Genetic Influences in Breast Cancer Drug Resistance

Figures & data

Figure 1 Flowchart representing the literature search process.

Table 1 Association Between Genetic Polymorphism and Therapy Response

Genes	Therapy	Study Population	Ethnic	Clinical Setting	Method Used for Genotyping	Results	References
ABCB1
rs2032582 GT	FEC	991 breast cancer patients	–	Belgium	Sequenom MassARRAY	Had a significant association with better BCSS HR 0.5, 95% CI 0.3–0.9, p = 0.021	Vulsteke et al, 2014.
3435 C>T	Anthracycline-based, Anthracycline + Paclitaxel, FAC, FEC	770 patients (9 studies)	German (Caucasian), Indonesian (Asian), Korean (Asian), Indian, Slovak (Caucasian), Chinese (Asian), Chinos (Asian), Indiann, Spanish (Caucasian)		PCR-SEQ, PCR-RFLP, TAQMAN	Had no significant association with response to chemotherapy Dominant OR 0.888, 95% CI 0.558–1.413	Madrid-Paredes et al, 2017
3435 C>T	FEC/FAC	100 patients		India	PCR-RFLP	Had no significant association with better treatment response p = 0.110	Chaturvedi et al, 2013.
1236 C>T	Anthracycline-based, FAC, FEC	566 patients (6 studies)	Chinese (Asian), Chinos (Asian), Arabic, Indian, Spanish (Caucasian)		PCR-RFLP, TAQMAN	No significant association with response to chemotherapy Dominant OR: 1.968, 95% CI 0.609–6.362	Madrid-Paredes et al, 2017.
1236 C>T	FEC/FAC	100 patients		India	PCR-RFLP	Better treatment response compared with TT OR: 5.17 95% CI 1.3–20.2, p = 0.018	Chaturvedi et al, 2013.
2677 G>T/A	Anthracycline-based, Anthracycline+Paclitaxel	367 patients (3 studies)	Korean (Asian), Chinos (Asian), Indian		PCR-SEQ, PCR-RFLP	Had no significant association with response to chemotherapy OR 0.854. 95% CI 0.418–1.744	Madrid-Paredes et al, 2017.
2677 G>T/A	FEC/FAC	100 patients		India	PCR-RFLP	Had no significant association with better treatment response p = 0.421	Chaturvedi et al, 2013.
rs1045642	Cyclophosphamide, doxorubicin, TA/TAC, FAC, Gemcitabine, paclitaxel, Docetaxel, doxorubicin	684 patients (4 studies)		UK, China, Korea	Genes were extracted from 555,117 genotyped SNPs in the Affymetrix Genome-Wide Human SNP array 6.0 chip	Had a significant association with worse progression-free survival HR 1.33, 95% CI 1.07–1.64	Kim et al, 2018
BARD1
rs2070096	TCH	157 primary breast cancer patients		Ireland	Mass Spectrometry based Genotyping	Had a significant association with worse RFS p = 0.05	Coté et al, 2018
rs2229571	TCH	157 primary breast cancer patients		Ireland	Mass Spectrometry based Genotyping	Had no significant association with OS and RFS Carboplatin p = 0.04, cisplatin p = 0.02	Coté et al, 2018
BRCA1 & BRCA2
90 SNPs	Carboplatin	291 patients			SNP Type Assay	Had no significant association in overall pCR and DFS OR 3.50, 95% CI, 1.39–8.84, p = 0.008	Hahnen et al, 2017.
CD24
Ala/Val genotype	Anthracycline	257 patients		Germany	TaqMan	Had a significant association with better pCR OR 4.97, 95% CI 1.72–14.33, P = 0.003	Marmé et al, 2010.
	Taxane	257 Patients		Germany	TaqMan	Had a significant association with better pCR OR 4.97, 95% CI 1.72–14.33, P = 0.003	Marmé et al, 2010.
CYBA
rs4673 CT	FEC	991 breast cancer patients		Belgium	Sequenom MassARRAY	Had a significant association with worse RFI HR 1.8, 95% CI 1.2–2.7; p = 0.006	Vulsteke et al, 2014.
CYP19A1
rs4646	Aromatase Inhibitor	2646 patients (12 studies)	Caucasian, Asian, Black, Others	Netherlands, China, Italy, USA, UK, Korea, Spain		Had a significant association with increased TTP compared with wild type gene HR = 0.51, 95% CI = 0.33–0.78, p = 0.002	Artigalás et al, 2015
CYP2C19
