Background About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody–drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC). Patients and methods The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included. Results As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74–1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68–1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients. Conclusion Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.

Background: Bendamustine, a medication approved for the treatment of indolent non-Hodgkin lymphoma, has already shown anticancer activity in metastatic breast cancer (MBC). Here, we present the results of a phase II trial of bendamustine in combination with capecitabine in pre-treated patients with MBC. Patients and methods: AGMT MBC-6 is a multicentre, open-label, single-arm phase II study in HER2-negative MBC. All patients were pre-treated with anthracyclines and/or taxans and had measurable disease. Patients received per os 1000 mg/m2 capecitabine twice daily on days 1 to 14 in combination with 80 mg/m2 bendamustine intravenously on days 1 and 8 of a 3-week cycle for a maximum of eight cycles, followed by a capecitabine maintenance therapy. The primary endpoint was overall response rate (ORR). Results: From September 2013 to May 2015, 40 patients were recruited in eight Austrian centres. The median age was 60 years (range 29–77). Twenty-five per cent of patients had triple-negative breast cancer (TNBC) and 93% showed visceral involvement. With 17 partial and one complete remission, ORR was 46%. Median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI) 6.1–10.7]. The most common non-haematological adverse events (AEs) of grade 3 were hand-foot syndrome (13%), fatigue (10%), nausea (8%), and dyspnoea (8%). One grade 4 non-haematological AE (hepatic failure) and three grade 4 haematological AEs (neutropenia) were observed. One patient died of restrictive cardiomyopathy, in which a relationship to capecitabine cannot be excluded, but seems unlikely. Conclusion: The combination of capecitabine and bendamustine shows promising efficacy and moderate toxicity. Further evaluation of this drug combination is warranted. The clinical trial AGMT MBC-6 was registered at ClinicalTrials.gov , ( https://clinicaltrials.gov/ ; identifier: NCT01891227).

Background: New anti-HER2 drugs such as tucatinib and trastuzumab deruxtecan (T-DXd) have shown to improve survival of HER2+ MBC in clinical phase III trials. To allow a future confirmation of this survival advantage in real world, we evaluated the prognosis of HER2+ MBC patients before the availability of tucatinib and T-DXd in Austria. Furthermore, we analyzed the treatment landscape and the drop-out rate between subsequent lines of therapy as documented in the MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT). Patients and methods: The AGMT-MBC-Registry is a multicenter nationwide ongoing retrospective and prospective registry for MBC patients in Austria. In this analysis, patients with known HER2 status, available survival data, at least one treatment line and diagnosis of metastatic disease after 01/04/2013 (pertuzumab available) were included. Follow-up was censored at Dec 31, 2020, when tucatinib und T-DXd became available. Results: As of 04/05/2022, 2,235 patients have been included in the registry. Out of 2,000 evaluable patients, 362 (18.1%) were HER2+, of which 171 (47.2%) fulfilled the inclusion criteria. Out of them 69.0% were hormone-receptor positive. In patients with metachronous metastatic disease (53.2%), 61.5% had received trastuzumab-based treatment for early breast cancer. Median overall survival (OS) for all patients was 50.1 months (95%CI 40.7-73.0), and 66.1 months (95%CI 50.1-NA) for those who received a pertuzumab combination as first-line treatment. The drop-out rate from 1st- to 5th-line was 26.9%, 24.4%, 28.3% and 36.7%, respectively. This yields an estimated percentage of patients that received at least 3, 4, and 5 treatment lines for advanced disease of 55.2%, 39.6% and 25.1%, respectively. In first line, 50.9% received trastuzumab plus pertuzumab and 11.1% T- DM1. In second line, 38.9% were treated with T-DM1 and 35.6% with trastuzumab-based chemotherapy or endocrine therapy. In third line, 11.3%, 17.0% and 49.1% received T-DM1, lapatinib-based and trastuzumab-based therapy, respectively. Outcomes according to treatment line are shown in Table 1. Conclusion: Median overall survival of HER2+ MBC in Austria who received a pertuzumab combination treatment is comparable to the results reported in the registration CLEOPATRA trial. In this analysis, only ~40% of patients are estimated to receive more than three treatment lines and treatment benefit diminished from line to line. This underlines the importance of investigating and ultimately using the most effective compounds in early treatment lines in order to allow more patients to benefit from these life prolonging drugs. Table 1: Outcome according to treatment line Citation Format: Simon P. Gampenrieder, Gabriel Rinnerthaler, Christoph Tinchon, Andreas Petzer, Marija Balic, Sonja Heibl, Margit Sandholzer, August F. Zabernigg, Daniel Egle, Christopher Hager, Petra Pichler, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Michael Knauer, Michael Hubalek, Christian F. Singer, Richard Greil. Prognosis and treatment landscape of HER2-positive metastatic breast cancer (MBC) before the availability of tucatinib and trastuzumab-deruxtecan: Results from the Austrian AGMT_MBC-Registry [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-27.

