Abstract
PURPOSE
The pan-cancer presence of microsatellite instability (MSI)–positive tumors demonstrates its clinical utility as an agnostic biomarker for identifying immunotherapy-eligible patients. Additionally, MSI is a hallmark of Lynch syndrome (LS), the most prevalent cancer susceptibility syndrome among patients with colorectal and endometrial cancer. Therefore, MSI-high results should inform germline genetic testing for cancer-predisposing genes. However, in clinical practice, such analysis is frequently disregarded.
METHODS
A next-generation sequencing (NGS)–based technique was used for MSI analysis in 4,553 patients with various tumor types. Upon request, somatic BRAF gene analysis was conducted. In addition, hereditary testing of cancer-associated genes was performed in MSI-high cases using a capture-based NGS protocol. MLH1 promoter methylation analysis was conducted retrospectively in patients with colorectal and endometrial cancer to further investigate the origin of MSI at the tumor level.
RESULTS
The MSI positivity rate for the entire cohort was 5.27%. Endometrial, gastric, colorectal, urinary tract, and prostate cancers showed the highest proportion of MSI-high cases (15.69%, 8.54%, 7.40%, 4.55%, and 3.19%, respectively). A minority of 45 patients (22.73%) among the MSI-high cases underwent germline testing to determine whether the mismatch repair pathway deficiency was inherited. 24.44% of those who performed the genetic test carried a pathogenic variant in an LS-associated gene. Three MSI-high individuals had non-LS gene alterations, including BRCA1, BRCA2, and CDKN2A pathogenic variants, indicating the presence of non–LS-associated gene alterations among MSI-high patients.
CONCLUSION
Although MSI analysis is routinely performed in clinical practice, as many as 77% of MSI-high patients do not undergo LS genetic testing, despite international guidelines strongly recommending it. BRAF and MLH1 methylation analysis could shed light on the somatic origin of MSI in 42.50% of the MSI-high patients; however, MLH1 analysis is barely ever requested in clinical practice.
INTRODUCTION
The mismatch repair pathway (MMR) is one of the primary DNA repair mechanisms, responsible for maintaining genomic stability and correcting DNA mismatches. MMR-deficient cells are susceptible to mismatch errors during replication in the microsatellite regions.1 Tumors exhibiting microsatellite instability (MSI) are characterized as MSI-high. The MSI-high phenotype has been observed in a wide variety of tumor types, with higher prevalence in colorectal cancer (CRC) and endometrial carcinoma (EC).2,3
CONTEXT
Key Objective
The objective of this study is to examine the prevalence of microsatellite instability (MSI) in Greek patients with cancer and determine the proportion of MSI-high patients referred for germline testing as indicated by international guidelines.
Knowledge Generated
MSI analysis has pan-cancer applicability, as evidenced by the prevalence of positive cases in a variety of tumor types. In addition, the clinical value of MSI testing as a screening tool to identify patients with a higher likelihood of a germline etiology of tumor development is not well recognized. Consequently, a significant percentage of individuals with Lynch syndrome remain undiagnosed.
Relevance
MSI-positive patients constitute a high-risk group for hereditary cancer; therefore, it is critical to raise awareness of the value of genetic testing in this population immediately.
