Abstract
Tamoxifen, a selective estrogen receptor modulator, is used to treat hormone receptor‐positive breast cancer. Tamoxifen acts as a prodrug, with its primary therapeutic effect mediated by its principal metabolite, endoxifen. However, tamoxifen has complex pharmacokinetics involving several drug‐metabolizing enzymes and transporters influencing its disposition. Genes encoding enzymes involved in tamoxifen disposition exhibit genetic polymorphisms which vary widely across world populations. This review highlights the lack of data on tamoxifen pharmacogenetics among African populations. Gaps in data are described in this study with the purpose that future research can address this dearth of research on the pharmacogenetics of tamoxifen among African breast cancer patients. Initiatives such as the African Pharmacogenomics Network (APN) are crucial in promoting comprehensive pharmacogenetics studies to pinpoint important variants in pharmacogenes that could be used to reduce toxicity and improve efficacy.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
The current Clinical Pharmacogenetics Implementation Consortium
(CPIC) guidelines for utilizing CYP2D6 genotype testing to guide tamoxifen treatment predominantly rely on data derived from European and Asian populations.
WHAT QUESTION DID THIS STUDY ADDRESS?
Does pharmacogenetics play a role in tamoxifen treatment outcomes in Africans?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The findings reveal that there is lack of inclusion of African populations in pharmacogenomics research, particular that of tamoxifen and breast cancer.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The lack of African studies in available datasets implies that the dosing guidelines approved based on European data are likely to be inappropriate in African populations due to differences in important pharmacogenetic variants.
INTRODUCTION
The burden of breast cancer is a global phenomenon. As of 2020, breast cancer is the most frequently diagnosed cancer and the top cause of cancer‐related deaths in women worldwide. 1 Breast cancer also dominates among African women and accounts for nearly 30% of all new cancer diagnoses. Despite a lower incidence compared with other regions, Africa reports one of the highest breast cancer mortality rates globally. 1 Hence, the development of improved breast cancer surveillance programs and treatment strategies are warranted for African populations.
Estrogen receptor‐positive (ER+) breast cancer, which constitutes the majority of breast cancer cases in Africa, 2 is traditionally treated with tamoxifen. In Africa, the use of tamoxifen to treat breast cancer ranges from 38% in Uganda to 93% in Cameroon. 3 As the only hormonal agent approved by the United States Food and Drug Administration to treat ER+ breast cancer in pre‐menopausal women, tamoxifen is one of the most important medications used to treat the growing number of young women being diagnosed with breast cancer. 4 Patient responses to tamoxifen, however, exhibit variability, largely due to an interplay of environmental and genetic factors. Genetic causes of patient variability in tamoxifen treatment response are largely due to pharmacogenetics.
The impact of genetic variation in pharmacogenes involved in the metabolism of tamoxifen on treatment response has been studied extensively. Nevertheless, the influence of genotype, particularly that of cytochrome P450 2D6 (CYP2D6), on tamoxifen clinical outcomes, remains a highly controversial and disputed topic. Despite the ongoing debate, the Clinical Pharmacogenetics Implementation Consortium (CPIC) issued guidelines for utilizing CYP2D6 genotype testing to direct tamoxifen treatment. 5 , 6 However, these guidelines primarily rely on research conducted in individuals of European or Asian ancestry.
The CPIC guidelines underwent a recent re‐evaluation, which involved adjusting the activity value of the CYP2D6*10 allele from 0.5 to 0.25, aligning it more accurately with the allele's true activity level. 6 This adjustment has improved the accuracy of predicting tamoxifen metabolism by CYP2D6, a development of particular significance for Asian populations where the CYP2D6*10 allele is most prevalent. 7 A review by van der Lee et al. 8 revealed that the CYP2D6*17 allele, which is mainly present in African populations, exhibits in vitro activity levels comparable to that of the CYP2D6*10 allele. The review also raised the prospect of a substrate‐specific effect associated with this allele. 8 In accordance with these findings, an activity score of 0.34 for the CYP2D6*17 allele in relation to tamoxifen metabolism has recently been reported. 9 Yet, an activity score of 0.5 is assigned to the CYP2D6*17 allele in current CPIC guidelines. 6 To refine the precision of tamoxifen treatment for African patients, it is evident that a comprehensive re‐evaluation of the guidelines is warranted, accompanied by the incorporation of more extensive data from African populations. However, a comprehensive review assessing the extent to which pharmacogenetics influences tamoxifen treatment outcomes in African patients is currently unavailable.
This review, therefore, aims to gather all available tamoxifen pharmacogenetics data on Africans and populations of African ancestry to determine whether pharmacogenetics influences tamoxifen response among these patients.
METHODS
Search strategy
Following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, 10 a methodical search of four databases – PubMed, EBSCOhost, MEDLINE, and Scopus – was conducted to identify studies published from 1960 up to 24 March 2023 for possible inclusion in the review. Combinations of MeSH terms and keywords were used to carry out the following search strategy: “breast cancer” AND “tamoxifen” AND “outcome” AND “pharmacogene.” The full search strategy employed for each database is presented in Tables S1 and S2. Searches were limited to human studies with female participants. Additionally, language restrictions were applied so that searches returned only English‐language publications. Reference lists of previously published reviews were also manually screened to identify additional articles.
