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BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide.

Purpose: In recent years there has been an increased interest in gynecological oncology in the use of complementary and alternative methods (CAM). The lack of data on side effects and the fact that the posited survival advantage is still unproven appear to have no influence on the decision on whether to use CAM or not. This was the basis for our interest in the motivation and goals of women who use CAM and led us also to inquire which specific CAM are used for which purposes. Material and Methods: 1030 women between the ages of 20 - 92 years and diagnosed with either breast, endometrial, cervical or ovarian cancer were asked to participate in this study which consisted of a questionnaire and a personal interview. The case reports were comprised of two parts: 1. a socio-economic satisfaction questionnaire (SES-QoL), and 2. a complementary and alternative medicine module (CAM-module). Therapy groups were statistically compared using the motives named by patients to search for possible associations (X 2 -test). Results: Out of the entire group of women 48.7% (n=502) used CAM. 50.1% of breast cancer patients stated that they used CAM, as did 44.0% of women with gynaecological cancer. Mistletoe use was widespread (72.9%) and psychological methods were only seldom used (19.1%). In the statements a strengthening of the immune system was given as the most common motivation (n=434), whereas the motivation of doing something oneself to combat the disease (n = 68) was least often mentioned. The strongest association between the patient's expectations and the CAM used was demonstrated in the evaluation of physiotherapy. Conclusions: Although the proof of a survival advantage is lacking and studies on undesirable side effects are inadequate, there is a marked interest in such treatment methods as shown by the prevalence of CAM usage. Transparency of the CAM types and methods of application should be assured. Patient-oriented information comparing standard therapies with complementary, alternative methods (CAM) should be made generously available and the patient's expectations with respect to the effects of CAM use should be discussed between the physician and the patient.

Ductal carcinoma in situ in men is incredibly rare and detection by conventional mammography and ultrasound is often challenging. We report an unusual case of a 50-year-old male, with no family history of breast cancer, who presented with an 8-year history of left-sided breast pain and recurrent bloody nipple discharge without any significant suspicious imaging features in mammography and targeted high-resolution ultrasound. Breast magnetic resonance imaging was performed as an adjunct modality. Magnetic resonance imaging findings revealed a suspicious retroareolar non-mass abnormality of segmental, linear and dendritic pattern, which was highly suspicious for a ductal carcinoma in situ. Stereotactic guided biopsy and subsequent mastectomy were consistent with pure high-grade ductal carcinoma in situ of the left breast. Overall, this case highlights the challenges in diagnosing ductal carcinoma in situ in men and demonstrates the importance for further investigating clinical suspicions of the male breast.

To prospectively evaluate and compare the accuracy of contrast-enhanced spectral mammography (CESM) and ultrasound (US) in size measurement of breast cancer with histologic tumor sizes as gold standard.Twenty women aged between 40-73 years (mean age, 57 ± 10 years) with histologically proven invasive ductal/lobular carcinomas were included in the study. Agreement between imaging tumor size (CESM and US) and histopathologic tumor size was evaluated with Bland-Altman analysis. Stereotactically guided vacuum biopsy was performed in four patients after CESM. Two independent reviewers described artifacts of CESM.Motion artifacts did not occur in the study. CESM-specific artifacts caused by scattered radiation mostly occurred in oblique view of CESM. Background enhancement of breast tissue was seen in four patients. Mean difference of tumor sizes was 0.3 mm (6.34%) between CESM and histology and -2.2 mm (-7.59%) between US and histology. Limits of agreement ranged from -18.9 to 19.48 mm for CESM and from -17.1 to 12.7 mm with US. Especially smaller tumors with a size23 mm were measured more precisely with CESM. Enhancement of breast tissue around microcalcifications correlated with abnormalities.CESM is accurate in size measurements of small breast tumors. On average CESM leads to a slight overestimation of tumor size, whereas US tends to underestimate tumor size. Assessment of the breast tissue can be limited by the scattered radiation artifact and background enhancement of breast tissue. CESM seems to be helpful in the characterization of breast tissue around microcalcifications.

The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.

