Das Swiss Cancer Institute lanciert 2026 bereits zum elften Mal die Young Oncology Academy (YOA), ein Förderprogramm für den forschenden Nachwuchs. Es richtet sich an engagierte junge Ärztinnen und Ärzte aus den Berei­chen Onkologie, Hämatologie, Radioonkologie, Urologie, Gynäkologie, Patholo­gie oder Dermatologie, welche sich in onkologischen/hämatologischen Fragestellungen vertiefen wollen.

Das vielseitige einjährige Curriculum umfasst unter anderem Kongressbesuche im In- und Ausland (ESMO, EHA, ESTRO, ESP etc.), Präsentations- und Schreib­trainings, Networking, Grant-Submission-Workshops, Einblicke in Phase-I-Studien und die klinische und translationale Forschung sowie Einführungen in statistische Grundlagen. Die Teilnehmer werden von erfahrenen onkologischen Fachpersonen (Mentorinnen / Mentoren) begleitet und erhalten auch die Möglich­keit, eigene Studienprojekte zu entwickeln und vorzustellen.

Zum Jahresende publizieren die YOA-Teilnehmer ein Paper zu ihren persönlichen Highlights eines internationalen Kongresses. Wir freuen uns, die Arbeiten aus dem Jahr 2025 hier präsentieren zu dürfen. Die verschiedenen Artikel der Mentees werden in drei nacheinander folgenden Zeitschriften publiziert.

Wir beide haben diese YOA besucht und können diese sehr ­empfehlen. Weitere Informationen finden sich auf der Website des Swiss Cancer Institute:
https://www.swisscancerinstitute.ch/de/forschende/young-oncology-academy/

Dr. med. Tämer El Saadany                                                   Dr. med. Eveline Daetwyler

Novel Genetic Insights in Lymphoma Biology: Follicular Lymphoma Subtypes and ASXL1-Related Disease

Review YOA 2025: Annaïse Julie Jauch

Mentee: Annaïse Julie Jauch, University Hospital Basel
Mentor: Prof Ubran Novak, University Hospital of Bern/Inselspital
Speciality: Mentee Haematology, Mentor Prof Urban Novark Medical Oncology
Year: Young Oncology Academy 2025

Review paper on ESID EHA SIOPE Focused Symposium 2025 I Vienna November 18–20, 2025. The scientific meeting was dedicated to the interplay of immunology and haematology, with particular emphasis on the somatic and germline genetic landscapes shaping malignancies.

Whole-genome sequencing reveals three follicular lymphoma subtypes with distinct cell of origin and patient outcomes (by Weicheng Ren et al. 2025)

Follicular lymphoma (FL) is a malignancy of germinal-center B-cells and a common non-Hodgkin lymphoma subtype in Western Europe (1). While FL typically follows an indolent course and recent advances in treatment avenues have significantly improved patient survival, the disease remains incurable and demonstrates a considerable clinical heterogeneity. A patient subset experiences early progression, treatment refractoriness, or histological transformation (2).

The WHO 2022 classification recognises four FL-subtypes: Classical FL, FL with unusual cytological features, follicular large B-cell lymphoma and FL with a predominantly diffuse growth pattern (3). Although, this classification enhances our understanding of FL biology, genetic-based sub-classification remains challenging. The m7-FLIPI risk model integrates seven somatic mutations with clinical parameters to predict progression-free survival (4), however the algorithm does not incorporate FL hallmark translocations (BCL-2::IGH, BCL-6 associated rearrangements).

The work by Ren et al. aimed to define clinically relevant genetic FL subtypes, through whole-genome and transcriptomic sequencing of 131 primary FL samples. Using integrated clustering of copy number variants (CNVs), somatic mutations and structural variants, they identified three genetic subtypes. Cluster 1 (C1) was characterised by recurrent BCL-6 translocations and mutations in NOTCH and NF-κB. C2 on the other hand was defined by high frequency of BCL2 translocations and genetic alterations in chromatin modifier genes (CREBBP, KMT2D, EZH2). C3 lacked BCL2/BCL6 translocations but exhibited a high CNV burden. Clinically, C1 was associated with a favourable prognosis, while C3 correlated with inferior progression-free survival and overall survival.

