Abstract
The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2024 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer.
Introduction
For the last 22 years, the Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) has been preparing and updating evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer (mBC). The AGO Breast Committee consists of gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiologic diagnostics, medical oncology, and radiation oncology. This update has been performed according to a documented rule-fixed algorithm by thoroughly reviewing and scoring chapter by chapter the recent publications for their scientific validity (Oxford level of evidence [LoE], www.cebm.net) and clinical relevance (AGO grades of recommendation [GR]; Table 1). Here, we present the 2024 update of diagnosis and treatment of patients with locally advanced and mBC; the full version of the updated slide set is available online as a PDF file in both English and German [1]. Moreover, a special version for patients is also available at www.ago-online.de.
++ | This investigation or therapeutic intervention is highly beneficial for patients, can be recommended without restrictions, and should be performed |
+ | This investigation or therapeutic intervention is of limited for patients and can be performed |
+/− | This investigation or therapeutic intervention has not shown benefit for patients and may be performed only in individual cases. According to current knowledge a general recommendation cannot be given |
− | This investigation or therapeutic intervention can be of disadvantage for patients and might not be performed |
-- | This investigation or therapeutic intervention is of clear disadvantage for patients and should be avoided or omitted in any case |
++ | This investigation or therapeutic intervention is highly beneficial for patients, can be recommended without restrictions, and should be performed |
+ | This investigation or therapeutic intervention is of limited for patients and can be performed |
+/− | This investigation or therapeutic intervention has not shown benefit for patients and may be performed only in individual cases. According to current knowledge a general recommendation cannot be given |
− | This investigation or therapeutic intervention can be of disadvantage for patients and might not be performed |
-- | This investigation or therapeutic intervention is of clear disadvantage for patients and should be avoided or omitted in any case |
Prognostic and Predictive Factors
Loco-regional tumor burden together with tumor biology (ER, PR, HER2, Ki-67) are the known major prognostic drivers and the key determinants of therapy decisions in early breast cancer. Use of these factors allows definition of patient groups with a low or high-risk profile, and it is important to state that an ER expression between 1 and 9%, defined as ER low, is associated with a loss of ER function and endocrine treatment (ET) is not indicated. However, use of adjuvant chemotherapy remains one of the most controversial issues in patients with an intermediate risk (HR+/HER2- BC with 0–3 positive lymph nodes). Gene expression tests like the prospective evaluated Mammaprint® or Oncotype DX RS® tests [2] can help in the decision-making process (LoE 1b/A/AGO +). Additional informations regarding the intrinsic subtypes can be provided with the Blueprint® test, a classifier that comes together with the Mammaprint®. It can be beneficial in neoadjuvant chemotherapy (LoE 2b/B/AGO +/−) to estimate a better response [3]. Evaluation of endocrine sensitivity by measurement of Ki-67 after 2–4 weeks of preoperative endocrine therapy provides further important informations beyond classical clinical and/or genomic prognostic factors (LoE 1b/A/AGO+). Results from an exploratory analysis in the ADAPT trial suggest an excellent survival in RS 0–25 and low post-endocrine Ki-67 values (≤10%) without chemotherapy use even in premenopausal women [4], whereas a missing Ki-67 drop of <10% is associated with a primary endocrine resistance. The combination of post-endocrine Ki-67 with genomic assays as a treatment decision marker is currently under investigation in the ongoing ADAPTCycle trial, which compares chemotherapy versus ET plus ribociclib in patients with HR+/HER2− BC [5]. For HER2-positive disease, the HER2DX test is available to estimate the benefit of trastuzumab +/− pertuzumab (LoE 2b/B/AGO +/−) in the neoadjuvant treatment of HER2-positive disease. The HER2DX pCR-score and risk-score might help identifying the right patient for neoadjuvant dual HER2 blockade in combination with a single taxane [6].
If chemotherapy is indicated, it is recommended to perform it in a neoadjuvant manner. A poor response to neoadjuvant chemotherapy resulting in a non-pCR can be used to indicate post-neoadjuvant treatments. Two scores are able to provide additional and more detailed information regarding the prognostic meaning of the residual cancer tissue for indicating further treatment, the CPS-EG (LoE 2b/B/AGO +) [7] and the RCB score (LoE 2a/b/AGO +) [8]. Both scores are recommended to be used in daily routine, for example, to select HR+/HER2− patients for olaparib after neoadjuvant chemotherapy.
