Prediction of recurrent gestational diabetes mellitus: a retrospective cohort study.

BACKGROUND: Women after gestational diabetes mellitus (GDM) are at increased risk for development of GDM recurrence. It was the aim of our study to evaluate factors for prediction of risk of recurrence. METHODS: In this retrospective cohort study we included 159 women with GDM and a subsequent pregnancy. Putative risk factors for GDM recurrence were analyzed by logistic regression models. Results were compared to a cohort of age-matched women without GDM as controls (n = 318). RESULTS: The overall risk of GDM recurrence was 72.3% (115/159). Risk factors of recurrence were a body mass index (BMI) ≥ 30 kg/m2 before the index pregnancy (odds ratio (OR) 2.8 [95% CI 1.3-6.2], p = 0,008), a BMI ≥ 25 kg/m2 before the subsequent pregnancy (OR 2.7 [95% CI 1.3-5.8]. p = 0.008), a positive family history (OR 4.3 [95% CI 1.2-15.4], p = 0.016) and insulin treatment during the index pregnancy (OR 2.3 [95% CI 1.1-4.6], p = 0.023). Delivery by caesarean section (index pregnancy) was of borderline significance (OR 2.2 [95% CI 0.9-5.2], p = 0.069). Interpregnancy weight gain, excessive weight gain during the index pregnancy and fetal outcome where not predictive for GDM recurrence. Neonates after GDM revealed a higher frequency of transfer to intensive care unit compared to healthy controls (OR 2.3 [95% CI 1.1-4.6], p = 0.0225). The best combined risk model for prediction of GDM recurrence including positive family history and a BMI ≥ 25 kg/m2 before the subsequent pregnancy revealed moderate test characteristics (positive likelihood ratio 7.8 [95% CI 1.1-54.7] and negative likelihood ratio 0.7 [95% CI 0.6-0.9]) with a positive predictive value of 96.6% in our cohort. CONCLUSIONS: A positive family history of diabetes mellitus in combination with overweight or obesity were strongly associated with recurrence of a GDM in the subsequent pregnancy. Normalization of the pregravid BMI should be an effective approach for reducing the risk of GDM recurrence.

False-negative rate in the extended prospective TATTOO trial evaluating targeted axillary dissection by carbon tattooing in clinically node-positive breast cancer patients receiving neoadjuvant systemic therapy.

PURPOSE: In clinically node-positive breast cancer patients receiving neoadjuvant systemic therapy (NST), nodal metastases can be initially marked and then removed during surgical axillary staging. Marking methods vary significantly in terms of feasibility and cost. The purpose of the extended TATTOO trial was to report on the false-negative rate (FNR) of the low-cost method carbon tattooing. METHODS: The international prospective single-arm TATTOO trial included clinically node-positive breast cancer patients planned for NST from November 2017 to January 2021. For the present analysis, patients who received both the targeted procedure with or without an additional sentinel lymph node (SLN) biopsy and a completion axillary lymph node dissection (ALND) were selected. Primary endpoint was the FNR. RESULTS: Out of 172 included patients, 149 had undergone a completion ALND. The detection rate for the tattooed node was 94.6% (141 out of 149). SLN biopsy was attempted in 132 out of 149 patients with a detection rate of 91.7% (121 out of 132). SLN and tattooed node were identical in 58 out of 121 individuals (47.9%). The combined procedure, i.e. targeted axillary dissection (TAD) was successful in 147 of 149 cases (98.7%). Four out of 65 patients with a clinically node-negative status after NST had a negative TAD but metastases on ALND, corresponding to a FNR of 6.2%. All false-negative TAD procedures were performed in the first 2 years of the trial (2018-2019, p = 0.022). CONCLUSION: Carbon tattooing is a feasible marking method for TAD with a high detection rate and an acceptably low FNR. The TATTOO trial was preregistered as prospective trial before initiation at the University of Rostock, Germany (DRKS00013169).

[Management of Infection in Threatened Preterm Birth - A Survey of German Perinatal Centers]. / Infektionsmanagement bei drohender Frühgeburt ­ eine Umfrage an deutschen Perinatalzentren.

