Abstract
Background
For hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC), adjuvant chemotherapy (ACT) is recommended in the case of high-risk features only. The MINDACT trial showed that patients with high clinical risk (CR) but low genomic risk (GR) defined by the 70-gene signature (MammaPrint®; 70-GS) did not benefit from ACT. In this registry, we investigated the frequency and feasibility of 70-GS and concurrent 80-gene subtyping (BluePrint®) use in HR-positive, HER2-negative EBC. Furthermore, we recorded the frequency of ACT recommendation and the adherence to it when the “MINDACT strategy” was used.
Methods
This prospective registry included patients from 2 Austrian cancer centers. Similar to MINDACT, a modified version of Adjuvant!Online was used to determine CR, and 70-GC was used to determine GR in high-CR patients. ACT was recommended to patients with high CR and high GR.
Results
Of 224 enrolled patients, 76 (33.9%) had high CR and 67 (88.2%) received genomic testing. Of those, 43 (64.2%) were classified as low and 24 (35.8%) as high GR, respectively. All 24 patients with high CR and GR (10.7% of all patients) received the recommendation for ACT, but ACT was started in only 15 patients (62.5%). The median time from surgery to the start of ACT was 45 days (range 32–68), and the median time from test decision to the test result was 15 days (range 9–56).
Conclusion
We showed that the results of the MINDACT trial are reproducible in an Austrian population. Incorporating 70-GS into the daily clinical routine is feasible and mostly accepted by physicians for the guidance of treatment recommendations.
Keywords: MammaPrint, 70-Gene signature, Adjuvant chemotherapy, Adjuvant!Online, Genomic testing, Gene expression assay
Introduction
The hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative subgroup of early breast cancer (EBC) represents a heterogeneous collection of diseases with strongly divergent risks for local or distant recurrence. By gene expression analysis, these tumors can be classified into 2 main “intrinsic subtypes” called luminal A and luminal B (besides a small group of basal-like and HER2-enriched tumors). Luminal A tumors are associated in general with a much better prognosis than luminal B tumors even in higher pathologic stages [1, 2, 3]. Therefore, international guidelines recommend adjuvant chemotherapy (ACT) in addition to endocrine therapy for luminal B tumors only [4, 5, 6].
MammaPrint® or Amsterdam 70-gene breast cancer signature (70-GS; Agendia, Amsterdam, The Netherlands), is a commercially available genomic test that analyzes the expression of 70 genes on the mRNA level that are strongly associated with distant recurrence [7]. The genomic risk (GR) assessment helps physicians to determine whether or not a patient will benefit from ACT. Similar to Oncotype DX® and in contrast to Endopredict® and Prosigna®, MammaPrint® is a centralized test, which is performed in Irvine, CA, USA and previously in Amsterdam, The Netherlands.
The MINDACT trial, published in the New England Journal of Medicine in August 2016, was the first prospective clinical trial that investigated the clinical utility of a genomic test for clinical decision making in EBC. Treatment recommendations within the trial were based on a clinical and a GR stratification, respectively. The clinical risk (CR) was assessed by a modified version of Adjuvant!Online (AoL), an online tool that estimates the risk of EBC-related relapse or mortality without systemic adjuvant therapy based on CR factors. The GR was assessed by 70-GS [8, 9]. Patients with discordant risk groups in the clinical and genomic classification were randomized to follow the CR or the GR to determine the use of ACT. Among patients with high CR and low GR, who did not receive ACT, the 5-year distant metastases-free survival rate was 94.7% (95% CI 92.5–96.2). Thus, the primary endpoint of the study was met: the lower boundary of 95% CI was ≥92%. Furthermore, ACT did not significantly improve 5-year distant metastases-free survival (95.9 vs. 94.4%, hazard ratio 0.78, 95% CI 0.50–1.21, p = 0.27). Since this study provides a high level of evidence for 70-GS, both university clinics in Salzburg and Graz decided to introduce 70-GS into the daily routine for clinical high-risk patients with HR-positive, HER2-negative tumors. Today, most guidelines have incorporated genomic testing as an option for risk stratification in HR-positive, HER2-negative early BC [4, 5, 6].
