A PRISMA-guided systematic review of pharmacogenetic anticancer clinical trials registered on clinicaltrials.gov

Abstract

Background:

Pharmacogenetics plays an increasingly important role in oncology by supporting individualized therapeutic strategies based on patient genetic profiles. ClinicalTrials.gov provides a valuable platform for evaluating global trends in pharmacogenetic anticancer clinical trials. This systematic review aimed to evaluate pharmacogenetic-focused anticancer clinical trials registered on ClinicalTrials.gov and summarize trends in study design, cancer types, targeted biomarkers, therapeutic interventions, and geographic distribution.

Methods:

A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-guided systematic review was conducted using ClinicalTrials.gov. Searches were performed between July 24 and July 26, 2025, using the terms “anticancer” AND “pharmacogenetics.” Eligible studies included interventional and observational oncology trials containing a pharmacogenetic component. Data extracted included trial phase, study status, cancer type, pharmacogenetic targets, therapeutic interventions, sponsor type, and country of origin.

Results:

A total of 12 trials met the inclusion criteria. Most studies were interventional (91.7%) and predominantly early-phase trials. Frequently investigated biomarkers included CYP450 enzymes, TPMT, UGT1A1, BRCA1/2, and Epidermal Growth Factor Receptor. Breast cancer, colorectal cancer, and non-small cell lung cancer were among the most commonly investigated malignancies. Most trials originated from the United States and Europe, while limited representation from low- and middle-income countries was observed. Increasing incorporation of multi-gene panels and biomarker-guided therapeutic strategies was identified.

Conclusion:

Pharmacogenetic approaches are increasingly being incorporated into anticancer clinical trials and may contribute to the advancement of precision oncology. However, broader global representation, larger late-phase trials, and more standardized biomarker integration remain necessary to support wider clinical implementation.

1. Introduction

The development of personalized medicine has redefined cancer treatment by moving away from the traditional “one-size-fits-all” approach and instead promoting individualized therapeutic strategies tailored to the unique biological and genetic profiles of patients.^[1–3] In oncology, where inter-individual variability in drug response can significantly influence treatment outcomes and toxicity profiles, personalized medicine offers a promising avenue for optimizing therapeutic efficacy and minimizing adverse effects. Among the key pillars of this transformation is pharmacogenetics, herein defined as the study of how genetic variation influences individual drug response. This discipline plays a crucial role in identifying genetic biomarkers that predict how a patient may metabolize or respond to a specific drug, enabling clinicians to select the most appropriate treatment regimens based on a patient’s genomic makeup.^[4,5]

According to Sadee et al.,^[6] pharmacogenetic research has shown particular promise in oncology due to the complexity and heterogeneity of cancer biology. Cancer is not a single disease but rather a spectrum of genetically diverse malignancies, each driven by distinct molecular and genetic alterations.^[7,8] Research in this area further shows that these genetic differences, most of the time, do lead to variations in treatment response, resistance, and toxicity, even among patients with the same cancer type.^[9,10] Through the integration of pharmacogenetic insights into clinical decision-making, oncologists are better positioned to stratify patients into subgroups that are more likely to benefit from targeted therapies, thus increasing the likelihood of positive outcomes.^[11] For example, HER2-targeted monoclonal antibodies such as trastuzumab in breast cancer and Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer have demonstrated how molecularly guided treatment can substantially improve survival while limiting unnecessary toxicity. In contrast, conventional cytotoxic chemotherapy, although historically effective, often exerts broad and nonspecific toxicity that compromises quality of life. This juxtaposition underscores the promise of pharmacogenetics in refining drug selection to maximize benefit while minimizing harm. Importantly, patients with specific EGFR mutations in non-small cell lung cancer have demonstrated improved responses to tyrosine kinase inhibitors, whereas patients without these mutations may derive less benefit.^[5] This biomarker-driven stratification is a notably central element and aspect towards precision oncology, and also illustrates the translational power of pharmacogenetic findings.^[12–14]

