Philip Hepp

Circulating Tumor Cells Predict Survival in Early Average-to-High Risk Breast Cancer Patients

Background Circulating tumor cells (CTCs) have been shown to predict reduced survival outcomes in metastatic breast cancer. Methods CTCs were analyzed in 2026 patients with early breast cancer before adjuvant chemotherapy and in 1492 patients after chemotherapy using the CellSearch System. After immuno-magnetic enrichment for cells expressing the epithelial-cell adhesion molecule, CTCs were defined as nucleated cells expressing cytokeratin and lacking CD45. The patients were followed for a median of 35 months (range = 0–54). Kaplan–Meier analyses and the log-rank test were used for survival analyses. All statistical tests were two-sided. Results Before chemotherapy, CTCs were detected in 21.5% of patients (n = 435 of 2026), with 19.6% (n = 136 of 692) of node-negative and 22.4% (n = 299 of 1334) of node-positive patients showing CTCs (P < .001). No association was found with tumor size, grading, or hormone receptor status. After chemotherapy, 22.1% of patients (n = 330 of 1493) were CTC positive. The presence of CTCs was associated with poor disease-free survival (DFS; P < .0001), distant DFS (P < .001), breast cancer-specific survival (P = .008), and overall survival (OS; P = .0002). CTCs were confirmed as independent prognostic markers in multivariable analysis for DFS (hazard ratio [HR] = 2.11; 95% confidence interval [CI] = 1.49 to 2.99; P < .0001) and OS (HR = 2.18; 95% CI = 1.32 to 3.59; P = .002). The prognosis was worst in patients with at least five CTCs per 30mL blood (DFS: HR = 4.51, 95% CI = 2.59 to 7.86; OS: HR = 3.60, 95% CI = 1.56 to 8.45). The presence of persisting CTCs after chemotherapy showed a negative influence on DFS (HR = 1.12; 95% CI = 1.02 to 1.25; P = .02) and on OS (HR = 1.16; 95% CI = 0.99 to 1.37; P = .06) Conclusions These results suggest the independent prognostic relevance of CTCs both before and after adjuvant chemotherapy in a large prospective trial of patients with primary breast cancer.

Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients

Significance The infrequent detection of circulating tumor cells (CTCs) has hindered their clinical implication and their potential use in the sense of a “liquid biopsy” for cancer diagnosis and therapy. Hypothesizing that the limited blood volume commonly used for CTC analysis (1–10 mL) accounts for variable detection rates, we used leukapheresis to screen large blood volumes for CTCs. This enabled a more reliable detection of CTCs at high frequency even in nonmetastatic cancer patients. Thus, diagnostic leukapheresis may facilitate the routine clinical use of CTCs as biomarkers for personalized medicine. Combined with technologies for single-cell molecular genetics or cell biology, it may significantly improve prediction of therapy response and monitoring, especially in early systemic cancer. Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and therapy in systemic cancer. However, their infrequent and unreliable detection, especially in nonmetastatic cancer, currently impedes the clinical use of CTCs. Because leukapheresis (LA) targets peripheral blood mononuclear cells, which have a similar density to CTCs, and usually involves processing the whole circulating blood, we tested whether LA could substantially increase CTC detection in operable cancer patients. Therefore, we screened LA products generated from up to 25 L of blood per patient in two independent studies, and found that CTCs can be detected in more than 90% of nonmetastatic breast cancer patients. Interestingly, complete white blood cell sampling enabled determining an upper level for total CTC numbers of about 100,000 cells (median, 7,500 CTCs) per patient and identified a correlation of CTC numbers with anatomic disease spread. We further show that diagnostic leukapheresis can be easily combined with the US Food and Drug Administration-approved CellSearch system for standardized enumeration of CTCs. Direct comparison with 7.5 mL of blood revealed a significantly higher CTC frequency in matched LA samples. Finally, genomic single-cell profiling disclosed highly aberrant CTCs as therapy-escaping variants in breast cancer. In conclusion, LA is a clinically safe method that enabled a reliable detection of CTCs at high frequency even in nonmetastatic cancer patients, and might facilitate the routine clinical use of CTCs as in the sense of a liquid biopsy. Combined with technologies for single-cell molecular genetics or cell biology, it may significantly improve prediction of therapy response and monitoring of early systemic cancer.