BluePrint® (Agendia N.V.) is an 80-gene subtyping test performed simultaneously with 70-GS that allows for classification into the luminal-type, basal-type, and HER2-type molecular breast cancer subtypes. BluePrint provides the subtype information based on the expression patterns of genes associated with the aforementioned subtypes that are involved in downstream signaling and activation pathways below the cell surface.
This prospective registry investigated the feasibility of the “MINDACT strategy” with routine genomic testing in daily practice in an Austrian population. The percentage of patients with indication for genomic testing and indication for ACT was compared to those in the MINDACT trial. BluePrint testing was performed to look for subtype heterogeneity and further potential clinical value in the preformed HR-positive, HER2-negative subgroup. Furthermore, adherence of treatment recommendations according to the 70-GS test result by physicians and patients was investigated, respectively. The time needed to obtain the 70-GS result and the percentage of valid test results were further evaluated in this registry.
Materials and Methods
Patients
Patients aged between 18 and 70 years, with histologically confirmed EBC, without evidence of metastatic disease, with estrogen receptor (ER)- or progesterone receptor (PR)-positive (≥1%), HER2-negative EBC (immunohistochemistry 1+ or 2+ with an in situ hybridization ratio < 2.0 between the HER2 gene copy number and centromere of chromosome 17, or a copy number of 4 or less), without prior neoadjuvant therapy, after R0 resection of the primary tumor (defined as no ink on tumor), tumor stage pT1–3 (operable) and pN0–1 (0–3 positive lymph nodes) were included. All patients provided their signed informed consent.
Local treatment guidelines for ACT decision in HR-positive, HER-2-negative EBC were based on the results of the MINDACT trial. The modified version of AoL from the trial was used to classify CR. In those patients with AoL high-risk, a genomic testing with the 70-GS was recommended. All paraffin-embedded tumor samples (10 slides of 5-µm thickness) were processed at Agendia's core laboratory facilities in Amsterdam (The Netherlands). For those patients with high CR (according to AoL) and high GR (according to 70-GS), recommendation for chemotherapy was given (Fig. 1). For all patients, therapy recommendation was defined by a multidisciplinary tumor board (MDTB).
Fig. 1.
Consort diagram of the registry. ACT, adjuvant chemotherapy; MDTB, multidisciplinary tumor board.
The objective of this registry was to evaluate ACT recommendations based on the AoL/70-GS diagnostic strategy according to the local standard of care and acceptance by the patients. Therefore, the proportion of patients with an indication for genomic testing based on AoL, the proportion of both MDTB recommendations and patients adhering to the ACT indication determined by the AoL/70-GS strategy, the proportion of valid 70-GS results, and the time to 70-GS results were investigated.
Statistics
All statistical analyses were performed using IBM® SPSS® statistics software (Windows version 25). Continuous data are summarized as the mean ± SD or median (range), and count data as absolute frequencies (%). Associations between variables were evaluated using Mann-Whitney U tests, t tests, χ2 tests, and Fisher exact tests, as appropriate. All statistical tests were two-sided with a significance level of 5%.
Results
CR according to the Modified Version of AoL
From July 2017 to February 2019, 224 patients were enrolled in 2 tertiary Austrian cancer centers (Salzburg and Graz). All analyzed patients were female. Out of these, 148 (66.1%) were clinically low risk and 76 (33.9%) were clinically high risk according to AoL. The AoL low- and AoL high-risk cohort showed a similar age and ECOG performance status. However, given the clinical selection criteria of AoL (tumor size, nodal status and grading), patients in the AoL high-risk group had higher rates of tumors larger than 2 cm (≥pT2), nodal positivity, and grade ≥2 (Table 1).
