Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522.

BACKGROUND: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. PATIENTS AND METHODS: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. RESULTS: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. CONCLUSIONS: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.

Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.

X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis.

Incidence and oncological implication of adrenal incidentalomas in esophageal cancer patients.

Adrenal incidentalomas are regularly encountered during imaging for esophageal cancer patients, but their oncological significance remains unknown. This study aimed to describe the incidence and etiology of adrenal incidentalomas observed throughout the diagnostic workup. This retrospective cohort study included all esophageal cancer patients referred to or diagnosed in the Amsterdam UMC between January 2012 and December 2016. Radiology and multidisciplinary team meeting reports were reviewed for adrenal incidentalomas. In case of adrenal incidentaloma, the 18FDG-PET/CT was reassessed by a radiologist blinded for the original report. In case of a metachronous incidentaloma during follow-up, visibility on previous imaging was reassessed. Primary outcome was the incidence, etiology and oncological consequence of synchronous adrenal incidentalomas. This study included 1,164 esophageal cancer patients, with a median age of 66 years. Patients were predominantly male (76.1%) and the majority had an adenocarcinoma (69.0%). Adrenal incidentalomas were documented in 138 patients (11.9%) during the diagnostic workup. At primary esophageal cancer workup, 22 incidentalomas proved malignant. However, follow-up showed that four incidentalomas were inaccurately diagnosed as benign and three malignant incidentalomas were visible on staging imaging but initially missed. Stage migration occurred in 15 of 22 (68.2%), but this would have been higher if none were missed or inaccurately diagnosed. The oncological impact of adrenal incidentalomas in patients with esophageal cancer is significant as a considerable part of incidentalomas changed treatment intent from curative to palliative. As stage migration is likely, pathological examination of a synchronous adrenal incidentaloma should be weighted in mind.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

The EMA review of trastuzumab emtansine (T-DM1) for the adjuvant treatment of adult patients with HER2-positive early breast cancer.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab [a monoclonal antibody against human epidermal growth factor receptor 2 (HER2)] and DM1 (an inhibitor of tubulin polymerisation). It was initially approved in the European Union for the treatment of adult patients with HER2-positive unresectable locally advanced or metastatic breast cancer (BC) who had previously received trastuzumab and taxanes. On 18 December 2019, a variation of the marketing authorisation was approved extending this use to the adjuvant therapy of adult patients with HER2-positive early BC who have residual invasive disease in the breast and/or lymph nodes after neoadjuvant taxane-based and HER2-targeted therapy. A phase III randomised, multicentre, open-label trial compared T-DM1 with trastuzumab as adjuvant therapy in patients with HER2-positive early BC who had received preoperative chemotherapy and HER2-targeted therapy followed by surgery, with a finding of invasive residual disease in the breast and/or axillary lymph nodes. The study met its primary endpoint by showing an increased 3-year invasive disease-free survival rate in the T-DM1 arm (88.3%) compared with the trastuzumab arm (77.0%), with an unstratified hazard ratio of 0.50 (95% confidence interval: 0.39-0.64). There was a higher incidence of hepatotoxicity (37.3% versus 10.6%), thrombocytopenia (28.5% versus 2.4%), peripheral neuropathy (32.3% versus 16.9%), haemorrhage (29.2% versus 9.6%) and pulmonary toxicity (2.8% versus 0.8%) in the T-DM1 arm compared with the control arm. The aim of this manuscript was to summarise the scientific review of the application leading to regulatory approval of this additional indication in the European Union.

Association of secondary displacement of distal radius fractures with cortical bone quality at the distal radius.

