Skip to main content
Erschienen in:

Open Access 12.12.2022 | short review

Biomarkers and translational research approaches in breast cancer—an update

verfasst von: Angelika M. Starzer, Anna S. Berghoff, Rupert Bartsch

Erschienen in: memo - Magazine of European Medical Oncology | Ausgabe 1/2023

Summary

Diagnosis and decision-making in the treatment of breast cancer patients is vastly dependent on the exploration of biomarkers. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are long-standing biomarkers, which determine the breast cancer subtype. In current practice, gene expression analyses further define the molecular breast cancer subtype and give additional information on disease characteristics. Prognostic biomarkers provide information regarding recurrence risk and survival. Predictive biomarkers, such as programmed cell death ligand 1 expression, are tools for identifying patients who can benefit from specific therapy regimens in order to choose the best treatment option for the patient. While some biomarkers are affordable and readily available, others remain technically complex to access. Translational research builds the bridge from discovering novel biomarkers in preclinical studies to testing their application utility in the clinical setting. Integrating translational studies into clinical trials is therefore essential to find novel and reliable biomarkers for an optimal personalized treatment approach for patients with breast cancer.
Hinweise

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Introduction

Biomarkers, essential tools in the treatment of cancer patients, are used to make precise diagnoses and determine the optimal treatment approach for each patient. Prognostic biomarkers give patients and caregivers an estimated survival prognosis. Predictive biomarkers are used to identify patients who can benefit from specific therapies in order to spare patients from non-effective and potentially toxic treatments. Demands on feasible biomarkers are high specificity, technical validity, wide and timely availability across cancer centers, and a cost-effective and material-sparing analysis.
More and more biomarkers are discovered by genome sequencing techniques. The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) criteria was implemented to rank biomarkers according to their clinical relevance [1]. In breast cancer (BC), ER, PR, HER2, PD-L1, PIK3CA, and gBRCA have the highest ESCAT score tier I‑A [2].
In BC patients, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are long-standing biomarkers determining the BC subtype, prognosis, and therapy options. Nowadays multiple additional biomarkers, summarized in Table 1, exist to guide the optimal treatment of BC patients and are discussed in this short review.
Table 1
Biomarkers in breast cancer
Name
Status
Assessment
ESCAT tier
Function
Relevance for BC subtype
Reference
Estrogen receptor (ER)
Expression, mutation
IHC, sequencing
I‑A
Prognostic and predictive, classification of BC
HR+ BC (Luminal A/B)
[5]
Progesterone receptor (PR)
Expression, mutation
IHC, sequencing
I‑A
Prognostic and predictive, classification of BC
HR+ BC (Luminal A/B)
[4]
Human epidermal growth factor receptor 2 (HER2)
Overexpression, gene amplification, mutation
IHC, in situ hybridization, sequencing
I‑A,
(HER2 low: II-B)
Prognostic and predictive, classification of BC
HER2+ BC (Luminal B)
[9, 11]
Programmed cell death ligand 1 (PD-L1)
Expression (IC, CPS)
IHC, sequencing
I‑A
Prognostic and predictive
TNBC
[13]
Tumor-infiltrating lymphocytes (TIL)
Expression
IHC
NA
Prognostic and predictive
All BC subtypes
[17]
Molecular Intrinsic subtype
Multi gene expression (recurrence risk, chemotherapy benefit (assay dependent))
Gene expression profiling
NA
Prognostic and predictive
All BC subtypes
[18]
Germline BRCA1/2
(somatic BRCA1/2)
Mutation
Sequencing
I‑A (II-A)
Prognostic and predictive
HR+ BC,
TNBC
[20, 21]
PALB2
Mutation
Sequencing
II‑A
Prognostic and predictive
HR+ BC,
TNBC
[21]
Phosphatidylinositol 3‑kinase (PI3K) catalytic subunit (PIK3CA)
Mutation
Sequencing
I‑A
Prognostic and predictive
HR+/HER2− BC
[24]
Microsatellite instability (MSI)
MSI-high/low
Sequencing
I‑C
Predictive
HR+, HER2+, TNBC
[25]
Tumor mutational burden (TMB)
TMB-high/low
Sequencing
I‑C
Predictive
HR+, HER2+, TNBC
[25]
Neurotrophic tyrosine receptor kinase (NTRK)
Fusion
IHC, in situ hybridization, sequencing
I‑C
Predictive
HR+, HER2+, TNBC
[27]
Circulating tumor DNA (ctDNA)
Expression
Isolation from liquid biopsies
NA
Predictive and prognostic
All BC subtypes
[28]
Homologous recombination deficiency (HRD)
HRD-high/low
Sequencing
NA
Predictive and prognostic
All BC subtypes
[22]
BC breast cancer, HR+ hormone receptor positive, HER2+ human epidermal growth factor receptor 2 positive, TNBC triple negative breast cancer, IHC immunohistochemistry, NA not applicable