Table 1.
Patient characteristics according to CR
| All (n = 224) | AoL low risk (n = 148) | AoL high risk (n = 76) | p value | |
|---|---|---|---|---|
| Age, years | 55 (26–70) | 56 (39–70) | 53 (26–70) | 0.156 |
| Menopausal status | 0.658 | |||
| Premenopausal | 81 (36.2) | 51 (34.5) | 30 (39.5) | |
| Postmenopausal | 126 (56.3) | 87 (58.8) | 39 (51.3) | |
| Perimenopausal | 15 (6.7) | 9 (6.1) | 6 (7.9) | |
| Unknown | 2 (0.8) | 1 (0.7) | 1 (1.3) | |
| ECOG PS | 0.594 | |||
| 0 | 209 (93.3) | 139 (93.9) | 70 (92.1) | |
| 1 | 7 (3.1) | 6 (4.1) | 1 (1.3) | |
| 2 | 2 (0.9) | 1 (0.7) | 1 (1.3) | |
| Unknown | 6 (2.7) | 2 (1.4) | 4 (5.3) | |
| Subtype | 0.564 | |||
| No special type (NST) | 169 (75.4) | 112 (75.7) | 57 (75.0) | |
| Lobular | 28 (12.5) | 18 (12.2) | 10 (13.2) | |
| Tubular | 6 (2.7) | 6 (4.1) | 0 (0.0) | |
| NST and lobular | 9 (4.0) | 5 (3.4) | 4 (5.3) | |
| Mucinous | 7 (3.1) | 4 (2.7) | 3 (3.9) | |
| Other | 5 (2.2) | 3 (2.0) | 2 (2.6) | |
| T-stage | <0.001 | |||
| pT1 | 171 (76.3) | 143 (96.6) | 28 (36.8) | |
| pT2 | 49 (21.9) | 5 (3.4) | 44 (57.9) | |
| pT3 | 4 (1.8) | 0 (0.0) | 4 (5.3) | |
| N-stage | <0.001 | |||
| pN0 | 152 (67.9) | 127 (85.8) | 25 (32.9) | |
| pN1 | 45 (20.0) | 5 (3.4) | 40 (52.6) | |
| pNi+ | 5 (2.2) | 4 (2.7) | 1 (1.3) | |
| pN1mi | 15 (6.7) | 5 (3.4) | 10 (13.2) | |
| pNx | 7 (3.1) | 7 (4.7) | 0 (0) | |
| Grade | <0.001 | |||
| G1 | 71 (31.7) | 65 (43.9) | 6 (7.9) | |
| G2 | 136 (60.7) | 82 (55.4) | 54 (71.1) | |
| G3 | 17 (7.6) | 1 (0.7) | 16 (21.1) | |
| HR status | 0.192 | |||
| ER+/PR+ | 200 (89.3) | 135 (91.2) | 65 (85.5) | |
| ER+/PR– | 24 (10.7) | 13 (8.8) | 11 (14.5) | |
| Ki-67 | 0.002 | |||
| <20% | 175 (78.1) | 127 (85.8) | 48 (63.2) | |
| 20–50% | 43 (19.2) | 17 (11.5) | 26 (34.2) | |
| >50% | 6 (2.7) | 4 (2.7) | 2 (2.6) | |
| Type of initial surgery | <0.001 | |||
| Breast-conserving surgery | 190 (84.8) | 134 (90.5) | 56 (73.7) | |
| Mastectomy | 33 (14.7) | 13 (8.8) | 20 (26.3) | |
| Unknown | 1 (0.4) | 1 (0.7) | 0 (0) |
Age is given as the median (range); all other parameters are given as number of patients (%). CR, clinical risk; AoL, clinical risk according to the modified version of Adjuvant! Online; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hormone receptor; ER, estrogen receptor; PR, progesterone receptor.
