Abstract
Breast cancer (BC) among Asians accounts for ~ 40% of the global BC burden. Differences in BC risk, presentation, tumor biology, and response to treatment exist between Asian and non-Asian patients; however, Asian patients are often under-represented in clinical trials. This narrative review summarizes the efficacy and safety of pharmacological therapies for BC in Asian populations, with a focus on outcomes in Asian versus non-Asian patients treated with chemotherapy, hormone therapy, anti-human epidermal growth factor receptor-2 targeted therapies, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, mammalian target of rapamycin inhibitors, bone-targeted therapies, poly-ADP ribose polymerase, phosphoinositide 3-kinase, and checkpoint inhibitors. While most therapies have demonstrated comparable efficacy and safety in Asian and non-Asian patients with BC, differences that are largely attributed to pharmacogenetic variations between populations exist. Pharmacogenetic differences may contribute to a reduced clinical benefit of tamoxifen, whereas improved clinical outcomes have been reported with tyrosine kinase inhibitors and CDK4/6 inhibitors in Asian versus non-Asian patients with BC. In particular, Asian patients have an increased incidence of hematological toxicities, including neutropenia, although adverse events can be effectively managed using dose adjustments. Recent trials with CDK4/6 inhibitors have increased efforts to include Asians within study subsets. Future clinical trials enrolling higher numbers of Asian patients, and an increased understanding of differences in patient and tumor genetics between Asians and non-Asians, have the potential to incrementally improve the management of BC in Asian patients.
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Avoid common mistakes on your manuscript.
Data suggest important differences in tumor biology, treatment response, and metabolism of anticancer drugs between Asians and non-Asians with breast cancer (BC), yet the majority of clinical trials are conducted in Western settings. |
A review of the literature suggests that while many treatments for Asians and non-Asians with BC often have similar efficacy and safety, important differences have been reported, particularly regarding hematological toxicities. |
There is a need for future studies to enroll a higher proportion of Asian patients, and for further research into the reasons behind the differences seen between Asians and non-Asians with BC, in order to improve the management of Asian patients with this disease. |
1 Introduction
Breast cancer (BC) in Asian women accounts for ~ 40% of the global BC incidence [1], and is rising [2,3,4,5]. Age-standardized incidence rates in Asia vary considerably across the continent, but are lower than in Western countries. Mortality rates are substantially higher compared with Western populations, although there also are large variations in BC mortality rates across Asia [1,2,3]. Furthermore, BC in Asia typically affects a younger population at a more advanced stage [1, 4, 5].
Patients in Asian and non-Asian countries share several risk factors contributing to BC development, including early menarche, late menopause, older age at first pregnancy, and absence of breastfeeding [1, 4, 5]. In contrast, dietary and lifestyle factors, including lower alcohol consumption, less hormone replacement therapy, lower body mass index (BMI), and increased consumption of soy-based products reduce the risk of BC in Asian women [5]. Although an increasingly Westernized lifestyle accounts for rapidly rising BC incidence among East Asian women, a recent study demonstrated significant differences in secular trends with age-specific incidences of female BC in Asians versus a USA-based population [6]. Furthermore, the age-specific pathological features of BC in East Asian countries were distinct from the USA, but similar to Asian Americans, thereby suggesting ethnic differences in its etiology and biology [6].
Genetic differences between Asians and non-Asians may also contribute to differences in tumor biology, response to treatment, and metabolism of anticancer drugs [3,4,5, 7]. Initial speculations focusing on early onset of BC in Asians suggested a higher frequency of the basal-like subtype BC, characterized by poor differentiation, resulting in a relatively poor prognosis [8, 9]. However, recent studies in Taiwan and Japan indicated that women aged < 50 years have a higher probability of hormone receptor-positive disease and lower probability of triple-negative BC than those ≥ 50 years of age [8,9,10]. Evidence also suggests that pharmacogenetic differences contribute to chemotherapy having poorer tolerability and higher toxicity among Asians [3]. The majority of clinical trials are conducted in Western settings, limiting the applicability of their data to Asian populations.