Background: International guidelines recommend endocrine-based first-line therapy [ET] in hormone receptor-positive, HER2-negative (HR+/HER2- or luminal) metastatic breast cancer (MBC), nowadays in combination with a CDK4/6 inhibitor. Several real-word data suggest, however, that in daily practice up to 40% of patients with luminal MBC receive chemotherapy in first-line. To clarify the treatment landscape in an Austrian population of HR+/HER2- MBC patients, we analyzed the data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). In addition, we investigated the influence of different treatment strategies on overall survival (OS). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Only patients with HR+/HER2- MBC with available ER and HER2 status and sufficient outcome data were included in this analysis. Unadjusted, univariate survival probabilities of PFS and OS were calculated by the Kaplan-Meier method and compared by the log-rank test, multivariate hazard ratios (HR) were estimated by Cox regression models. A multivariate analysis including the following parameters was performed for first-line PFS and OS: age (continuous, as interaction with menopausal status), menopausal status (pre- vs postmenopausal vs unknown,), DFS (de novometastatic vs < 24 months vs ≥ 24 months), (neo)adjuvant chemotherapy (yes vs no), grading (1+2 vs 3 vs unknown), visceral disease (yes vs no) and number of metastatic sites (1 vs 2-3 vs ≥4), first-line treatment (ET+CDK4/6i vs ET vs chemotherapy +/- bevacizumab +/- ET). Results: As of 24/06/2020, 1904 patients were included in the AGMT-MBC-Registry. Out of 1633 evaluable patients, 931 (57.01%) had HR+/HER2- disease and had received at least one treatment line for metastatic disease. In first-line, 577 (62.0%) patients received endocrine-based therapy (356 [61.7%] ET, 172 [29.8%] ET+CDK4/6i, 49 [8.5%] ET+Targeted other), and 354 (38.0%) received chemotherapy. The proportion of chemotherapy treated patients was slightly higher in pre- vs. postmenopausal women (41/94=43.6% vs. 222/664=33.4%) but decreased significantly over time (<2010: 60.3%; 2010-2015: 44.8%; >2015: 19.7%). In multivariate analysis, both ET and ET+CDK4/6i were significantly associated with longer first-line PFS and OS compared to chemotherapy (Table 1). The most frequently used drugs across all treatment-lines were aromatase inhibitors (77.9%), fulvestrant (53.9%; 39.8% in first-line and 36.3% in second-line), tamoxifen (17.2%), CDK4/6 inhibitors (40.0%; 48.9% in first-line and 21.8% in second-line), everolimus (18.9%; 30.7% in second-line and 69.3% in ≥ third-line), taxanes (41.6%), capecitabine (35.0%), anthracyclines (28.6%), vinorelbine (17.0%) and eribulin (12.6%). Conclusion: In our registry, first-line chemotherapy for luminal MBC was significantly associated with an inferior PFS and OS compared to endocrine-based therapy. Because of the retrospective design of the study, biases influencing these results cannot be fully excluded, however, our data suggest that first-line chemotherapy should be avoided in luminal MBC. Adjusted analysisET vs. chemotherapyET+CDK4/6i vs. chemotherapy1st-line PFSHR 0.63; 95%CI 0.52-0.77; P<0.001HR 0.19; 95%CI 0.13-0.29; P<0.001OSHR 0.59; 95%CI 0.49-0.72; P<0.001HR 0.35; 95%CI 0.23-0.51, P<0.001 Citation Format: Gabriel Rinnerthaler, Simon P Gampenrieder, Christoph Tinchon, Andreas Leo Petzer, Christoph Suppan, Sonja Heibl, Daniela Voskova, August F Zabernigg, Daniel Egle, Margit Sandholzer, Christian F Singer, Florian Roitner, Johannes Andel, Michael Hubalek, Michael Knauer, Richard Greil. First-line treatment of hormone receptor positive metastatic breast cancer (MBC) in everyday practice: Results from the Austrian AGMT_MBC-Registry [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-21.

Background: Hormone-receptor (HR) status, HER2 Status, de novo metastatic disease, distant recurrence-free interval (DRFI), and visceral disease are known prognostic factors in metastatic breast cancer (MBC). Therefore, in the majority of clinical trials, randomization is stratified for these parameters. Whether the number of involved organs at baseline has an additional prognostic value was examined in this analysis. Patients and methods: The AGMT-MBC-Registry is a multicenter nationwide ongoing retrospective and prospective registry for MBC patients in Austria. In this analysis, patients with known HR status, HER2 status, and available survival data were included. Multivariable hazard ratios were estimated by COX proportional hazard models. For variable selection a backward stepwise model selection using the Akaike information criterion was performed. Results: As of 04/05/2022, 2,235 patients have been included in the registry, of which 1,840 patients fulfilled the inclusion criteria. In two different multivariable COX proportional hazard models for overall survival, the number of involved organs was a highly statistically significant independent prognostic factor: (1) a model including the number of involved organs at baseline together with known prognostic factors (see Table 1); (2) a stepwise selection model additionally including menopausal status and involved metastatic organ sites (bone, liver, lung, brain, and lymph nodes) separately. This effect was maintained in sensitivity analysis taking different breast cancer subtypes as well as visceral and non-visceral disease into account. Conclusion: The number of involved organs at baseline is an independent prognostic factor in MBC and should be considered as a stratification factor in randomized trials. Table 1. Multivariable Model for overall survival. Citation Format: Gabriel Rinnerthaler, Simon P. Gampenrieder, Christoph Tinchon, Andreas Petzer, Marija Balic, Sonja Heibl, Margit Sandholzer, August F. Zabernigg, Daniel Egle, Christopher Hager, Petra Pichler, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Michael Knauer, Michael Hubalek, Christian F. Singer, Richard Greil. Number of involved organs at baseline is prognostic for overall survival in patients with metastatic breast cancer: Results from the AGMT_MBC-Registry [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-49.