Clinical outcomes of chemotherapy in cancer patients with different ethnicities

Abstract Background Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti‐cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup. Recent findings Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing. Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti‐cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed. Conclusion Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.

cases of cancer worldwide and approximately 10 million cancerrelated mortalities in the year 2018. It is projected that in 2040 there will be 28 million new cancer cases and 16 million cancer-related deaths. 2 This projection highlights the potential drastic escalation of the global cancer burden, which is likely due to the increase in worldwide prevalence of several inciting risk factors. An increase in the aging population, smoking habits, unhealthy diet, and sedentary lifestyle all contribute to the growing number of new malignancies which tend to display a more aggressive presentation with an higher mortality rate. Other exacerbating factors include iatrogenesis and the lack of proper pharmacotherapeutics in developing nations. Treating cancer varies by origin and can be achieved through different modalities such as: chemotherapy, radiation, surgical removal, immunotherapy, hormonal therapy, or stem cell/bone marrow transplant. 3 Outside of primary therapy, additional treatments may be divided into specific categories depending on their rationale and timing. Neoadjuvant therapy is delivered to reduce the size of the tumor and increase the cells' susceptibility to the primary treatment prior to its administration 4 Adjuvant therapy prevents the reemergence of malignant cells that remain past initial treatment. Lastly, palliative treatment is not seen as curative, however, it aims to manage the symptoms of cancer as well as any potential side effects of cancer treatment. 5 The major chemotherapeutic classes available are alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant alkaloids, biological response modifiers, and hormonal anti-cancer agents.
Despite the evolution of novel therapeutic approaches and an increased understanding of the pathophysiology behind certain cancers, there are discrepancies in the clinical outcomes depending on an individual's racial background or ethnicity after chemotherapy treatment.
With chemotherapy administration, the primary goal is to identify the dose of drug with the greatest efficacy while minimizing adverse effects. These cytotoxic agents undergo rigorous testing through randomized clinical trials to determine the optimal dose that takes this into consideration. A standardized dosing scheme is then recommended from the finalized clinical trial. Routinely, further dose adjustments may vary per individual based on body surface area or renal clearance. Several interindividual differences play a critical role in the variation of pharmacological efficacy, adverse effects, hypersensitivity reactions, and drug interactions despite receiving similar chemotherapeutic doses. One factor with the ability to affect drug disposition is an individual's ethnic background. Variations in pharmacokinetic and pharmacodynamic properties have been observed between ethnic populations which can influence therapeutic results. 6 The term pharmacoethnicity involves the study of nongenetic and genetic factors that affect the differences in drug response or toxicity based on an individual's ethnicity. The majority of drugs target enzymes, receptors, ion-channels, pumps, transporters, and nucleic acids (DNA/RNA). 7 Within the last decade, advancements in pharmacogenomics have identified genetic polymorphisms in the expression and/or activities of human drug targets specific to an individual's ethnicity. 8 This change is also seen within enzymes responsible for the metabolism of certain chemotherapeutics. These polymorphisms may influence drug disposition in certain populations. Any deviation in the pharmacokinetic and pharmacodynamic properties can lead to adverse outcomes when dosing is decided without the consideration of these changes. Alterations in pharmacokinetics may be caused by variations in allele frequencies and types of allelic variants of nuclear receptors, transporters, and drugmetabolizing enzymes in individuals from different ethnic backgrounds. 9,10 Several variations in drug metabolizing enzymes and transporter proteins have been identified. Additionally, changes in protein structure can either cause the protein to decrease or increase its function ultimately changing the PK and PD parameters of certain drugs. These alterations can also lead to chemotherapeutic resistance. 11 Genetic pharmacoethnicity could be a critical contributing factor to the disparities seen in chemotherapeutic clinical outcomes of individuals of different backgrounds.
Outside of genetic polymorphisms, several other nongenetic factors can influence the clinical outcomes of cancer patients of different ethnicities. These factors include the lack of access to healthcare, suboptimal use of therapy, and lower utilization of cancer screening methods. All of these discrepancies can lead to a more aggressive tumor biology and stage at presentation which contributes to the poorer outcomes observed in some ethnic minorities. 12 A patient's socioeconomic status, education, insurance, misconceptions, and preferences can all impact the care received. One study revealed that African American Medicare beneficiaries were less likely to encounter specialists and high-quality imaging compared to their Caucasian counterparts. 13 Additionally, African American patients living further away from cancer treatment centers or areas of higher poverty underwent less radiation after breast-conserving therapy. 14 A detailed study of cancer risk factors based on ethnicity revealed that people of Hispanic, Asian, and American Indian/Alaska Native descent are less likely to undergo screening for breast, cervical, and colorectal cancers compared to their Caucasian and African American counterparts. 15 Additionally, patient misconceptions and preferences also play a role in the disparity of cancer treatment outcomes. In one study, African American patients felt that their quality of life would worsen after lung cancer surgery which resulted in fewer surgical resections compared to Caucasian patients. 16 These factors all contribute heavily to the disparities observed in clinical outcomes seen with ethnic minorities and cannot be ignored when devising solutions to address them.
Part of the cancer disparities observed between ethnicities may be attributed to the increased frequency of specific germ line and somatic mutations known to cause certain types of cancer. Most cancer types are associated with a high-mutation burden 17 either from an increased susceptibility to genetic mutations or due to mutagenic environmental exposure. For example, African American males have the highest rate of aggressive prostate cancer mortality compared to other ethnicities. A possible reason for this finding is due to differences in the frequency of specific tumor mutations within prostate cancer of African American men. In one study, African American males displayed less somatic alterations of Transmembrane serine protease 2-erythroblast transformation-specificrelated gene (TMPRSS2-ERG), less Phosphatase and tensin homolog (PTEN) deletions, and higher overexpression of serine peptidase inhibitor Kazal type 1 (SPINK1) compared to Caucasian males. SPINK1 mutation is associated with a more aggressive phenotype of prostate cancer. 18 Furthermore, in the case of lung cancer, activating epidermal growth factor receptor (EGFR) mutations (base pair deletion in exon 19 and point mutation in exon 21) are significantly higher in people of Chinese, Japanese, and Korean descent compared to Caucasian individuals in Europe and the United States. 19 Findings of genetic variations of cancer inducing mutations between different populations highlights an important factor to consider for treatment choice and outcomes. Therefore, expanding the awareness of inherited and somatic mutations across populations can be used to improve the strategies for cancer prevention and treatment. 11 Different clinical biomarkers are also implicated among different ethnic populations as listed in Table 1. Population-based differences have shown to impact chemotherapeutic treatment and safety outcomes. 20 Several studies have proven variations in chemotherapy drug responsiveness among different ethnicities as well as differences in clinical outcomes. 10 Predicts the sensitivity to EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib 19,49 Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, v-raf murine sarcoma viral oncogene homolog B1; CA-125, cancer antigen 125; EGFR, epidermal growth factor receptor; ERG, erythroblast-transformation-specific (ETS) Related Gene; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene; MSI, microsatellite instability; PI3K, phosphoinositide 3-kinases; PRAP, poly ADP ribose polymerase; PSA, Phosphoinositide 3-kinases; PSA, Prostate-specific antigen; PTEN, Phosphatase and tensin homolog gene; TMPRSS, transmembrane serine protease 2.
ethnic populations (ACS citation). This increased threat of colorectal cancer in American Indian/Alaska Natives is thought to be attributed to differences observed in diet, lifestyle, and genetic makeup.

