Abstract
Background
Comprehensive genomic profiling (CGP) has become more generally accessible to patients with rare cancer, but data on the results and benefits are limited.
Objective
Our objective was to gain a real-world understanding of the molecular landscape and targeted treatment options in neuroendocrine tumors, neuroendocrine carcinomas, adrenocortical carcinomas, pheochromocytomas, and carcinoids.
Patients and Methods
In this retrospective cohort study, we analyzed CGP results and clinical data from patients with neuroendocrine tumors, neuroendocrine carcinomas, adrenocortical carcinomas, pheochromocytomas, and carcinoids who were discussed in the CCCMunichLMU Molecular Tumor Board (MTB) between May 2017 and April 2023.
Results
In total, 104 patients with endocrine and neuroendocrine neoplasms were discussed in the MTB. CGP was technically successful in 99 patients. The most commonly mutated genes were TP53 (29.3%), RB1 (11.1%), and KRAS (10.1%). The highest overall prevalence of pathogenic alterations was detected in neuroendocrine carcinomas (76.9%) and carcinoids (83.3%), and the lowest prevalence of pathogenic alterations was seen in adrenocortical carcinoma (37.5%). Of the 99 patients with successful CGP, 35 received a treatment recommendation from the MTB based on the CGP results. Of these, ten patients ultimately received the recommended treatment. Of the ten treated patients, four experienced a longer progression-free survival under the targeted treatment than under their previous treatment.
Conclusions
One-third of patients with rare endocrine and neuroendocrine neoplasms who underwent CGP had a druggable alteration and received a treatment recommendation from the MTB. However, only 28.6% of these patients were treated accordingly. Our experience highlights the unmet medical need for targeted treatment options in patients with rare cancers.
Key Points
| The spectrum of molecular alterations in rare endocrine and neuroendocrine malignancies is broad. The most common pathogenic alterations found in our cohort of patients with neuroendocrine tumors, neuroendocrine carcinomas, adrenocortical carcinomas, pheochromocytomas, and carcinoids were TP53 (29%), RB1 (11%), and KRAS (10%) mutations. |
| The most frequent treatment recommendation by the Molecular Tumor Board was immune checkpoint inhibition. Although 35 of 99 patients received a molecularly informed treatment recommendation from the Molecular Tumor Board, only one-third of these received the recommended targeted treatment, resulting in a survival benefit in four of ten of these patients. |
Introduction
Neuroendocrine neoplasms (NENs) are a rare and heterogeneous subset of tumors that originate from cells with a neuroendocrine phenotype and can occur at many different anatomical sites [1]. The International Agency for Research on Cancer and World Health Organization expert consensus proposal recommends a uniform classification for NENs. Depending on their differentiation, NENs can be divided into neuroendocrine tumors (NETs, well-differentiated) and neuroendocrine carcinomas (NECs, poorly differentiated). Furthermore, NETs should be graded as low grade, intermediate grade, and high grade (G1, G2, and G3, respectively), depending on mitotic count, ki67, and presence of necrosis, whereas NECs are always high grade [2]. Pheochromocytomas are another subgroup of NETs that originate in the adrenal medulla and can produce catecholamines [3]. The most frequent anatomical site for NENs is the digestive system, followed by the lung [4]. Along with the profound heterogeneity of NENs, oncogenic molecular drivers and epigenetic profiles also vary greatly [5, 6].
Therapeutic options of chemotherapy and immunotherapy in metastatic extrapulmonary NECs of gastroenteropancreatic and other rare primary tumor locations are limited [4, 7, 8]. In contrast, treatment of gastroenteropancreatic NETs encompasses somatostatin analogs, peptide receptor radionuclide therapy, chemotherapy in NETs of pancreatic origin, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors [4, 6, 9, 10]. Treatment of metastatic pheochromocytoma involves chemotherapy, radionuclide therapies, and tyrosine kinase inhibitors [11]. Treatment strategies for lung typical and atypical carcinoids are similar to those for NETs but with specific guideline recommendations [12].
Although some of these approaches are targeted therapies, the treatment decisions are usually not based on the molecular pathology of the tumors, but rather the anatomical site, grading, growth dynamics, and somatostatin receptor status assessed by imaging of the NEN, as well as the patient’s comorbidities and preferences [6].