Endocrine and Targeted Therapy in mBC
Using a CDK4/6 inhibitor in combination with ET is the recommended first-line treatment for HR+/HER2-mBC patients, as well as for later-line patients who have not yet received a CDK4/6 inhibitor (LoE 1a/A/++). All studies evaluating the addition of a CDK4/6 inhibitor to ET successfully met their primary endpoint of progression-free survival (PFS). However, there are differences with regard to the overall survival benefit. Thus, for postmenopausal women ribociclib with AI or fulvestrant is recommended with AGO++, abemaciclib with AI with AGO + and in combination with fulvestrant with AGO ++, and palbociclib with AI or fulvestrant with AGO + (LoE 1b/A). The optimal sequence upon progression on endocrine first-line treatment is not well defined, and different options depending on the detection of druggable mutations/alterations are possible. For those patients with ESR1 mutations and who have particularly experienced prolonged PFS on the prior line of ET and CDK 4/6 inhibitors, the SERD Elacestrant should be offered based on the data from the EMERALD trial (LoE 1b/B/+) [9]. The combination of AKTi capivasertib and fulvestrant is not yet approved by the EMA but will be an appropriate treatment option for those who have alteration/mutations in the PIK3CA/AKT1/PTEN pathway (LoE 1b/B/+) [10]. Currently, only fulvestrant and alpelisib are available for patients with activating PIK3CA mutations [11]. However, alpelisib is associated with higher rates of hyperglycemia (any grade 64%) and treatment discontinuation (25%) compared to capivasertib (any grade 16% and 13%, respectively) [10, 11]. All HR + mBC patients should also be assessed for gBRCA1/2 mutations regardless of family history since they may be eligible for PARPi therapy with either olaparib (LoE 1b/A/AGO ++) or talazoparib (LoE 1b/A/AGO ++).
A substantial subset of patients will have no druggable mutations. Nevertheless, several options are available. Everolimus in combination with either Fulvestrant (LoE 2b/B/AGO +) or Tam (LoE 2b/B/AGO +) or Exemestane (LoE 1b/A/AGO +) is associated with a prolonged PFS compared to endocrine monotherapy alone. Patients with prolonged PFS on CDK 4/6i may also benefit from CDK 4/6i treatment beyond progression but only if ET has been changed (LoE 2b/B/AGO +/−) [12]. Figure 1 illustrates the current algorithm.
Chemotherapy with or without Targeted Drugs in mBC
In mBC, effective symptom control is essential to maintain the best possible quality of life (QoL) (LoE 1a/A/AGO ++). If chemotherapy is indicated in the course of the disease, mono-chemotherapy is the treatment of choice or if secondary resistance to ET arises (LoE 1b/A/AGO ++). In mBC, treatment selection is based on ER and/or PR, HER2-status, PD-L1, and several germline and somatic gene mutations/alterations (i.e., gBRCA/sBRCA, gPALB2, PIK3CA, PTEN, AKT, ESR1 mutation). For patients with HER2 low expression (HER2 1+ or 2+/FISH-) in the primary tumor or metastasis, treatment with the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) is highly recommended, especially for patients with HER2 low/HR + disease (LoE 1b/A/AGO ++) [13]. In later lines, sacituzumab govitecan is another good therapeutic option with overall survival benefit in patients with HR+, HER2− mBC after failure to CDK4/6i-based therapy (LoE 1b/A/AGO ++) [14].
In triple-negative breast cancer (TNBC) patients with PD-L1-positive metastatic disease and a treatment-free interval (TFI) of more than 6 months, the combination of pembrolizumab with chemotherapy is recommended (LoE 1b/B/AGO ++). The addition of atezolizumab to nab-paclitaxel has resulted in a nonsignificant, though clinically relevant improvement in OS. Therapy should be limited to this specific combination therapy (LoE 1b/B/AGO+) [15]. Sacituzumab govitecan (LoE 1b/A/AGO ++) as well as T-DXd (LoE 2b/C/AGO +) are good options for patients with TNBC and relapse after >1 line of therapy.
PARPi improved PFS in two trials (OlympiAD, EMBRACA) compared to any mono-chemotherapy as “physicians” best choice” in HER2− mBC with gBRCA1/2 mutation. Thus, olaparib (LoE 1b/B/AGO ++) or talazoparib (LoE 1b/B/AGO ++) are highly recommended in this setting [16]. Furthermore, olaparib showed activity in mTNBC with either somatic BRCA (LoE 2b/B/AGO +/−) or germline PALB2 (LoE 2b/B/AGO +/−) mutations [17].
