Publications by authors named "Gabriel Rinnerthaler"

39 Publications

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer.

N Engl J Med 2021 Jul;385(5):395-405

From the Comprehensive Cancer Center (M.G., C.F.S., C.D., F.F., K.W., S.K.-S.), the Department of General Surgery (F.F., K.W., S.K.-S.), the Department of Internal Medicine I, Division of Oncology (G.G.S., R.B.), and the Department of Obstetrics and Gynecology (C.F.S., C.D.), Medical University of Vienna, Austrian Breast and Colorectal Cancer Study Group (M.G., R.J., L.S., C.F.), Breast Care Center, Hanusch Hospital (U.W.), the Department of Gynecology, Hospital Hietzing, and Karl Landsteiner Institute for Gynecological Oncology and Senology (P.S.), Vienna, the Department of Internal Medicine III and Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, Paracelsus Medical University Salzburg, Salzburg (G.R., S.G.-R., S.P.G., R.G.), the Departments of Oncology (M.B., C.S.) and Gynecology (V.B.-R.), Medical University Graz, Graz, the Department of Surgery, Ordensklinikum Linz, Linz (D.H.), the Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels (J.T.), the Department of Gynecology, Medical University Innsbruck, Innsbruck (D.E., C.B.), Doctor's Office Manfreda, Klagenfurt (D.M.), the Department of Surgery, Hospital Wolfsberg, Wolfsberg (E.M.-Z.), the Department of Internal Medicine, Hospital Vöcklabruck, Vöcklabruck (F.H.), the Department of Surgery, General Hospital Baden, Baden (H.T.), and the Breast Center, Doctor's Office Wette, Sankt Veit an der Glan (V.W.) - all in Austria; and the Breast Unit, University Hospital Helios, University Witten Herdecke, Wuppertal, Germany (V.B.-R.).

Background: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear.

Methods: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture.

Results: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84).

Conclusions: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).
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http://dx.doi.org/10.1056/NEJMoa2104162DOI Listing
July 2021

Deregulated glutamate to pro-collagen conversion is associated with adverse outcome in lung cancer and may be targeted by renin-angiotensin-aldosterone system (RAS) inhibition.

Lung Cancer 2021 Jul 16;159:84-95. Epub 2021 Jul 16.

Department of Internal Medicine V (Haematology & Oncology), Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background: The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC.

Methods: Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis.

Results: Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a 'Collagen Signature' which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids.

Conclusion: We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.020DOI Listing
July 2021

Prognostic and Predictive Factors in Advanced Head and Neck Squamous Cell Carcinoma.

Int J Mol Sci 2021 May 7;22(9). Epub 2021 May 7.

Oncologic Center, Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Paracelsus Medical University, 5020 Salzburg, Austria.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials.
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http://dx.doi.org/10.3390/ijms22094981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125786PMC
May 2021

Expert Discussion: Immunotherapy in Breast Cancer - Ready for Prime Time?

Breast Care (Basel) 2021 Apr 26;16(2):188-191. Epub 2021 Mar 26.

Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.

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http://dx.doi.org/10.1159/000515746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114073PMC
April 2021

Results of a hospitalization policy of asymptomatic and pre-symptomatic COVID-19-positive long-term care facility residents in the province of Salzburg-a report from the AGMT COVID-19 Registry.

Geroscience 2021 Apr 10. Epub 2021 Apr 10.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

COVID-19-associated case fatality rates up to 48% were reported among nursing facility residents. During the first wave of the COVID-19 pandemic, routine SARS-CoV-2 testing in long-term care facilities in the Province of Salzburg and centralized hospitalization in the COVID-19 unit of the Paracelsus Medical University Salzburg (Austria) irrespective of symptoms was implemented. Baseline characteristics and the course of COVID-19 disease were assessed among hospitalized long-term care facility residents within the COVID-19 Registry of the Austrian Group Medical Tumor Therapy (AGMT; NCT04351529). Between the 24 of March and the 20 of April 2020, 50 COVID-19-positive residents were hospitalized. The median age was 84.5 years (range: 79-88) and the median number of comorbidities and baseline medication classes was 6 (IQR: 4-7) and 5 (IQR: 3-6), respectively. At admission, 31 residents (62%) were symptomatic, nine residents (18%) pre-symptomatic whereas ten residents (20%) remained asymptomatic. The 30-day mortality rate from hospitalization was 32% and significantly higher in symptomatic residents at admission when compared to asymptomatic residents including pre-symptomatic residents (48% [95% CI: 27-63%] versus 5% [95% CI: 0-15%], p=0.006). The Early Warning Score (EWS) at admission was associated with 30-day mortality: high risk: 100%, intermediate risk: 50% (95% CI: 0-78%), and low risk: 21% (95% CI: 7-32%) (p<0.001). In light of comparably low mortality rates between asymptomatic and pre-symptomatic hospitalized COVID-19-positive residents, we suggest the supply of comparable intensity and quality of monitoring and care in long-term care facilities as an alternative to immediate hospitalization upon a positive COVID-19 test in asymptomatic residents.
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http://dx.doi.org/10.1007/s11357-021-00352-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035610PMC
April 2021

Spatial Heterogeneity in Large Resected Diffuse Large B-Cell Lymphoma Bulks Analysed by Massively Parallel Sequencing of Multiple Synchronous Biopsies.

Cancers (Basel) 2021 Feb 6;13(4). Epub 2021 Feb 6.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Müllner Hauptstraße 48, 5020 Salzburg, Austria.

