Luisenkrankenhaus

Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

PURPOSE: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer, with mutations in PIK3CA being the most common. This study investigated the association between PIK3CA genotype and pathologic complete response (pCR) rates in human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with either dual or single anti-HER2 treatment in addition to neoadjuvant chemotherapy. PATIENTS AND METHODS: PIK3CA mutations in 504 tumor samples from participants in the neoadjuvant GeparQuattro, GeparQuinto, and GeparSixto studies were evaluated. All HER2-positive patients received either trastuzumab or lapatinib or the combination plus anthracycline-taxane chemotherapy. PIK3CA mutations were evaluated in formalin-fixed, paraffin-embedded tissues from core biopsies with a tumor cell content of ≥ 20% by using classical Sanger sequencing of exon 9 and exon 20. RESULTS: Overall, 21.4% of the patients harbored a PIK3CA mutation. Detection of a PIK3CA mutation was significantly associated with a lower pCR rate (19.4% with PIK3CA mutation v 32.8% with PIK3CA wild-type; odds ratio [OR], 0.49; 95% CI, 0.29 to 0.83; P = .008). In the 291 hormone receptor (HR) -positive tumors, pCR rate was 11.3% with a PIK3CA mutation compared with 27.5% with PIK3CA wild-type (OR, 0.34; 95% CI, 0.15 to 0.78; P = .011). In 213 patients with HR-negative tumors, pCR rate was 30.4% with PIK3CA mutation and 40.1% without (OR, 0.65; 95% CI, 0.32 to 1.32; P = .233; interaction test P = .292). In multivariable analysis, HR status and PIK3CA status provided independent predictive information. In patients with PIK3CA mutation, the pCR rates were 16%, 24.3%, and 17.4% with lapatinib, trastuzumab, and the combination, respectively (P = .654) and in the wild-type group, they were 18.2%, 33.%, and 37.1%, respectively (P = .017). Disease-free survival and overall survival were not statistically significantly different between patients with mutant and wild-type PIK3CA. CONCLUSION: HER2-positive breast carcinomas with a PIK3CA mutation are less likely to achieve a pCR after neoadjuvant anthracycline-taxane-based chemotherapy plus anti-HER2 treatment, even if a dual anti-HER2 treatment is given.

PURPOSE: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. EXPERIMENTAL DESIGN: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS. RESULTS: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR. CONCLUSIONS: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747-54. ©2016 AACR.

Abstract Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy. Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.

<b>Aim:</b> Breast reconstruction has become increasingly important for the body image of women with breast cancer. We conducted a study to investigate how patient characteristics correlate with surgical outcome after breast reconstruction with implant after mastectomy and to identify risk factors which could facilitate patient selection for reconstruction. <b>Patients and Methods:</b> For this case cohort analysis (n = 257 patients with 318 heterologous reconstructions), we analyzed BMI, smoking, pre-existing disease, chemotherapy and radiotherapy, one-stage/two-stage reconstruction, immediate/delayed reconstruction, antibiotic therapy and complications, partner interaction and adherence to the decision for reconstruction using a customized questionnaire. <b>Results:</b> 257 patients with 318 implant reconstructions (196 unilateral, 61 bilateral) were eligible for inclusion in the study. Median follow-up time was 3.1 years (range: 1 month to 10 years). Response rate to the questionnaire was 71.8 %. Median age was 49 years (range 24–79 years), median BMI was 22.44 (range 16.33–40.09). A BMI > 30 was inversely correlated with positive self-image (p = 0.004), and implant loss/rotation was more frequent in this group (p < 0.05). Smoking > 10 cigarettes/day had a negative impact on surgical outcome. A positive self-image had a positive impact on partner interaction (p < 0.001) and was correlated with a lower perception of pain. Aesthetic results did not vary with age (p = 0.054). Titanized polypropylene meshes were used to protect against implant rotation (p = 0.034). Rates of capsular fibrosis were low in our cohort (< 10 %), and implant loss rate was less than 2 %. <b>Conclusions: </b>This study offers a differentiated approach for the pre-surgical counselling of patients and shows that patients up to 80 years of age are highly satisfied with implant reconstruction. A high BMI and smoking > 10 cigarettes/day are unfavorable preconditions for implant reconstruction. The use of prophylactic antibiotics was confirmed as beneficial for surgical outcome. A positive self-image after reconstruction strongly influences partner interaction.