CYP2C19*2	Tamoxifen	494 patients		Netherlands	Taqman Allelic Discrimination Assay	Had a significant association with better TTF HR 0.26, p = 0.001	Beelen et al, 2013.
CYP2C19*2 and *17	Tamoxifen	787 patients (6 studies)	Netherland, USA, Germany, Switzerland	Caucasians		Had a significant association with better survival of disease OR 0.46 95% CI 0.21–1.01, p = 0.233	Bai et al, 2014
CYP2C9
rs1057910	FEC	991 breast cancer patients		Belgium	Sequenom MassARRAY	Had a significant association with worse RFI HR 30.4, 95% CI 6.1–151.5, p<0.001	Vulsteke et al, 2014.
CYP2D6
CYP2D6*4	Tamoxifen	4861 postmenopausal women with hormone receptor and breast cancer without previous therapy		Worldwide	PCR-based GenomeLab SNPstream Geontyping System & 7900HT Fast Real-Time PCR System	No significant association with BCFI p = 0.35	Regan et al, 2012.
5 SNPs	Tamoxifen	731 patients	Dutch		TAQMAN, *3 with pyrosequencing	No significant association in DFS compared with extensive metabolizers Unadjusted HR 1.33, 95% CI 0.52–3.43, p = 0.55	Dezentjé et al, 2013.
12 SNPs	Tamoxifen	297 patients	Caucasian,	Belgium & Switzerland	Sequenom MassARRAY	No significant association with endoxifen concentration and ORR and PFS p = 0.56	Neven et al, 2018.
CYP2D6*10	Tamoxifen	667 patients		Belgium & Netherlands	Amplichip CYP450 Test	No significant association with endoxifen concentration and RFS HR 0.989, 95% CI 0.945–1.035, p = 0.627	Sanchez-Spitman et al, 2019.
Poor Metabolizers (two inactive alleles: *3-*8, *11-*16, *19-*21, *38, *40, *42)	Endoxifen	13,001 patients (29 studies)	NA	NA	TAQMAN, Tag-It, Amplichip, SNaPshot, BioTools Taq, BeadChip SNP, 9700 Thermal Cycler	Had a significant association with lower endoxifen concentration and/or clinical outcomes compared with extensive metabolizers Mean ± s.d endoxifen concentration 8.8±,7.2 versus 22.3±,11.8, p < 0.05	Hwang, et al, 2018.
CYP2D6*1,*10,*17,*41,*4, dan *5	Tamoxifen	5183 patients (10 studies)	Asian and Caucasians		PCR-based method, TAQMAN, PCR-RFLP	Had a significant association with increased risk of disease recurrence. HRs (95% CIs) were 1.44 (1.15–1.80) in the fixed effect model and 1.60 (1.04–2.47) in the random effect model	Jung, et al, 2014
CYP3A4
*1B*/*1A	CAF	350 patients	White, Black, Other		PyroSequencing & TAQMAN Real-Time PCR	Had a significant association with worse DFS compared with *1A/*1A’ HR 2.44, 95% CI 1.52–5.14	Gor, et al, 2010.
FCGR
FCGR2A 131H/H	Trastuzumab	76 patients			Goldgate Genotyping	Had a significant association with better PFS compared with 131R/R p = 0.034	Tamura, et al, 2011
FCGR2A 131H/H	Trastuzumab	1189 patient with HER2-positive, invasive, high-risk, node-negative or node-positive adenocarcinoma		Worldwide	Sanger sequencing and Sequenom mass spectrometry	No significant association with DFS compared with 131R/R p = 0.76	Hurvitz et al, 2012
FCGR2A 131H/H	Trastuzumab	1325 patients			TaqMan Real-Time PCR	No significant association with DFS compared with 131R/R p = 0.64	Norton et al, 2014
FCGR2A 131H/H	Trastuzumab	1251 patients		United States	iPLEX Pro Chemistry & Mass Spectrometry	Had a significant association with better DFS compared with 131R/R HR 0.31, 95% CI 0.19–0.49, P < 0.001	Gavin et al, 2017.
FCGR2A 131H/H	Trastuzumab	132 patients			Fluorogenic PCR with GeneAmp	Had a significant association with better EFS compared with 131R/R p = 0.027	Roca et al, 2013.
FCGR2B 232I/I	Trastuzumab	1325 patients			TaqMan Real-Time PCR	Had a significant association with better DFS compared with 232T/T p = 0.03	Norton et al, 2014
FCGR3A 158V/V	Trastuzumab	76 patients			Goldgate Genotyping	No significant association with PFS compared with 158F/V and 158F/F, but showed overall higher response rate p = 0.37	Tamura, et al, 2011.