Genomic Testing
Genomic testing with the 70-GS was performed in 67 (88.2%) of 76 AoL high-risk patients. The test was successful in all 67 patients. However, a second tissue sample was required in 2 patients. Reasons why no genomic testing was performed despite the clinical high-risk situation were: patient judged as not fit enough for ACT (1/76; 1.3%), ACT was indicated according to the MDTB regardless of genomic testing due to advanced tumor stage or very young patient age (4/76; 5.3%), no ACT (and therefore no 70-GS) indicated according to the investigator due to low tumor stage or advanced patient age (2/76; 2.6%), and logistical reasons (1/76 = 1.3%).
Of the 67 analyzed patients, 43 (64.2%) were classified as low GR and 24 patients (35.8%) as high GR, respectively. The characteristics of patients and tumors by GR groups are provided in Table 2.
Table 2.
Patient characteristics according to GR
| AoL high (n = 76) | MammaPrint low risk (n = 43) | MammaPrint high risk (n = 24) | p value | |
|---|---|---|---|---|
| Age, years | 53 (26–70) | 53 (34–69) | 54 (36–70) | 0.349 |
| Menopausal status | 0.287 | |||
| Premenopausal | 30 (39.5) | 21 (48.8) | 8 (33.3) | |
| Postmenopausal | 39 (51.3) | 20 (46.5) | 14 (58.3) | |
| Perimenopausal | 6 (7.9) | 1 (2.3) | 2 (8.3) | |
| Unknown | 1 (1.3) | 1 (2.3) | 0 (0) | |
| ECOG PS | 0.693 | |||
| 0 | 70 (92.1) | 40 (93.0) | 22 (91.7) | |
| 1 | 1 (1.3) | 1 (2.3) | 0 (0) | |
| 2 | 1 (1.3) | 0 (0) | 0 (0) | |
| Unknown | 4 (5.3) | 2 (4.7) | 2 (8.3) | |
| Subtype | 0.490 | |||
| No special type (NST) | 57 (75.0) | 34 (79.1) | 20 (83.3) | |
| Lobular | 10 (13.2) | 6 (14.0) | 1 (4.2) | |
| Tubular | 0 (0.0) | 0 (0) | 0 (0) | |
| NST and lobular | 4 (5.3) | 2 (4.7) | 1 (4.2) | |
| Mucinous | 3 (3.9) | 1 (2.3) | 1 (4.2) | |
| Other | 2 (2.6) | 0 (0) | 1 (4.2) | |
| T-stage | 0.074 | |||
| pT1 | 28 (36.8) | 22 (51.2) | 4 (16.7) | |
| pT2 | 44 (57.9) | 19 (44.2) | 19 (79.2) | |
| pT3 | 4 (5.3) | 2 (4.7) | 1 (4.2) | |
| N-stage | 0.854 | |||
| pN0 | 25 (32.9) | 12 (27.9) | 7 (29.2) | |
| pN1 | 40 (52.6) | 24 (55.8) | 14 (58.3) | |
| pNi+ | 1 (1.3) | 0 (0) | 0 (0) | |
| pN1mi | 10 (13.2) | 7 (16.3) | 3 (12.5) | |
| pNx | 0 (0) | 0 (0) | 0 (0) | |
| Grade | 0.044 | |||
| G1 | 6 (7.9) | 4 (9.3) | 1 (4.2) | |
| G2 | 54 (71.1) | 35 (81.4) | 15 (62.5) | |
| G3 | 16 (21.1) | 4 (9.3) | 8 (33.3) | |
| HR status | 0.373 | |||
| ER+/PR+ | 65 (85.5) | 39 (90.7) | 20 (83.3) | |
| ER+/PR– | 11 (14.5) | 4 (9.3) | 4 (16.7) | |
| Ki-67 | <0.001 | |||
| <20% | 48 (63.2) | 36 (83.7) | 8 (33.4) | |
| 20–50% | 26 (34.2) | 7 (16.3) | 14 (58.3) | |
| >50% | 2 (2.6) | 0 (0) | 2 (8.3) | |
| Type of initial surgery | 56 (73.7) | 0.372 | ||
| Breast-conserving surgery | 20 (26.3) | 33 (76.7) | 16 (66.7) | |
| Mastectomy | 0 (0) | 10 (23.3) | 8 (33.3) |
Age is given as the median (range); all other parameters are given as number of patients (%). GR, genomic risk; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hormone receptor; ER, estrogen receptor; PR, progesterone receptor.