BACKGROUND: The main study objectives were: to establish a nationwide voluntary collaborative network of breast centres with independent data analysis; to define suitable quality indicators (QIs) for benchmarking the quality of breast cancer (BC) care; to demonstrate existing differences in BC care quality; and to show that BC care quality improved with benchmarking from 2003 to 2007. METHODS: BC centres participated voluntarily in a scientific benchmarking procedure. A generic XML-based data set was developed and used for data collection. Nine guideline-based quality targets serving as rate-based QIs were initially defined, reviewed annually and modified or expanded accordingly. QI changes over time were analysed descriptively. RESULTS: During 2003-2007, respective increases in participating breast centres and postoperatively confirmed BCs were from 59 to 220 and from 5,994 to 31,656 (> 60% of new BCs/year in Germany). Starting from 9 process QIs, 12 QIs were developed by 2007 as surrogates for long-term outcome. Results for most QIs increased. From 2003 to 2007, the most notable increases seen were for preoperative histological confirmation of diagnosis (58% (in 2003) to 88% (in 2007)), appropriate endocrine therapy in hormone receptor-positive patients (27 to 93%), appropriate radiotherapy after breast-conserving therapy (20 to 79%) and appropriate radiotherapy after mastectomy (8 to 65%). CONCLUSION: Nationwide external benchmarking of BC care is feasible and successful. The benchmarking system described allows both comparisons among participating institutions as well as the tracking of changes in average quality of care over time for the network as a whole. Marked QI increases indicate improved quality of BC care.

OBJECTIVE: The 21-gene assay (Oncotype DX Breast Cancer Test (Genomic Health Inc., Redwood City, CA)) is a well validated test that predicts the likelihood of adjuvant chemotherapy benefit and the 10-year risk of distant recurrence in patients with ER+, HER2- early-stage breast cancer. The aim of this analysis was to evaluate the cost-effectiveness of using the assay to inform adjuvant chemotherapy decisions in Germany. METHODS: A Markov model was developed to make long-term projections of distant recurrence, survival, quality-adjusted life expectancy, and direct costs for patients with ER+, HER2-, node-negative, or up to 3 node-positive early-stage breast cancer. Scenarios using conventional diagnostic procedures or the 21-gene assay to inform treatment recommendations for adjuvant chemotherapy were modeled based on a prospective, multi-center trial in 366 patients. Transition probabilities and risk adjustment were based on published landmark trials. Costs (2011 Euros (€)) were estimated from a sick fund perspective based on resource use in patients receiving chemotherapy. Future costs and clinical benefits were discounted at 3% annually. RESULTS: The 21-gene assay was projected to increase mean life expectancy by 0.06 years and quality-adjusted life expectancy by 0.06 quality-adjusted life years (QALYs) compared with current clinical practice over a 30-year time horizon. Clinical benefits were driven by optimized allocation of adjuvant chemotherapy. Costs from a healthcare payer perspective were lower with the 21-gene assay by ∼€561 vs standard of care. Probabilistic sensitivity analysis indicated that there was an 87% probability that the 21-gene assay would be dominant (cost and life saving) to standard of care. LIMITATIONS: Country-specific data on the risk of distant recurrence and quality-of-life were not available. CONCLUSIONS: Guiding decision-making on adjuvant chemotherapy using the 21-gene assay was projected to improve survival, quality-adjusted life expectancy, and be cost saving vs the current standard of care women with ER+, HER2- early-stage breast cancer.

The detection of deleterious germline mutations in BRCA1 and BRCA2 considerably influences the clinical management of healthy and diseased carriers. Therefore, the identification of persons at risk who could uptake genetic counseling and testing is pivotal. We developed a checklist with validated criteria to improve the identification, and prospectively evaluate the incidence, of familial cancer history in 5091 breast cancer patients. The rate of 30.4% of patients at high genetic risk underpins the demand for care in risk identification and counseling. The easy-to-use instrument promotes the implementation and dissemination of risk counseling by physicians.