Even today metastatic breast cancer remains incurable disease. Therefore most clinical trials in the last decade aimed at an improvement of the therapeutical ratio. In this context high-dose chemotherapy with therapy related mortality of 2 %–5 % seems to be justified only if long term survival or relevant prolongation of progression free survival is attainable. Survival data from early phase I–II trials show the same initial high relapse rates as after conventional chemotherapy. On the contrary, HDC data from the early 80 s suggest that after three years survival plateaus at 14 %–20 % long term survivors. Data from European and American transplant registries reporting about 4000 patients show the same trend. For the whole population the survival advantage by high dose chemotherapy is estimated to be about one year. Maximum benefit is demonstrable in patients with chemosensitive disease. Data from one phase III trial comparing early tandem HDC with conventional chemotherapy show significant survival advantages for the HDC group with 20 % survivors at 400 weeks. Data from other phase III trials will be published in 1999. In Germany patients can be randomized to two ongoing prospective randomized trials.

Purpose : The total number of breast cancer survivors - including pre-menopausal women - is growing. Amenorrhoeic periods due to adjuvant breast cancer treatments are prolonged and secondary treatment side effects are increasingly experienced during lifetime. Hence, the question concerning the use of HRT after breast cancer treatment is of keen interest. Method and Material: In an observational study 185 breast cancer patients were included from whom complete documentation was available. 64 patients received HRT after or simultaneous with adjuvant breast cancer treatment, 121 died not use HRT during the study period. Results: Most patient and tumour characteristics, surgical, radiation and adjuvant chemo- and/or (anti-)hormonal therapies did not differ significantly. In a 60 months surveillance period differences in the number of deaths and recurrences as well as the disease-free (DFS) or overall survival (OS) were not significant between both study groups. Conclusion: Results of this study agree with other pilot studies on the administration of HRT in breast cancer survivors. The studies do not indicate an increased risk due to HRT application. However, results from randomised prospective trials should be awaited before modifying the management of the individual breast cancer patient.

Background: In the routine work-up of suspect breast lesions, ultrasound-controlled core needle biopsy (CNB) is the most common tool to acquire tissue for histopathologic analysis in a safe, quick and convenient way. Complications are generally rare. The most common complications are hematoma and infection, each with less than 1 in 1000 cases. Case Report: Here, we present a case of a 48-year-old patient who underwent CNB for several lesions that were assessed as Breast Imaging Report and Data System (BI-RADS) IV in breast ultrasound and mammography. In the past, she had had 2 bilateral breast reduction surgeries and 1 open biopsy of a fibroadenoma. Histology revealed a phyllodes tumor. Following this, mastitis occurred which was resistant to common conservative measurements such as intravenous antibiotics over months. Finally, mastectomy was performed, followed by adequate wound healing. Conclusions: In the presented case, the prolonged course of breast infection after CNB was not as expected. If this occurs, conservative treatment with antibiotics can be initiated. Possible additional risk factors such as diabetes mellitus, steroid therapy, or immunosuppression should be identified. However, in case of missing recovery, wide surgical excision is recommended.

Einleitung: Das mannliche Mammakarzinom ist selten (Pravalenz 1/100000). Das Erkrankungsalter liegt zwischen 60 und 70 Jahren. Risikofaktoren sind familiare Belastung, erhohte Ostrogenspiegel und vorangegangene Bestrahlung. Invasiv-duktale Adenokarzinome, die Ostrogen- und Progesteronrezeptoren und einen negativen Her2neu-Status aufweisen, sind typisch. Die Therapie der Wahl ist bei Operabilitat die radikal modifizierte Mastektomie. Die Sentinellymphonodektomie scheint ahnlich effektiv wie bei Frauen zu sein. Die adjuvante Therapie ist vom Tumorstadium abhangig und kann Chemotherapie, Radiatio und endokrine Therapie (Tamoxifen) beinhalten. Kasuistiken: Wir berichten uber drei Patienten, die sich durch den besonderen Verlauf der Erkrankung vom typischen virilen Mammakarzinom unterscheiden. Der erste Patient fiel durch ein fortgeschrittenes, metastasiertes, inflammatorisches Mammakarzinom auf, welches 8 Wochen nach einer Bypassoperation auftrat. Beim zweiten Patienten wurde man auf das Mammakarzinom durch ein paraneoplastisches bulloses Pemphigoid aufmerksam. Der dritte Patient zeigte die untypische Histologie eines muzinosen G1-Karzinoms. Im Vergleich dazu zeigt der vierte Fall das typische Bild des invasiv-ductalen Mammakarzinoms bei einem 79-jahrigen Patienten. Zusammenfassung: Ein inflammatorisch-fortgeschrittenes Mammakarzinom 8 Wochen nach thorakaler Operation bei zuvor klinisch unauffalligem Lokalbefund ist eine Raritat. Ein Zusammenhang mit der Hypoxie im Rahmen der Bypassoperation und einer HIF-1 vermittelten Tumorprogression kann hypothetisiert werden. Im Gegensatz dazu steht das in dem anderen Fall berichtete lokal langsames Wachstum bei einem muzinosen G1-Karzinom. Bei unklaren persistierenden Hautveranderungen sollte ein paraneoplastisches Syndrom in die differenzialdiagnostischen Uberlegungen einbezogen werden. Insgesamt zeigt sich, dass das seltene virile Mammakarzinom Verlaufe mit unter Umstanden erschwerter Diagnosefindung aufweisen kann, so dass auch bei untypischen Symptomen oder Anamnese beim Mann die ausfuhrliche Untersuchung der Brust erfolgen muss.