Adjuvant aromatase inhibitor therapy: Outcomes and safety

Adjuvant therapy with the third-generation aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane has largely replaced the use of tamoxifen (TAM) as standard adjuvant endocrine treatment for postmenopausal women with hormone-sensitive early breast cancer. Treatment strategies investigated in large, randomized, well-controlled clinical studies include the use of an AI as an upfront replacement for TAM, as an alternative to continued treatment with TAM, and in the extended adjuvant setting after at least 5 years of TAM. The efficacy of AIs over TAM has been demonstrated, particularly in terms of improving disease-free survival (DFS), and reductions in early distant metastasis with AIs may ultimately translate into improved overall survival. As AI therapy offers prolonged DFS, safety is an important concern over the long term. The AIs are better tolerated than TAM in terms of troublesome gynecologic adverse events such as vaginal bleeding and discharge, as well as life-threatening complications such as venous thromboembolic events and endometrial cancer. On the other hand, AI therapy has been associated with losses in bone density and a potential effect on lipids and cardiovascular risk. In trials comparing AIs with TAM, only limited conclusions can be made because of the putative cardioprotective, lipid-lowering, and bone-sparing effects of TAM. Studies comparing AIs with placebo, and/or in healthy women, may be more useful in understanding the long-term safety of adjuvant AI therapy. Results of ongoing safety analyses within some of the large AI trials should provide further insight into the long-term tolerability of AI therapy in the adjuvant setting.

The German SUCCESS C Study - The First European Lifestyle Study on Breast Cancer.

Cohort trials have shown 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. The SUCCESS C study is the first European trial to evaluate the effect of an intensive lifestyle intervention program on disease-free survival in women with early breast cancer and to examine the predictive value of selected biomarker candidates. A total of 3,547 women with early-stage, Her2/neu-negative breast cancer will be included. The first randomization will compare disease-free survival in patients treated with either 3 cycles of FEC (epirubicine, fluorouracil, cyclophosphamide), followed by 3 cycles of docetaxel or 6 cycles of docetaxel-cyclophosphamide, and thus assess the role of anthracycline-free chemotherapy. The second randomization compares disease-free survival in patients with a body mass index of 24–40 kg/m2 receiving either a telephone-based individualized lifestyle intervention program aiming at moderate weight loss or general recommendations for a healthy lifestyle alone. In addition, the study will evaluate the predictive role of cancer-associated and obesity-related biomarkers for the prediction of disease recurrence and survival. This SUCCESS C trial will provide valuable information on the effects of a lifestyle intervention program on the prognosis of early breast cancer patients.

Toxicity Analysis in the ADEBAR Trial: Sequential Anthracycline-Taxane Therapy Compared with FEC120 for the Adjuvant Treatment of High-Risk Breast Cancer.

Background: Data from meta-analyses have shown taxane-containing therapies to be superior to anthracycline-based treatments for high-risk breast cancer. Patients and Methods: The ADEBAR trial was a multicenter phase III trial in which patients with lymph node-positive breast cancer were prospectively randomized for either sequential anthracycline-taxane or FEC120 therapy. Patients received 4× epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (q3w), followed by 4× docetaxel (100 mg/m2) q3w (EC-Doc arm), or 6× epirubicin (60 mg/m2) and 5-fluorouracil (500 mg/m2) on days 1 and 8 and cyclophosphamide (75 mg/m2) on days 1–14, q4w (FEC arm). We compared both arms with respect to toxicity and feasibility. Results: Hematological toxicity was found significantly more often in the FEC arm. Febrile neutropenia was seen in 11.3% of patients in the FEC arm and in 8.4% of patients in the EC-Doc arm (p = 0.027). Non-hematological side effects of grade 3/4 were rarely seen in either arm. Therapy was terminated due to toxicity in 3.7% of the patients in the EC-Doc arm and in 8.0% of the patients in the FEC arm (p = 0.0009). Conclusion: The sequential anthracycline-taxane regimen is a well-tolerated and feasible alternative to FEC120 therapy.

Sequential Treatment with Epirubicin/Cyclophosphamide, Followed by Docetaxel Is Equieffective, but Less Toxic Than FEC120 in the Adjuvant Treatment of Breast Cancer Patients with Extensive Lymph Node Involvement: The German ADEBAR Phase III Study.