BACKGROUND: The First International Breast (Implant) Conference was held by the EAoS® (European Academy of Senology) in cooperation with the German Society of Senology during its 29th annual meeting in Düsseldorf, Germany, on 13 June 2009. METHODS: It was performed as a whole-day interactive workshop in which the standards of implant surgery within reconstructive and aesthetic breast surgery were discussed and defined by telecommunication dialogue voting. RESULTS: This article describes the conference results concerning pre- and post-procedural imaging in patients with breast implants. Both before and after augmentation, imaging is mandatory and provides essential information concerning tissue and implant integrity. Whereas mammography is the first-line method before surgery, ultrasound is the mainstay of post-procedural imaging. Cancer screening in augmented breasts generally follows the same guidelines as for non-augmented breasts. CONCLUSION: Whereas agreement about the indications for mammographical and sonographical evaluations is largely unanimous, there was substantial disagreement as far as the application of magnetic resonance imaging is concerned. There is an obvious demand for an evidence-based evaluation of this modality and the implementation of appropriate guidelines.

INTRODUCTION: Functional and aesthetic outcome after breast-conserving surgery are vital endpoints for patients with primary breast cancer. A large variety of oncoplastic techniques exist; however, it remains unclear which techniques yield the highest rates of local control at first surgery, omission of reexcision or subsequent mastectomy, and merits the highest degree of patient satisfaction. METHODS: In this retrospective case cohort trial with a customized investigational questionnaire for assessment of patient satisfaction with the surgical result, we analyzed 1,035 patients with primary, unilateral breast cancer and oncoplastic surgery from 2004 to 2009. RESULTS: Analysis of patient reported outcome (PRO) revealed that 88 % of the cohort was satisfied with their aesthetic result using oncoplastic techniques following the concept presented. These results also were achieved in difficult tumor localizations, such as upper inner and lower inner quadrant. Conversion rate from breast-conserving therapy to secondary mastectomy was low at 7.2 % (n = 68/944 patients). The systematization of oncoplastic techniques presented-embedded in a multimodal concept of breast cancer therapy-facilitates tumor control with a few number of uncomplicated techniques adapted to tumor site and size with a median resection of 32 (range 11-793) g. Five-year recurrence rate in our cohort was 4.0 %. CONCLUSIONS: Patient's satisfaction was independent from age, body mass index, resection volume, tumor localization, and type of oncoplastic surgery (p > 0.05). We identified postoperative pain as an important negative impact factor on patient's satisfaction with the aesthetic result (p = 0.0001).

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.

INTRODUCTION: Breast conservation is a legacy of Umberto Veronesi who laid the groundwork for the preservation of the body image of women affected by breast cancer (BC) with the Milan I study in the late 70ies of the last millennium. Breast conservative surgery (BCS) has two aspects: oncological safety of tumour resection with free margins and aesthetic preservation of the breast. Determinants of local control used to be T-size, nodal status and receptor status until biologically driven concepts defined risk of recurrence on the basis of molecular portraits. We explored whether these concepts of intrinsic subtypes prove at a large scale in the context of BCS and which surgical techniques procure best oncological and aesthetic outcomes, avoiding re-excision and necessity of conversion to mastectomy. PATIENTS AND METHODS: We analyzed 1035 BCS patients with primary unilateral breast cancer (2004-2009) with regards to the local recurrence as a function of tumour location, surgical technique, resection volume, T-size, nodal status, grading, histopathological and intrinsic subtype and margins. RESULTS: Five surgical techniques were applied to 944 eligible patients at a median follow-up of 5.2 years with the following frequency: Glandular rotation mammoplasty (63.8%), tumour-adapted rotation mammoplasty (20.9%), dermoglandular rotation mammoplasty (6.7%), 4.4% (lateral thoracic wall advancement), 0.7% latissimus dorsi flap (0.7%) and others (13.5%). Tumour-free margins were achieved in 88.6% of all patients at first surgery. Recurrence was independent of the surgical technique used, resection volume, T-size (in a T1/T2-cohort), nodal status (in low N-stages: NO/N1) and histopathology (inv.-ductal vs. lobular), however non-invasive subtype (DCIS), high grading (G3 vs. G1), non-luminal Her2 positive BC and triple-negative breast cancer (TNBC) were significantly associated with local recurrence. CONCLUSIONS: Five defined oncoplastic principles presented in our nomogramme (targeted breast surgery) allow the reconstruction of major segmental resection defects during breast-conserving therapy with high clinical applicability and result in favorable oncological and aesthetic outcome. Recurrence was not a function of traditional prognostic factors like T-size or nodal status (in a T1/T2, N0/N1 cohort), but of grading, intrinsic subtypes and non-invasive breast cancer components. Lobular histology, multi-centricity and DCIS were predictive for breast preservation failure and conversion to mastectomy.

