Summary
Background
Patients with osseous metastatic breast cancer receive bone-modifying agents (BMAs) as part of their standard care. Medication-related osteonecrosis of the jaw (MRONJ) is one of the most important toxicities of this class of drugs. MRONJ heavily impacts patients’ quality of life and represents a major medical burden necessitating a discontinuation of treatment. Currently, the diagnosis of MRONJ is established upon the manifestation of clinical symptoms like exposed necrotic jawbone, pain, swelling or signs indicative of infection of the jaw. The objective of this study was to assess the potential of imaging modalities, specifically FDG-PET/CT (positron emission tomography with computed tomography) in the early detection of MRONJ.
Methods
This cohort study in Austria included all patients with metastatic breast cancer who were receiving denosumab and regular PET/CTs, diagnosed with MRONJ between 2000 and 2022 at the Department of Obstetrics and Gynecology Innsbruck. For each of the patients in the study cohort, two control patients with comparable clinical characteristics were matched to serve as a control group. Control patients with metastasized breast cancer did not develop MRONJ but did receive denosumab and regular FDG-PET/CTs. Imaging data were independently assessed by two experienced nuclear medicine physicians.
Findings
Baseline characteristics were well balanced. Patients received 120 mg denosumab once per month subcutaneously without de-escalation of therapy. The median time to develop MRONJ was 23 months (range 5–71, lower Quartile (Q1), upper Quartile (Q3) 16, 40 months). Nuclear medicine physicians detected jaw alterations in 91% (19/21) of MRONJ cases (sensitivity, 95% CI: 70%–98.8%) and in 29% (12/42) of controls, corresponding to a specificity of 71% (30/42; 95% CI: 55%–84%). Median lead time of imaging by demonstrating lesion in the jaw was 238 days (range 11–1118, Q1, Q3 106,494) prior to MRONJ diagnosis. In 68% (13/19) of MRONJ cases the nuclear medicine physicians were able to predict the exact tooth location of MRONJ with a deviation of no more than two teeth.
Interpretation
The high sensitivity and negative predictive value of imaging for early detection of MRONJ underscore its significance for clinical practice. Given that the majority of patients receive regular PET/CTs, our results provide an excellent opportunity for early intervention when MRONJ is detected with a considerable lead time.
Funding
This study received no external funding.
Keywords: Breast cancer, Antiresorptive therapy, Bone-modifying agents, Medication-related osteonecrosis of the jaw, PET/CT
Research in context.
Evidence before this study
Currently, the diagnosis of medication-related osteonecrosis of the jaw (MRONJ) is established upon the manifestation of clinical symptoms like exposed necrotic jawbone, pain, swelling or signs indicative of infection of the jaw. We searched pubmed and Clinical trials database from 2005 to January 2025 for paper published in English using the terms “MRONJ” or “BRONJ (Bisphosphonate-related osteonecrosis of the jaw) “and “imaging” as well as “PET-CT scans (positron emission tomography with computed tomography)”. Our research yielded that few studies reported the superior diagnostic performance of FDG-PET/CT compared to conventional imaging modalities such as CT, orthopantomography (OPG), cone-beam CT (CBCT) and MRI (magnetic resonance imaging), especially in early stage MRONJ. But these studies did not use the imaging for the detection of MRONJ.
Added value of this study
This study is one of the first to assess the potential of imaging modalities, specifically FDG-PET/CT in the early detection of MRONJ.
Implications of all the available evidence
The high sensitivity and negative predictive value of imaging for early detection of MRONJ found in our study underscore its significance for clinical practice. Given that the majority of patients receive regular PET/CTs, our results provide an excellent opportunity for early intervention when MRONJ is detected with a considerable lead time.