Hormone receptors

The hormone receptors (HR) ER and PR were the first relevant biomarkers discovered in BC. Approximately 70–80% of BC patients express HR, defining the most frequent BC subtype [3]. HR are prognostic and predictive for endocrine therapy (ESCAT tier I-A) [4]. On the molecular level, estrogen receptor 1 (ESR1) mutations occur in around 40% of BC patients. ESR1 mutations were shown to be predictive for therapy resistance to aromatase inhibitors (ESCAT tier II-A) and prognostic for a worse progression-free survival (PFS) [5].
Furthermore, the expression of androgen receptor is investigated which occurs in 50–90% of BC patients, predominantly in the HR+/HER2− subtype [6]. Androgen receptor expression (ESCAT tier II-B) was associated with lower pathologic complete response rates after neoadjuvant chemotherapy in HR+/HER2− BC patients but conversely with a better overall survival (OS) [7]. First reports of phase II trials investigating antiandrogen receptor-targeting therapies with enzalutamide in BC patients suggested limited clinical activity in a population selected by androgen receptor status [8].

Human epidermal growth factor receptor 2

HER2 overexpression or amplification is used to determine the HER2+ BC subtype (luminal B in case of co-expression of HR) and is prevalent in approximately 20% of BC patients. HER2 is prognostic and predictive for HER2-targeting therapies (ESCAT tier I-A). Furthermore, a translational study investigating HER2 hotspot mutations (tier II-B) postulated that it could be beneficial in identifying patients who are resistant to HER2-targeting agents [9]. HER2 hotspot mutation was a negative prognostic factor for PFS [9].
Tumors with HER2 low expression (1+ or 2+ on IHC staining without amplification in in situ hybridization; ESCAT II-B) were previously classified as HER2 negative. While not a separate subtype defined by a distinct biological behavior, HER2 low status has recently gained clinical importance as the novel HER2-directed antibody drug conjugate trastuzumab deruxtecan has shown clinical activity with prolonged survival in pretreated HER2 low BC patients in a phase III study [10, 11]. Trastuzumab deruxtecan is therefore proposed as a new therapy approach in this patient population.
Notably, ongoing investigations are exploring targeting HER3 in BC given HER3 expression has been described in all BC subtypes and could potentially bear a new treatment strategy particularly for patients who have thus far had limited therapeutic options such as TNBC (triple-negative breast cancer) [12].