In some tumor entities, such as cholangiocarcinoma and lung adenocarcinoma, comprehensive genomic profiling (CGP) is routinely recommended to detect targetable alterations [13, 14]. Although CGP is not routinely recommended in NENs, European Society of Medical Oncology (ESMO) recommendations include determining the tumor mutational burden (TMB) in well-to-moderately differentiated NETs [13].
To gain a better understanding of the molecular profiles, therapeutic options, and potential differences within the heterogeneous group of NENs, we collected real-world data from our Molecular Tumor Board (MTB) from 2017 to 2023. Although adrenocortical carcinoma (ACC) is a rare endocrine neoplasm and treatment also differs [15, 16], we included this entity in our analysis because of the high therapeutic need and rarity. We report the retrospective analysis of CGP results and medical charts of 104 patients with rare endocrine tumors and NETs, including NET, NEC, pheochromocytoma, carcinoids, and ACC. Hereafter, we collectively refer to these tumor entities as NENs to improve readability.
Material and Methods
Molecular Tumor Board
The University Hospital Munich’s interdisciplinary MTB consists of clinicians, pathologists, tumor geneticists, and experts for precision oncology and takes place weekly. It is a platform to discuss patients’ CGP results and targeted treatment options [17]. Treatment recommendations are based on CGP results, the clinical situation and medical history of the patient, and literature research. After the interdisciplinary discussion, recommended treatments include approved targeted therapies, available clinical trials, and off-label treatments. Recommendations are annotated with the evidence level according to the ESMO Scale for Clinical Actionability of molecular Targets and the National Center for Tumor Diseases. The treating physician then discusses the results of the MTB, and the decision whether to follow the recommendations is ultimately made by the physician and the patient.
Patient Population
In this retrospective cohort study, patients with NET, NEC, ACC, pheochromocytoma, and carcinoids who were discussed in the University Hospital Munich’s MTB between May 29, 2017, and April 3, 2023, were included in the analysis (Fig. 1). During this period, 2587 cases of various tumor entities were discussed in the MTB. The study was approved by the local ethics committee of the Ludwig-Maximilians-University Munich (project number 21-0869). Median follow-up was 20.8 months (range 0.3–158.7). Molecular testing had been recommended beforehand, either by the entity-specific tumor board or by the coordinator of the precision oncology program, or patients already had CGP results and had been referred by external physicians for discussion.
Fig. 1.
Flowchart of included patients. ACC adrenocortical carcinoma, CGP comprehensive genomic profiling, MTB Molecular Tumor Board, NEC neuroendocrine carcinoma, NET neuroendocrine tumor
Sequencing Assays
The various sequencing assays performed at the accredited pathology of the University Hospital Munich have been described in a previous report [17]. With the addition of broader panels and the analysis of the TMB, the number of assays for molecular testing has increased over recent years. Since December 2021, the most frequently used panel at our center has become the TruSightOncology500 assay, covering 523 genes for assessment of DNA and RNA variants, TMB, and microsatellite instability [18]. Other sequencing assays that were used in this analysis are Oncomine, Oncomine Comprehensive, Oncomine Comprehensive TMB, Oncomine Comprehensive Assay v3, FoundationOne, Archer FUSIONPlex, and the AmpliSeq for Illumina BRCA panel. The allele frequency threshold for inclusion in the analysis was set at 5%.
Follow-Up
We retrospectively reviewed patients’ medical charts, pathologist reports, and MTB statements to collect baseline characteristics, treatment outcomes, results of molecular testing, and MTB treatment recommendations. We also collected whether the recommendations were put into practice and/or which other treatments the patients received after the MTB.
Statistical Analysis
We used IBM SPSS Statistics version 29.0 and Microsoft Excel version 16.84 to perform descriptive and statistical analysis and generate graphs and tables. We calculated the survival time from the date of initial diagnosis to the date of death or last contact. We used the Kaplan–Meier method to estimate survival curves and statistically compared them using the Log-rank test. Statistical significance was determined as p-values < 0.05. To evaluate the clinical benefit of targeted therapies, we calculated the progression-free survival (PFS) ratio by dividing the PFS during targeted treatment by the PFS of the last prior systemic therapy [19]. We used a cut-off of > 1.3 as an indicator of clinical benefit, in accordance with previous studies [20, 21].
