Ruth Exner

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. METHODS In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING Amgen.

Surgical Treatment of Severe Acute Pancreatitis: Timing of Operation is Crucial for Survival

BACKGROUND In patients operated on for severe acute pancreatitis (SAP) the impact of the timing of operation on outcome is controversial. MATERIALS AND METHODS In a retrospective analysis of a prospectively documented database, we studied 250 patients suffering from SAP, who were in need for surgical treatment during their course of disease. RESULTS From 1982 to 1998, 250 patients with the diagnosis of SAP who required operative treatment were admitted to the intensive care unit (ICU) of a university hospital. The mean APACHE II score on the day of admission was 16.1 (8-35). One hundred eighty-five patients (74%) required reoperation, of whom 111 patients (60%) underwent reoperation on demand and 74 (40%) patients a pre-planned reoperation. Overall mortality was 38.8% (97 patients). In patients who were operated during the first three weeks after onset of disease, mortality was significantly higher than in patients who were operated after three weeks (46% vs. 25%, p < 0.01). Besides patient age (p < 0.05), APACHE II score at admission (p < 0.01), multiple organ dysfunction (p < 0.01), infection of pancreatic necrosis (p < 0.05), surgical control of pancreatic necrosis (p < 0.0001), and the time of surgical intervention (p < 0.05) determined survival significantly. CONCLUSION Patients who were operated later than three weeks after onset of disease had a significantly better outcome. In patients suffering from SAP who required surgical treatment, the timing of operation is crucial for survival.

Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer

Background:Body mass index (BMI) has an impact on survival outcome in patients treated with aromatase inhibitors (AIs). Obesity is associated with an increased body aromatisation and may be a cause of insufficient estradiol depletion.Methods:Sixty-eight postmenopausal oestrogen receptor-positive patients with early breast cancer were prospectively included in this study. Follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were analysed immediately in the clinical routine lab and in a dedicated central lab before (T1) and 3 months after start with aromatase inhibitors (T2).Results:A total of 40 patients were normal or overweight (non-obese: BMI 18.5–29.9 kg m−2) and 28 were obese (BMI⩾30 kg m−2). Aromatase inhibitors significantly suppressed estradiol serum levels (T1: 19.5 pg ml−1, T2: 10.5 pg ml−1, P<0.01) and increased FSH serum levels (T1: 70.2 mIU ml−1, T2: 75.7 mIU ml−1, P<0.05). However, after 3 months of AI treatment, estradiol levels of obese patients were nonsignificantly higher compared with non-obese patients (12.5 pg ml−1 vs 9.0 pg ml−1, P=0.1). This difference was reflected by significantly lower FSH serum levels in obese compared with non-obese patients (65.5 mIU ml−1 vs 84.6 mIU ml−1, P<0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine as well as in the dedicated central lab.Conclusion:Aromatase inhibitors are less efficient at suppressing estradiol serum levels in obese when compared with non-obese women.

The multigene signature MammaPrint impacts on multidisciplinary team decisions in ER+, HER2- early breast cancer.

Background:Validated multigene signatures (MGS) provide additional prognostic information when evaluating clinical features of ER+, HER2− early breast cancer. We have studied the quantitative and qualitative impact of MGS on multidisciplinary team (MDT) recommendations.Methods:We prospectively recruited 75 ER+, HER2− breast cancer patients. Inclusion was based on biopsy assessment of grade, hormone receptor status, HER2, clinical tumour and nodal status. A fresh tissue sample was sent for MammaPrint (MP), TargetPrint analysis at surgery. Clinical risk was decided by the MDT in the absence of MP results and repeated following the collection of MP results. Decision changes were recorded and a health technology assessment was undertaken to compare cost effectiveness.Results:The majority of patients were assigned low to intermediate clinical risk by the MDT. According to MP, 76% were low risk. A very high correlation between local IHC and the TargetPrint assessment was shown. In over a third of patients, discordance between clinical and molecular risk was observed. Decision changes were recorded in half of these cases (18.6%) and resulted in two out of three patients not requiring chemotherapy. The use of MP was also found to be more cost effective.Conclusions:The multigene signature MP revealed clinical and molecular risk discordance in a third of patients. The impact of this on MDT recommendations was most profound in cases where few clinical risk factors were observed and enabled some women to forgo chemotherapy. The use of MGS is unlikely to have an impact in either clinically low-risk women or in patients with more than one relative indication for chemotherapy.