INTRODUCTION: In spite of insufficient evidence, we assume a high willingness to diagnose and treat vaginal infections in threatened preterm births in Germany. METHODS: Online survey on the management of infection in threatened preterm birth in all 212 German perinatal centers. RESULTS: The response rate was 31.6% (n=67). 78.8% disclaim an empirical antibiotic treatment in threatened preterm birth below 34 weeks of gestation. Half of the remaining 14 centers always start an antibiotic treatment in cases with signs or symptoms of threatened preterm birth. 94% perform vaginal swabs for culture. 37.3% use a microscopic assessment by vaginal Nugent score or Amsel score. An abnormal vaginal microbiota is mostly treated (bacterial vaginosis 79.1%, n=53, Candida spp. 77.6%, n=52, Ureaplasma spp. 49.3%, n=33). After treatment, 70.1% agree with repeating the culture diagnosis. There is common consensus for antibiotic treatment in cases with preterm premature rupture of membranes. 72.6% favor a monotherapy with a ß-lactam antibiotic. Statements on duration of therapy were inconsistent, whereby 58% of centers treat for more than 7 days. CONCLUSION: In German perinatal centers, we observed a great willingness to diagnose and treat infections in threatened preterm birth. However, the management of infection is heterogeneous and partly contradicts the present guidelines.

Uterocervical angle as a predictor of preterm birth on a high-risk collective between 20 and 31 weeks of gestation: A cohort analysis.

INTRODUCTION: The cervical length (CL) measurement is a widely used method to estimate the risk of preterm birth. Due in particular to the high false-positive rate, the establishment of markers with improved test characteristics is a great challenge. A potential predictor of preterm birth is the uterocervical angle (UCA) and this additional measurement may improve the risk assessment. It was the aim of this study to compare the test properties of CL and UCA on patients at risk for preterm birth. MATERIAL AND METHODS: 109 patients with at least one of the following signs of threatening preterm birth between 20+0/7 and 31+6/7 weeks were included in a prospective cohort analysis: regular (>3/30 min) or painful uterine contractions, CL below 25 mm or a history of preterm birth. Exclusion criteria were premature rupture of membranes, hypertensive disorders, vaginal bleeding, surgical cerclage, Arabin pessary or cervical dilation of more than 30 mm. The determination of the UCA was carried out in a standardized manner using the image documents captured by vaginal sonographic CL measurement. The primary endpoint was preterm birth <34 weeks, secondary endpoints were delivery <37 weeks and within 7 days. RESULTS: The UCA was on average 103° and the mean UCA in preterm and term groups did not differ significantly (P = .924). The UCA was not predictive for threatened preterm birth, even if only singletons were considered. For CL the best predictive accuracy for preterm birth <34 weeks was observed at a cut-off value of 14 mm with sensitivity 0.50, specificity 0.80, positive predictive value 0.30, negative predictive value 0.90, positive likelihood ratio 2.4, negative likelihood ratio 0.6 and an odds ratio of 3.9 (95% confidence interval 1.3-11.7, P = .016). CONCLUSIONS: The assessment of UCA in patients at risk for preterm birth was not suitable to predict the probability of a threatened preterm birth. Measurement of UCA cannot be recommended in this situation.

Post-Mastectomy Radiotherapy After Neoadjuvant Chemotherapy in Breast Cancer: A Pooled Retrospective Analysis of Three Prospective Randomized Trials.

BACKGROUND: The impact of locoregional radiotherapy (RT) after neoadjuvant chemotherapy (NACT) and mastectomy in breast cancer patients is currently unclear. Several publications have suggested that patients with a favorable response to NACT might not benefit from RT after mastectomy. METHODS: A retrospective analysis of three prospective randomized NACT trials was performed. Information on the use of RT was available for 817 breast cancer patients with non-inflammatory breast cancer who underwent mastectomy after NACT within the GeparTrio, GeparQuattro, and GeparQuinto-trials. RT was administered to 676 of these patients (82.7%). RESULTS: The 5-year cumulative incidence of locoregional recurrence (LRR) was 15.2% (95% confidence interval [CI] 9.0-22.8%) in patients treated without RT and 11.3% in patients treated with RT (95% CI 8.7-14.3%). In the multivariate analysis, RT was associated with a lower risk of LRR (hazard ratio 0.51, 95% CI 0.27-1.0; p = 0.05). This effect was shown especially in patients with cT3/4 tumors, as well as in patients who were cN+ before neoadjuvant therapy, including those who converted to ypN0 after neoadjuvant therapy. In the bivariate analysis, disease-free survival was significantly worse in patients who received RT, however this was not confirmed in the multivariate analysis. CONCLUSIONS: Our results suggest that RT reduces the LRR rates in breast cancer patients who receive a mastectomy after NACT without an improvement in DFS. Prospective randomized controlled trials such as the National Surgical Adjuvant Breast and Bowel Project B-51/RTOG 1304 trial will analyze whether RT has any benefit in patients who have a favorable response after NACT.