In summary, the work by W. Ren and colleagues proposes three genetic FL subtypes with distinct biological features, genetic propensities and clinical outcome. Future work will have to validate the proposed risk stratification, and define its clinical use in view of the current and future therapeutic options.

ASXL1 deficiency causes epigenetic dysfunction, combined immunodeficiency, and EBV-associated lymphoma (by Maggie P. Fu et al. 2025)

Inborn errors of immunity (IEI) are germline disorders affecting immune system development and/or function (5). Malignancy is the second leading cause of death in IEI patients (6). Notably, one third of newly identified monogenetic disorders are established by studying a single case (7), following methodical validation to establish causality.

Fu and colleagues described a female patient, with recurrent pneumonia requiring hospitalisation, including one severe EBV-related episode. At the age of three, she developed vaccine-strain rubella-positive granulomas following live-attenuated MMR vaccination that persisted over 10 years. Laboratory findings revealed erythrocytic macrocytosis, T-cell lymphopenia and hypogammaglobulinaemia. Chronic EBV replication was noted. At the age of 14 years, she developed EBV-associated advanced Hodgkin lymphoma (stage IVA, mixed cellularity subtype). Following polychemotherapy and checkpoint inhibitors, persistent disease necessitated allogeneic haematopoietic stem cell transplantation from a matched-unrelated donor. The patient remained well 18 months post- trans-plantation.

Given the severe clinical phenotype and young age, a genetic cause was assumed, and whole-genome and exome sequencing was performed. Two novel compound heterozygous missense mutations in ASXL1 were identified. While somatic alterations in the epigenetic modifier ASXL1 are well-characterised in clonal haematopoiesis and haematological malignancies, germline variants have not been previously associated with immune dysfunction.

The authors demonstrated reduced ASXL1 protein levels in patient-derived T-cells and fibroblasts. Cells transfected with the ASXL1 variants recapitulated the low protein levels. This was paralleled with the loss of differentially methylated sites and accelerated epigenetic aging compared to healthy controls. To address causality, the authors transduced patient-derived T-cells with wild-type ASXL1, partially rescuing the methylation defects and epigenetic aging.

Profound T-cell exhaustion, reduced T- and NK-cell numbers as well as impaired cytotoxicity, suggested that chronic viral replication and impaired immunosurveillance lead to Hodgkin lymphoma development.

In summary, the authors identified biallelic germline ASXL1 missense mutations as a novel IEI (8). They suggest genetic testing in patients with chronic viral infections, viral-associated malignancy and combined immunodeficiency. Allogeneic bone marrow transplantation in such rare cases will likely cure the immunodeficiency, and the related haematologic malignancy.

Literatur
1. Dreyling M, Ghielmini M, Rule S, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):298-308.
2. Carbone A, Roulland S, Gloghini A, et al. Follicular lymphoma. Nat Rev Dis Primers. 2019;5(1):83.
3. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organiza-tion Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720-1748.
4. Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16(9):1111-1122.
5. Notarangelo LD, Bacchetta R, Casanova JL, Su HC. Human inborn errors of immunity: An expanding universe. Sci Immunol. 2020;5(49).
6. Fekrvand S, Abolhassani H, Esfahani ZH, et al. Cancer Trends in Inborn Errors of Immunity: A Systematic Review and Meta-Analysis. J Clin Immunol. 2024;45(1):34.
7. Poli MC, Aksentijevich I, Bousfiha AA, et al. Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. Journal of Human Immunity. 2025;1(1).
8. Fu MP, Sharma M, Yousefi P, et al. ASXL1 deficiency causes epigenetic dysfunction, com-bined immunodeficiency, and EBV-associated lymphoma. J Exp Med. 2025;222(10).