Treatment of patients with HER2+ advanced BC has become increasingly diversified. The algorithm was previously outlined in detail and has not changed [18].
Briefly, in the first-line setting, trastuzumab/pertuzumab with 3-weekly docetaxel (LoE 1b/A/AGO ++) or weekly paclitaxel (LoE 2b/B/AGO ++) is recommended for patients with primary metastatic disease after adjuvant trastuzumab therapy prior to a TFI of >6 months. T-DXd (LoE 1b/B/AGO ++) or tucatinib/trastuzumab/capecitabine after prior therapy with T-DM1 (LoE 1b/B/AGO ++) are recommended in the second-line setting. In the randomized phase 3 trial HER-2CLIMB-02, the combination of T-DM1 and tucatinib was evaluated in patients who were largely in the second-line setting [19]. Median PFS improved by about 2 months compared to T-DM1 alone HR 0.76 (95% CI: 0.61–0.95; p = 0.0163). About 40% of the patients enrolled had active or treated stable brain metastases. A 36% relative risk reduction of disease progression or death was observed among this group of patients. The most common severe adverse event with the combination was elevated liver enzymes. One potential limitation of this trial is that it did not compare the experimental regimen with tucatinib, trastuzumab, and capecitabine or with T-DXd. The combination T-DM1 and Tucatinib can be an option in individual cases (LoE 1b/B/AGO +/−).
Bone Metastasis
More than 65–70% of patients with advanced breast cancer develop skeletal metastasis. Bisphosphonates and denosumab (Dmab) have been successfully used to reduce hypercalcemia (LoE 1a/A/AGO ++), skeletal events/complications (LoE 1a/A/AGO ++), bone pain (LoE 1a/A/AGO ++), and prolong bone PFS (bisphosphonates: LoE 1a/A/AGO ++; Dmab: LoE 1b/A/AGO ++) [20]. Based on a difference regarding the evidence for a de-escalation of Dmab, pamidronate, and zoledronic acid (i.e., every 12 weeks rather than every 3–4 weeks), de-escalation is only recommended in case of zoledronate (LoE 1a/A/AGO ++) but not in case of the other two bone-targeted agents (LoE 2b/B/AGO +/−) [21]. Severe side effects must be considered and prevention of osteonecrosis of the jaw should be performed based on the ASORS (Supportive Maßnahmen in der Onkologie, Rehabilitation and Sozialmedizin) evaluation [22]. Planned sequential therapy with multiple bone-targeted agents should be approached with caution based on higher osteonecrosis of the jaw rates (LoE 2b/B/AGO +/−) [23]. In case of spinal cord compression, treatment should begin immediately (LoE 1c/D/AGO ++) and steroids should be started at first symptoms (LoE 2a/C/AGO +) [24]. If radiotherapy is indicated, the choice of regimen (1 × 8–10 Gy vs. multiple fractions) depends on prognosis, performance status, and patient preference.
CNS Metastases
Due to prolonged survival times and better systemic control, brain metastases (BM) in mBC occur in up to 40% of patients, depending on the subtype. There is a lack of specific knowledge about treatment of BM in breast cancer since most studies are not breast cancer specific. Therefore, participation in the German registry study is recommended (BMBC, GBG-79). If BM is diagnosed, the therapy focus initially lies on local therapy of the brain, in addition with systemic therapy. Local therapy consists of surgical resection with post-irradiation of the tumor bed, stereotactic irradiation of metastases, or whole-brain radiotherapy. Local therapy can be offered as stereotactic radiosurgery in single/solitary BM up to 2 or 3 cm or as stereotactic radiotherapy in metastases from 2 to 4 cm (LoE 1b/B/AGO ++). The irradiation of the tumor bed is recommended after resection (LoE 1b/B/AGO ++). In oligo-brain metastases, the combination of resection (if indicated) and SRS or SRT of unresected metastases can be offered (LoE 1b/B/AGO ++). Particularly in the context of stereotactic radiotherapy, radionecrosis must be considered as a differential diagnosis in the event of suspected intracranial progression. Whole-brain radiotherapy should be avoided although it improves intracranial control but does not improve duration of functional independence and overall survival. The choice of systemic therapy depends primarily on the extracranial disease situation and the subtype of breast cancer. The continuation of the current systemic therapy is feasible in patients with stable extracranial disease (LoE 2C/C/AGO +). In the case of HER2-positive mBC in particular, studies have been carried out explicitly in patients with BM in recent years. The use of the tyrosine kinase inhibitor tucatinib in the HER2CLIMB study has created a clinical scenario that allows patients with asymptomatic BM to initially receive systemic therapy without local therapy (LoE 2b/B/AGO +) [25, 26]. There is also evidence that the ADC T-DXd has intracranial effectiveness (LoE 2b/B/AGO +) [27]. Leptomeningeosis carcinomatosa is a clinical problem that is associated with a particularly poor prognosis. Here too, local therapy, usually carried out as intrathecal therapy, is at the forefront of the treatment concept in combination with systemic therapy [28].