A randomized phase II study to determine the efficacy and tolerability of two doses of eribulin plus lapatinib in trastuzumab-pretreated patients with HER-2-positive metastatic breast cancer (E-VITA).

The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m (equivalent to 1.4 mg/m eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m (equivalent to 2.0 mg/m eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8-9.4] in the split-dose arm and 6.5 months (95% CI: 4.6-13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0-73.7) in the split-dose arm and 45.0% (95% CI: 23.2-66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1-90.8) and 75.0% (95% CI: 56.0-94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3-4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted.

Oncoplastic breast-conserving surgery: More relevant than ever? Results of a survey among breast surgeons.

PURPOSE: Oncoplastic breast-conserving surgery has been part of clinical routine for several years without an internationally accepted nomenclature, standardization or a systematic evaluation of single surgical procedures. METHODS: We carried out a structured survey of breast surgeons (n = 50) during the annual meeting of the German Society for Senology in Berlin 2017. In the run-up to the event, 10 questions were determined and released for an anonymous survey during the consensus meeting. RESULTS: Most surgeons participating in the consensus meeting had an expertise of more than 200 oncologic breast surgeries in the last 3 years and approved the need of a higher rate of standardization in oncoplastic techniques. From the oncological standpoint, oncoplastic surgery is considered safe with a comparable rate of compilations as seen in conventional breast-conserving procedures. Most surgeons approve that using oncoplastic surgery, higher rates of breast conservation and improved aesthetic results can be accomplished. The majority of the participants would endorse a more systematic review of subjective aesthetic results in clinical routine. CONCLUSIONS: A higher degree in standardization of oncoplastic breast surgery is required for surgical-technical, educational, and scientific reasons as well as for a more differentiated monetary compensation of the surgical procedures. This process has already been started.

Accuracy of immediate antepartum ultrasound estimated fetal weight and its impact on mode of delivery and outcome - a cohort analysis.

BACKGROUND: The aim of the study was to investigate the accuracy of ultrasound-derived estimated fetal weight (EFW) and to determine its impact on management and outcome of delivery. METHODS: In this single-center cohort analysis, women with a singleton term pregnancy in the beginning stages of labor were included. Women with immediately antepartum EFW (N = 492) were compared to women without ultrasound (N = 515). RESULTS: EFW was correct (deviation from birth weight ≤ 10%) in 72.2% (355/492) of patients with fetal biometry; 19.7% (97/492) were underestimated, and 8.1% (40/492) were overestimated. Newborns with a lower birth weight were more frequently overestimated, and newborns with higher birth weight were more frequently underestimated. The mean difference between EFW and real birth weight was - 114.5 g (standard deviation ±313 g, 95% confidence interval 87.1-142.0). The rate of non-reassuring fetal heart tracing (9.8% vs. 1.9%, P < 0.001) and of caesarean delivery (9.1% vs. 5.0%, P = 0.013) was higher in women with EFW. Overestimation was associated with an increased risk for delivery by caesarean section (odds ratio 2.80; 95% confidence interval 1.2-6.5, P = 0.017). After adjustment, EFW remained associated with increased non-reassuring fetal heart tracing (odds ratio 4.73; 95% confidence interval 2.3-9.6) and caesarean delivery (odds ratio 1.86; 95% confidence interval 1.1-3.1). The incidence of perineal tears of grade 3/4, shoulder dystocia, postnatal depression and neonatal acidosis did not differ between groups. CONCLUSIONS: Antepartum ultrasound-derived EFW does not improve maternal and fetal outcome and is therefore not recommended.

First international consensus conference on standardization of oncoplastic breast conserving surgery.