Diffuse large B-cell lymphoma (DLBCL) usually needs to be treated immediately after diagnosis from a single lymph node biopsy. However, several reports in other malignancies have shown substantial spatial heterogeneity within large tumours. Therefore, we collected multiple synchronous biopsies of twelve patients that had diagnostic or therapeutic resections of large lymphoma masses and performed next-generation sequencing of 213 genes known to be important for lymphoma biology. Due to the high tumour cell content in the biopsies, we were able to detect several mutations which were present with a stable allelic frequency across all the biopsies of each patient. However, ten out of twelve patients had spatially discordant mutations and similar results were found by the analysis of copy number variants. The median Jaccard similarity coefficient, a measure of the similarity of a sample set was 0.77 (range 0.47-1), and some of the involved genes such as , , , and have a known prognostic or therapeutic relevance in DLBCL. This shows that single biopsies underestimate the complexity of the disease and might overlook possible mechanisms of resistance and therapeutic targets. In the future, the broader application of liquid biopsies will have to overcome these obstacles.
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http://dx.doi.org/10.3390/cancers13040650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914762PMC
February 2021

Overcoming negative predictions of microRNA expressions to gemcitabine response with FOLFIRINOX in advanced pancreatic cancer patients.

Future Sci OA 2020 Nov 30;7(2):FSO644. Epub 2020 Nov 30.

IIIrd Medical Department with Hematology & Medical Oncology, Hemostaseology, Rheumatology & Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstrasse 48, Salzburg 5020, Austria.

FOLFIRINOX is superior to gemcitabine in patients with pancreatic cancer, but this regimen is associated with toxicity and biomarkers for response are warranted. MicroRNAs can mediate drug resistance and could provide predictive information. Altered expressions of several microRNAs including miR-21-5p, miR-10b-5p and miR-34a-5p have been previously linked to a worse response to gemcitabine. We investigated the influence of expression levels in tumor tissue of those three microRNAs on outcome to FOLFIRINOX. Twenty-nine patients with sufficient formalin-fixed paraffin-embedded tumor tissue were identified. There was no significant association between high and low expression groups for these three microRNA. We conclude that polychemotherapy combination can overcome intrinsic negative prognostic factors.
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http://dx.doi.org/10.2144/fsoa-2020-0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787156PMC
November 2020

Treatment Landscape for Patients with HER2-Positive Metastatic Breast Cancer: A Review on Emerging Treatment Options.

Cancer Manag Res 2020 27;12:10615-10629. Epub 2020 Oct 27.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, Salzburg, Austria.

The prognosis of HER2-positive metastatic breast cancer (MBC) has radically changed in recent years and continues to improve due to the broad application of effective therapies like monoclonal antibodies and small molecules targeting HER2. Persistent dependency of tumor cells on the oncogene HER2, on one hand, as well as low expression levels in healthy tissue, on the other hand, make this protein an ideal target for anti-cancer therapy. New HER2 targeting strategies including targeted delivery of cytotoxic drugs via HER2 receptor have been developed. Recently, the US Food and Drug Administration (FDA) approved three new drugs for the treatment of HER2-positive MBC: the antibody-drug conjugate trastuzumab deruxtecan and the two tyrosine kinase inhibitors neratinib and tucatinib. Here, we summarize recent publications and developments of novel anti-HER2 therapies like monoclonal antibodies with improved properties compared to trastuzumab and bispecific antibodies, which bind two different HER-epitopes or bring T cells closer to tumor cells. Furthermore, novel antibody-drug conjugates and small molecules against HER2 are discussed. These developments coupled with new combination strategies (eg, with CDK4/6 inhibitors or immunotherapy) will change the treatment landscape for patients with HER2-positive MBC very soon and will hopefully further improve clinical outcomes.
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http://dx.doi.org/10.2147/CMAR.S235121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602897PMC
October 2020

Hospitalizations and Clinical Outcome in Metastatic Colorectal Cancer During Regorafenib or TAS-102 Therapy.

Cancers (Basel) 2020 Sep 30;12(10). Epub 2020 Sep 30.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria.

Current National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines recommend regorafenib or trifluridine/tipiracil (TAS-102) for the third-line therapy of metastatic colorectal cancer (mCRC). In this analysis, we evaluated hospitalizations during regorafenib or TAS-102 treatment and the impact of hospitalizations on overall survival (OS). This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 at the tertiary cancer centers in Salzburg and Wels-Grieskirchen, Austria. Between January 2013 and May 2019, 93 patients started third- or fourth-line therapy with regorafenib or TAS-102. Tumor therapy (regorafenib versus TAS-102, HR: 1.95 [95% CI: 1.07-3.54], = 0.03) and the Eastern Cooperative Oncology Group (ECOG) performance status (2-3 versus 0-1, HR: 4.04 [95% CI: 2.11-7.71], < 0.001) showed a statistically significant association with hospitalization risk in multivariate analysis. The corresponding hospitalization probability from initiation of third- or fourth-line was 30% with regorafenib versus 18% with TAS-102 at five weeks and 41% versus 28% at ten weeks, respectively. Hospitalizations irrespective of cause during regorafenib or TAS-102 therapy did neither impact median survival in patients undergoing only third-line therapy (never-hospitalized: 5.7 months [95% CI: 3.9-10.5] versus hospitalized: 5.4 months [95% CI: 2.8-9.6], = 0.45), nor in patients receiving third- and fourth-line therapy (12.2 months [95% CI: 10.6-28.8] versus 18.6 months [95% CI: 6.3-not reached], = 0.90). In conclusion, apart from poor ECOG performance status, regorafenib therapy was associated with an increased hospitalization probability during palliative systemic third- and fourth-line therapy in mCRC. However, hospitalizations during regorafenib or TAS-102 therapy did not impact OS beyond second-line therapy.
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http://dx.doi.org/10.3390/cancers12102812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599669PMC
September 2020

Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

J Clin Med 2020 Aug 27;9(9). Epub 2020 Aug 27.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, Austria.