International audience; The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 ( = 128) and CD105/endoglin ( = 130). Protein molecular breast cancer subclasses were analyzed by -means clustering ( = 5). The univariate impact of factors on event-free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 ( = 0.004) and VSA/CD105 ( = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes (

Background: Breast cancer in men is an uncommon disease. Little is known about its etiology, clinical behavior, treatment, and outcome. Retrospective data indicate that stage- and age-matched male and female breast cancer is similar in presentation. The aim is to find an adequate treatment for male breast cancer, which is not just extrapolated from its female counterpart. Case Report: We present the history of a 41-year-old man who was diagnosed with pT2 (3 cm) breast cancer in 2001. After mastectomy without axillary dissection, 4 cycles of adjuvant epirubicin and cyclophosphamide and radiation therapy were performed followed by hormonal treatment with tamoxifen until 2003. In 2003, 2004, 2005, and 2006, there were relapses with skin metastases, treated with several courses of chemotherapy. In 2006, an inflammatory carcinoma in the contralateral breast was revealed during the course of epirubicin chemotherapy. In May 2007, the patient passed away from extensive tumor progression despite numerous attempts of local and systemic chemotherapeutic treatment. Conclusion: Here, an unusual case of male breast cancer is reported. It was first diagnosed at the age of 41 years, which is relatively young for male breast cancer. Although the treatment was started at an early stage, several relapses and contralateral breast cancer occurred within 5 years and could no be controlled.

Purpose: To characterize the prognostic and predictive impact of protein expression profiles in high-risk breast cancer patients who had previously been shown to benefit from high-dose chemotherapy (HDCT) in comparison to dose-dense chemotherapy (DDCT).Experimental Design: The expression of 34 protein markers was evaluated using tissue microarrays containing paraffin-embedded breast cancer samples from 236 patients who were randomized to the West German Study Group AM01 trial.Results: (a) 24 protein markers of the initial panel of 34 markers were sufficient to identify five profile clusters (subtypes) by K-means clustering: luminal-A (27%), luminal-B (12%), HER-2 (21%), basal-like (13%) cluster, and a so-called “multiple marker negative” (MMN) cluster (27%) characterized by the absence of specifying markers. (b) After DDCT, HER-2 and basal-like groups had significantly worse event-free survival [EFS; hazard ratio (HR), 3.6 [95% confidence interval (95% CI), 1.65-8.18; P = 0.001] and HR, 3.7 (95% CI, 1.68-8.48; P < 0.0001), respectively] when compared with both luminal groups. (c) After HDCT, the HR was 1.5 (95% CI, 0.76-3.05) for EFS in the HER-2 subgroup and 1.1 (95% CI, 0.37-3.32) in the basal-like subgroup, which indicates a better outcome for patients in the HER-2 and basal-like subgroups who received HDCT. The MMN cluster showed a trend to a better EFS after HDCT compared with DDCT.Conclusions: Protein expression profiling in high-risk breast cancers identified five subtypes, which differed with respect to survival and response to chemotherapy: In contrast to luminal-A and luminal-B subtypes, HER-2 and basal-like subgroups had a significant predictive benefit, and the MMN cluster had a trend to a predictive benefit, both from HDCT when compared with DDCT.

Purpose To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. Patients and Methods Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. Results One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. Conclusion Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.