Introduction
Standard care for patients with osseus metastasized breast cancer includes treatment with bone-modifying agents (BMAs). Currently, monoclonal antibody denosumab is the most frequently used agent.1 Before its introduction in 2010, bisphosphonates were the treatment of choice. One of the most important toxicities of BMAs is medication-related osteonecrosis of the jaw (MRONJ). Incidence of MRONJ depends on a variety of factors like duration of BMA treatment, ill-fitting dentures and inflammatory dental and periodontal disease.2, 3, 4, 5, 6
The reported incidence of MRONJ for denosumab varies tremendously across studies ranging from 1% to 12%.7, 8, 9, 10 According to ASCO guidelines the clinical diagnosis of MRONJ is established in patients who present with exposed bone or bone that can be probed through a fistula after receiving bone-modifying agents (BMAs), persisting for more than eight weeks.6 If conservative measures like antimicrobial mouth rinses or antibiotics prove ineffective more aggressive surgical inventions are required. Treatment with BMAs may be deferred at the discretion of the treating physician.6
Currently there is no established method or marker to reliably predict MRONJ. Imaging is used to diagnose the extent of MRONJ. A study published by Huber et al. states that imaging like magnetic resonance (MR) imaging as well as cone-beam computed tomography (CBCT) can significantly distinguish diseased from normal bone.11 Also, an increased uptake in bone scans with Tc-99m has been associated with MRONJ.12, 13, 14, 15, 16
A review published by Wongratwanich et al. concluded that functional imaging is the most sensitive method but is usually performed in metastasis detection and response evaluation rather than serving as a diagnostic tool for early MRONJ. Additionally, the article describes a potential early detection of MRONJ via PET (positron emission tomography).17 Similarly, Khan et al. state that in 67.5% of patients with MRONJ increased Tc99m methylene diphosphonate (MDP) or hydroxymethylene diphosphonate (HDP) were observed in regions that subsequently progressed to clinically manifest osteonecrosis.18
Our main objective was to assess whether FDG-PET/CTs can be utilized for predictions of MRONJ development before the onset of clinical symptoms. Furthermore, we evaluated lead time between first appearance of lesion on imaging clinical diagnosis of MRONJ as well as the accuracy of imaging.
Methods
Study design
For this analysis we used data from our retrospective study cohort investigating the incidence of MRONJ with a population-based design with a 20-year follow-up. All patients diagnosed with breast cancer in Tyrol, Austria were screened for a diagnosis of bone metastases as well as treatment with BMAs. The observed incidence was considerably higher than previously reported data at the time. These results of the population-based incidence of MRONJ have recently been published by our group.10
The current study included all patients with metastatic breast cancer receiving BMAs and continuous PET/CTs, diagnosed at the Department of Obstetrics and Gynecology Innsbruck from 2000 to 2022. For each of the patients in the study cohort, two control patients with comparable clinical characteristics were matched to serve as a control group. All patients included in this study were without a confirmed diagnosis of MRONJ at the time of initial FDG-PET scan. Control patients with metastasized breast cancer developed no MRONJ but also received denosumab and regular PET/CTs. Characteristics for matching consisted of age, duration of treatment with BMAs, menopausal status, BMI and type of metastasis. All patients received 120 mg Denosumab once per month subcutaneously without de-escalation of therapy.
The study was registered and approved by the local ethics committee (NCT 1062/2025). The data for the retrospective analysis was collected using an electronic case report form (e-CRF) and managed via the web-based database AskiMed.19 Due to the retrospective study design and the use of anonymized data collected via the electronic case form, no consent was required.
Imaging protocol and analysis
18F-FDG-PET/CT imaging was conducted using a dedicated PET/CT system (Advance, Discovery 690, and Discovery MI; GE Healthcare, Milwaukee, WI). Sixty minutes after injection of 2–3 MBq/kg body mass, a whole-body PET scan (skull vertex to upper thighs) in three-dimensional mode was acquired (2 min per bed position).
All 18F-FDG-PET/CT images were analyzed with dedicated commercially available software (GE Advance Workstation SW Version AW3.2 Ext. 6.0), which allowed the review of PET, CT and fused imaging data in axial, coronal and sagittal slices. Two board-approved nuclear medicine physicians interpreted PET, CT and fused images independently, starting from the beginning of treatment with BMAs until first appearance of elevated metabolic activity in the jaw or present time. In cases of differing assessments, a consensus was reached through joint re-evaluation.
Study endpoints
The primary outcome of this study was to assess the sensitivity and predictive value of elevated metabolic activity in the jaw in PET/CTs for the prediction of the development of MRONJ. This included sensitivity regarding the recognition of elevated metabolic activity in the jaw in PET/CTs in MRONJ patients and predictive value evaluating whether a lesion could be detected prior to a diagnosis of MRONJ.
The secondary endpoints included the time to onset of MRONJ and the accuracy of predicting its exact tooth location with a deviation of no more than 2 teeth.
