Progression-specific genes identified in microdissected formalin-fixed and paraffin-embedded tissue containing matched ductal carcinoma in situ and invasive ductal breast cancers.

BACKGROUND: The transition from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) is an important step during breast carcinogenesis. Understanding its molecular changes may help to identify high-risk DCIS that progress to IBC. Here, we describe a transcriptomic profiling analysis of matched formalin-fixed and paraffin-embedded (FFPE) DCIS and IBC components of individual breast tumours, containing both tumour compartments. The study was performed to validate progression-associated transcripts detected in an earlier gene profiling project using fresh frozen breast cancer tissue. In addition, FFPE tissues from patients with pure DCIS (pDCIS) were analysed to identify candidate transcripts characterizing DCIS with a high or low risk of progressing to IBC. METHODS: Fifteen laser microdissected pairs of DCIS and IBC were profiled by Illumina DASL technology and used for expression validation by qPCR. Differential expression was independently validated using further 25 laser microdissected DCIS/IBC sample pairs. Additionally, laser microdissected epithelial cells from 31 pDCIS were investigated for expression of candidate transcripts using qPCR. RESULTS: Multiple statistical calculation methods revealed 1784 mRNAs which are differentially expressed between DCIS and IBC (P < 0.05), of which 124 have also been identified in the gene profiling project using fresh frozen breast cancer tissue. Nine mRNAs that had been selected from the gene list obtained using fresh frozen tissues by applying pathway and network analysis (MMP11, GREM1, PLEKHC1, SULF1, THBS2, CSPG2, COL10A1, COL11A1, KRT14) were investigated in tissues from the same 15 microdissected specimens and the 25 independent tissue samples by qPCR. All selected transcripts were also detected in tumour cells from pDCIS. Expression of MMP11 and COL10A1 increased significantly from pDCIS to DCIS of DCIS/IBC mixed tumours. CONCLUSION: We confirm differential expression of progression-associated transcripts in FFPE breast cancer samples which might mediate the transition from DCIS to IBC. MMP11 and COL10A1 may characterize pure DCIS with a high risk developing IDC.

Prognostic impact of residual disease in simultaneous additional excision specimens after one-step breast conserving therapy with negative final margin status in primary breast cancer.

PURPOSE: The purpose of this study was the evaluation of risk factors for local recurrence after breast conserving surgery (BCS) with special focus on the impact of residual disease in specimens of simultaneous additional excisions (AE) from the tumor cavity on patients' outcome in patients with negative final margin status after one-step BCS. METHODS: This study was designed as a single center retrospective cohort study. Patients with primary non-metastatic breast cancer treated by one-step BCS with pathologically confirmed negative resection status between 1990 and 2006 were included. Ipsilateral breast tumor recurrence (IBTR) and overall survival (OS) were evaluated by Kaplan-Meier-estimates. A multivariate Cox proportional hazards regression model was used to identify potential independent prognostic factors associated with the risk of IBTR. RESULTS: A total of 1081 patients were included in this analysis. Simultaneous additional excisions were performed in 79.4% of patients (tumor positive: 12.2%). Median follow-up after primary diagnosis was 124 months. The IBTR rate after 15 years was significantly higher in the group with tumor positive AE (no AE (10.2%) vs. AE tumor positive (27.5%) p = 0.002; AE tumor negative (14.0%) vs. AE tumor positive (27.5%) p = 0.008). The OS rate did not differ significantly between groups. Multivariate analysis revealed residual cancer in AE being associated with a significantly increased relative risk of IBTR of 2.0 (p = 0.014). CONCLUSION: In the current analysis residual disease in simultaneous additional excisions was associated with an increased risk for IBTR despite negative final margin status. This should be considered in the overall therapeutic concept.

Local Resection of Primary Tumor in Upfront Stage IV Breast Cancer.