Specific Sites of Metastases
Individual local treatment approaches based on special localizations of metastatic spread (e.g., pleural or peritoneal effusions or singular metastases) are stepping into the background due to more and more effective systemic therapies. Therefore, systemic therapy remains the mainstay of stage IV breast cancer (LoE 2a/B/AGO ++). Interventional regional procedures are an option, such as thermoablation for lung metastases (LoE 3b/C/AGO +/−) or interventional regional radiotherapy (SIRT/TARE) (LoE 3a B/AGO +/−) and regional ablative procedures (RFA/MWA) for liver metastases (LoE 3b/C/AGO +/−). Local forms of chemotherapy, like in the case of ascites, are not recommended (LoE 3b/D/AGO −) but could be an option to reduce dyspnea in pleural effusion (LoE 2b/C/AGO +/−). Whether radiation in addition to systemic therapy is beneficial remains unclear. Metastases should be biopsied before interventions to exclude secondary malignancies. The method of confirmation should be histology (LoE 3b/B/AGO ++). Fine-needle aspiration and cytology should remain exceptions (LoE 3b/B/AGO +).
There has been an ongoing debate whether surgical removal of the primary tumor improves survival. To date, results of four randomized phase 3 trials have been reported [29‒32]. Only in one of these trials early local therapy of the primary breast tumor improved overall survival in patients with de novo metastatic disease after 10 years of follow-up in a very selected group of patients (i.e., those with HR+/HER2-breast cancer of less than 55 years of age and solitary bone-only metastasis) [32]. Despite better local control, surgery did not improve QoL [29‒31]. Consequently, primary tumor removal in stage IV breast cancer is not recommended with the expectation of survival improvement even in patients with bone-only disease (LoE 1b/B/AGO +/−) [29‒34].
Breast Cancer – Supportive Care and Side Effect Management
Optimal management of side effects and supportive care is essential for therapeutic success. Since the last update, elacestrant as first oral SERD was approved, with an acceptable toxicity profile [9] including nausea, vomiting, elevated liver enzymes, and pain as well as diarrhea and arthralgia. These side effects compare favorably with all other endocrine/endocrine-based therapies. However, they might also require interdisciplinary management and patient coaching particularly in case of alteration of drug dosing and scheduling.
Side effect management of immunotherapies (checkpoint inhibitors, CPI) and its high variability of toxicity in various organs is a challenge, both as monotherapy and even more in combination with chemotherapy or targeted drugs. Specific “Immunotoxboards” in centers with high expertise might be helpful in emergency cases or challenging differential diagnosis. Investigators brochures and adequate patient information are relevant for patient management and in any uncertain situation, start of corticosteroides and interdisciplinary management might very well be life-saving. Of interest is the surveillance of up to 2 years after use of pembrolizumab in the neoadjuvant and adjuvant setting in curative TNBC patients [35]. We expect for 2024 the new S3 guidelines in supportive management to support these strategies.
Two novel ADCs have become available in Germany: main toxicities of T-DXd are interstitial lung disease (ILD), neutropenia, nausea, and alopecia, and those of sacituzumab govitecan are (febrile) neutropenia, leukopenia, anemia, diarrhea, nausea, alopecia. Other ADCs are under evaluation. Importantly, most ADCs require special multi-professional management. ILD remains a topic of special interest in different drug groups, including ADCs and oral therapies such as CDK 4/6 inhibitors. ILD requires proactive management according to grade and causing agents. The diagnostic work-up starts with chest CT once symptoms arise. Corticosteroids (starting dose ≥0.5 mg/kg/d prednisolone-equivalent) need to be commenced early. It is important to note that still, rechallenge of T-DXd is only recommended in patients with grade 1 ILD/pneumonitis that resolves; in patients with grade ≥2 ILD/pneumonitis, T-DXd should be permanently discontinued. Recommendations for dose holds or therapy discontinuations are detailed in the respective product information. Proactive and successful side effect management requires a truly interprofessional approach by nursing staff and physicians as well as thorough patient education. Patient-reported outcomes (PROs) are of high relevance in preservation of QoL and patient management (LoE 2b/B/+/−) [36]. eHealth and specially the introduction of breast cancer-specific DiGAs [37] show first promising results in support management and improving symptoms as well as adherence from patients side. These tools need to be monitored carefully; more data are needed.
