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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.). [ABSTRACT FROM AUTHOR]

BACKGROUND: Adjuvant aromatase inhibitors increase osteoporosis and fractures in patients with hormone receptor–positive breast cancer. We have previously reported outcomes of the ABCSG-18 (study 18 from the Austrian Breast & Colorectal Cancer Study Group) trial showing that adjuvant anti–receptor activator of nuclear factor-κB ligand denosumab treatment counteracts these adverse effects and may improve outcomes. We report here the final long-term outcomes. METHODS: ABCSG-18 is a prospective, double-blind, placebo-controlled, phase 3 trial in which 3425 postmenopausal patients with early hormone receptor–positive breast cancer receiving aromatase inhibitor therapy were randomly assigned in 58 trial centers to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months. The primary end point was the time to first clinical fracture after randomization. Secondary disease outcome–related end points were disease-free survival (DFS), bone metastasis–free survival (BMFS), and overall survival (OS). RESULTS: For this final protocol-defined analysis, median follow-up is 8 years (interquartile range, 6 to 9.6 years). There were 309 versus 368 DFS events (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.97) in the denosumab versus the placebo group, respectively, resulting in an absolute 9-year DFS benefit of 3.5 percentage points (79.4 vs. 75.9%). Adjuvant denosumab improved BMFS by 2.5 percentage points (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00) and OS by 1.0 percentage point (90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01). No new toxicities for this dose of adjuvant denosumab were observed. CONCLUSIONS: DFS, BMFS, and OS continued to show benefit in this final long-term analysis of ABCSG-18. There were no new toxicities. (Funded by Amgen; ClinicalTrials.gov number, NCT00556374.)

