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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Purpose We aimed to explore the trajectory of financial difficulties among breast cancer survivors in the German health system and its association with migration background. Methods In a multicentre prospective study, breast cancer survivors were approached four times (before surgery, before and after adjuvant therapy, five years after surgery) and asked about their migration history and financial difficulties. Migrants were defined as born/resided outside Germany or having citizenship/nationality other than German. Financial difficulties were ascertained with the financial difficulties item of the European Organisation for Research and Treatment of Cancer Core Instrument (EORTC QLQ-C30) at each time-point (cut-off > 17). Financial difficulties were classified in trajectories: always (every time-point), never (no time-point), initial (first, not fourth), delayed (only fourth), and acquired (second and/or third, not first). A logistic regression was conducted with the trajectories of financial difficulties as outcome and migration background as exposure. Age, trends in partnership status, and educational level were considered as confounders. Results Of the 363 participants included, 49% reported financial difficulties at at least one time-point. Financial difficulties were reported always by 7% of the participants, initially by 5%, delayed by 10%, and acquired by 21%. Migrants were almost four times more likely to report delayed (odds ratio [OR] = 3.7; 95% confidence interval [CI] 1.3, 10.5) or acquired (OR = 3.6; 95% CI 1.6, 8.4) financial difficulties compared to non-migrant participants. Conclusion Survivors with a migration background are more likely to suffer from financial difficulties, especially in later stages of the follow-up. A linguistically/culturally competent active enquiry about financial difficulties and information material regarding supporting services/insurances should be considered.

Multifocal (MF) and multicentric (MC) breast cancers have been comprehensively studied, and their outcomes have been compared with unifocal (UF) tumors. We attempted to answer the following questions: (1) Does MF/MC presentation influence the outcome concerning BC mortality?, (2) Is there an impact of guideline-adherent adjuvant treatment in these BC subtypes?, and (3)What is the influence of guideline violations concerning surgery (breast-conserving surgery versus mastectomy) on the survival of MF/MC BC patients? Between 1992 and 2008, we retrospectively analyzed 8,935 breast cancer patients from 17 participating breast cancer centers within the BRENDA study group. Of 8,935 breast cancer patients, 7,073 (79.2 %) had UF tumors, 1,398 (15.6 %) had MF tumors, and 464 (5.2 %) had MC tumors. RFS was significantly worse for MF/MC BC patients compared to patients with UF tumors (MF p = 0.007; MC p = 0.019). OAS was significantly worse for MC patients but not for MF patients compared to patients with UF tumors (MF p = 0.321; MC p = 0.001). Guideline adherence was significantly lower in patients with MF (n = 580; 41.5 %) and MC (n = 204; 44.0 %) compared to patients with UF (n = 3,871; 54.7 %) (p < 0.001) tumors. Guideline violations were associated with a highly significant deterioration in survival throughout all subgroups except for MC, with respect to RFS and OAS. For 100 %-guideline-adherent patients, we could not find any significant differences in RFS and OAS after adjusting by nodal status, grade, and tumor size. Furthermore, we could not find any significant differences in RFS and OAS in patients with MF or MC stratified by breast-conserving therapy (BCT lumpectomy and radiation therapy) and mastectomy. There is a strong association between improved RFS and OAS in patients with MF/MZ BC. There are no significant differences in RFS and OAS for patients with breast-conserving therapy or mastectomy.

Background: In younger patients (pts) breast cancer (BC) is associated with a worse prognosis compared to older pts. Only few data are available presenting the development of prognostic factors regarding a period of several decades. This 40 year (y) longitudinal comparison of the main prognostic factors was performed to investigate differences in younger women with primary BC in contrast to older women over time. Patients and Methods: In this retrospective analysis a consecutive pts cohort of 4010 pts was analyzed. Pts were documented and treated for primary invasive breast cancer between 1963 and 2003 at two University Hospitals in Germany. To be eligible, pts were required to have identified tumor characteristics, including TNM-status. Pts with carcinoma in situ or distant metastases were excluded. The cohort was divided in two age groups, ≤40y and >40y. Furthermore to reveal trends and changes over the duration of 41 years the period of analysis was split into 3 time frames: 1963–1976, 1977–1989 and 1990–2003. We analyzed the main prognostic factors for BC including tumor size, grading, nodal status and HR-status in longitudinal comparison regarding the three time frames, respectively. During 1963–77 HR-status was determined in just 12.6% of pts. Thus, this time frame was excluded in the analysis of HR-status. Results: In 41 yrs, 747 (18.6%) pts were treated between 1963–76, 1722 pts (42.9%) in 1977–89 and 1541 pts (38.4%) in 1990–2003. Overall 358 pts were ≤40y and 3652 pts were over the age of 40. A significant reduction of tumor size (metric assessment) at primary diagnosis was observed for both age groups (pts≤40y: p = 0.012; pts>40y: p < 0.0001) with no difference between the time frames, respectively (1963–76: p = 0.289; 1977–89: p = 0.647; 1990–2003: p = 0.937). The number of node-positive pts significantly decreased in pts >40 y (p = 0.001) whereas no difference could be seen in pts aged ≤40 y (p = 0.991). In both age groups the number of G2/3 tumors increased over the yrs (pts≤40y: p = 0.001; pts>40y: p < 0.0001). Between 1963–76 more G1-tumors were diagnosed in younger pts (p = 0.041) whereas in the two following periods significantly more G2/3 tumors (p = 0.001; p = 0.002) were observed in this group. In young pts, 54.2% were HR-negative in 1977–89 and 47.6% in 1990–2003 (p = 0.323). In pts >40y 38.4% and 21.7% were HR-negative, respectively (p < 0.0001). Comparing the age groups, significantly more pts were HR-negative in the young patient group (p = 0.001 (1977–89) and p < 0.0001 (1990–2003)). Conclusions: Concerning the large period of 40yrs, technical improvement and increasing awareness for BC are reasons for decreasing tumor size at the time of primary diagnosis. However, the rate of node-positive pts in the young patient group remained stable. Furthermore, the high percentage of HR-negative pts and the increasing number of pts with unfavorable tumor grade demonstrate more aggressive tumor types in younger pts. These data confirm the need to improve screening tools to early identify young women with the risk to develop breast cancer, and for personalized treatment approaches in these patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-11.

Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced non-inflammatory breast cancer (LABC) has now been updated with a follow up of more than 15 years. Long- term outcome data and predictive factors for pathologic complete response (PCR) were analyzed. Patients and Methods: 315 LABC patients (cT1-cT4/cN0-N1) were treated during 1991–1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or – in case of breast conservation – an 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival. Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p < 0,01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80 to 0.99], p = 0.03) could be obtained. Importantly, a pCR was the strongest prognostic factor for long term survival (HR 0.28 [95% CI 0.19–0.56], p < 0.001). Conclusions: A PCR identifies patients with a significant better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of a pCR after NRT-CHX. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-04.

An earlier published series of neoadjuvant radiochemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (pCR) were analyzed.During 1991-1998, 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 ? 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or-in case of breast conservation-a 10-Gy interstitial boost with (192)Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow-up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX, and the time interval between end of RT and surgery were examined in multivariate terms with pCR and overall survival as end point.The total pCR rate after neoadjuvant RT-CHX reached 29.2%, with LABC breast conservation becoming possible in 50.8% of cases. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1.17 [95% CI 1.05-1.31], p 2 months) increases the probability of pCR after NRT-CHX.

Aim Adjuvant chemotherapy has changed dramatically in the last decades. Anthracycline-/Taxane-based and dose-dense chemotherapy regimens improved survival in node positive breast cancer. This study tries to answer the following questions: (1)Are there differences in survival dependent on chemotherapy regimens in stratified by number of positive lymph nodes/grading (G)/hormone receptor-status (HR)/T-stage? (2)Is it possible to attribute these effects to chemotherapy by only investigating patients who received 100% guideline-conform surgery, radiotherapy and endocrine therapy? Methods This is a German multi-centre (17 participating hospitals all certified as breast cancer centres) retrospective cohort study. We included patients that received CMF-like (CMF) ( n =1308), Anthracycline-based (A) (1046), Anthracycline-Taxane-based (AT) (1110) and dose-dense chemotherapy (DD) (213) into this analysis. Results In case of N0 and 1–3 pos LN we did not observe statistically significant differences in overall (OS) and disease-free survival (DFS) between CMF/A/AT and (for 1–3 pos LN) DD. In the group of 4–10 pos LN we observe an improvement by the use of AT-based chemotherapy, which cannot further be improved by DD chemotherapy. However in the highest risk group, defined as ⩾11 pos LN, we observed a statistically significant improvement in survival by the use of DD chemotherapy. Also a statistically slightly non-significant trend towards improvement of survival parameters by the use of DD compared to AT chemotherapy could be observed. Only for G3 subtypes we could observe a survival benefit for DD. These results remain consistent after exclusion of non-guideline adherent patients (surgery, radiotherapy and endocrine therapy) in order to reduce the bias of guideline violations in other adjuvant treatment modalities. Conclusion DD chemotherapy is associated with improved survival parameters in patients with ⩾11 positive LN.

Background The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline–taxane–based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. Patients and methods Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms. Results With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1–3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. Conclusions Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline–taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. Clinical trial number NCT 00567554, www.clinicaltrials.gov .

154 Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (PCR) were analyzed. Methods: 315 LABC patients (cT1-cT4 /cN0-N1) were treated during 1991-1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or—in case of breast conservation—a 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival. Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p 2 months) increases the probability of a pCR after NRT-CHX.