Lynch syndrome (LS), the most prevalent inherited CRC syndrome, with an autosomal dominant inheritance pattern, has been linked to MMR deficiency and occurs in 3% of patients with CRC and 6% of patients with EC, but it is also associated with other tumor types.1,4-6 It is caused by inactivating germline variants in one of the primary MMR genes (MSH2, MLH1, MSH6, PMS2, and EPCAM).1,6 MMR deficiency is observed in 90% of individuals with LS but it can also be detected in sporadic malignancies.7-10
Additionally, in dMMR/MSI-H CRC, the identification of a BRAF V600E gene mutation or MLH1 gene promoter hypermethylation reveals the sporadic nature of the MMR deficiency, whereas LS should be suspected in the case of a negative result for both tests.11,12
The clinical utility of MSI analysis has increased since the association between MSI-high malignancies and anti–PD-L1 treatment response was established.13-15 The prevalence of MSI varies among tumor types, with the rates ranging from 10% to 15% in CRC and EC to 0% in other tumor histologic types, including lung cancer, thereby limiting its impact on clinical decision making for certain malignancies.2,3,16 Significantly, tumor MSI analysis could inform patient selection for inherited cancer susceptibility testing.11,17,18
This study aims to determine the prevalence of MSI among Greek patients with cancer. Additionally, we will examine the proportion of MSI-high patients referred for germline testing as indicated by international guidelines. Finally, the influence of additional factors, such as the patient's age and tumor histology, on the clinicians' decision for germline testing requests will be evaluated.
METHODS
Patients' Selection
In this study, 4,553 patients with metastatic cancer were referred by their treating oncologist for MSI analysis from January 2020 to April 2023. All the patients who participated in the study provided written informed consent. This study was approved by the Ethics Committee of the General Hospital of Volos. All treatment physicians were informed about the utility of BRAF analysis in patients with CRC and hereditary cancer predisposition testing in MSI-high patients, and the tests were performed upon request. The detailed study design can be seen in the Data Supplement (Fig S1).
Tumor Biomarkers Analysis
The Ion AmpliSeq Microsatellite Instability Panel (Thermo Fisher Scientific, Waltham, MA) was used for next-generation sequencing (NGS)–based MSI analysis in DNA extracted from formalin-fixed paraffin-embedded tumor biopsies as described previously.19 BRAF analysis was conducted using a custom 23-gene Ion AmpliSeq panel (Thermo Fisher Scientific).20 Sequencing was performed on an Ion GeneStudio S5 Prime System NGS platform (Thermo Fisher Scientific). The methylation pattern in the promoter of the MLH1 gene was determined by methylation-specific polymerase chain reaction as previously described.21
NGS-Based Germline Genetic Testing
DNA extracted from peripheral blood was analyzed using a capture-based approach with custom-designed probes (KAPA HyperExplore Max 3 Mb T1, NimbleGen, Roche) targeting all coding exons and 20 bp of flanking intronic regions of 52 genes involved in hereditary predisposition to cancer. Sample preparation was performed according to the SeqCap EZ HyperCap Workflow (Roche NimbleGen, Pleasanton, CA) as previously described.19 Sequencing was performed on the DNBSEQ-G400 NGS platform (MGI Tech, Beishan Industrial Zone, Shenzhen, PR China).
Statistical Analysis
SPSS (version 20, IBM SPSS Statistics, Armonk, NY) was used to compare the age of cancer diagnosis and the implementation of germline testing as well as the age and detection of a germline mutation using the t-test for independent means. A P value of <.05 was considered statistically significant. The Plotly.js charting library was used to generate box plots.
RESULTS
A total of 4,553 patients were referred by their treating physician for tumor MSI analysis. Approximately half of the cases (2,289) consisted of CRCs. The remaining tumor types included those with known MSI occurrences, such as gastric, endometrial, breast, and prostate cancers, as well as tumors where MSI is not typically detected, such as pancreatic, lung, ovarian, breast, and brain tumors (Fig 1, Data Supplement).
FIG 1.
Tumor types of patients who were referred for microsatellite instability analysis by their respective treating physicians.
The increased awareness of the value of MSI testing as a predictive marker for immune-checkpoint Inhibitors (ICI) has led to an increase in the number of patients undergoing such analysis, from 1,016 in 2020 to 1,370 in 2021 and 1,571 in 2022, with 571 patients already tested in the first 4 months of 2023.