FCGR3A 158V/V	Trastuzumab	1189 patient with HER2-positive, invasive, high-risk, node-negative or node-positive adenocarcinoma		Worldwide	Sanger sequencing and Sequenom mass spectrometry	No significant association with DFS compared with 158F/F p = 0.98	Hurvitz et al, 2012
FCGR3A 158V/V	Trastuzumab	1325 patients			TaqMan Real-Time PCR	No significant association with DFS compared with 158F/F p = 0.77	Norton et al, 2014
FCGR3A 158V/V	Trastuzumab (ACT Arm)	1251 patients		United States	iPLEX Pro Chemistry & Mass Spectrometry	Had a significant association with worse prognosis compared with 158 F/F HR 1.57, 95% CI 1.15–2.14, p = 0.005	Gavin et al, 2017.
FCGR3A 158V/V	Trastuzumab (ACTH Arm)	1251 patients		United States	iPLEX Pro Chemistry & Mass Spectrometry	Had a significant association with better prognosis compared with 158 F/F HR 0.68, 95% CI 0.48–0.96, p = 0.03	Gavin et al, 2017.
FCGR3A 158V/V	Trastuzumab	132 patients			Fluorogenic PCR with GeneAmp	No significant association with EFS compared with 158F/F p = 0.08	Roca et al, 2013.
FGFR4
arg388	AC-Doc	257 patients diagnosed with T2-4, N0-2, M0 breast cancer		Germany	TaqMan Genotyping Assay	Had a significant association with better pCR rate OR 3.79, p = 0.03	Marmé et al, 2010.
arg388	AP-Doc	257 patients diagnosed with T2-4, N0-2, M0 breast cancer		Germany	TaqMan Genotyping Assay	No significant association with pCR rate OR 3.18, p = 0.018	Marmé et al, 2010.
GSTP1 & GSTT1
GSTP1 c.313A>G	Doxorubicin	159 patients		Spain	TaqMan	Had an association with lower chemoresistance risk OR 0.106, CI95% 0.012–0.898, p = 0.040	Romero et al, 2012.
GSTP1 c.313A>G	Docetaxel	159 patients		Spain	TaqMan	No significant association with chemoresistance risk p = 0.016	Romero et al, 2012.
GSTP1 105Val/Val genotype	CTX	120 patients			PCR-RFLP	Had a significant association with worse DFS PR = 0.35, 95% CI = 0.13–0.78, p = 0.006	Zhang et al, 2011.
GSTP1 GG genotype	Cyclophosphamide	1332 patients		North America	MALDI-TOF	No significant association with treatment outcome p = 0.83	Yao et al, 2010.
GSTT1 null genotype	CAF	350 patients	White, Black, Other		PyroSequencing & TAQMAN Real-Time PCR	Had a significant association with better DFS and OS compared with other variant Adjusted DFS HR 1.95 p = 0.053	Gor, et al, 2010.
GSTM null genotype	Anthracycline based chemotherapy	1468 patients (11 studies)	Asians, Caucasians, Mixed	Tunisia, China, Brasil, USA, Spain, Iran, India	PCR-RFLP	Had a significant association with worse responsiveness to chemotherapy OR 0.74, CI 0.60–0.92, p = 0.006	Kong et al, 2016
HER2
−3444C>T	Trastuzumab-Lapatinib-Bevacizumab	94 metastatic breast cancer patients		United States	Sanger Sequencing	No significant association with SD≥6 months/PR/CR rate and TTF p = 0.038	Falchook et al, 2015.
−1985G>T	Trastuzumab-Lapatinib-Bevacizumab	94 metastatic breast cancer patients		United States	Sanger Sequencing	No significant association with SD≥6 months/PR/CR rate and TTF p = 0.038	Falchook et al, 2015.
1655A A>G	Trastuzumab-Lapatinib-Bevacizumab	94 metastatic breast cancer patients		United States	Sanger Sequencing	No significant association with SD≥6 months/PR/CR rate and TTF p = 0.038	Falchook et al, 2015.
P1170A C>G	Trastuzumab-Lapatinib-Bevacizumab	94 metastatic breast cancer patients		United States	Sanger Sequencing	No significant association with SD≥6 months/PR/CR rate and TTF p = 0.038	Falchook et al, 2015.
rs1810132 (STR C>T)	Trastuzumab-Lapatinib-Bevacizumab	94 metastatic breast cancer patients		United States	Sanger Sequencing	No significant association with SD≥6 months/PR/CR rate and TTF p = 0.038	Falchook et al, 2015.
