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There has been some discussion about the effect of antineoplastic agents on the trophoblast, and whether this is associated with abnormal placental function such as an increased risk of pre-eclampsia/eclampsia. We discuss a possible causal relationship between chemotherapy for breast cancer during pregnancy and the development of pre-eclampsia based on the occurrence of both in a recent pregnancy.We report the case of a 34-year-old gravida 4, para 1 with unilateral ductal invasive breast cancer, treated by surgery and subsequent chemotherapy during pregnancy. At 36 + 2 weeks of gestation a growth restricted male infant (1,680 g,5th percentile) was born by urgent caesarean section because of acute pre-eclampsia, pathologic CTG and umbilical end-diastolic reverse flow. This case is reported in detail, and literature and databases reviewed.So far there have been no reports suggesting an increased risk of pre-eclampsia following chemotherapy for breast cancer in pregnancy from the second trimester onwards, and the most probable is an accidental occurrence from pre-eclampsia and chemotherapy.Whenever possible, pregnant patients with breast cancer should receive the same treatment as those who are not pregnant. Should chemotherapy for breast cancer be indicated in pregnancy from the second trimester onwards only, contraindications would be other risks for pre-eclampsia and intrauterine growth restriction, such as smoking and gestational diabetes.

Background:Currently, breast cancer during pregnancy (BCP) is not believed to be biologically different from breast cancer unrelated to pregnancy based on limited datasets mainly obtained by immunohistochemistry. However, some groups report that BCP patients have an inferior survival compared to young non-pregnant breast cancer patients. The largest analysis based on the BCP registry by the German Breast Group (GBG) revealed however, no difference between pregnant and non-pregnant breast cancer patients, indicating that treatment rather than biology might be the reason for the inferior survival reported by others. Methods: The BCP study (GBG 29/BIG 03-02) is a multicentre observational study for breast cancer during pregnancy. In tumour tissue collected within this study from pregnant M0 patients we investigated the following genes: AKT1, ATM, BRAF, CBFB, CCND1, CDH1, CDKN2A, CTCF, EGFR, ERBB2, ESR1, FGFR2, GATA3, KRAS, MAP2K4, MAP3K1, MDM2, MED12, MYC, PIK3CA, PIK3R1, PTEN, RB1, RUNX1, and TP53 by massive parallel sequencing (MPS). This included patients with all molecular subtypes: HR+/-, HER2+/-. Sequencing was done on an IonTorrent Proton using a custom designed Breast Cancer Panel (BCPv2). This panel comprises 236 amplicons split into two primer pools and covers hotspot regions of 138 exons of the 25 genes. To test the hypothesis that breast cancer diagnosed during pregnancy is biologically not different from breast cancer diagnosed in young non-pregnant women, we compared the molecular profiles obtained, with genetic data from M0 patients not known to be pregnant from TCGA with age Results: Material from 141 patients from the BCP study was available from which ultimately 109 fully evaluable MPS datasets could be obtained. In the TCGA data set 114 breast cancer patients Exact matching by variables age, HR, HER2 and grade yielded 40 patients from both datasets. In these subcohorts, still divergent mutational rates for TP53 and PIK3CA between pregnant and non-pregnant women were noted, however, the differences failed to reach statistical significance. Conclusions: Overall the mutational landscapes do not seem to be overtly different between pregnant patients and no-pregnant controls, although slight imbalances in mutational rates occurred, which might be partly explained by a selection bias and a small sample size after matching. Further comparisons using other datasets, looking into survival and regarding copy number variation are currently conducted. This research is been funded by the German Cancer Consortium-DKTK and the BANSS Foundation. Citation Format: Loibl S, Pfarr N, Weber K, Neunhöffer T, Villegas S, Stenzinger A, Furlanetto J, Aktas B, Budczies J, Marmé F, Kahmann L, Denkert C, Weichert W. Comparison of the mutational landscape of breast cancer during pregnancy and non-pregnant controls [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-09.

Background: The oral signal transduction inhibitor everolimus (RAD001 = R), binds selectively to mTOR (mammalian target of rapamycin), an intracellular protein kinase implicated in the control of cellular proliferation of activated T-lymphocytes and neoplastic cells. Phase II data suggested that R can enhance the clinical efficacy of endocrine treatment in the metastatic and neoadjuvant setting. The GeparQuinto phase III study had 3 settings (HER2−positive: trastuzumab vs lapatinib; HER2−negative: +/− bevacizumab (Bev); HER2−negative non-responder: +/− R). Primary aim of the last setting was to improve pathological complete response (pCR) for patients with HER2−negative breast cancer not responding to 4x epirubicin/cyclophosphamide (EC) +/− Bev by adding R to weekly paclitaxel as neoadjuvant chemotherapy. Patients and Methods: Patients with untreated HER2−negative breast cancer were eligible if their tumors were stage cT3/4a-d; or estrogen (ER) and progesterone (PgR) receptor-negative; or ER/PgR-positive tumors with clinically N+ (for cT2) or pNSLN+ (for cT1). Only patients without response ( Results: Between 11/07 and 15/06/11 402 P were randomized to Pac (N=201) and Pac+R (N=201). Median age was 51.0 and 50.0 [-R/+R] years. Median clinical tumor size was 40/40 mm; 62%/55% had cT2, 18% / 20% cT3, and 16.7% / 16.7% cT4a-d tumors; 88% / 89% had non-lobular; 35% / 33% grade 3; 55% / 57% node-positive; and 29% / 27% ER and PgR-negative (triple-negative) disease. The futility interim analysis was performed in 02/10, futility boundary was not reached and the trial was continued. After the other 2 settings completed accrual in 06/10, recruitment to the 3rd setting dropped such that it appeared not possible to recruit the full number of patients.. The trial will therefore close recruitment on June, 30th 2011 with an estimated statistical power of 65%. Results on histological response and surgical outcome will be reported. Conclusion: This will be the first report on efficacy data of neoadjuvant R + Pac for patients with early breast cancer. The results of the GeparQuinto study will have to be set into context with the results from the Bolero studies in metastatic disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-6.