Liquid Biopsy in the clinic – My highlights from the European Congress of Pathology 2025

Review YOA 2025: Albert Baschong

Mentee: Dr. med. Albert Baschong, Institut für Pathologie und Molekularpathologie Universitätsspital Zürich
Mentor: Prof. Matthias Matter, Institut für Pathologie Universitätsspital Basel
Speciality: Pathology
Year: Young Oncology Academy 2025

In recent years, it has been evident that pathology is in a state of profound change. The advent of novel molecular and digital methods has influenced pathology substantially. This was also demonstrated at this year’s European Congress of Pathology in Vienna, which took place under the motto “Tradition meets Future.” I would therefore like to give a brief insight into the session liquid biopsy in solid tumors and introduce an exciting analysis method and its potential applications in Ewing sarcoma. This review has been adapted from a presentation given to the SCI Sarcoma Interest Group.

Liquid biopsy is a procedure that extracts molecular information from bodily fluids. Tumour cells release their molecular signature in various forms, whether as circulating tumour cells (CTCs), in exosomes or, as free DNA (circulating tumour DNA, ctDNA) after apoptosis. CtDNA is a part of cell-free DNA (cfDNA). The majority of cfDNA consists of leukocyte residues. Blood is typically used as the fluid for liquid biopsy, but other body fluids (e.g. pleural effusion, ascites, cerebrospinal fluid) can also be employed.
This “liquid” molecular tumour analysis has a wide range of applications, but includes mainly the analysis of mutational signatures, methylation and changes in fragmentation.

The ease with which samples can be obtained also highlights their greatest advantage over traditional tissue biopsies: low invasiveness. In addition, multiple metastatic sites can be detected in their entirety, as can the reflection of a tumor’s heterogeneity. On the other hand, ctDNA may be completely absent or only present at low concentrations in liquid samples. This makes the samples very sensible and requires highly sensitive detection methods (e.g. digital droplet PCR, NGS). In addition, some analyses, such as fusion analyses, CNV and TMB, are more challenging. CtDNA levels can also vary greatly within and between tumour types. Consequently, the use of liquid biopsy is not yet widely adopted.
However, there are various established applications of liquid biopsies. Examples include ESR1 testing in breast cancer and resistance mutation testing in lung cancer.

Liquid biopsy is not yet widely used in soft tissue tumours. Ewing sarcoma is a tumour that develops in bones and soft tissues. It has a low mutational rate and highly fragmented DNA. Its detection in liquid biopsies proves difficult. Peneder et al. developed a bioinformatic tool, called LIQUORICE, to detect ctDNA using fragmentation patterns. Interestingly, DNA methylation influences fragmentation patterns by affecting chromatin structure. Their developed algorithm uses epigenetic signals and fragmentation patterns for determining the tumor of origin. With this they were able to distinguish liquid biopsies from Ewing sarcoma patients from other sarcomas, quantify tumor burden and track treatment response.
In summary, liquid biopsy is an exciting analytic method. Combining it with digital solutions opens up new possibilities for its broader application.

Literatur
Peneder P, Bock C, Tomazou EM. LIQUORICE: detection of epigenetic signatures in liquid biopsies based on whole-genome sequencing data. Bioinform Adv. 2022;2(1):vbac017. Published 2022 Mar 23. doi:10.1093/bioadv/vbac017

Peneder P, Stütz AM, Surdez D, et al. Multimodal analysis of cell-free DNA whole-genome sequencing for pediat-ric cancers with low mutational burden. Nat Commun. 2021;12(1):3230. Published 2021 May 28. doi:10.1038/s41467-021-23445-w

ESMO 2025 Highlights in Gastric and Gastroesophageal ­Junction Adenocarcinoma (GC/GEJA) – Insights from ­MATTERHORN, PHER-FLOT/IKF-053 and FORTITUDE-101

Review YOA 2025: Sabine Raimann

Mentee: Dr. med. Sabine Raimann, Cantonal Hospital Winterthur
Mentor: Prof. Dr. med. Viviane Hess, University Hospital Basel
Speciality: Medical Oncology
Year: Young Oncology Academy 2025

GC/GEJA remain a major global health concern, with poor survival despite aggressive treatment. Molecular insights have enabled the integration of immunotherapy and targeted agents into advanced disease treatment, guided by biomarkers such as HER2, PD-L1, MSI and CLDN18.2 (1–5). Explorative biomarkers such as FGFR2b are being investigated with targeted therapies in development.