Eligibility criteria
The following PICOS (Population, Intervention, Comparison, Outcomes, Study design) criteria were checked for inclusion of articles identified in the database and manual searches:
Population: African women or women of African descent, including the African diaspora, treated for breast cancer.
Intervention: Tamoxifen treatment alone.
Comparison: Single nucleotide polymorphisms (SNPs) and/or genotypes of pharmacogenes affecting tamoxifen pharmacokinetics and pharmacodynamics.
Outcome: The influence of the above comparators on tamoxifen response with respect to patient survival or tamoxifen‐associated adverse effects.
Study design: All qualitative or quantitative research designs that contain original data.
Selection process, quality assessment, and data collection
Database searches and retrieval of titles were performed by two reviewers (B.K. and D.S.). Following the removal of duplicates, titles were independently screened for inclusion by these two reviewers. Subsequently, using the aforementioned eligibility criteria, one author (B.K.) examined the abstracts of the remaining records. In cases where the abstracts did not provide information on the ethnic backgrounds of the study populations, full texts were examined for keywords such as “African”, “Afro”, and “Black.” Studies that did not state the race of research participants but otherwise satisfied all other inclusion criteria were initially accepted for inclusion until the race of participants could be confirmed. Authors of such papers were contacted in an attempt to elucidate the race of their study participants. Studies not including any African individuals or individuals with African ancestry were subsequently excluded. The eligibility of the remaining records was confirmed by two other review authors (D.S. and C.D.) and any differences among the authors were settled during a consensus meeting prior to data extraction.
To evaluate study risk and reporting bias, four reviewers (B.K., D.S., N.D.S., and C.D.) independently appraised the selected full manuscripts using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and Strengthening the Reporting of Pharmacogenetic Studies (STROPS) checklists. 11 , 12 The quality of each study was evaluated using 25 items from these checklists and results relevant to the review were compiled into a data extraction sheet (Table 1). Studies were assessed according to each item reported, and the number of completed items served as a measure for the study's overall reporting quality. Results were compared, and a consensus was reached among all authors. Data from the eligible studies were subsequently collected and summarized by one author (B.K.) and verified by another (N.D.S.).
TABLE 1.
Data extraction and critical appraisal of studies included in the systematic review.
| Abraham et al. 27 | Damkier et al. 19 | De Ameida Melo et al. 28 | Goetz et al. 29 | Goetz et al. 20 | Henry et al. 30 | Hertz et al. 21 | Martins et al. 22 | Moyer et al. 23 | Nowell et al. 24 | Nowell et al. 25 | Regan et al. 31 | Saladores et al. 32 | Schroth et al. 33 | Tucker et al. 26 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rationale reported | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Reasons for genotyping selected SNPs provided | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Objectives stated | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Study design reported | Y | Y | Y | N | N | Y | Y | Y | Y | Y | Y | N | Y | Y | Y |
| Study setting reported | Y | N | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Participant eligibility criteria reported | Y | Y | Y | Y | Y | N | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Participant drug regime reported | Y | Y | Y | Y* | Y* | Y | Y | N | Y* | N | N | Y | Y | Y* | Y |
| Patient cohort overlap | N | Y | N | Y | Y | N | N | N | Y | Y | Y | N | N | Y | N |
| Variables and outcomes defined | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Genetic variants genotyped clearly defined | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Data sources reported | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Laboratory methods described | Y | N/A | Y | Y | N | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Sources of bias addressed | N | Y | N | N | N | N | Y | N | N | N | N | Y | Y | N | N |
| Adherence to treatment assessed | N | N | Y | Y* | Y* | N | N | N | Y* | N | N | N | Y | Y* | N |
| Study size explained | Y* | N | N | N | N | N | N | N | Y | N | N | N | Y | Y | Y |
| Statistical methods described | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Confounders and HWE considered | Y | Y | N | Partial | N | N | N | N | Y | Partial | Partial | Partial | Y | Partial | Y |
| Numbers of participants at each study stage reported | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Participant characteristics reported | Y | Y | Y | Y | Y | Y* | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| SNPs excluded from analyses reported | Y | Y | N/A | Y | N/A | N/A | Y | Y | N/A | N/A | Y | N/A | N | N/A | N/A |
| Study outcome data reported | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Main results reported | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Key results and generalizability of study discussed | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
| Limitations of study reported | Y | Y | Y | Y | N | Y | Y | Y | Y | Y | Y | Y | Y | Y | N |
| Interpretation of results provided | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y | Y |
Abbreviations: HWE, Hardy–Weinberg equilibrium; N, no; N/A, not applicable; SNPs, single nucleotide polymorphisms; Y, yes.
Reader is referred to another article or supplementary materials for information (information reported elsewhere).
Data analysis
Authors were contacted to request genotype and tamoxifen response data specifically for participants of African descent only. Due to the scarcity of studies that met the inclusion criteria and the limited raw data available on the subject, a meta‐analysis could not be carried out. Accordingly, we performed a comprehensive narrative review of the influence of genetic variation in pharmacogenes affecting tamoxifen metabolism on treatment response (survival outcomes and side effects) in African individuals or individuals of African descent.