Background: The EndoPredict (EP) score is a multigene classifier to predict the likelihood of distant recurrence in ER-positive, HER2−negative breast cancer patients treated with adjuvant endocrine therapy. Two large randomized phase III trials involving endocrine therapy only (n > 1700) demonstrated additional prognostic information of the EP score independent from clinicopathological parameters by classifying 49% as low risk. However, the predictive role of the EP is not clear. Therefore, we examined whether the EP Score also predicts sensitivity towards neoadjuvant chemotherapy in ER-positive, HER2−negative breast cancer patients. Methods: Four publicly available gene expression data sets (Affymetrix HG-U133A) were retrieved from the gene expression omnibus (GEO) data repository. All analyzed breast cancer patients were treated with anthracycline or taxane/anthracycline-based neoadjuvant chemotherapy. Microarray cel files were MAS5 normalized with a global scaling procedure and a target intensity of 500. The analysis was restricted to ER-positive, HER2−negative breast cancer patients according to pre-specified cut-off levels for the respective ESR1/ERBB2 Affymetrix probesets. The EP score was calculated and patients were classified as having low or high risk according to the pre-specified validated cut-off value. Pathological complete response (pCR) — defined as no residual invasive cancer in the breast or lymph nodes — was used as the primary endpoint for the assessment of treatment response. Results: The EP Score was examined in 221 ER-positive, HER2−negative breast cancer patients treated with neoadjuvant therapy. Among the 221 patients, 61 tumors (27.6%) were classified as EP-low-risk, whereas 160 tumors (72.4%) were EP-high-risk. Only one of the EP-low-risk tumors achieved a pCR after neoadjuvant therapy, whereas 24 of the 25 pCR events were classified as EP high risk. The sensitivity of the EP score was 96% and the negative predictive value 98% with an area under the receiver operating characteristic curve of 0.73. Conclusions: The EP Score is a predictor of chemosensitivity in the neoadjuvant setting. The test correctly identified all but one of the patients achieving a pCR suggesting that the benefit of cytotoxic chemotherapy is limited to the EP high risk group. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-26.

Background Neoadjuvant chemotherapy (NT) has become an important approach to assess therapeutic efficacy of new treatment strategies. We observed a predictive role of of serum HER2 (sHER2) with neoadjuvant trastuzumab treatment in the previous trial “Geparquattro”. Predictive markers for response to new HER2−targeted therapies are still lacking. Therefore, we investigated the role of sHER2 in the context of trastuzumab and lapatinib treatment. Methods: The clinical trial Geparquinto incorporated either trastuzumab or lapatinib treatment combined with chemotherapy for HER2−positive breast cancer patients. Serum samples were taken at three different time points: before initiation of NT, after 4 cycles of chemotherapy with epirubicin and cyclophophamide and after finalization of NT with 4 cycles of docetaxel (pre-surgery). Only those patients were included in the analysis with serum available at all three time points. sHER2 levels were measured by a commercially available ELISA in 159 patients with a HER2−positive primary tumor, 77 (48%) patients were treated with trastuzumab, 82 (52%) with lapatinib. Pathological complete remission (pCR) was defined as no microscopic evidence of invasive residual tumor cells in the breast and lymph nodes. Results: Overall pCR rate in this cohort was 28%. sHER2 levels were higher in patients with larger tumors (> 5cm, p=0.012) and positive nodal status (p=0.001). Higher pre-chemotherapy sHER2 levels were associated with higher pCR rates in the entire study cohort (OR 2.9, 95% CI 1.3−6.7, p=0.012). Additionally, in the lapatinib treated patient group, a decrease of serum levels of more than 20% after 4 cycles of chemotherapy showed a tendency to be associated with higher pCR rates (OR 7.7, 95% CI 0.8- 70, p=0.071). In contrast to the finding of the previous trial Geparquattro, this was not the case in the trastuzumab-treated patient group (p=n.s.). Conclusion: Results of this study demonstrate pre-chemotherapy sHER2 levels to be an independent predictor of response to NT with both trastuzumab and lapatinib treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-08-01.

Background: 1-year of adjuvant trastuzumab (T) is the standard of care in managing patients (pts) with early HER2−positive breast cancer (BC). As T is not known to alter fertility, pts with childbearing potential could become pregnant during or following treatment with T. Cases of oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus have been reported in women receiving T during pregnancy (preg). Here we report the outcome of preg in all pts enrolled in the HERA trial. Methods: Pregnancies in the HERA trial are reported on a distinct “pregnancy form” for up to 10 years following T completion. The form includes information on approximate date of conception, preg course & outcome, fetal measurements at birth, and congenital anomalies. Any missing data were retrieved from the study site, if available. For this analysis, pts were grouped into 3 groups: 1) preg during and up to 3 months after T, 2) preg > 3 months of last T dose, and 3) preg with no prior exposure to T. Results: By March 2010, 70 preg were reported in 58 out of 5102 pts randomized. Five, 30 and 7 completed preg were reported in groups 1, 2 & 3 respectively. As per protocol, all pts on T were required to use adequate contraceptive measures, yet 16 pts became pregnant during the course of T and up to 3 months thereafter. The percentage of completed preg was lowest in group 1, with 4 spontaneous and 7 induced abortions. In group 2, preg occurred at a mean of 29 months following completion of T, with 6 spontaneous and 4 induced abortions. In group 3, abortion was induced in 3 pts and no spontaneous abortions reported. Across all 3 groups, all but 1 spontaneous abortion occurred during the 1st trimester. Two congenital anomalies were reported; a Down's syndrome in a 43 year old pt >5 years after completing T for which abortion was induced, and one with partial fusion of the 2nd and 3rd toe born to a pt in group 3. Conclusions: Unintentional exposure to T during preg may be associated with spontaneous abortion, yet the numbers remain low to draw firm conclusions (spontaneous abortion rate in general population is up to 20%). No oligohydramnios or anomalies were observed in group 1. While an increased risk of oligohydramnios has been reported when T is administered after the 1st trimester, T administered to Cynomolgus monkeys during organogenesis did not cause fetal harm (Pentsuk et al; 2009). Nevertheless, women of childbearing potential should be advised to use effective contraception during and up to 6 months after treatment with T. On the other hand, prior exposure to T did not appear to affect the preg course or outcome. We are planning to collect information from the other T adjuvant trials to confirm our findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-01.