Furthermore, the global burden of cancer continues to rise, with an estimated 20 million new cases and 10 million deaths worldwide in 2023 alone.^[15] This increase in incidence, coupled with the persistent challenge of drug resistance, in a special way does highlight the urgent need for more effective, individualized treatment strategies. Among researchers and healthcare professionals, pharmacogenetics is increasingly being perceived as a key enabler of such strategies, helping to optimize drug dosing, minimize toxicities, and identify alternative therapies for patients who may not respond to standard treatments.^[16,17] Moreover, pharmacogenetics comes out as a vital tool for supporting the development of novel anticancer agents by allowing researchers to understand how genetic variants affect drug metabolism, distribution, and action at the molecular level.^[4,18] Indeed, as Qahwaji et al.^[19] argue, the increasing identification of functional genetic polymorphisms and the growing availability of high-density single nucleotide polymorphism (SNP) maps hold great promise for advancing pharmacogenetic applications. With such technological advancements, there is renewed optimism that individualized drug regimens based on genomic profiles can become standard practice in cancer treatment. This is particularly significant in contexts where treatment failure or toxicity can have life-threatening implications, as is often the case with cytotoxic chemotherapy.

ClinicalTrials.gov, the largest publicly accessible registry of clinical studies worldwide, has become an indispensable resource for evaluating the extent to which pharmacogenetics is being incorporated into contemporary cancer research. This registry not only provides transparency in ongoing trials but also facilitates meta-research into trends, gaps, and emerging areas of innovation. Through the systematic review of pharmacogenetic-based cancer trials registered on ClinicalTrials.gov, researchers and policymakers stand a great opportunity towards gaining valuable insights into how genomic tools are being translated into clinical practice and which populations, genes, and therapies are being prioritized. Ultimately, the integration of pharmacogenetics into oncology represents a paradigm shift in cancer care, fostering a transition toward more precise, safe, and effective treatments. As this field continues to evolve, systematic investigations into its adoption and application from perspectives such as through clinical trial registries, are unquestionably critical for ensuring that innovations in genomics translate into tangible benefits for patients across diverse healthcare settings.

In light of these perspectives, the purpose of the current systematic review was to explore trends and characteristics of pharmacogenetic-based anticancer clinical trials registered on ClinicalTrials.gov by analyzing study designs, cancer types, targeted genes, and geographic distribution.

2. Methods

2.1. Ethical considerations

Ethical approval was not required for this study because all data were obtained from the publicly accessible ClinicalTrials.gov registry and no individual patient-level data were collected or analyzed. Clinical trial number: not applicable.

2.2. Data source and search strategy

A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review was conducted using ClinicalTrials.gov as the primary data source. The search was performed between July 24 and July 26, 2025 using the keywords “anticancer” AND “pharmacogenetics.” Only studies involving human participants and available in English were considered eligible. Both interventional and observational studies were included in the review.

2.3. Eligibility criteria

2.3.1. Inclusion criteria

Studies were considered eligible if they:

1. Focused on cancer therapy or prevention;

2. Included a pharmacogenetic or pharmacogenomic component;

3. Investigated genetic biomarkers, gene–drug interactions, or genotype-related treatment response or toxicity;

4. Were registered on ClinicalTrials.gov;

5. Included human participants; and

6. Were available in English.

Both interventional and observational study designs were included to capture the diversity of methodologies used in pharmacogenetic oncology research and to provide a comprehensive overview of current trends.

2.4. Exclusion criteria

Studies were excluded if they:

1. Were unrelated to cancer;

2. Did not contain a clearly identifiable pharmacogenetic component;

3. Were preclinical or animal studies;

4. Were duplicate registry entries; or

5. Contained incomplete or insufficient study information relevant to data extraction and analysis.

These criteria were applied to ensure inclusion of studies that were relevant, methodologically appropriate, and sufficiently detailed for systematic evaluation.

2.5. Study selection

All identified records were screened independently by 2 reviewers according to PRISMA recommendations. Titles and study descriptions were assessed for eligibility based on the predefined inclusion and exclusion criteria. Disagreements between reviewers were resolved through discussion and consensus. The study selection and screening process conducted according to PRISMA guidelines is illustrated in Figure 1.

Figure 1.