Purpose: Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions., Experimental Design: We profiled 93 genes in tissue from 193 patients with early breast cancer. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release., Results: At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR = 0.062; 95% CI, 0.01-0.48; P = 0.0077). Of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were nonresponders (RCB II, n = 8; RCB III, n = 22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, whereas 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result., Conclusions: Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS., Methods: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS., Results: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11)., Conclusion: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies., Competing Interests: Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, AstraZeneca, Gilead SciencesResearch Funding: Pfizer (Inst) Christian FeslResearch Funding: Pfizer (Inst) Dominik HlauschekResearch Funding: Pfizer (Inst) Laura Garcia-EstevezConsulting or Advisory Role: Daiichi Sankyo/Astra Zeneca, Palex, Seattle GeneticsResearch Funding: Roche/Genentech (Inst) Nicholas ZdenkowskiHonoraria: Roche, Pfizer, EisaiConsulting or Advisory Role: Lilly, AstraZeneca, EisaiResearch Funding: Roche (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Roche, Amgen, Novartis Kathy D. MillerThis author is the Senior Deputy Editor of Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Merck, Genentech/Roche, Athenex, AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Seattle Genetics (Inst), Pfizer (Inst), Astex Pharmaceuticals (Inst), British Biotech (Inst), CytomX Therapeutics (Inst), Alphamab (Inst) Marija BalicConsulting or Advisory Role: Amgen, AstraZeneca, Daiichi Sankyo/Astra Zeneca, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, SamsungSpeakers' Bureau: Amgen, AstraZeneca, Daiichi Sankyo/Astra Zeneca, Lilly, Novartis, Pierre Fabre, Pfizer, Roche, Seattle GeneticsResearch Funding: Lilly (Inst), Novartis (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: MSD Ingrid A. MayerConsulting or Advisory Role: Novartis, AstraZeneca, Lilly, Genentech, GlaxoSmithKline, Immunomedics, Macrogenics, Pfizer, AbbVie, Seattle Genetics, Puma Biotechnology, Cyclacel, Blueprint Medicines, SanofiResearch Funding: Novartis (Inst), Pfizer (Inst), Genentech (Inst) David CameronConsulting or Advisory Role: Lilly (Inst), Novartis (Inst), Novartis (Inst), Research Triangle Institute RTI Health Solutions (Inst), Daiichi Sankyo (Inst), Prima BioMed (Inst), Merck Sharp & Dohme (Inst), Zymeworks (Inst), Eisai (Inst), Puma Biotechnology (Inst), Pfizer (Inst), Oncolytics (Inst), Roche (Inst), Roche (Inst), Samsung Bioepis (Inst), Seattle Genetics (Inst), Synthon (Inst), Clarity Pharmaceuticals (Inst), Bexon/Zymeworks (Inst), Sanofi (Inst)Research Funding: Roche (Inst), Novartis (Inst), AstraZeneca (Inst) Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other Relationship: InfiniteMD José Juan Ponce LorenzoHonoraria: Seattle Genetics, Novartis, Pfizer, AstraZeneca/Daiichi Sankyo, Lilly, RocheConsulting or Advisory Role: Seattle Genetics, Novartis, AstraZeneca/Daiichi Sankyo, Roche Tufia C. HaddadResearch Funding: Takeda (Inst) Hiroji IwataHonoraria: Chugai Pharma, AstraZeneca, Eisai, Pfizer, Daiichi Sankyo, Lilly Japan, Kyowa Hakko Kirin, Taiho PharmaceuticalConsulting or Advisory Role: Chugai Pharma, Daiichi Sankyo, Pfizer, AstraZeneca, Lilly Japan, Kyowa Hakko Kirin, NovartisResearch Funding: MSD (Inst), AstraZeneca (Inst), Kyowa Hakko Kirin (Inst), Daiichi Sankyo (Inst), Chugai Pharma (Inst), Nihonkayaku (Inst), Lilly Japan (Inst), Novartis (Inst), Bayer (Inst), Pfizer (Inst), Boehringer Ingelheim (Inst), Sanofi (Inst) Matthew GoetzConsulting or Advisory Role: Lilly, bioTheranostics, Genomic Health, Novartis, Eisai, Sermonix Pharmaceuticals, Context Therapeutics, Pfizer, BiovicaResearch Funding: Lilly (Inst), Pfizer (Inst), Sermonix Pharmaceuticals (Inst)Patents, Royalties, Other Intellectual Property: Methods and Materials for Assessing Chemotherapy Responsiveness and Treating Cancer, Methods and Materials for Using Butyrylcholinesterases to Treat Cancer, Development of Human Tumor Xenografts from Women with Breast Cancer Treated with Neoadjuvant Chemotherapy (Inst)Travel, Accommodations, Expenses: Lilly Fatima CardosoConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Teva, Astellas Pharma, Merus, Celgene, Eisai, Daiichi Sankyo, Genentech, Merck Sharp & Dohme, Sanofi, Pierre Fabre, Macrogenics, Amgen, GE Healthcare, GlaxoSmithKline, Mylan, Mundipharma, Seattle Genetics, Samsung Bioepis, Medscape, Prime OncologyTravel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Tiffany A. TrainaConsulting or Advisory Role: Genentech/Roche, Pfizer, AstraZeneca, Merck, Puma Biotechnology, Athenex, Daiichi Sankyo, Ionis Pharmaceuticals, Seattle Genetics, Eisai, Exact Sciences, Foundation Medicine, Ayala Pharmaceuticals, Gilead Sciences, Blueprint Medicines, Ellipses Pharma, Fuji Pharma, ITeos Therapeutics, AgendiaResearch Funding: Eisai (Inst), Pfizer (Inst), Novartis (Inst), Innocrin Pharma (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Immunomedics (Inst), Genentech/Roche (Inst), Daiichi Sankyo (Inst), Carrick Pharm (Inst), Ayala Pharmaceuticals (Inst) Urs BreitensteinConsulting or Advisory Role: AstraZeneca (Inst), Elie Lilly (Inst), Novartis (Inst), Pierre Fabre (Inst), Roche (Inst) Kerstin AckerlResearch Funding: Pfizer (Inst) Otto Metzger FilhoHonoraria: Grupo Oncoclinicas, RocheResearch Funding: Susan G. Komen for the Cure (Inst), Pfizer (Inst), Roche/Genentech (Inst), Eisai (Inst), Cascadian Therapeutics (Inst), AbbVie (Inst)Travel, Accommodations, Expenses: Grupo Oncoclinicas Karin ZehetnerResearch Funding: Pfizer (Inst) Kadine SolomonEmployment: Alliance Foundation TrialsStock and Other Ownership Interests: Pfizer, Merck, Moderna Therapeutics Sarra El-AbedEmployment: Astellas Pharma (I), argenx (I)Research Funding: Novartis (Inst), Roche/Genentech (Inst), Pfizer (Inst) Kathy Puyana TheallEmployment: Pfizer (I)Stock and Other Ownership Interests: Pfizer (I)Honoraria: PfizerTravel, Accommodations, Expenses: Pfizer Dongrui Ray LuEmployment: PfizerStock and Other Ownership Interests: Pfizer Amylou DueckPatents, Royalties, Other Intellectual Property: Royalties from licensing fees for a patient symptom questionnaire (MPN-SAF) Michael GnantEmployment: Sandoz (I)Honoraria: Amgen, Novartis, AstraZeneca, LillyConsulting or Advisory Role: Daiichi-Sankyo, Veracyte, Tolmar, LifeBrain, Lilly Angela DeMicheleResearch Funding: Pfizer (Inst), Genentech (Inst), Calithera Biosciences (Inst), Novartis (Inst)No other potential conflicts of interest were reported.