Background: Bevacizumab has been reported to increase the risk of surgical complications, especially in pts treated with neoadjuvant chemotherapy. Methods: In January 2010 it was decided to collect surgical complications prospectively on a specifically developed from. All patients received chemotherapy with epirubicin/cyclophosphamide (EC) followed by docetaxel (T) with or w/o bevacizumab. Patients not responding to the first 4 cycles of EC+/−B were enrolled in another setting. All patients receiving bevacizumab were supposed to be operated at 5 weeks after the last infusion of bevacizumab. Results: Data from 699 patients have been prospectively collected, 329 received EC-T and 370 ECB-TB. Median age was 48 years in both arms. Median tumor size was 30mm in the ET-C arm vs 35mm in the ECB-TB arm (p=0.13). Multifocal or multicentric disease was present in 21% in the EC-T arm vs 22.4% (p=0.74). 36% of the patients received a sentinel node biopsy prior to start of neoadjuvant chemotherapy in both groups. 68.7% of patients received breast conserving therapy in the EC-T arm compared to 71.1% in the ECB-TB arm (p=0.54). The rate of pathological complete response was 19.5% with EC-T compared to 23.2% with ECB-TB (p=0.26). The median time from last CHT+/− bevacizumab to surgery was 29 days in EC-T and 34 days in ECB-TB. Bleeding or hematoma were reported in 6.7% of the patients treated by EC-T and 7.1% with ECB-TB (p=0.88). Wound infections or abscess were reported in 2.5% with EC-T and 3.9% with ECB-TB (p=0.39). Delayed wound healing was reported in 3.4% with EC-T and 6.3% with ECB-TB (p=0.11). Necrosis was reported in 1.9% with EC-T and 2.5% with ECB-TB (p=0.80). Any complication was reported in 11% with EC-T compared to 15.3% with ECB-TB (p=0.12). Conclusion: In general the rate of surgical complications was low. Patients treated with bevacizumab had a numerical increase of surgical complications. However, none of the differences were statistically significant. The intervals from last infusion to surgery as defined by the study protocol appear to be safe. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-05.

Background The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. Patients and methods A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks followed by four cycles of paclitaxel 175 mg/m2 every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m2 every 2 weeks followed by three cycles of paclitaxel 225 mg/m2 every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (Edd→Tdd→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of Edd→Tdd→CMF compared with EC→T. Results Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with Edd→Tdd→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). Conclusion Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

Background: Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. Patients and methods: Patients received neoadjuvant epirubicin 90 mg/m 2 plus cyclophosphamide 600 mg/m 2 followed by paclitaxel 175 mg/m 2 (EC/T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m 2 followed by paclitaxel 225 mg/m 2 with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m 2 , methotrexate 40 mg/m 2 , fluorouracil 600 mg/m 2 ) on days 1 and 8 (Edd/Tdd/CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). Results: Pathological complete response (pCR) rate (breast) was higher with Edd/Tdd/CMF, 18.7% versus 13.2% with EC/T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). Edd/Tdd/CMF regimen showed more grade 3–4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). Conclusion: Dose-dense and -intensified neoadjuvant chemotherapy with Edd/Tdd/CMF was potentially superior to EC/T in terms of pCR. Primary use of DA did not affect pCR.

Background: Docetaxel and paclitaxel are among the most active substances for the treatment of breast cancer. As both drugs are used today in adjuvant regimens, efficacy data from pivotal trials in the metastatic setting in taxanenaive populations cannot reliably be used as references. Patients and Methods: The Taxane Re-Challenge Cohort Study identified participants from 6 prospective (neo-)adjuvant taxane-based studies with recurrent disease and collected data on their subsequent treatment. Out of 381 recurrent patients, 106 (27.8%) were re-challenged with a taxane-based treatment as first- or later-line therapy for recurrent disease. Results: Taxanes were used as first-line therapy in 74 patients and showed a response rate of 48.6% (including complete responses in 27.0%). The response rate was dependent on the disease-free interval (< 1 year: 34.8%; 1–2 years: 42.9%; > 2 years: 63.3%; p = 0.04) and visceral metastasis (present: 62.5%; not present 32.4%; p = 0.01). Patients without visceral metastasis and with a disease-free interval of > 2 years achieved the longest overall survival. Hormone and HER2 receptor status were not predictive; however, triple-negative tumors responded in 50.0%. The overall response rate of later-line taxane-based treatment was 28.2%. Conclusion: Re-challenging taxanes appears to be effective and therefore represents a reasonable option in this population. Hintergrund: Docetaxel und Paclitaxel gehören zu den aktivsten Substanzen in der Behandlung des Mammakarzinoms. Da sie heute häufig bereits zur adjuvanten Behandlung eingesetzt werden, können Effektivitätsdaten von früheren Studien mit Taxan-naiven, metastasierten Patientinnen nicht mehr als zuverlässig angesehen werden. Patienten und Methoden: Für die Taxane Re-Challenge Kohortenstudie haben wir Teilnehmerinnen 6 prospektiver Taxanbasierter (neo-)adjuvanter Studien mit rezidivierter Erkrankung identifiziert und Daten zur weiteren Behandlung gesammelt. Bei 106 (27,8%) von 381 Patientinnen mit einem Rezidiv oder einer Metastase wurde erneut ein Taxan in der ersten oder späteren Behandlung eingesetzt. Ergebnisse: Taxane wurden in der Erstlinie bei 74 Patientinnen angewandt und zeigten eine Ansprechrate von 48,6% (inklusive Komplettremissionen in 27,0%). Die Ansprechrate war vom krankheitsfreien Intervall (< 1 Jahr: 34,8%; 1–2 Jahre: 42,9%; > 2 Jahre: 63,3%; p = 0,04) und dem Vorhandensein viszeraler Metastasen (vorhanden: 62,5%; nicht vorhanden: 32,4%; p = 0,01) abhängig. Patientinnen ohne viszerale Metastasen und mit einem krankheitsfreien Intervall > 2 Jahre überlebten am längsten. Hormon- und HER2-Rezeptorstatus waren für das Ansprechen nicht prädiktiv, jedoch sprachen tripelnegative Tumoren in 50.0% auf die erneute Taxan-Therapie an. Die Gesamtansprechrate auf ein erneutes Taxan in der späteren Linie betrug 28.2%. Schlussfolgerung: Der Wiedereinsatz von Taxanen erscheint effektiv und steht somit als sinnvolle Option für mit Taxanen (neo-)adjuvant vorbehandelte Patientinnen zur Verfügung.