In this review, we provide an overview of the efficacy and safety of pharmacological therapies for BC in Asians, with a focus on comparing outcomes in Asian versus non-Asian patients.
2 Search Strategy
This article is a narrative review. A series of free-text searches in PubMed for papers published between January 2000 and June 2021 were conducted using various combinations of keywords, including: breast cancer; anastrozole, letrozole, goserelin, tamoxifen, fulvestrant, lapatinib, pertuzumab, neratinib, ribociclib, abemaciclib, palbociclib, everolimus, denosumab, zoledronic acid, talazoparib, veliparib, olaparib, rucaparib, niraparib, Talzenna, AZD-281, MK-7339, Lynparza, pembrolizumab, atezolizumab, tislelizumab, avelumab, durvalumab, alpelisib, BYL719, idelalisib, copanlisib, duvelisib, taselisib, buparlisib, BMK120, and umbralisib; and Asian, Japan, Japanese, China, Chinese, Taiwan, Taiwanese, Korea, Korean, and ethnicity. In addition, a search of key congresses was undertaken, the reference lists of papers found in the search were examined for relevant studies, and key papers were included based on the authors’ clinical experience and knowledge of the field.
3 Chemotherapy
The efficacy of chemotherapy in Asians is generally comparable to that observed in Caucasians, based on a retrospective comparison of East Asian and global studies using paclitaxel and gemcitabine [11]. Slightly higher response rates (44.6–50.0% vs. 41.4%), 12-month overall survival (OS) (78.6–86.5% vs. 71.1%), and progression-free survival (PFS) (7.6–7.7 months vs. 5.9 months) were observed in East Asians receiving paclitaxel–gemcitabine therapy for metastatic BC compared with the global population [11]. Of note, these findings are based on a limited number of studies with relatively small sample sizes that were subject to high censoring rates, and the global studies included more patients with worse performance status [11]. Despite this, several differences were observed in the pharmacological properties of chemotherapy in Asians compared with other races. East Asian patients are generally more susceptible to chemotherapeutic side effects compared with patients in Western countries [12]. A larger population of Japanese patients had grade 4 neutropenia with carboplatin-paclitaxel combination therapy, a long-standing doublet regimen that was well tolerated in patients with lung and ovarian cancers in the USA [13, 14].
Hematological toxicities are key areas of difference between Asians and other races. Several studies have reported a higher prevalence of neutropenia in Asian versus non-Asian patients administered chemotherapy, despite lower dosage in some Asian countries [11, 15]. For example, > 30% of Asians treated with four cycles of adjuvant docetaxel–cyclophosphamide experienced grade ≥ 3 neutropenia compared with < 5% of Caucasians [16]. Increased hematological toxicity was reported in Asians administered taxane-based therapy [11, 17]. Notably, increased risk of docetaxel-related hematological adverse events (AEs) is associated with a lower clearance rate of docetaxel in Asians [18]. An increased incidence of edema, myalgia, nail disorder, febrile neutropenia, upper respiratory tract infection, reduced appetite, and rash were reported for Asians treated with either trastuzumab or pertuzumab and trastuzumab, in combination with docetaxel [19]. These AEs led to 47% of docetaxel dose reductions in Asians versus 13% in non-Asians, though a similar number of treatment cycles were administered in both groups and treatment efficacy was not significantly affected [19]. Cyclophosphamide in combination with doxorubicin was also linked to higher rates of hematological toxicity [20, 21]. In particular, low BMI may be a risk factor for hematological toxicities in Asians, although the risk may be effectively managed using a dose adjustment or titration strategy [20,21,22,23]. Potential interactions related to co-exposure with traditional medicine and chemotherapy remain largely unknown [20].
Despite the absence of relevant differences in clinical antitumor activity, regional disparity exists in tolerability profiles and phenotypic characteristics of some cytotoxic agents among Asians and non-Asians [24, 25]. Asians are known to metabolize capecitabine faster than Caucasians, and hence are more likely to tolerate higher doses, without influencing efficacy [26]. Patients from the USA were ~ 3.5 times more susceptible to developing grades 3 and 4 gastrointestinal toxicities compared with Asians when receiving fluoropyrimidine treatment [24]. In contrast, no clinically relevant differences in pharmacokinetics, efficacy, or safety were observed with gemcitabine, paclitaxel, or vinorelbine [11, 23, 27, 28].