Background: Based on meta-analytic evidence, taxane containing adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. However, in the MA-21 study, adriamycin-cyclophosphamide, followed by paclitaxel (AC-P) was significantly inferior to the gold standard of anthracycline treatment, FEC 120 (Burnell, SABCS 2006). We prospectively compared a sequential epirubicin-docetaxel chemotherapy regimen to FEC 120 . Patients and Methods: The ADEBAR study was a multicenter phase III trial (n=1502) to evaluate whether breast cancer (BC) pts with > 3 axillary lymph node metastases benefit from a sequential anthracycline-docetaxel regimen (E 90 C–D: 4 cycles epirubicin [E] 90 mg/m 2 plus cyclophosphamide [C] 600 mg/m 2 q21 days followed by 4 cycles docetaxel [D] 100mg/m 2 q21 days) compared to dose-intensive anthracycline-containing polychemotherapy (FE 120 C: 6 cycles E 60 mg/m² d 1+8, 5-FU 500mg/m² d 1+8 and C 75 mg/m² d 1-14, q4 weeks). The median follow-up time was 47 mts.(range 2-83 mts). Results: Treatment was stopped prematurely in 3.7% of the pts in the E 90 C–D arm and in 8.0% in the FE 120 C arm due to toxicity (p=0.0009). Antibiotic treatment was given in 10.4% (E 90 C–D) vs. 19.7% (FE 120 C), G-CSF support in 39.2% vs 61.4 % and erythropoietin stimulation in 8.7% vs. 20.0%, respectively (p 120 C-arm.At the time of the current analysis, 281 events of recurrence of breast cancer, were observed: 128 events in the FE 120 C group and 153 in the E 90 C–D group. The unadjusted hazard ratio (HR) was 0.88 (95 percent confidence interval, 0.694 to 1.115; p=0.2197, log-rank test). Overall survival in the two groups was not significantly different: (84 deaths with FE 120 C vs. 88 with E 90 C–D (HR 0.999, 0.738-1.352, p=0.99). Subgroup analyses, stratifying for tumor size, lymph node involvement, hormone receptor and HER2-neu status showed no significant difference between the two treatment arms. Conclusion: Different toxicity profiles given, hematological toxicity in the FE 120 C group was more severe than in the E 90 C–D.In contrast to AC-P in earlier studies, EC-Doc provides a feasible and effective alternative option to dose-intensified FEC with different saftey profile in this high risk breast cancer cohort. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 604.

DTCs in Breast Cancer: Clinical Research and Practice

Minimal residual disease (MRD), i.e., isolated tumor cells (ITC) in bone marrow, may be the source of potentially fatal overt distant metastases in solid tumors even years after primary treatment. MRD can be detected by immunohistochemical methods using antibodies directed against cytokeratins, cell-surface markers, or molecular PCR-based techniques. Among solid tumors, the clinical relevance of MRD has been most extensively studied in breast cancer patients. The highest level of evidence for the prognostic impact of MRD in primary breast cancer was reached by a pooled analysis comprising more than 4,000 patients, showing poor outcome in patients with MRD at primary therapy. Yet, clinical application of MRD detection is hampered by the lack of a standardized detection assay. Moreover, clinical trial results demonstrating the benefit of a therapeutic interference derived from bone marrow status are still missing. Recent results suggest that in addition to its prognostic impact, MRD can be used for therapy monitoring or as a potential therapeutic target after phenotyping of the tumor cells. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. In a pooled analysis bone marrow aspirates of 726 patients from academic breast cancer units in Oslo (n=356), Munich (n=228), and Tuebingen (n=142) were analyzed during recurrence-free follow-up at a mean interval of 31.7 months after primary diagnosis of breast cancer pT1-4, pN0-3 pM0. Persistent ITC was detected in 15.4% of the patients (n=112). The Kaplan-Meier estimate for mean distant relapse-free survival estimate was 163.6 months in patients with negative and 105.2 months in patients with positive BM status. Patients without evidence of persistent ITC had a significantly longer overall survival (165.6), than patients with positive bone marrow status (103.3 months, p < .0001). Given these inspiring results on ITC in the bone marrow, several trials currently analyze the prognostic relecance of circulating tumor cells (CTC) in peripheral blood in the adjuvant setting. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. However, until clinical consequences of MRD detection in solid tumors and particularly in breast cancer have been validated, the detection of isolated tumor cells in bone marrow should be performed mainly in clinical trials.