INTRODUCTION: The aim of this study was to investigate the associations of patient characteristics, bone mineral density (BMD), bone microarchitecture and calculated bone strength with secondary displacement of a DRF based on radiographic alignment parameters. MATERIALS AND METHODS: Dorsal angulation, radial inclination and ulnar variance were assessed on conventional radiographs of a cohort of 251 patients, 38 men and 213 women, to determine the anatomic position of the DRF at presentation (primary position) and during follow-up. Secondary fracture displacement was assessed in the non-operatively treated patients (N = 154) with an acceptable position, preceded (N = 97) or not preceded (N = 57) by primary reduction (baseline position). Additionally, bone microarchitecture and calculated bone strength at the contralateral distal radius and tibia were assessed by HR-pQCT in a subset of, respectively, 63 and 71 patients. OUTCOME: Characteristics of patients with and without secondary fracture displacement did not differ. In the model with adjustment for primary reduction [OR 22.00 (2.27-212.86), p = 0.008], total [OR 0.16 (95% CI 0.04-0.68), p = 0.013] and cortical [OR 0.19 (95% CI 0.05-0.80], p = 0.024] volumetric BMD (vBMD) and cortical thickness [OR 0.13 (95% CI 0.02-0.74), p = 0.021] at the distal radius were associated with secondary DRF displacement. No associations were found for other patient characteristics, such as age gender, BMD or prevalent vertebral fractures. CONCLUSIONS: In conclusion, our study indicates that besides primary reduction, cortical bone quality may be important for the risk of secondary displacement of DRFs.

Improved Detection of Scaphoid Fractures with High-Resolution Peripheral Quantitative CT Compared with Conventional CT.

BACKGROUND: Computed tomography (CT), magnetic resonance imaging, and bone scintigraphy are second-line imaging techniques that are frequently used for the evaluation of patients with a clinically suspected scaphoid fracture. However, as a result of varying diagnostic performance results, no true reference standard exists for scaphoid fracture diagnosis. We hypothesized that the use of high-resolution peripheral quantitative CT (HR-pQCT) in patients with a clinically suspected scaphoid fracture could improve scaphoid fracture detection compared with conventional CT in the clinical setting. METHODS: The present study included 91 consecutive patients (≥18 years of age) who presented to the emergency department with a clinically suspected scaphoid fracture between December 2017 and October 2018. All patients were clinically reassessed within 14 days after first presentation, followed by CT and HR-pQCT. If a scaphoid fracture was present, the fracture type was determined according to the Herbert classification system and correlation between CT and HR-pQCT was estimated with use of the Kendall W statistic or coefficient of concordance (W) (the closer to 1, the higher the correlation). RESULTS: The cohort included 45 men and 46 women with a median age of 52 years (interquartile range, 29 to 67 years). HR-pQCT revealed a scaphoid fracture in 24 patients (26%), whereas CT revealed a scaphoid fracture in 15 patients (16%). Patients with a scaphoid fracture were younger and more often male. The correlation between CT and HR-pQCT was high for scaphoid fracture type according to the Herbert classification system (W = 0.793; 95% confidence interval [CI], 0.57 to 0.91; p < 0.001) and very high for scaphoid fracture location (W = 0.955; 95%, CI 0.90 to 0.98; p < 0.001). CONCLUSIONS: In the present study, the number of patients diagnosed with a scaphoid fracture was 60% higher when using HR-pQCT as compared with CT. These findings imply that a substantial proportion of fractures-in this study, more than one-third-will be missed by the current application of CT scanning in patients with a clinically suspected scaphoid fracture. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Approaches to management of cardiovascular morbidity in adult cancer patients - cross-sectional survey among cardio-oncology experts.

BACKGROUND: In cardio-oncology, a range of clinical dilemmas can be identified where high-quality evidence for management is still lacking. The aim of this project was to study clinical practices and expert approaches to several clinical cardio-oncological dilemmas regarding prediction, prevention and treatment of cardiovascular disease in adult cancer patients. METHODS: A cross-sectional online survey was sent out to internationally renowned experts in the field of cardio-oncology. Participants were selected based on being first or last authors of papers in the field of cardio-oncology, or principal investigators to trials in this field. RESULTS: Topics discussed include, among others, the use of biomarkers for subclinical cardiovascular toxicity, approaches towards primary prevention and follow-up with medication and life-style recommendations, and management of fluoropyrimidine-vasospasm, QTc-prolongation and asymptomatic declines in left ventricular ejection fraction. CONCLUSION: The answers provided in this survey have shed light on expert-based practices in cardio-oncologic dilemmas. Attitudes towards, as well as discrepancies in those dilemmas are presented. Existing discrepancies clearly indicate the need for generation of high-quality data that allows for more evidence-based recommendations in the future.

The risk of new fragility fractures in patients with chronic kidney disease and hip fracture-a population-based cohort study in the UK.