Two hundred forty (5.27%) patients exhibited MSI, with an average age of cancer diagnosis of 67 years. MSI-high patients comprised 57.92% female and 42.08% male. The occurrence varied among different histologic types. MSI was detected in 7.40% of patients with CRC, and in 15.69% of endometrial cancer tumors; the percentage was also high for gastric cancer, tumors of the urinary tract, prostate cancer, and tumors of unknown origin. Brain, lung, and biliary tract tumors, as well as sarcomas, did not exhibit MSI (Fig 2). The pan-cancer presence of MSI-positive tumors supports its use as an agnostic biomarker, suggesting the utility of this analysis in immunotherapy-considering patients.
FIG 2.
MSI prevalence in various tumor histologic types in the cohort of 4,553 patients with solid tumors. MSI, microsatellite instability.
MSI should also serve as an indicator of a possible hereditary cancer syndrome. In 42 patients with CRC, a BRAF V600E mutation was also present, which indicates that the MMR deficiency has a somatic cause. This variant was identified in 24.85% of the MSI-high patients with CRC. No BRAF mutation was detected in the patients with EC tested.
Excluding these cases, 198 MSI-high patients were eligible for genetic testing with a hereditary cancer panel. Nevertheless, such a test was requested for only 45 of the eligible patients, accounting for 22.73% of the MSI-high cases. Patients with a germline test tended to have a lower median age at disease diagnosis of 59 years compared with 66 years for those without germline genetic analysis (Fig 3). Age and test implementation were highly correlated, indicating that the age of disease onset was a main criterion for genetic analysis requisition from the treating physician (t = 3.12112, P = .001037). Patients with colorectal (28), endometrial (nine), gastric (four), ovarian (two), breast (one), and gallbladder (one) malignancies underwent germline analysis. Requests for testing differed according to the tumor's histologic type. A discrete percentage of 60% (3/5) of MSI-high patients with breast and ovarian cancer underwent the analysis, predominantly because of the elevated germline analysis surveillance in these tumor types. Among other histologies, a smaller proportion of MSI-high patients underwent germline analysis, including 28.13% (9/32) of MSI-high patients with endometrial cancer, 22.05% (28/127) of MSI-high CRC patients with BRAF wild-type, and 19.05% (4/21) of MSI-high patients with gastric cancer. Only 2.94% of MSI-high patients with other tumor types received a germline analysis.
FIG 3.
Boxplots displaying the age distribution and median age of disease diagnosis of microsatellite instability-high patients who requested genetic testing with an inherited cancer gene panel versus those who did not.
Eleven patients diagnosed with colorectal or endometrial cancer (24.44%) had a positive germline MMR gene result. In addition, an endometrial cancer patient with both MSH2 and BRCA2 variants and a CRC patient with both MLH1 and CDKN2A variants harbored double mutations. MSI was also observed in one patient with breast cancer carrying a germline variant of the BRCA1 gene. Additionally, a variant of uncertain significance was detected in 16/45 (35.55%) of the patients (Fig 4). Individuals with a pathogenic or likely pathogenic variant had a median cancer diagnosis of 48.5 years, whereas those without a clinically significant finding had a median age of 60 years. Nonetheless, 41.67% (5/12) of the patients with a pathogenic germline variant identified had a disease onset age of over 50 years. The presence of germline variants in older MSI-high individuals indicates that the analysis is also informative in this age group, as indicated by international guidelines.
FIG 4.
Germline testing outcomes and distribution of the pathogenic variants in the 45 microsatellite instability-high individuals who underwent a germline analysis. VUS, variant of uncertain significance.
Since MLH1 methylation is an established origin of somatically driven MSI instability in CRC and EC, we conducted a retrospective analysis of the MLH1 status in BRAF wild-type patients with these tumor types who either did not undergo germline analysis or were MMR germline-negative. MLH1 hypermethylation was present in 58 (58.58%) of the 99 patients with CRC and 20 (86.96%) of the 23 patients with EC who did not perform germline testing. Among the 26 germline MMR-negative cases, MLH1 methylation was present in all seven EC but only in 11/19 (57.89%) patients with CRC. These results indicate that although MLH1 methylation appears to be the most prevalent mechanism of somatic MMR dysregulation in EC, alternative mechanisms, such as somatic MMR or other cancer gene alterations, are also implicated in CRC.22
DISCUSSION
The utility of MSI analysis as a biomarker for the selection of patients eligible for ICI treatment has been well documented, thereby enhancing its implementation in clinical practice.15,17,23-27 Consequently, the number of patients evaluated for MSI continues to rise, providing a greater understanding of its prevalence in various tumor types. Since its approval in 2017 as an ICI predictive biomarker, the number of patients undergoing such a test has doubled in our laboratory, from <450 patients per year in 2016 to over 1,500 patients per year in 2022.