Results
Patient Characteristics
During the study period, 104 patients with NEN were discussed in the MTB. Most patients had NECs (n = 52), followed by NETs (n = 36). The median age of all patients at initial diagnosis was 54.2 years (range 19–82), and the patients with pheochromocytoma and ACC were youngest at initial diagnosis (37.1 and 36.0 years, respectively). The most common location of the primary tumor was the pancreas (32.7%). Of all patients, 67.3% presented with synchronous metastatic disease. The median time between initial diagnosis and diagnosis of metastatic disease was 4.8 months (range 0.0–78.0), and patients were discussed in the MTB a median of 24.5 months (range 1.0–158.0) after initial diagnosis. The included patients with NEC of the lung had large-cell NEC in six cases and small-cell lung cancer in one case. Of the six patients with carcinoid tumor, five had an atypical carcinoid. Baseline characteristics of the 104 included patients are presented in Table 1. Testing was done with liquid biopsy in only two cases. In all other patients, testing was performed on tissue from the primary tumor (27.9%) or metastatic tissue (68.3%). CGP was successful in 91.3% of cases; the reason for unsuccessful testing was insufficient quality of tumor material. In some cases, testing was repeated with different material, and—ultimately—CGP results from 99 patients (95.2%) were obtained.
Table 1.
Baseline characteristics of patients included in the study (n=104)
| Characteristic | All pts (n = 104) | NETa (n = 36) | NEC (n = 52) | Pheochr. (n = 2) | ACC (n = 8) | Carcinoidb (n = 6) |
|---|---|---|---|---|---|---|
| Age (years) | 54.2 (19–82) | 53.5 (23–78) | 59.1 (27–82) | 37.1 (26–47) | 36.0 (19–59) | 61.9 (27–69) |
| Sex | ||||||
| Male | 60 (57.7) | 22 (61.1) | 32 (61.5) | 1 (50) | 3 (37.5) | 2 (33.3) |
| Female | 44 (42.3) | 14 (38.9) | 20 (38.5) | 1 (50) | 5 (62.5) | 4 (66.7) |
| Status at last follow up | ||||||
| Deceased | 54 (51.9) | 14 (38.9) | 32 (61.5) | 2 (100) | 4 (50) | 2 (33.3) |
| Alive | 50 (48.1) | 22 (61.1) | 20 (38.5) | – | 4 (50) | 4 (66.7) |
| Tumor stage at initial diagnosis | ||||||
| Locally limited | 34 (32.7) | 9 (25.0) | 16 (30.8) | 2 (100) | 5 (62.5) | 2 (33.3) |
| Metastatic | 70 (67.3) | 27 (75.0) | 36 (69.2) | – | 3 (37.5) | 4 (66.7) |
| Tumor stage at time of MTB | ||||||
| Locally limited | 10 (9.6) | 3 (8.3) | 7 (13.5) | – | – | – |
| Metastatic | 94 (90.4) | 33 (91.7) | 45 (86.5) | 2 (100) | 8 (100) | 6 (100) |
| Location of primary tumor | ||||||
| Adrenal glands | 10 (9.6) | – | – | 2 (100) | 8 (100) | – |
| Colorectal | 11 (10.6) | 2 (5.6) | 9 (17.3) | – | – | – |
| Lung | 12 (11.5) | – | 7 (13.5)c | – | – | 4 (66.7) |
| Pancreas | 34 (32.7) | 23 (63.9) | 11 (21.2) | – | – | – |
| Small intestine | 4 (3.8) | 3 (8.3) | 1 (1.9) | – | – | – |
| Unknown | 13 (12.5) | 4 (11.1) | 9 (17.3) | – | – | 1 (16.7) |
| Other | 20 (19.2) | 4 (11.1) | 15 (28.8) | – | – | 1 (16.7) |
Data are presented as median (range) or n (%)
ACC adrenocortical carcinoma, MTB Molecular Tumor Board, NEC neuroendocrine carcinoma, NET neuroendocrine tumor, Pheochr. Pheochromocytoma, pt(s) patient(s)
aThree pts with low-grade NET, 15 pts with intermediate-grade NET, 18 pts with high-grade NET
bFive pts with atypical carcinoid, one pt with typical carcinoid
cSix pts with large-cell NEC, one pt with small-cell lung cancer
Molecular Alterations
Of the 99 patients with technically successful CGP, a pathogenic alteration was found in 71 patients (71.7%). A median of one pathogenic alteration was detected (range 0–12). Figure 2 shows an oncoplot of the altered genes among all patients with technically successful CGP. The most commonly mutated genes in this population were TP53 (29.3%), RB1 (11.1%), and KRAS (10.1%). In total, 31.3% of tumors harbored alterations that were not present in any other case in the study population. The highest prevalence of pathogenic alterations was detected in NEC (76.9%) and carcinoids (83.3%), whereas the lowest prevalence of pathogenic alterations was seen in ACC (37.5%). Targetable molecular alterations were found in 40.0% of NEC cases, 33.3% of NET G1 cases, 42.9% of NET G2 cases, and 52.9% of NET G3 cases.
