Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6)

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). </jats:sec

Abstract P1-21-08: Brain metastases (BM) from breast cancer: Real-word data from the Austrian AGMT_MBC-registry

Abstract Background: BM are generally associated with poor prognosis and with neurological impairments making BM a major limitation of life expectancy and quality of life in MBC. Real-world data are needed in order to quantify and better characterize this special clinical situation. Here, we present data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Patients with available hormone receptor and HER2 status and sufficient outcome data were included in this analysis. Unadjusted, univariate overall survival (OS) probabilities were calculated by the Kaplan-Meier method and compared by the log-rank test; multivariable adjusted hazard ratios (HR) were estimated by Cox regression models. HR were estimated with diagnosis of BM as time-dependent variable. Logistic regression was performed to investigate the probability of developing BM. Multivariable analyses included the following parameters: breast cancer subtype (luminal-like vs. HER2+ vs. TNBC), age at diagnosis of metastatic disease (continuous, in Cox regression as interaction with menopausal status), DFS (de novo metastatic or ≥ 24 months vs. &amp;lt; 24 months), visceral disease (yes vs. no) and number of metastatic sites (1 vs 2-3 vs. ≥4) at diagnosis of metastatic disease. Results: As of 15/04/2021, 2024 patients were included in the registry. Out of 1691 evaluable patients, 306 (18.1%) had documented BM. The incidence at diagnosis of metastatic disease and the overall incidence during the course of disease was significantly higher in HER2+ (9.5% [13/137] and 36.5% [50/137]) and triple-negative tumors (11.9% [38/318] and 27.7% [88/318]) compared to luminal-like tumors (3.3% [41/1236] and 13.6% [168/1236]) (both P&amp;lt;0.001). Besides subtype, ≥4 metastatic sites at diagnosis of metastatic disease and age were statistically significant associated with BM in logistic regression analysis.Median time to BM calculated from the date of diagnosis of metastatic disease was 11.3 months (95%CI 9.3-13.3) in the total population with BM, 12.7 months (95%CI 7.3-16.0) in HER2+, 5.2 months (95%CI 1.8-10.3) in triple-negative and 15.4 months (95%CI 8.4-19.5) in luminal disease, respectively. Interestingly, 13.7% of patients (42/306) had BM as first metastatic site without extracranial disease. The median number of systemic therapy-lines before and after diagnosis of BM was 1 (range 0-8) and 1 (range 0-10), respectively. Most of the patients with BM (80.1%) received radiotherapy; 12.7% focal radiotherapy, 69.8% whole brain irradiation and 9.0% both types of radiotherapy (8.5% unknown). After a median follow-up of 72.3 months (95%-CI 68.6-80.0), patients with BM had a significantly shorter median OS (7.5 months) compared to patients without BM (38.4 months) both in univariate (HR 3.58; 95%CI 3.11-4.11; P&amp;lt;.001) and multivariable analysis (HR 3.70; 95%CI 3.18-4.32; P&amp;lt;.001). OS in patients with BM differed significantly between the three breast cancer subtypes with a median OS of 36.3 months (95%CI 30.5-47.9), 33.5 months (95%CI 22.9-45.5) and 13.2 months (95%CI 11.1-18.4) in luminal, HER2+ and TNBC, respectively (overall log-rank P&amp;lt;0.001). Similarly, the time from diagnosis of BM and death was significantly shorter in TNBC (4.1 months; 95%CI 3.4-6.3) compared to luminal (9.7 months; 95%CI 6.8-13.7) and HER2+ breast cancer (10.7 months; 95%CI 9.1-26.2) (overall log-rank P&amp;lt;0.001). Conclusion: Almost 20% of patients with MBC develop BM during their course of disease, with a higher incidence in HER2+ and triple-negative disease. Besides effective prevention strategies improved systemic and local therapies are needed to minimize morbidity and improve outcome in these patients. Citation Format: Simon Peter Gampenrieder, Gabriel Rinnerthaler, Christoph Tinchon, Andreas Petzer, Marij Balic, Sonja Heibl, August F Zabernigg, Daniel Egle, Margit Sandholzer, Florian Roitner, Johannes Andel, Petra Pichler, Christopher Hager, Michael Knauer, Michael Hubalek, Christian F Singer, Richard Greil. Brain metastases (BM) from breast cancer: Real-word data from the Austrian AGMT_MBC-registry [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-08.</jats:p

Abstract P4-01-27: 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 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.</jats:p

Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry

AbstractBackgroundAbout 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 methodsThe 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.ResultsAs 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.ConclusionLow-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.</jats:sec

Abstract P1-16-03: Response pattern to chemotherapy in metastatic breast cancer (MBC): Real-word data from the Austrian AGMT_MBC-Registry