MSI instability was identified in 5.19% of the cases within a cohort of 4,553 patients with cancer of Greek origin. Consistent with previous reports, the highest prevalence in MSI-high patients was detected in endometrial cancer, gastric cancer, and CRC, accounting for 15.69%, 8.54%, and 7.40% of cases, respectively.2
In addition, several other tumor types showed modest but substantial percentages of positivity. These findings suggest that MSI analysis of various malignancies is warranted, particularly for neoplasms affecting the urinary tract, prostate, and those with an uncertain origin. The cohort under investigation did not exhibit MSI positivity in brain tumors, cholangiocarcinoma, lung cancer, and sarcomas. Nonetheless, other studies have shown that although uncommon, MSI can also be detected in these tumors, so testing is advised.2,3
The utility of MSI analysis is also essential for identifying patients with a cancer-related pathogenic germline variant.10,23 Germline testing for LS was performed in only 45 of the 240 MSI-high patients. In 42 cases, exclusion from germline testing was justifiable because of the presence of a BRAF mutation associated with somatic MMR inactivation in CRC. Therefore, only 45 of the 198 patients (22,73%) eligible for germline analysis were referred by the treating physician for the test. Contrary to the current guidelines, which recommend germline testing for patients with colorectal, endometrial, ovarian, high-grade prostate, and pancreatic adenocarcinomas, this has not been the case.
MLH1 methylation analysis is another method to evaluate the necessity of germline testing since its presence indicates a somatic etiology of the MSI, but it is almost never requested in clinical practice. Retrospective evaluation of the MLH1 methylation could exclude the germline origin of MSI in an additional 96 patients with CRC and EC diagnosis. Hence, 102 of the 240 (42.50%) patients had a confirmed somatic origin of the MSI, while 57.50% (138/240) of the patients would be eligible for germline testing, considering both BRAF and MLH1 methylation analysis. This is in accordance with previous studies indicating the necessity of BRAF and MLH1 methylation analysis in patients with CRC and of MLH1 methylation in those with EC.12,28
Moreover, current evidence supports germline genetic testing for LS in patients with MSI-high/MMR-deficient tumors, independently of the cancer type or family history.29 According to a recent report, germline testing for cancer susceptibility genes should be implemented universally as nearly equivalent percentages of inherited alterations are detected in patients with cancer who adhere to genetic testing guidelines and those who do not (7.4% and 8.1%, respectively).30 In addition, it is well known that patients with CRC may be carriers of non–LS-inherited variants.5 However, as many as 6.3% of those with an MMR gene–inherited alteration could be missed using tumor MMR analysis only.31 On the basis of these and other studies, evidence is accumulating in favor of germline testing in all patients with solid tumors.32
In our cohort, however, 77% of MSI-high patients did not undertake a test for LS-associated inherited mutations. In addition, unlike breast cancer, inherited CRC is underdiagnosed as the number of patients who undergo germline testing appears to be substantially lower. The surveillance of hereditary breast and ovarian cancer syndrome has been intensified in Greece, as evidenced by the referral of over 5,000 individuals with a personal and family history of breast cancer for germline analysis in our laboratory over the past 3 years. By contrast, the number of referrals for individuals diagnosed with CRC in the past 3 years was limited to 120, although it is the third most prevalent malignancy. During the same time frame, 4,553 MSI tests were requested, indicating that somatic testing surveillance is considerably more extensive. Therefore, it appears that <3% (1 in every 37 cases) of patients with CRC undergo testing for germline alterations. In accordance with a recent study indicating suboptimal rates of MSI/IHC screening and germline genetic testing adoption in patients diagnosed with CRC, despite universal eligibility, our findings support such a hypothesis.33
