutations or deletions of chromosome 17p are associated with poor prognosis in oligometastatic CUP 2

Technical Requirements and Quality Standards

Laboratory Certification

• All molecular testing used for patient management must be performed in CLIA-certified laboratories 1
• Laboratories must validate assays and participate in proficiency testing at least semiannually 1

Specimen Requirements

• Formalin-fixed paraffin-embedded (FFPE) tissue is the standard specimen type, with cytology preparations increasingly accepted 1
• Next-generation sequencing (NGS) for comprehensive genomic profiling, real-time PCR for highly targeted mutation detection, and FISH for copy number alterations and gene rearrangements are the recommended methodologies 1

Critical Limitations

Screening Limitations

• Most tumor markers lack sufficient sensitivity and specificity for population-based screening and are primarily used for prognosis, treatment selection, and monitoring 1
• Cell-free DNA testing is most effective when combined with other biomarkers rather than as standalone screening, with particularly low sensitivity for early-stage disease 1

Intratumoral Heterogeneity

• Approximately 80% of prostatectomy specimens are multifocal, and intratumoral heterogeneity for DNA and RNA markers may limit prognostic utility due to sampling bias 2
• Approximately 20% of lymph node metastases derive from nonindex lesions, potentially limiting molecular testing accuracy 2