Introduction
Biomarker testing has revolutionized cancer care by enabling more precise and personalized treatment strategies (1). Within this landscape, comprehensive genomic profiling (CGP) and companion diagnostics (CDx) serve distinct yet complementary roles. CGP is a broad genomic testing approach used in cancer genomic medicine to detect molecular alterations that may be clinically relevant across multiple cancer types, even if targeted therapies are not yet available. In contrast, CDx tests identify specific biomarkers that determine patient eligibility for approved targeted therapies.
Beyond genomic testing, biomarker assessment also includes methods such as immunohistochemistry (IHC) and general blood-based biomarkers (e.g., tumor markers), which provide additional insights into cancer biology. Since the approval of genomic panel testing in Japan in 2019 as part of Japan's Cancer Genomic Medicine program, biomarker-based precision treatment has become increasingly accessible to patients (2). However, because CGP is still relatively new in Japan and several CDx tests have only recently become eligible for reimbursement under the national health insurance system, real-world data on the utilization of biomarker testing remain limited.
According to Japanese cancer statistics, approximately one million new cancer cases were diagnosed in 2019. The most common cancer types were colorectal, lung, and stomach cancer, with prostate cancer being the most common among males and breast cancer among females (3). Biomarker testing, particularly CDx and CGP, plays a critical role in optimizing treatment for these prevalent cancers (4). CDx tests enable clinicians to select targeted therapies by identifying biomarkers that predict a patient's response to treatment, thereby helping to optimize the risk-benefit profile of the selected therapy (5). In contrast, CGP enables the simultaneous analysis of multiple genes and molecular alterations, thereby providing a comprehensive genomic overview of a tumor (6,7). By identifying potential therapeutic targets and improving understanding of tumor heterogeneity, CGP serves as a valuable tool in advancing precision oncology.
Tumor-agnostic approaches, which classify tumors based on molecular and genomic characteristics rather than tissue of origin, represent an emerging area of precision oncology. Biomarkers such as microsatellite instability-high (MSI-H), NTRK fusions, and high tumor mutational burden (TMB) are used to guide treatment selection across multiple cancer types.
Numerous biomarker tests have been approved for various targets since the first CDx was approved in Japan in 2011(8). Additional CDx platforms are now used in clinical practice and research in Japan for specific cancer types, including BRACAnalysis CDx® and myChoice® CDx (9), OncoBEAM™ RAS Colorectal Cancer (CRC) kit (10), RASKET™-B kit (11) and the Microsatellite Instability In Vitro Diagnostic (MSI-IVD) kit (12). This study aimed to provide a comprehensive overview of biomarker testing practices across cancer types prevalent in Japan, thereby providing insights into the implementation of precision medicine and personalized treatment approaches in the Japanese population.
Discussion
This study provides a unique nationwide, multi-cancer perspective on biomarker testing patterns within a single healthcare system in Japan, addressing limitations of previous studies focusing on specific tumor types or geographic regions. Although testing levels quickly plateaued within the first few years after approval, the initial increase, particularly in MSI and BRCA1/2 testing, is consistent with global trends in oncology practice and epidemiology (14,15). For example, the National Comprehensive Cancer Network (NCCN) guidelines recommend MSI testing for all patients with a history of colorectal cancer (16). Recent real-world studies from the United States and Spain report relatively high MSI testing rates and increasing utilization over time (17,18), reflecting improved adherence to guideline recommendations, although variability across settings remains. These findings are consistent with our results, which demonstrated increased MSI testing following regulatory approval in Japan. Notably, our study extends prior evidence by providing a nationwide, multi-cancer overview of biomarker testing patterns and addressing gaps in existing country-specific and tumor-specific analyses.
Emerging insights from large genomic datasets reveal differences between ethnicities, such as White and Asian populations, in genomic alteration patterns, including the frequency of cancer driver mutations (19), and real-world evidence indicates that MSI testing uptake also varies by tumor type. Although MSI testing is relatively well established in colorectal cancer, earlier studies in endometrial cancer reported lower testing rates (approximately one-third in Europe), with more recent data demonstrating increasing uptake over time (20,21). In Japan, treatment guidelines for genomic medicine primarily focus on other biomarkers but also recommend MSI testing to guide decisions regarding further treatment with ICI (22). The observed differences in MSI testing utilization likely reflect variations in clinical practice and disease characteristics rather than superiority of testing in any specific cancer (20,21). These findings suggest that discrepancies in testing and clinical application may be driven by a combination of factors, including disease-specific characteristics, regulatory timelines, and practical barriers in clinical adoption. Because the MDV database did not include individual biomarker test results, these discrepancies should be interpreted as differences in test use and post-testing treatment initiation, rather than biomarker-positive detection rates. Furthermore, although biomarker testing plays an important role in treatment selection, patients in routine clinical practice often present with more heterogeneous characteristics than those in clinical trials. Consequently, even when biomarker results are positive, they may not necessarily lead to the use of the corresponding recommended therapies in routine care.
