Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2024.

Introduction: Each year the interdisciplinary AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, German Gynecological Oncology Group) Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Methods: The updated evidence-based treatment recommendations for early and metastatic breast cancer have been released in March 2024. Results and Conclusion: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2024.

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.

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023.

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2023 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer (mBC).

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial.

Importance: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. Objective: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. Design, Setting, and Participants: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Interventions: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. Main Outcomes and Measures: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Results: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. Conclusions and Relevance: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. Trial Registration: ClinicalTrials.gov Identifier: NCT03272477.

Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR- Trial.

PURPOSE: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). EXPERIMENTAL DESIGN: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. RESULTS: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures. CONCLUSIONS: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.

Inflammation and vascular remodeling in COVID-19 hearts.

A wide range of cardiac symptoms have been observed in COVID-19 patients, often significantly influencing the clinical outcome. While the pathophysiology of pulmonary COVID-19 manifestation has been substantially unraveled, the underlying pathomechanisms of cardiac involvement in COVID-19 are largely unknown. In this multicentre study, we performed a comprehensive analysis of heart samples from 24 autopsies with confirmed SARS-CoV-2 infection and compared them to samples of age-matched Influenza H1N1 A (n = 16), lymphocytic non-influenza myocarditis cases (n = 8), and non-inflamed heart tissue (n = 9). We employed conventional histopathology, multiplexed immunohistochemistry (MPX), microvascular corrosion casting, scanning electron microscopy, X-ray phase-contrast tomography using synchrotron radiation, and direct multiplexed measurements of gene expression, to assess morphological and molecular changes holistically. Based on histopathology, none of the COVID-19 samples fulfilled the established diagnostic criteria of viral myocarditis. However, quantification via MPX showed a significant increase in perivascular CD11b/TIE2 + -macrophages in COVID-19 over time, which was not observed in influenza or non-SARS-CoV-2 viral myocarditis patients. Ultrastructurally, a significant increase in intussusceptive angiogenesis as well as multifocal thrombi, inapparent in conventional morphological analysis, could be demonstrated. In line with this, on a molecular level, COVID-19 hearts displayed a distinct expression pattern of genes primarily coding for factors involved in angiogenesis and epithelial-mesenchymal transition (EMT), changes not seen in any of the other patient groups. We conclude that cardiac involvement in COVID-19 is an angiocentric macrophage-driven inflammatory process, distinct from classical anti-viral inflammatory responses, and substantially underappreciated by conventional histopathologic analysis. For the first time, we have observed intussusceptive angiogenesis in cardiac tissue, which we previously identified as the linchpin of vascular remodeling in COVID-19 pneumonia, as a pathognomic sign in affected hearts. Moreover, we identified CD11b + /TIE2 + macrophages as the drivers of intussusceptive angiogenesis and set forward a putative model for the molecular regulation of vascular alterations.

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2022.

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2022 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer.

De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial.

PURPOSE: Although optimal treatment in early triple-negative breast cancer (TNBC) remains unclear, de-escalated chemotherapy appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial. EXPERIMENTAL DESIGN: ADAPT-TN is a randomized neoadjuvant multicenter phase II trial in early patients with TNBC (n = 336) who were randomized to 12 weeks of nab-paclitaxel 125 mg/m2 + gemcitabine or carboplatin d 1,8 q3w. Omission of further (neo-) adjuvant chemotherapy was allowed only in patients with pathological complete response [pCR, primary endpoint (ypT0/is, ypN0)]. Secondary invasive/distant disease-free and overall survival (i/dDFS, OS) and translational research objectives included quantification of a predictive impact of markers regarding selection for chemotherapy de-escalation, measured by gene expression of 119 genes (including PAM50 subtype) by nCounter platform and stromal tumor-infiltrating lymphocytes (sTIL). RESULTS: After 60 months of median follow-up, 12-week-pCR was favorably associated (HR, 0.24; P = 0.001) with 5y-iDFS of 90.6% versus 62.8%. No survival advantage of carboplatin use was observed, despite a higher pCR rate [HR, 1.04; 95% confidence interval (CI), 0.68-1.59]. Additional anthracycline-containing chemotherapy was not associated with a significant iDFS advantage in pCR patients (HR, 1.29; 95% CI, 0.41-4.02). Beyond pCR rate, nodal status and high sTILs were independently associated with better iDFS, dDFS, and OS by multivariable analysis. CONCLUSIONS: Short de-escalated neoadjuvant taxane/platinum-based combination therapy appears to be a promising strategy in early TNBC for using pCR rate as an early decision point for further therapy (de-) escalation together with node-negative status and high sTILs. See related commentary by Sharma, p. 4840.