HER3
rs2229046	TCH	157 primary breast cancer patients	Caucasian	Ireland	Mass spectrometry-based genotyping	Had a significant association with worse RFS p = 1.51x10^−3	Coté et al, 2018
rs77123	TCH	157 primary breast cancer patients	Caucasian	Ireland	Mass spectrometry-based genotyping	Had a significant association with worse RFS p = 0.05	Coté et al, 2018
KDR/VEGFR2
rs2071559 (A>G)	Bevacizumab	113 HER2 positive patients	Caucasian	Italia	TaqMan	No significant association with PFS p=0.03	Allegrini et al, 2014.
rs2071559	Capecitabine	70 TN breast cancer patient	Caucasian	Rusia	TaqMan	Had a significant association with better pCR rate p = 0.016	Babyshkina et al, 2018.
rs11133360 (T>C)	Bevacizumab	113 HER2 positive patients	Caucasian	Italia	TaqMan	Had a significant association with worse PFS and OS for patients carrying SNP IL-8 rs4073 p=0.73	Allegrini et al, 2014.
IL12B
rs2546892 (G > A)	Chemotherapy	499 patients	Caucasians	Eropa	iCOGS	Had a significant association with worse OS HR 1.50 95% CI 1.21–1.86, p = 1.81 × 10^−4	Lei et al, 2015
rs2853694 (A > C)	Chemotherapy	499 patients	Caucasians	Eropa	iCOGS	Had a significant association with better OS HR 0.73 95% CI 0.61–0.87, p = 3.67 × 10^−4	Lei et al, 2015
MDM2
rs2279744 (309 T>G)	Paclitaxel & Epirubicin	223 patients with primary stage III breast cancers	Caucasian	Norwegian	PCR	No significant association with RFS p= 0.012	Chrisanthar et al, 2011
MEG3
rs10132552 TT genotype	Cisplatin	144 patients			Mass Array	Had a significant association with worse DFS HR = 0.257, 95% CI 0.069–0.951, p = 0.042	Bayarmaa et al, 2019.
SLC
rs7867504 (CC and CT genotype)	Paclitaxel & Gemcitabine	324 MBC Patients	Asian	Korea	MassArray	Had a significant association with better OS HR 2.6, 95% CI 1.1–6.3, p = 0.027	Lee et al, 2014
rs747199 and rs760370 (GA haplotype)	Paclitaxel & Gemcitabine	324 MBC paients	Asian	Korea	MassArray	Had a significant association with better OS p = 0.030, HR 3.391, 95% CI 1.13–10.19	Lee et al, 2014
rs4149056	Aromatase Inhibitors	503 patients		US	PCR	Had a significant association with worse outcome OR 1.84; 95% CI 1.08–2.14; p = 0.025)	Dempsey et al, 2019.
rs10841753	Aromatase Inhibitors	503 patients		US	PCR	Had a significant association with lower risk of detectable estrone OR: 0.61, 95% CI 0.41–0.90, p = 0.013	Dempsey et al, 2019.
TGFBR2
rs1367610 (G > C)	Chemotherapy	499 patients	Caucasians	Eropa	iCOGS	Had a significant association with worse OS 95% CI 1.22–1.95, p = 3.08 × 10^−4	Lei et al, 2015
TP53
	Paclitaxel & Epirubicin	223 patients with primary stage III breast cancers	Caucasian	Norwegian	PCR	Had a significant association with worse RFS and DSS p= 0.007	Chrisanthar et al, 2011
UGT
UGT2B15*2	Tamoxifen	9799 postmenopause early stage breat cancer	Caucasian	Netherland	Taqman	May be associated with worse DFS 95% CI 0.25–0.89; p = 0.015)	Dezentjé et al, 2013.
UGT2B15*2	Tamoxifen	541 breast cancer recurrent cases	Caucasian	Denmark	Taqman Kit	Had no significant association with OR OR 1.0, 95% CI 0.70–1.5	Ahern et al, 2011
UGT2B7*2	Tamoxifen	541 breast cancer recurrent cases	Caucasian	Denmark	Taqman Kit	Had no significant association with OR OR 0.96, 95% CI 0.65–1.4	Ahern et al, 2011
UGT2B7 rs3924194	FEC	991 breast cancer patients	Caucasian	Belgium	Sequenom MassARRAY	Had an association with worse RFI HR 3.4, 95% CI 1.2–9.7, p = 0.023.	Vulsteke et al, 2014.
UGT1A8*3	Tamoxifen	541 breast cancer recurrent cases	Caucasian	Denmark	Taqman Kit	Had no significant association with OR OR = 0.95, 95% CI, 0.49–1.9	Ahern et al, 2011