Continuous therapeutic epinephrine but not norepinephrine prolongs splanchnic IL-6 production in porcine endotoxic shock.

Catecholamines play a central role in the treatment of sepsis-associated hypotension. However, these hormones have also been shown to modulate the lipopolysaccharide (LPS)-induced induction of cytokines such as tumor necrosis factor alpha, interleukin (IL)-10, and IL-6 in vitro and in human endotoxemia. We hypothesized that catecholamines applied therapeutically in septic shock also influence cytokine patterns. We studied the cytokine response in tissues of the splanchnic compartment in a porcine endotoxin shock model up to 4 h. Shock was induced by a short infusion of LPS, and animals were treated either with fluid resuscitation alone or in combination with continuous epinephrine or norepinephrine. Animals, receiving epinephrine therapy, showed a significantly prolonged upregulation of IL-6 mRNA expression at 4 h after LPS application in liver (P = 0.0014), spleen (P < 0.0001), and mesenteric lymph nodes (P = 0.0078) as compared with animals treated with norepinephrine or fluid resuscitation. Serum IL-6 increased over time in all groups. The total concentration of the cytokine (area under the curve) was significantly higher in the epinephrine group as compared with the norepinephrine and fluid resuscitation groups (P = 0.017). The peak of serum tumor necrosis factor alpha at 1 h after LPS application was already significantly reduced by epinephrine, which was only administered at a mean of less than 0.05 &mgr;g/kg/min at this time point (P < 0.01). None of the catecholamines had a significant effect on IL-10 serum levels when compared with animals receiving fluid resuscitation alone. Our data suggest that the therapeutic application of epinephrine but not of norepinephrine is associated with a profound effect on the IL-6 response of splanchnic reticuloendothelial tissues.

Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers

Background:Aberrant DNA methylation is more prominent in proximal compared with distal colorectal cancers. Although a number of methylation markers were identified for colon cancer, yet few are available for rectal cancer.Methods:DNA methylation differences were assessed by a targeted DNA microarray for 360 marker candidates between 22 fresh frozen rectal tumour samples and 8 controls and validated by microfluidic high-throughput and methylation-sensitive qPCR in fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples, respectively. The CpG island methylator phenotype (CIMP) was assessed by MethyLight in FFPE material from 78 patients with pT2 and pT3 rectal adenocarcinoma.Results:We identified and confirmed two novel three-gene signatures in fresh frozen samples that can distinguish tumours from adjacent tissue as well as from blood with a high sensitivity and specificity of up to 1 and an AUC of 1. In addition, methylation of individual CIMP markers was associated with specific clinical parameters such as tumour stage, therapy or patients’ age. Methylation of CDKN2A was a negative prognostic factor for overall survival of patients.Conclusions:The newly defined methylation markers will be suitable for early disease detection and monitoring of rectal cancer.

Abstract S2-02: The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial

Background: Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer (BC) patients. Bisphosphonates have been shown to prevent and counteract these side effects of endocrine therapy, and to improve disease-free and overall survival outcomes in postmenopausal (natural or induced) BC patients (EBCTCG meta-analysis, Lancet 2015). The aim of ABCSG-18 was to investigate the effects of adjuvant anti-RANK-ligand Denosumab on bone health and disease outcomes in postmenopausal patients with early hormone receptor+ (HR+) BC receiving AI treatment. Patients and Methods: 3,425 postmenopausal patients with HR+ BC receiving AI were recruited in 58 trial sites into this prospective, randomized, double-blind, placebo-controlled, phase-III trial. Patients were randomized 1:1 to either Denosumab 60mg or placebo q6mo s.c. Bone end point results showed that adjuvant denosumab significantly reduced clinical fractures (primary endpoint, HR=0.5, p Results: With a median follow-up of 4 years, 370 DFS events were recorded. 203 DFS events occurred in the placebo group, and 167 in the Denosumab group (HR 0.816, p=0.051). Subgroup analyses indicate that the Denosumab benefit (overall absolute 2.1% at 5 years) may be particularly driven by tumors larger than 2cm (HR=0.66, p=0.016), ductal breast cancer histology type (HR=0.79, p=0.048), and tumors with both ER and PR positive (HR=0.75, p=0.013). Summary and conclusion: Adjuvant Denosumab 60mg q6mo s.c. improves disease-free survival of HR+ breast cancer patients receiving aromatase inhibitors. Numerically, this benefit of adjuvant Denosumab is at least comparable to the DFS-benefit of adjuvant bisphosphonates. Bases on these results and the previously reported dramatic reduction of fractures, adjuvant Denosumab should be offered to all postmenopausal HR+ breast cancer patients on AI. Citation Format: Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF, On behalf of the Austrian Breast and Colorectal Cancer Study Group. The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-02.