Curative surgical resection remains the cornerstone of localized GC/GEJA management. Perioperative chemotherapy improves prognosis with the FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) regimen widely recognized as the standard of care (6, 7). To further improve the efficacy of perioperative treatment, two trials presented at the 2025 ESMO Congress assessed novel regimens with already proven benefit in the palliative setting. The final overall survival (OS) results from the Phase III MATTERHORN trial were presented, comparing perioperative PD-L1 inhibitor durvalumab plus FLOT with placebo plus FLOT in 948 patients with resectable, locally advanced GC/GEJA (8). At a median follow-up of 43 months durvalumab plus FLOT reduced the risk of death by 22 % (HR 0.78; 95 % CI 0.63-0.96; P=0.021) regardless of PD-L1 status. Three-year OS was 69 % with the durvalumab-based regimen compared to 62 % with FLOT. 5 % of patients had MSI-high tumor tissue, evenly distributed between arms. However, MSS status was unknown in around 30 % of patients. HER2 was not assessed. 20 % of patients died within 15 months in both arms, underscoring the need for biomarker-driven approaches to tackle the problem of early mortality.

A biomarker-driven strategy in the same setting was chosen in the phase II, single-arm PHER-FLOT/IKF-053 trial for patients with HER2-positive GC/GEJA. This trial evaluated the efficacy and safety of combining FLOT, trastuzumab, and pembrolizumab in the perioperative setting in 31 patients with resectable, locally advanced HER2-positive GC/GEJA (9). This trial follows the KEYNOTE-811 trial that established this combination for advanced disease (10). The pathological complete response rate was 48.4 % (15 of 31), meeting the co-primary endpoint and exceeding historical FLOT benchmarks of 15–20 %. Two-thirds of patients achieved major pathological response. The safety profile aligned with expectations, except the elevated grade 3 diarrhea (12 of 31) and reoperation rate (8 of 30). No 30-day postoperative mortality occurred. The long-term results – particularly the 2-year disease-free survival data (co-primary endpoint) – will determine whether this perioperative approach should be further explored in larger trials aiming for a new benchmark for this molecular subgroup.

Shifting focus to an emerging biomarker in the palliative setting: the randomized, placebo-controlled Phase III FORTITUDE-101 trial evaluated bemarituzumab, a first-in-class anti-FGFR2b antibody, added to mFOLFOX6 (fluorouracil, leucovorin, oxaliplatin) in 547 patients with unresectable or metastatic FGFR2b-expressing (2+/3+ staining in ≥ 10 % of tumor cells), non-HER2-positive GC/GEJA. At the primary analysis (median follow-up 11.8 months), median OS was 17.9 months with bemarituzumab and 12.5 months in the placebo arm (HR 0.61; 95 % CI, 0.43 to 0.86; P=0.005). With a longer median follow-up of 19.4 months no OS benefit was observed (14.5 months versus 13.2 months; HR 0.82; 95 % CI 0.62–1.08). Grade ≥ 3 treatmentrelated adverse events occurred in 60 % of patients receiving bemarituzumab, mainly reversible corneal events, compared with 18.4 % in the placebo arm. The converging OS curves suggest a limited efficacy, likely due to data maturity and biomarker heterogeneity rather than treatment imbalance, as treatment exposure and subsequent therapy were similar between arms. Preclinical studies showed bemarituzumab sensitizes tumors to anti-PD-1 antibodies by modulating the microenvironment (11). The ongoing phase Ib/III FORTITUDE-102 trial is exploring mFOLFOX6 plus nivolumab and either bemarituzumab or placebo in patients with advanced FGFR2b-expressing GC/GEJA.
These trials highlight the evolving landscape of GC/GEJA research with a move toward precision-based medicine. Furthermore, it is crucial to develop strategies targeting tumor heterogeneity and biomarker-based focal positivity, as these could significantly impact treatment responses.