Statistical analysis
Data are analyzed descriptively. Categorical variables are summarized as counts with percentages n (%); continuous variables as median (Q1, Q3). Diagnostic performance metrics including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) are reported with 95% exact (Clopper–Pearson) binomial confidence intervals calculated from the study counts. In addition, prevalence-adjusted PPV and NPV are presented as point estimates derived from sensitivity, specificity, and an assumed disease prevalence of 11.6% using Bayes’ theorem.10 Percentages were rounded to the nearest integer except for values close to 0% or 100%. Wherever percentages are reported, the corresponding counts are shown as n/N. Analyses were performed using SPSS, version 29 (IBM Corp., Armonk, NY, USA).
Role of the funding source
This study received no external funding.
Results
Study population
The characteristics of our study population are shown in Table 1. The groups were well balanced regarding age, menopausal status, BMI, type of metastasis and duration of BMA. The median age was 60 (Q1 = 25th percentile (lower quartile), Q3 = 75th percentile (upper quartile) 51, 71) years in the MRONJ group and 58 (Q1, Q3 50, 71) years in the control group. Primary metastasized patients already had metastasized breast cancer during their initial diagnosis, secondary metastasized patients had the diagnosis of metastases later during treatment.
Table 1.
Patient characteristics.
| MRONJ (N = 21) | No MRONJ (N = 42) | All (N = 63) | |
|---|---|---|---|
| Age in years, median (Q1, Q3) | 60 (51,71) | 58 (50,71) | 58 (51,71) |
| Menopausal status n (%) | |||
| Premenopausal | 5 (24%) | 12 (29%) | 17 (27%) |
| Postmenopausal | 15 (71%) | 29 (69%) | 44 (70%) |
| Unknown | 1 (5%) | 1 (2%) | 2 (3%) |
| BMI, median (Q1, Q3) | 26.3 (21, 30) | 26.1 (22, 29) | 26.2 (22, 30) |
| Metastasis, n (%) | |||
| Primary metastases | 10 (48%) | 23 (55%) | 33 (52%) |
| Secondary metastases | 11 (52%) | 19 (45%) | 30 (48%) |
| Duration of antiresorptive therapy in months, median (Q1, Q3) |
36 (26,60) | 32 (24,46) | 34 (24,53) |
| Time to MRONJ from Start Antiresorptive treatment |
23 (16,40) |
BMI = body mass index; MRONJ = medication-related osteonecrosis of the jaw Q1 = 25th percentile (lower quartile), Q3 = 75th percentile (upper quartile).
In both groups, the majority of patients were postmenopausal (70%, 44/63) and had a BMI of 26.2 (Q1, Q3 22, 30). The median time to develop MRONJ was 23 months (range 5–71, Q1, Q3 16, 40 months). The median time to develop MRONJ and the duration of antiresorptive treatment in the MRONJ group differ as some patients received Denosumab following surgical revision and subsequent approval by the maxillofacial surgeon.
Sensitivity and specificity of early detection of MRONJ
Nuclear medicine physicians found alterations in 19 (of 21) patients in the MRONJ group and in 12 (of 42) in the control group. Sensitivity of PET/CTs for the early prediction of MRONJ in this study was 91% (19/21; 95% CI: 70%–98.8%) and the specificity 71% (30/42; 95% CI: 55%–84%).
The study PPV was 61% (19/31; 95% CI: 42%–78%) and the study NPV was 94% (30/32; 95% CI: 79%–99.2%). Adjusting to an assumed MRONJ prevalence of 11.6%, the adjusted positive predictive value for developing a MRONJ in presence of a jaw lesion was 29% (95% CI: 17%–45%) and the negative predictive value was 98.3% (95% CI: 93%–99.8%), as shown in Table 2.10 Median lead time from first detectable jaw lesion to clinical MRONJ diagnosis was 238 days (range 11–1118, Q1, Q3 106, 494) before the clinical diagnosis of MRONJ.
Table 2.