Palliative Care
It is well accepted that mBC in an early phase is incurable but treatable. However, the late “palliative” phase must be differentiated as the focus is set on end-of-life care. Early introduction of palliative care concurrent with active treatment is important to improve symptoms and QoL. Furthermore, discussions about patient preferences at the end of life should begin early in the course of metastatic disease. At that phase of MBC, advance care planning should be routinely implemented in an multi-professional approach [38]. It is very important to point out that with the recent therapeutic progress with innovative and effective compounds, the patient goals are differing in each phase. Meanwhile, we are in the position to prolong PFS and OS without increasing toxicity. The recent results of studies with targeted drugs and ADCs present with OS benefit. With such compounds, targeted and more individual treatment strategies take center stage. Patient-reported outcome data are crucial to estimate treatment success and course and balance this to patient preferences.
Conflict of Interest Statement
Prof. Dr. med. Marc Thill was a member of advisory board Agendia, Amgen, AstraZeneca, Aurikamed, Becton/Dickinson, Biom‘Up, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Science, Grünenthal, GSK, Lilly, MSD, Neodynamics, Novartis, Onkowissen, Organon, Pfizer, pfm medical, Pierre Fabre, Roche, RTI Surgical, Seagen, Sirius Medical, and Sysmex; received manuscript support from Amgen, ClearCut, Clovis, Organon, pfm medical, Roche, and Servier; received travel expenses from Amgen, Art Tempi, AstraZeneca, Clearcut, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Hexal, I-Med-Institute, Lilly, MCI, MSD, Neodynamics, Novartis, Pfizer, pfm medical, Roche, RTI Surgical, and Seagen; received congress support from Amgen, AstraZeneca, Celgene, Daiichi Sanyko, Gilead, Hexal, Lilly, Neodynamics, Novartis, Pfizer, Pierre Fabre, Roche, and Sirius Medical; has received lecture honoraria from Amgen, Art Tempi, AstraZeneca, Clovis, Connect Medica, Eisai, Exact Sciences, Gedeon Richter, Gilead Science, GSK, Hexal, I-Med-Institute, Jörg Eickeler, Laborarztpraxis Walther et al. Lilly, MCI, Medscape, MSD, Medtronic, Novartis, Onkowissen, Pfizer, pfm medical, Roche, Seagen, StreamedUp, Stemline, Sysmex, Vifor, Viatris, and ZP Therapeutics; has received trial funding from Endomag, Exact Sciences; and received trial honoraria (institutional) from AstraZeneca, Biom’Up, Cairn Surgical, Celgene, Clearcut, Neodynamics, Novartis, pfm medical, Roche, and RTI Surgical. Prof. Dr. med. Wolfgang Janni has received research grants and/or honoraria from AstraZeneca, Celgene, Chugai, Daiichi Sankyo, Eisai, ExactScience, GSK, Janssen, Lilly, Menarini, MSD, Novartis, Sanofi Aventis, Roche, Pfizer, Seagen, Gilead, Inivata, and Guardant Health. Prof. Dr. med. Ute-Susann Albert has received lectures from Pfizer, Novartis, AstraZeneca, was a member of advisory board Daiichi Sankyo, and Pfizer. Prof. Dr. Malgorzata Banys-Paluchowski has received honoraria for lectures and advisory from Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Stemline, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Medical, Syantra, Pierre Fabre, and ExactSciences; received study support from EndoMag, Mammotome, MeritMedical, Gilead, Hologic, and ExactSciences; and received travel/congress support from Eli Lilly, ExactSciences, Pierre Fabre, Pfizer, AstraZeneca, Daiichi Sankyo, and Roche.
Dr. med. Ingo Bauerfeind has received honoraria and travel reimbursement from Brustkrebs Deutschland e.V., Krankenhaus Kempten, Akademie für Psychoonkologie, IF-Kongress Management.