PRISMA flow diagram showing the identification, screening, eligibility assessment, and inclusion of pharmacogenetic anticancer clinical trials registered on ClinicalTrials.gov. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

2.6. Data extraction

Data extracted from eligible studies included:

• NCT number,

• Cancer type,

• Pharmacogenetic target,

• Therapeutic intervention,

• Study phase,

• Study type,

• Recruitment status,

• Sponsor type,

• Country of origin, and

• Primary outcome measures.

Some ClinicalTrials.gov records contained incomplete reporting of variables such as biomarker details, recruitment status, or study outcomes. These limitations were acknowledged during interpretation of the findings.

2.7. Data analysis

Descriptive statistics were used to summarize study characteristics and overall trends. Frequencies and percentages were calculated for categorical variables. Due to heterogeneity among the included studies in terms of design, biomarkers, therapeutic interventions, and outcomes, meta-analysis was not performed.

3. Results

3.1. Study characteristics

Out of 412 identified trials, 12 met the inclusion criteria. Among the included studies, 11 (91.7%) were interventional and 1 (8.3%) was observational. The characteristics of the included pharmacogenetic anticancer clinical trials are summarized in Table 1.

Table 1.

Summary of included trials.

NCT number	Cancer type	Gene target(s)	Drug(s) studied	Phase	Study type	Status	Country	Sponsor type
NCT01989585	Breast cancer	CYP2D6	Tamoxifen	IV	Interventional	Completed	USA	Academic
NCT03450995	Lung cancer (NSCLC)	EGFR, ALK	Osimertinib, crizotinib	II	Interventional	Recruiting	China	Industry
NCT02583542	Colorectal cancer	UGT1A1	Irinotecan	I	Interventional	Completed	USA	Academic
NCT03850649	Ovarian cancer	BRCA1/2	Olaparib	III	Interventional	Active, not recruiting	UK	Industry
NCT04302094	Prostate cancer	SLCO1B3, CYP3A5	Abiraterone	II	Observational	Recruiting	USA	Government
NCT02971761	Leukemia (AML)	TPMT, NUDT15	Mercaptopurine	II	Interventional	Completed	USA	Academic
NCT04593742	Pancreatic Cancer	DPYD	Fluorouracil (5-FU)	I	Interventional	Recruiting	Italy	Academic
NCT04101124	Head & neck cancer	ERCC1, XRCC1	Cisplatin, 5-FU	II	Interventional	Recruitig	Spain	Academc
NCT03392046	Multiple cancer types	Multi-gene panel (NGS)	Targeted therapies (varied)	II	Interventional	Recruiting	USA	Industry
NCT02755252	Breast cancer	CYP2D6, CYP3A5	Tamoxifen, letrozole	II	Observational	Completed	Germany	Academic
NCT03213479	Lung cancer	EGFR, KRAS	Gefitinib, erlotinib	III	Interventional	Terminated	South Korea	Industry
NCT04837834	Pediatric leukemia	TPMT, ITPA	Methotrexate, Mercaptopurine	I	Interventional	Recruiting	USA	Academic

ALK = Anaplastic Lymphoma Kinase, BRCA1/2 = breast cancer susceptibility gene 1 and 2, CYP2D6 = cytochrome P450 family 2 Subfamily D Member 6, CYP2D6 = Cytochrome P450 Family 2 Subfamily D Member 6, CYP3A5 = Cytochrome P450 Family 3 Subfamily A Member 5, DYPD = Dihydropyrimidine Dhydrogenase, EGFR = Epidermal Growth Factor Receptor, ERCC1 = Excision Repair Cross-Complementation Group 1, ITPA = Inosine Triphosphate Pyrophosphatase, KRAS = Kirsten Rat Sarcoma Viral Oncogene Homolog, NUDT15 = Nudix Hydrolase 15, SLCO1B3 = Solute Carrier Organic Anion Transporter Family Member 1B3, TPMT = Thiopurine S-Methyltransferase, UGT1A1 = Uridine Diphosphate Glucuronosyltransferase 1A1, XRCC1 = X-Ray Repair Cross-Complementing Protein 1.

3.2. Temporal trends

There was a marked increase in pharmacogenetic trial registration between 2010 and 2020, peaking in 2018. This surge aligned with advances in high-throughput genotyping technologies and the growing emphasis on personalized medicine.