International audience; Human epidermal growth factor receptor 2 (HER2) testing is an essential part of pathological assessment in breast cancer patients, as HER2 provides not only prognostic but also predictive information on response to targeted therapy. So far, HER2 test accuracy of immunohistochemistry/in situ-hybridization techniques is still under debate, and more reliable and robust technologies are needed. To address this issue and to evaluate the predictive value of HER2 on chemotherapy, we investigated a cohort of 278 patients from the GeparTrio trial, a prospective neoadjuvant anthracycline/taxane-based multicenter study. In the GeparTrio trial, patients were not treated with any anti-HER2 therapy, as this was not standard therapy at this time. The HER2 status was analyzed by three different approaches: local and central evaluation using immunohistochemistry combined with in situ-hybridization as well as evaluation of HER2 mRNA expression using kinetic RT-PCR from formalin-fixed, paraffin-embedded (FFPE) tissue samples using a predefined cutoff. HER2 overexpression/amplification was observed in 37.3% (91/244) and 17.9% (41/229) of the informative samples in the local and central evaluations, respectively. Positive HER2 mRNA levels were found in 19.8% (55/278). We observed a highly significant correlation between central HER2 expression and HER2 status measured by kinetic RT-PCR ( = 0.856

Background: Although many emerging regimens that incorporate targeted agents may produce increased myelosuppressive side-effects, clinical data guiding colony-stimulating factor (CSF) use with these regimens are not readily available. This review assessed the reporting diligence around febrile neutropenia and the related use of CSF and antibiotics in published clinical trials evaluating emerging regimens for breast cancer treatment. Methods: We searched Medline, EMBASE, and Cochrane databases to identify randomized, controlled phase 3 breast cancer studies published between Jan 2005 and June 2009. After excluding trials of vaccines, hormonal therapy alone, and stem cell transplantation/mobilization, corresponding publications were retrieved and data extracted on the incidence of neutropenia and its complications and CSF/antibiotic use. We then calculated the percentage of these publications that reported each outcome. Results: Of 463 trials identified from the search, only 73 met the inclusion criteria. Overall, 70% and 55% of trials reported the incidence of grade 3/4 neutropenia and febrile neutropenia, respectively (Table). Neutropenia-related hospitalizations were reported in 3% of trials. Prophylactic use of CSF and antibiotics was defined in the methods section of 59% and 23% of trials, respectively; and only reported in the results section of 22% and 5% of trials, respectively. Conclusion: Clinically significant neutropenia and neutropenia-related events (including febrile neutropenia) were generally described in the studies evaluated; however, the reported use of CSF and/or antibiotics was infrequent and inconsistent in the published literature of emerging regimens. A standardized approach to reporting neutropenic outcomes as well as the use of supportive care measures can assist cliniciansto prospectively manage the relevant toxicities associated with these emerging regimens and thereby facilitate their safe and effective use in clinical practice. Table: Reporting of myelotoxicity data in published phase 3 trials CSF = colony-stimulating factor Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-02.

Purpose: To evaluate the efficacy and safety of epirubicin/cyclophosphamide followed by paclitaxel/trastuzumab as neoadjuvant treatment in patients with HER2-overexpressing primary breast cancer (BC). Patients and Methods: Patients with HER2-overexpressing primary BC (≥2cm or inflammatory BC) received preoperative 4 cycles epirubicin/cyclophosphamide (90/600 mg/m2), q3w) followed by 4 cycles paclitaxel 175 mg/m2 q3w with trastuzumab 6 mg/kg body weight q3w (8 mg/kg as loading dose) followed by surgery. Trastuzumab was continued after surgery until completion of 12 months treatment. The primary endpoint was pathological complete response (pCR) defined as no invasive tumor in the breast and axillary lymph nodes. Results: Two hundred seventeen patients were enrolled. 39% achieved a pCR. Breast conserving surgery was possible in 138/217 (64%) of the patients. Median follow-up was 41 months and 3-year disease-free survival (DFS) was 88% in patients with pCR compared to 73% in patients without pCR (p=0.01). Three year overall survival (OS) was 96% in patients with pCR compared to 86% without pCR (p=0.025). In multivariate analysis pCR remained a significant prognostic factor for DFS and OS (DFS hazard ratio (HR) 2.5 [95% CI 1.2-5.1] p=0.013; OS HR 4.9 [95% CI 1.4-17.4] p=0.012). A cardiac event was reported in 8/217 (3.7%) patients; 6 had an LVEF decrease and two developed 2 (0.9%) clinical congestive heart failure. Conclusion: The neoadjuvant combination of trastuzumab and chemotherapy results in a high chance for a pCR. However, those patients without a pCR have an increased risk for relapse and death and are therefore candidates for further improvement of anti-HER2 directed therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-03.

Background: There is a paucity on toxicity (tox) data in elderly patients (pts) above 65 years (yrs) treated with anthracycline containing standard chemotherapy (ct) for primary breast cancer. We investigated the tox of standard anthracycline based regimen (AC/EC) and compared those with alternatives like dose-dense monotherapies and combinations (Edd; ADdd), intensified combinations (Canadian FEC) and taxane/anthracycline combinations (TAC) in various age groups. Patients and methods: In this pooled analysis, individual pts data from 4 German randomized trials (n= 4775) were evaluated regarding tox and compliance. Docetaxel/doxorubicin/cyclophosphamide (75/500/500mg/m2) 3qw (A=TAC), 5-fluorouracil/epirubicin (500/60mg/m2) iv d1+8 followed by cyclophosphamide (75mg/m2) po d1-14 q4w (B=cFEC), doxorubicin (epirubicin)/cyclophosphamide (60(90)/600mg/m2) q3w followed by docetaxel (100mg/m2) or paclitaxel (175mg/m2) q3w (C= AC/EC-D/p), doxorubicin/docetaxel (50/75mg/m2) q2w (D= AD dose dense(dd)) and epirubicin-paclitaxel q2w (120/175 mg/m2) (E= sequence dd) were given. Only the anthracycline containing cycles were investigated. A descriptive analysis was performed on compliance and (non-) hematological tox. Pts were grouped according to their age: < 60yrs [1], 60-64 yrs [2] and >64yrs [3]. Primary G-CSF support was given in A, D, E. Results: 73.6% were 64. A total of 22,306 anthracycline containing cycles were administered, of those 74.6% were given to [1], 15.2% to [2] and 10.0 % to [3]. 41.6% of the pts received TAC; 11.5% cFEC; 29.2% AC/EC-D/P; 8.2% ADoc dd and 9.5% Edd-Pdd. The incidence of febrile neutropenia (FN) did not significantly differ between the 3 age groups (overall A:10.0%; B:2.9%; C:1.0%; D:4.7%) apart from E with 0.9% ([1]0%; [2]6.4%; [3]0% P64 was lower in B (2.4%) than in A (14.4%) and D (5.1%). Diarrhea grade 3+4 increased with age to 8.2% for [3] under TAC (p= 0.01) and mucositis grade 3+4 under E to 12% for >64 (P In total, range and intensity of tox increased with age. Neutropenia did significantly increase with age in standard regimen but not in the dd groups Rate of dose reduction increased with age in A ([1] 6.1%; [2]6.5%; [3] 11.5; p=0.02) and B ([1]15.7%; [2]26.9%; [3]39.3%; p< 0.001). Similar significant results were observed for discontinuations and hospitalizations in A, B, D. Neutropenia grade 3+4 in [3] was 77% with cFEC, vs 55%with TAC (with primary G-CSF). Leucopenia Grade 3+4 in % (D, E). The severity of the non-hematotox differed between age groups and regimen. Monotherapies and sequential regimen seem more favorable in elderly pts. cFEC without G-CSF is not an option in pts >64. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-09.