Immune cells and immune checkpoint molecules

Immune checkpoint inhibitors (ICI) have shown clinical activity in TNBC patients and are now used in the early setting in addition to the metastatic setting [13, 14]. Programmed cell death ligand 1 (PD-L1) expression on tumor and on immune cells such as tumor-infiltrating lymphocytes (TIL) and macrophages serves as a predictive biomarker (ESCAT tier I-A) which guides the application of PD-L1-targeting therapies in TNBC patients. PD-L1 expression (prevalence 20–40%) is a prognostic and predictive biomarker in metastatic TNBC but has no predictive role in early TNBC in which pembrolizumab yielded survival benefits regardless of PD-L1 status [14]. There are some limitations regarding PD-L1 as biomarker, for example in ICI pivotal studies, different applied staining antibodies resulted in the implementation of different scores (for atezolizumab: antibody SP142, immune cell score [IC]; for pembrolizumab: antibody 22C3, combined positive score [CPS]). Furthermore, divergences in PD-L1 positivity rates according to the applied antibody were described [15]. Further, PD-L1 positivity rates vary according to the organ site with lower PD-L1 positivity rates in metastatic lesions (42.2%), such as in liver (17.4%), skin (23.8%), and bone (16.7%) metastases, compared to primary tumor sites (63.7%) which should be taken into account when planning a biopsy [16].
TILs in the inflammatory tumor microenvironment have been shown to be a strong prognostic biomarker in HER2+ and TNBC patients, with higher TIL counts being associated with better prognosis [17]. Furthermore, TILs were shown to serve as predictive biomarkers for response to chemotherapy regimens as well as PD-1/PD-L1-directed therapies [17].

Genomic signatures in breast cancer

Molecular intrinsic subtype

Multigene sequencing assays (i.e., Mamma Print [Agendia, Agendia NV, Amsterdam, The Netherlands], Oncotype DX [Exact Sciences Corporation, Madison, WI, USA], Prosigna [Vercyte, San Francisco, CA, USA], Endopredict [MYRIAD SERVICE GmbH, Munich, Germany]) are developing and identifying molecular intrinsic BC subtypes as prognostic and predictive biomarkers in BC patients [18]. Molecular intrinsic subtypes are currently being clinically applied in early stage diseases to refine the prognosis and to help identify high-risk patients that should receive (neo)adjuvant chemotherapy.

BRCA mutation status and homologous recombination deficiency

BRCA1 and BRCA2 are involved in maintaining genomic stability by repairing DNA double-strand breaks and are the most frequently affected mutated genes causing the development of BC. Germline BRCA1/2m occur in around 5% of BC patients with the highest incidence in TNBC, followed by HR+/HER2− BC patients [19]. Patients with gBRCA1/2m (tier I-A) are eligible for poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy [20]. A phase II study looked at homologous recombination-related genes aside from gBRCA1/2m and showed clinical activity of PARP inhibitors in partner and localizer of BRCA2 mutation (PALB2m) carriers (ESCAT tier II-A) and in patients harboring somatic BRCA1/2 mutations (ESCAT tier II-A) [21].
The homologous recombination deficiency (HRD) score emerged as a novel biomarker for genomic instability and BC was classified as HRD-high among multiple tumor types [22]. HRD score can be determined by multigene sequencing techniques and is primarily determined by BRCA1/2 mutation and loss of heterogeneity. The HRD-high genotype showed an immune-sensitive tumor microenvironment with increased TIL count, higher tumor mutational burden, and higher neoantigen load compared to the HRD-low genotype. Furthermore, HRD-high genotype was associated with ICI therapy response [22].

Phosphatidylinositol 3-kinase catalytic subunit mutation status

Around 40% of HR+/HER2− BC patients harbor an activating phosphatidylinositol 3‑kinase catalytic subunit (PIK3CA) hotspot mutation [23]. Alpelisib, a PI3K inhibitor, is a therapeutic option in combination with endocrine therapy as second-line treatment in HR+/HER2− BC patients with PIK3CA (ESCAT I-A) mutated tumors in exons 7, 9 and 20 [24].
Another targetable gene alteration of the PI3K/AKT/mTOR signaling pathway is AKT serine/threonine kinase 1 (AKT1) mutation (ESCAT tier II-B), and phase III trials are currently ongoing (i.e., NCT03337724, NCT04305496).