Reports on the prognostic role of programmed death-ligand 1 (PD-L1) expression in rectal cancer are controversial. We investigated expression patterns and changes of PD-L1 in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Seventy-two patients diagnosed with rectal cancer and/or treated with fluorouracil-based neoadjuvant CRT at the Department of Internal Medicine III of the Paracelsus Medical University Salzburg (Austria) between January 2003 and October 2012 were included. PD-L1 scoring was performed according to the tumor proportion score (TPS), combined positive score (CPS), and immune cell score (IC). PD-L1 TPS prior to neoadjuvant CRT had a statistically significant impact on survival (median: ≤1%: 95.4 months (95% CI: 51.8-not reached) vs. >1%: not reached, = 0.03, log-rank). Patients with a PD-L1 TPS ≤1% prior to and after CRT showed an inferior survival compared to all other patients (median: 56.7 months (95% CI: 51.4-not reached) vs. not reached, = 0.005, log-rank). In multivariate analysis, PD-L1 TPS prior to neoadjuvant CRT (>1% vs. ≤1%, hazard ratio: 0.29 (95% CI: 0.11-0.76), = 0.01) remained independently associated with survival. In conclusion, low PD-L1 TPS was associated with inferior survival in rectal cancer patients undergoing neoadjuvant CRT. A prospective validation of the prognostic value of PD-L1 expression in rectal cancer patients within a clinical trial is necessitated.
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http://dx.doi.org/10.3390/jcm9092775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563312PMC
August 2020

Low Expression of miR-20a-5p Predicts Benefit to Bevacizumab in Metastatic Breast Cancer Patients Treated within the TANIA Phase III Trial.

J Clin Med 2020 Jun 1;9(6). Epub 2020 Jun 1.

Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Department of Internal Medicine III with Haematology, Salzburg Cancer Research Institute, Oncologic Center Salzburg, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

Background: In metastatic breast cancer (MBC) patients, no biomarker predicting benefit to a bevacizumab-containing therapy has been established yet. MicroRNAs (miRNAs) are involved in angiogenesis and treatment resistance and therefore could be of predictive value.

Methods: Profiling of 754 miRNAs was performed in tumor samples of 58 MBC patients treated with a bevacizumab-containing first-line regimen (learning set). Based on progression-free survival (PFS), patients were divided into responders (R) and non-responders (NR). Differentially expressed miRNAs between R and NR were analyzed in a cohort of 57 patients treated with first-line chemotherapy without bevacizumab (control set), to exclude miRNAs providing prognostic information. MiRNA candidates significantly associated with PFS in multivariate analysis were further validated in tumor samples of 203 patients treated within the phase III trial TANIA randomizing between chemotherapy either alone or with bevacizumab after progression on first-line bevacizumab.

Results: Low expression of miR-20a-5p (multivariate = 0.035) and miR-21-5p (multivariate = 0.004) were significantly associated with longer PFS in the learning set, but not in the control set. In samples from the TANIA trial, low expression of miR-20a-5p was also significantly associated with longer PFS (hazard ration (HR) 0.60; 95%-CI 0.37-0.89; = 0.012) and longer overall survival (OS; HR 0.54; 95%-CI 0.32-0.83; = 0.007) in the bevacizumab arm but not in the chemotherapy-only arm (PFS: HR 0.73, = 0.119; OS: HR 1.01; = 0.964). For miR-21-5p no significant association with PFS or OS in both treatment arms was observed.

Conclusion: MiR-20a-5p expression in breast cancer tissue was predictive for a greater benefit from bevacizumab-containing therapy in two independent cohorts.
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http://dx.doi.org/10.3390/jcm9061663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355487PMC
June 2020

Comparison of high tone therapy and transcutaneous electrical nerve stimulation therapy in chemotherapy-induced polyneuropathy.

Medicine (Baltimore) 2020 May;99(19):e20149

Institute of Physical Medicine and Rehabilitation.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a worldwide concern in patients receiving neurotoxic agents for cancer therapy. High tone external muscle stimulation is a promising therapeutic approach to alleviate symptoms of CIPN.

Methods: This pilot study aims to investigate whether the application of home-based high-tone external muscle stimulation therapy (HTEMS) improves symptoms of CIPN. The trial is planned as a therapist- and assessor-blinded, 1:1 randomized controlled study. A total of 50 patients with chemotherapy-induced peripheral polyneuropathy will be included. All patients will perform therapy at home. Study participants will be allocated randomly to the HTEMS therapy (intervention group) or to the transcutaneous electrical nerve stimulation (TENS, control group), respectively, following a standardized therapy schedule. Compliance of participants can be verified by reading out the tool box. Outcomes will be evaluated at baseline and after 8 weeks of home-based therapy. The primary outcome includes improvement of CIPN according to the patient-reported EORTC QLQ-CIPN 20 questionnaire. Secondary outcomes are the patient-reported change in health-related quality of life and clinician-reported changes of vibration sensibility, tendon reflexes, temperature sensibility, perception of touch, and strength of the lower leg muscles. Further a safety- and process evaluation will be performed.

Discussion: This pilot RCT aims to evaluate the impact of home-based HTEMS as compared to TENS in CIPN. There is a need for an effective treatment for CIPN and the results of this study are expected to possibly identify a novel and effective treatment strategy in the future.
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http://dx.doi.org/10.1097/MD.0000000000020149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220357PMC
May 2020

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence.

Int J Mol Sci 2020 Apr 19;21(8). Epub 2020 Apr 19.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020 Salzburg, Austria.