RESULTS
Study selection
Figure 1 illustrates the retrieval process of studies included in the review. After removing studies that did not meet the inclusion criteria, 20 studies remained, with only eight explicitly mentioning the inclusion of Africans or women of African descent. To ensure that the remaining 12 studies met this criterion, the authors of these studies were contacted to confirm the racial backgrounds of their study participants (Table S3). Four authors confirmed the absence of African women in their studies, leading to the subsequent exclusion of said studies. 13 , 14 , 15 , 16 One study from the United States (US) matched participants who had experienced a disease recurrence to disease‐free patients by race. 17 However, no specific racial information was provided within the study, and the authors were unresponsive when contacted for clarification. As a result, it was decided that the study should be excluded from the review. 17 Another study was conducted in an Algerian population; however, since the majority of the study population was classified as “White”, this study was also excluded. 18 This left a total of 15 studies that qualified for final inclusion in the review. 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 Among them, the proportion of participants of African descent reported remained unknown for seven studies.
FIGURE 1.
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) diagram of the selection process of studies included in the review.
Data extraction and quality assessment
The evaluation of the reporting quality for each study included in the review is presented in Table 1. Of the 25 items that were assessed, none of the individual studies fulfilled all the criteria. All the studies did, however, address certain key aspects in their reporting. These include providing a rationale for the study, specifying the reasons for genotyping selected SNPs, and clearly stating the objectives, variables, and outcomes under investigation. Additionally, all the studies ensured that genetic variants were clearly defined, data sources were disclosed, statistical methods employed were specified, and the number of participants at each stage of the study was reported. Each study also presented their outcomes and main results along with a comprehensive interpretation of the results. It is worth noting that the majority of studies overlooked several key aspects. These included neglecting to address potential sources of bias, insufficient clarity regarding their chosen study sizes, disregard for Hardy–Weinburg equilibrium (HWE) testing, and no consideration for confounders.
Study characteristics
Table 2 summarizes key characteristics of the studies included in this review. The inclusion of participants of African descent was specified in eight studies. The studies included were published between 2002 and 2017, with six of the studies being retrospective cohort studies. The studies were conducted in various countries, including the United States of America (USA, n = 9), United Kingdom (UK, n = 2), Brazil (n = 2), Germany (n = 1), and none from African countries. Various statistical methods were utilized, with the most common ones being log‐rank test (n = 9), Kaplan–Meier (n = 9), and Cox regression (n = 10). A wide range of outcomes were assessed, including overall survival (OS) and disease‐free survival (DFS), each analyzed in six studies. Twelve studies provided data on CYP2D6 genetic variants, while one study reported on CYP2C9 variants. CYP2C19, CYP3A5, and SULT1A1 variants were examined in three studies each. Furthermore, one study reported on UGT2B15 variants. Seven studies revealed a significant association between the investigated variants and measured outcomes, while a total of five studies performed analyses stratified by race.
TABLE 2.
Characteristics of studies included in the systematic review.
| Study (year) | Study design | Study population | Sample size | Proportion of African descent | Statistical methods | Outcomes measured | Variants studied | Findings | Analysis stratified by race |
|---|---|---|---|---|---|---|---|---|---|
| Known inclusion of participants with African descent | |||||||||
| Damkier et al. (2017) 19 | Prospective cohort | International (ITPC) | 2102 | 0.5% | Cox regression | DFS | CYP2C19*2, *17 | No significant association | Yes |
| Goetz et al. (2007) 20 | Not reported |
USA (NCCTG Trial) |
180 | 1% | Log‐rank test, Kaplan–Meier, Cox regression | TTBR, RFS, DFS, OS | CYP2D6*4 | Decreased CYP2D6 activity significantly associated with poorer TTBR, RFS, and DFS | No |
| Hertz et al. (2016) 21 | Prospective cohort | USA | 480 | 15.4% | Linear regression, paired t‐test | FACT‐B scale, BCPT‐MSS | AmpliChip® CYP450 Test, Roche a | No significant association | No |
| Martins et al. (2014) 22 | Retrospective cohort | Brazil | 58 | 22.4% Black, 46.6% Mulatto | Log‐rank test, Kaplan–Meier, odds ratio | DFS | CYP2D6*3, *4, *10 | No significant association | No |
| Moyer et al. (2011) 23 | Retrospective cohort |
USA (NCCTG Trial) |
190 | 1.6% | Log‐rank test, Wilcoxon tests, Cox regression | DFS | SULT1A1 CNV; CYP2C19*17; (CYP2D6*3, *4, *6, *10, *17, *41) b | No significant association | No |
| Nowell et al. (2002) 24 | Retrospective cohort | USA | 337 (160 tamoxifen; 177 no tamoxifen) | 18.4% | Log‐rank test, Kaplan–Meier, Cox regression | OS | SULT1A1*2 | SULT1A1*2/*2 significantly associated with poorer OS | Yes |