Literatur
1. Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).
2. Tabernero, J. et al. KEYNOTE-859: a Phase III study of pembrolizumab plus chemotherapy in gastric/gastroesophageal junction adenocarcinoma. Future Oncol. 17, 2847–2855 (2021).
3. Janjigian, Y. Y. et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398, 27–40 (2021).
4. Chao, J. et al. Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability–High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials. JAMA Oncol. 7, 895–902 (2021).
5. Shitara, K. et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 401, 1655–1668 (2023).
6. Lordick, F. et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33, 1005–1020 (2022).
7. Al-Batran, S. E. et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a r…. Lancet 393, 1948–1957 (2019).
8. Janjigian, Y. Y. et al. Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer. N. Engl. J. Med. 393, 217–230 (2025).
9. Stein, A. et al. Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial. Nat. Med. 2025 1–8 (2025). doi:10.1038/s41591-025-03979-y
10. Janjigian, Y. Y. et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet 402, 2197–2208 (2023).
11. Xiang, H. et al. Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer. MAbs 13, (2021).

Trastuzumab Deruxtecan in the neoadjuvant and post neoadjuvant treatments

Review YOA 2025: Artemisia Kakourou

Mentee: Artemisia Kakourou, medical oncologist, CHUV
Mentor: Professor Miklos Pless, Cantonal Hospital Winterthur
Speciality: Medical Oncology
Year: Young Oncology Academy 2025

Introduction

Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate (ADC) that has emerged as one of the most active HER2-targeted ADC, demonstrating superior survival outcomes compared with earlier HER2-directed therapies in metastatic disease. Two major clinical trials, the DESTINY-Breast11 and DESTINY-Breast05 extend T-DXd evaluation into the neoadjuvant and post-neoadjuvant settings, respectively, addressing major unmet needs for patients with high-risk HER2-positive early breast cancer (eBC). This review summarizes the results for efficacy, safety and implications of these two pivotal trials, and proposes considerations for optimal integration of T-DXd in curative treatment strategies.

DESTINY-Breast11: Neoadjuvant T-DXd–THP Versus ddAC–THP

Pathologic complete response (pCR) is a strong predictor of improved event-free and overall survival in HER2-positive eBC (1, 2, 3). Standard neoadjuvant regimens combining chemotherapy with HER2-targeted therapy achieve a pCR of about 39–69 % (4, 5, 6, 7, 8, 9), with lower rates in hormone-receptor–positive and clinically high-risk patients (5, 10). Traditional regimens also carry significant acute toxicities (9, 11) and long-term risks such as cardiotoxicity (12, 13), neuropathy (5) and secondary leukemias (12). Because T-DXd has already shown superior survival compared with prior standard therapies in metastatic disease (14, 15), DESTINY-Breast11 was designed to explore whether incorporating T-DXd in the neoadjuvant setting could improve efficacy and safety.

DESTINY-Breast11 compared neoadjuvant T-DXd combined with paclitaxel, trastuzumab, and pertuzumab (THP) versus dose-dense doxorubicin plus cyclophosphamide (ddAC) followed by THP, with patients receiving either 4 cycles of T-DXd followed by 4 cycles of THP, or 4 cycles of ddAC followed by 4 cycles of THP before surgery (16). A third arm evaluated T-DXd alone but was closed early following the Independent Data Monitoring Committee recommendation, for several reasons, including a lower pCR rate. T-DXd-THP demonstrated a statistically significant improvement in pathologic complete response with a pCR rate of 67.3 % and an improvement of 11.2 % over ddAC-THP (95 % CI, 4.0–18.3 %; P=0.003). Benefits were seen in both hormone receptor (HR)-positive tumors (61.4 % vs 52.3 %; ΔpCR 9.1 %, 95 % CI 0.2–17.9 %) and HR-negative tumors (83.1 % vs 67.1 %; ΔpCR 16.1 %, 95 % CI 3.0–28.8 %). Also, early event free survival (EFS) data (4.5 % maturity) showed a hazard ratio of 0.56 (95 % CI 0.26–1.17). This is the first phase III evidence showing that replacing chemotherapy with an ADC in neoadjuvant setting improves pCR. Residual cancer burden analysis showed that more than 81 % of patients in the T-DXd-THP arm had no or minimal residual invasive disease (RCB-0 or RCB-I), compared with 69 % in the ddAC-THP arm. Of note, 78 % of hormone-receptor-positive tumors achieved RCB-0/I, highlighting the benefit in a group that traditionally responds less well. Importantly, the safety profile of T-DXd-THP was more favorable than ddAC-THP, with fewer grade 3 or higher adverse events, fewer serious adverse events, and reduced ventricular dysfunction (1.3 % vs 6.1 %). Rates of interstitial lung disease were low and comparable between groups (4.4 % vs. 5.1 %).