Background: In women with HER2-positive breast cancer progressing during trastuzumab treatment, continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone (von Minckwitz et al, J Clin Oncol 27:1999-2006, 2009). Here we report the final analysis of overall survival (OS). Methods: Patients (pts) with HER2-positive, locally advanced or metastatic breast cancer who progressed during treatment with trastuzumab with or without adjuvant and/or 1st-line metastatic chemotherapy were prospectively randomized to X (2500 mg/m2 on days 1-14, q3w) or XH (6 mg/kg, q3w). OS was a pre-specified secondary endpoint of the study. Results: Median follow up at June 2010 was 20.7 months. 59 of 74 and 60 of 77 pts died in the X alone and XH arm, respectively. Median OS was 20.6 and 24.9 months with X alone and XH, respectively. This difference was not statistically significant (HR=0.94 [0.65-1.35]; p=0.73). Cox proportional hazard model showed performance status, hormone receptor status and metastatic site as independent prognosticators for survival. No difference between treatment arms was observed for pts with a clinical response or clinical benefit, respectively. Pts who continued/restarted anti-HER2 treatment (trastuzumab or lapatinib) after 2nd progression (N=88) had an OS of 18.8 compared with 13.3 months for those who did not receive 3rd line treatment with anti-HER2 agents (N=52) (HR 0.63; p=0.02). Pts who continued treatment after progression as initially randomized (anti-HER2 treatment after XH (N=31) or no anti-HER2 treatment after X alone (N=53)) had an OS of 26.7 months and 20.4 months (HR 0.71; p=0.2). Conclusions: Final OS analysis of the GBG-26 study could not demonstrate a survival benefit for treatment beyond progression with trastuzumab. However in a post-hoc analysis, pts receiving anti-HER2 treatment as 3rd line therapy showed a better OS than those not receiving this targeted treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-05.

Background: Little is known about the mechanisms of resistance to trastuzumab (T). We investigated markers which may indicate resistance to trastuzumab in a cohort of HER2 positive patients treated in a neoadjuvant phase 3 trial. Patients and methods: In the neoadjuvant GeparQuattro trial 1495 patients with operable and locally advanced tumors were randomized to 3 different chemotherapy regimens (4 x EC ≥4 x docetaxel (D) vs 4 x EC ≥4 x D/capecitabine (C) vs 4 x EC ≥4x D ≥4 X C). All HER2 positive patients (n=445 assessed by local testing) received trastuzumab concurrently with chemotherapy. 216 pretherapeutic core biopsies were available for tissue microarrays (TMA). For this evaluation only cases with sufficient tumor tissue on TMA (>30%) and positive HER2 status by central reassessment (IHC and CISH) were used (n=153). Expression of different markers possibly associated with resistance to T-based treatment were immunohistochemically (IHC) investigated. Marker expression was assessed with Immunoreactive-Score (IRS) combining intensity and % of positive cells. Resistance to treatment was defined as minimal or no microscopic changes in surgically excised tumor tissue (regression grade RG 0-1 according to Sinn et al). Results: The 153 centrally HER2 positive cases were taken for analysis. Median age was 49 years (22-78). Clinical T stadium was T1,2,3,4a-c/4d in 3%/70%/11%/8%/8% respectively, 59%/41% of these tumors were G2/G3; 51% hormone receptor (HR) positive. 44 (29%) did not show any response to treatment (RG 0-1) indicating resistance. In the chi2 test (2-sided) the following parameters were significantly associated with resistance (RG0- 1) to combined trastuzumab-cytotoxic therapy: insulin like growth factor receptor-1 (IGFR-1; IRS >3 resistant; p=0.029, insulin receptor (IR: IRS >1 resistant; p=0.028), Notch1(IRS>8 resistant; p= 0.037), ALDH1(IRS > 4 resistant; p=0.001), p4E-BP1 (IRS> 4resistant; p =0.017), p27 (IRS > 4 resistant; p=0.032). In multivariable testing (backward selection) ALDH 1 (OR 6.65 95%CI 1.78-24.76; p= 0.005) and p4E-BP1 (OR 3.2595% CI 1.36-9.06 p=0.009) remained significantly associated with resistance to trastuzumab containing therapy. Univariate and multivariate analysis for resistance markers to trastuzumab Conclusions: Our results suggest that an activated mTOR pathway characterized by increased levels of p4EBP1 and stem cell features described by enhanced ALDH1 expression are involved in resistance to trastuzumab containing treatment in primary HER2 positive breast cancer. These resistance markers will be validated in the neoadjuvant GeparQuinto trial investigating in a randomized design the effect of trastuzumab compared to lapatinib in HER2 positive primary breast cancer patients in addition to EC-D. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-06.

To determine activity and safety of capecitabine at a moderate dose of 2000 mg/m(2) as first-line therapy for metastatic breast cancer.In this prospective phase II trial, patients with HER2-negative metastatic breast cancer received first-line capecitabine 2000 mg/m(2) on days 1-14 every 3 weeks. The primary aim was to exclude a time to progression (TTP)6 months. Secondary end-points were overall response rate, overall survival (OS), toxicity and quality of life.Median age of the 161 included patients was 65 years. Median TTP and OS were 7.3 months [95% (confidence interval) CI: 6.2-8.4] and 17.1 months (95% CI: 14.0-20.3), respectively. An overall response rate of 26.1%, including 13 complete remissions was observed. Patients developing grade I-III hand-foot syndrome had a significantly longer TTP and OS and patients65 years also achieved a significantly longer TTP. Haematological grade I-IV toxicities were leucopenia (64.0%), anaemia (50.9%) and thrombocytopenia (28.0%). Relevant non-haematological toxicities were hand-food-syndrome (37.3%), fatigue (34.2%), nausea (29.8%) and diarrhoea (20.5%). Quality of life assessment revealed an improved emotional function, but worsening of nausea and vomiting from cycle 1-10.Capecitabine at a dose of 2000 mg/m(2) is active and safe as first-line treatment of patients with metastatic breast cancer.