TPS1146 Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.

e11556 Background: In contrast to neoadjuvant chemotherapy they are no predictive factors to estimate the pathologic complete remission (pCR) rate after preoperative chemotherapy (NRT-CHX) in locally advanced breast cancer (LABC). Methods: 315 LABC patients were included in this trial. They were treated during 1991-1998. The last follow up was in November 2011. Radiotherapy was applied with 50 Gy (5x2 Gy / week) to the breast and the supra-/infraclavicular lymph nodes. 101 patients received a 10 Gy interstitial boost (breast conservation). Chemotherapy (CMF, EC or Mitoxantron was applied in 192 patients prior to radiotherapy and in 113 patients simultaneously. Ten patients had no chemotherapy. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time period up to surgery were examined in multivariate terms for pCR and overall survival. Results: The pCR rate for NRT-CHX after surgery was 29.2%. In multivariante analysis a longer time interval to surgery increased the probability of a pCR (HR 1,17 [95% CI 1,05-1,31], p 2 months) increases the probability of a pCR after NRT-CHX. Like in neoadjuvant CHX the achievement of a pCR is an important prognostic factor for long term survival.

5097 Background: Micro RNAs (miRNAs) are small non-coding RNAs which plays an important role in tumorigenesis and mutation of a miRNA gene or miRNA regulation-related gene may cause butterfly effect on alteration of global gene expression.In order to investigate this hypothesis,high resolution melting analysis (HRM) and denaturing high-performance liquid chromatography (DHPLC) were used to screen 20 miRNA genes and 6 miRNA regulation-related genes for mutations in gynecologic cancers. Methods: In this study,182 DNA samples from breast cancer tumors,42 from ovrian cancers and 28 from endometrial cancers were obtained.18 human cancer cell lines were also included.We used HRM and/or DHPLC to screen mutations of these genes in human cancer cell lines and tumor tissues. All samples with curves that differed in shape compared to wild-type were directly sequenced for confirmation.Secondary structures for the wild-type and variant primary precursor of miRNA sequences obtained from sequencing were predicted using RNAfold software.Western blot and immunohistochemistry were used to evaluate the related protein change in cancer cell line and tumor tissues. Results: Polymorphisms of these genes were very frequently observed in gynecologic cancers.Two rare variants were found in the primary precursor sequences of mir-200c and mir-142 gene.Moreover,a novel frameshift mutation( c.3547_3548insA) in TNRC6A gene was found in two endometrial cacner cell lines (RL95-2 and Hec-1A) and endometrial cancers (1/28).Western blot and immunohistochemistry showed loss of expression of TNRC6A protein in the endometrial cacner cell lines and endometrial cancers with this mutation. Conclusions: Two rare novel variants in 20 miRNA genes and a novel frameshift mutation in TNRC6A gene were identified in gynecologic cancers.Oue data indicate that mutations in TNRC6A gene may contribute to the cancer development and might be a potential new therapeutic target in endometrial cacner.

1020 Background: The prevalence of obesity increases throughout most industrialized countries. Epidemiological studies have shown not only an increase in breast cancer (BC) among obese women but al...

10626 Background: While evidence for the prognostic value of circulating tumor cells (CTC) in the adjuvant setting is swiftly increasing the role of tumor markers like CA27.29 in this setting is still controversial. In the SUCCESS Trial CTC and CA27.29 have been measured before, after and 2 years after adjuvant chemotherapy. Our goal was to examine the correlation of these 2 factors at the 3 points in time. Methods: The SUCCESS Trial compared FEC-docetaxel (Doc) vs. FEC-Doc-gemcitabine (Doc-G) regime and 2 vs. 5 year treatment with zoledronat in 3754 patients with primary breast cancer (N+ or high risk). CA27.29 has been measured with ST AIA-PACK Ca27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Belgium). The cutoff for positivity of CA27.29 was >31 U/ml. CTC were assessed with the CellSearchSystem (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labeled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish between epithelial cells and le...

Effects of G-CSF on circulating tumor cells (CTC) and CA 27.29 in breast cancer patients Andergassen Ulrich 1, Rack Brigitte 1, Schneider Achim 2, Rezai Mahdi 3, Tesch Hans 4, Beck Thomas 5, Soling Ulrike 6, Beckmann Mathias W. 7, Lichtenegger Werner 8, Janni Wolfgang 9 All the following institutions are located in Germany: 1 Ludwig-Maximilians University of Munich; 2 Charite Berlin; 3 Luisenkrankenhaus Dusseldorf; 4 Praxis Prof. Dr. Tesch Frankfurt am Main; 5 Klinikum Rosenheim; 6 Praxis Dr. Soling Kassel; 7 Friedrich-Alexander University of Erlangen; 8 Charite Berlin; 9 Heinrich Heine University of Dusseldorf

551 Background: In several randomized trials, taxane-containing regimens have demonstrated superiority compared to mere anthracycline-containing schedules for the adjuvant treatment of patients wit...