Prof. Dr. med. Jens-Uwe Blohmer has received honoraria for advisory boards and lectures from Astra Zeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen. Prof. Dr. med. Wilfried Budach has received honoraria for lectures and advisory boards from Merck, BMS, Jörg Eickeler Veranstaltungen, medpublico GmbH, and BVDST. Prof. Dr. med. Peter Dall has received honoraria for lectures and advisory boards from Novartis, Pierre Fabré, MSD, Lilly, and AstraZeneca. Prof. Dr. Nina Ditsch was a member of advisory boards and speakers bureaus AstraZeneca, Aurikamed, BGGF, Daiichi Sankyo, Elsevier Verlag, ESO, Exact Sciences, Gilead Sciences, GSK, if-Kongress, KelCon, Leopoldina Schweinfurt, Lilly, Lukon, Molekular Health, MSD, Novartis, onkowissen, Pfizer, RG-Ärztefortbildungen, Roche, and Seagen. Prof. Dr. med. Eva Maria Fallenberg has received research grant from DFG and speaker honorarium from GE Healthcare, Bayer Healthcare, Guerbet, Siemens, BD, Roche, EUSOBI, ESOR, ESMO, and B-Rayz. Prof. Dr. med. Peter A. Fasching participate on a data safety monitoring board or advisory board: Novartis, Pfizer, Roche, Daiichi Sankyo, AstraZeneca, Lilly, Eisai, Merck Sharp and Dohme, Pierre Fabre, SeaGen, Agendia, Sanofi Aventis, Gilead, and Mylan; has received honoraria for lecture, speakers bureaus, manuscript writing, or educational events from Novartis, Pfizer, Roche, Daiichi Sankyo, AstraZeneca, Lilly, Eisai, Merck Sharp and Dohme, Pierre Fabre, SeaGen, Agendia, Sanofi Aventis, Gilead, and Mylan; and has received consulting from Novartis, Pfizer, Roche, Daiichi Sankyo, AstraZeneca, Lilly, Eisai, Merck Sharp and Dohme, Pierre Fabre, SeaGen, Agendia, Sanofi Aventis, Gilead, and Mylan. Medical Writing: Merck, to institution: Biontech, Cepheid, Pfizer.
Prof. Dr. med. Tanja N. Fehm has receiverd honoraria from Onkowissen.
Prof. Dr. med. Michael Friedrich was a member of advisory board: Gilead Sciences has received other honoraria from Roche, MSD. Prof. Dr. med. Bernd Gerber has received travel support from Pfizer.
PD Dr. med. Oleg Gluz has received honoraria for lectures and/or consulting from Amgen, AstraZeneca, Daiichi Sanyko, Eisai, Gilead Science, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Exact Sciences, Agendia, MedConcept, and GynUpdate, Minority share holder: Westdeutsche Studiengruppe (WSG).
Prof. Nadia Harbeck, MD has received honoraria for lectures and/or consulting from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Viatris, and Zuelligpharma; received other from Co-Director West German Study Group (WSG). Prof. Dr. med. Andreas Daniel Hartkopf has received honoraria for consulting and speaking engagements from AstraZeneca, Agendia, Amgen, Clovis, Daichi Sankyo, Eisai, ExactScience, Gilead, GSK, Hexal, Lilly, MSD, Novartis, Onkowissen, Pfizer, Roche, Pierre Fabre, Seagen, Stemline, and Verazyte. Prof. Dr. med. Jens Huober has received honoraria for lectures from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Seagen, Gilead, and Daiichi; has received honoraria for consulting/advisory board from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Daiichi, and Gilead; and has received travel grants from Roche, Pfizer, Daiichi, and Gilead. Prof. Dr. med. Christian Jackisch was a member of advisory board Astra Zeneca, Novartis, Lilly, Gilead, Exact Sciences, Pfizer, Roche, GSK, Pierre Fabre, Roche, and Seagen and received lecture from Art tempi, AstraZeneca, Lilly, Novartis, Roche, Amgen, Pierre Fabre, Exact Sciences, MSD, GynUpdate, and StreamedUp. Prof. Dr. med. Cornelia Kolberg-Liedtke was a member of advisory board: SeaGen, Exact Sciences, Pfizer, Novartis, AstraZeneca, Lilly, SeaGen, Daiichi Sankyo, Agendia, Gilead, and Onkowissen; has received lecture from NOGGO, CECOG, PINK, Pfizer, Roche, AstraZeneca, Carl Zeiss Meditec, Lilly, SeaGen, and Daiichi Sankyo; received other honoraria from Gilead Science and POMME; and stockholding Theraclion SA. Prof. Dr. med. Hans-Heinrich Kreipe was a member of advisory board: Lilly; has received lecture from AstraZeneca, Roche, Daiichi Sankyo, and Pfizer. PD Dr. David Krug has received lecture from Merck Sharp and Dohme, Pfizer, Astra Zeneca, onkowissen, med update; was a member of advisory board: Gilead; and has received research funding from Merch KGaA and Deutsche Krebshilfe. Prof. Dr.med. Thorsten Kühn was a member of advisory board/lecture Sysmex, Neodynamics, Pfizer, MSD, Merit