Microsatellite instability, tumor mutational burden, and NTRAK fusion

Further molecular biomarkers investigated with regard to ICI therapy response are microsatellite instability (MSI; ESCAT tier I-C) and tumor mutational burden (TMB; ESCAT tier I-C). MSI-high and TMB-high tumors (cut off of 10 mut/Mb) were associated with better response to ICI therapy but their prevalence in BC is low with 1–2% for MSI-high and 5% for TMB-high [25].
Neurotrophic tyrosine receptor kinase (NTRK) fusions can be detected across a wide range of cancers but are very rare (< 0.1%); however, NTRK fusions were found to be oncogenic drivers in secretory breast carcinoma with a prevalence of up to 92% [26]. With an ESCAT tier I‑C, NTRK fusions can serve as predictive biomarkers for TRK inhibitors [27]. MSI-high and NTRK fusions are approved as agnostic biomarkers for targeted therapies.

Circulating tumor DNA

Another biomarker currently being widely explored in cancer types is circulating tumor DNA (ctDNA). It negates the need for invasive procedures as it is procured from liquid biopsies [28]. Hence, multiple samplings of ctDNA are feasible for patients and ctDNA can potentially be utilized for longitudinal disease monitoring. Measuring ctDNA was shown to serve as predictive biomarker and its measurement is part of many translational exploratory analyses of clinical trials.

Tumor DNA methylation

Tumor DNA methylation as an epigenetic phenomenon is investigated as a predictive and prognostic biomarker in multiple tumor types, including BC [29]. Tumor DNA methylation profiling was associated with response to PD-1/PD-L1-targeting therapies in translational studies of sarcomas, head and neck, and lung cancers and is also being investigated in TNBC [30].

Conclusion

Translational research builds the bridge from discovering novel biomarkers in preclinical studies to testing their utility in the clinical setting that directly affects patient care. Biomarker research is a rapidly emerging field with novel approaches such as liquid biomarkers and omics methods. Integrating translational studies in clinical trials is essential to identify novel, clinically relevant biomarkers with the aim to work towards a personalized treatment strategy in BC patients.
Take home message
Biomarkers are important for diagnosis, treatment, and prognosis. Translational research is needed to identify biomarkers for optimal personalized therapy strategies in breast cancer patients.

Acknowledgements

The financial support by the Austrian Federal Ministry for Digital and Economic Affairs, the National Foundation for Research, Technology and Development and the Christian Doppler Research Association is gratefully acknowledged.

Conflict of interest

A.M. Starzer has received honoraria for lectures from Astra-Zeneca and travel support from Pharma Mar and MSD. A.S. Berghoff has research support from Daiichi Sankyo and Roche, honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo as well as travel support from Roche, Amgen, Daiichi Sankyo and AbbVie. R. Bartsch has received honoraria for advisory role from Astra-Zeneca, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, Seagen, lecture honoraria from Astra-Zeneca, Celgene, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen and research support from Daiichi, MSD, Novartis, Roche.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Unsere Produktempfehlungen