De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Several de-escalation neoadjuvant strategies have been investigated to reduce the use of chemotherapy in HER2-positive early breast cancer using pathological complete response as a surrogate endpoint; there are few survival data from these trials. Here, we report 5-year survival data in the WSG-ADAPT-HER2+/HR- trial and address the effect of pathological complete response, early therapy response, and molecular subtype. METHODS: WSG-ASAPT-HER2+/HR-, a part of the ADAPT umbrella trial performed in patients with different subtypes of early breast cancer, was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 40 Breast Cancer Centres in Germany. Eligible patients were aged 18 years or older with histologically confirmed, unilateral, primary invasive, non-inflammatory early breast cancer, hormone receptor-negative and HER2-positive status, and an Eastern Cooperative Oncology Group performance status of 0 or 1 or a Karnofsky performance status of at least 80%. Patients were randomly assigned (5:2, block size 21, stratified by centre and clinical nodal status) to 12 weeks of either trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) plus pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) or trastuzumab plus pertuzumab plus paclitaxel (80 mg/m2 weekly); all drugs were administered intravenously. The primary objective of the trial was to compare the number of patients with a pathological complete response at surgery (ie, no invasive tumour cells in breast and lymph nodes [ypT0/is ypN0], the primary endpoint) in early responders (ie, low cellularity or Ki67 decrease ≥30% after 3 weeks) in the trastuzumab plus pertuzumab group versus all patients (irrespective of an early response) in the trastuzumab plus pertuzumab plus paclitaxel group. Non-inferiority was defined as a pathological complete response no worse than 23% lower in the early-responder proportion of patients in the trastuzumab plus pertuzumab group than in the entire trastuzumab plus pertuzumab plus paclitaxel group. The primary endpoint has been reported previously. Additionally, the primary objective of the ADAPT umbrella trial was the evaluation of the effect of pathological complete response on invasive disease-free survival. At investigator's discretion, further chemotherapy could be omitted in patients with a pathological complete response. Secondary survival endpoints were 5-year invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. The effect of pathological complete response on survival was estimated by Cox regression analysis. All analyses are reported in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01817452, and is closed to recruitment. FINDINGS: Between March 3, 2014, and Oct 6, 2015, 134 patients were recruited and randomly assigned to treatment, 92 to trastuzumab plus pertuzumab and 42 to trastuzumab plus pertuzumab plus paclitaxel. Median follow-up in survivors was 59·9 months (IQR 53·4-61·4). There were no significant differences between the treatment groups in invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. In the trastuzumab plus pertuzumab plus paclitaxel group and in the trastuzumab plus pertuzumab group, the proportions of patients achieving 5-year survival respectively were 98% (95% CI 84-100) and 87% (78-93) for invasive disease-free survival (hazard ratio [HR] 0·32, 95% CI 0·07-1·49; p=0·15); 98% (95% CI 84-100) and 89% (79-94) for relapse-free survival (HR 0·41, 95% CI 0·09-1·91; p=0·25); 100% (95% CI not estimable) and 95% (88-98) for locoregional relapse-free survival (HR 0·41, 95% CI 0·05-3·75; p=0·43); 98% (95% CI 84-100) and 92% (83-96) for distant disease-free survival (HR 0·35, 95% CI 0·04-3·12; p=0·36), and 98% (95% CI 84-100) and 94% (86-97) for overall survival (HR 0·41, 95% CI 0·05-3·63; p=0·43). Pathological complete response was associated with improved invasive disease-free survival (HR 0·14, 95% CI 0·03-0·64; p=0·011). Two invasive disease-free survival events occurred after a pathological complete response (one in each treatment group). INTERPRETATION: The WSG-ADAPT-HER2+/HR- trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing. FUNDING: Roche, Bayer. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Correction: AGO Recommendations for the Surgical Therapy of the Axilla After Neoadjuvant Chemotherapy: 2021 Update.

[This corrects the article DOI: 10.1055/a-1499-8431.].

AGO Recommendations for the Surgical Therapy of the Axilla After Neoadjuvant Chemotherapy: 2021 Update.

For many decades, the standard procedure to treat breast cancer included complete dissection of the axillary lymph nodes. The aim was to determine histological node status, which was then used as the basis for adjuvant therapy, and to ensure locoregional tumour control. In addition to the debate on how to optimise the therapeutic strategies of systemic treatment and radiotherapy, the current discussion focuses on improving surgical procedures to treat breast cancer. As neoadjuvant chemotherapy is becoming increasingly important, the surgical procedures used to treat breast cancer, whether they are breast surgery or axillary dissection, are changing. Based on the currently available data, carrying out SLNE prior to neoadjuvant chemotherapy is not recommended. In contrast, surgical axillary management after neoadjuvant chemotherapy is considered the procedure of choice for axillary staging and can range from SLNE to TAD and ALND. To reduce the rate of false negatives during surgical staging of the axilla in pN+ CNB stage before NACT and ycN0 after NACT, targeted axillary dissection (TAD), the removal of > 2 SLNs (SLNE, no untargeted axillary sampling), immunohistochemistry to detect isolated tumour cells and micro-metastases, and marking positive lymph nodes before NACT should be the standard approach. This most recent update on surgical axillary management describes the significance of isolated tumour cells and micro-metastasis after neoadjuvant chemotherapy and the clinical consequences of low volume residual disease diagnosed using SLNE and TAD and provides an overview of this year's AGO recommendations for surgical management of the axilla during primary surgery and in relation to neoadjuvant chemotherapy.