Moreover, it has been demonstrated that a familial or personal CRC history is not predictive of CRC patients with an inherited cancer susceptibility syndrome including LS.5 In addition, a study involving more than 15,000 patients with over 50 categories of cancer revealed that LS is detectable in 16% of MSI-H patients. Half of the LS patients with MSI-high tumors had histologic types other than CRC or EC. Moreover, on the basis of personal/family history, 45% of these patients with non-CRC/EC tumors did not meet LS genetic testing criteria. Therefore, it is recommended that all patients with MSI-high phenotype, independently of cancer type, should undergo laboratory genetic testing for LS.29
Despite these data, it appears that age at disease diagnosis was the primary criterion for selecting patients to undergo germline analysis. In our study, the mean age of disease diagnosis for patients who requested germline testing was 59 years, compared with 66 years for those who did not undergo germline testing. This criterion will undoubtedly result in a higher germline variant positivity rate, yet it is also stringent enough to exclude many patients with inherited mutations. In our cohort, 41.67% of patients with germline pathogenic variants were older than 60 years (range, 61-77 years). The analysis provides information regarding the patient's current condition and the likelihood of developing other LS-associated cancers, allowing the implementation of prophylactic surveillance to prevent their occurrence.6 Moreover, the multigene analysis permits the identification of pathogenic variants in non–LS-associated genes. For example, a BRCA1-positive woman was identified despite her breast cancer diagnosis at age 66 years and the absence of a family history of the disease. Beyond that, the presence of double gene alterations in two patients may enhance surveillance for a variety of other tumor types in addition to the primary tumor diagnosis. The CDKN2A/MLH1-positive patient with CRC should also undergo preventive screening tests for pancreatic cancer and melanoma, while the BRCA1/MSH2-positive patient with endometrial cancer should also be screened for tumors associated with the hereditary breast and ovarian cancer syndrome.34-36 Tumor analysis of double heterozygotes revealed a biallelic inactivation of the MMR gene with germline alteration in both samples (as defined by a variant allele frequency of >85%), whereas the other alteration was monoallelic. This finding suggests that the presence of MSI in these patients was driven by double somatic hits in the MMR genes.
Furthermore, it is essential to consider the clinical utility of the genetic analysis for the patient's relatives, as genetic counseling may provide them with crucial information regarding their own susceptibility to cancer and the necessary preventive measures.31 Therefore, if a pathogenic variant at a high-risk gene for cancer predisposition is identified, cascade analysis of at-risk relatives for the variant identified in the proband should be offered. A positive outcome could result in appropriate monitoring and management. Conversely, unnecessary concern can be avoided in case the tested relative does not carry the pathogenic variant detected in the proband.
The dissemination of information on the importance of germline analysis, particularly in patients with high microsatellite instability (MSI-high), has been a longstanding focus of our laboratory. To achieve this aim, conferences and educational sections for physicians on LS screening have been organized. Additionally, physicians are always made aware of the need for such analysis in the event of a high MSI result. In most cases, however, they respond that the patient's priority is to identify the most effective treatment and that he or she is unwilling to undergo a germline analysis because of the worry of receiving a positive result and the high analysis cost. However, lowering the test's price had little impact on the quantity of tests requested. Therefore, the annual number of MSI-high patients undertaking germline testing has increased marginally from eight patients in 2020 to 13 in 2021 and 16 in 2022.