Background: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences., Methods: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint., Results: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation., Conclusion: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

Background: Neoadjuvant chemotherapy (NaCT) and neoadjuvant endocrine therapy (NET) can reduce pre-operative tumour burden in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. This prospective translational study assessed the ability of a 12-gene molecular score (MS; EndoPredict®) to predict response to NaCT or NET within the ABCSG-34 trial., Patients and Methods: Hormone receptor (HR)-positive, HER2-negative samples from patients in the ABCSG-34 randomized phase II trial were selected and EndoPredict testing was performed to generate a 12-gene MS. ABCSG-34 patients were assigned to receive either NaCT or NET based on menopausal status, HR expression, grade and Ki67. Response was measured by residual cancer burden (RCB)., Results: Patients selected for NaCT generally had high-risk disease by 12-gene MS (125/134), while slightly more patients treated with NET had low-risk disease (44/83). Low-risk NaCT-treated and high-risk NET-treated tumours responded poorly (NPV 100% [95% CI 66.4%-100%] and NPV 92.3% [95% CI 79.1%-98.4%], respectively]. The 12-gene MS significantly predicted treatment response for NaCT (AUC 0.736 [95% CI 0.63-0.84]) and NET (AUC 0.726 [95% CI 0.60-0.85])., Conclusions: The 12-gene MS predicted RCB after treatment with neoadjuvant therapies for patients with HR-positive, HER2-negative early-stage breast cancer. Tumours with low MS were unlikely to benefit from NaCT, whereas a high MS predicted resistance to NET. This additional biologic information can aid personalized treatment selection in daily practice and builds a strong rationale to use EndoPredict in biomarker-driven studies in the neoadjuvant setting., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients., Patients and Methods: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life., Findings: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone., Interpretation: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To investigate long-term results of patients with hormonal receptor-positive breast cancer treated with breast-conserving surgery (BCS) and consecutive endocrine therapy (ET) with or without whole breast irradiation (WBI)., Methods and Materials: Within the 8 A trial of the Austrian Breast and Colorectal Cancer Study Group, a total of 869 patients received ET after BCS which was randomly followed by WBI (n = 439, group 1) or observation (n = 430, group 2). WBI was applied up to a mean total dosage of 50 Gy (+/- 10 Gy boost) in conventional fractionation., Results: After a median follow-up of 9.89 years, 10 in-breast recurrences (IBRs) were observed in group 1 and 31 in group 2, resulting in a 10-year local recurrence-free survival (LRFS) of 97.5% and 92.4%, respectively (p = 0.004). This translated into significantly higher rates for disease-free survival (DFS): 94.5% group 1 vs 88.4% group 2, p = 0.0156. For distant metastases-free survival (DMFS) and overall survival (OS), respective 10-year rates amounted 96.7% and 86.6% for group 1 versus 96.4% and 87.6%, for group 2 (ns). WBI (hazard ratio [HR]: 0.27, p < 0.01) and tumour grading (HR: 3.76, p = 0.03) were found as significant predictors for IBR in multiple cox regression analysis., Conclusions: After a median follow-up of 10 years, WBI resulted in a better local control and DFS compared with ET alone. The omission of WBI and tumour grading, respectively, were the only negative predictors for LRFS., Competing Interests: Conflict of interest statement F.S. reports a research collaboration with Elekta, during the conduct of the study. R.G. has received honoraria, has been a consultant or has served an advisory role, has received research funding and has received travel and accommodations expenses from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Janssen. G.M. has received institutional research support from AstraZeneca, Roche, Novartis, and Pfizer and has received lecture fees, honoraria for participation on advisory boards, and travel support from Amgen, AstraZeneca, Celgene, EliLilly, Invectys, Pfizer, Nanostring, Novartis, Roche, and Medison. He has served as a consultant for AstraZeneca and EliLilly and an immediate family member is employed by Sandoz. The other authors report no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported., Methods: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up., Findings: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group., Interpretation: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy., Funding: Amgen., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the impact that pre- and postoperatively administered chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) and postoperative chemotherapy vs. postoperative chemotherapy alone have on long-term prognosis., Patients and Methods: The ABCSG conducted a nationwide randomized phase III trial in high-risk endocrine non-responsive breast cancer patients comparing pre- and postoperative chemotherapy containing CMF as preoperative treatment vs. postoperative chemotherapy alone between 1991 and 1999. From 1996 the ABCSG-07 protocol was amended to also allow randomization of high-risk endocrine-responsive patients. Of 423 eligible patients with high-risk primary breast cancer, 203 patients were randomly assigned to preoperatively receive three cycles of CMF (cyclophosphamide, methotrexate, fluorouracil; 600/40/600 mg/m(2)) intravenously on day 1 and 8, while 195 patients received postoperative chemotherapy alone. In both groups, three cycles of CMF were given initially, and another three cycles of CMF were administered in node-negative patients, whereas node-positive patients received three cycles of EC (epirubicin, cyclophosphamide; 70/600 mg/m(2))., Results: Overall response rate to preoperative chemotherapy with three cycles of CMF was 56.2%; complete pathological response was achieved in 12 patients (5.9%). Recurrence-free survival was significantly better in patients receiving chemotherapy postoperatively (HR 0.7, 0.515-0.955; P = 0.024). No survival difference was observed between the two therapy groups (HR 0.800, 0.563-1.136; P = 0.213)., Discussion: Preoperative chemotherapy with CMF has to be considered as insufficient in high-risk breast cancer patients. Delayed surgery and anthracycline-based chemotherapy result in shorter recurrence-free survival but not overall survival.