The therapeutic concept of unleashing a pre-existing immune response against the tumor by the application of immune-checkpoint inhibitors (ICI) has resulted in long-term survival in advanced cancer patient subgroups. However, the majority of patients do not benefit from single-agent ICI and therefore new combination strategies are eagerly necessitated. In addition to conventional chemotherapy, kinase inhibitors as well as tumor-specific vaccinations are extensively investigated in combination with ICI to augment therapy responses. An unprecedented clinical outcome with chimeric antigen receptor (CAR-)T cell therapy has led to the approval for relapsed/refractory diffuse large B cell lymphoma and B cell acute lymphoblastic leukemia whereas response rates in solid tumors are unsatisfactory. Immune-checkpoints negatively impact CAR-T cell therapy in hematologic and solid malignancies and as a consequence provide a therapeutic target to overcome resistance. Established biomarkers such as programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) help to select patients who will benefit most from ICI, however, biomarker negativity does not exclude responses. Investigating alterations in the antigen presenting pathway as well as radiomics have the potential to determine tumor immunogenicity and response to ICI. Within this review we summarize the literature about specific combination partners for ICI and the applicability of artificial intelligence to predict ICI therapy responses.
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http://dx.doi.org/10.3390/ijms21082856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215892PMC
April 2020

Therapy Line and Associated Predictors of Response to PD-1/PD-L1-Inhibitor Monotherapy in Advanced Non-small-Cell Lung Cancer: A Retrospective Bi-centric Cohort Study.

Target Oncol 2019 12;14(6):707-717

Department of Pulmonology, Kepler University Hospital Linz, Krankenhausstrasse 9, 4020, Linz, Austria.

Background: Evidence on PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy for advanced non-small-cell lung cancer (NSCLC) is mainly based on clinical trials in first- or second-line settings.

Objective: We aimed to investigate response and prognostic factors with special regard to third- or later-line therapy.

Patients And Methods: We retrospectively analyzed all patients who had received ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab for advanced NSCLC. Computed tomography evaluations were analyzed using response evaluation criteria in solid tumors (RECIST, version 1.1). Kaplan-Meier analyses were conducted to calculate progression-free (PFS) and overall (OS) survival; the impact of influencing variables was evaluated using uni- and multivariate Cox-regression analyses.

Results: Among 153 patients (59% men, mean age 66 years), median PFS was 4 months [mo; 95% confidence interval (95% CI) 3-5], OS was 13 mo (10-17), and objective response rate (ORR) was 22%. Therapy line ≥ 3 was associated with significantly inferior PFS (p = 0.003) and OS (p = 0.001). In first-line therapy PFS, OS, and ORR were 7 mo (3-11), 17 mo [9-not evaluable (n.e.)], and 36%; in second-line 4 mo (3-7), 18 mo (13-n.e.) and 19%, and in ≥ third-line 2 mo (1-3), 9 mo (4-12), and 13%. PFS was significantly influenced by PD-L1 expression in first-line therapy (p = 0.006). In ≥ third-line patients, Eastern Cooperative Oncology Group (ECOG) performance status significantly affected PFS and OS (both p < 0.001).

Conclusions: Third- or later-line single-agent anti-PD-1/PD-L1 therapy is less efficacious as compared to first- and second-line treatment. In that setting, ECOG performance status predominates known predictors like PD-L1 expression or presence of an alteration in EGFR or ALK.
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http://dx.doi.org/10.1007/s11523-019-00679-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875512PMC
December 2019

Baseline Absolute Lymphocyte Count and ECOG Performance Score Are Associated with Survival in Advanced Non-Small Cell Lung Cancer Undergoing PD-1/PD-L1 Blockade.

J Clin Med 2019 Jul 10;8(7). Epub 2019 Jul 10.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, 5020 Salzburg, Austria.

Immune-checkpoint blockade in front-line or second-line treatment improves survival in advanced non-small cell lung cancer (aNSCLC) when compared with chemotherapy alone. However, easily applicable predictive parameters are necessary to guide immune-checkpoint inhibition in clinical practice. In this retrospective bi-centric analysis, we investigated the impact of baseline patient and tumor characteristics on clinical outcome in aNSCLC patients treated with programmed cell death protein 1(PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors. Between May 2015 and January 2018, 142 unselected consecutive NSCLC patients received PD-1/PD-L1 inhibitors during the course of disease. In multivariate analysis, we identified the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG > 1 versus ECOG ≤ 1, HR: 3.23, 95%CI: 1.58-6.60, = 0.001), baseline absolute lymphocyte count (ALC; high: >0.93 × 10/L versus low: ≤ 0.93 × 10/L, HR: 0.38, 95%CI: 0.23-0.62, < 0.001), prior or concomitant anti-vascular endothelial growth factor (VEGF) targeting therapy (yes versus no, HR: 2.18, 95%CI: 1.15-4.14, = 0.017) and TNM stage (IV versus III, HR: 4.18, 95%CI: 1.01-17.36, = 0.049) as the most relevant parameters for survival. Neither antibiotic exposure (antibiotic-positive versus antibiotic-negative, HR: 0.90, 95%CI: 0.56-1.45, = 0.675), nor PD-L1 expression on tumor cells (≥1% versus <1%, HR: 0.68, 95%CI: 0.41-1.13, = 0.140) was associated with survival. Baseline ECOG performance status and ALC were associated with survival in aNSCLC patients treated with PD-1/PD-L1 inhibitors and assessment of these parameters could be suitable in clinical practice.
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http://dx.doi.org/10.3390/jcm8071014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678702PMC
July 2019

Regorafenib Is Associated With Increased Skeletal Muscle Loss Compared to TAS-102 in Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2019 06 11;18(2):159-166.e3. Epub 2019 Apr 11.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology, and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute, Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, Salzburg, Austria. Electronic address:

Background: Current guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology recommend regorafenib or trifluridine/tipiracil (TAS-102) for third-line therapy of metastatic colorectal cancer (mCRC). We evaluated the impact of regorafenib and TAS-102 treatment on skeletal muscle dynamics and sarcopenia.