BACKGROUND: This study aimed to identify the association of local surgery of the primary tumor in metastatic breast cancer (MBC) patients with overall survival (OS) and prognostic factors. PATIENTS AND METHODS: Patients with primary MBC (1990-2006) were included in our retrospective analysis (n = 236). 83.1% had surgery for the primary tumor. OS was evaluated using Kaplan-Meier estimates. Predictive factors for OS were determined. RESULTS: Median follow-up was 123 months for all patients still alive at the time of analysis. In univariate analysis, patients with surgery of the primary tumor had significantly prolonged OS (28.9 vs. 23.9 months). Within the surgery group, patients with MBC limited to 1 organ system had a better outcome (39.3 vs. 24.9 months), as did asymptomatic patients. Independent risk factors for shorter OS were hormone receptor negativity, symptoms, and involvement of ≥ 1 organ system. CONCLUSION: Patient selection for local therapy was confounded by a more favorable profile and a lesser tumor burden before surgery, which might implicate a bias. Nevertheless, our univariate results indicate that local surgery of the primary tumor in MBC patients could be considered as part of the therapeutic regimen in selected patients. However, larger patient numbers are needed to prove these findings in the multivariate model.

Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation.

Master regulators of the epithelial-mesenchymal transition such as Twist1 and Snail1 have been implicated in invasiveness and the generation of cancer stem cells, but their persistent activity inhibits stem-cell-like properties and the outgrowth of disseminated cancer cells into macroscopic metastases. Here, we show that Twist1 activation primes a subset of mammary epithelial cells for stem-cell-like properties, which only emerge and stably persist following Twist1 deactivation. Consequently, when cells undergo a mesenchymal-epithelial transition (MET), they do not return to their original epithelial cell state, evidenced by acquisition of invasive growth behavior and a distinct gene expression profile. These data provide an explanation for how transient Twist1 activation may promote all steps of the metastatic cascade; i.e., invasion, dissemination, and metastatic outgrowth at distant sites.

FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients.

BACKGROUND: The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL). METHODS: Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data. RESULTS: Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm. CONCLUSION: No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid.

Serum HER2 supports HER2-testing in tissue at the time of primary diagnosis of breast cancer.

AIM: HER2 in tissue is of high prognostic value. Soluble HER2, the extracellular domain (ECD), has been suggested to be a helpful biomarker. We investigated whether there is a relationship between HER2 ECD and HER2 in tissue and whether this relationship could be used for diagnostic purposes. METHODS: HER2 ECD was measured in healthy individuals (N=283, 184 females, 99 males), in patients with history of breast cancer (BC) with no evidence of disease (N=249) as well as in BC patients before any treatment (N=565). HER2 in tissue was determined by immunohistochemistry and HER2 ECD was analyzed by immunoassay. RESULTS: HER2 ECD levels were higher in healthy men than in healthy women (medians 12.9 ng/mL vs. 9.9 ng/mL, p<0.001). We observed an age dependency in women that means the older the women the higher the HER2 ECD level. In treated BC patients there was only a weak difference between younger and older women. For patients without distant metastases as well as patients with metastatic disease we observed a correlation of HER2 in serum and tissue. The median concentrations of HER2 ECD were 11.7 ng/mL (13.2 ng/mL) for the HER2-negative (HER2-positive) patients in the non-metastatic-group (p<0.001) and 11.9 ng/mL (16.0 ng/mL) in the metastatic-group (p=0.01). Using a cut-off of 30 ng/mL the HER2 in tissue was always positive, corresponding to a specificity of 99.8% and a sensitivity of 10.3%. CONCLUSIONS: There is a strong correlation between HER2 ECD and HER2 in tissue. HER2 ECD supports the HER2 testing in tissue and may reveal false-negative tissue findings.

Her-2/neu and topoisomerase IIα in advanced breast cancer: a comprehensive FISH analysis of 245 cases.