Einleitung: Bis in die spaten 90er-Jahre haben die meisten Studien beim Mammakarzinom keine Patientinnen jenseits des 65. Lebensjahres eingeschlossen. Daher harren viele Fragen fur diese zunehmend groser werdende Altersgruppe der Beantwortung. Die ICE-Studie widmet sich der Frage nach der Durchfuhrbarkeit und der Wertigkeit der adjuvanten Chemotherapie in dieser Altersgruppe. Design/Methoden: Die Indikationsstellung erfolgt in Extrapolation der St. Gallen Leitlinien. Randomisierbar sind Frauen uber 64 mit einem N+ Mammakarzinom oder einer N0 Hochrisikosituation (Tumordurchmesser >2cm und/oder G II/III und/oder HR negativ). Zum Ausschluss von Patientinnen, deren Lebensspanne fuhrend durch die Komorbidat bestimmt wird, erfolgt die Beurteilung anhand des Charlson Score und des VES 13-Score. Therapie: Alle Patienten erhalten Ibandronat (p.o. oder 6mg i.v.) uber 2 Jahre und bei hormonrezeptorpositiven Tumor sequenziell Anastrozol uber 5 Jahre. Randomisiert werden 6 Zyklen Capecitabine 2000mg/m2p.o. b.i.d Tag 1–14 q3w versus nihil. Primares Studienziel: Vergleich des ereignisfreien Uberlebens. Sekundare Studienziele: Vergleiche des Gesamtuberlebens, der Compliance, Nebenwirkungen, Lebensqualitat, Anzahl osteoporosebedingter Ereignisse, geriatrische Beurteilung und die Bestimmung der Praferenz fur orale oder intravenose Gabe des Biphosphonats. Statistik: Angenommen wird eine Verbesserung des ereignisfreien Uberlebens von 65% auf 71,5% durch die adjuvante Chemotherapie. Bei einem a-Fehler von 5%, einem b-Fehler von 20% betragt die Zielzahl 1394. Ergebnisse: Von 4/04 bis 02/06 wurden insgesamt 517 Patientinnen randomisiert. (257 N-; 260 N+, 408 HR+). 62 SAEs wurden bislang gemeldet (54 Arm A/8 Arm B). Die Haupttoxizitaten beziehen sich auf Diarrhoe, Mukositis und Hand-Fus-Syndrome. Schlussfolgerung: Die bisher monitorierten Toxizitatsdaten und die gemeldeten SAEs sprechen fur die Durchfuhrbarkeit der adjuvanten Capecitabine-Therapie. Ein aktualisierter Statusreport wird vorgestellt.

Summary Background Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial. Methods Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol. Findings 403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17·6, and median follow-up was 48·6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53–67) in the high-dose chemotherapy group and 44% (37–52) in the control group (p=0·00069). The corresponding overall survival was 75% (69–82) versus 70% (64–77; p=0·02). There were no treatment-related deaths. Interpretation Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.

Capecitabine is a rationally designed oral, tumor-activated fluoropyrimidine carbamate with high activity in metastatic breast cancer. This multicenter phase II study was designed to evaluate further the efficacy and safety of capecitabine in patients with metastatic breast cancer previously treated with a taxane-containing regimen.All patients had to have documented progression after paclitaxel- or docetaxel-containing chemotherapy. Treatment comprised 3-week cycles of oral capecitabine 1250 mg/m(2) twice-daily for 14 days followed by a 7-day rest period.One hundred and thirty-six patients were enrolled. Disease stabilization occurred in 63 patients (46%) and the overall response rate was 15% (95% confidence interval 10% to 23%), providing an overall tumor control rate of 62%. Median time to progression was 3.5 months, median duration of response was 7.5 months and median overall survival was 10.1 months. Capecitabine was generally well-tolerated: most treatment-related adverse events were grade 1/2 in intensity; grade 3/4 treatment-related adverse events were hand-foot syndrome (13%), diarrhea (8%), vomiting (4%) and nausea (3%). There were no treatment-related deaths.This study confirms that capecitabine achieves a high tumor control rate in heavily pretreated patients with metastatic breast cancer. Due to its favorable safety profile and convenient oral administration, capecitabine can be given as an outpatient therapy. Capecitabine should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.

11018 Background: DNA copy number profiles identify patients with a defect in BRCA1 associated with a homologous recombination DNA repair defect. We previously showed that patients with a BRCA1-lik...