| Asian
One of the leading causes of death among Asian populations is cancer. 22 Asian Americans display lower rates of cancer overall compared to non-Hispanic Caucasian Americans; however, disparities exist among the specific cancer types. 23 In 2020, the most common incidences of cancer among Asian populations were lung, breast, and colorectal cancer with lung cancer being the leading cause of cancerrelated mortality. More specific to Korea, Japan, and Kuwait, the incidence of cancer is rising among young females. This is thought to be due to increased screening programs, changes in reproductive factors, and a delayed tobacco epidemic in women 24,25 (Harris, 1983.
Overall, cancer-related mortality is declining within Asian countries. 26

| Black or African American
Of all ethnic minority populations, Black or African American individuals have the highest rates of cancer-related mortality for most cancer types. Cancer prevalence based on ethnicity is summarized in the paragraphs above and the specific prevalence of certain clinical biomarkers specific to ethnicity are listed in Table 1. The incidence rates and death rates for different cancers by race and ethnicity from 2014 to 2018 is displayed in Figure 1 and Figure 2, respectively.
Based on the data presented, there is an imminent need to explore the outcomes influenced by differences in chemotherapeutic dosage forms, routes of administration, pharmacokinetics, pharmacodynamics, and toxic effects in patients of various ethnic backgrounds. This current study focuses on the disparities in the efficacy of commonly used chemotherapeutic drug classes such as, alkylating agents, antimetabolites, antitumor antibiotics, and other miscellaneous chemotherapeutics.