BluePrint was conducted in addition to 70-GS in 66 (86.8%) of 76 AoL high-risk patients. A valid result was provided in all 66 patients (100%). With only one exception, all tumors were classified as luminal type (65/66 = 98%), one tumor was classified as basal type (1/66 = 2%).
Patient Treatment and Timeline
The MDTB recommended ACT to all 24 patients with a high GR. This corresponds to 10.7% of all 224 patients in the registry. However, chemotherapy was started in only 15 (62.5%) of 24 genomic high-risk patients. The reasons why no chemotherapy was initiated were: patient's decision in 7/9 (78%), comorbidities preventing ACT in 1/9 (11%), and unknown reason in 1/9 (11%). The 7 patients who decided against chemotherapy despite high GR and MDTM recommendation were older (52–70 years, median age 63 years) and had a slightly higher tumor stage (grade 3, 43%; pT3, 14%; node positivity, 71%) than the overall genomic high-risk population (Table 2). In 4 patients, the MDTB recommended ACT without 70-GS testing. One of those patients was low CR and 3 patients were high CR.
Figures 2 and 3 show the time intervals for each postoperative step between surgery and the start of chemotherapy in patients with 70-GS testing. The median time from surgery to MDTB was 12 days (range 6–47), from MDTB to tissue shipment was 7 days (range 1–29), from shipment to test result was 8 days (range 4–56), and from test result to the start of chemotherapy was 17 days (range 7–39; Fig. 2). The median time from surgery to the start of chemotherapy was 45 days (range 32–68), and the median time from the MDTB with the decision for 70-GS testing to the test result was 15 days (range 9–56).
Fig. 2.
Median time in days of the postoperative stage interval from surgery to the start of ACT in patients with 70-GS testing. Time is giving in number of days (range). MDTB, multidisciplinary tumor board; ACT, adjuvant chemotherapy.
Fig. 3.
Patient distribution for time intervals of each postoperative step from surgery to the start of chemotherapy in patients with 70-GS testing. MDTB, multidisciplinary tumor board; ACT, adjuvant chemotherapy.
Discussion
The major goal of this registry was to evaluate ACT recommendations based on the MINDACT AoL/70-GS strategy in daily routine and their acceptance by patients in an Austrian population. We adapted our inclusion criteria from the MINDACT trial (protocol version August 2009). While the MINDACT trial also included ER/PR-negative (12%) and HER2-positive (9.5%) patients, we focused on HR-positive, HER2-negative patients only as this subgroup is especially challenging for chemotherapy recommendation and well represented in the MINDACT trial. Age older than 70 years was an exclusion criterion for both the MINDACT trial and our registry, therefore patients were comparable in age (median age 55 years in both). Also, the Eastern Cooperative Oncology Group (ECOG) performance status in the registry was similar to the MINDACT trial (ECOG ≥1: 6.7 vs. 3.8%). Like the revised MINDACT trial protocol, we also included node-positive tumors (up to 3 positive lymph nodes) as they are especially difficult to judge clinically. Fewer patients in our registry had node-negative disease (Ni+ tumors included; 70.1 vs. 79.0%), tumors were slightly smaller (pT1 76.3 vs. 71.6%), and we included more patients with G1 tumors (31.7 vs. 21.6%) [10]. Besides the inclusion criteria shown above, this registry was open to all patients to collect real-world experience.