| Nowell et al. (2005) 25 | Retrospective cohort | USA | 337 (162 tamoxifen; 175 no tamoxifen) | 19% | Log‐rank test, Kaplan–Meier, Cox regression | OS, PFS | CYP2D6*3, *4, *6; UGT2B15*2; (SULT1A1*2) c | Survival significantly decreased with increasing number of variant alleles when considering SULT1A1*2 and UGT2B15*2 together | Yes |
| Tucker et al. (2005) 26 | Cross‐sectional | USA | 98 | 49% | Linear regression | Tamoxifen side effects | CYP3A5*3, *6 | No significant association | No |
| Unknown inclusion of participants with African descent | |||||||||
| Abraham et al. (2010) 27 | Case–cohort | UK | 6640 (3155 cases; 3485 controls) | Unspecified (98.8% White) | Cox regression | BCSS, OS | CYP2D6*4, *5, *6b/*6c, *9, *10, *41, duplication | No significant association | No |
| De Ameida Melo et al. (2016) 28 | Case–control | Brazil | 80 (40 cases; 40 controls) | Unspecified | Fisher exact test | Distant recurrence | CYP2D6*4, *10, *17 | No significant association | No |
| Goetz et al. (2005) 29 | Not reported | USA (NCCTG Trial) | 256 | Unspecified (~92% White) | Log‐rank test, Kaplan–Meier, Cox regression, Wilcoxon rank sum test, Fisher exact test | RT, DFS, OS, incidence of hot flashes | CYP2D6*4, *6; CYP3A5*3 | Women with CYP2D6*4/*4 genotype tended to have worse RT and DFS, and fewer moderate/severe hot flashes | No |
| Henry et al. (2009) 30 | Prospective cohort | USA | 297 | Unspecified (92.6% White) | Linear regression, Fisher exact test, log‐rank test, Kaplan–Meier | Hot flash score | AmpliChip® CYP450 Test, Roche a ; xTAG CYP2D6 Assay, Luminex | IM had a significantly higher hot flash score than EM and PM | No |
| Regan et al. (2012) 31 | Not reported | International (BIG 1–89 trial) | 2537 (1243 tamoxifen; 1294 no tamoxifen) | Unspecified (98% White) | Kaplan–Meier, Cox regression | BCFI, time to onset of hot flushes or night sweats | CYP2D6*2, *3, *4, *5, *6, *7, *10, *17, *41 | PM and IM had a significantly higher risk of tamoxifen‐induced hot flashes than EM (among patients without previous chemotherapy) | Yes |
| Saladores et al. (2015) 32 | Retrospective cohort | UK | 306 | Unspecified | Log‐rank test, Kaplan–Meier, Cox regression | DRFS | CYP2D6*3, *4, *5, *6, *9, *10, *41, gene duplication; (CYP2C9*2, *3; CYP2C19*2, *3, *17; CYP3A5*3) d | No significant association | Yes |
| Schroth et al. (2009) 33 | Retrospective cohort | Germany, USA (NCCTG Trial) | 1325 | Unspecified (~92% White in USA cohort) | Log‐rank test, Kaplan–Meier, Cox regression | Time to recurrence, event‐free survival, DFS, OS | CYP2D6*3, *4, *5, *10, *41, gene duplication | PM and heterozygous EM/IM had significantly worse event‐free survival and DFS than EM | No |
Note: Studies in bold type explicitly specified the percentage of participants of African descent included in their study population.
Abbreviations: BCFI, breast cancer‐free interval; BCPT‐MSS, Breast Cancer Prevention Trial Menopausal Symptom Scale; BCSS, breast cancer‐specific survival; BIG, Breast International Group; CNV, copy number variation; DFS, disease‐free survival; DRFS, distant relapse‐free survival; EM, extensive metabolizers; FACT‐B, Functional Assessment of Cancer Therapy‐Breast; IM, intermediate metabolizers; ITPC, International Tamoxifen Pharmacogenomics Consortium; NCCTG, North Central Cancer Treatment Group; OS, overall survival; PFS, progression‐free survival; PM, poor metabolizers; RFS, recurrence/relapse‐free survival; RT, relapse‐free time; TTBR, time to breast cancer recurrence; UK, United Kingdom; USA, United States of America.
CYP2D6 polymorphisms detected: *1, *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *14A/14B, *15, *17, *18, *19, *20, *25, *26, *29, *30, *31, *35, *36, *40, *41, *1xN, *2xN, *4xN, *6xN, *10xN, *17xN, *29xN, *35xN, *41xN.
Genotyped in study by Goetz et al. (2007) 20 but also included in a sub‐set of the association analysis of selected study.
Genotyped in study by Nowell et al. (2002) 24 but also included in association analysis of selected study.
Not included in association analysis.
Constraints on accessing data from individual studies
Raw data from only one study was shared by its authors. 26 As for the raw data of five other studies, 19 , 20 , 23 , 29 , 33 we were directed to access the online dataset provided by the International Tamoxifen Pharmacogenomics Consortium (ITPC). Four of these studies shared a common patient database, as specified by a coauthor involved in each of the studies. 20 , 23 , 29 , 33 Minor modifications or additions were incorporated into the database for each study. The original patient database first used by Goetz et al. (2005) 29 was supplemented at a later stage by adding information about concomitant use of CYP2D6 inhibitors. 20 The same database was utilized by Moyer et al. 23 ; however, with investigation of additional genes. Finally, the entire study cohort was genotyped again by Schroth et al. 33 using non‐tumor DNA to reduce genotyping errors identified in the initial laboratory testing. Considering the high degree of variation among the included studies regarding study design, genetic variants investigated, and outcomes assessed (Table 2 and Table S4), as well as the limited availability of data for participants of African descent, a meta‐analysis could not be conducted. Thus, this review focuses on a descriptive analysis.