Chronic kidney disease (CKD) is a risk factor for fractures. However, in hip fracture patients, CKD G3-G5 was associated with a higher mortality risk and not associated with a higher risk of subsequent non-hip fractures compared to eGFR > 60 ml/min. The higher mortality risk may, as competing risk, explain our findings. INTRODUCTION: Chronic kidney disease (CKD) is a known risk factor for fragility fractures. Patients aged 50+ with a recent fragility fracture have an increased risk of subsequent fractures. Our aim was to evaluate the association between CKD stages G3-G5 versus estimated glomerular filtration rate (eGFR) > 60 ml/min and the risk of a new non-hip fracture or fragility fracture in patients with a first hip fracture. METHODS: Population-based cohort study using the UK general practices in the Clinical Practice Research Datalink. Associations between CKD stage and first subsequent fracture were determined using Cox proportional hazard analyses to estimate hazard ratios (HRs). To explore the potential competing risk of mortality, cause-specific (cs) HRs for mortality were estimated. RESULTS: CKD G3-G5 was associated with a lower risk of any subsequent non-hip fracture (HR: 0.90, 95%CI: 0.83-0.97), but not with the risk of subsequent major non-hip fragility fracture. CKD G3-G5 was associated with a higher mortality risk (cs-HR: 1.05, 95%CI: 1.01-1.09). Mortality risk was 1.5- to 3-fold higher in patients with CKD G4 (cs-HR: 1.50, 95%CI: 1.38-1.62) and G5 (cs-HR: 2.93, 95%CI: 2.48-3.46) compared to eGFR > 60 ml/min. CONCLUSIONS: The risk of a subsequent major non-hip fragility fractures following hip fracture was not increased in patients with CKD G3-G5 compared to eGFR > 60 ml/min. Mortality risk was higher in both hip fracture and non-hip fracture patients with CKD G4 and G5. The higher mortality risk may, as competing risk, explain our main finding of no increased or even decreased subsequent fracture risk after a hip fracture in patients with CKD G3-G5.

Ancient Schwannoma of the Gallbladder.

Schwannomas are benign tumors which arise in the Schwann cells of the peripheral nerves. They develop anywhere in the human body but are less frequent found in the digestive tract. A 67-year-old female patient was referred to our tertiary HPB department with a asymptomatic mass of the gallbladder. Contrast-enhanced computed tomography revealed a rather homogeneous, well-circumscribed, high-density ovoid mural mass. An open cholecystectomy was performed. A final diagnosis of schwannoma with degenerative atypia, so-called "ancient schwannoma", was made. Clinical recovery and follow-up was uneventful, with no signs of recurrence.

Association between vertebral fractures and coronary artery calcification in current and former smokers in the ECLIPSE cohort.

In smokers and former smokers from the ECLIPSE cohort, there is an association between prevalent vertebral fractures (VFs) and coronary artery calcification (CAC). Chest CT scans provide the opportunity to evaluate VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions. INTRODUCTION: Prevalence of VFs among smokers and patients with chronic obstructive pulmonary disease (COPD) is high, and an association between CAC and osteoporosis has been described. We investigated the associations between VFs and CAC (expressed in Agatston score) in (former) smokers. METHODS: Current and former smokers from the ECLIPSE study (designed to determine underlying COPD progression mechanisms) were studied. Baseline Agatston score (zero (0), medium (1-400), or high (> 400)), baseline bone attenuation (BA), and prevalent and incident VFs (vertebrae T1-L1) were assessed on CT. RESULTS: A total of 586 subjects were included (mean age 59.8 ± 8.3; 62.3% men; 70.1% with COPD; 21.0% with prevalent VFs; 196 with zero, 266 with medium, and 124 with high Agatston score). Of these, 23.4% suffered incident VFs within 3 years. In multivariate models, prevalent VFs were associated with medium (1.83 [95% CI 1.01-3.30]) and with high (OR = 3.06 [1.45-6.47]) Agatston score. After adjustment for BA, prevalent VFs were still associated with high (OR = 2.47 [1.13-5.40]), but not significantly with medium Agatston score (OR = 1.57 [0.85-2.88]). Similarly, after adjustment for BA, high (OR = 2.06 [1.02-4.13]) but not medium Agatston score (OR = 1.61 [0.88-2.94]) was associated with prevalent VFs. Agatston score at baseline was not associated with short-term VF incidence. CONCLUSION: In (former) smokers, there was an association between prevalent VFs and Agatston score. Chest CT scans provide the opportunity to also evaluate for VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions.