Patients And Methods: This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 during third or later line of therapy at our tertiary-care cancer center in Salzburg, Austria. The skeletal muscle index (SMI, cm/m) and sarcopenia were evaluated from cross-sectional computed tomographic images at the level of the third lumbar vertebra.

Results: Between January 2013 and April 2018, a total of 45 patients had received regorafenib and/or TAS-102. At initial mCRC diagnosis and at initiation of third-line therapy, 24% and 54% of patients presented with sarcopenia. A statistically significant skeletal muscle loss was observed during regorafenib treatment (median SMI change: -2.75 cm/m [-6.3%]; P < .0001), which was not the case during TAS-102 therapy (-1.5 cm/m [-3.5%]; P = .575). Furthermore, subclassification of patients into 3 groups-normal muscle mass, stable sarcopenia, and new-onset sarcopenia-at initiation of third-line therapy permitted discrimination of overall survival, with 1-year overall survival rates of 61%, 29%, and 16%, respectively (P = .04).

Conclusion: The frequency of sarcopenia increases during the course of mCRC and negatively affects survival. In contrast to TAS-102, regorafenib is associated with increased skeletal muscle loss during mCRC treatment and should therefore be used with caution in mCRC patients with preexisting sarcopenia or a history of recent weight loss.
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http://dx.doi.org/10.1016/j.clcc.2019.04.003DOI Listing
June 2019

HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer.

Int J Mol Sci 2019 Mar 5;20(5). Epub 2019 Mar 5.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.
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http://dx.doi.org/10.3390/ijms20051115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429068PMC
March 2019

MiR-1287-5p inhibits triple negative breast cancer growth by interaction with phosphoinositide 3-kinase CB, thereby sensitizing cells for PI3Kinase inhibitors.

Breast Cancer Res 2019 02 1;21(1):20. Epub 2019 Feb 1.

Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.

Background: Non-coding RNAs and especially microRNAs have been discovered to act as master regulators of cancer initiation and progression. The aim of our study was to discover and characterize the function of yet functionally uncharacterized microRNAs in human breast carcinogenesis.

Methods: In an unbiased approach, we utilized an established model system for breast cancer (BC) stem cell formation ("mammosphere assay") to identify whole miRNome alterations in breast carcinogenesis. Clinical samples of BC patients were used to evaluate the human relevance of the newly identified miRNA candidates. One promising candidate, miR-1287-5p, was further explored on its impact on several hallmarks of cancer. The molecular mode of action was characterized by whole transcriptome analysis, in silico prediction tools, miRNA-interaction assays, pheno-copy assays, and drug sensitivity assays.

Results: Among several other microRNAs, miR-1287-5p was significantly downregulated in mammospheres and human BC tissue compared to normal breast tissue (p < 0.0001). Low expression levels were significantly associated with poor prognosis in BC patients. MiR-1287-5p significantly decreased cellular growth, cells in S phase of cell cycle, anchorage-independent growth, and tumor formation in vivo. In addition, we identified PIK3CB as a direct molecular interactor of miR-1287-5p and a novel prognostic factor in BC. Finally, PI3Kinase pathway chemical inhibitors combined with miR-1287-5p mimic increased the pharmacological growth inhibitory potential in triple negative BC cells.

Conclusion: Our data identified for the first time the involvement of miR-1287-5p in human BC and suggest a potential for therapeutic interventions in difficult to treat triple negative BC.
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http://dx.doi.org/10.1186/s13058-019-1104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359814PMC
February 2019

Radiologic complete response (rCR) in contrast-enhanced magnetic resonance imaging (CE-MRI) after neoadjuvant chemotherapy for early breast cancer predicts recurrence-free survival but not pathologic complete response (pCR).

Breast Cancer Res 2019 01 31;21(1):19. Epub 2019 Jan 31.

Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center; Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria.

Background: Patients with early breast cancer (EBC) achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) have a favorable prognosis. Breast surgery might be avoided in patients in whom the presence of residual tumor can be ruled out with high confidence. Here, we investigated the diagnostic accuracy of contrast-enhanced MRI (CE-MRI) in predicting pCR and long-term outcome after NACT.

Methods: Patients with EBC, including patients with locally advanced disease, who had undergone CE-MRI after NACT, were retrospectively analyzed (n = 246). Three radiologists, blinded to clinicopathologic data, reevaluated all MRI scans regarding to the absence (radiologic complete remission; rCR) or presence (no-rCR) of residual contrast enhancement. Clinical and pathologic responses were compared categorically using Cohen's kappa statistic. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS) and overall survival (OS).

Results: Overall rCR and pCR (no invasive tumor in the breast and axilla (ypT0/is N0)) rates were 45% (111/246) and 29% (71/246), respectively. Only 48% (53/111; 95% CI 38-57%) of rCR corresponded to a pCR (= positive predictive value - PPV). Conversely, in 87% (117/135; 95% CI 79-92%) of patients, residual tumor observed on MRI was pathologically confirmed (= negative predictive value - NPV). Sensitivity to detect a pCR was 75% (53/71; 95% CI 63-84%), while specificity to detect residual tumor and accuracy were 67% (117/175; 95% CI 59-74%) and 69% (170/246; 95% CI 63-75%), respectively. The PPV was significantly lower in hormone-receptor (HR)-positive compared to HR-negative tumors (17/52 = 33% vs. 36/59 = 61%; P = 0.004). The concordance between rCR and pCR was low (Cohen's kappa - 0.1), however in multivariate analysis both assessments were significantly associated with RFS (rCR P = 0.037; pCR P = 0.033) and OS (rCR P = 0.033; pCR P = 0.043).

