Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer

Multiple biomarkers are being evaluated to select treatment with an FDA-approved targeted treatments for patients with unresectable, recurrent, relapsed, refractory, advanced or metastatic cancer. These include tissue-based testing as well as circulating tumor DNA and circulating tumor cell testing (known as liquid biopsy). The objective of this evidence review is to examine whether genetic biomarker testing for BRCA1, BRCA2 , PIK3CA, ESR1, BRAF, EGFR, EZH2, HER2, FOLR1, FLT3, CLDN18, FGFR3, PDGFRA, TP53, KRAS, NRAS, IDH1, IDH2, HLA, KIT, MET, homologous recombination deficiency (HDR), and homologous recombination repair (HRR) gene variants, ALK, ROS1, RET, FGFR2, PDGFR, NTRK, Philadelphia chromosome rearrangements or fusions, and other molecular signatures, such as, PD-L1, MSI/MMR, and TMB status, in tumor tissue, or circulating tumor DNA improves the net health outcome in patients with unresectable, recurrent, relapsed, refractory, advanced or metastatic cancer who are considering targeted therapy (Table 1). Table PG1. Gene Variants Found in DNA for Targeted Therapy Biomarker Indication ALK rearrangements/fusions NSCLC ATM Prostate BRAF Breast, NSCLC, metastatic CRC, Melanoma, Glioma, and ATC BRCA1/2 Breast, Ovarian, Pancreatic, and Prostate CLDN18 Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma EGFR NSCLC, CRC, ERBB2 (HER2) Breast, NSCLC, Gastric and Gastroesophageal Cancer, and Biliary Tract Cancer (gallbladder adenocarcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma) ESR1 Breast EZH2 Follicular Lymphoma FGFR2 Cholangiocarcinoma FGFR3 Urothelial Cancer FLT3 (ITD/TDK) Acute Myelogenous Leukemia FOLR1 Epithelial Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer HER2 NSCLC and metastatic CRC HLA Uveal Melanoma HRDa Ovarian HRR (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) Prostate IDH1 Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Cholangiocarcinoma, Astrocytoma, Oligodendroglioma, and Glioma IDH2 Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Astrocytoma, Oligodendroglioma, and Glioma KIT Aggressive Systemic Mastocytosis KRAS NSCLC and metastatic CRC MET NSCLC MSI (MLH1, MSH2, MSH6, PMS1 and PMS2)/MMR (MLH1, MSH2, PMS2, and MSH6) Solid tumors Not MSI-H Endometrial Carcinoma NRAS metastatic CRC NTRK rearrangements/fusions Breast, NSCLC, metastatic CRC, Ovarian, Prostate, Melanoma, Glioma, and other solid tumors PDGFRA Gastrointestinal Stromal Tumors PDGFRB Myelodysplastic Syndrome/Myeloproliferative Disease PD-L1 Solid tumors PIK3CA Breast RET rearrangements/fusions Breast, NSCLC, metastatic CRC, Medullary Thyroid Cancer, Thyroid Cancer, and other solid tumors ROS1 rearrangements/fusions NSCLC TMB Solid tumors TP53 B-cell Chronic Lymphocytic Leukemia ATC: anaplastic thyroid cancer; CRC: colorectal cancer; HRD: homologous recombination deficiency; HRR: homologous recombination repair; NSCLC: non-small cell lung cancer; TMB: tumor mutational burden. a Genomic instability score