Genetic variation in pharmacogenes and tamoxifen response among individuals of African descent
Survival outcomes
CYP2D6
Nine studies examined the impact of genetic variation in CYP2D6 on patient survival outcomes. Within this set of studies, three shared a patient database, and all reported that individuals with poor CYP2D6 metabolism experienced significantly worse survival outcomes compared with those with normal metabolism. 20 , 29 , 33 Researchers in these studies aimed to genetically characterize patients participating in the North Central Cancer Treatment Group (NCCTG) 89‐30‐52 tamoxifen trial and relate their findings to tamoxifen clinical outcomes. The first of these studies found that CYP2D6*6 was absent from the cohort, and all patients homozygous for the reduced function allele (CYP2D6*4) were “White.” 29 Approximately 92% of the study participants were characterized as “White” in this study, while the ethnic background of the remaining participants was not provided. The results indicated significantly reduced benefits from tamoxifen therapy in individuals with diminished CYP2D6 activity; however, analysis did not adjust for race. 29 Building upon this investigation, another study by Goetz and colleagues 20 considered the concomitant use of CYP2D6 inhibitors together with CYP2D6 genotype on the same cohort and, once again, showed that poor metabolizers had significantly poorer therapeutic benefit and were nearly three times more likely to experience disease recurrence compared with extensive (normal) metabolizers. 20 This study population consisted of less than 2% “Afro‐American” participants and race was not taken into consideration during data analysis. 20 Schroth et al. 33 utilized the same patient database as the abovementioned studies, with the distinction that the entire cohort was genotyped again using non‐tumor DNA and included patients from a German breast cancer cohort. Comparable to the previous findings, poor metabolizers reportedly faced double the risk of breast cancer recurrence compared with extensive metabolizers. Similar to the earlier studies, this analysis was performed using pooled data without making adjustments for race. 33 Of note, none of the three studies investigated potential sources of bias, provided insights into their criteria for determining the sample size, or conducted a power calculation. 20 , 29 , 33
Six studies did not find any association between CYP2D6 and tamoxifen clinical outcomes. 22 , 25 , 27 , 28 , 31 , 32 In the study carried out by Nowell and colleagues, 25 the study population comprised nearly 20% “African American” participants. The frequency of CYP2D6*3 and CYP2D6*6 were rare, prompting the focus on CYP2D6*4 for the association analysis. After controlling for various confounders, including race, no significant associations between CYP2D6*4 and overall survival (OS) or progression‐free survival were observed. Similar to previous studies, potential sources of bias were not addressed, and sample size or power calculations were omitted. The study also did not test for HWE. 25
In Abraham et al.'s study, 27 98.8% of this cohort from the UK were classified as “Caucasian,” with the ethnic background of the remaining participants not disclosed. Analysis (not stratified by race) revealed no significant association between CYP2D6 genotype or metabolizer status and survival outcomes, regardless of tamoxifen treatment. 27 Saladores and colleagues 32 observed that individuals classified as CYP2D6 poor metabolizers had significantly poorer clinical outcomes than compared with extensive metabolizers. However, upon adjusting for covariates, the initial association became non‐significant. This study involved participants from three ethnic groups, but analysis was ultimately limited to the UK group from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer. Initially, this group comprised 345 participants, with 4% classified as “African.” However, due to the restriction of analysis to only 306 individuals, the exact proportion of Africans within this subset remains unknown (unable to communicate with the study authors). Despite this, these authors' analysis was stratified by race. 32
In a study by De Ameida Melo et al., 28 a cohort from Northeast Brazil was used, which may have included participants of African descent due to the region's “high level of ethnic miscegenation with a predominance of Afro‐Brazilians.” The CYP2D6*17 allele, mostly found among Africans, was present in 10% (8 individuals) of the participants. However, no significant difference in the distribution of any of the analyzed alleles or metabolizer status was reported between patients with and without breast cancer recurrence (no adjustments made for race). 28 Another study conducted in a Brazilian group included “Black” and “Mullato” breast cancer patients. 22 All “Black” participants were classified as extensive metabolizers, whereas almost 26% of “Mullato” participants were predicted to have reduced CYP2D6 enzymatic activity. Nonetheless, this study found no significant association between CYP2D6*3, CYP2D6*4, or CYP2D6*10 and disease‐free survival (DFS). The analysis conducted in this study did not incorporate adjustments for race or any other potential confounding factors. The study also failed to address sources of bias, omitted testing for HWE, and did not provide an explanation for the authors’ chosen study size. 22 Another study involving participants from an international trial found no relationship between CYP2D6 phenotype and breast cancer recurrence. 31 It is noteworthy that the study population comprised 98% “White” participants, and interestingly, the African‐specific CYP2D6*17 allele was not detected in this cohort. Adjustments were made for race during analysis, distinguishing between “White” and “All other”, but further clarification on the specific racial groups encompassed within the “All other” category was not provided. 31
Raw data for participants of African descent were available from the online ITPC dataset (http://www.pharmgkb.org). Of 4973 individuals included in this dataset, only 56 individuals were classified as “Black or African American,” representing the entirety of individuals of African descent. With the exception of one participant, CYP2D6*4 was successfully genotyped in all individuals. Among them, 13 women carried one copy of the variant allele, while no homozygotes for the variant allele were identified. Genetic data for CYP2D6*10, CYP2D6*17, and CYP2D6*41 were available for 14 patients. Two individuals were heterozygous, and one was homozygous for the CYP2D6*10 allele. Additionally, two women were identified as heterozygous for CYP2D6*17, while only one woman carried the CYP2D6*41 allele. Based on the genotype results, a total of 38 women were classified as extensive metabolizers, while 17 were classified as intermediate metabolizers. Fourteen women experienced a disease recurrence, with one case being non‐invasive. Of these 14 patients, three were classified as intermediate metabolizers, while the remaining 11 were classified as extensive metabolizers. A further three patients, all of whom were extensive metabolizers, passed away without developing a recurrence.