SCOPUS: ar.j, info:eu-repo/semantics/published

Background Inhibition of COX-2 has been shown to attenuate the metastatic process in pre-clinical models of human breast cancer (BC). The primary aim of this study was to assess the effect of 2 years adjuvant therapy with the COX-2 inhibitor celecoxib compared with placebo in HER2-ve primary BC patients. Patients & Methods Patients were randomised in a 2:1 ratio to receive celecoxib 400mg once daily or placebo for 2 years. Patients had to have completely resected BC with prior local and systemic adjuvant treatment according to local practice. Concurrent radiotherapy was permitted and hormone receptor +ve patients received endocrine therapy according to local practice. Patients with HER2+ or node negative, T1 and grade 1 disease were excluded. Median age of patients was 55 years (IQR: 49-63). 50% of patients had tumours >2cm; 42% were grade 3; 48% had node +ve disease. According to local assessment 73% were ER/PgR +ve. Primary endpoint was Disease Free Survival (DFS); defined as time from randomisation to date of first event, with events contributing to analysis defined as recurrence (distant/local), new primary BC (ipsilateral/contralateral) and death. Secondary endpoints included Overall Survival (OS), toxicity, cardiovascular mortality and incidence of second primaries. Subgroup analysis by hormone receptor status was pre-planned. Survival endpoints are analysed using Cox-proportional hazards and log-rank tests; restricted mean survival is used where proportional hazards do not hold. Results Between January 2007 and November 2012, 2639 patients were randomised (1763 celecoxib; 876 placebo) from 181 centres across the UK and Germany. At 13th April 2017, median follow up was 60 months (IQR: 48-72) with 428 DFS events reported. Unadjusted survival analysis results are presented below, with hazard ratio 5 year survival estimate (95% CI)Hazard ratio (95% CI)p-valueDFS (all patients) Celecoxib83% (81, 85)1.02 (0.83 – 1.24)0.88Placebo83% (80, 86)1- DFS within ER+ Celecoxib87% (85, 89)0.89 (0.69 – 1.16)0.40Placebo86% (83, 89)1- DFS within ER- Celecoxib72% (68, 76)1.17 (0.85 – 1.61)0.33Placebo75% (69, 80)1- OS (all patients) Celecoxib90% (88, 91)0.97 (0.75 – 1.25)0.81Placebo90% (88, 92)1- The interaction between ER status and treatment was not significant; p=0.36. In the celecoxib and placebo groups there were 17 and 8 deaths respectively in patients who had not relapsed. These were due to cardiac (n=3; 2) and other (n=14; 6) in the celecoxib and placebo groups respectively; none were GI related. In total 304 serious adverse events were observed in 265 patients (186/1763 celecoxib; 79/876 placebo). In the celecoxib and placebo groups respectively these were related to cardiac (n=12; 7), GI (n=9; 2) and other (n=193; 81). Work is ongoing to determine whether a subset of ER+ patients whose primary tumours show the characteristics of a COX-2 signature receive greater benefit from celecoxib. Conclusions There is no benefit of celecoxib in the ITT population. Further exploratory studies focussing on the ER+ subpopulation are ongoing. Celecoxib treatment is not associated with significant toxicity when compared to placebo in this population of BC patients. Citation Format: Coombes RC, Tovey H, Kilburn L, Mansi J, Palmieri C, Bartlett J, Hicks J, Makris A, Evans A, Loibl S, Denkert C, Murray E, Grieve R, Coleman R, Schmidt M, Klare P, Rezai M, Rautenberg B, Klutinus N, Rhein U, Mousa K, Ricardo-Vitorino S, von Minckwitz G, Bliss J. A phase III multicentre double blind randomised trial of celecoxib versus placebo in primary breast cancer patients (REACT – Randomised EuropeAn celecoxib trial) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-03.

Background The role of temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients remains highly controversial. This option is considered experimental by the ASCO and ESMO guidelines on fertility preservation in cancer patients. The present pooled analysis aimed at elucidating the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients. Patients and methods This study included individual patient data from 5 trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) in which premenopausal women with early breast cancer were randomized to receive (neo)adjuvant chemotherapy alone or with concurrent administration of GnRHa. Efficacy endpoints were premature ovarian insufficiency (POI, according to the definition used as primary endpoint in the included trials), 1- and 2-year amenorrhea rates and post-treatment pregnancy rate. Safety endpoints were disease-free survival (DFS) and overall survival (OS). Odds ratio (OR), incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CI) were calculated for the effect of adding GnRHa to chemotherapy alone. As each study represents a cluster, statistical analysis has been performed using a random effects model. The study is registered with the PROSPERO registration number CRD42014015638. Results A total of 873 patients from 5 randomized trials were included. Median age was 38 years (interquartile range: 34-42 years). POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted OR 0.38; 95% CI 0.26-0.57; p < 0.001). The incidence of 1-year amenorrhea was 36.8% in the GnRHa group and 40.4% in the control group (adjusted OR 0.92; 95% CI 0.66-1.28; p = 0.623). The incidence of 2-year amenorrhea was 18.2% in the GnRHa group and 30.0% in the control group (adjusted OR 0.51; 95% CI 0.31-0.85; p = 0.009). A total of 37 patients had at least one post-treatment pregnancy in the GnRHa group and 20 in the control group (IRR 1.83; 95% CI 1.06-3.15; p = 0.030). There were no significant differences in DFS (adjusted HR 1.01; 95% CI 0.72-1.42; p = 0.999) or OS (adjusted HR 0.67; 95% CI 0.42-1.06; p = 0.083) between the GnRHa and control groups. Subgroup analyses of both efficacy and safety endpoints according to age of the patients, hormone receptor status, type and duration of chemotherapy will be presented at the conference. Conclusions This study provides level 1A of evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy in premenopausal early breast cancer patients. Given the findings of this pooled analysis, temporary ovarian suppression with GnRHa during chemotherapy should be considered as a new standard option to reduce the likelihood of chemotherapy-induced POF and possibly improve future fertility in premenopausal early breast cancer patients. Citation Format: Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, Unger JM, Anderson RA, Mehta K, Minton S, Poggio F, Albain KS, Adamson DJA, Gerber B, Cripps A, Bertelli G, Seiler S, Ceppi M, Partridge AH, Del Mastro L. Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-01.