Within this registry we tested the percentage of patients with indication for genomic testing and indication for ACT. In our cohort, 33.9% had high CR according to AoL and therefore fulfilled the criteria for genomic testing. In the luminal HER-2-negative cohort of the MINDACT trial, 42.5% of patients were clinical high risk.
Genomic testing with the 70-GS was recommended and performed in 88% of high-risk patients in the registry. Although this percentage shows a good acceptance of the test by physicians, we believe that this percentage could increase further over time as the 70-GS was newly introduced in the hospitals with the beginning of the registry.
This difference in percentage of high CR did convert into a small difference in chemotherapy indication between our cohort and the MINDACT trial. Of the tested patients in our cohort, 35.8% (24/67) were genomic high-risk and received a recommendation for ACT. This corresponds to 10.7% (24/224) of all patients in the registry. This compares to 39.0% of clinical and genomic high-risk patients in the MINDACT trial, which corresponded to 16.6% of all luminal HER2-negative patients in the trial [10].
BluePrint was conducted in addition to 70-GS in 87% of all AoL high-risk patients. However, the additional clinical value of the test was low, since 98% of the tumors in our registry were classified as luminal and therefore no additional information was generated by testing.
A major difference compared to the MINDACT trial was the adherence to ACT recommendation in the clinical high-risk/genomic high-risk group. In MINDACT only 3.9% of patients did not receive ACT compared to 37.5% in our registry. Our data are in line with European registry data from the Netherlands, where 39% of EBC patients did not receive chemotherapy despite indication [11]. The main reason for the omission of ACT in our cohort was patient's decision (89%). Since the registry was conducted in Austria, a country with an equal access to healthcare and full reimbursement of adjuvant systemic therapy by the health insurance system, we do not expect financial burden to have been the major reason for this decision, as it might be in other regions [11, 12, 13]. Presumably, this relatively high non-compliance rate was a result of the logistic concept used to keep the waiting times low: genomic testing was frequently ordered before ACT and its potential side effects could be discussed with the patients.
The RNA-based microarray for 70-GS requires tissue samples to be sent to Agendia for analysis [7]. Several older studies have looked at tissue sample eligibility rates with fresh frozen tissue samples, which were between 77 and 87% [14, 15, 16]. A shift from fresh frozen tissue to formalin-fixed paraffin-embedded (FFPE) tissue led to a major improvement in the procedure and turnaround time. Concordance between fresh frozen tissue samples and FFPE samples was analyzed in in a series of 211 matched tissue samples with a concordance of 91.5% [17]. Similar results were reported by Beumer et al. [18] in a series of 552 sample pairs with a Pearson correlation coefficient of 0.93 (95% CI 0.92–0.94). Although there were some delays due to hospital-intern organizational reasons, our initial sample eligibility rate was high (65/67; 97%).
The median time from tissue shipment to the test result was 8 days (range 4–56), and the median time from surgery to the start of chemotherapy was 51 days (range 32–68). The reasons for process delays have not been evaluated systematically for this registry. However, common reasons for outliers included secondary breast surgery due to insufficient tumor margins, logistic and organizational obstacles, as well as patient wish (delay in ACT start). The European Society of Medical Oncology recommends starting adjuvant systemic therapy without undue delays, as data show an important decrease in efficiency when it is administered more than 12 weeks after surgery [5, 19]. Decentralized genomic testing is possible with other genomic tests like EndoPredict® or Prosigna®, which represents an opportunity to ease and shorten the testing procedure [20, 21, 22, 23]. Unfortunately, no data from prospective, randomized trials are available for these decentralized tests. Currently, Agendia has developed an FFPE-based next-generation sequencing kit for the implementation of 70-GS in a decentralized setting, which allows central laboratories to process the samples within country borders [24]. Recently reported validation results are promising and select laboratories in Belgium and Germany have implemented this process already [25].