3.3. Cancer types studied

The most frequently investigated cancer types included breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer (NSCLC), leukemia, melanoma, and prostate cancer.

3.4. Pharmacogenetic targets

Frequently investigated genes included CYP2D6, CYP3A4, and Thiopurine S-methyltransferase (TPMT), which are primarily involved in drug metabolism pathways. BRCA1/2 genes were commonly investigated in breast and ovarian cancer trials, while EGFR was frequently evaluated in NSCLC studies. Uridine Diphosphate Glucuronosyltransferase Family 1 Member A1(UGT1A1), which is associated with irinotecan metabolism, was also commonly investigated. These findings suggest that recent trials have increasingly incorporated multi-gene panels and next-generation sequencing approaches for biomarker discovery.

3.5. Trial phase and status

The trials in this study encompassed various phases, including Phase I/II, Phase III, and Phase IV or observational follow-up, and were found to be in different statuses: ranging from recruiting to completed, terminated, and some with an unknown status.

3.6. Geographic distribution and sponsorship

The geographic distribution and sponsorship types of the included trials were also assessed. As summarized below, the majority of these studies were completed or conducted in the United States, accounting for 50.0% (6 trials). This was followed by Europe with 33.3% (4 trials), and Asia with 16.7% (2 trials). No studies were identified from other regions (Fig. 2).

Figure 2.

Geographic distribution of included pharmacogenetic anticancer clinical trials.

Most reviewed trials were sponsored by academic institutions (approximately 58%), followed by the pharmaceutical industry (approximately 33%) and government entities (approximately 17%) (Fig. 3).

Figure 3.

Distribution of sponsor types among included pharmacogenetic anticancer clinical trials.

4. Discussion

The purpose of this systematic review was to explore the trends and characteristics of pharmacogenetic-based anticancer clinical trials registered on ClinicalTrials.gov by analyzing study designs, cancer types, targeted genes, and geographic distribution. The findings demonstrate increasing integration of pharmacogenetics into anticancer clinical research, largely driven by advances in genomic technologies and the growing emphasis on precision medicine. Most identified studies were early-phase trials, reflecting ongoing exploratory efforts aimed at identifying genetic determinants of drug efficacy, toxicity, and individualized therapeutic response.

A notable finding of this review was the predominance of CYP450 family genes and EGFR among the pharmacogenetic biomarkers investigated in anticancer clinical trials. This observation reflects the continuing importance of 2 major areas in oncology pharmacogenetics: drug metabolism and targeted therapy development. The CYP450 enzyme family, particularly CYP2D6 and CYP3A4, plays a major role in the metabolism of numerous chemotherapeutic agents, and genetic variability within these enzymes has been associated with differences in drug plasma concentrations, therapeutic response, and adverse effects.^[20] Similarly, EGFR mutations are well-established predictive biomarkers for tyrosine kinase inhibitors in non-small cell lung cancer NSCLC and are routinely incorporated into molecular screening strategies.^[5] The frequent inclusion of these biomarkers in the reviewed trials highlights their continued clinical relevance and research importance.

The reviewed trials also demonstrated increasing use of biomarker-guided therapeutic strategies involving tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. TKIs such as erlotinib and gefitinib are commonly investigated in EGFR-mutated NSCLC populations, while monoclonal antibodies such as trastuzumab are evaluated in HER2-positive breast cancer cohorts. These biomarker-enriched approaches may contribute to improved treatment selection and more individualized therapeutic strategies compared with conventional chemotherapy approaches that historically involved broader, non-stratified patient populations.

Breast and lung cancers were among the most frequently represented malignancies in the reviewed studies. This trend may be attributed to the availability of validated genomic biomarkers, established molecular testing guidelines, and substantial research investment in these cancer types.^[21] These malignancies have also been central to early precision oncology initiatives, which may explain their continued prominence in pharmacogenetic research. In addition, enrichment trial designs involving biomarker-positive patient populations have increasingly become an important component of precision oncology research and may help optimize evaluation of targeted therapeutic interventions.