Therefore, it appears that patients remain unaware of the benefits of hereditary analysis for most tumor types, except for breast cancer, where the Angelina Jolie effect has led to an increase in genetic testing.37 Therefore, it is essential to enhance the public's awareness about the necessity of preventive measures against hereditary cancer and the value of genetic analysis. To achieve this objective, implementing of a comprehensive national strategy is vital, requiring the participation of authorities within the public health system and medical organizations. These entities will be responsible for effectively disseminating information to the general population about the potential hazards associated with undiagnosed inherited cancer susceptibility. In Greece, for example, the national health system reimburses the cost of germline BRCA1/2 testing for all patients with ovarian cancer, patients with breast cancer younger than 45 years, and their relatives. Germline testing reimbursement should also be extended to MSI-high patients. Doing so will render such analysis accessible to patients who cannot afford it. Additionally, it will emphasize its significance to those in a dilemma.
This research has a number of limitations. We do not have data on the proportion of patients with metastatic cancer who undertake MSI or LS analysis; we can only report the decreased proportion of MSI-high patients who undergo germline analysis for LS. Similarly, we cannot exclude the possibility that patients who did not perform germline analysis in our laboratory will pursue such testing at an alternative facility or in the future. Actually, the median time between MSI analysis result release and germline analysis request varied from 0 to 748 days (median, 45.42 days). Another limitation is the lack of somatic analysis data from patients with MSI-high tumors to ascertain other potential somatic origins of the MSI presence.
In conclusion, our study indicates that the implementation of MSI analysis has broad applicability in the context of diverse malignancies, as demonstrated by the presence of positive cases in a wide range of tumor types. In addition, it designates that, in clinical practice, MSI testing is used primarily as a predictive biomarker for ICI response evaluation. Underappreciated, however, is its potential as a screening tool for identifying patients with a higher likelihood of a germline origin of tumor manifestation. More than half of the MSI-high cases without a known somatic etiology of MSI, and therefore eligible for germline testing, do not undergo such testing, resulting in misdiagnosis of LS and other inherited cancer syndromes.
Elena Fountzilas
Stock and Other Ownership Interests: Deciphera, Genprex
Honoraria: AstraZeneca, Roche, Amgen, Roche/Genentech, Pfizer, AstraZeneca
Consulting or Advisory Role: Pfizer, Sanofi, Roche, Amgen
Travel, Accommodations, Expenses: Genesis Pharmaceuticals, AstraZeneca, Pfizer
Anastasios Boutis
Honoraria: Amgen, AstraZeneca, MSD, Roche, Ipsen, Merck, Boehringer Ingelheim
Consulting or Advisory Role: BMS GmbH & Co KG, Ipsen, Novartis, Pfizer, Servier
Danai Daliani
Consulting or Advisory Role: Astellas Scientific and Medical Affairs Inc, Pfizer Hellas
Travel, Accommodations, Expenses: Hospira
Michalis Liontos
Employment: Pfizer
Stock and Other Ownership Interests: Pfizer
Honoraria: MSD Oncology, Roche, Janssen, Bristol Myers Squibb/Celgene, AstraZeneca, Ipsen, Astellas Pharma, GlaxoSmithKline
Consulting or Advisory Role: Amgen, GlaxoSmithKline, AstraZeneca, Janssen
Travel, Accommodations, Expenses: Pfizer, Janssen, MSD Oncology
Vasileios Ramfidis
Speakers' Bureau: MSD Oncology, Pfizer, Bristol Myers Squibb/Medarex, Sanofi, AstraZeneca
Travel, Accommodations, Expenses: Pfizer, Bristol Myers Squibb/Medarex, MSD Oncology, Sanofi
Theofanis Floros
Speakers' Bureau: Roche, MSD, Merck Serono, AstraZeneca, Pierre Fabre, Bristol Myers Squibb/Greece
Expert Testimony: Pfizer Hellas, Merck/Greece, MSD/Greece
Travel, Accommodations, Expenses: ENORASIS/Greece, INNOVIS/Greece
Anastasia Katseli
Employment: Genekor SA, ALPHA LAB
No other potential conflicts of interest were reported.