Presence of jaw PET/CT alteration.
| MRONJ (N = 21) | No MRONJ (N = 42) | Predictive value | Prevalence-adjusted predictive value | |
|---|---|---|---|---|
| Jaw lesion | 19 | 12 | Positive predictive value (PPV) (n/N; 95%-CI) 61% (19/31; 42%–78%) |
Prevalence-adjusted PPV(95%-CI)a 29% (17%–45%) |
| No jaw lesion | 2 | 30 | Negative predictive value (NPV) (n/N; 95%-CI) 94%(30/32; 79%–99.2%) |
Prevalence-adjusted NPV(95%-CI) 98.3%(93%–99.8%) |
| Sensitivity (n/N; 95%-CI) 91%(19/21; 70%–98.8%) |
Specificity (n/N; 95%-CI) 71% (30/42; 55%–84%) |
MRONJ = Medication-related osteonecrosis of the jaw, NPV = Negative predictive value PPV = Positive predictive value.
Adjusted PPV/NPV computed from sensitivity, specificity, and an assumed prevalence of 11.6% https://doi.org/10.1200/JCO.24.00171.
Fig. 1 shows the PET/CT images of a patient who started receiving Denosumab in December 2015, the first PET/CT showing elevated metabolic activity in the jaw is from January 2018. The patient was later diagnosed with MRONJ in February 2019.
Fig. 1.
PET/CT scans (positron emission tomography with computed tomography) images of a patient who started receiving Denosumab in December 2015, the first PET/CT showing elevated metabolic activity in the jaw is from January 2018. The patient was later diagnosed with MRONJ (medication-related osteonecrosis of the jaw) in February 2019.
Precision of prediction
Regarding precision of the prediction by PET/CT scans, in 68% (13/19) of the MRONJ cases nuclear medicine physicians were able to accurately predict the exact tooth involved in the MRONJ with a deviation of no more than two teeth. In all other cases the correct quadrant or antagonist tooth was identified. A complete comparison can be found in the Supplementary Data.
Discussion
In order to reduce risk of MRONJ, the ASCO Clinical Practice Guideline recommends coordination of care, addressing modifiable risk factors like poor oral health and the omission of elective dentoalveolar surgery during treatment with BMAs.6 Risk factors can be classified into three groups: demographic, systemic, and local.20,21 Demographic risk factors include age and gender, systemic risk factors imply other medications local risk factors entail dentoalveolar surgeries and denti-peridontal infections.20 The ASCO guideline highlights the importance of patient education about modifiable risk factors and a lifelong commitment to oral care.6 From our clinical experience we, strongly emphasize that all patients scheduled for BMAs should undergo a dental examination ideally at a specialized MRONJ clinic, to diagnose and - if indicated–eliminate dentoalveolar pathologies before initiation of BMAs. A recently published paper by Yarom et al. emphasizes that imaging and laboratory tests should be interpreted alongside the patient's medical history, medication use and clinical symptoms. Imaging modalities including nuclear imaging should be used to diagnose, stage, monitor and inform treatment decisions for MRONJ. The choice of imaging modality depends on clinical findings and the need for detailed assessment.22
If dentoalveolar surgery became necessary, patients should be frequently evaluated by a dental specialist and administration of BMA might be deferred at the discretion of the treating physician.6 While there are many studies reporting on the preventative effect of proper oral care methods and effective oral health practices, literature regarding predictive tools of MRONJ is very scarce. In the ASCO guideline the expert panel encourages the creation of predictive tools for the development of MRONJ.6 This underlines the high clinical value of our study.