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2+ve and triple negative (TN) primary BC by treated with neoadjuvant therapy. Methods: We prospectively evaluated PIK3CA mutations in the 512 participants of the neoadjuvant Geparsixto (G6) study (von Minckwitz et al. ASCO 2013) and validated in 225 participants of the GeparQuinto (G5) study (Untch et al. 2012). The G6 study investigates the effect of adding carboplatin to a non-pegylated liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. All HER2+ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. The G5 study showed that trastuzumab added to EC-Doc results in a significantly higher pCR rate than lapatinib. HER2, hormone receptors (HR), and Ki67 were centrally assessed in both studies. PIK3CA was genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy with a tumor cell content of ≥20% using classical Sanger sequencing of exon 9 and 20. Results: In the G6 study, 595 patients with HER2+ve or TN primary BC have been randomized from 09/2011 to 11/2012. Median age was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2+ve group 62% were HR-positive. Currently, PIK3CA genotype is available from 512 randomized patients - 240 with HER2+ve and 272 with TN disease. Overall, 13.1% were found to have at least one mutation, in HER2+ve: 19.2% and TNBC: 7.7%. PIK3CA mutations were numerically more frequent in the HER2+ve/HR+ve compared to the HER2+ve/HR-ve group: 21.5% vs 15.4% respectively (p = 0.245. Overall, pCR rate was significantly lower in the PIK3CA mutant compared to wt group (22.7% vs. 43.6%; p = 0.001).This effect was only significant within the HER2+ve group (17.8% vs. 36.8%; p = 0.015) compared to TNBC (33.3% vs. 49%; p = 0.168). Within the HER2+ve/HR+ subgroup the PIK3CA mutant pts had a pCR rate of only 6.5% compared to 30.8% in the wt group (p = 0.005). In contrast there was no difference in pCR (42.9% vs. 46.1%) according to PIK3CA mutation status in the HER2+ve/HR-ve (p = 0.825) group. In the G5 study, 225 of 620 HER2+ve pts have biomaterial available for PIK3CA genotyping and central confirmation of HER2 and hormone-receptor status. The analyses are ongoing and the results for the trastuzumab and lapatinib treated cohorts will be presented at the meeting. Conclusion: Pts with PIK3CA mutant HER2+ve/HR+ve breast cancer are resistant to chemotherapy and dual anti-HER2 treatment. Other treatment options are needed to be tested in this group. The project has been funded within the EU-FP7 project RESPONSIFY No 278659. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S4-06.

Translational Research in oncology links experimental and clinical science with the aim of transferring knowledge from research laboratories and hospitals and translating it into new therapy concepts. The definition of standards for the collection of biomaterials and the continued development of technologies are preconditions for Translational Research. Nevertheless new approaches are required to advance Translational Research. Following the invitation of the Banss Foundation, in September 2007 leading clinicians and scientists from German university hospitals and research facilities met together in Biedenkopf, near Marburg. The symposium aimed to develop new scientific concepts using aspects and features of innovation management. The topic was introduced by presenting general therapy concepts in breast cancer treatment (Prof. C. Thomssen) as well as current clinical breast cancer trials (Prof. G. von Minckwitz). Translational Research was described from a clinical point of view (Prof. N. Harbeck) and from the point of view of the laboratory (Dr. D. Niederacher). The question “what we know and what we really should know” (Prof. B. Groner) was discussed during a presentation on the current state of knowledge in cancer research. This article summarizes the results of the discussion on central aspects of Translational Research in this workshop and offers new approaches.

Over the last decades, many changes have occurred in oncology with new chemotherapy combinations and more complex application schemes becoming available. Central venous catheters and implantable venous port systems have become widely used and have facilitated the problem of vascular access. However, important complications are associated with permanent central venous catheters.This review summarizes evidence on venous port system use published in Medline up to February 2007. Moreover, recent guidelines for the prevention and management of catheter-related infections issued by the Infectious Diseases Society of America, the American College of Critical Care Medicine, the Society for Healthcare Epidemiology of America, the Center for Disease Control and Prevention, Atlanta, and the Infectious Diseases Working Party of the German Society of Hematology and Oncology are included.Sterile precautions are essential when implanting and accessing port systems. Infections must be treated with adequate antimicrobial therapy. Catheter-related thromboembolic complications were found at a rate of 12-64% in retrospective studies. Five current clinical trials investigated the effect of prophylactic anticoagulation with either low molecular weight heparin or warfarin in cancer patients with central venous devices. On the basis of these results, routine anticoagulation cannot be recommended.This article reviews the current literature on long-term complications of venous port systems, focusing on infection and thrombosis. In addition, it summarizes the evidence regarding routine maintenance of port systems in follow-up care.

Objective. A multicenter non-randomized phase II study was initiated to evaluate tolerability and efficacy of pegylated liposomal doxorubicin (PLD) in combination with carboplatin in gynecologic malignancies. Methods. One hundred forty women with recurrent or advanced endometrial ( n =31), cervical or vaginal cancer ( n =31), uterine sarcomas ( n =11), or recurrent platinum-sensitive ovarian cancer ( n =67) received six courses of PLD 40 mg/m 2 and carboplatin (AUC 6) every 28 days. Results. Hematological toxicities with NCI-CTC grade 3/4 were anemia in 8%, thrombocytopenia in 14%, neutropenia in 24%, and febrile neutropenia in 2% of 652 cycles. Grade 3/4 non-hematological toxicities included fatigue (14% of patients), pain (10%), dyspnea (9%), palmar–plantar erythrodysesthesia (7%), and nausea/vomiting (7%). Dose intensity reached 87.2% for PLD and 88.2% for carboplatin. Seventy-four percent of all non-progressive patients received at least 5 cycles. Overall response rates were (116 patients evaluable for response): ovarian cancer ( n =54) 68%, endometrial cancer ( n =27) 44%, uterine sarcomas ( n =9) 33%, and cervical/vaginal cancer ( n =26) 12%. Median progression-free survival was 11.6 months (95%CI 9.6–14.1) for ovarian cancer and 9.5 months (95%CI 6.6–12.6) for endometrial cancer. Median overall survival was 23.8 months (95%CI 19.0–30.2) and 21.4 months (95%CI 11.9–), respectively. Conclusions. The combination of PLD and carboplatin was well tolerated and feasible in patients with gynecologic malignancies. Efficacy was low in cervical/vaginal cancer, but promising in patients with endometrial cancer. Efficacy was within the expected range in recurrent platinum-sensitive ovarian cancer and is currently under further investigation in a prospective randomized phase III trial comparing PLD/carboplatin with paclitaxel/carboplatin (CALYPSO-trial; AGO-OVAR 2.9).

Background: Classical hormone replacement therapy for hot flashes is contraindicated in breast cancer especially in endocrine responsive disease. Patients and methods: In a double-blind, randomized phase III study, breast cancer patients suffering from hot flashes at least twice a day, who were not taking any medication against hypertension and depression received either clonidine 0.075 mg twice a day or venlafaxine 37.5 mg twice a day for 4 weeks. The primary end point was defined as the frequency of hot flashes after 4 weeks of treatment. A self-reported 1-week hot flash and other symptom questionnaire were kept before the start of treatment until the end of treatment course. Results: From April 2002 to October 2004, 80 patients were recruited of whom 64 were assessable for efficacy analyses. Thirty-three received clonidine and 31 venlafaxine, nine patients stopped early because of side-effects and seven withdrew consent. At the end of treatment week 4, the median hot flash frequency dropped by 7.6 hot flashes per day for patients receiving venlafaxine and 4.85 hot flashes per day for those receiving clonidine (P = 0.025). Conclusion: Venlafaxine is significantly more effective in reducing the frequency of hot flashes in breast cancer patients than clonidine.