| LITERATURE SEARCH METHODS
This study was performed by manually searching published scientific research articles through March 2023 from the following databases: PubMed central, Medline, Google Books, Science.gov, Worldwide Science, and Google Scholar. Search terms included the following: "Chemotherapy", "Chemotherapeutics", "Ethnicity", "Racial", and "Therapeutic outcome." Relevant clinical content was obtained using CDC and Lexi-Comp. References of selected articles were manually searched for additional information. A total of 159 articles were covered in our study. We encompassed clinical trials, journal articles, meta-analyses, randomized control trials, reviews, and systematic reviews. Articles were searched under English language restrictions.

| RESULTS
The definition of ethnicity and ethnic groups are variable based on country, region, background, and individual basis. For this reason and the specific studies investigated, this review will focus mainly on the five-race classifications and will include pertinent information regarding specific ethnic groups where possible.

| ALKYLATING AGENTS
The first nonhormonal medications to successfully treat cancer were alkylating agents. 50 Alkylating agents exert their anti-cancer activities primary through DNA alkylation, a process in which alkyl groups are added to the DNA bases. This induces DNA strand breaks and DNA crosslinking which leads to cell death. 51 Alkylation also results in the production of different DNA adducts, which in turn prevent the prolif- Platinum-based drugs (cisplatin, carboplatin, and oxaliplatin) are another form of alkylating agents which are widely used for the treatment of many types of cancer. 58 Several studies noted an increased frequency of toxicities (mainly hematological) in Asian patients in comparison to non-Asians (Caucasians) treated with standard doses of platinum-based drugs. 59,60 Interestingly, the incidence of these toxicities was still higher among Asians despite appropriate dose reduction. 11 In a study comparing Russian These findings indicate the existence of ethnicity-related molecular mechanisms underlying the sensitivity of patients treated with platinum-based drugs. These findings are listed in Table 2.

| ANTIMETABOLITE CHEMOTHERAPY
Approximately 70 years ago, Farber discovered the potential anticancer effect of aminopterin, an antimetabolite, by inducing remission in patients with acute leukemia. The antimetabolites are a class of anti-cancer agents that mimic natural substrates structurally, however, their structure differs enough to obstruct their metabolism. 74 Antimetabolites' primary mechanism of action is to cause depletion of nucleotides, which in turn halts DNA replication. Some antimetabolites are able to mimic nucleic acids falsely, creating structural defects that result in cell death via other pathways, such as DNA breakage. 75 Common routes of administration for antimetabolites are orally, intravenously, and subcutaneously.
Notably, the prevalence of any complication with antimetabolite chemotherapy was lower in African Americans when compared to Caucasians. However, the overall incidence of other toxicities (diarrhea, nausea and vomiting and mucositis) were lower in African Americans compared to Caucasians. 76 The ethnic disparity of hematological toxicities are attributed to lower levels of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism, in peripheral blood mononuclear cells. 77 80 The population frequency of the TSER*3 allele in Caucasians (54%) is similar to that of African Americans (52%); however, two rare alleles (TSER*4 and TSER*9) are found at a higher frequency in African Americans (2%) than in Caucasians (0%). 81 These studies indicate that ethnic differences play a significant role in the metabolism and toxicities of several antimetabolites. Genotyping prior to the administration of these chemotherapeutics in select T A B L E 2 Pharmacokinetics and Pharmacodynamics and racial/ethnic differences in the treatment outcomes with Alkylating agents. PK/PD data of various drugs was obtained from ref. [65][66][67][68]  T A B L E 4 Pharmacokinetics, pharmacodynamics, and ethnic differences in the treatment outcomes with antitumor antibiotics. PK/PD data of various drugs was obtained from ref. [65][66][67][68]. Two phase I studies studied the pharmacokinetics of and risk factors were comparable. However, Japanese patients experienced a smaller reduction in BMD and a lower incidence of bone fractures after anastrozole treatment compared to Caucasian patients. 111 Another study showed that shifting tamoxifen to anastrozole in postmenopausal Japanese breast cancer patients decreased the risk of disease recurrence. 112 One study of lanreotide showed that the agent was well-tolerated and efficacious in Korean patients with welldifferentiated gastroenteropancreatic-neuroendocrine tumors. 113

| Protein kinase inhibitors
Protein kinases regulate the activity of cellular enzymes through phosphorylation. These proteins come in several varieties and interact with a wide range of cellular processes including cell growth, division, and  Individuals of European and East Asian descent appear to respond differently depending types of TKIs. Significant evidence shows that East Asian patients exhibit a greater response and improved survival outcomes to erlotinib, gefitinib, lapatinib, and regorafenib compared to individuals who are non-East Asian. [120][121][122][123][124][125][126][127] As of now, no specific studies regarding inter-ethnicity disparities of treatment response have been done for ruxolitinib and Osimertinib. 128 Cytochrome-P450 (CYP) enzymes are primarily responsible for metabolizing TKI by phase I and UDP-glucuronosyltransferases (UGTs) by phase II reactions. 142 The enzyme CYP3A4 is principally responsible for metabolism of sunitinib and imatinib into the biologically active metabolites N-desethyl (SU12662) and N-demethylated piperizine and have similar potencies to their parent medications.