In past decades, oncologists frequently relied on bone scans (Tc-99m scintigraphy), which were used for evaluating patients with suspected bone lesions as well as for monitoring those with confirmed bone metastases, often alongside other imaging modalities such as X-rays, ultrasound, and later computed tomography (CT). There are various papers investigating the usage of scintigraphy (Tc-99m scans) as an early diagnostic tool for bisphosphonate-related osteonecrosis of the jaw and increased uptake being associated with osteonecrosis of the jaw.12, 13, 14, 15, 16 A Study by O'Ryan et al. showed uptake before the development of BRONJ (Bisphosphonate-related osteonecrosis of the jaw) in almost 66% of patients and in a paper published by Fusco et al. eight out of twelve patients showed uptake in the jaw in later ONJ sites in their Bone Scan (99mTc-MDP scintigraphy).12,14 Thomas et al. even mention the possibility of bone scinigraphy having the potential to unveil or detect MRONJ in the asymptomatic stage.15
More recently, PET/CT scans have gained popularity as a single comprehensive tool for both staging and surveillance of metastatic breast cancer. A study by Pergolini et al. compared BS (Bone scintigraphy) to PET-CT and came to the conclusion, that both may be accurate techniques for an early prediction of MRONJ and can be used as an valid aid in the early diagnosis of MRONJ.23
Our findings suggest that it also serves as a valuable tool for the early detection of MRONJ. This aligns with observations from other studies reporting the superior diagnostic performance of FDG PET/CT compared to conventional imaging modalities such as CT, orthopantomography (OPG), cone-beam CT (CBCT), and MRI, especially in early stage MRONJ.17,18,24,25 According to a study by Bianchi et al., CT was the superior imaging method compared to panoramic radiographs.26 Similarly, Fleisher et al. compared imaging of 23 patients with ONJ (osteonecrosis of the jaw) retrospectively and found that FDG PET/CT detects local and diffuse metabolic changes that may not be detected by plain radiography for patients with ONJ related to BMAs.27 Some papers mention the possibility of detecting MRONJ early with PET/CTs but do not provide further detail.17 According to Berg et al., in PET/CT imaging infected bone tissue will show increased glucose metabolism and it is therefore a valuable tool for the early detection of MRONJ, especially when routine nuclear imaging is acquired for metastasis screening or follow-up purposes.28
While it is not a substitute for routine dental evaluations, FDG PET/CT should be regarded as a complementary tool for the early detection MRONJ. Timely identification of MRONJ through PET/CT imaging can significantly contribute to improving patient outcomes. Early stages of MRONJ can be treated with local wound care and improved oral hygiene. However, studies suggest that conservative treatment of early stage MRONJ does not lead to improve quality of life.29, 30, 31 While early detection of MRONJ offers the seemingly advantageous chance of avoiding surgery, it additionally has substantial clinical value by in influencing the choice, extent and success of surgical intervention. Early stage MRONJ tends to be smaller. This in itself improves the success rate of surgery.32 Moreover, both the stage and size of the lesion at the time of diagnosis determine the surgical approach required. For low-stage, small sized MRONJ cases less invasive procedures such as decortication, sequestrectomy, or limited marginal resection can be effective in healing the disease. Furthermore, early detection and thus intervention reduces the risk of recurrence.33,34
In contrast, stage 3 MRONJ disease often necessitates more extensive surgical interventions, including segmental mandibular resections or partial maxillectomies.35 Although these invasive procedures may resolve the infection, halt the progression of MRONJ, and prevent further complications, they often result in compromised oral function and diminished quality of life. Restoration of function and improvement in quality of life, in case of a stable disease status, may require long reconstructive surgeries followed by an extended rehabilitation period.36, 37, 38, 39, 40 The most challenging scenario arises in patients with a combination of stage 3 MRONJ, poor oncological prognosis, and comorbidities that preclude surgical treatment.41,42 In such cases, definitive management of the disease and its associated complications may not be possible. Early detection of MRONJ using FDG PET/CT may help prevent progression to such advanced cases with limited therapeutic options.
Our study shows a very high sensitivity (91% (19/21); 95% CI: 70%–98.8%) and prevalence adjusted negative predictive value (98.3%, 95% CI: 93%–99.8%), for early detection of MRONJ with PET/CTs. These results are highly relevant for clinical practice as many patients receive regular PET/CTs during their treatment for metastasized breast cancer. Therefore, no additional intervention is needed to gain more information that allows for a considerable lead time before the development of MRONJ. Further, it should take into account that the 12 patients in our study exhibiting jaw PET/CT alterations have not yet developed MRONJ, but might do so in the future. The authors acknowledge that some patients with observed FDG uptake might not have developed a MRONJ but currently have a dental or periodontal infection that puts them at high risk for MRONJ. We believe that our results are clinically very useful, as patients in both scenarios should be seen and treated by a specialist.
A relatively low adjusted positive predictive value (29%, 95% CI: 17%–45%) is somewhat a consequence of the low incidence of MRONJ. Here it is extremely important to raise awareness amongst physicians and educate patients accordingly. Elevated metabolic activity in a jaw lesion in PET/CT leads to a diagnosis of MRONJ in 29%. On the other hand, a negative predictive value 98.3% demonstrates that in the absence of lesions, MRONJ is very unlikely. Furthermore, the false positive patients merely receive a consultation from a specialist for Oral and Maxillofacial Surgery trained in MRONJ care. With appropriate education of both patients and physicians regarding these data, we believe that PET/CT holds the potential to contribute valuable further information to support treatment planning.