4 Hormone Therapy
The efficacy, safety, and pharmacokinetic characteristics of hormone therapy are generally comparable between Asian and Caucasian patients with early or advanced BC [29,30,31,32,33,34,35,36,37,38,39,40,41,42]. For example, a subgroup analysis of the FALCON study showed that the treatment effects of fulvestrant versus anastrozole were generally consistent between the Asian and non-Asian populations (Table 1) [38]. However, differences in the clinical benefit and toxicity profile of some hormone therapies exist among non-Caucasians.
Pharmacogenetic differences may contribute to a reduced clinical benefit of tamoxifen therapy in Asians with BC [34, 35]. Tamoxifen is metabolized to its highly potent active metabolites endoxifen and 4-hydroxytamoxifen. Several cytochrome P450 (CYP) enzymes, including CYP2D6, perform an important step in the bioactivation process [43,44,45]. Furthermore, the CYP2D6 gene is highly polymorphic, leading to altered enzyme expression and function [45]. Accordingly, clinically relevant variations in CYP2D6 phenotype frequency between individuals and races could impact the efficacy of tamoxifen therapy [33, 34, 46]. The CYP2D6*10 variant, associated with reduced enzyme activity, is more common in Asians, and this results in significantly lower plasma concentrations of endoxifen and 4-hydroxytamoxifen, and poorer clinical outcomes for Asians with metastatic BC [34]. A meta-analysis investigating the effect of CYP2D6*10 polymorphisms on clinical outcomes in 1,794 Asian patients with BC across 15 retrospective studies concluded that the CYP2D6*10 variant reduces the efficacy of tamoxifen treatment, as illustrated by lower disease-free survival (DFS) and higher recurrence rates [35, 36].
Letrozole, an aromatase inhibitor, has been shown to be better tolerated by Black, Hispanic, Asian, Pacific Island, and native North American/Alaskan women, who reported a significantly lower incidence of hot flashes (49% vs. 58%; p = 0.02), fatigue (29% vs. 39%; p = 0.005), diarrhea (3% vs. 7%; p = 0.033), and arthritis (2% vs. 7%; p = 0.006) than Caucasians; these women did not achieve the same improvement in DFS [36]. This variability in letrozole efficacy and safety in Asians has been attributed to pharmacokinetic differences, poorer treatment adherence, and divergent menopausal experiences between races [36]. These results need confirmation in other trials of aromatase inhibitors, given the heterogeneity of the non-Caucasian cohort and the limited number of Asian patients.
5 Anti-Human Epidermal Growth Factor Receptor 2 (HER2)-Targeted Therapies
The recommended dosages of molecular targeted therapies are not based on body mass or surface area. In general, the pharmacokinetics, efficacy, and safety profiles of targeted therapies such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody–drug conjugates are comparable across races in patients with advanced BC (Table 1) [19, 47,48,49,50,51,52,53,54]. However, several studies have reported superior clinical outcomes with TKIs among Asians.
A numerically improved objective response rate (ORR; 66.4% vs. 51.3%), clinical benefit rate (CBR; 70.2% vs. 60.2%), and PFS [55.6 (95% confidence interval (CI) 44.1–64.0) vs. 36.1 (95% CI 32.1–40.0) weeks] have been observed in Asian patients with advanced disease who were administered neratinib-based therapy compared with non-Asians [53], which correlates with similar or greater invasive DFS in early BC [52, 53]. Likewise, disease control with lapatinib in combination with capecitabine is considerably higher in Asian than Caucasian populations (58–59% vs. 27–29%) [51, 54], but these outcomes may not be entirely attributable to racial differences because Asian patients exhibited greater treatment adherence and a longer duration of treatment [52, 53]. In addition, whether the improved efficacy was a result of the epidermal growth factor receptor inhibitor or the partner drug capecitabine could not be determined. A subgroup analysis of the DESTINY-Breast01 study showed that race (Asian vs. non-Asian) did not impact the efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic BC previously treated with trastuzumab emtansine [55].
