Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT ...HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy.
Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m2. Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients.
From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population.
Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.
Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and ...cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1–3 positive lymph nodes (LNs) only.
A total of 2011 BC patients (18–65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors.
Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide) was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18–0.82) for EC-Doc versus FEC (test for interaction; P = 0.01).
EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1–3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.
ClinicalTrials.gov, NCT02115204.
Abstract The study aim is to assess associations between chronic kidney disease (CKD) and blood transfusions during hospitalization for joint arthroplasty. Patients with Stage IV–V CKD who underwent ...elective total knee or hip arthroplasty from 2007 to 2010 were matched 2:1 with age, gender, and surgery type controls without kidney disease. Multivariable analyses for transfusion risk with preoperative hemoglobin, body mass index, cardiovascular disease, and surgical complexity as explanatory variables were performed. Ninety CKD patients were identified and had lower preoperative hemoglobin, higher incidence of cardiovascular disease and blood transfusions. CKD was independently associated with increased odds of transfusions (2.88, 95% confidence interval 1.33–6.23, P = 0.007). Preoperative optimization of CKD patients should be considered to reduce transfusion rates.
Taxane-containing adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. This study compared efficacy and tolerability of epirubicin (E)/cyclophosphamide (C) ...followed by docetaxel (Doc) with a dose-dense 5-fluorouracil (F)+E+ C regimen.
The ADEBAR study was a randomised phase III trial for women with primary invasive breast cancer and ⩾4 metastatic axillary lymph nodes (n=1364). Treatment consisted of four 21-day cycles of E plus C, followed by four 21-day cycles of Doc (EC-Doc), or six 28-day cycles of E plus F plus C (FEC120).
Disease-free survival (DFS) was similar in the two treatment arms as shown by multivariate Cox regression adjusted for other prognostic factors (EC-Doc vs FEC120, hazard ratio (HR): 1.087; 95% confidence interval (CI): 0.878-1.346, P=0.444). In addition, there was no significant difference in overall survival (OS) between the two groups (HR: 0.974; 95% CI: 0.750-1.264, P=0.841). Haematologic toxicity was more common in FEC120 recipients; non-haematologic toxicities occurred more frequently in the EC-Doc arm. The serious adverse event rate was significantly higher in the FEC120 group (29.7% vs 22.5%).
EC-Doc provides a feasible and effective alternative therapy option to FEC120 with a different safety profile in this high-risk breast cancer cohort.
Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic ...subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1–3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC).
In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459).
Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.
In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01, displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.
In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype HR+ and (Ki-67 ≥20% or HER2+) was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients.
In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone.
The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.
Interest in an aetiopathogenic role for Helicobacter in neuropsychiatric diseases started with idiopathic parkinsonism (IP), where the cardinal signs can be assessed objectively. This systematic ...review, using an EMBASE database search, addresses Oxford Centre for Evidence-Based Medicine based questions on the inter-relationship of Helicobacter and IP, the benefits of eradicating Helicobacter in IP and the outcome of not treating. The search strategy was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines: 21 of 204 articles met the inclusion criteria. The results show that the assumption that any benefit of Helicobacter eradication results from improved levodopa bioavailability is unjustified. The inter-relationship between Helicobacter and IP is well-established. H. pylori virulence markers (associated with autoimmunity and immune tolerance) influence the risk, severity and progression of IP. The birth cohort effect for virulence marker antibodies, seen in controls, is obliterated in IP, suggesting causality. Successful H. pylori eradication in IP is disease-modifying (even in anti-parkinsonian treatment-naïve patients) but not preventive. Hypokinesia regresses with eradication and overall motor severity lessens. Eradication may influence gastrointestinal microbiota adversely, unlocking the next stage in the natural history, the development of rigidity. Failed eradication worsens hypokinesia, as does the presence/persistence of H. pylori at molecular level only. Adequate prognostic assessment of the consequences of not treating Helicobacter, for IP, is prevented by a short follow-up. We conclude that Helicobacter is a pathophysiological driver of IP.
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