To conclude, this registry showed that the results of the MINDACT trial are reproducible in an Austrian population. The incorporation of 70-GS into daily clinical practice is feasible and mostly accepted by physicians for guidance of treatment recommendations in early-stage breast cancer. However, real-world patient adherence to chemotherapy recommendation was lower than in clinical trials. In addition, good logistics, multidisciplinary cooperation, and a low rate of ineligible samples are required to avoid a delayed start of ACT.
Statement of Ethics
The study protocol was approved by the independent medical Ethics Committee of the Province of Salzburg (Ethikkommission des Landes Salzburg, Austria, EC No. 415-E/2173/3-2017 and 415-E/2105/70-2018). All subjects in this registry gave their written informed consent.
Conflict of Interest Statement
T.W.: speakers honoraria: Novartis; travel grants: Roche, Pfizer; advisory board: Lilly. S.P.G.: honoraria: Novartis, Roche, BMS, AstraZeneca, MSD; consulting or advisory role: Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD; research funding: Roche; travel, accommodation, expenses: Roche, Amgen, Shire, Novartis, Pfizer, Bayer, Celgene, Daiichi Sanky. G.R.: consulting or advisory role: Pierre Fabre, Roche, Novartis, Pfizer, Eli Lilly; speakers' bureau: Amgen, AstraZeneca, Novartis, Bristol-Myers Squibb, Roche, Pfizer, Eli Lilly; research funding: Roche; travel, accommodation, expenses: Roche, Novartis, Amgen, Pfizer, Bristol-Myers Squibb. M.B.: consulting fees, lecture honoraria, advisory board memberships, and travel grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, and Roche, as well as research funding from Eli Lilly, Pfizer, Novartis, and Samsung. K.S.: consulting or advisory role: Novartis, BMS, Palleos Healthcare; speakers bureau: Novartis; travel, accommodation, expenses: Novartis, BMS. B.R.: travel, accommodation, expenses: AstraZeneca, Bayer, Baxter, Ipsen, Merck, Novartis, La Roche, Sanofi, AOP Orphan Pharmaceutical. C.S.: travel, accommodation, expenses, honoraria: Roche, Pfizer, Novartis, Pierre Fabre, Astellas. R.G.: honoraria: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie Gilead Daiichi Sankyo; consulting or advisory role: Celgene, Novartis, Roche, BMS, Takeda, Abbvie, AstraZeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo; research funding: CelgeneMerck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Gilead, Roche; travel, accommodation, expenses: Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead, BMS, Abbvie, Daiichi Sankyo. F.P., N.D., C.H.-K., R.R., and H.S. have nothing to declare.
Funding Sources
There are no funding sources to declare.
Author Contributions
S.P.G., G.R., M.B., F.P., K.S., C.S., and R.G. were involved in conceptualization and protocol development, and worked together with T.W., R.R., and C.H.-K. on the methodology of this prospective registry. T.W., S.P.G., G.R., N.D., C.H.-K., R.R., K.S., C.S., R.G., and H.S. were involved in organization. T.W., G.R., M.B., N.D., B.R., and C.S. performed data curation. T.W., S.P.G., G.R., F.P., and R.G. performed the formal analysis. F.P. was the registry statistician. The original draft was written by T.W. and S.P.G. Review and editing of the manuscript was done by G.R., M.B., F.P., H.S., and R.G. R.G. was the principal investigator of the registry. All authors read and approved the final manuscript.
Acknowledgements
We thank Dr. Daniela Wolkersdorfer, clinical trials lead manager and data protection officer of the AGMT, for her help and support conducting the registry. Furthermore, we thank Mag. Ingrid Liedtke, clinical trials coordinator and deputy clinical trials lead manager and Mag. Michaela Schachner, clinical trials lead manager of the Center for Clinical Cancer and Immunology Trials (CCCIT) Salzburg, for logistic support and specimen shipment. Special thanks goes to Ersan E. Lujinovic, MS. Agendia's European Manager of EU Medical and Scientific Affairs, who provided helpful input to the final manuscript.
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