Fig. 2.
Oncoplot of molecular alterations in patients with neuroendocrine neoplasm (NEN). The oncoplot shows altered genes (rows) among 99 patients with NEN (columns). Genes altered in at least two cases are depicted separately; genes altered in only one case are summarized as “other”. The tumor mutational burden is depicted in the upper panel; the lower panel shows a heatmap of the patients’ sex, age, primary site, Ki67%, and differentiation of the tumor. ACC adrenocortical carcinoma, Adrenal gl. adrenal glands, GI gastrointestinal tract, NEC neuroendocrine carcinoma, NET neuroendocrine tumor, Pheochr. pheochromocytoma
Targeted Treatment Recommendations
Of the 99 patients with successful CGP, 35 (35.4%) received a treatment recommendation from the MTB (19 with NEC, 13 with NET, three with atypical carcinoids). Of these, ten ultimately received the recommended treatment (Table 2). The most frequently proposed treatment option was checkpoint inhibition in patients with either high TMB or pathogenic molecular alterations that have been described as associated with sensitivity to checkpoint inhibition [22, 23]. Four of the treated patients experienced a clinical benefit under the targeted treatment (PFS ratio > 1.3), four patients were lost to follow-up, and two patients had a PFS ratio of 0.19 and 1.14. One patient with atypical carcinoid with high TMB reached a PFS ratio of 8.16 during checkpoint inhibition and was still receiving treatment at data cut-off. The reasons that the remaining patients did not receive the recommended targeted treatment options included rapid deterioration of the patient or death before the recommendation could be implemented, refusal of cost coverage by the insurance company, and treating physician’s choice; however, in many cases the specific reason was not known.
Table 2.
Treatments recommended by the Molecular Tumor Board (MTB)
| Recommendationa | NEC | NET | Carcinoid |
|---|---|---|---|
| Checkpoint inhibition | |||
| ARID1A mutation | – | 2 | 1 |
| PBRM1 mutation | – | 2 | – |
| High TMB | 6 (3 pts treated, LTFU) | 2 | 1 (treated, PFS ratio 8.16) |
| Crizotinib, cabozantinib | |||
| MET amplification | – | 1 | |
| MET mutation | 1 | ||
| Crizotinib | |||
| ROS1 mutation | 1 | ||
| BRAF inhibitor | |||
| BRAF V600E mutation | 2 (treated, PFS ratios 2.33 and 1.14) | 1 | |
| BRAF V600R mutation | – | 1 | |
| BRAF fusion | – | 1 | |
| ALK inhibitor | |||
| ALK fusion | 1 | 1 | |
| Sotorasib | |||
| KRAS G12C mutation | 1 (treated, PFS ratio 0.19) | ||
| PARP inhibitor | |||
| ATM mutation | 1 | – | |
| BRCA1 mutation | – | 2 | |
| BRCA2 mutation | 2 (1 pt treated, LTFU) | ||
| Alpelisib | |||
| PIK3CA mutation | 2 | 1 | |
| Neratinib | |||
| ERBB2 mutation | 1 | ||
| Osimertinib | |||
| EGFR mutation | 1 (treated, PFS ratio 1.43) | ||
| CDK4/6 inhibitor | |||
| CDK4 amplification | 1 | ||
| Everolimus | |||
| PTEN mutation | 1 (treated, PFS ratio 1.43) | ||
| Pralsetinib, selpercatinib | |||
| RET fusion | 1 | ||
| Erdafitinib | |||
| FGFR3 fusion | 1 | ||
| Fulvestrant after ER IHC | |||
| ESR1 mutation | 1 | ||
| Regorafenib | |||
| FLT3 amplification | 1 |
EGFR epidermal growth factor receptor, ER IHC estrogen receptor immunohistochemistry, LTFU long-term follow-up, NEC neuroendocrine carcinoma, NET neuroendocrine tumor, PFS progression-free survival, pt(s) patient(s), TMB tumor mutational burden
aDepending on the exact MTB recommendation, either a drug class or a specific drug is indicated
Outcome
Median overall survival (mOS) across all included patients was 45.6 months (95% confidence interval [CI] 26.8–64.5). Although patients who received a recommended targeted treatment had a numerically longer mOS than patients who received a treatment recommendation but were not treated accordingly (102.0 vs. 44.6 months, respectively; Fig. 3), this difference was not statistically significant (p = 0.232). In patients with NEC, mOS was 19.3 months (95% CI 11.9–26.7). Female patients with NEC had a numerically longer mOS than male patients (43.1 vs. 18.9 months, respectively); however, this difference was also not statistically significant (p = 0.156). Patients with NET had an mOS of 82.0 months (95% CI 28.1–135.9).