Other cytochrome P450 enzymes
In the study by Goetz et al., 29 where the ethnic background of approximately 8% of the participants was unspecified, CYP3A5*3 did not have any impact on patient survival outcomes. CYP2C19*17 genotype showed no association with DFS in a study that also utilized participants from the NCCTG study. 23 The study included only three “African American” participants, and neither survival outcomes nor the distribution of the CYP2C19*17 allele were specified for these individuals. 23 Neither of these studies adjusted for race during analysis. 23 , 29 Of the 2102 participants from the ITPC dataset included in Damkier et al.'s study, 19 genetic data for CYP2C19*2 and CYP2D6*17 were obtained for 2055 and 1253 individuals, respectively. Among the 11 “African American” participants included in the study, only one individual could not be genotyped for CYP2C19*17. CYP2C19*2 was genotyped successfully in all 11 participants. Four individuals were found to be heterozygous for each of the two variants in question. None of the “African American” participants experienced a breast cancer recurrence. During their analysis, race was considered as a covariate; however, it was limited to the “Caucasian” and “Asian” ethnic groups and was only done for CYP2C19*2. 19
Phase II pharmacogenes
The impact of sulfotransferase 1A1 (SULT1A1), the primary tamoxifen phase II metabolizing enzyme, on tamoxifen efficacy garnered attention in a few studies. SULT1A1 copy number showed no association with survival outcomes in a study that involved nearly 2% of “African Americans.” 23 The distribution of SULT1A1 gene copies was not separated by race; instead, it was pooled across all racial groups. Similarly, data analysis was conducted on pooled data rather than stratifying it based on race. 23 In another study, patients treated with tamoxifen who were homozygous for SULT1A1*2 showed significantly worse overall survival (OS), facing a threefold higher risk of death compared with those carrying the wildtype allele. 24 This association was not seen in patients not undergoing tamoxifen treatment. Among the 62 “African American” women included in the study, approximately 10% were homozygous for the SULT1A1*2 allele, while 46% carried one copy of this variant. Notably, the analysis did adjust for race. 24 In another study building on the previous one, no significant associations were found between UDP‐glucuronosyltransferase 2B15 (UGT2B15) genotypes and OS, even after adjusting for race. 25 When the SULT1A1 data from earlier analysis was considered together with the current UGT2B15 genetic data, a significant association with OS emerged. The survival rate decreased as the number of variant alleles increased. This association was observed only in the tamoxifen‐treated group. 25 Neither of these studies reported the calculations performed to obtain the study sample size, nor did they make any efforts to mitigate potential sources of bias. 24 , 25
Tamoxifen side effects
CYP2D6
The study carried out by Hertz et al. 21 aimed to assess the potential impact of dose escalation on tamoxifen toxicity or quality of life. Participants, of which 15.4% identified as “Black,” were grouped into different CYP2D6 phenotypes based on their CYP2D6 genetic data. Those classified as poor or intermediate metabolizers had their tamoxifen dose doubled to 40 mg/day, while extensive and ultra‐rapid metabolizers continued with the standard 20 mg/day treatment. To compare the results, quality of life data were collected before and after dose escalation. The findings revealed no clinically significant increases in treatment‐related toxicity or decreases in quality of life resulting from tamoxifen dose escalation. Consequently, no associations were observed between CYP2D6 phenotype and toxicity (analysis did not adjust for race or any other potential confounders). 21 In the study performed by Goetz et al., 29 there was a trend towards lower incidence of hot flashes among patients who were homozygous for the CYP2D6*4 allele, although the results did not reach statistical significance. This allele was observed at a frequency of 17% within the study population. However, it is important to note that the ethnic background of 8% of the population was not specified in this study, and therefore the inclusion of participants of African descent remains unknown. This study also failed to account for race during their analysis. 29
Two studies identified significant associations between CYP2D6 and tamoxifen‐induced hot flashes. 30 , 31 These studies did not provide information on the proportion of participants of African descent, as they solely reported on the proportion of “White” or “Caucasian” participants. Additionally, in both studies, there was no mention of the methodology behind their choice of study sizes, and they also omitted testing for HWE. The study by Henry et al. 30 revealed that intermediate metabolizers had a significantly higher hot flash score compared with extensive and poor metabolizers after 4 months of tamoxifen treatment. Conversely, Regan et al. 31 found that poor metabolizers and intermediate metabolizers had a significantly higher likelihood of experiencing hot flashes than extensive metabolizers. As mentioned previously, Regan et al. 31 did make adjustments for race during analysis, and Henry et al. 30 did not.