Vertebral bone attenuation in Hounsfield Units and prevalent vertebral fractures are associated with the short-term risk of vertebral fractures in current and ex-smokers with and without COPD: a 3-year chest CT follow-up study.

CT scans performed to evaluate chronic obstructive pulmonary disease (COPD) also enable evaluation of bone attenuation (BA; a measure of bone density) and vertebral fractures (VFs). In 1239 current/former smokers with (n = 999) and without (n = 240) COPD, the combination of BA and prevalent VFs was associated with the incident VF risk. INTRODUCTION: Chest CT scans are increasingly used to evaluate pulmonary diseases, including COPD. COPD patients have increased risk of osteoporosis and VFs. BA on CT scans is correlated with bone mineral density and prevalent VFs. The aim of this study was to evaluate the association between BA and prevalent VFs on chest CT scans, and the risk of incident VFs in current and former smokers with and without COPD. METHODS: In participants of the ECLIPSE study with baseline and 1-year and 3-year follow-up CT scans, we evaluated BA in vertebrae T4-T12 and prevalent and incident VFs. RESULTS: A total of 1239 subjects were included (mean age 61.3 ± 8.0, 61.1% men, 999 (80.6%) COPD patients). The mean BA was 155.6 ± 47.5 Hounsfield Units (HU); 253 (20.5%) had a prevalent VF and 296 (23.9%) sustained an incident VF within 3 years. BA and prevalent VFs were associated with incident VFs within 1 (per - 1SD HR = 1.38 [1.08-1.76] and HR = 3.97 [2.65-5.93] resp.) and 3 years (per - 1SD HR = 1.25 [1.08-1.45] and HR = 3.10 [2.41-3.99] resp.), while age, sex, body mass index (BMI), smoking status and history, or presence of COPD was not. In subjects without prevalent VFs and BA, and for 1-year incidence, BMI values were associated with incident fractures (1 year, BA per - 1SD HR = 1.52 [1.05-2.19], BMI per SD HR = 1.54 [1.13-2.11]; 3 years, per - 1SD HR = 1.37 [1.12-1.68]). CONCLUSIONS: On CT scans performed for pulmonary evaluation in (former) smokers with and without COPD, the combination of BA and prevalent VFs was strongly associated with the short-term risk of incident VFs.

Avoiding over- and undertreatment in patients with resected node-positive breast cancer with the use of gene expression signatures: are we there yet?

Prediction of benefit from adjuvant chemotherapy following resection of early breast cancer and, as a result, proper selection of candidates remains an elusive goal since the relative magnitude of benefit is the same regardless of the presence of clinicopathologic factors. Multiple studies, including randomized trials, establish the role of certain gene expression signatures in node-negative disease since they predict the risk of breast cancer relapse being so low that adjuvant chemotherapy can be omitted. In contrast, more limited data are available in higher risk, node-positive breast cancer patients, making the exclusion of adjuvant chemotherapy potentially hazardous. 'Prospective-retrospective' studies and limited prospective data show that several signatures, namely Oncotype Dx, MammaPrint, Prosigna, EndoPredict and Breast Cancer Index, select with different levels of success node-positive patients at very low risk for distant recurrence despite not receiving chemotherapy, although the long-term follow-up is still awaited. Pending, however the publication of the results from ongoing randomized studies which enroll patients with node-positive disease, major caution is warranted. Improper use and misinterpretation of these transcriptomic profiles can lead to undertreatment and exposure of patients to unnecessary risks resulting in increased breast cancer mortality for patients with axillary node-positive disease. With this review we critically discuss the available data on gene expression signatures that are used in clinical practice and offer practical recommendations regarding the management of patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive breast cancer.

Dose tailoring of adjuvant chemotherapy for breast cancer based on hematologic toxicities: further results from the prospective PANTHER study with focus on obese patients.

Background: Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial. Patients and methods: PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT. Results: Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups. Conclusions: Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies. ClinicalTrials.gov identifier: NCT00798070.