The limitations of this study include that due to logistical challenges it was not feasible to obtain PET/CT images of all patients of Tyrol and therefore our study cohort was limited to patients treated at the University Hospital in Innsbruck. Consequently, this analysis did not allow for inclusion of more possible factors like chemotherapy regimens or comorbidities. Multicenter studies are needed to further evaluate all possible confounders. Given the retrospective nature of our study and the limited sample size, patient matching was conducted to the best extent possible. Furthermore, due to the nature of a retrospective analysis, follow-up for these patients varies greatly depending on their survival. Of 12 patients without MRONJ and showing jaw PET/CT alterations, the alterations were still there in the next imaging in six patients, three patients showed curing artifacts following dental restoration. However, this process could be improved through the inclusion of data from a multicenter cohort.
In conclusion, the study provides evidence that advanced imaging, particularly PET/CTs, can serve as valuable tool for early intervention when MRONJ is detected with a considerable lead time. The early detection of MRONJ offers the advantageous chance of avoiding surgery as well as providing valuable information for the choice, extent and success of surgical intervention.
Contributors
Miriam Emmelheinz: Data curation, Formal analysis, Investigation Methodology, Writing—original draft, Writing—review & editing.
Daniel Egle: Investigation, Writing—review & editing.
Samira Abdel Azim: Investigation, Writing—original draft, Writing—review & editing.
Angela Augustin: Investigation, Writing—review & editing.
Florentina Baumgart: Project administration, Investigation, Writing—review & editing.
Benjamin Walch: Investigation, Writing—original draft, Writing—review & editing.
Johannes Laimer: Conceptualization, Investigation, Writing—review & editing.
Emanuel Bruckmoser: Investigation, Writing—original draft, Writing—review & editing.
Lisa-Maria Rossetti: Investigation, Writing—review & editing.
Steffen Bayerschmidt: Investigation, Writing—review & editing.
Christian Uprimny: Conceptualization, Investigation, Writing—review & editing.
Marjan Arvandi: Formal analysis, Methodology, Writing—review & editing.
Uwe Siebert: Formal analysis, Methodology, Validation, Writing—review & editing.
Christian Marth: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing—original draft, Writing—review & editing.
Christine Brunner: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing—original draft, Writing—review & editing.
Miriam Emmelheinz, Christine Brunner, Marjan Arvandi, Uwe Siebert and Christian Marth accessed and verified the data.
Data sharing statement
The data that support the findings of this study are available from the corresponding author Christine Brunner (c.brunner@tirol-kliniken.at, Tel.: +43 (0) 512 504 81194) upon reasonable request.
Declaration of interests
Miriam Emmelheinz reports receiving support for attending meeting from Teva Ratiopharm, Sandoz and Lilly.
Daniel Egle reports receiving consulting fees from AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, and Seagen and honoraria for presentations from Amgen, AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Sandoz, and Seagen and support for attending meetings from DaiichiSanyko, Gilead, Pfizer, and AstraZeneca.
Angela August reports receiving support for attending meeting from Gilead, Roche and Merck Sharp & Dohme Ges.m.b.H.
Florentina Baumgart reports receiving support for attending meeting from Sandoz.
Steffen Bayerschmidt reports stock/stock options from Siemens Healthineers, Eckert + Ziegler and Pentixapharm holding.
Christian Marth reports receiving consulting fees from Amgen, AstraZeneca; GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche and Seagen and honoraria for presentations from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche, and Seagen and support for attending meetings from AstraZeneca and Roche.
Uwe Siebert reports being current President of ISPOR (ISPOR—Professional Society for Health Economics and Outcomes Research) The scientific society OSPOR involves methodological work on outcomes research and health-economic evaluation of medicines. No payments.
Christine Brunner reports receiving consulting fees from Gilead Sciences and Novartis, honoraria for presentations from AMGEN, DaiichiSanyko, AstraZeneca, Gilead Sciences, SEAGEN, Pfizer, and Novartis and support for attending meetings from DaiichiSanyko, AstraZeneca, and Novartis and participation on advisory board for Pfizer. All other authors declare no conflicts of interest.
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2026.103763.
Appendix A. Supplementary data
References
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