Prognostic value of HMGB1 in early breast cancer patients under neoadjuvant chemotherapy.

The response to neoadjuvant chemotherapy in breast cancer patients is usually assessed by pCR and RCB score. However, the prognostic value of these parameters is still in discussion. We showed recently that an epirubicin/docetaxel therapy is associated with an increase in the cell death marker high‐mobility group box 1 protein (HMGB1) in the circulation. Here, we investigate whether this increase correlates with the long‐term outcome. Thirty‐six early breast cancer patients under neoadjuvant epirubicin/docetaxel combination chemotherapy were included in this study. To determine the immediate effect of this treatment on HMGB1, we collected blood samples before and 24–96 h after the initial dose. This time course was then compared to the 5‐year follow‐up of the patients. HMGB1 levels varied before chemotherapy between 4.1 and 11.3 ng/mL and reacted differently in response to therapy. Some patients showed an increase while others did not show any changes. Therefore, we subdivided the patient collective into two groups: patients with an at least 1.1 ng/mL increase in HMGB1 and patients with smaller changes. The disease‐free survival was longer in the HMGB1 increase group (56.2 months vs. 46.6 months), but this difference did not reach significance. The overall survival (OS) was significantly better in patients with an increase in HMGB1 (log rank P = 0.021). These data suggest that an immediate increase in HMGB1 levels correlates with improved outcome in early breast cancer patients receiving neoadjuvant chemotherapy, and may be a valuable complementary biomarker for early estimation of prognosis.

Pathological Complete Response to Neoadjuvant Trastuzumab Is Dependent on HER2/CEP17 Ratio in HER2-Amplified Early Breast Cancer.

Purpose: To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification. Experimental Design: 114 HER2-overexpressing early breast cancer patients who had received neoadjuvant trastuzumab were included in this study. Absolute HER2 and chromosome 17 centromere (CEP17) were measured by in situ hybridization analysis, and associations were examined between HER2/CEP17 ratio and tumor pCR status (commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is). Results: In trastuzumab-treated patients, ypT0 ypN0 was achieved in 69.0% of patients with high-level amplification (HER2/CEP17 ratio > 6), but only in 30.4% of tumors with low-level amplification (ratio ≤ 6; P = 0.001). When pCR was defined by ypT0/is ypN0 or ypTis, 75.9% and 82.8% of tumors with high-level amplification had a complete response, whereas only 39.1%, and 38.3% with low-level amplification achieved pCR (P = 0.002 and P < 0.001, respectively). Logistic regression revealed that tumors with high-level amplification had a significantly higher probability achieving ypT0 ypN0 (OR, 5.08; 95% confidence interval, 1.86–13.90; P = 0.002) than tumors with low-level amplification, whereas no other clinicopathologic parameters were predictive of pCR. The association between high-level HER2 amplification and pCR was almost exclusively confined to hormone receptor (HR)–positive tumors (ypT0 ypN0: 62.5% vs. 24.0%, P = 0.014; ypT0/is ypN0: 75.0% vs. 28.0%, P = 0.005; and ypT0/is: 87.5% vs. 28.0%, P < 0.001), and was largely absent in HR-negative tumors. Conclusions: An HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, particularly in HER2/HR copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab is initiated. Clin Cancer Res; 23(14); 3676–83. ©2017 AACR.