Abstract Background: Recent trials have provided evidence that obesity and a low level of physical activity are not only associated with a higher risk of developing breast cancer, but also with an increased risk for recurrence and reduced survival in breast cancer patients (pts). The SUCCESS C study is the first randomized Phase III trial to evaluate the effect of an intensive lifestyle intervention program, focusing on both physical activity and healthy diet following adjuvant chemotherapy on disease-free survival in women with early breast cancer. Methods: SUCCESS C is a German multicenter, 2×2 factorial design, randomized phase III study comparing disease-free survival (DFS) in pts with HER2-negative early breast cancer treated with either 3 cycles of epirubicine, fluorouracil, cyclophosphamide chemotherapy followed by 3 cycles of docetaxel (FEC-D) or 6 cycles of docetaxel-cyclophosphamide (DC). The second randomization compares DFS in pts with a body mass index (BMI) of 24—40 kg/m2 receiving either a telephone-based individualized lifestyle intervention (LI) program aiming at moderate weight loss for 2 years (LI arm) or general recommendations for a healthy lifestyle alone (non-LI arm). DFS according to lifestyle intervention was analyzed using both univariable cox regressions and multivariable cox regressions adjusted for age (years, continuous), BMI (kg/m2, continuous), menopausal status (premenopausal, postmenopausal), tumor size (pT1, pT2, pT3/pT4), nodal stage (pN0, pN1, pN2, pN3), hormone receptor status (positive, negative), grading (G1, G2, G3), histological type (ductal, lobular, other) and chemotherapy randomization (FEC-D, DC). Median follow-up was 64.2 months. Results: Overall, 2292 of the 3643 pts recruited for the SUCCESS C study were randomized for the lifestyle intervention program (1146 pts in both the non-LI arm and the LI arm). The Intention-to-treat analysis revealed no difference in DFS between the two treatment arms (LI vs. non-LI) in univariable analysis (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.76 — 1.28, p = 0.922) and in adjusted multivariable cox regression (HR 0.91, 95% CI 0.70 — 1.18, p = 0.48). At the 2-year follow up, pts in the LI arm lost on average 1.0 kg weight compared to the start of the LI program, while pts in the non-LI arm gained on average 0.95 kg (p &amp;lt; 0.001). Overall, 1477 pts completed the 2-year LI program (non-LI arm: 80.7%, 925 of 1146 pts; LI arm: 48.2%, 552 of 1146 pts; p &amp;lt; 0.001). Pts that completed the 2-year LI program had a significant better DFS than non-completers (HR 0.35, 95% CI 0.27 — 0.45, p &amp;lt; 0.001). Among completers, pts in the LI arm had a significantly better DFS than pts in the non-LI arm both in univariable analysis (HR 0.53, 95% CI 0.35 — 0.82, p = 0.004) and in adjusted multivariable cox regression (HR 0.51, 95% CI 0.33 — 0.78, p = 0.002). Conclusions: This explorative and non-planned interim analysis indicates that the completion of a systematic telephone life style intervention program may positively impact patient outcome in early breast cancer. Citation Format: Janni W, Rack BK, Friedl TW, Müller V, Lorenz R, Rezai M, Tesch H, Heinrich G, Andergassen U, Harbeck N, Schochter F, De Gregorio A, Tzschaschel M, Huober J, Hepp P, Fehm TN, Schneeweiss A, Lichtenegger W, Blohmer J, Hauner D, Beckmann MW, Häberle L, Fasching PA, Hauner H. Lifestyle Intervention and Effect on Disease-free Survival in Early Breast Cancer Pts: Interim Analysis from the Randomized SUCCESS C Study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-03.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. METHODS: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1-3c (modified to stage 2-3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. RESULTS: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72-2.50; P = 0.357). Neratinib's effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17-0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36-1.41; P = 0.34). The interaction test was non-significant (P = 0.309). CONCLUSIONS: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