Data regarding the safety profiles of targeted therapies are conflicting. For example, Asians treated with trastuzumab demonstrate fewer instances of cardiac toxicity compared with non-Asians [56], but patients treated with neratinib have higher rates of grade 3/4 diarrhea and hematological events [52, 53]. Similarly, trastuzumab emtansine (T-DM1) poses a greater risk of thrombocytopenia among Asians [57].
6 Cyclin-Dependent Kinase (CDK) 4/6 Inhibitors
The more recently conducted trials on CDK4/6 inhibitors have demonstrated increased effort to include Asians within the study subsets, especially for premenopausal patients. In the first-line setting for patients with advanced BC, consistent data have shown Asians deriving greater benefit from CDK4/6 inhibitors than their non-Asian counterparts or the overall intent-to-treat population (Table 2) [58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74]. For example, ~ 70% of East Asian patients with measurable disease [PFS hazard ratio (HR) 0.33 (95% CI 0.20–0.56)] responded to abemaciclib–anastrozole therapy versus 59% of the overall population [PFS HR 0.54 (95% CI 0.42–0.70)] in the MONARCH-3 study, although interactions between race/geographical location and outcomes for Asians were not formally tested [60, 73]. The PFS HR in Asians treated with palbociclib in combination with letrozole was 0.48 (95% CI 0.27–0.87) while that of non-Asians was 0.58 (95% CI 0.45–0.74) in the PALOMA-2 study (Table 2) [59]. The MONALEESA-2 study of ribociclib and letrozole combination therapy also demonstrated clinically meaningful PFS in Asians [HR 0.30 (95% CI 0.13–0.66)] compared with the non-Asians [HR 0.60 (95% CI 0.46–0.79)] [74]. Asians treated with ribociclib in the MONALEESA-7 study had greater benefits when compared with the non-Asians; the PFS HR in Asians was 0.41 (95% CI 0.26–0.66) versus 0.66 (95% CI 0.48–0.92) in non-Asians. Higher ORR and CBR was also achieved with ribociclib in Asians compared with non-Asians (ORR 59% vs. 47%; CBR 86% vs. 80%) [61]. Furthermore, the HR for OS in Asians was 0.40 (95% CI 0.22–0.72) versus 0.91 (95% CI 0.64–1.30) in non-Asians [75]. A recent meta-analysis confirmed that ethnicity influences efficacy of CDK4/6 inhibitor therapies (abemaciclib, palbociclib, ribociclib) as first-line treatment options in patients with advanced BC [76]. Specifically, among Asians (n = 492), the HR for PFS was 0.39 (95% CI 0.29–0.51; p < 0.0001) for combination CDK4/6 inhibitor–endocrine therapy compared with endocrine monotherapy, while in non-Asians (n = 2007) the HR for PFS for combination CDK4/6 inhibitor–endocrine therapy versus endocrine monotherapy was 0.62 (95% CI 0.54–0.71; p < 0.0001), demonstrating a significant interaction between ethnicity and treatment effect on PFS (p = 0.002) [76].
In the second-line and beyond setting in advanced BC, the benefits of adding a CDK4/6 inhibitor to fulvestrant in Asian patients were less apparent compared with benefits seen in Caucasian patients. While the MONARCH-2 study demonstrated the addition of abemaciclib led to comparable outcomes between East Asians versus the overall population in terms of PFS HR [0.52 (95% CI 0.36–0.74) vs. 0.55 (95% CI 0.45–0.68)] [70, 71] and OS HR [0.80 (95% CI 0.52–1.24) vs. 0.76 (95% CI 0.61–0.95)] [77], results from the PALOMA-3 and MONALEESA-3 studies did not show similar findings [78]. These results may be limited by the small number of Asians being included in the trials and subtle differences in eligibility criteria used in each study. The median PFS and OS HRs for the Asian population in the MONALEESA-3 study were 1.35 (95% CI 0.57–3.19) and 1.42 (95% CI 0.46–4.33), respectively [68, 79]. In the PALOMA-3 study, OS HR was 1.04 (95% CI 0.57–1.93) in Asian patients versus 0.78 (95% CI 0.60–1.01) in Caucasian patients, despite a similar PFS HR between Asian and non-Asian patients [Asian 0.49 (95% CI 0.27–0.87); non-Asian 0.45 (95% CI 0.34–0.59)] [63, 78]. In the monarchE study, Asian patients with high-risk early BC had clinically meaningful improvements in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) with abemaciclib plus endocrine therapy versus endocrine therapy alone [80]. There was a 22.3% reduction in the risk of developing invasive disease with abemaciclib plus endocrine therapy versus endocrine therapy alone, while 2-year IDFS rates were 93.2% versus 90.1%, and 2-year DRFS rates were 94.4% versus 91.7%. The benefits seen in Asian patients in monarchE were consistent with those seen in the overall population [80].