DESTINY-Breast11 concluded that T-DXd-THP achieved higher pCR rates and a more favorable safety profile than ddAC–THP. However, the trial has important limitations: the comparator arm no longer reflects current standard-of-care chemotherapy (which is mainly carboplatin, a taxane plus (HP17), and only about half of patients without pCR received post-neoadjuvant trastuzumab emtansine (T-DM1), which is now recommended. Since the chemotherapy regimen in the standard arm does not meet current standards – which achieve pCR rates comparable to T-DXd-THP and are also anthracycline-free – the definitive role of T-DXd-THP in the neoadjuvant setting remains to be established.

DESTINY-Breast05: Adjuvant T-DXd Versus T-DM1 for Residual Disease

The DESTINY-Breast05 trial evaluated the use of adjuvant T-DXd in HER2-positive eBC patients who had residual invasive disease following neoadjuvant therapy (NAT) – a group known to have higher recurrence risk. In the earlier KATHERINE trial, T-DM1 had become the standard adjuvant therapy in this setting, after showing significant improvements in invasive disease-free survival (IDFS) and over-all survival (OS) (18, 19) over trastuzumab. Still, outcomes in patients with advanced locoregional disease or positive nodal status remained modest (19, 20), and CNS recurrence was not reduced (20). Given the superiority of T-DXd over T-DM1 in metastatic disease (21, 22), DESTINY-Breast05 compared these two agents in patients with high-risk HER2 positive early breast cancer who had residual disease after neoadjuvant therapy. High-risk was defined as either inoperable disease prior to neoadjuvant therapy (cT4, N0 3, M0 or cT1 3, N2 3, M0) or operable disease (cT1 3, N0 1, M0) with axillary node–positive residual disease (ypN1 3) after neoadjuvant therapy. In the experimental arm, patients received T-DXd every 3 weeks for 14 cycles, while in the comparator arm, patients received T-DM1 3.6 mg/kg IV every 3 weeks for 14 cycles. Notably, nearly half of the study population were of Asian descent.

DESTINY-Breast05 demonstrated that at 3 years, IDFS was 92.4 % with T-DXd versus 83.7 % with T-DM1, corresponding to a hazard ratio (HR) of 0.47 (95 % CI, 0.34–0.66). The IDFS benefit was consistent across all prespecified subgroups, regardless of hormone-receptor status, nodal involvement, baseline stage, or residual disease characteristics. Secondary endpoints also showed advantages for T-DXd. Three year disease free survival (DFS) was 92.3 % with T-DXd versus 83.5 % with T-DM1 (HR 0.47; 95 % CI, 0.34–0.66), and 3 year distant recurrence free interval (DRFI) was 93.9 % versus 86.1 % (HR 0.49; 95 % CI, 0.34–0.71), favoring T-DXd. Notably, fewer central nervous system (CNS) metastases were reported in the T-DXd arm, with a 3-year brain metastasis–free interval of 97.6 % versus 95.8 % with T-DM1. Safety was considered manageable. Interstitial lung disease (ILD) occurred in 9.6 % of patients receiving T-DXd, mostly grade 1–2. Three deaths occurred in the T-DXd arm (two due to ILD/pneumonitis and one due to unrelated respiratory infection), while five occurred in the T-DM1 arm from various unrelated causes. Cardiotoxicity was rare, occurring in 2.9 % of T-DXd patients versus 1.7 % of T-DM1 patients, with mostly asymptomatic left ventricular declines and no treatment-related heart failure. More than 72 % of patients in both arms completed the full 14 cycles of therapy.