Conclusion: Preoperative CE-MRI did not accurately predict pCR after NACT for EBC, especially not in HR-positive tumors. However, rCR was strongly associated with favorable RFS and OS.
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http://dx.doi.org/10.1186/s13058-018-1091-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357474PMC
January 2019

ASCO 2018 highlights: metastatic breast cancer.

Memo 2018 20;11(4):276-279. Epub 2018 Nov 20.

1IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.

This article reviews the clinically most relevant presentations at the American Society of Clinical Oncology (ASCO) annual meeting 2018 on the topic of metastatic breast cancer. In the randomized placebo-controlled phase 3 trial MONALEESA-3, testing ribociclib vs. placebo in combination with fulvestrant in postmenopausal women or men with hormone receptor-positive (HR+) and HER2-negative (HER2-) advanced breast cancer (ABC), an increase of median progression-free survival (PFS) from 12.8 months to 20.5 months by the addition of the CDK4/6 inhibitor was reported (HR 0.59;  > 0.01). Taselisib, an alpha specific PI3K inhibitor, was tested in combination with fulvestrant in pretreated HR+/HER2- ABC patients with PIK3CA mutations in the placebo-controlled phase 3 trial SANDPIPER. PFS was significantly longer (7.4 months vs 5.4 months; HR 0.70,  < 0.01) but severe adverse events were more frequent (32% and 9%) in the taselisib group. In triple-negative breast cancer, the AKT inhibitor capivasertib (AZD5363) was combined with paclitaxel as first-line treatment in the placebo-controlled phase 2 trial PAKT. In patients with altered PIK3CA, AKT1 or PTEN, median PFS increased from 3.7 months to 9.3 months (HR 0.30; two-sided  = 0.01). No treatment effect was shown in the non-altered group. The most common adverse events attributed to capivasertib were diarrhea, fatigue and stomatitis. Results of two phase I trials of trastuzumab antibody-drug conjugates (ADCs) indicated HER2 as a non-oncogenic surface target in breast cancer patients expressing HER2.
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http://dx.doi.org/10.1007/s12254-018-0450-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280779PMC
November 2018

Supervised versus autonomous exercise training in breast cancer patients: A multicenter randomized clinical trial.

Cancer Med 2018 12 10;7(12):5962-5972. Epub 2018 Nov 10.

Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.

Background: There is a well-known correlation between obesity, sedentary lifestyle, and breast cancer incidence and outcome. The Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) exercise study was a multicenter, randomized clinical trial and assessed the feasibility and efficacy of physical training in 50 breast cancer patients undergoing aromatase inhibitor treatment.

Methods: Postmenopausal, estrogen receptor-positive breast cancer patients under aromatase inhibitor treatment were randomized 1:1 to counseling and unsupervised training for 48 weeks (unsupervised arm) or counseling and a sequential training (supervised arm) with a supervised phase (24 weeks) followed by unsupervised physical training (further 24 weeks). Primary endpoint was the individual maximum power output on a cycle ergometer after 24 weeks of exercise. A key secondary endpoint was the feasibility of achieving 12 METh/week (metabolic equivalent of task hours per week).

Results: Twenty-three patients (92%) in the unsupervised arm and 19 patients (76%) in the supervised arm with early-stage breast cancer completed the study. After 24 weeks, the supervised arm achieved a significantly higher maximum output in watt (mean 132 ±  standard deviation [SD] 34; 95% confidence interval [CI] 117-147) compared to baseline (107 ± 25; 95%CI 97-117; P = 0.012) with a numerically higher output than the unsupervised arm (week 24 115 ± 25; 95%CI 105-125; P = 0.059). Significantly higher METh/week was reported in the supervised arm compared to the unsupervised arm during the whole study period (week 1-24 unsupervised: 18.3 (7.6-58.3); supervised: 28.5 (6.7-40.1); P = 0.043; week 25-48; P = 0.041)).

Conclusion: This trial indicates that patients in an exercise program achieve higher fitness levels during supervised than unsupervised training.
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http://dx.doi.org/10.1002/cam4.1851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308077PMC
December 2018

Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial).

BMC Cancer 2018 Nov 6;18(1):1074. Epub 2018 Nov 6.

IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstrasse 48, 5020, Salzburg, Austria.

Background: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87-92 2009, J Thorac Oncol 7:1032-1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC.

Methods: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years.

Discussion: Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination.

Trial Registration: EudraCT Number: 2016-001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively.
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http://dx.doi.org/10.1186/s12885-018-4979-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220453PMC
November 2018

SABCS 2017: lifestyle factors, hormone receptor-positive advanced disease, liquid biopsies, and prognosis.

Memo 2018 21;11(3):208-212. Epub 2018 Aug 21.

1IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.

This article reviews the clinically most relevant presentations at the San Antonio Breast Cancer Symposium (SABCS) 2017 on the topics lifestyle factors, hormone receptor-positive advanced disease, liquid biopsies, and prognosis. In a retrospective analysis of the Women's Health Initiative Observational Study, a reduction in the body mass index (BMI) of at least 5% within 3 years significantly reduced the risk of breast cancer compared to women with a stable weight (HR 0.77; 95% CI 0.78-0.98). In the MONALEESA-7 trial investigating ribociclib or placebo in combination with endocrine therapy as first-line treatment in pre- and perimenopausal women with hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer, a significantly longer progression-free survival was shown for patients treated with ribociclib compared to the placebo group (23.8 vs. 13.0 months; HR 0.55; 95% CI 0.43-0.72;  < 0.001). In a pooled toxicity and efficacy analysis of elderly women treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in combination with an aromatase inhibitor in first-line, toxicities of higher grade were more common in elderly compared to younger patients, despite comparable efficacy. And the Clinical Treatment Score post-5 years (CTS5), accurately estimated the risk of late recurrence after 5 years of adjuvant endocrine treatment using routinely available clinical parameters.
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http://dx.doi.org/10.1007/s12254-018-0433-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132796PMC
August 2018

Cure in metastatic breast cancer.

