Prognostic and predictive response factors in colorectal cancer patients: Between hope and reality

Table 1 Synopsis of major biomarkers derived from clinical studies for use with epidermal growth-factor receptor-targeted therapies in colorectal cancer, chemotherapy

Biomarkers	Prognostic	Predictive	Predictive efficacy	Methodology used	Clinical status
EGFR copy number[71]	Yes	Yes	Raised EGFR GCN and chromosome 7 polysomy associated with response rate (RR) of 30% vs 0% (PAN)	Fluorescence in situ hybridization	Awaiting further clinical validation
EGFR ligand expression (epiregulin and amphiregulin)[72,73]	Yes	Yes	Higher gene-expression profile of ligands in patients with disease control compared to non-responders to CET; OR for response 1.90 for epiregulin and 1.86 for amphiregulin	Gene-expression profiles using RNA and FFPE tumors	Awaiting further clinical validation
Activating KRAS mutations in codon 12 and 13[48,74]	Yes	Predictive for lack of response	RR of 12%-17% for KRAS WT patients vs 0%-1% for KRAS mutations (PAN and CET)	PCR on DNA extracted from FFPE samples	FDA-approved clinical biomarker
KRAS G13D mutations[59,75]	Yes	Predictive for lack of response	No difference in response rates between G13D and activating KRAS mutations but, 3.6- and 2.1-mo improvement in OS and PFS[75] ,improved RR, OR 3.38, 40.5% vs 22%[59] (CET + chemo)	PCR on DNA extracted from FFPE samples from multiple studies	Small patient numbers; awaiting results of prospective study (ICECREAM)
NRAS and BRAF mutations[49,76-78]	Yes	Predictive for lack of response	Lower RR for NRAS and BRAF mutations vs WT (7.7% and 0%-8.3% vs 38% and 17%-47%, respectively) (all KRAS WT patients treated with CET and PAN)	Mutation-frequency analysis using PCR and mass spectrometry (FFPE and fresh-frozen samples)	Evidence for significant negative association, but further clinical validation required
PIK3CA exon 20 mutations[77]	No	Predictive for lack of response	0% vs 36.8% RR for exon 20 mutations vs WT	Mutation-frequency analysis using PCR and mass spectrometry (FFPE and fresh-frozen samples)	Conflicting evidence when compared to other studies, further validation required
Serpin B5	Yes	No	No	HE	Awaiting further clinical validation
Mucinous histology	Yes	Yes	No	HE	Confirmed data

All figures shown are statistically significant (P < 0.05). PAN: Panitumumab; CET: Cetuximab; CRC: Colorectal cancer; Chemo: Chemotherapy; EGFR: Epidermal growth-factor receptor; GCN: Gene copy number; RR: Response rate; RNA: Ribonucleic acid; FFPE: Formalin-fixed paraffin-embedded; WT: Wild type; OS: Overall survival; PFS: Progression-free survival; PCR: Polymerase chain reaction; HE: Histology exam.

Table 2 Synopsis of major prognostic clinical factors derived from clinical studies on colorectal cancer, chemotherapy

Prognostic clinical factors	Positive	Negative	Methodology used	Predictive of response to therapy
Age:			CE
Young	No	Yes		No
Elderly (according to CGA):				Some limitations to choose the T
Fit	Yes	No
Unfit	No	Yes
Frail	No	Yes
PS-WHO:			CE	No
≤ 1	Yes	No
≥ 2	No	Yes
HIV+	No	Yes	LT, CE	Poor
Advanced clinical state	No	Yes	TNM, CE	No
Elevated CEA levels:			LT	No
Adjuvant	No	Yes
Metastatic	No	Yes
Elevated Ca19.9 levels	No	Yes	LT	No
Elevated ALP levels	No	Yes	LT	Poor
Skin rash[79,80]	Yes	Yes	HE	Further clinical validation required
Hypomagnesaemia[81,82]	Conflicting evidence	Conflicting evidence	Plasma magnesium levels	Further clinical validation required
Co-morbidities	No	Yes	ACE-27[83]/CE	Some limitation to choose the T

CE: Clinical evaluation; LT: Laboratory test; HE: Histology exam; T: Treatment (including surgery, chemotherapy, radiation therapy); TNM: Tumor node metastasis.