Music in Obstetrics: An Intervention Option to Reduce Tension, Pain and Stress

In recent years, the effect of music interventions and music therapy has experienced increased attention in the literature. It has been shown that music has positive effects on cognitive and physical performance, such as concentration and endurance, as well as on psychological parameters, such as anxiety and relaxation. Studies within the context of medicine in particular are increasingly indicating that music may be used as an intervention for relief against anxiety, stress and pain. Music is therefore seen in actual practice as a supplement to conventional pharmacological and non-pharmacological forms of treatment - and the trend is rising. Studies involving music interventions in the field of obstetrics have shown, amongst other things, that music improves the ability to relax during pregnancy and can reduce anxiety. It was also discovered that during childbirth music interventions resulted in a reduction of pain and stress. Music also has the effect of reducing stress, pain and anxiety in expectant mothers during deliveries by caesarean section. This review intends to provide an overview of the literature on music interventions in the field of obstetrics and to give a resume on the current state of research around the topic of music in relation to pregnancy, spontaneous deliveries and caesarean sections. Furthermore, the relevance of music for everyday obstetrics will be illustrated.

Use of Granulocyte-colony Stimulating Factor During Chemotherapy and Its Association With CA27.29 and Circulating Tumor Cells—Results From the SUCCESS A Trial

Background Little is known about the effect of granulocyte colony‐stimulating factor (G‐CSF) treatment during adjuvant chemotherapy on prognostic markers. The present study explored the association between G‐CSF and changes in cancer antigen (CA)27.29 and circulating tumor cell (CTC) levels during therapy. Patients and Methods A total of 3754 node‐positive or high‐risk node‐negative early‐stage breast cancer patients were treated within the SUCCESS‐A trial (simultaneous study of gemcitabine‐docetaxel combination adjuvant treatment, as well as extended bisphosphonate and surveillance‐trial). CA27.29 and CTCs were determined before the start and within 6 weeks after the end of chemotherapy. Results Overall, 1324 of the 2646 patients (50.0%) available for analysis had ≥ 1 G‐CSF applications during chemotherapy. G‐CSF application was significantly associated with CA27.29 status before and after chemotherapy (χ2 = 30.6, df = 3; P < .001), because 238 patients (18.0%) with G‐CSF treatment but only 146 (11.0%) without G‐CSF treatment switched from a negative CA27.29 status before to a positive CA27.29 status after chemotherapy. In addition, patients with G‐CSF application showed a significantly greater increase in CA27.29 levels after chemotherapy compared with patients without any G‐CSF application during chemotherapy (Mann‐Whitney U test; Z = −7.81, P < .001). No significant association was found between G‐CSF application and CTC status before or after chemotherapy (χ2 = 1.2, df = 3; P = .75). Conclusion Cautious interpretation is needed regarding elevated levels of MUC‐1–derived tumor markers such as CA27.29 shortly after adjuvant chemotherapy when G‐CSF has been given, because G‐CSF treatment was associated with increased CA27.29 levels after chemotherapy. Micro‐Abstract The present study examined the association between granulocyte colony‐stimulating factor (G‐CSF) and prognostic markers cancer antigen (CA)27.29 and circulating tumor cells (CTCs) in 2646 early‐stage breast cancer patients. Those with G‐CSF application showed a significantly greater increase in CA27.29 levels after chemotherapy than those without any G‐CSF application during chemotherapy, although no association with CTCs was found.

Uterine rupture of uterus bicornis at 19 weeks of gestation organ preservation by performing a hemihysterectomy

Introduction: Since reproduction techniques become more and more successful, we have to be alert to a rising incidence of pregnant women with uterine malformations. The preand perinatal care for these women is a challenge for obstetricians all around the world. We would like to draw attention to a rare obstetric emergency – the uterine rupture in a pregnant uterus bicornis – and suggest diagnostic and therapeutic approaches in an emergency setting. Materials and methods: To do so we present the case of a 35 year old GII/PI who suffered from this rare condition at 19 weeks of gestation. Furthermore we conducted a pubmed research regarding that topic. Results and Discussion: Uterine rupture is a very rare complication. Since the diagnostic process using ultrasound alone is often misleading, the medical history of the patient (e.g. previously known uterine malformations) becomes more important. Our case showed that the preservation of the intact horn is possible – even in an emergency setting. Conclusion: Given the rising number of women having uterine malformations and becoming pregnant, obstetricians have to be aware of rare complications. A special follow-up for these patients is necessary as well. In our case we suggest avoiding pregnancy for one year is sensible considering the uterine scar. In a future pregnancy we suggest frequent monitoring and a caesarean section at term. Correspondence to: Dr. med. Simon Binder, Lukaskrankenhaus Neuss, Frauenklinik Preußenstraße 84 41464 Neuss, Germany, Tel: 02131/888–2501, 02131/888 – 2599; E-mail: simon.binder@gmx.de