| Tyrosine kinase inhibitors
Additionally, sorafenib and erlotinib are metabolized into their respective pharmacologically active metabolites, sorafenib N-oxide and OSI-420. Reduced transcription and reduced UGT1A1 enzyme activity is noted when there is presence of additional TA repeat in the TATA sequence of the UGT1A1 promotor (UGT1A1*28). 143,144 Similarly, polymorphisms in the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR), which regulate the transcription of genes encoding drug metabolizing enzymes and transporters can be affected causing inter-ethnic differences in metabolism. 9,145 More studies are needed to understand the diverse variability in metabolizing TKIs.
TKIs are largely excreted from the body by hepatic metabolism and P-gp-mediated biliary excretion, with less than 10% of total systemic clearance coming from unchanged drug elimination in urine. 142 With the exception of afatinib, which is primarily excreted intact in feces, the majority of TKIs undergo substantial metabolic processing before biliary elimination. 146 The  F I G U R E 3 Various challenges in deriving the ethnicity/racial differences data for cancer drugs. associated with oral or parenteral route of anti-cancer drugs.
Therefore, it is important to consider other relevant extrinsic factors (dosage forms, route of administration) that may influence the study results. 5. In addition to relevant intrinsic and extrinsic factors, another key factor for the success of all the studies is the appropriate sample size, that is, the number of subjects from each ethnic group should be sufficient enough to allow comparison of interethnic effects. In this regard, it is important to point out that majority of the clinical evidence obtained so far was only from three major ethnic groups: African Americans, Caucasians and Asians, thus ignoring other groups such as American Indians and Hispanics. As reported in 2020, the industry sponsored clinical trials of new biologics and drugs included only 8% of African Americans, 11% Hispanics or Latinos and 6%Asians. 154 When the participants are homogenous, the results may be skewed leading to PK/PD data that is not generalizable. Therefore, it is important to consider large enough sample size for each of the ethnicities to draw meaningful conclusions on PK/PD data for different ethnicities. In order to advance equity in clinical trials for new drugs, there is a need to implement a combination of federal incentives and regulations such as providing grants and support for increasing enrolment capacity and infrastructure at trial sites and lowering the financial barriers by reimbursing the costs incurred by trial participants. 114 6. Obtaining PK/PD data for different ethnicities is hindered by several challenges, including inadequate screening of subjects, small sample sizes, insufficient consideration of intrinsic and extrinsic factors, and the absence of population-based clinical databases.
These factors must be addressed to obtain accurate PK/PD comparisons for different racial/ethnic groups. 76,[155][156][157][158] 10 | CONCLUSION AND FUTURE PERSPECTIVE Pharmacoethnicity impacts the treatment outcomes of patients undergoing various forms of anti-cancer therapy. Primarily through polymorphisms within the genes responsible for metabolism, several PK and PD parameters can be impacted. These polymorphisms are observed at different frequencies within certain ethnic populations which lead to the wide range of outcomes observed after chemotherapy treatment. This paper discusses the clinical outcomes of different chemotherapeutics in regards to ethnicity. Ethnic diversity in chemotherapeutic drug response or toxicity is becoming increasingly recognized as an important healthcare burden globally. These differences can be attributed to both genetic and non-genetic factors. Taking into account the significance of pharmacoethnicity will further the process of individualizing chemotherapy, which in turn will improve chemotherapeutic tolerance and efficacy. This review covers the current clinical literature for ethnicity specific differences in chemotherapeutic drug disposition (ADME), effectiveness, toxicity, and potential health outcomes from the treatment interventions. A multifaceted approach is necessary to address racial and ethnic disparities in chemotherapy outcomes. The clinical trials should cover diverse population groups/races/ethnicities. Furthermore, these disparities can be addressed by considering social determinants of health, developing personalized treatment plans, improving communication and cultural competence, and addressing implicit biases can help improve outcomes. These strategies can identify more effective treatments for specific racial and ethnic groups, ensure access to high-quality cancer care for all patients, personalize treatment plans, improve communication, and address implicit biases among healthcare providers. All the concerned parties such as healthcare providers, researchers, and policymakers should work together and ensure that the patients receive appropriate care, drugs and dosing regiments to fight cancer.