The predominance of MSI testing in colorectal cancer patients and the high frequency of multiple tests in this group suggest a more integrated role of MSI tests in managing colorectal cancer. This pattern may reflect the specific molecular characteristics of colorectal cancer, which require assessment of a broader range of biomarkers (including KRAS/BRAF) for effective treatment stratification (23). The relationship between MSI-H and BRAF mutations in colorectal cancer is crucial for predicting clinical characteristics and prognosis, as described in the Japanese treatment guidelines (24). However, since this study was based on claims data, biomarker test results were unavailable, including the percentage of MSI-H and BRAF-mutated cancers. Future research should further investigate this relationship and its clinical implications.
Differences in MSI testing utilization across cancer types may reflect variation in clinical guidelines and the prevalence of individual cancer types. Akagi et al (25) tested 26,237 clinical samples of multiple cancer types and reported a relatively high MSI-H prevalence in several cancers with historically limited treatment options, including endometrial (16.9%), colorectal (3.8%), gastric (6.7%), esophageal (1.1%), as well as ovarian (2.2%) and pancreatic (0.8%) cancers. In the current nationwide analysis, testing rates were high in gastric cancer (97.3%) and endometrial cancer (98.2%), but lower in ovarian cancer (47.1%). However, patients in this study were required to have at least one claim for any of these five biomarkers. Therefore, the reported testing rates reflect the distribution of biomarker testing among tested patients rather than among all patients diagnosed with a given cancer type. This distinction should be considered when interpreting the results.
During the study period, Japanese treatment guidelines recommended MSI testing before initiating second-line treatment, particularly for gastric cancer (26), based on the effectiveness of pembrolizumab in MSI-H tumors. Similarly, Japanese treatment guidelines for endometrial cancer also recognize the effectiveness of pembrolizumab for MSI-H cases (27). In contrast, ovarian cancer guidelines only make a cautious reference to pembrolizumab use in patients with MSI-H tumors because of insufficient supporting data (28). These differences reflect a more selective and evidence-based application of genomic testing across cancer-specific treatment strategies.
The relatively stable mean time to treatment initiation post-MSI testing across tumor types suggests a relatively uniform response to testing results in routine clinical practice in Japan. However, the low proportion of patients who received a new treatment after testing indicates potential barriers to translating test results into therapeutic action (29). Detection of MSI-H is important for identifying tumors that may respond to pembrolizumab in gastric cancer and potentially other ICIs (30). Furthermore, emerging real-world evidence suggests that not only testing itself but also the time from biomarker testing to treatment initiation is critical, as delays in testing or subsequent therapy initiation may be associated with poorer survival outcomes (31). The relatively low proportion of patients who newly initiated treatment after biomarker testing may have several explanations, including negative or non-actionable test results, prior use of relevant therapy before the index date, clinical deterioration before treatment initiation, limited treatment access, or transfer to another institution following testing, resulting in subsequent therapies not being captured in the database. Because claims data do not include reasons for clinical decision-making, these factors could not be separately evaluated.
BRCA1/2 testing plays an important role not only in detecting germline mutations but also in guiding treatment decisions. The introduction of BRCA1/2 testing for hereditary breast and ovarian cancer (HBOC) syndrome has been a key factor driving its utilization. Following approval of BRCA analysis as a CDx for olaparib treatment for BRCA1/2 mutated ovarian cancer, the number of BRCA1/2 tests increased from 2019 onward (32). Consistent with this observation, real-world evidence demonstrates a marked increase in BRCA testing uptake over time, with the proportion of patients tested within one year of diagnosis increasing substantially across successive years (33).
However, the adoption of BRCA1/2 testing declined following approval of HRD tests as CDx for the PAOLA-1 regimen at the end of 2020(34). Real-world evidence suggests that, despite widespread BRCA testing, the uptake of HRD testing remains relatively low, with substantially fewer patients undergoing HRD testing compared with BRCA testing in clinical practice. This pattern may reflect the later approval and gradual adoption of HRD testing, as well as practical considerations such as testing complexity, and suggests that HRD testing is likely to increase over time in a manner similar to the earlier expansion of BRCA testing following its clinical adoption (35). It indicates that the landscape of biomarker testing in clinical practice is substantially influenced by the availability of specific tests and the approval of associated therapies.
One real-world study in Japan found that 26.8% of newly diagnosed advanced ovarian cancer patients had tissue BRCA1/2 mutations, with 60.0% having HRD (36). Considering the high prevalence of HRD in ovarian cancer, and the convenience of MyChoice CDx test from Myriad Genetics, HRD testing may become more common than BRCA1/2 testing in current clinical situation (37). The MyChoice CDx test assesses both HRD positivity and tumor BRCA1/2 mutation status; however, it cannot distinguish between germline and somatic BRCA1/2 mutations.
Olaparib was approved in Japan in 2020 as a treatment option for BRCA mutated pancreatic and metastatic castration-resistant prostate cancer (34). Given this relatively recent approval during the study inclusion period, the lower testing rates observed in these cancer types may reflect later adoption of BRCA CDx testing compared with ovarian cancer, where BRCA testing and PARP inhibitor use were established earlier. This relatively low prevalence of BRCA mutations in pancreatic cancer (38) and metastatic castration-resistant prostate cancer (39) may also have contributed to the lower utilization of BRCA CDx testing.