Her-2/neu gene amplification is an established prognostic factor in breast cancer, and Her-2/neu protein is the target of the therapeutic monoclonal antibody Herceptin. More recently, topoisomerase IIα became a new focus of breast cancer research because of its role as a target for anthracycline therapy. Therefore, we compared Her-2/neu and topoisomerase IIα amplification/deletion in a large series of advanced breast cancer using fluorescence in situ hybridization. Paraffin-embedded archival tissue from 245 patients was retrieved and assessed for Her-2/neu and topoisomerase IIα amplification/deletion by fluorescence in situ hybridization according to standard protocols. Relation to clinical data and survival was sought. A total of 245 cases were analyzed. Amplification for Her-2/neu was seen in 57 cases (23.3%), and for topoisomerase IIα in 12 cases (4.9%). Coamplification was found in 9 samples (3.7%), 3 cases (1.2%) showed amplification of topoisomerase IIα but not of Her-2/neu, and 48 samples (19.8%) displayed amplification for Her-2/neu but not for topoisomerase IIα. Correlation to the histologic type, the stage, or the grade could not be found. Only the amplification of topoisomerase IIα was associated with very poor outcome; survival of cases with amplification of Her-2/neu only was slightly lower than the mean overall survival (27.4 vs. 31.9 mo). Amplification of Her-2/neu and/or topoisomerase IIα is associated with poor overall survival. Amplification of topoisomerase IIα does not seem to be necessarily linked to Her-2/neu-amplification. However, independent determination of these 2 markers seems to be valuable for an individualized therapy of breast cancer patients.

Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups.

PURPOSE: To evaluate efficacy and safety of epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab as neoadjuvant treatment in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. PATIENTS AND METHODS: Patients with centrally confirmed HER2-overexpressing breast cancer (≥ 2 cm or inflammatory) received four 3-week cycles epirubicin and cyclophosphamide (90/600 mg/m(2)) followed by four 3-week cycles paclitaxel (175 mg/m(2)) and trastuzumab (6 mg/kg) before surgery. Trastuzumab was continued after surgery to complete 1 year of treatment. Primary end point was pathologic complete response (pCR) defined as no residual invasive tumor in breast and lymphatic tissue. RESULTS: Thirty-nine percent of 217 enrolled patients achieved a pCR. Breast conservation was possible in 64% of patients. Three-year disease-free survival (DFS) was 88% in patients with pCR compared to 73% in patients without pCR (P = .01). Three-year overall survival (OS) was 96% in patients with pCR compared to 86% in patients without pCR (P = .025). pCR was the only significant prognostic factor for DFS (hazard ratio [HR] 2.5; 95% CI, 1.2 to 5.1; P = .013) and OS (HR, 4.9; 95% CI, 1.4 to 17.4; P = .012) in multivariable analysis. Cardiac toxicity was reported in eight patients (3.7%) of whom six presented with an asymptomatic left ventricular ejection fraction decrease and two with symptomatic chronic heart failure. CONCLUSION: Neoadjuvant combination of trastuzumab and chemotherapy resulted in a high pCR rate in HER2-overexpressing primary breast cancer. Patients with a pCR after neoadjuvant anti-HER2 therapy in combination with chemotherapy followed by maintenance trastuzumab have an improved long-term outcome. Patients without a pCR had an increased risk for relapse and death.

Kinetics of CEA and CA15-3 correlate with treatment response in patients undergoing chemotherapy for metastatic breast cancer (MBC).