Although CDK4/6 inhibitors are generally well tolerated and exhibited an acceptable safety profile that is comparable between Asians and non-Asians [61, 74], ethnic variation in AE profiles has been observed. For palbociclib, compared with non-Asians, a reduced rate of fatigue (19% vs. 44%), but increased incidence of neutropenia (92% vs. 78%), stomatitis (41% vs. 24%), rash (32% vs. 11%), and nasopharyngitis (21% vs. 10%) have been reported for Asians [63]. In the PALOMA-3 study, Asian ethnicity was significantly associated with an increased chance of developing grade 3/4 neutropenia with palbociclib [81]. A similar finding was observed in the PALOMA-2 study, and the investigation of pharmacokinetics showed that geometric mean palbociclib Ctrough values were higher in Asians relative to non-Asians (93.8 vs. 61.7 ng/mL), which indicated greater palbociclib exposure in Asians [82]. Pharmacogenetic analyses of the PALOMA-2 and PALOMA-3 studies have suggested an association of drug-related polymorphisms with palbociclib-related neutropenia [83, 84]. Compared with the global study population, a higher rate of neutropenia was also seen among East Asian patients treated with abemaciclib for metastatic or recurrent BC, along with a greater incidence of leukopenia, alopecia, and increased alanine aminotransferase and aspartate aminotransferase levels [73]. In PALOMA-2 dose reductions were used to manage tolerability issues, and Asian patients had dose reductions more frequently than non-Asian patients [82], which has the potential to affect efficacy; however, an exposure-response analysis showed that palbociclib exposure had no impact on PFS [85].
For ribociclib, a higher rate of grade 3/4 QT-interval prolongation occurs among Asians than non-Asians (3.8% vs. 0.6%) [61]. The low number of Asians enrolled across studies greatly limits the ability to make formal inter-ethnic comparisons. A meta-analysis assessing the influence of ethnicity on toxicity associated with combination CDK4/6 inhibitor and endocrine therapy reported that the addition of a CDK4/6 inhibitor resulted in a higher incidence of neutropenia in Asians when compared with non-Asians (91% vs. 75%; p-value between groups 0.00001; p-value for ethnicity interaction 0.07) [76]. Likewise, Asians tended to experience lower rates of diarrhea compared with non-Asians, although the interaction was not statistically significant (15% vs. 32%; p-value between groups 0.003; p-value for ethnicity interaction 0.35) [76]. While Asian ethnicity was generally associated with a significantly lower risk of nausea (p-value for ethnicity interaction 0.007), the difference was not significant (39.4% vs. 42.4%; p-value between groups 0.76) [76]. Interstitial lung disease (ILD) is another class of AE noted in the Asian population, especially in Japan [86]. Differences in genetic sensitivity and variation in reporting ILD as an adverse drug reaction may play a prominent role in the higher incidence rates, although further studies are warranted for validation [86, 87].