BACKGROUND: Breast cancer patients often use complementary and alternative medicine, but few prospectively collected data on the topic are available specifically for postmenopausal breast cancer patients. A large prospective study was therefore conducted within a noninterventional study in order to identify the characteristics of patients interested in integrative medicine. METHODS: The EvAluate-TM study is a prospective, multicenter noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive primary breast cancer. Between 2008 and 2009, 5045 postmenopausal patients were enrolled at 339 certified breast centers in Germany. As part of the data collection process, patients were asked at the baseline about their interest in and information needs relating to integrative medicine. RESULTS: Of the 5045 patients recruited, 3411 responded to the questionnaire on integrative medicine and took part in the analysis, 1583 patients expressed an interest in integrative medicine, and 1828 patients declared no interest. Relevant predictors of interest in integrative medicine were age, body mass index, tumor size, previous chemotherapy, and use of concomitant medications for other medical conditions. Interest in integrative medicine declined highly significantly ( P < .001) with age (<50 years, 74.1%; 50-60 years, 54.1%; >65 years, 38.0%). Patients in favor of integrative medicine were significantly less satisfied with the information received about individual treatments and antihormonal therapy. Patients with interest in integrative medicine were more often interested in rehabilitation and fitness, nutritional counseling, and additional support from self-help organizations. These women were mostly interested in receiving information about their disease and integrative medicine from a physician, rather than from other sources. CONCLUSIONS: This study shows that a considerable proportion of postmenopausal breast cancer patients are interested in integrative medicine. Information about integrative medicine should therefore be provided as part of patient care for this group. It was found that receiving concomitant medication for other medical conditions is one of the main predictors for women not being interested in integrative medicine. This group of patients may need special attention and individualized information about integrative medicine. Additionally, most patients were interested in obtaining the relevant information from their doctor.

508 Background: Neratinib (N) is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab (T) pre-treated HER2-positive (HER2+) metastatic breast cancer. In HER2+ early breast cancer (EBC), a significant proportion of patients (pts) recur with invasive disease despite T-containing adjuvant therapy. Methods: Women with stage 1–3c EBC with the last T dose ≤2y (later modified to stage 2–3c and ≤1y, respectively) and locally confirmed HER2+ were eligible. Pts were randomized to N 240mg PO once daily or placebo (P) for 12m, stratified by ER/PR, nodal status and T schedule. A global amendment reduced follow-up to 2y from study entry. A current amendment restores the original 5-y follow-up. Invasive DFS (IDFS) at 2y is the primary endpoint and other secondary endpoints include DFS + DCIS, distant DFS (DDFS), CNS incidence, and patient-reported outcomes. Overall survival (OS) is an event-driven secondary endpoint. Efficacy analyses were ITT using a stratified Cox model and log-rank test (1-sided α=0.025). Results: 2,821 pts were randomized between 07/2009 and 10/2011 (1,409 N; 1,412 P). Median time from last T was 4.4m N vs 4.7m P. Baseline characteristics were balanced between arms. Efficacy results are shown below. Pre-planned subset analyses showed a lower IDFS HR in ER/PR+ pts (n=1,616; HR=0.51 [0.33–0.77]) and in a centrally confirmed HER2+ cohort (HR=0.52 [0.34–0.79]). Diarrhea was the most common adverse event (AE) for N pts with 40% G3 (1pt G4). Other individual AEs ≥G3 occurred in < 4% N pts. Ejection fraction decrease ≥G2 was seen in 1.3% N vs 1.1% P pts. Mean relative dose intensity (RDI) was 88% in N vs 98% in P pts. Conclusions: ExteNET demonstrates that 12m of N following standard chemotherapy + T improves IDFS and DFS-DCIS at 2y in HER2+ EBC. Diarrhea, the most common AE, was manageable. Additional follow-up will allow assessment of 5-y IDFS and OS. ClinicalTrials.gov: NCT00878709. Clinical trial information: NCT00878709. Efficacy endpoint 2-y rate, % HR (95% CI) P-value (1-sided) stratified log rank N (n=1,409) P (n=1,412) IDFS 93.9 91.6 0.67 (0.50–0.91) 0.0046 DFS-DCIS 93.9 91.0 0.63 (0.46–0.84) 0.0009 DDFS 95.1 93.7 0.75 (0.53–1.05) 0.0447