Memo 2018 17;11(3):172-179. Epub 2018 Aug 17.

1IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.

Oligometastatic disease characterizes a distinct subgroup of metastatic breast cancer patients that might benefit from different treatment strategies to achieve long-lasting remission and potentially cure. Those long-lasting remissions are reported after locoregional treatment of the primary tumor and all metastatic sites in several case series; however, unlike other tumor entities, prospective data are lacking. Furthermore, tumor eradication by excellent systemic anticancer therapy with novel chemotherapies and targeted agents can lead to long-term survival. In addition, reactivation of the host immune defense by immuno-oncologic drugs can achieve long-lasting tumor control. So far, unfortunately, checkpoint inhibitors as monotherapy have led to responses only in a small percentage of patients with metastatic breast cancer. This short review summarizes available data on long-lasting remissions and potential cure in metastatic breast cancers. It describes and discusses data on locoregional treatment, chemo-, antibody- and immunotherapy and tries to select individual patients for whom a multidisciplinary treatment approach with curative intention might be an option to achieve long-term survival.
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http://dx.doi.org/10.1007/s12254-018-0426-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132799PMC
August 2018

DNA Methylation Signatures Predicting Bevacizumab Efficacy in Metastatic Breast Cancer.

Theranostics 2018 11;8(8):2278-2288. Epub 2018 Mar 11.

III rd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center; Salzburg Cancer Research Institute (SCRI) with Laboratory of Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT); Paracelsus Medical University Salzburg, Salzburg, Austria.

Biomarkers predicting response to bevacizumab in breast cancer are still missing. Since epigenetic modifications can contribute to an aberrant regulation of angiogenesis and treatment resistance, we investigated the influence of DNA methylation patterns on bevacizumab efficacy. Genome-wide methylation profiling using the was performed in archival FFPE specimens of 36 patients with HER2-negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (). Based on objective response and progression-free survival (PFS) and considering ER expression, patients were divided in responders (R) and non-responders (NR). Significantly differentially methylated gene loci (CpGs) with a strong change in methylation levels (Δβ>0.15 or Δβ<-0.15) between R and NR were identified and further investigated in 80 bevacizumab-treated breast cancer patients () and in 15 patients treated with chemotherapy alone () using targeted deep amplicon bisulfite sequencing. Methylated gene loci were considered predictive if there was a significant association with outcome (PFS) in the but not in the using Spearman rank correlation, Cox regression, and logrank test. Differentially methylated loci in 48 genes were identified, allowing a good separation between R and NR (odds ratio (OR) 101, p<0.0001). Methylation of at least one cytosine in 26 gene-regions was significantly associated with progression-free survival (PFS) in the , but not in the . Using information from the , the panel was reduced to a 9-gene signature, which could divide patients from the into 2 clusters, thereby predicting response with an OR of 40 (<0.001) and an AUC of 0.91 (LOOCV). A further restricted 3-gene methylation model showed a significant association of with longer PFS in the and even in multivariate analysis with an excellent and good separation of R and NR with AUC=0.94 and AUC=0.86, respectively. Both a 9-gene and 3-gene methylation signature can discriminate between R and NR to a bevacizumab-based therapy in MBC and could help identify patients deriving greater benefit from bevacizumab.
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http://dx.doi.org/10.7150/thno.23544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928889PMC
April 2019

Impact of antibiotic treatment on immune-checkpoint blockade efficacy in advanced non-squamous non-small cell lung cancer.

Oncotarget 2018 Mar 27;9(23):16512-16520. Epub 2018 Mar 27.

IIIrd Medical Department, Paracelsus Medical University Salzburg, Salzburg, Austria.

Introduction: Despite durable responses from immune-checkpoint blockade (ICB) in a subset of patients with advanced non-small cell lung cancer (NSCLC), the majority of patients do not derive benefit from this treatment. In this analysis we evaluated the impact of concomitant administration of antibiotics during initiation of ICB on clinical outcome.

Methods: Advanced non-squamous NSCLC patients receiving ICB as second- or later line between 2015 and 2017 at our tertiary cancer center in Salzburg (Austria) were included. Concomitant use of antibiotics was defined as administration of antibiotics within a time frame of one month before or one month after initiation of ICB (AB-group).

Results: Of the 30 patients included, 11 (36.7%) received antibiotics one month before or one month after start of ICB (AB-group). Median PFS on ICB was in favor of the AB-group (AB: 3.1 months [95%CI: 3.0-16.3]; AB: 2.9 months, [95%CI: 1.9-NA]; HR=0.46 [95%CI: 0.12-0.90], p=0.031). Furthermore, median OS was significantly longer in the AB-group (AB: 15.1 months [95%CI: 11.1-NA]; AB: 7.5 months [95%CI: 6.3-NA]; HR=0.31 [95%CI: 0.02-0.78], p=0.026). In a multivariate analysis, the antibiotic treatment status was identified as the only parameter statistically significantly associated with PFS (p=0.028) and OS (p=0.026).