Background: Despite promising evidence regarding outcome prediction, endocrine sensitivity, as determined by proliferation response to short-term preoperative endocrine therapy, is currently not included in adjuvant chemotherapy decisions in early HR+/HER2- breast cancer (BC). Methods: The prospective WSG-ADAPT HR+/HER2- trial includes early BC patients with 0-3 positive LN who are candidates for adjuvant chemotherapy based on clinical-pathological criteria alone; it aims to spare chemotherapy in a substantial proportion utilizing a combination of genomic assessment by Oncotype DX and endocrine sensitivity testing. All patients received 3-week preoperative endocrine induction therapy (ET): aromatase inhibitors (AI) if postmenopausal, tamoxifen if premenopausal. Patients with low (0-11) Recurrence Score (RS) or intermediate RS (12-25) and ET response (centrally tested, post-therapy Ki-67 Results: As of 6/2013, 380 patients from 30 study centers had been enrolled in the ADAPT HR+/HER2- trial. Median age was 54 years. At first pre-planned analysis (5/2013), paired Ki-67 measurements (pre-/post-therapy) were available in 241 patients; RS was available in 208 cases (201 with paired Ki-67). RS was low in 21.6%, intermediate in 57.7%, and high in 20.7%; the respective risk group responder percentages (post-treatment Ki 67 70% endocrine responders in the intermediate genomic risk group, who could potentially be spared adjuvant chemotherapy. Median Ki 67 level decreases (as percentage of pre-treatment value) were 25% in premenopausal patients (tamoxifen, n = 101) vs. 75% in postmenopausal patients (AI, n = 115) (p Conclusions: The Run-In Phase of the WSG ADAPT HR+/HER2- trial confirms trial design estimates of RS and proliferation response to induction ET. It indicates that the multicenter prospective ADAPT concept combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible. Proliferation response was strongly associated with therapy group (AI/post-menopausal vs. tamoxifen/pre-menopausal). Survival non-inferiority of intermediate Recurrence Score proliferation responders vs. low Recurrence Score patients (active control) will be tested in the ADAPT main phase to determine if adjuvant chemotherapy can be spared in 70% of patients with 0-3 positive LN classified as “intermediate risk” by conventional factors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-11.

e21020 Background: Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and systemic therapy. However, their infrequent detection rates limit currently their clinical use. Here we tested whether leukapheresis could be a suitable method to increase CTC yields and detection rates by increasing dramatically the analyzed blood volume. Methods: We screened 3x106 PBMNCs of 48 historical leukapheresis products harvested from 24 breast cancer patients in the setting of high-dose chemotherapy and from a non-cancer control group (n=10), respectively, with a standard immuno-assay using an anti-cytokeratin antibody (A45/BB3) to detect CTCs. Detected CTCs were isolated, their genomic DNA amplified, and the whole genome screened for chromosomal aberrations using comparative genomic hybridization (CGH) (n=48). To validate the CTC detection frequencies in leukapheresis products, we initiated a prospective pilot-study and performed leukapheresis in 13 cancer patients (breast and pancreatic cancer). 1 mL of the leukapheresis product (total volume: up to 150 ml) was analyzed using the CellSearch® system as well as 7.5 ml peripheral blood taken from the same patients. Results: 44/48 (91.7%) of leukapheresis samples contained CTCs with a median count of 3.0 in 3x106 PBMNC (range: 1-35 CTCs). None of the 10 analyzed healthy controls displayed CTCs. We successfully performed single cell CGH of 48 CTCs from 19 patients revealing aberrant CGH profiles in 56% with gains and losses typical for breast cancer. Interestingly, CTCs with high aberration numbers were associated with early metastatic relapse. The validation study using CellSearch® in 13 cancer patients demonstrated in leukapheresis products significantly higher CTC detection frequencies (13/13 vs. 5/13) and CTC numbers (median: 13, range: 1-51 vs. median 0, range: 0-7; p