Other cytochrome P450 enzymes
Two research groups examined the role of CYP3A5 in tamoxifen side effects. Tucker and colleagues 26 investigated the effect of CYP3A5*3 and CYP3A5*6 on various tamoxifen side effects, including hot flashes, vaginal dryness, and depression. Meanwhile, Goetz et al. 29 focused solely on the influence of CYP3A5*3 on hot flash severity. Both studies found no significant association between CYP3A5 genetic variations and tamoxifen side effects. Tucker et al. 26 included a mixed cohort of which 49% of participants identified as “African American.” Among these patients, the frequency of the CYP3A5*3 allele was 0.22, while the CYP3A5*6 allele was present at a frequency of 0.13. The reported side effects were not specifically categorized by race but were rather combined as a whole, resulting in an absence of information regarding the number of “African Americans” experiencing each specific side effect of interest. This study also did not acknowledge any sources of bias or recognize the limitations in their study. 26 The proportion of individuals with African ancestry was not specified by Goetz et al., 29 and genotype and side effect results were pooled for all participants. Neither of the studies adjusted for race during their analysis. 26 , 29
Raw data specifically for participants of African descent was only provided for one study. 26 Among these “African American” patients, one individual was identified as homozygous for the CYP3A5*3 allele, while 18 patients carried one copy of this variant allele. The remaining patients were homozygous for the wildtype allele, except for two participants whose genotyping was unsuccessful. Regarding CYP3A5*3, three women were homozygous for the variant allele, and six women were heterozygous. Thirty‐nine participants carried two copies of the wildtype allele. Most women in the study reported experiencing tamoxifen side effects (~75%). The most frequently experienced observed side effects were hot flashes (~92%), irritability (~38%), and depression (~35%). Nausea was the least common side effect, reported by almost 19% of participants. Interestingly, all three patients who did not experience hot flashes were homozygous for the CYP3A5*3 allele. No notable differences in the distribution of genotypes for either CYP3A5*3 or CYP3A5*6 were observed among any of the side effects reported. It was reported that 73% of the women who experienced vaginal dryness carried at least one copy of the CYP3A5*3 allele compared with 30% among those who did not experience vaginal dryness. 26
DISCUSSION
Genetic diversity is notably higher among African populations compared with others, and this diversity extends to genes coding for enzymes that are important in pharmacogenetics/pharmacogenomics. 34 Tamoxifen is primarily metabolized via cytochrome P450 (CYP) enzymes to produce its active metabolite, endoxifen, which is responsible for the drug's pharmacological activity. 35 Genetic variation in genes coding most of these CYPs potentially influences not only tamoxifen clinical outcomes but also increases the likelihood of adverse events among African patients. This concern is particularly pronounced in Africa, since the standard prescription dose of 20 mg/day of tamoxifen, established through trials conducted in Western populations, 36 , 37 , 38 is being used in Africa without sufficient trials demonstrating its effectiveness in African populations. Thus, the genetic diversity among Africans, coupled with the high breast cancer mortality rates on the continent, 1 emphasizes the need for optimizing tamoxifen treatment strategies among African patients.
The influence of pharmacogenetics on tamoxifen response has been extensively reviewed, yielding multitudes of conflicting conclusions. Notably, most reviews have primarily centred around studies conducted among populations of European or Asian ancestry, while only a single review has addressed the pharmacogenetics of tamoxifen in Africans, but these researchers focused only on sub‐Saharan African women. 39 Consequently, this gap in research highlights a significant limitation in our understanding of tamoxifen response among African populations. The present review, which evaluates the role of pharmacogenetics in influencing tamoxifen response among African patients or patients of African ancestry, cannot draw any conclusions that genetics contributes to tamoxifen treatment response among Africans. Several factors influenced the current observation and included limited available data and study heterogeneity.
The paucity of data on populations of African descent is attributed to a lack of studies on these populations. From over 100 studies that have investigated the interplay between genetic variations and tamoxifen response, a mere eight of these studies specified the inclusion of individuals of African ancestry (Table 2). Additionally, within this limited subset of studies, the representation of African patients remained modest, as the majority of studies, bar two, included less than 20% of individuals of African ancestry within their study cohorts. The study with the largest inclusion of individuals of African ancestry comprised approximately 74 individuals. 21 As highlighted by Ross et al., 40 pharmacogenetics studies must be sufficiently powered to detect effects of both common and rare variants with small to large effect sizes. Additionally, most studies neglected to address certain aspects that impact the overall quality of the research. These omissions include, but are not limited to, the examination of potential sources of bias and the provision of study size justification. These gaps contribute to the dearth of comprehensive data available for populations of African descent.