Purpose: To determine whether the addition of aminoglutethimide to tamoxifen is able to improve the outcome in postmenopausal patients with hormone receptor-positive, early-stage breast cancer., Patients and Methods: A total of 2,021 postmenopausal women were randomly assigned to receive either tamoxifen for 5 years alone or tamoxifen in combination with aminoglutethimide (500 mg/d) for the first 2 years of treatment. Tamoxifen was administered at 40 mg/d for the first 2 years and at 20 mg/d for 3 years., Results: All randomized and eligible patients were included in the analysis according to the intention-to-treat principle. After a median follow-up of 5.3 years, the 5-year disease-free survival in the aminoglutethimide plus tamoxifen group was 83.6% versus 83.7% in the monotherapy group (P =.89). The corresponding data for overall survival at 5 years were 91.4% and 91.2%, respectively (P =.74). More patients failed to complete combination treatment (13.7%) because of side effects as compared to tamoxifen alone (5.2%; P =.0001)., Conclusion: Aminoglutethimide given for 2 years in addition to tamoxifen for 5 years does not improve the prognosis of postmenopausal patients with receptor-positive, lymph node-negative or lymph node-positive breast cancer.

Purpose: Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy., Patients and Methods: Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death., Results: With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed in OS (P =.195)., Conclusion: Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer.