PURPOSE: To obtain consensus recommendations for the standardization of oncoplastic breast conserving surgery (OPS) from an international panel of experts in breast surgery including delegates from the German, Austrian and Swiss societies of senology. METHODS: A total of 52 questions were addressed by electronic voting. The panel's recommendations were put into context with current evidence and the report was circled in an iterative open email process until consensus was obtained. RESULTS: The panelists considered OPS safe and effective for improving aesthetic outcomes and broadening the indication for breast conserving surgery (BCS) towards larger tumors. A slim majority believed that OPS reduces the rate of positive margins; however, there was consensus that OPS is associated with an increased risk of complications compared to conventional BCS. The panel strongly endorsed patient-reported outcomes measurement, and recommended selected scales of the Breast-Q™-Breast Conserving Therapy Module for that purpose. The Clough bi-level classification was recommended for standard use in clinical practice for indicating, planning and performing OPS, and the Hoffmann classification for surgical reports and billing purposes. Mastopexy and reduction mammoplasty were the only two recognized OPS procedure categories supported by a majority of the panel. Finally, the experts unanimously supported the statement that every OPS procedure should be tailored to each individual patient. CONCLUSIONS: When implemented into clinical practice, the panel recommendations may improve safety and effectiveness of OPS. The attendees agreed that there is a need for prospective multicenter studies to optimize patient selection and for standardized criteria to qualify and accredit OPS training centers.

Efficacy and safety of nab-paclitaxel 125 mg/m2 and nab-paclitaxel 150 mg/m2 compared to paclitaxel in early high-risk breast cancer. Results from the neoadjuvant randomized GeparSepto study (GBG 69).

PURPOSE: The GeparSepto study demonstrated that the use of nab-paclitaxel instead of paclitaxel prior to anthracycline-based chemotherapy could lead to a significantly increased pCR rate, especially in the triple negative subpopulation. We report efficacy and safety for patients treated with two different doses of nab-paclitaxel in comparison to weekly solvent-formulated paclitaxel. METHODS: Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m2 (nP150) weekly, after study amendment 125 mg/m2 (nP125) weekly or solvent-based paclitaxel 80 mg/m2 (P80) weekly followed by epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 on day 1 for four 3-week cycles. RESULTS: 229 patients received nP150, 377 nP125. Baseline characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for hormone receptor status, HER2 status, and Ki67. Taxane treatment was discontinued in 26.8% (nP150), 16.6% (nP125), and 13.3% of (P80) patients, respectively. Median relative total dose intensity (mRTDI) based on 125 mg/m2 for nP was 103% with nP150, 95% with nP125, 99% with P80 before and 98% with P80 after the amendment. PSN grade 3-4 was observed in 14.5% of patients with nP150, 8.1% of patients with nP125 (p = 0.018), and 2.7% of patients with P80. Overall pCR before the amendment was 33.6% after nP150 and 23.5% after P80 (OR 1.65 [95% CI 1.10-2.50]; p = 0.022); pCR after the amendment was 41.4% after nP125, and 32.4% after P80 (1.48 [95% CI 1.10-1.99]; p = 0.013). CONCLUSIONS: Nab-paclitaxel 125 mg/m2 was associated with a better safety profile and compliance without compromising the efficacy compared to nab-paclitaxel 150 mg/m2.

Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial.

