Table 3.

PGx of miscellaneous toxicities in BC associated with different chemotherapeutic regimens.

Regimen	Sample	Toxicity definition	Rational of gene selection	Studied genes**	Significant genetic associations	Reference
AC	230 Early-stage BC patients*	- Need for dose delay - Need for dose reduction - Inability to complete the planned course.	Genes involved in the metabolism or transport of AC.	ABCB1 CYP2B6 CYP2C19 CYP2C9 CYP3A5 SLC22A16	- CYP2B6*5 and *2 associated with a greater incidence of dose delay - SLC22A16 T1226C was associated with a greater incidence of dose delay and leucopenia	(Bray et al., 2010)
AC	227 Early-stage BC patients*	- Need for dose delay	Prior data for the effect of NQO1 on the outcomes of anthracycline regimens. NQO2 was added due to its functional homology to NQO1.	NQO1 NQO2	Carriers of the minor allele at NQO1 rs1800566 showed lower frequency of dose delay (P=0.01)	(Jamieson and Boddy, 2011)
AC	822 BC patients	Grade III gastrointestinal toxicity	variants in Pharmacokinetic genes for CP and DOXO	ABCB1 ABCC1 ALDH1A1	None	(Yao et al., 2014)
AC	265 Early-stage BC patients*	- Grade III infections (infections that lead to hospitalization). - Other lower grade infections “any infection.”	Two genes that are known to have a function in the immune response	CD95 MBL2	CD95 (rs2234767) minor allele is significantly associated with grade III infections (p=0.048) and any infection (p=0.047) (but not significant when corrected for multiple testing). MBL2-221 (rs7096206_ minor allele is significantly associated with grade III infection (p=0.048)	(Jamieson et al., 2017)
Multiple regimens (CP-based)	403 BC patients (184 cases; i.e. suffered from adverse reactions and 219 controls)	- Grade≥ III gastrointestinal toxicity	Tag and functional SNPs in 13 genes involved in activation, detoxification, or transportation of CP	ABCC2 ABCC4 ALDH1A1 ALDH3A CYP2B6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 GSTA1 GSTM1 GSTP1 GSTT1	ABCC4 (rs9561778)	(Low et al., 2009)
Multiple regimens	50 primary BC patients	Any kind and grade of toxicity	SNPs in genes related to folate metabolism pathway	ABCB1 MTHFR TYMS	-Allele T at MTHFR (rs1801131) (p=0.029) -Allele G (Argenin) at P53 (rs1042522) (p=0.018)	(Henríquez-Hernández et al., 2010)
Taxane-based	152 BC patients	Gastrointestinal, cutaneous, asthenia, mucositis, neurotoxicity, and others.	Genes on the metabolic pathway of taxanes	ABCB1 CYP3A4 CYP3A5	None	(Angelini et al., 2017)
Taxane-based	120 BC patients	Any kind and grade of toxicity	Genes involved in taxanes pathways or implied in DNA repair or ROS metabolism	ABCB1 ABCC2 ABCG2 CBR3 CYP1B1 CYP2C8 CYP3A4 CYP3A5 ERCC1 ERCC2 GSTM3 GSTP1 MTHFR NOS3 NQO1 TP53 UGT1A1 UGT1A9 XPC XRCC1	Docetaxel: ERCC1 (rs3212986) with mucositis grade ≥2 and CYP3A4*1B (rs2740574) with IRR grade ≥2 (p < 0.01) Paclitaxel: CYP2C8 (rs1113129) and CYP2C8 (rs1934951) with anemia grade ≥2 and ERCC1 rs3212986 with neuropathy grade ≥2	(Bosó et al., 2014)
Taxane-based	95 BC patients	- Neurological toxicity - Hypersensitivity reactions	Paclitaxel metabolism pathway	CYP2C8 CYP1B1 ABCB1	CYP1B1* 1 with hypersensitivity reaction (p < 0.0001)	(Rizzo et al., 2010)
AC/TC	155 early stage BC patients	Febrile neutropenia occurrence	Genes involved in the metabolism or transportation of docetaxel	1239 SNP in 183 gene	Haplotype TT at SLCO1A2 (rs4762699) and (rs2857468) (p < 0.0001) in patients in taxane arm	(Callens et al., 2015)
AC-T	59 BC patients	- Fever (temperature ≥38.5 or >38 twice 2 h apart) or infection with leucopenia or neutropenia - The need for antidiarrhea medication prescription - Edema - Plural effusion	Genes involved in the metabolism or transportation of docetaxel	ABCB1 CYP3A4 CYP3A5	None	(Tsai et al., 2009)

AC, anthracycline and cyclophosphamide; AC-T, anthracycline and cyclophosphamide followed by taxane; CP, cyclophosphamide; FN, febrile neutropenia; TC, taxane and cyclophosphamide.

*The three studies were applied on the same cohort.

**The mentioned genes were not fully covered in these studies, only specific polymorphisms in these genes were tested.