Despite the improvement in its prognosis in most Western countries, death from colon cancer is still a major problem. In a prospectively planned observation study, a large patient collective from a single institution in Austria was analyzed in terms of the surgical approach and factors influencing survival. A total of 696 patients with colonic carcinomas were admitted to our surgical department between January 1, 1984 and December 31, 1997. Radical surgery for localized tumors was consistently performed, including wide resection margins and complete removal of the regional lymph drainage zones. Clinical, histopathologic, and therapy-related factors were examined for their influence on long-term survival by means of univariate and multivariate analysis. The overall tumor resection rate was 99.3% (691/696); complete tumor removal (R0) was possible for 84.8% (590/696) of all patients. The overall postoperative hospital mortality rate was 3.2% (22/696), and it was 13% (7/556) for potentially curative resections. Five- and ten-year tumor-specific survival rates for stage I to III R0 resections were 83.8% and 78.8%, respectively. Adjuvant chemotherapy reduced tumor recurrence for stage III patients by 52.4%. The depth of tumor infiltration, lymph node status, and adjuvant chemotherapy were found to have an independent influence on survival as identified by the Cox models. In conclusion, a consistent radical surgical approach for potentially curative resected colonic cancer patients had survival rates that surpassed those of most published series without sacrificing low complication rates. In addition, adjuvant chemotherapy for stage III substantially improved survival.

A retrospective 10-year study was conducted on 473 patients who underwent rectal cancer surgery, to evaluate a surgical procedure which has been generally abandoned, but which we believe has a significant potential to reduce the incidence of the severe and often fatal complications caused by anastomotic breakdown following low anterior resection, especially when a covering stoma is absent. This procedure involves separating the anastomosis and sacral drain from the abdominal cavity by suturing the parietal peritoneum to the colon and mesocolon, and placing the sacral drain outside the peritoneal cavity, whereby contamination of the abdominal cavity is avoided should anastomostic leakage occur. Sphincter preservation was possible in 343 patients (72.5%) while 116 (24.5%) underwent abdominoperineal resection (APR). Of 331 patients who underwent sphincter-saving resection (SSR), 31 (9.4%) had primary protective colostomies. Radical RO-resection according to the International Union Against Cancer (UICC) was performed in 405 patients, and 65 (19.6%) underwent extended resections. Anastomotic leakage became clinically manifest in 33 patients (10%; or 11% when those with primary colostomies were excluded). Only 1 patient required relaparotomy while 32 were successfully treated with temporary loop colostomy in the right epigastrium. No deaths occurred following anastomotic leakage breakdown. Overall operative hospital mortality was 3.0%; 2.7% and 2.6% in the SSR and APR groups, respectively. The adjusted 5-year survival rates were 60% for APR and 72% for SSR.

Background: Recurrent laryngeal nerve paralysis is one of the most frequent and serious complications after thyroid operation. The routine dissection and demonstration of the recurrent nerve remain controversial. In a retrospective study in an endemic region, patients operated on with principal nerve identification were investigated for vocal paralysis., Methods: Eight hundred and three consecutive goiter operations were analyzed. Because six patients had undergone isthmusectomies only, the recurrent laryngeal nerves were at risk in 797 operations. For 736 patients the surgical procedure was primary for benign disease, for 40 patients the operation was secondary for recurrent goiters, and 21 patients underwent operation for thyroid cancer. All patients underwent preoperative and postoperative laryngoscopic examination of the vocal cords by an ear, nose, and throat specialist., Results: Rate of primary postoperative vocal cord paralysis was 3.6%, and the permanent palsy rate was 0.5% with a recurrent laryngeal nerve recovery rate of 86%. In a literature survey, reports with identification of the recurrent nerve had significantly lower primary and permanent palsy rates when compared with reports without obligatory identification of the nerve (p < 0.01)., Conclusions: Our results and those of reports in the literature indicate that recurrent nerve paralysis is a less frequent complication when the nerve is identified.