Immune Markers and Tumor-Related Processes Predict Neoadjuvant Therapy Response in the WSG-ADAPT HER2-Positive/Hormone Receptor-Positive Trial in Early Breast Cancer.

Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of PIK3CA mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in PIK3CA-mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC.

The use of breast ultrasound for prediction of pathologic complete response in different subtypes of early breast cancer within the WSG-ADAPT subtrials.

OBJECTIVE: We assessed the value of breast ultrasound (US) performed at week 3 and 6 and at the end (EOT) of neoadjuvant therapy (NAT) for prediction of pathologic complete response (pCR, ypT0/is ypN0) in patients with HR+/HER2+, HR-/HER2-or HR-/HER2+ early breast cancer enrolled in the WSG-ADAPT subtrials. METHODS: US was performed at week 3 and 6 of NAT and at EOT in 401, 517, and 553 patients, respectively. Tumors with complete or partial response by US (RECIST 1.1) were classified as responders and those with stable or progressive disease as non-responders. RESULTS: pCR rate was higher in US responders than in non-responders. US tended to yield the highest positive predictive value in HR-/HER2+ (69%) and HR-/HER2-tumors (65%) at week 3, and the highest negative predictive value in HR+/HER2+ tumors at week 6 and at EOT (88.9% and 86.9%, respectively) and in HR-/HER2-tumors at EOT (87.9%). Multivariable analysis of patients with US at week 3 and 6 identified tumor subtype (HR-/HER2+ vs HR+/HER2+; odds ratio (OR) 2.77, 95%CI 1.45-5.29, and OR 4.17, 95%CI 2.26-7.68, respectively) and each 10% change in lesion dimension on US from baseline (OR 1.15, 95%CI 1.08-1.24, and OR 1.25, 95%CI 1.16-1.35, respectively) as parameters associated with pCR. CONCLUSIONS: Our data support the use of week 3 and EOT US for prediction of pCR in response-guided NAT and in planning of breast-conserving surgery. Change in tumor diameter on US as a continuous variable could be a valuable alternative to categorical RECIST 1.1 criteria.

Immune cell composition and functional marker dynamics from multiplexed immunohistochemistry to predict response to neoadjuvant chemotherapy in the WSG-ADAPT-TN trial.

BACKGROUND: The association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored. METHODS: Multiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression. RESULTS: Compared with no change in immune cell composition and functional markers, transition from 'cold' to 'hot' (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after 'hot-to-cold' transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with 'altered' distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14). CONCLUSION: Our exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC.

A multicentre analytical comparison study of inter-reader and inter-assay agreement of four programmed death-ligand 1 immunohistochemistry assays for scoring in triple-negative breast cancer.

AIMS: Studies in various cancer types have demonstrated discordance between results from different programmed death-ligand 1 (PD-L1) assays. Here, we compare the reproducibility and analytical concordance of four clinically developed assays for assessing PD-L1-positivity in tumour-infiltrating immune cells in the tumour area (PD-L1-IC-positivity) in triple-negative breast cancer (TNBC). METHODS AND RESULTS: Primary TNBC resection specimens (n = 30) were selected based on their PD-L1-IC-positivity per VENTANA SP142 (<1%: 15 cases; 1-5%: seven cases; >5%: eight cases). Serial histological sections were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3 and DAKO 28-8. PD-L1-IC-positivity and tumour cell expression (≥1 versus <1%) were scored by trained readers from seven sites using online virtual microscopy. The adjusted mean of PD-L1-IC-positivity for SP263 (7.8%) was significantly higher than those for the other three assays (3.7-4.9%). Differences in adjusted means were statistically significant between SP263 and the other three assays (P < 0.0001) but not between the three remaining assays when excluding SP263 (P = 0.0961-0.6522). Intra-class correlation coefficients revealed moderate-to-strong inter-reader agreement for each assay (0.460-0.805) and poor-to-strong inter-assay agreement for each reader (0.298-0.678) on PD-L1-IC-positivity. CONCLUSIONS: In this first multicentre study of different PD-L1 assays in TNBC, we show that PD-L1-IC-positivity for SP142, 22C3 and 28-8 was reproducible and analytically concordant, indicating that these three assays may be analytically interchangeable. The relevance of the higher PD-L1-IC-positivity for SP263 should be further investigated.