Abstract P3-11-06: Bevacizumab in combination with docetaxel+trastuzumab +/- non-pegylated liposomal doxorubicin: Final results of ABCSG-32, a prospective, randomized phase II-study

BACKGROUND Pathological complete response (pCR) after neoadjuvant systemic therapy is correlated with better prognosis in HER2-positive, early breast cancer. Bevacizumab (B) was shown to add efficacy to neoadjuvant systemic treatment in HER2-negative, early breast cancer in terms of pCR-rate but failed in the adjuvant setting of both, HER2-negative and HER2-positive disease. The role of B in the neoadjuvant treatment of HER2-positive, early breast cancer is not defined. Thus, ABCSG-32 was designed as a randomized phase II trial to evaluate the efficacy, the non-cardiac safety, and the cardiac toxicity of B when added to docetaxel + trastuzumab (DT) +/- non-pegylated liposomal doxorubicin (N) in the neoadjuvant setting of early, HER2-positive breast cancer. METHODS 100 patients with biopsy-proven, invasive, early, HER2-positive breast cancer were stratified according to major risk factors including estrogen receptor (ER)-status, histology, tumor grade, and center and were randomized to receive 6 cycles (q 21 days) of either D100 mg/m2+T8/6mg/kg (DT, n=25), DT+B15mg/kg (DTB, n=25), D75T+N50 mg/m2 (DTN, n=26), or D75TN+B15 mg/m2 (DTNB, n=24). All patients received pegfilgrastim 6 mg sc on day 2. pCR was defined as the absence of invasive tumor cells in the breast and total pCR (tpCR) was defined as the absence of invasive tumor cells in the breast and axillary nodes after NST. Left ventricular (LV) ejection fraction (EF) was measured at baseline, before each treatment cycle, and before sugery. A cardiac toxicity event (CTE) was defined as the occurrence of either symptomatic LV dysfunction NYHA II-III, or an asymptomatic drop of EF (adEF) of >15% from baseline, or an adEF RESULTS The overall rate of pCR in all patients was 52% (DT: 36%, DTB: 51%, DTN: 63%, DTNB: 62%). In the ER-negative subgroup (n=43) the overall pCR rate was 63% (DT: 31%, DTB: 70%, DTN: 75%, DTNB: 88%) and the overall tpCR rate was 60% (DT: 31%, DTB: 60%, DTN: 75%, DTNB: 88%). Cardiac toxicity was low with a CTE in only3 patients (DT:0, DHB:1, DTN:1, DTNB:1). Non-cardiac toxicity/patient as evaluated by the incidence of serious adverse events (SAE,n=50) and significant safety events (SSE, n=114) was acceptable (SAE: DT:8, DTB:12, DTN:14, DTNB: 16; SSE: DT: 23, DTB: 31, DTN: 29, DTNB: 31). No differences in the incidence of non-serious AE and no new safety signals for B and N were detected. In 8 patients the treatment was terminated early (DT: 0, DTB: 3, DTN: 2, DTNB: 3). CONCLUSIONS Our data show that all regimens tested are effective in inducing pCR in HER2-positive early breast cancer. The addition of B and/or N to DT may lead to pCR/tpCR-rates of 51-88% with the highest activity seen in the ER-negative subgroup. 6 cycles of these regimens can safely be administered to patients with HER2-positive early breast cancer and further phase III-evaluation appear to be warranted. Citation Format: Guenther G Steger, Richard Greil, Michael Hubalek, Michael A Fridrik, Christian F Singer, Rupert Bartsch, Marija Balic, Peter Dubsky, Daniel Egle, Simon P Gampenrieder, Georg Pfeiler, David Mayr, Theresa Czech, Gabriel Rinnerthaler, Ruth Exner, Andreas L Petzer, Paul Sevelda, Alois Lang, Margaretha Rudas, Barbara Krause, Michael Seifert, Sophie Frantal, Christoph C Zielinski, Michael Gnant. Bevacizumab in combination with docetaxel+trastuzumab +/- non-pegylated liposomal doxorubicin: Final results of ABCSG-32, a prospective, randomized phase II-study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-06.