Abo für kostenpflichtige Inhalte

Literatur
1.
Zurück zum Zitat Mateo J, et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol. 2018;29:1895–902.CrossRefPubMedPubMedCentral Mateo J, et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol. 2018;29:1895–902.CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Gennari A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer 5 behalf of the ESMO Guidelines Committee. Ann Oncol. 2021;32:1475–95.CrossRefPubMed Gennari A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer 5 behalf of the ESMO Guidelines Committee. Ann Oncol. 2021;32:1475–95.CrossRefPubMed
4.
Zurück zum Zitat Yamashita H, et al. Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer. Breast Cancer. 2006;13:74–83.CrossRefPubMed Yamashita H, et al. Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer. Breast Cancer. 2006;13:74–83.CrossRefPubMed
5.
Zurück zum Zitat Fribbens C, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34:2961–8.CrossRefPubMed Fribbens C, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34:2961–8.CrossRefPubMed
8.
Zurück zum Zitat Wardley A, et al. The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer. Breast Cancer Res Treat. 2021;187:155–65.CrossRefPubMedPubMedCentral Wardley A, et al. The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer. Breast Cancer Res Treat. 2021;187:155–65.CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Modi S, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387:9–20.CrossRefPubMed Modi S, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387:9–20.CrossRefPubMed
12.
Zurück zum Zitat Drago JZ, Ferraro E, Abuhadra N, Modi S. Beyond HER2: Targeting the ErbB receptor family in breast cancer. Cancer Treat Rev. 2022;109:102436.CrossRefPubMed Drago JZ, Ferraro E, Abuhadra N, Modi S. Beyond HER2: Targeting the ErbB receptor family in breast cancer. Cancer Treat Rev. 2022;109:102436.CrossRefPubMed
13.
Zurück zum Zitat Emens LA, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021;32:983–93.CrossRefPubMed Emens LA, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021;32:983–93.CrossRefPubMed
14.
Zurück zum Zitat Schmid P, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556–67.CrossRefPubMed Schmid P, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556–67.CrossRefPubMed
15.
Zurück zum Zitat Rugo HS, et al. PD-L1 immunohistochemistry assay comparison in atezolizumab plus nab-paclitaxel-treated advanced triple-negative breast cancer. J Natl Cancer Inst. 2021;113:1733–43.CrossRefPubMedPubMedCentral Rugo HS, et al. PD-L1 immunohistochemistry assay comparison in atezolizumab plus nab-paclitaxel-treated advanced triple-negative breast cancer. J Natl Cancer Inst. 2021;113:1733–43.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Rozenblit M, et al. Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers. J Immunother Cancer. 2020;8:1558.CrossRef Rozenblit M, et al. Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers. J Immunother Cancer. 2020;8:1558.CrossRef
17.
Zurück zum Zitat Loi S, et al. Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer. NPJ Breast Cancer. 2022;81(8):1–4. Loi S, et al. Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer. NPJ Breast Cancer. 2022;81(8):1–4.
18.
Zurück zum Zitat Prat A, et al. Correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA phase III studies. J Clin Oncol. 2021;39:148–1467.CrossRef Prat A, et al. Correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA phase III studies. J Clin Oncol. 2021;39:148–1467.CrossRef
19.
Zurück zum Zitat Tomasello G, et al. Characterization of the HER2 status in BRCA-mutated breast cancer: a single institutional series and systematic review with pooled analysis. Esmo Open. 2022;7:100531.CrossRefPubMedPubMedCentral Tomasello G, et al. Characterization of the HER2 status in BRCA-mutated breast cancer: a single institutional series and systematic review with pooled analysis. Esmo Open. 2022;7:100531.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Tung NM, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38:4274–82.CrossRefPubMed Tung NM, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38:4274–82.CrossRefPubMed
22.
Zurück zum Zitat Yang C, et al. Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders. Hum Cell. 2022;35:199–213.CrossRefPubMed Yang C, et al. Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders. Hum Cell. 2022;35:199–213.CrossRefPubMed
24.
Zurück zum Zitat André F, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380:1929–40.CrossRefPubMed André F, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380:1929–40.CrossRefPubMed
26.
Zurück zum Zitat Tognon C, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2:367–76.CrossRefPubMed Tognon C, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2:367–76.CrossRefPubMed
28.
Zurück zum Zitat Rothé F, et al. Circulating tumor DNA in HER2-amplified breast cancer: a translational research substudy of the NeoALTTO phase III trial. Clin Cancer Res. 2019;25:3581–8.CrossRefPubMed Rothé F, et al. Circulating tumor DNA in HER2-amplified breast cancer: a translational research substudy of the NeoALTTO phase III trial. Clin Cancer Res. 2019;25:3581–8.CrossRefPubMed
29.
Zurück zum Zitat De Almeida BP, Apolónio JD, Binnie A, Castelo-Branco P. Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers. BMC Cancer. 2019;19:1–12.CrossRef De Almeida BP, Apolónio JD, Binnie A, Castelo-Branco P. Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers. BMC Cancer. 2019;19:1–12.CrossRef
Metadaten
Titel
Biomarkers and translational research approaches in breast cancer—an update
verfasst von
Angelika M. Starzer
Anna S. Berghoff
Rupert Bartsch
Publikationsdatum
12.12.2022
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology / Ausgabe 1/2023
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-022-00855-0

Weitere Artikel der Ausgabe 1/2023

memo - Magazine of European Medical Oncology 1/2023 Zur Ausgabe