Overall, neutropenia appears to be the most common treatment-related AE in Asians treated with a CDK4/6 inhibitor. This is usually manageable through dose reduction or delay and does not affect treatment efficacy, or increase the incidence of neutropenic fever [61, 63, 73, 76, 88, 89]. The generally lower body mass in Asians under a recommended flat dose of CDK 4/6 inhibitors has been proposed as a possible factor that leads to higher toxicities [25]. Genetic factors also play a role, with a Phase 1b study finding that the maximum tolerated dose of ribociclib was 300 mg in Japanese patients versus 600 mg in non-Japanese Asians [90]. Drug exposure seems relatively similar among Asian and non-Asian patients according to the pharmacokinetic profiles [63, 91].
7 Mammalian Target of Rapamycin (mTOR) Inhibitors
Few studies have explored racial differences in the efficacy and safety of mTOR inhibitors in patients with BC, but currently available data suggest similar efficacy and safety profiles for Asian and non-Asian patients with advanced BC (Table 3) [92,93,94,95]. Specifically, the addition of everolimus to exemestane treatment produces similar benefits in survival among Asian (Chinese and Japanese) and non-Asian patients, with a median PFS of 8.5 months versus 7.3 months [93]. The addition of everolimus is associated with more toxicity compared with hormone therapy alone, resulting in a higher proportion of dose reductions and treatment discontinuations [96]. Although everolimus treatment is considered to be well tolerated and safe to use in Asians, some AEs are more common among Asians when compared with non-Asians, such as dysgeusia (31% vs. 20%), pneumonitis (23% vs. 15%), nail disorder (22% vs. 5%), increased lactate dehydrogenase (14% vs. 4%), ILD (13% vs. < 2%), and stomatitis (80% vs. 54%) [93]. These AEs can generally be managed through early intervention and dose modification [93].
8 Bone-Targeted Therapies
Due to an increased risk of bone metastases and treatment-related bone loss, patients with BC are often treated with denosumab or bisphosphonates to prevent and treat skeletal-related events [97,98,99]. Several studies have demonstrated comparable efficacy, safety, and pharmacokinetics for denosumab and zoledronic acid in Asian (predominantly Japanese) cohorts (Table 4) [97, 98, 100] and non-Asian cohorts [101,102,103,104]. For example, Japanese women with BC-related bone metastases show similar baseline levels of the bone turnover marker urinary N-telopeptide corrected for creatinine (uNTx/Cr) to non-Japanese (White and Hispanic) patients following denosumab treatment, along with comparable sustained suppression of uNTx/Cr [97]. Similarly, zoledronic acid is effective for preventing aromatase inhibitor-associated bone loss in postmenopausal Japanese women [98], and has been shown to significantly reduce skeletal complications by 39% in Japanese women with BC and bone metastases [100]. While higher rates of low-grade pyrexia, fatigue, abdominal pain, and hypocalcemia have been reported in Japanese women with zoledronic acid compared with placebo, zoledronic acid is generally well tolerated [100].
9 Poly-ADP Ribose Polymerase (PARP), Phosphoinositide 3-Kinase (PI3K), and Checkpoint Inhibitors
Of the PARP inhibitors under investigation for the treatment of locally advanced/metastatic BC, olaparib and talazoparib have data available for both overall populations and Asian subgroups (Table 5), which generally show that efficacy in Asian subgroups was similar to that in the overall population [105,106,107,108,109,110]. The OlympiAD study investigated olaparib versus physician’s choice of chemotherapy, and while the study was not powered to detect differences between races, the Asian subgroup analysis found that similar to the overall population, there was a greater clinical benefit with olaparib than with chemotherapy with regard to PFS and response rates [106]. Olaparib was well tolerated in Asian patients, having a lower rate of grade ≥ 3 AEs than chemotherapy [106]. The number of Asian patients in the EMBRACA studies of talazoparib versus chemotherapy was limited (n = 33; Table 5); however, both efficacy (as measured by PFS and response rates) and AEs were all consistent with the overall population [110].