Introduction: The expression of the estrogen receptor (ER) and/or the progesterone receptor (PR) is a predictive factor for the response to endocrine treatment and to chemotherapy in primary breast cancer. Knowledge about the prognostic relevance of the PR is rare and partly controversial. Aim of this retrospective study was to analyze the prognostic relevance of PR. Methods: Between 1995 and 2008, data from 5,144 patients with heterogeneously treated primary breast cancers have been collected in 3 German university hospitals. The laboratories used immunhistochemical assays for the investigation of the ER and PR. The PR-expression was correlated with patient and tumor characteristics. For each outcome parameter overall survival (OS), distant disease free survival (DDFS) and local recurrence free survival (LRFS) cox proportional hazad models were built. Furthermore the effect of the PR status was analyzed according to tumor subgroups. Results: PR status was associated with a more favourable OS, DDFS and LRFS in the univariate analysis. PR remained an independent prognostic factor for OS and DDFS but not for LRFS in the cox proportional hazard model. For OS and DDFS the prognostic effect of PR seemed to be consistent among the subgroups and was significant for most of them. Comparing subgroups there was a difference between the HR for ER negatives and ER positives. In ER negative tumors the prognostic effect of the PR seemed to be larger (HR=0.40; 95%CI: 0.25−0.63) than in ER positives (HR=0.68; 95%CI: 0.53−0.87). For all other subgroups there seemed to be no interaction between PR status and the other prognostic factors. Conclusion: PR positivity results into a similarly favourable prognosis in ER negative and ER positive patients. ER positivity alone seems not to be sufficient to define a group of patients with the most favourable prognosis. On the contrary, patients with ER positive, PR negative tumors have a signicantly deteriorated prognosis and seem to be a patient group, which should be investigated concerning drug resistance mechanisms. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-07.

e11119 Background: The expression of the estrogen receptor (ER) and the progesterone receptor (PR) is a predictive factor for the response to an endocrine treatment and to chemotherapy in primary breast cancer. Aim of this retrospective study was to analyse the prognostic relevance of PR in interaction with other prognostic factors. Methods: Between 1995 and 2008, data from 5144 patients with primary breast cancer have been collected in 3 German university hospitals. The PR-expression was correlated to clinical-pathological variables like tumor stage, nodal status, grading and the expression of ER. Overall survival (OS), distant disease free survival (DDFS) and local recurrence free survival (LRFS) were the main outcomes of interest. PR was analysed for interaction with each other prognostic factor in cox proportional hazard models. Results: The expression of the progesterone receptor had an effect on overall and distant disease free survival (each < 0,001), but no effect on local recurrence free survival...

1021 Background: Obesity has been reported to be associated with aggressive tumor characteristics and poor prognosis in early BC in mostly unselected collectives. This study was performed to investigate the prognostic impact of obesity taking into account molecular subtypes in randomized node-positive BC cohort treated by chemotherapy (Cht). Methods: Pooled analysis in 2353 patients was done using data from the WSG-AM-01 (high risk BC with >9 positive lymph nodes (LN), treated by either tandem high dose or dose-dense Cht) and AM-02 trials (intermediate risk BC with 1−3 positive LN treated by CEF/CMF or EC-Doc). Data on hormone receptors (HR) and HER2 were available in 2045 pts, molecular subtypes (luminal A vs. B (by Ki-67 or HER2), basal/non-basal triple negative (TN) BC and HER2) by central pathology review in 865 pts. Time-varying Cox proportional hazards regression models were used to assess the prognostic impact of BMI after adjusting for other factors. Results: Median follow up was 59 months. BMI wa...