Background: Secreted protein acidic and rich in cysteine (SPARC) has been suggested as a new biomarker and therapeutic target in breast cancer, as well as other tumor types. Patients and methods: We evaluated the frequency of SPARC expression among different molecular breast cancer subtypes and its role for therapy response after neoadjuvant chemotherapy. In this study, pretherapeutic core biopsies of 667 patients from the neoadjuvant GeparTrio trial were evaluated for SPARC expression by immunohistochemistry using a standardized immunoreactive score (IRS). Results: An increased SPARC expression (IRS ≥6) was observed in 26% of all tumors. In triple-negative tumors, SPARC expression was increased in 37% of tumors, compared with other molecular subtypes (23% HR+/HER2−, 29% HR+/HER2+ and 22% HR−/HER2+; P = 0.038). Increased SPARC expression was associated with an increased pathological complete response (pCR) rate of 27%, compared with 15% in tumors with low SPARC expression (P < 0.001). In the triple-negative subgroup, pCR rates were 47% in tumors with high SPARC expression, compared with 26% in tumors with low SPARC expression (P = 0.032). In multivariable analysis, SPARC was independently predictive in the overall population (P = 0.010) as well as the triple-negative subgroup (P = 0.036). Conclusions: SPARC is frequently expressed in breast cancer with triple-negative breast cancer revealing the highest expression rate. High SPARC expression of the primary tumor is associated with a higher chance of achieving a pathological complete remission after TAC or TAC-NX chemotherapy. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of albumin bound drugs, SPARC should be further evaluated as a predictive marker especially for response to albumin-bound drugs like nab-paclitaxel. Clinical trial number: NCT00544765.

BACKGROUND Bone metastases belong to the most frequent metastases in breast cancer. Currently there exist no serum markers which allow early detection of bone metastases. PATIENTS AND METHODS 89 patients with primary breast cancer have been investigated for parathyroid-hormone-related peptide (PTHrP) in the tumour and bone sialoprotein (BSP) in the serum. Both markers have been correlated with classical prognostic factors and survival. RESULTS The median age of the patients was 56 years. 17 of the 89 patients developed bone metastases and 25 died during the observation period of 5 years. PTHrP correlated significantly with bone metastases free survival (p = 0.0004) and overall survival (p = 0.0005), whereas BSP correlated only with the bone metastases free survival (p = 0.03). Both markers were shown to be independent prognostic factors for the bone metastases free survival in the multivariate analysis. PTHrP was also found to be an independent prognostic factor for the overall survival. CONCLUSION The investigation of PTHrP could be a prognostic marker for the presence of bone metastases while BSP could be a marker for the early detection of bone metastases.

Background: Abagovomab is a murine anti-idiotypic antibody against the antigen CA-125 which has been shown to elicit humoral and cellular immune responses against ovarian cancer (oc). Patients and methods: This phase I trial included 36 patients with recurrent oc comparing two subcutaneous (s.c.) vaccination schedules: nine (group L) versus six injections (group S), 18 patients in each group. Four injections of 2.0 mg abagovomab were administered every 2 weeks and then two or five additional doses monthly. Primary endpoint was drop-out rate due to toxicity, and the secondary endpoint was analysis of immunological response. Results: Treatment was completed in eight (44%) and 16 (89%) patients in groups L and S, respectively. Premature termination occurred due to patient withdrawal or disease progression. No treatment-limiting toxicities occurred in either group. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Induction of Ab3 was observed in all evaluable patients. There were no differences between the groups with regard to induction of human anti-mouse antibody (P = 0.1006). IFNγ-expressing CA125-specific CD8+ T-cells were significantly more frequent in group L, while there was no significant difference between CD4+ T-cells in the two groups. Conclusions: Abagovomab s.c. vaccination is safe and well tolerated. The long vaccination schedule tended to be more effective with regard to AB3-induction and cellular cytotoxicity.

This years ASCO-meeting reinforced the trend of the recent years to get off from empirical treatment concepts to tailored and individualized diagnostics and therapy. However, the basis for an individual therapy is a specific molecular diagnostic which can be reflected in the analysis of hormonal receptor, HER-1, HER-2 and topoisomerase IIalpha in breast cancer. All these markers are not only able to prognosticate the course of disease but they also can predict the success of specific treatment approaches. Trastuzumab is standard therapy in HER-2 positive breast cancer both in the adjuvant and palliative setting. But new therapeutic agents, as e. g. lapatinib, are promising in the treatment of HER-2 positive breast cancer even if trastuzumab is failing. Otherwise it might possibly be an alternative option but adequate clinical results have to be awaited. The targeted inactivation of EGFR-related signal transduction pathways by e. g. gefitinib did not show a substantial improvement neither as a single agent nor in combination with endocrine treatment. However, the appropriate subgroup which might benefit from this therapy has to be defined even if molecular data suggest that patients with ER positive and PR negative breast cancer might be such a group. The increasing knowledge in terms of the biology of bone metastasis led to the development of new treatment options as e. g. denosumab, a humanized monoclonal antibody for RANK ligand. Two adjuvant cytotoxic treatment trials revealed that taxanes improve the prognosis of node positive breast cancer and should be administered sequentially. The advantage of switching to an aromatase inhibitor after two to three years of tamoxifen in endocrine treatment of postmenopausal patients is proved by two clinical trials (IES, ARNO) which could demonstrate a survival benefit. In conclusion it seems to be evident that new targeted therapy options are effective and will set new standards for the treatment of breast cancer patients in the near future. The presentation for the ovarian cancer focused on the addition of a third cytotoxic agent to carboplatin and paclitaxel as the standard therapy for the primary treatment of ovarian cancer. New data of Bevacizumab in the treatment of primary and recurrent ovarian cancer were presented. However, this is not yet a standard treatment for all patients and needs further investigations within large, multicentre, randomised trials. The lymphonodectomy as part of the primary therapy of the endometrial cancer seems to be a benefit at least in patients with advanced disease or high risk stage I tumours. The adjuvant therapy of uterine sarcomas is still not yet very well investigated and clear. A trial which recruited 12 years demonstrated a benefit in overall survival which has to be interpreted with caution. In this year again there have been registered an increasing number of interesting contributions from Germany, which also received international attention.