3.

Genetic markers evaluated as predictive biomarkers for BEV treatment

Author	Trial	Cancer	Sample size	Markers	Assessment method	Finding
BEV, bevacizumab; Doc, docetaxel; NVB, vinorelbine; Cap, capecitabine; Gem, gemcitabine; PTX, paclitaxel; CTX, cyclophosphamide; CBP, carboplatin; Tras, trastuzumab; MBC, metastatic breast cancer; LABC, locally advanced breast cancer; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PGF, placental growth factor; HER2, human epidermal growth factor receptor 2; EGFR, epidermal growth factor receptor; Flt4, fms-related tyrosine kinase 4; PDGF, platelet-derived growth factor; Dll4, delta like ligand (Dll)4; p53, protein 53; AGTR1, angiotensin type 1 receptor; PAKT, phosphate-AKT; PMAPK, phosphorylated mitogen-activated protein kinase; KISS1, kisspeptin 1; HIF, hypoxia-inducible factor; eNOS, endothelial nitric oxide synthase; IGF, insulin-like growth factor; qRT-PCR, quantitative reverse transcriptase polymerase chain reaction; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; PFS, progression-free survival; ORR, objective response rate; pCR, pathologic complete response; OS, overall survival; TGF-β, transforming growth factor beta; TNBC, triple negative breast cancer.
Miles et al. (9)	AVADO: phase III, Doc vs. Doc + BEV 7.5 mg/kg or 15 mg/kg	First line MBC	176	VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, VEGFR-3, PGF, neuropilin-1, HER2, EGFR	qRT-PCR and IHC	No consistent predictive effect was seen
Curigliano et al. (56)	BEVIX: phase II, two arms, BEV with sequential or concurrent oral NVB + Cap	More than first line LABC/MBC with lymphangitic spread to chest wall or skin	66	Gene-chip, more than 50,000 human transcripts		A set of 16 genes (C11orf45, DNASE1L2, KIAA0930, FRMD4A, ZBTB7C, PLA2G4C, HBG2, ATP2C1, FAM178A, SRSF7, TMEM48, FBXO32, DENR, HELLS, ARMC8, SEL1L) was selected to predict the response to BEV
Jubb et al. (61)	AVF2119g: phase III, Cap vs. Cap + BEV	First to fifth line MBC	223	VEGF-A, VEGF-B, thrombospondin-2, Flt4, VEGF-C, PDGF-C, neuropilin-1, Dll4, Bv8, p53, thymidine phosphorylase	In situ hybridization and IHC	Low scores for Dll4, VEGF-C and neuropilin-1 showed trends toward improvement in PFS
Salvador et al. (62)	AVALUZ: phase II, single arm, BEV + Gem + PTX	First line MBC	53	AGTR1	RT-PCR	Intense AGTR1 expression was associate better ORR
Sánchez-Rovira et al. (63)	Phase II, single arm, doxorubicin + CTX followed BEV + Doc	Neoadjuvant breast cancer	49	VEGF, VEGFR, PAKT, PMAPK, KISS1, RKISS1, HIF, eNOS, AGTR1, IGF	RT-PCR	Higher pCR was related with AGTR1 overexpression
Mendiola et al. (64)	Retrospective study BEV + PTX	Multiple line MBC	60	Real-Time ready qPCR assays, this platform enables the quantitation of 168 genes selected from literature plus 19 housekeeping genes and 5 internal controls per sample.		Gene model and Gene & Clinic model predict improved PFS and OS with BEV-PTX therapy in the first 6 months
Varadan et al. (65)	BR-211A and BR-211B: phase II, BEV or Tras or nab-paclitaxel (single dose) followed BEV + nab-paclitaxel + CBP or Tras + nab-paclitaxel + CBP	Neoadjuvant breast cancer	44	RNA sequencing		A 61-gene TGF-β signature showed unique predictive power to BEV
Schneider et al. (66)	E2100: phase III, PTX vs. PTX + BEV	First line ABC	367	VEGFA	FISH	VEGFA amplification in univariate analysis was associated with worse OS; particularly prominent in HER2 + or TNBCs