Fig. 3.
Survival curves of patients who received the treatment recommended by the Molecular Tumor Board and patients who were given a treatment recommendation but were not treated accordingly
Discussion
This retrospective cohort study analyzed patients with NET, NEC, ACC, pheochromocytoma, and carcinoids whose CGP results were discussed in the University Hospital Munich MTB. Patients with pheochromocytoma or ACC had a lower median age at diagnosis (37.1 and 36.0 years, respectively) than those in the other subgroups. As only a few patients with pheochromocytoma, ACC, or carcinoids were included in the analysis, this limits the representability of these subgroups; however, a median age < 50 years at diagnosis has been reported previously for pheochromocytoma and ACC [24, 25].
The most common pathogenic alterations found in our cohort of patients with NENs were TP53 (29%), RB1 (11%), and KRAS (10%) mutations. A different study of patients discussed in an MTB included 114 patients with NET or NEC and also found TP53 and RB1 mutations to be common, but KRAS mutations were markedly less frequent; instead, MEN1 mutations were more common than in our cohort [26]. The rate of cases in which no pathogenic alteration was identified by CGP was comparable, with 72% in our cohort and 74% in the cohort from Boilève et al. [26]. The mutational spectrum of gastroenteropancreatic NEC and NET differs from, for example, MEN1, DAXX, and ATRX mutations, which are frequently found in pancreatic NETs but rarely in gastroenteropancreatic NECs [27]. In our cohort, no ATRX mutations were found, whereas MEN1 mutations were found in NET and NEC, and DAXX mutations were only detected in pancreatic NET.
After receiving a treatment recommendation from the MTB, only 28.6% of patients (10/35) received the recommended targeted therapy. In most cases, the reasons for not initiating the recommended treatment were not known, but possible reasons could be deterioration of the patient’s clinical state before treatment initiation, patient wishes, treating physician’s choice, or denial of cost reimbursement by the health insurance provider. Patients with other entities discussed in the MTB, such as pancreatic cancer (3.2%), cholangiocellular carcinoma (19.4%), cancer of unknown primary (14%), and gynecological cancers including cervical, vaginal, and vulvar cancer (7%), received recommended targeted treatments even less frequently, possibly due to a more aggressive tumor biology and therefore faster clinical deterioration of patients [28–31]. Boilève et al. [26] described an implementation rate of 35% in patients with NET or NEC, which is slightly higher than in our patient cohort. Patients treated according to MTB recommendations in the cohort from Boilève et al. [26] mostly had NETs, whereas most of the patients in our cohort who received the targeted treatment had NECs; however, the proportion of all NECs in the cohort was higher in our analysis. In the future, the implementation rate could possibly be improved upon with the implementation of standardized follow-up of patients after MTB.
Encouragingly, four of the ten patients who received the recommended targeted treatment benefitted in terms of the PFS ratio. ESMO recommendations include testing of TMB in well-to-moderately differentiated NETs [13]; however, in our cohort, high TMB was detected in six patients with NEC and one patient with atypical carcinoid, who ultimately benefitted by far the most, with a PFS ratio of 8.16 during checkpoint inhibition. However, ESMO recommendations also include testing for tumor-agnostic alterations, including TMB, in patients with metastatic cancers when access to matched therapies is available [13, 14], and our study highlights the relevance of this. Neither patients with ACC nor those with pheochromocytoma received treatment recommendations from our MTB. This may be due to the low patient numbers in our cohort but emphasizes the need for ongoing research to identify targeted treatment options for these rare tumor entities.
Patients who received a recommended targeted treatment had a numerically longer mOS than those who received a treatment recommendation but were not treated accordingly; however, this difference was not statistically significant, and larger patient numbers would most likely be needed to show possible significant differences in survival. Nevertheless, considering the survival curves and the PFS ratios, CGP followed by MTB discussion can lead to meaningful clinical benefit in a few selected patients with NENs.