Due to the limited representation of individuals of African ancestry in these studies, a large proportion of the studies focused on investigating genetic variants that are more prevalent among European or Asian populations. As a result, very few studies have investigated genetic variants that are specific to African populations, even among the few Africans included in existing studies, and their potential implications for tamoxifen clinical outcomes. One example is the African‐specific CYP2D6 allele, CYP2D6*17, which is associated with reduced enzyme activity. 41 Recently, it has been reported that individuals homozygous for CYP2D6*17 allele exhibit a significant reduction in endoxifen formation and are, therefore, more likely not to benefit from tamoxifen treatment. 9 Five studies under review conducted genotyping for CYP2D6*17. 21 , 23 , 28 , 30 , 31 This allele was either absent from the study cohort or the distribution of the allele among participants of African ancestry remained inconclusive. This lack of clarity, often associated with a lack of racial stratification in the analyses, makes it challenging to draw generalized conclusions about the impact of CYP2D6, including CYP2D6*17, on tamoxifen response among African populations.
The omission of race as a potential confounder during analyses is an issue in this review. Consequently, any outcome concerning the impact of pharmacogenetics on tamoxifen response were derived from pooled data including multiple ethnic groups. This point may be particularly valid for the seven studies where the ethnic background of a proportion of the participants was neither specified nor verified by the authors (Table 2). All but one study was primarily composed of participants of European ancestry. 22 Thus, in studies that failed to stratify their analyses according to race, any potential associations that might be unique to individuals of African ancestry could be masked by the larger European population group dominance. It is worth noting that two studies that did adjust for race during analysis reported a significant association between SULT1A1 genotype and overall patient survival. 24 , 25 As such, these two studies shed light on a potential involvement of SULT1A1 in variable patient response to tamoxifen within African populations. These findings, while suggestive, are grounded in a rather limited dataset. Thus, further research within African populations is needed to discern the true impact of SULT1A1 on tamoxifen response.
The present analysis has several limitations which include considerable heterogeneity across studies, characterized by variations in design, genetic variants investigated, outcomes examined, as well as the statistical methods employed, which then created a significant challenge in terms of data aggregation for meta‐analysis. Consequently, the final analysis became a descriptive analysis of the studies, aiming to provide insights within these constraints. Moreover, our efforts were impeded by limited raw data availability that could have contributed to our analysis. Additionally, the inclusion of solely English‐language publications might have led to selection bias.
Future research
Considering the current scarcity of studies addressing the subject, a substantial need exists for additional research focusing specifically on the pharmacogenetics of tamoxifen among African populations. Future studies should make a conscious effort to investigate African‐specific variants, which may have been overlooked in earlier studies. Key elements that have been lacking in the current body of work should also be attended to. This includes addressing sources of bias, thorough consideration of confounding factors, adherence to HWE principles, and explicit explanations for study sizes, all of which collectively enhance the overall quality of research. Future investigations would benefit from a shift towards prospective data collection, given that retrospective data collection can introduce bias through missingness. Initiatives like the African Pharmacogenomics Network (APN) should be supported as they play an instrumental role in advancing comprehensive pharmacogenetic studies. The APN could potentially serve as a centralized platform for the pooling or sharing of tamoxifen pharmacogenetic data specifically tailored to African populations. Moreover, the APN could take the lead in creating guidelines for conducting future studies in Africa, addressing key aspects to mitigate the potential for heterogeneity across studies. By doing so, the APN can significantly contribute to elevating the quality and consistency of research outcomes and contribute to the improvement of breast cancer treatment on the continent.
CONCLUSIONS
Owing to the inadequate representation of individuals of African ancestry in current research, coupled with race not being considered during analyses, the findings from these studies cannot be extrapolated to individuals of African descent. Consequently, this adds to the growing calls for the inclusion of African populations in genomics research to tap into the known vast genomic diversity in order to identify markers of drug response.
AUTHOR CONTRIBUTIONS
All authors wrote the manuscript, designed the research, performed the research, and analyzed the data.
FUNDING INFORMATION
The Platform for Pharmacogenomics Research and Translation (PREMED) is supported with a grant from the South African Medical Research Council (SAMRC). C.D.'s research is funded by the University of Cape Town Research Council and the South African Medical Research Council (SAMRC). B.K.'s PhD fellowship is funded by the Council for Scientific and Industrial Research (CSIR).
CONFLICT OF INTEREST STATEMENT
The authors declared no competing interests for this work.
Supporting information
Table S1.
Table S2.
Table S3.
Table S4.
ACKNOWLEDGMENTS
The authors would like to acknowledge the various participants in the different studies who have enabled this research to be carried out. Words of appreciation are also sent to authors who agreed to share data that is under their custodianship. The authors would also like to acknowledge the various funders, including the South African Medical Research Council (SAMRC), National Research Foundation (NRF), Council for Scientific and Industrial Research (CSIR), and the University of Cape Town Research Council, that have made this research possible.
Kruger B, Shamley D, Soko ND, Dandara C. Pharmacogenetics of tamoxifen in breast cancer patients of African descent: Lack of data. Clin Transl Sci. 2024;17:e13761. doi: 10.1111/cts.13761
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1.
Table S2.
Table S3.
Table S4.