The number tissue-based CGP tests was 45-fold higher than that of liquid biopsy-based CGP during the study period. One factor contributing to this difference is the earlier regulatory approval of tissue-based CGP (2018) compared with liquid biopsy-based CGP (2021) in Japan (40,41). Given the study period, this difference in timing likely had a substantial impact on utilization. Although Japanese clinical oncology practice guidelines authored by the Japanese Cancer Association, the Japanese Society of Medical Oncology, and the Japan Society of Clinical Oncology have recommended the use of liquid biopsy in certain situations (40), several factors may have contributed to its lower use in practice. These include challenges in determining the optimal timing of testing, concerns regarding false-negative results due to limited ctDNA sensitivity, and practical barriers such as lack of familiarity and variability in reimbursement. Although specific reasons could not be evaluated in this descriptive database study, such barriers may nevertheless exist and may have influenced the observed adoption patterns (42,43). These include the limited availability of approved liquid biopsy tests, as well as perceived differences in sensitivity and reliability compared to tissue biopsies. Additionally, ICI treatments were frequently initiated after tissue-based CGP but not after liquid biopsy-based CGP, suggesting a higher level of clinical confidence in tissue-based results for guiding immunotherapy decisions. However, a recent study investigating FoundationOne Liquid testing in Japan between 2021 and 2023 reported increasing utilization over time and suggested that liquid biopsy testing may provide therapeutic benefits in several distinct cancer types (44).
Biomarker-driven treatment selection plays a critical role across multiple cancer types, guiding the use of targeted therapies and immunotherapies. MSI-H testing helps identify patients eligible for treatment with ICI (25,41), while other biomarkers, such as BRAF and KRAS mutations, influence treatment selection by predicting treatment response or resistance. Similarly, BRCA1/2 and HRD testing inform the use of PARP inhibitors, particularly in cancers in which deficiencies in DNA repair influence therapeutic response.
In the context of CUP and rare cancers, the high percentage of patients not receiving treatment after CGP testing warrants attention. The notable low rate of access to treatment following both tissue-based and liquid biopsy-based CGP highlights challenges in identifying actionable targets and the limited availability of testing options for Japanese patients. Limited access to genotype-matched therapy post-CGP is a known issue in Japan (45-47). To address these obstacles, academic institutions are actively working to enhance patient enrollment in clinical studies guided by CGP results. For CGP, this gap may reflect the absence of actionable alterations, limited access to approved genotype-matched therapies or clinical trials, deterioration of patient condition before treatment initiation, and institutional restrictions because CGP is available through designated cancer genomic medicine institutions.
A recent systematic review has highlighted the important role for liquid biopsy in prostate cancer for accurately detecting multiple biomarkers and reducing costly false positives (48). This situation accentuates the need for more research and drug development in these areas.
Limitations of the claims database include the inability to track patients across institutions and the lack of information on biomarker test results, actionable alterations, performance status, disease stage, line of therapy, treatment intent, and reasons for not receiving subsequent treatment. Therefore, subsequent treatments after transfer to another institution may have been underestimated. In addition, differences between CDx and CGP testing may partly reflect institutional resource differences, because CDx tests are more widely available whereas CGP is restricted to designated cancer genomic medicine institutions. These limitations should be considered when interpreting the observed gap between biomarker testing and treatment initiation. Therefore, the present study focused on descriptive analyses of nationwide biomarker testing and treatment initiation patterns.
Although formal statistical comparisons across cancer types or trend analyses over time could technically be performed, we considered such analyses unlikely to provide clinically meaningful insights within the context of this study. The included cancer types differ fundamentally with respect to biomarker indications, clinical practice guidelines, regulatory approval and reimbursement timelines, and available targeted therapies, all of which substantially influence testing practices. As a result, statistical comparisons would largely reflect these inherent differences rather than differences attributable to biomarker utilization itself. Furthermore, because study eligibility criteria required patients to have undergone at least one biomarker test, the reported proportions describe biomarker testing patterns within a selected cohort of tested patients rather than the frequency of biomarker testing among all patients with a given cancer type. Accordingly, inferential comparisons across cancer types or formal trend analyses were considered unlikely to provide additional clinically meaningful insight beyond the descriptive findings presented.
In conclusion, biomarker testing in routine oncology care in Japan is still emerging, driven by rapidly expanding treatment options and growing insights into tumor biology. This nationwide real-world study provides an early comprehensive view of biomarker testing prevalence and utilization trends, revealing a persistent gap between testing and treatment initiation. Although descriptive in nature, this study provides clinically meaningful insights, particularly given the lack of available methodologies at the time of study initiation for comprehensively characterizing real-world testing patterns.
Although biomarker testing is increasing, its effective integration into clinical practice remains limited. Further analyses of large healthcare databases may help identify barriers and support the development of targeted strategies to advance precision oncology, including broader dissemination of guideline-recommended testing and improved integration of biomarker testing into treatment decision-making. These findings provide clinically relevant insights to inform strategies for optimizing the implementation of biomarker-driven treatment in routine practice.