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.