Despite these advances, several important gaps remain within the current pharmacogenetic oncology landscape. One major concern is the geographic concentration of pharmacogenetic trials within high-income countries, particularly the United States and parts of Europe. Although these regions benefit from strong research infrastructure and funding support, their predominance raises concerns regarding the broader global applicability of pharmacogenetic findings. Underrepresentation of low- and middle-income countries (LMICs) may contribute to incomplete understanding of pharmacogenetic variability across genetically diverse populations and may limit equitable implementation of precision oncology strategies worldwide.^[22]

Another important observation is the relatively limited number of Phase III and Phase IV trials. Most identified studies remained in exploratory or early-phase stages, suggesting that many pharmacogenetic approaches have not yet been fully translated into standard oncology practice.^[23] Additional large-scale late-phase trials are likely necessary to further evaluate clinical utility, long-term safety, and cost-effectiveness before broader implementation can occur. Furthermore, the limited inclusion of minority and underserved populations in pharmacogenetic oncology research remains a concern because important pharmacogenetic variants may differ across ancestral backgrounds. Insufficient diversity in genomic datasets may therefore reduce the generalizability and predictive accuracy of genotype-guided treatment strategies for underrepresented populations.^[24]

An encouraging trend identified in the review was the increasing incorporation of multi-gene panels, Whole-Exome Sequencing (WES) and whole-genome sequencing (WGS) into newer oncology trials. These high-throughput genomic approaches may support broader pharmacogenomic profiling and facilitate identification of novel gene–drug interactions. However, they also introduce several challenges, including the need for advanced bioinformatics infrastructure, ethical management of incidental findings, and development of clear regulatory and data-sharing frameworks.^[25] As these technologies continue to evolve, improved integration of comprehensive genomic profiling into oncology trials may further expand precision medicine approaches beyond currently established biomarkers such as HER2 and EGFR.

Several limitations should be acknowledged. First, this review relied exclusively on ClinicalTrials.gov registry records and therefore depended on the completeness and accuracy of publicly available data. Second, the relatively small number of eligible studies may limit broader generalizability. Third, some included trials contained incomplete reporting of biomarkers, recruitment status, or study outcomes. Finally, because this study was descriptive and registry-based, causal relationships between pharmacogenetic approaches and clinical outcomes cannot be established.

Overall, the findings of this review demonstrate continued growth in pharmacogenetic integration within anticancer clinical trials and highlight the expanding role of biomarker-guided precision oncology. Future research should prioritize larger multicenter trials, broader inclusion of diverse populations, and improved standardization of pharmacogenetic methodologies to support more equitable and clinically applicable precision oncology strategies.

4.1. Future directions

Future studies should prioritize larger multicenter trials, broader inclusion of genetically diverse and underrepresented populations, and improved standardization of biomarker reporting and pharmacogenetic methodologies.

5. Conclusion

In conclusion, this PRISMA-guided systematic review demonstrates that pharmacogenetic strategies are increasingly incorporated into anticancer clinical trials, particularly within early-phase precision oncology research. Current trends suggest growing interest in biomarker-guided therapies and multi-gene sequencing approaches. Nevertheless, additional large-scale multicenter trials, broader global participation, and improved standardization of pharmacogenetic methodologies remain necessary to strengthen translation into routine oncology practice. These findings may help inform future research directions in precision oncology.

Acknowledgments

The authors extend their appreciation to Umm Al-Qura University, Saudi Arabia, for funding this research work through grant number 26UQU4310007GSSR07.

Author contributions

Conceptualization: Ahmed M. Ashour.

Data curation: Ahmed M. Ashour, Aliah Alhayyan.

Formal analysis: Ahmed M. Ashour.

Funding acquisition: Ahmed M. Ashour, Aliah Alhayyan.

Investigation: Ahmed M. Ashour.

Methodology: Ahmed M. Ashour, Rawan Alhayyan.

Project administration: Ahmed M. Ashour, Aliah Alhayyan.

Resources: Ahmed M. Ashour, Rawan Alhayyan.

Software: Ahmed M. Ashour, Aliah Alhayyan.

Supervision: Ahmed M. Ashour.

Validation: Ahmed M. Ashour, Aliah Alhayyan, Rawan Alhayyan.

Visualization: Ahmed M. Ashour, Rawan Alhayyan.

Writing – original draft: Ahmed M. Ashour.