BACKGROUND: In metastatic breast cancer, nab-paclitaxel has been shown to significantly increase progression-free survival compared with solvent-based paclitaxel. The GeparSepto (GBG 69) trial assessed whether weekly nab-paclitaxel could increase the proportion of patients achieving pathological complete response compared with weekly solvent-based paclitaxel, both followed by epirubicin plus cyclophosphamide as neoadjuvant treatment. METHOD: In a phase 3 randomised trial, we enrolled patients with previously untreated unilateral or bilateral primary invasive breast cancer and randomly assigned them in a 1:1 ratio using dynamic allocation and Pocock minimisation by breast cancer subtype, Ki67 and SPARC expression. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m(2) (after study amendment, 125 mg/m(2)) on days 1, 8, and 15 for four 3-week cycles, or solvent-based intravenous paclitaxel 80 mg/m(2) on days 1, 8, and 15 for four 3-week cycles. Taxane treatment was followed in both groups by intravenous epirubicin 90 mg/m(2) plus intravenous cyclophosphamide 600 mg/m(2) on day 1 for four 3-week cycles. Patients with HER2-positive tumours received concurrent trastuzumab 6 mg/kg (loading dose 8 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) on day 1 of every 3-week cycle. Trastuzumab and pertuzumab were given every 3 weeks concomitantly with chemotherapy for all cycles. This report is the final analysis of the primary endpoint, pathological complete response (ypT0 ypN0), analysed for all patients who started treatment (modified intention to treat). We used a closed test procedure to test for non-inferiority, with the nab-paclitaxel group calculated as non-inferior to the solvent-based paclitaxel group if the lower 95% CI for the OR was above 0·858 (OR equivalent to pathological complete response [33%] minus a 10% non-inferiority margin [3·3%]; 29·7%). We planned to test for superiority only in case of a positive non-inferiority test, using an α of 0·05. Safety was assessed in all patients who received study drug. The trial is registered with ClinicalTrials.gov, number NCT01583426. FINDINGS: Between July 30, 2012, and Dec 23, 2013, we randomly assigned 1229 women, of whom 1206 started treatment (606 with nab-paclitaxel and 600 with solvent-based paclitaxel). The nab-paclitaxel dose was reduced after enrolment of 464 participants to 125 mg/m(2) due to increased treatment discontinuation and sensory neuropathy in this group. Pathological complete response occurred more frequently in the nab-paclitaxel group (233 [38%, 95% CI 35-42] patients) than in the solvent-based paclitaxel group (174 [29%, 25-33] patients; OR 1·53, 95% CI 1·20-1·95; unadjusted p=0·00065). The incidence of grade 3-4 anaemia (13 [2%] of 605 patients in the nab-paclitaxel group vs four [1%] of patients in the solvent-based paclitaxel group; p=0·048) and peripheral sensory neuropathy grade 3-4 (63 [10%] patients receiving any nab-paclitaxel dose; 31 [8%] of patients starting with 125 mg/m(2) and 32 [15%] of patients starting with 150 mg/m(2); vs 16 [3%] in the solvent-based paclitaxel group, p<0·001) was significantly higher for nab-paclitaxel than for solvent-based paclitaxel. Overall, 283 (23%) patients were noted to have at least one serious adverse event (based on study drug received), 156 (26%) in the nab-paclitaxel group and 127 (21%) in the solvent-based paclitaxel group (p=0·057). There were three deaths (during epirubicin plus cyclophosphamide treatment) in the nab-paclitaxel group (due to sepsis, diarrhoea, and accident unrelated to the trial) versus one in the solvent-based paclitaxel group (during paclitaxel treatment; cardiac failure). INTERPRETATION: Substituting solvent-based paclitaxel with nab-paclitaxel significantly increases the proportion of patients achieving a pathological complete response rate after anthracycline-based chemotherapy. These results might lead to an exchange of the preferred taxane, solvent-based paclitaxel, for nab-paclitaxel in therapy for primary breast cancer. FUNDING: Celgene, Roche.

SLCO1B1*5 polymorphism (rs4149056) is associated with chemotherapy-induced amenorrhea in premenopausal women with breast cancer: a prospective cohort study.

BACKGROUND: Because inheritance is recognized as playing a role in age at menarche and natural menopause, the development of chemotherapy-induced amenorrhea (CIA) might depend on inherited genetic factors; however, studies that explore such a correlation are few and have received scant attention. Given the importance of this topic we conducted a comprehensive genotype study in young women (≤45 years) with early-stage breast cancer. METHODS: Our approach tested the effect of variant polymorphisms in drug metabolism enzymes (DMEs) using a predesigned pharmacogenomics panel (TaqMan® OpenArray®, Life Technologies GmbH, Darmstadt, Germany) in premenopausal women (n = 50). Patients received contemporary chemotherapy; in all cases a cyclophosphamide-based regimen with a dose of at least 500 mg/m(2) for six cycles. CIA was considered to be present in women with no resumption of menstrual bleeding within 12 months after completion of chemotherapy or goserelin. RESULTS: Twenty-six patients (52 %) showed CIA during follow-up whereas 24 women (48 %) remained premenopausal. Of all the DMEs studied, only the SLCO1B1*5 (rs4149056) genotype was associated with the development of CIA (P = 0.017). Of the 26 patients who were homozygous for the T/T allele SLCO1B1*5, 18 (69.2 %) developed CIA compared with 8 (30.8 %) of the 22 patients who were heterozygous (C/T allele). The association of heterozygous SLCO1B1*5 allele (OR 0.038; 95%CI: 0.05-0.92) with a lower risk of developing CIA remained significant in a binary logistic regression analysis that include age, SLCO1B1*5 allele variants, and goserelin therapy. CONCLUSIONS: Patient age and SLCO1B1*5 allele variants predict the likelihood of young women with breast cancer developing CIA.

Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.

BACKGROUND: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. METHODS: We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. FINDINGS: We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). INTERPRETATION: Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. FUNDING: US Food and Drug Administration.

Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer. METHODS: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk. RESULTS: Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P=0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P=1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.).

Outcome after neoadjuvant chemotherapy in young breast cancer patients: a pooled analysis of individual patient data from eight prospectively randomized controlled trials.

Young women with breast cancer (BC) have a worse survival partly due to more aggressive tumor characteristics; however, their response to chemotherapy seems better. We investigated to what extent the prognostic factor pathological complete remission (pCR) after neoadjuvant chemotherapy is applicable to young women. 8949 patients with primary BC and follow-up from eight German neoadjuvant trials were included. A subgroup of 1453 patients <40 years was compared with women aged 40-49 and ≥50 years regarding pCR (ypT0 ypN0), as well as disease free survival (DFS), local recurrence free survival (LRFS), distant disease free survival (DDFS), and overall survival (OS) overall, according to pCR status and subtypes defined by hormone-receptor (HR) status and HER2. pCR was strongly associated with age without a clear age cut-off. The pCR rate was significantly higher in the young compared with other age groups (20.9 vs. 17.7 vs. 13.7 %; p < 0.001). This difference was confined to triple-negative breast cancer (TNBC) and HR +/HER2-. DFS, DDFS, LRFS, and OS were significantly worse for young women. Age was independently prognostic for survival in HR +/HER2-, with women <40 years without pCR having a worse DFS compared to their counterparts with pCR. Young women are more likely to achieve pCR after neoadjuvant chemotherapy, especially in HR +/HER2- and TNBC. Age is not an important prognostic factor in TNBC and HR-/HER2 + but is in HR +/HER2-. Young women with a luminal-like BC seem to benefit more from neoadjuvant chemotherapy than older women, which needs to be taken into account.

Impact of body mass index on neoadjuvant treatment outcome: a pooled analysis of eight prospective neoadjuvant breast cancer trials.

Obesity is associated with an increased risk of breast cancer (BC) and poorer outcome. We assessed the impact of body mass index (BMI) on pathological complete response (pCR), disease-free (DFS), and overall survival (OS), according to BC subtypes in patients with primary BC treated with neoadjuvant chemotherapy. 8,872 patients with primary BC from eight neoadjuvant trials were categorized according to BMI: underweight (<18.5 kg/m(2)), normal weight (18.5 to <25 kg/m(2)), overweight (25 to <30 kg/m(2)), obese (30 to <40 kg/m(2)), and very obese (≥40 kg/m(2)). BC subtypes were defined as luminal-like (ER/PgR-positive and HER2-negative), HER2/luminal (ER/PgR-positive and HER2-positive), HER2-like (ER/PgR-negative and HER2-positive), and triple-negative (TNBC; ER/PgR- and HER2-negative). pCR rate was higher in normal weight patients compared with all other BMI groups (P = 0.003). Mean DFS and OS were shorter in obese (87.3 months, P = 0.014 and 94.9 months, P = 0.001, respectively) and very obese (66.6 months, P < 0.001 and 75.3 months, P < 0.001, respectively) compared with normal weight patients (91.5 and 98.8 months, respectively) which was confirmed by subpopulation treatment effect pattern plot analyses and was consistent in luminal-like and TNBC. No interaction was observed between BMI and pCR. Normal weight patients experienced less non-hematological adverse events (P = 0.002) and were more likely to receive full taxane doses (P < 0.001) compared with all other BMI groups. In multivariable analysis, the dose of taxanes was predictive for pCR (P < 0.001). Higher BMI was associated with lower pCR and a detrimental impact on survival. Normal weight patients had the best compliance to chemotherapy and received the highest taxane doses, which seems to be related with treatment outcomes.