Abstract Background: Despite the advances by targeted therapies, particularly in HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC), chemotherapy remains a mainstay of the treatment in all breast cancer subtypes. Response probabilities to chemotherapy seem to decrease with increasing lines of treatment, but little is known about the response dependency on the previous therapy line. Here, we present data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Patients with available hormone receptor and negative HER2 status, at least two consecutive lines of chemotherapy and sufficient progression-free survival (PFS) data were included in this analysis. Multivariable adjusted hazard ratios (HR) for PFS were estimated by Cox regression models and included the following parameters: age, HR status, disease-free survival (de novo metastatic or ≥ 24 months vs. &amp;lt; 24 months), visceral disease, number of involved metastatic sites at diagnosis of MBC, chemotherapy treatment line, and response in previous treatment line. Response was defined as PFS &amp;gt; 4 month and non-response as a PFS ≤ 4 month. Cox model was extended as proposed by Andersen and Gill due to possibility of multiple events per patient and thereby resulting dependencies (Sousa-Ferreira &amp; Abreu, 2019). Results: As of 15/04/2021, 2024 patients were included in the registry. Out of them, 405 patients (20.0%) had documented HER2 negative disease with at least two lines of consecutive chemotherapy. Median PFS for first-, second-, third-, and forth-line chemotherapy were 6.0 months (95% CI 5.5-6.5), 3.7 months (95% CI 3.1-4.3), 2.9 months (95% CI 2.5-3.2), and 2.8 months (95% CI 2.6-3.2), respectively. Median overall survival was 31.8 months (95% CI 27.2-34.8). Median number of chemotherapy lines was 3 (range 2-8). The most commonly used cytotoxic agents were paclitaxel and capecitabine in first- and second-line, and eribulin in third-, and fourth-line chemotherapy. Combinations of more than one cytotoxic drug were given in 36%, 29%, 28% in first-, second-, and third/fourth-line. Patients who did not respond to the previous therapy line, had a response in 43% (95% CI 33-53), 34% (95% CI 25-43), and 30% (95% CI 21-39) to second-, third-, and fourth-line. In those patients, investigator assessed overall response rate (partial remission or complete remission) was 27% (95% CI 13-40), 23% (95% CI 9-37), and 33% (95% CI 16-51), respectively. A response to third-line chemotherapy in patients who did not respond to first- and second-line therapy, was seen in 16.7% of patients. Ratios between PFS of interest and PFS of the previous treatment line were 0.63 (95% CI 0.55-0.68), 0.57 (95% CI 0.41-0.62), and 0.76 (95% CI 0.58-0.9) in second-, third-, and forth-line therapy. In multivariable analysis, responses in second- to fourth-line therapy were statistically significant associated with disease-free survival (HR 0.75, P=0.022), and treatment line (HR 1.17 per increasing treatment line, P=0.004), but not for the response to the previous treatment line (HR 0.85, P=0.068). Conclusion: A continuously decreasing PFS for cytotoxic drugs from treatment line to treatment line was confirmed in our analysis. However, in multivariable analysis, response, defined as PFS &amp;gt; 4 months, was not statistically associated with response to the previous treatment line. Therefore, a lack of response to first, second-, - or third-line chemotherapy should not trigger discontinuation of anticancer therapy in case of further available treatment options. Citation Format: Gabriel Rinnerthaler, Simon P Gampenrieder, Christoph Tinchon, Andreas Petzer Petzer, Marija Balic, Heibl Sonja, August F Zabernigg, Daniel Egle, Margit Sandholzer, Florian Roitner, Johannes Andel, Petra Pichler, Christophe Hager, Michael Hubalek, Michael Knauer, Christian F Singer, Richard Greil. Response pattern to chemotherapy in metastatic breast cancer (MBC): Real-word data from the Austrian AGMT_MBC-Registry [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-03.</jats:p

sj-docx-1-tam-10.1177_17588359211042301 – Supplemental material for Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6)

Supplemental material, sj-docx-1-tam-10.1177_17588359211042301 for Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6) by Gabriel Rinnerthaler, Simon Peter Gampenrieder, Andreas Petzer, Michael Hubalek, Edgar Petru, Margit Sandholzer, Johannes Andel, Marija Balic, Thomas Melchardt, Cornelia Hauser-Kronberger, Clemens A. Schmitt, Hanno Ulmer and Richard Greil in Therapeutic Advances in Medical Oncology</p

Abstract P3-05-49: Number of involved organs at baseline is prognostic for overall survival in patients with metastatic breast cancer: Results from the AGMT_MBC-Registry

Abstract 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.</jats:p