The surgical procedure in acute complications of gastroduodenal ulcers is examined with regard to risk factors and mortality. Emergency admissions to an Austrian district hospital between 1. 1. 1984 and 31. 8. 1992 for peptic ulcer are retrospectively analyzed. 293 patients were admitted with a history of bleeding ulcers. Endoscopic haemostasis was achieved in 91 of 130 (70%) patients with active haemorrhage (Forrest Ia, Ib). For the other 39 patients with active haemorrhage as well as for 16 of 65 patients with signs of previous bleeding (Forrest II) emergency surgery was necessary. 33 patients were admitted for perforated ulcers and all underwent emergency surgery. Distral gastric resections were performed in 98% of cases (54/55) with bleeding ulcers and in 91% of cases (30/33) with perforated ulcers. The surgically treated patients had a high percentage of accompanying illness and females were significantly older (mean 68 years) than males (55 years) (p < 0.01). Postoperative mortality was 9.1% (5/55) for bleeding peptic ulcers and 6.1% (2/33) for perforated ulcers. Furthermore, mortality was zero in patients younger than 60 years (0/44), but 15.9% (7/44) in patients older than 60 years. Distal gastric resection was chosen as standard procedure for emergency operations.

Emergency operations due to acute colonic disease between 1. 1. 1984 and 31. 12. 1991 were retrospectively analyzed with regard to causality, surgical procedure, complications and mortality. 55 of 1105 colonic operations were emergency cases requiring immediate surgical intervention. Primary continuity preserving resections were carried out whenever possible, attending not only to the acute situation but also to the primary disease. The mean age of the 26 females and 29 males was 69 [1, 9] years. 29 patients had a colonic ileus, 21 a diffuse peritonitis and 5 patients had an uncontrolled haemorrhage. Colorectal carcinomas were initially diagnosed in 20 of the 50 patients; 14 of these patients (70%) could be operated for potential cure and primary continuity preserving resections were also possible for 14 patients (70%). Continuity preserving resections were possible for 18 of 21 patients with peritonitis and 3 colonic perforations were oversutured. In the 5 patients with acute haemorrhage, 4 resections and one transanal intervention were performed. Postoperative complications were observed in 19 patients (35%). Postoperative mortality was 16% (9/55), 5% for operations due to peritonitis, 24% for operations due to colonic ileus and 20% for operations due to haemorrhage. Primary continuity preserving resections were possible for 39 of 55 patients (71%).

Between 1.1. 1984-31.12. 1989, 263 rectal carcinomas were operated at the Department of Surgery, St. Veit/Glan. The resection rate was 68.4%, the excision rate was 27.8%, other procedures were carried out in 3.8%. Staple devices were used for all anastomoses following rectum resection. Whenever technically possible, the single-stapled procedure was used (EEA, ILS). For difficult or very low anastomoses, the double-stapled technique (DST) was utilized. The DST was employed in 47 cases. This approach contributed essentially to a relatively high resection rate at our department.

The resection rate of 216 gastric carcinomas, which were treated between January 1984 and October 1988, was 81.5%. Total gastrectomies were performed in 65.3%, distal resections in 33% and proximal resections in 1.7%. 68.1% of the operations were performed with curative intention, 13.4% were palliative, 18.5% were bypass operations and explorative laparotomies. In 52% the operations were extended to other organs. The total lethality of gastrectomies was 6.3% (for operations with curative intention 3.1%, for palliative ones 21%). None of the patients died of insufficiency of the anastomosis. The total lethality of distal and proximal resections was 3.7% (for operations with curative intention 0%, for palliative ones 20%). Explorative laparotomies and bypass operations had a lethality of 10%. According to the histo-pathological classification of the WHO 6% were well, 31% moderately and 46.8% poorly differentiated adenocarcinomas. Signet ring cell carcinomas were diagnosed in 9.3% of the cases. A histological classification of metastasis only was done in 3.2%. 3.7% of the cases were not examined histologically. 55.7% corresponded to the intestinal, 29.6% to the diffuse and 7% to the mixed type of Lauren. A Lauren classification was not possible in 7.8%. According to the UICC-criteria 13% were stage IA, 14.35% IB, 10.2% II, 14.35% IIIA, 10.2% IIIB and 6% IV(RO). In 31.9% a residual tumor (R1/R2) had to be left behind. The percentage of early cancer was 16%. 14 of the 34 early cancers corresponded to the mucosa and 20 to the submucosa type.(ABSTRACT TRUNCATED AT 250 WORDS)