The SOLAR-1 study showed that the PI3K inhibitor alpelisib plus fulvestrant prolonged PFS versus placebo plus fulvestrant in patients with PI3K-mutated, hormone-receptor positive, HER2-negative breast cancer who have previously received endocrine therapy (Table 5) [111,112,113]. An analysis of the SOLAR-1 results according to geographic region showed that in Asia, median PFS and response rates were improved with alpelisib plus fulvestrant versus placebo plus fulvestrant, consistent with the overall population; notably, the ORR in Asia was numerically higher than the ORRs seen in other regions (46.7% vs. 21.1% and 21.4% in North America and Latin America, respectively) [113]. The most common AEs of any grade in the Asian subgroup were hyperglycemia and decreased appetite (75 and 58%, respectively) [113]; these occurred in the alpelisib group of the main cohort at a frequency of 64 and 36% [111].
The checkpoint inhibitor atezolizumab was investigated in patients with advanced triple-negative BC in the IMpassion130 study (Table 5) [114,115,116]. In IMpassion130, the White and Asian subgroups had similar median PFS [115], and a subgroup analysis of the 65 Japanese patients participating in IMpassion130 showed consistent results to those in the overall population [114]. Fewer Japanese patients withdrew from IMpassion130 because of AEs compared with the overall population, and generally no new safety signals were observed in this subgroup [114]. Another checkpoint inhibitor that is being investigated in patients with BC is pembrolizumab, in the KEYNOTE studies (Table 5). To date, much of the KEYNOTE data in Asian patients are available only in abstract form; all abstracts reported a benefit of pembrolizumab versus comparator (placebo or standard therapy) that was consistent with the overall population [117,118,119]. Pembrolizumab was well tolerated, with AEs consistent with the known safety profile [117, 118].
10 Future Directions
Asians are often under-represented in clinical trials of BC therapies, limiting conclusions regarding the efficacy and safety of different therapies for this population [3, 120]. While subgroup analyses comparing Asian versus non-Asian populations have been performed in some large international studies, regional and local studies are often required to confirm outcomes in Asian populations. For example, China’s National Medical Products Administration requires large international trials that include at least 100 Chinese patients per intervention, in addition to local pharmacokinetic studies [3]. Similarly, Japan’s Ministry of Health, Labor, and Welfare and Pharmaceuticals and Medical Devices Agency regulatory review requires pharmacokinetic, efficacy, safety, and medical data for Japanese subjects, which leads to initiation of additional clinical trials in Japan [121]. This approval system has been criticized for requiring data from only a small number of Japanese patients that may be inadequate to detect ethnic differences in efficacy and safety [121]. Hence, pharmacovigilance programs in Asian countries play a critical role in post-approval safety monitoring and reporting of AEs [122].
A clear, stage-specific, survival gap remains among different ethnicities despite significant improvement in overall BC outcomes, suggesting the need for inclusion of non-biologic factors, including treatment differences, to explain observed outcome disparities [123]. A lack of understanding of racial and ethnic differences in patient response to pharmacological interventions also has downstream effects for patients by limiting their access to more effective or safer treatments. Likewise, the social, cultural, and economic settings represent challenges in applying the results and recommendations from studies enrolling largely non-Asian populations [1, 3]. Future studies can help to overcome these challenges by actively engaging clinical trial centers in Asia to facilitate greater recruitment of Asians into clinical trials and more robust subgroup analyses of outcomes in Asians [3].
The field of genomics is also providing greater insight in tumor biology, enabling molecularly defined prognostic staging, which could have important implications for Asians with BC [3, 7, 124, 125]. Currently, prognostic staging based on multigene analysis draws from a predominantly Caucasian dataset, offering limited usefulness for risk stratification and therapy selection in Asians, for whom these tests have not yet been validated [3, 124]. Genomics provides an opportunity to establish the molecular profiles and biomarkers for subtypes of BCs that are more prevalent in Asian populations, which can guide treatment selection, and may be used to guide dosing strategies and inform cost-benefit analyses [122, 124]. Used together, tumor genomics and patient pharmacogenetics may facilitate more effective, safer, highly personalized treatments for Asians [125].
11 Conclusions
Asian and non-Asian patients with BC have different risk profiles and tumor biology, in addition to possible race-related differences in pharmacogenetics and environmental factors [122, 124], which can influence the extent to which interventions and treatments validated in Western populations can be generalized and applied to Asian settings.