Conclusions: Stratification of patients according to the antibiotic treatment status is warranted in future trials investigating ICB.
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http://dx.doi.org/10.18632/oncotarget.24751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893258PMC
March 2018

Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes.

Nat Commun 2018 03 23;9(1):1219. Epub 2018 Mar 23.

Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ, 85040, USA.

Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan-Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.
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http://dx.doi.org/10.1038/s41467-018-03631-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865185PMC
March 2018

Nonmetastatic pancreatic cancer : Improved survival with chemoradiotherapy > 40 Gy after systemic treatment.

Strahlenther Onkol 2018 07 1;194(7):627-637. Epub 2018 Mar 1.

Department of Radiotherapy and Radio-oncology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria.

Purpose: The role of radiotherapy (RT) for nonmetastatic pancreatic cancer is still a matter of debate since randomized control trials have shown inconsistent results. The current retrospective single-institution study includes both resected and unresected patients with nonmetastasized pancreatic cancer. The aim is to analyze overall survival (OS) after irradiation combined with induction chemotherapy.

Patients And Methods: Of the 73 patients with nonmetastatic pancreatic cancer eligible for the present analysis, 42 (58%) patients had adjuvant chemoradiotherapy (CRT), while 31 (42%) received CRT as primary treatment. In all, 65 (89%) had chemotherapy at any time before, during, or after RT, and 39 (53%) received concomitant CRT. The median total dose was 50 Gy (range 12-77 Gy), while 61 (84%) patients received >40 Gy.

Results: With a median follow-up of 22 months (range 1.2-179.8 months), 14 (19%) are still alive and 59 (81%) of the patients have died, whereby 51 (70%) were cancer-related deaths. Median OS and the 2‑year survival rate were 22.9 months (1.2-179.8 months) and 44%, respectively. In addition, 61 (84%) patients treated with >40 Gy had a survival advantage (median OS 23.7 vs. 17.3 months, p = 0.026), as had patients with 4 months minimum of systemic treatment (median OS 27.5 vs. 14.3 months, p = 0.0004).

Conclusion: CRT with total doses >40 Gy after induction chemotherapy leads to improved OS in patients with nonmetastatic pancreatic cancer.
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http://dx.doi.org/10.1007/s00066-018-1281-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008353PMC
July 2018

Clonal evolution and heterogeneity in metastatic head and neck cancer-An analysis of the Austrian Study Group of Medical Tumour Therapy study group.

Eur J Cancer 2018 04 20;93:69-78. Epub 2018 Mar 20.

IIIrd Medical Department with Hematology and Medical Oncology, Paracelsus Medical University Salzburg, Salzburg, Austria; Salzburg Cancer Research Institute, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria. Electronic address:

Background: Tumour heterogeneity and clonal evolution within a cancer patient are deemed responsible for relapse in malignancies and present challenges to the principles of targeted therapy, for which treatment modality is often decided based on the molecular pathology of the primary tumour. Nevertheless, the clonal architecture in distant relapse of head and neck cancer is fairly unknown.

Patients And Methods: For this project, we analysed a cohort of 386 patients within the Austrian Registry of head and neck cancer. We identified 26 patients with material from the primary tumour, the distant metastasis after curative first-line treatment and a germline sample for analysis of clonal evolution. After pathological analyses, these samples were analysed using a targeted massively parallel sequencing (MPS) panel of 257 genes known to be recurrently mutated in head and neck cancer plus a genome-wide SNP-set.

Results: Despite histological diagnosis of distant metastasis, no corresponding mutation in the supposed metastases was found in two of 23 (8.6%) evaluable patients suggesting a primary tumour of the lung instead of a distant metastasis of head and neck cancer. We observed a branched pattern of evolution in 31.6% of the analysed patients. This pattern was associated with a shorter time to distant metastasis, compared with a pattern of punctuated evolution. Structural genomic changes over time were also present in 7 of 12 (60%) evaluable patients with metachronous metastases.

Conclusion: Targeted MPS demonstrated substantial heterogeneity at the time of diagnosis and a complex pattern of evolution during disease progression in head and neck cancer. Copy number analyses revealed additional changes that were not detected by mutational analyses. Mutational and structural changes contribute to tumour heterogeneity at diagnosis and progression.
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http://dx.doi.org/10.1016/j.ejca.2018.01.064DOI Listing
April 2018

SABCS 2016: systemic therapy for metastatic breast cancer.

Memo 2017 4;10(2):86-89. Epub 2017 Apr 4.

IIIrd Medical Department, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.

At the 2016 San Antonio Breast Cancer Symposium, several interesting phase II and phase III studies investigating systemic therapies for metastatic breast cancer were presented. The PrEGOC 0102 trial demonstrated that the combination of fulvestrant plus everolimus is safe and effective and could be an alternative to exemestane plus everolimus for selected patients with hormone-receptor positive, HER2-negative disease. The pan-PI3K inhibitor buparlisib showed some activity in combination with fulvestrant after failure of everolimus in the BELLE-3 trial. PIK3CA mutation detected in circulating tumor DNA (ctDNA) was predictive for a buparlisib efficacy. Unfortunately, the unfavorable toxicity profile precludes further development of this drug. Nonetheless, PI3K seems to be a valid target in tumors resistant to mTOR inhibition. The BROCADE phase II trial failed to show a statistically significant benefit by the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel in patients with BRCA1/2 germline mutation. The overall response rate, however, was statistically significant higher in the veliparib arm compared to the placebo arm. Data from the phase III trial BROCADE-3 are awaited. Finally, the TNT trial did not identify further biomarkers, in addition to BRCA1/2 germline mutation, for carboplatin benefit in patients with metastatic triple-negative breast cancer.
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http://dx.doi.org/10.1007/s12254-017-0326-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493725PMC
April 2017
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