Abbreviations: ACT, doxorubicin-cyclophosphamide-paclitaxel; AC-Doc, doxorubicin-cyclophosphamide-docetaxel; AP-Doc, doxorubicin-permetrexed-docetaxel; BCSS, breast cancer specific survival; BCFI, breast cancer free inteval; CMF, cyclophosphamide-metothrexate-fluorouracil; CTX, anthracycline-cyclophosphamide; DFS, disease-free survival; DSS, disease specific survival; CR, complete response; EFS, event free survival; FEC, fluorouracil-epirubicin-cyclophosphamide; OR, overall response; ORR, overall response rate; OS, overall survival; pCR, progression complete response; PFS, progression-free survival; PR, partial response; RFS, recurrence-free survival; SD, stable disease; TCH, docetaxel, cisplatin, trastuzumab; TTF, time-to-treatment failure; TTP, time to progression.

Figure 2 Influences of gene polymorphism with tamoxifen metabolism. Some of the chemoresistance mentioned in the paper are involving changes in drug metabolism and further decreased drug concentration in some individu. The decreased drug concentration may leads to suboptimal concentration needed to have therapeutic effect. CYP2C19 polymorphism may decrease CYP2C19 expression, which an enzyme that have a function in Phase I metabolism of tamoxifen needed to activate the substance into 4-hydroxy-tamoxifen and endoxifen, a more active metabolite in inhibiting estrogen-ER binding to halt tumor growth.

Notes:

Activates/transactivates/upregulates/expresses.

Inhibits/downregulates.

Converted into.

Figure 3 Possible mechanism of polymorphism influences related with MAPK and PI3K/AKT cell signaling. Drug resistance from some of the genes are resolved around MAPK and PI3K/AKT cell signaling. Polymorphisms in some genes mentioned may induce chemoresistance by disrupting the normal cell proliferation signaling and increase the aggressiveness of the tumor. The MAPK pathway are activated after Ras was phosphorylated and may induce cell proliferation, angiogenesis, and tumor growth. Ras may also activate PI3K, which further phosphorylating AKT that leads to activation of various signaling pathway leading to increase tumor growth rate. Genes that are hypothesized to disrupt these signaling are HER2, HER3, VEGFR2, and FGFR4. Polymorphism of HER2 and HER3 may increase receptor expression and this upregulation may further leads to increased MAPK/AKT signaling. In HER3 rs2229046 carrier, Src expression is increased and leads to increase MAPK/AKT signaling, and those with rs77123 had heightened concentration of GSK-3β, that may inhibit c-myc as tumor growth suppressor and is suggested as chemoresistance mechanism. In FGFR4 arg388 carrier, uPAR expression is increased and further inhibits TRAIL-induced apoptosis that leads to tumor cells resisting the induction of apoptosis.

Notes:

Indicates phosphorylation process.

Activates/transactivates/upregulates/expresses.

Inhibits/downregulates.