As this was a retrospective single-center study, this analysis has limitations. The inclusion of NET, NEC, ACC, pheochromocytoma, and carcinoids means that the analyzed patients represent a heterogeneous cohort with partially very small subgroups that can only be examined descriptively. Furthermore, given the low implementation rate of the recommended treatments, many patients need to receive CGP testing and subsequent MTB discussion for some to ultimately benefit. As described in previous publications from our center, the structured follow-up of patients discussed in the MTB is currently being improved upon and will facilitate future analysis, especially of patient outcomes [17].
Conclusion
This analysis showed that CGP can be a useful addition to current treatment options for certain patients with NENs. It shows the need for concepts to improve the implementation rate of treatments recommended after MTB, for example with structured follow-up, support with the application process for cost reimbursement from health insurance providers, and close communication with clinical trial units. Since the overall survival of patients with NET is relatively long, especially compared with patients with the more aggressive NECs, these patients often receive multiple therapy lines and would likely benefit from more targeted treatment options. However, as our and others’ analyses have shown, pathological alterations in NENs are very diverse, which complicates the development of targeted treatments suitable for a broader range of patients.
Declarations
Funding
Open Access funding enabled and organized by Projekt DEAL. This research received no specific funding, and no funding was provided for publication of this article.
Conflicts of Interest
KD has received honoraria from AstraZeneca and support for travel, accommodation, and expenses from Servier, GSK, Bristol Myers Squibb, and AstraZeneca. MK has received speaker honoraria and travel support from Recordati, Eisai, and Lilly. DZ has received travel support from AstraZeneca, Amgen, and BMS and honoraria from AstraZeneca. LW has received honoraria from Roche and Servier and support for travel from Amgen and Merck. SB has received honoraria for scientific presentations from Celgene, Servier, and MSD; fees for consultancy or advisory roles from Celgene, Servier, Incyte, Janssen-Cilag, AstraZeneca, MSD, and Bristol Myers Squibb; and support for travel, accommodation, and expenses from Lilly. MvB has received research support from and serves on the speakers’ bureau for Gilead, Miltenyi Biotec, Merck Sharp & Dohme, Roche, Mologen, Novartis, Astellas, and Bristol Myers Squibb. VH has received research funding paid to his institution from Merck, Amgen, and Roche; fees for consultancy and advisory roles from Merck, Amgen, Roche, MSD, Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, TERUMO, GSK, Servier/Pfizer, AstraZeneca, Oncosil, and Nordic Bioscience; honoraria from Roche, Amgen, Sanofi, Merck, Servier, Pfizer, Pierre Fabre, AstraZeneca, MSD, and Seagen; and support for travel, accommodation, and expenses from Merck. CBW has received honoraria from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, SIRTeX, and Taiho; has served on advisory boards for Bayer, BMS, Celgene, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, and Roche; has received travel support from Bayer, Celgene, Janssen, RedHill, Roche, Servier, and Taiho; and has received research grants (institutional) from Roche. CBW serves as an officer for ESMO, Deutsche Krebshilfe, and Arbeitsgemeinschaft internistische Onkologie and is a member of the EU Commission expert group: Mission Board for cancer. KH has received Honoraria from Amgen, BMS, Lilly, Merck, Roche, Taiho, Servier and streamedup!, fees for consulting or advisory role from Amgen, Servier, MSD (Institutional), Merck and Janssen; has received travel support from Amgen, Merck and Servier. CJA, CSp, RS, SN, MR, CSc, MA, JW, CS-T, JR, MZ, TK, JK, AJ, FK and AT, have no conflicts of interest that might be relevant to the contents of this manuscript.
Ethics Approval
This retrospective chart review study involving human participants was undertaken in accordance with the principles of the Declaration of Helsinki and its later amendments. The study was approved by the local ethics committee of the Ludwig-Maximilians-University Munich (project number 21-0869).
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Data Availability
The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.
Code Availability
Not applicable.
Author Contributions
All authors contributed to the study conception and design. Klara Dorman and Kathrin Heinrich prepared the material collected and analyzed the data. Klara Dorman wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Footnotes
The original online version of this article was revised: Typo in author name Stefan Boeck updated.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
8/27/2025
A Correction to this paper has been published: 10.1007/s11523-025-01171-3
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.