DESTINY-Breast05 concluded that adjuvant T-DXd showed better efficacy and a manageable safety profile in high-risk HER2-positive eBC patients with residual disease after NAT. High-risk was defined as either inoperable disease at presentation or residual axillary node–positive disease after neoadjuvant treatment; in this population, T-DXd represents a new post-neoadjuvant standard. For patients with residual disease who do not meet these high-risk criteria, T-DM1 remains the standard of care.

Discussion

When viewed together, DESTINY-Breast11 and DESTINY-Breast05 demonstrate that T-DXd has strong efficacy across both neoadjuvant and post-neoadjuvant settings. In the neoadjuvant trial, T-DXd-THP achieved high pCR rates with fewer severe side effects compared with an anthracycline base chemotherapy backbone. In the post-neoadjuvant trial, T-DXd outperformed T-DM1, further reducing recurrence risk in a high-risk group. The optimal sequencing T-DXd in early HER2-positive breast cancer remains an important unanswered question. Long-term outcomes with neoadjuvant T-DXd followed by THP are not yet known. In addition, the management of patients who receive neoadjuvant T-DXd-THP but still present with residual disease at surgery remains undefined. At the present time, it is unclear whether T-DXd should be preferentially used in the neoadjuvant setting, the post-neoadjuvant setting, or potentially both, leaving its optimal placement within the treatment sequence an active area of ongoing investigation. Continued follow-up is required to clarify long-term safety, survival outcomes, and the most effective therapeutic strategy for integrating T-DXd into curative-intent care.

Overall, these two trials show that trastuzumab deruxtecan is becoming an important component of curative-intent therapy in HER2-positive eBC and has the potential to redefine treatment strategies in both the neoadjuvant and post-neoadjuvant settings.

Literatur
1. Spring, L.M. et al. Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis. Clin Cancer Res 26, 2838-2848 (2020).
2. Cortazar, P. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164-172 (2014).
3. Davey, M.G., Browne, F., Miller, N., Lowery, A.J. & Kerin, M.J. Pathological complete response as a surrogate to improved survival in human epidermal growth factor receptor-2-positive breast cancer: systematic review and meta-analysis. BJS Open 6 (2022).
4. Gianni, L. et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13, 25-32 (2012).
5. Hurvitz, S.A. et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 19, 115-126 (2018).
6. Masuda, N. et al. A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer. Breast Cancer Res Treat 180, 135-146 (2020).
7. Schneeweiss, A. et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24, 2278-2284 (2013).
8. Swain, S.M. et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 29, 646-653 (2018).
9. van Ramshorst, M.S. et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19, 1630-1640 (2018).
10. Huober, J. et al. Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. J Clin Oncol 40, 2946-2956 (2022).
11. Hennessy, M.A. & Morris, P.G. Optimizing Anti-HER2 Therapy in early breast cancer: updates from the KRISTINE trial. Ann Palliat Med 9, 504-509 (2020).
12. Loibl, S. et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 35, 159-182 (2024).
13. van der Voort, A. et al. Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial. JAMA Oncol 7, 978-984 (2021).
14. Cortes, J. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med 30, 2208-2215 (2024).
15. Li, J., Hao, C., Wang, H., Pan, Y. & Jiang, Z. DESTINY-Breast09, new breakthroughs in first-line therapy for HER2-positive advanced breast cancer. Transl Breast Cancer Res 6, 28 (2025).
16. Harbeck, N. et al. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol (2025).
17. Burstein, H.J. et al. Tailoring treatment to cancer risk and patient preference: the 2025 St Gallen International Breast Cancer Consensus Statement on individualizing therapy for patients with early breast cancer. Ann Oncol (2025).
18. von Minckwitz, G. et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 380, 617-628 (2019).
19. Geyer, C.E., Jr. & Loibl, S. Switching to T-DM1 remains justified in patients with HER2-negative residual invasive breast cancer after neoadjuvant therapy. Breast 81, 104450 (2025).
20. Mamounas, E.P. Characteristics of residual invasive breast cancer after neoadjuvant therapy in the KATHERINE study. Ann Oncol 32, 1191-1192 (2021).
21. Modi, S. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 382, 610-621 (2020).
22. Hurvitz, S.A. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 401, 105-117 (2023).