Purpose: Several angiogenic factors have been reported to influence prognosis of breast cancer and spread to regional lymph nodes. CD105 (Endoglin) is expressed by human vascular endothelial cells and plays a major role in angiogenesis. Similarly, CD31 is a platelet endothelial cell adhesion molecule involved in normal and pathologic vessel function. In the prospective randomized WSG-AM-01 trial HRBC patients with more than 9 positive lymph nodes derived particular benefit from tandem high-dose (HD) rather than dose-dense (DD) chemotherapy with regard to both event-free (EFS) and overall survival (OS), particularly among tumors carrying a basal-like or HER2 molecular phenotype. The goal of the present study was to examine the interaction between angiogenic factors and efficacy of different dose intensification strategies in the WSG-AM-01 trial among both unselected patients as well as among distinct molecular disease subtypes.Methods: Immunohistochemical staining for CD31 (n=128) and CD105 (n=130) was performed to assess vascular surface area (VSA) separately for both factors using the Chalkley count method.Expression of estrogen (ER) and progesterone receptor (PR), HER2, Ki67, and epidermal growth factor receptor (EGFR) was analyzed immunohistochemically using tissue microarrays, allowing for stratification into molecular breast cancer subclasses (k-clustering k=5 by expression of 24 proteins). Correlation analysis between CD31 and CD105 expression and molecular subtypes was carried out using Pearson correlations. Univariate survival estimates were determined by Kaplan-Meier analysis and tested for significance by log rank statistics. Multivariate survival modeling was performed by a generalized Cox model, with linear proportional hazards terms in the first block and time-varying interactions in the second block.Results: Both VSA/CD 31 and VSA/CD105 showed significantly higher expression among HER-2 and basal-like breast cancer subtypes (p=0.007), as well as among cases wit increased Ki67 (p=0.005).Increased VSA/CD105 (above a median of 1.295) was associated with significantly decreases in both EFS (p=0.01) and OS (p=0.02). In multivariate analysis (including therapy, tumor size, age and grade as well as expression of ER, PR, HER-2 and Ki-67) increased VSA/CD 105 was an independent prognostic factor for decreased EFS (HR=1.68, p=0.05). Dose intensification showed significantly increased efficacy (for OS and EFS) only among patients with low VSA/CD105 tumors.Discussion: Expression of angiogenic markers may mirror/confer resistance to chemotherapy among patients with breast cancer, particularly in the context of dose intensified chemotherapy and may explain differences observed among distinct molecular breast cancer phenotypes. The correlation observed between angiogenic markers and distinct molecular subtypes may serve as a rationale for exploring antiangiogenic treatment options in patients carrying these tumors. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2154.

564 Background: TAC is one of the most effective regimens. It‘s associated with higher frequency of anemia and chemotherapy-induced neutropenia (CIN). The erythropoiesis stimulating factor (ESF) support of chemotherapy, its complications and survival effect remain unclear. Erythropoetins do prevent chemotherapy-associated anemia (CAA) and subsequent fatigue syndrome but their potential influence on survival is still unclear. One aim of this analysis is to investigate the correlation between CT, growth factor support and toxicity (SAE‘s). Methods: This ARA Plus phase III trial compare chemotherapy ±ARA in breast cancer patients >18 years old, with positive lymph nodes and with M0 disease. Pts get six cycles of of 5-fluoro-uracile 500mg/m2, epirubicine 100mg/m2 and cyclophosphamide 500mg/m2, (FEC, Bonneterre), 3-weekly or six cycles of docetaxcel 75mg/m2, adriamycin 50mg/m2 and cyclophosphamide 500mg/m2, (TAC, BCIRG) and are randomized to ARA 500μg q3w if Hb No significant financial relationships to disclose.

563 Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associated with up-regulation of MDR1, alters p53 function, and induces growth of an aggressive phenotype. In high-risk breast cancer, the prospective randomized WSG-AM-01 trial has reported significantly better event-free (EFS) and overall survival (OS) for tandem high-dose (HD) vs. dose-dense (DD) chemotherapy, especially in basal-like und HER2 subgroups. The present study examines the interaction of a drug resistant phenotype induced by YB-1 within the WSG-AM-01 collective at 5-year follow-up. Methods: 236 tumors (116 HD/120 DD) of 403 randomized patients (60%) were available for construction of tissue microarrays and determination of molecular classification by k-clustering of expression of 34 protein markers. Immunostaining of YB-1 by specific peptide antibody was scored semiquatitatively by intensity. Associations of YB-1 staining with other protein expression factors were studied by Pearson correlations. Univariate survival was estimated by Kaplan-Meier analysis and tested by log rank statistics. Multivariate survival modeling was performed by a generalized Cox model, with linear proportional hazards terms in the first block and time-varying interactions in the second block. Results: At a median follow-up of 61.7 months, the WSG-AM-01 confirms a significant EFS and OS benefit for HD in HRBC. In 60% of tumors, there was strong YB-1 expression. YB-1 was significantly associated with several proliferation and drug resistance markers, such as p53, EGFR, S6 and with basal-like/Her2 subtypes.YB-1 expression was highly predictive for response to HD: both EFS (HR=0.29, p=0.001) and OS (HR=0.16, p=0.0001) were significantly improved by HD compared to DD for YB-1 positive tumors; these favorable time-varying hazard ratios signify decreases in early (≤3 years) relapses and deaths, respectively. Conclusions: Among all investigated markers, only YB-1 expression was significantly associated by time- varying interaction analysis with efficacy of HD. The results suggest YB-1 as a potential stratification criterion for future trials as well as a target for treatment of drug resistant HRBC. No significant financial relationships to disclose.