SUPPORT
Supported in part by GENEKOR MSA which provided support in the form of salaries for authors E.P., C.F.-C., K.A., A.M., A.T., A.K., K.P., G.T., V.M.-M., and G.N. but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
AUTHOR CONTRIBUTIONS
Conception and design: Eirini Papadopoulou, George Rigas, Stylianos Giassas, Nikolaos Mitsimponas, Vasileios Ramfidis, Charalampos Christophilakis, Dimitris Matthaios, Theofanis Floros, George Nasioulas
Financial support: George Rigas, Stylianos Giassas
Administrative support: George Rigas, Anastasios Boutis, Stylianos Giassas, Dimitris Matthaios, Konstantinos Agiannitopoulos, Kevisa Potska
Provision of study materials or patients: George Rigas, Elena Fountzilas, Anastasios Boutis, Stylianos Giassas, Nikolaos Mitsimponas, Danai Daliani, Charalampos Christophilakis, Dimitris Matthaios, Theofanis Floros, Anastasia Katseli
Collection and assembly of data: George Rigas, Elena Fountzilas, Anastasios Boutis, Stylianos Giassas, Nikolaos Mitsimponas, Danai Daliani, Dimitrios C Ziogas, Michalis Liontos, Vasileios Ramfidis, Charalampos Christophilakis, Dimitris Matthaios, Theofanis Floros, Aikaterini Tsantikidi, Georgios Tsaousis
Data analysis and interpretation: Eirini Papadopoulou, George Rigas, Stylianos Giassas, Nikolaos Mitsimponas, Dimitrios C Ziogas, Vasileios Ramfidis, Dimitris Matthaios, Chrysiida Florou-Chatzigiannidou, Konstantinos Agiannitopoulos, Angeliki Meintani, Anastasia Katseli, Kevisa Potska, Georgios Tsaousis, Vasiliki Metaxa-Mariatou
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Elena Fountzilas
Stock and Other Ownership Interests: Deciphera, Genprex
Honoraria: AstraZeneca, Roche, Amgen, Roche/Genentech, Pfizer, AstraZeneca
Consulting or Advisory Role: Pfizer, Sanofi, Roche, Amgen
Travel, Accommodations, Expenses: Genesis Pharmaceuticals, AstraZeneca, Pfizer
Anastasios Boutis
Honoraria: Amgen, AstraZeneca, MSD, Roche, Ipsen, Merck, Boehringer Ingelheim
Consulting or Advisory Role: BMS GmbH & Co KG, Ipsen, Novartis, Pfizer, Servier
Danai Daliani
Consulting or Advisory Role: Astellas Scientific and Medical Affairs Inc, Pfizer Hellas
Travel, Accommodations, Expenses: Hospira
Michalis Liontos
Employment: Pfizer
Stock and Other Ownership Interests: Pfizer
Honoraria: MSD Oncology, Roche, Janssen, Bristol Myers Squibb/Celgene, AstraZeneca, Ipsen, Astellas Pharma, GlaxoSmithKline
Consulting or Advisory Role: Amgen, GlaxoSmithKline, AstraZeneca, Janssen
Travel, Accommodations, Expenses: Pfizer, Janssen, MSD Oncology
Vasileios Ramfidis
Speakers' Bureau: MSD Oncology, Pfizer, Bristol Myers Squibb/Medarex, Sanofi, AstraZeneca
Travel, Accommodations, Expenses: Pfizer, Bristol Myers Squibb/Medarex, MSD Oncology, Sanofi
Theofanis Floros
Speakers' Bureau: Roche, MSD, Merck Serono, AstraZeneca, Pierre Fabre, Bristol Myers Squibb/Greece
Expert Testimony: Pfizer Hellas, Merck/Greece, MSD/Greece
Travel, Accommodations, Expenses: ENORASIS/Greece, INNOVIS/Greece
Anastasia Katseli
Employment: Genekor SA, ALPHA LAB
No other potential conflicts of interest were reported.
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