Breast-conserving surgery combined with radiotherapy has become the treatment of choice for the majority of women presenting with primary breast cancer over the last 20 years. The extent of local excision remains a controversial issue in breast-conserving surgery. The wider the margins of clearance, the lower the risk of incomplete excision and thus of local recurrences, but the greater the amount of tissue removed, the higher the risk of visible deformity leading to an unacceptable cosmetic result. This clash of interests is most evident when attempting breast-conserving surgery in patients with smaller breast-tumor ratios. The widespread popularity of breast-conserving surgery has focused attention on new oncoplastic techniques that can avoid unacceptable cosmetic results. Partial mastectomy defects can be reconstructed by volume displacement, recruiting and transposing local glandular or dermoglandular flaps into the resection site, or by volume replacement, importing volume from elsewhere to replace the amount of tissue resected.

The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers ('average reader') was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.

Adult respiratory distress syndrome (ARDS) attributable to viral pneumonia is described mainly in immunodeficient persons. ARDS caused by human herpes virus 6 (HHV6) is extremely rare, and to our knowledge only 1 case has been reported in the literature. We present the case of a young woman who developed fatal pulmonary failure most probably attributable to HHV6 pneumonia.

PURPOSE: The aim of the current work was to clarify whether a preoperative lymphoscintigraphy (LSG) enhances staging accuracy of sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS: In a prospective, multicenter, randomized phase III trial, patients with cN0 early breast cancer or extensive/high-grade ductal carcinoma in situ planned for standard radioactive-labeled colloid LSG with subsequent SLNB were randomly assigned 1:1 to receive SLNB either with knowledge of the LSG findings or without. As the false-negative rate of SLNB correlates with the number of resected sentinel lymph nodes (SLNs), our primary end point was the mean number of histologically detected SLNs per patient. One thousand one hundred two evaluable patients were necessary to demonstrate noninferiority of SLNB without LSG. Stratified one-sided 95% CI for the difference (without LSG - with LSG) in the mean number of histologically detected SLNs had to be greater than -0.27 (10% noninferiority margin). Stratification was performed according to tumor focality and trial site. Additional predefined secondary end points (rates of node-positive patients and of completion axillary lymph node dissection) were analyzed to rule out differences in the reliable detection of nodal metastases. RESULTS: Between May 2014 and October 2015, 1,198 patients were randomly assigned in 23 German and Swiss breast centers. Modified intention-to-treat analysis (n = 1,163) showed a mean number of histologically detected SLNs of 2.21 with LSG and 2.26 without LSG (difference 0.05; stratified 95% CI, -0.18 to infinity), thus establishing noninferiority of omitting preoperative LSG. Secondary end points displayed no statistically significant differences. CONCLUSION: We show that SLNB is equally effective irrespective of the surgeon's knowledge of preoperative LSG results. SLNB without LSG will speed up the preoperative workflow and reduce cost.