Medical, Sirius Medical, Hologic, Endomag, Lilly; and has received trial funding from Merit Medical, Endomag, Mammotome. Prof. Dr. med. Sherko Kümmel has received lecture from Roche, Lilly, Exact Sciences, Novartis, Amgen, Daiichi Sankyo, AstraZeneca, MSD, Pfizer, Seagen, Gilead, Agendia; Hologic, PINK!, and Stemline; has received other honoraria from Roche, Daiichi Sankyo, and Sonoscape; was a member of advisory board Lilly, MSD, Roche, Astra Zeneca, Stemline, Novartis, Daiichi Sankyo, MSD, Seagen, Gilead, and Exact Science. Prof. Dr. med. Sibylle Loibl was a member of advisory board, institutional: Abbvie, Amgen, AstraZeneca, BMS, Celgene, DSI, Eirgenix, GSK, Gilead Science, Lilly, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeuticas, Puma, Roche, Seagen, and Stemline-Menarini; invited speaker, personal: Medscape; and has received trial funding/others from Astra Zeneca, Abbvie, Celgene, Daiichi Sankyo, Greenwich Life Sciences, GSK, Immunomedics/Gilead, Molecular Health, Novartis, Pfizer, Roche, Stemline-Menarini, and VM Scope GmbH. Prof. Dr. med. Diana Lüftner D.L. has received honoraria for advisory board activities and/or oral presentations from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, GSK, high5md, Loreal, MSD, Mundipharma, Novartis, onkowissen.de, Pfizer, Pierre Fabre, Roche, and TEVA. Prof. Dr. med. Michael Patrick Lux M.P.L. has received honoraria from Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, Exact Sciences, Agendia, Daiichi Sankyo, Grünenthal, Gilead, Pierre Fabre, PharmaMar, Samantree, Endomag, and medac for advisory boards, lectures, and travel support. Prof. Dr. med. Nicolai Maass was a member of advisory board Amgen, AstraZeneca, Clovis, Daiichi Sankyo, GSK, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, and Seagen has received lecture from Astra Zeneca, Daiichi Sankyo, GSK, Lilly, Novartis, Pfizer, and Roche. Prof. Dr. med. Christoph Mundhenke was a member of advisory board AstraZeneca, Pfizer, Daiichi Sankyo, Seagen, and Novartis and has received lecture from Pfizer and Novartis.
Prof. Dr. med. Toralf Reimer has received trial funding from German Cancer Aid and Else Kroener-Fresenius-Stiftungwas a member of advisory board MSD, Novartis, and Myriad; and has received lecture from Pfizer, Novartis, Roche, and AstraZeneca.
Prof. Dr. med. Kerstin Rhiem has received honoraria from AstraZeneca, Roche, Novartis, streamed up. Prof. Dr. med. Achim Rody was a member of advisory board AstraZeneca, Novartis, Roche, Exact Sciences, Pierre Fabre, Lilly, Seagen, Amgen, MSD, Gilead; has received lecture from Pfizer, Celgene, Eisai; and has received trial funding from Eisai. Prof. Dr. med. Marcus Schmidt M.S. reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, GILEAD, Lilly, Menarini-Stemline, Molecular Health, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, and SeaGen, His institution has received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre, and SeaGen. In addition, he has a patent for EP 2390370 B1 and a patent for EP 2951317 B1 issued. Prof. Dr. med. Andreas Schneeweiss has received research grants from Celgene, Roche; has received honoraria from Amgen, AstraZeneca, Aurikamed, Bayer, Celgene, ClinSol, Clovis Oncology, coma UroGyn, Connectmedica, Daiichi Sankyo, Gilead, GSK, if-kongress, I-MED, iOMEDICO, Lilly, MCI Deutschland, med publico, Metaplan, MSD, Mylan, NanoString Technologies, Novartis, onkowissen.de, Pfizer, Pierre Fabre, promedicis, Roche, Seagen, streamedup, and Tesaro; and has received travel support from AstraZeneca, Celgene, Daiichi Sankyo, Gilead, Pfizer, and Roche. Prof. Dr. med. Florian Schütz has received lecture from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, ExactSciences, Gilead, Lilly, MSD, Novartis, ClinSol, Pfizer, and Roche Pharma; was a member of advisory board Lilly, MSD, Gilead, Atheneum Partners, and ClinSol; and received travel expenses from Lilly, Gilead. Prof. Dr. med. Hans-Peter Sinn was a member of advisory board Astra Zeneca, Exact Sciences, and Daiichi Sankyo; has received lecture from AstraZeneca and Diacentus; and has received trial funding from AstraZeneca. Prof. Dr. med. Christine Solbach has received lecture from DiaLog Service GmbH, Jörg Eickeler, Pfizer, Roche, AstraZeneca, MedConcept, I-Med, GBG, BVF Akademie, and LÄK Hessen Akademie was a member of advisory board: MSD, Roche.