Impact of multifocal or multicentric disease on surgery and locoregional, distant and overall survival of 6,134 breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: The impact of tumor focality on type of surgery, local recurrence rate, and survival after neoadjuvant chemotherapy (NACT) for breast cancer is not fully understood. This study aimed to compare local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) according to focality stratified by type of surgery and pathologic complete response (pCR), with a focus on breast conservation. METHODS: Participants (n = 6,134) in the GeparTrio, GeparQuattro, and GeparQuinto trials with operable or locally advanced tumors receiving NACT were classified as having unifocal (1 lesion), multifocal (≥ 2 lesions in 1 quadrant), or multicentric (≥ 1 lesion in ≥ 2 quadrants) disease. The study investigated LRFS, DFS, and OS according to focality stratified by type of surgery and pathologic complete response. RESULTS: The patients were classified as having unifocal (n = 4,733, 77.1 %), multifocal (n = 820, 13.4 %), or multicentric (n = 581, 9.5 %) tumors. The respective pCR rates were 19.4, 16.5, and 14.4 %. Breast conservation was performed for 71.6, 58.5, and 30 % of these patients, respectively (P < 0.001). The LRFS rate was 92.9 % for the unifocal, 95.1 % for the multifocal, and 90.4 % for the multicentric tumors (P = 0.002). The patients with multicentric tumors but not the patients with multifocal tumors had worse DFS (P < 0.001) and OS (P = 0.009) than the patients with unifocal tumors. However, LRFS, DFS, and OS were not inferior for the patients with multicentric or multifocal tumors if pCR was achieved or breast conservation was performed after NACT. CONCLUSION: Breast conservation is feasible for clinically multifocal or multicentric breast cancer patients who undergo NACT without worsening LRFS if tumor-free margins can be attained or if patients achieve a pCR.

Non-invasive spectroscopic determination of the antioxidative status of gravidae and neonates.

Pregnancy and postpartum adaptation cause an increased formation of free radicals. This is associated with various perinatological diseases, e.g. necrotising enterocolitis. The human body has developed a protective system in the form of the antioxidative potential. The present study was the first to investigate the kinetics of the cutaneous antioxidative status in pregnant women and newborns using a non-invasive spectroscopic method. Eighteen pregnant women and their babies took part in the study. A light-emitting diode-based compact scanner system was used for quick non-invasive measurements of carotenoid antioxidants in human skin based on reflection spectroscopy. It could be shown that the antioxidative status of the expectant mothers significantly declined during labour (p < 0.001) and on day 1 after delivery (p < 0.01). Compared to the mothers, the newborns exhibited a significantly higher cutaneous carotenoid concentration on both day 1 (p < 0.01) and 5 (p < 0.01) after delivery. These results suggest that the oxidative stress due to postpartum adaptation is counteracted by an enhanced reservoir of carotenoid antioxidants in the subcutaneous fatty tissue. The peripartum cutaneous carotenoid level of mothers declines continuously, whereas term newborns show very high cutaneous antioxidant values.

Biocompatibility, cell growth and clinical relevance of synthetic meshes and biological matrixes for internal support in implant-based breast reconstruction.

PURPOSE: Biological matrixes and synthetic meshes are increasingly used in implant-based breast reconstruction (IBBR). The objective was to test different materials used for internal support in IBBR in regards to biocompatibility and discuss possible limitations in a clinical context. MATERIALS AND METHODS: In vitro investigations were performed on four relevant cell lines: Normal Human Dermal Fibroblasts (NHDF), Human White Preadipocytes (HWP), Endothelial cells (HDMEC) and Skeletal muscle cells (SkMC). A titanium-coated polypropylene mesh (TiLOOP Bra), a partially resorbable mesh (SERAGYN BR) and a porcine derived biologic matrix (Strattice) were investigated. Test of cytotoxicity, cell proliferation and oxidative stress was performed. Real-time cell analysis was used to determine adhesion rate. Light- and scanning electron microscopy investigated cell migration. RESULTS: No relevant cytotoxicity was detected for any mesh or matrix. Good cell proliferation was observed in all materials with best results for NHDF and SkMC. For HWP and HDMEC decreased proliferation and adherence to the synthetic meshes and biologic matrix were observed. Real-time cell analysis of fibroblasts incubated with the corresponding material, showed increased impedance for the synthetic meshes. A morphologic cell change was observed within all materials. Scanning electron microscopy showed good cell penetration into the meshes and matrix. The material compositions did not seem to influence the clinical outcome, although the biological matrix was much thicker compared to the synthetic meshes. CONCLUSION: Biochemical examination showed good biocompatibility for the investigated meshes and matrix. All products seem to have their value in IBBR and can be recommended for IBBR.