20032 Background: Hormone receptor and Her2neu negative breast cancer (triple negative, TN) presents an aggressive biological subtype with decreased survival. Basal-like BC identified by gene expression arrays (Perou CM, et al. Nature 2000) may be associated with TN breast cancer. Several studies defined the origin of TN or BBC breast cancer in a progenitor epithelial cell that is undifferentiated. Other studies investigated the association of TN with EGFR expression or BRCA1 mutations. The aim of our study was to analyze the expression of stem cell or basal markers in TN high risk breast cancer. Methods: We examined 236 patients from central tumour bank from high risk breast cancer patients (>9 positive LN), who were randomized to the WSG AM-01 trial (phase III tandem HDC versus DD CT). The following markers were profiled by IHC in TMA for all patients: ER, PR, Her2neu, MIB-1, EGFR, p53, Ck 5/6, CK17, c-kit, p63, Vimentin, ABCA3, and BCRP. Their correlation with survival was studied. Results: 65 patients (30%) of 218 patients assessable for hormone receptor and Her2neu staining, were identified as TN, surprisingly not indicating any higher incidence of TN tumors in this selected high risk collective, when compared to other more heterogeneous populations. This phenotype was significantly more frequent in premenopausal women, and was significantly associated with G3, MIB1 and EGFR, CK5/6 and 17, c-kit, vimentin, p53 and BCRP expression. No association with p63 and ABCA3 was found. Poor grading, MIB1+, CK5/6 and 17, c-kit, vimentin and BCRP+ strongly correlated with relapse. Patients with TN tumors had significantly worse overall survival (p = 0.002) in comparison to the remaining group. Conclusions: The triple negative BC-type is frequent in patients with multiple positive lymph nodes and has a poor prognosis. Its association with age and basal and progenitor cell molecular markers suggests correlation with BRCA1 mutations as a potential marker for resistance to alkylating agents (Sorlie, PNAS 2003). Modern experimental (chemo)-therapy designs in this subgroup should take into account the higher incidence of EGFR and basal stem cell marker expression, p53 mutations, the poor differentiation, the expression of chemoresistance markers and the high proliferative activity. No significant financial relationships to disclose.

665 Background: The WSG AM 01 trial is the first one to report superiority of HDC in terms of DFS and OS in patients with >9 positive axillary lymph nodes. Retrospectively we tried to identify patient subgroups with maximum benefit from HDC. Methods: 403 patients were randomized to tandem HDC or to dose-dense conventional chemotherapy (DD). 236 tumors were available for central pathologic review (117/119). A panel of 34 markers were determined by IHC in TMA. Kaplan-Meier, Log rank and Cox proportional hazard models were used for uni- and multivariate analysis. We choose K-means clustering with K=5 and using Manhattan distance as similarity measure. Results: Pts: n=236 (HDC/DD): mean age 47.3/47.4 yrs, mean tumor sizes 3.5/3.4cm, mean positive lymph nodes 17.2/17.0, HR+ 55%/53%, G3 44%/35%. HDC was superior to DD (p=0.02). Multivariate analysis demonstrated a significant correlation for grading, tumor size, PR+. HR > 2 were reported for the following markers: Her2neu+, p53+, bcl2−, Ck 5/6 and 17+, Ck8−, c-kit+, vimentin+, ETR 1/2, BCRP+. Triple negative tumors (TN) (31%) had a large benefit from HDC (HR DD vs. HD: 3.06, 95%CI:1.41–6.06). Groups identified by K-means clustering could be attributed to luminal-A-(31%), luminal-B-(27%), her2-(11%), basal like-(11%) type and a so far undefined proliferative group (20%) characterized mainly by the absence of specifying markers. Interestingly, the proportion of the above mentioned molecular subtypes within of high risk populations very similar to those reported for less selected populations. Her2, basal-like and the undefined proliferative group had significantly worse outcome when compared to luminal tumors (p2cm. Negative hormone receptor status, p53+, bcl2−, MIB/p16+ and BCRP+ predicted benefit from dose intensification. Subgroups are small and may help to generate further hypothesises. No significant financial relationships to disclose.

6665 Background: Optimal HDC strategy in breast cancer remains to be defined. This phase III trial evaluates the role of the number of HDC cycles. Methods: From 2/97 to 6/01 we randomised 187 patie...