Prof. Dr. med. Erich Solomeyer has received honoraria from Roche, Amgen, Celgen, Tesaro, Astra Zeneca, Pfizer, Storz, Erbe, Gedeon Richter, Eisai, Medac, MSD, Vifor, Teva, Ethikon, Johnson Johnson, Daiichi Sankyo, Gilead, Exact Sciences, GSK, and Pierre Fabre. Prof. Dr. med. Elmar Stickeler was a member of advisory boards Amgen, Astra Zeneca, Gilead, Iomedico, Lilly, MSD, Novartis, Seagen, and Roche and received lecture from Astra Zeneca, BSH Düsseldorf, Gilead, Iomedico, MSD, Novartis, Onkowissen, Pfizer, PharmaMar, and Roche. Prof. Dr. med. Christoph Thomssen has received compensation for advisory boards, lectures or publications from Amgen, AstraZeneca, Aurikamed, Daiichi Sankyo, Forum Sanitas, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD, Nanostring, Novartis, Onkowissen, Pfizer, Roche, Seagen, Vifor. Prof. Dr. med. Michael Untch M. U. has received honoraria to travel support, lectures, and consulting or advisory role from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi Aventis, Myriad, Seagen, Novartis, Gilead, Stemline, Genzyme, Agendia, Onkowissen, and Eisai, all honoraria and fees to the employer/institution. Prof. Dr. Isabell Witzel has received lecture from Astra Zeneca, Lilly, Seagen, Daiichi Sankyo, Gilead, Pfizer and Novartis, and Onkowissen and has received Travel support from Roche and Lilly. Prof. Dr. med. Achim Wöckel has received compensation for advisory boards, lectures, trial funding advisory board from Amgen, AstraZeneca, Aurikamed, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Exact Sciences, Pierre Fabre, Clovis, Organon, Daiji Sankyo, Seagen, Stemline, and Gilead. PD. Dr. Rachel Würstlein served as advisor, consultant, speaker, and travel grant Agendia, Amgen, Apogepha, Aristo, Astra Zeneca, Celgene, Clovis Oncology, Daiichi Sankyo, Eisai, Esteve, Exact Sciences, Gilead, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Sidekick, Stemline, Tesaro Bio, Teva, Veracyte, Viatris, Wiley, FOMF, Aurikamed, Clinsol, Pomme Med, medconcept, MCI, and MediSeminar. Prof. Dr. med. Volkmar Müller has received speaker honoraria Astra Zeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre, and i-MED Institute; has received consultancy honoraria from Roche, Pierre Fabre, PINK, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Seagen, Gilead, and Stemline; has received institutional research support from Novartis, Roche, Seagen, Genentech, and Astra Zeneca; and has received travel grants from Astra Zeneca, Roche, Pfizer, Daiichi Sankyo, and Gilead. Prof. Dr. Tjoung-Won Park-Simon has received honoraria for lectures and/or consulting from Roche, AstraZeneca, GSK, Pfizer, Lilly, MSD, Exact Sciences, Daiichi Sankyo, Seagen, Novartis, Gilead Science, NCO, Onkowissen, Exact Sciences, and Seagen and has received travel compensation from Roche, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Gilead, and Pierre Fabre. Prof. Dr. med. Jörg Heil has none to declare.
Funding Sources
There was no funding for this paper.
Author Contributions
Paper is written by all authors.