The efficacy of most BC chemotherapies and hormonal therapies appears to be broadly similar in Asian and non-Asian populations, with the exception of tamoxifen in patients with a CYP2D6*10 polymorphism, which is more common in Asians [29, 32, 35, 37, 38, 41, 42, 126,127,128]. Similarly, comparable efficacy is seen between Asian and non-Asian patients treated with anti-HER2-targeted therapies.
In contrast, the first-line studies with CDK4/6 inhibitors suggest potential race-related differences in the efficacy of these agents [76]. In particular, Asians appear to derive greater benefit from CDK4/6 inhibitor therapy than non-Asians [73, 76], which may be driven by variations in pharmacodynamics given the limited differences in pharmacokinetics [63, 129].
Furthermore, small Asian populations in clinical trials may limit insight into ethnic differences in efficacy and safety profiles of treatments for BC. Notably, differences in efficacy between Asian and overall populations have generally only been found in subgroup analyses with higher numbers of Asians, which has limited statistical validity and would be expected to increase the likelihood of any differences being observed [61, 63, 73]. In addition, the use of varying definitions of Asian race or ethnicity and combination therapies in studies of CDK4/6 inhibitors make it difficult to develop a clear understanding of the relative clinical profile of CDK4/6 inhibitors in Asian versus non-Asian patients [76]. Therefore, further studies are necessary to elucidate any race-related variation in response to CDK4/6 inhibitors and underlying mechanisms.
Asians experience a higher rate of hematological toxicity, particularly neutropenia, following administration of chemotherapy, targeted therapies, and possibly CDK4/6 inhibitors. The underlying mechanisms resulting in these outcomes are not well understood, but these AEs can generally be managed by dose adjustment, suggesting a pharmacokinetic mechanism.
Ethnic disparity has been ignored or meagerly addressed in the past, especially during the era of chemotherapies. With the emergence of evolving targeted agents, some evidence has shed light on ethnic differences in treatment response. This highlights the importance of considering ethnic differences in pharmacokinetics and pharmacodynamics when designing clinical trials of new therapies and it is expected that the greater insights into tumor and patient characteristics from future studies will help guide treatment selection for Asians. Combined with increased recruitment of Asians into clinical trials to facilitate robust subgroup analysis and ongoing pharmacovigilance reporting, incremental improvements in clinical outcomes for Asians with BC can be expected in the future.
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Editorial support was provided by Rangan Gupta, Eli Lilly Services India Private Limited. Sheridan Henness, PhD, of Rx Communications (Mold, UK), made revisions to later versions of the manuscript under the direction of the authors.
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Yen-Shen Lu reports grants and personal fees from Novartis, Pfizer, Roche, and Merck Sharp and Dohme. Winnie Yeo reports personal fees from advisory and speaker roles from Novartis, Eli Lilly and Company, AstraZeneca, Pfizer, Merck, and Eisai. Yoon-Sim Yap reports personal fees and non-financial support from Roche, Eli Lilly and Company, Novartis, AstraZeneca, Pfizer, and Eisai. Yeon Hee Park reports grants and non-financial support from Pfizer, AstraZeneca, Novartis, Merck, Roche, and grants from Eisai. Rebecca Cheng reports personal fees from Eli Lilly and Company. Kenji Tamura and Huiping Li indicated no financial relationships.
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Y-SL, RC, and HL contributed to the conception of the manuscript. Y-SL, Y-SY, RC, and HL contributed to the study design. Y-SL, HL, RC, and YHP contributed to data acquisition. Y-SL, WY, Y-SY, KT, RC, YHP, and HL contributed to data interpretation. RC, and KT drafted the manuscript. Y-SL, WY, Y-SY, KT, HL, RC, and YHP critically reviewed the manuscript. All authors approved the final submitted version.
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Lu, YS., Yeo, W., Yap, YS. et al. An Overview of the Treatment Efficacy and Side Effect Profile of Pharmacological Therapies in Asian Patients with Breast Cancer. Targ Oncol 16, 701–741 (2021). https://doi.org/10.1007/s11523-021-00838-x
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DOI: https://doi.org/10.1007/s11523-021-00838-x