The aim of this retrospective analysis is to determine the correlation between tumour marker kinetics (TMK) like carcinoembryonic antigen (CEA) and/or cancer antigen (CA) 15-3 and imaging concerning effectiveness of chemotherapy in metastatic breast cancer (MBC) patients. TMK (CEA, AxSYM, Abbott; CA15-3, Elecsys, Roche) were evaluated in MBC patients (n=77) at the beginning of chemotherapy (pre-treatment value=A), after 20-30 days (first intermediate value=B), after 40-60 days (second intermediate value=C) and at the time the effectiveness of chemotherapy was evaluated with imaging (D). Response to treatment was assessed by standard WHO criteria criteria. For the assessment of biochemical progression and response, four criteria based on TMK were established. The first criterion of progression required that there was an increase ≥ 25% after 40-60 days (C) and the slope per day from B to C exceeds the slope from A to B. The second criterion of progression required that, at the time of staging, the value be ≥ 25% of the pre-treatment value (A), and also, increasing values from C until staging (D) were required. The first criterion of response required that the second intermediate value (C) be decreased by ≥ 25% compared to A (pre-treatment value) and C be lower than B (first intermediate value). The second criterion of response required that D be ≤ 25% of B and D be lower than C. Fifty-four (70%) patients showed a correlation between TMK and imaging results during chemotherapy. In 10 (13%) patients, no correlation was obtained, and in 13 (17%) patients, no biochemical statement was possible because of divergent TMK. In summary, after 1 month, no statement about treatment response was possible by using TMK. The effectiveness or ineffectiveness of treatment could be determined correctly in 40% of patients after 2 months and in 70% of patients after approximately 3 months. The data presented support the hypothesis that TMK are clinically relevant tools to monitor treatment response. Further improvements on their sensitivity can be probably achieved by a prospective study design and by combining with other biomarkers like CA-125 and HER2 shed antigen.

Menopausal status in breast cancer patients with past chemotherapy determines long-term hypoactive sexual desire disorder.

INTRODUCTION: Chemotherapy and endocrine treatment in young breast cancer patients are frequently associated with abrupt menopause. Little is known about the long-term prevalence of hypoactive sexual desire disorder (HSDD) in these patients. AIMS: To examine the effects of adjuvant endocrine therapy on sexual desire in premenopausal patients with breast cancer and past chemotherapy. METHODS: A controlled, cross-sectional study enrolled 47 women with breast cancer or benign breast disease at a tertiary care center. A standardized questionnaire (Sexual Interest and Desire Inventory-Female; SIDI-F) on HSDD was utilized. Serum concentrations for estradiol were measured by a specific assay. MAIN OUTCOME MEASURES: The SIDI-F interview was applied in 35 women with breast cancer (mean age: 42.3 years) with eventual adjuvant endocrine therapy, 2-8 years after chemotherapy, and 13 women with benign breast tumors (mean age: 39.8 years), 2-5 years after diagnosis. RESULTS: Mean SIDI-F scores were similar in the breast cancer group (32.9) and the benign breast disease group (34.0). Subgroup analysis revealed no statistical differences in the mean SIDI-F scores with respect to the actual endocrine therapy. However, in breast cancer patients with menopause induced by chemotherapy or gonadotropin-releasing hormone (GnRH) agonists, the SIDI-F scores were significantly lower (30.7) compared to breast cancer patients with menorrhea (40.4). In breast cancer patients, amenorrhea was associated with significantly lower estradiol levels compared to menorrhea (24 pg/mL vs. 91 pg/mL; P = 0.02). CONCLUSIONS: Cancer treatment that leads to long-term ovarian failure in breast cancer patients has a negative impact on sexual desire. Patients with menopause induced by chemotherapy or GnRH agonists show significantly reduced sexual desire as compared to menstruating patients with past chemotherapy.

Cetuximab monotherapy in advanced cervical cancer: a retrospective study with five patients.

OBJECTIVE: Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Therefore, interest has increased in targeted therapeutics for the treatment of cervical cancer. Cetuximab, a monoclonal antibody, binds specifically to the epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor and other ligands. In cervical cancer the expression of EGFR is reported in up to 85% of the tumour cells. Therefore, Cetuximab monotherapy could be a new option in the treatment of patients with advanced cervical cancer. STUDY DESIGN: Five patients with advanced cervical cancer were treated with Cetuximab monotherapy as third- to fifth-line therapy between 2005 and 2008 in our institution. The tumour stage at the time of diagnosis ranged between IIB and IVB. Cetuximab was applied with an initial loading dose of 400 mg/m(2) followed by a dose of 250 mg/m(2) weekly. RESULTS: Only one patient (20%) had a stable disease, and the other four a progressive disease during Cetuximab monotherapy, after the RECIST criteria. Four out of five patients (80%) developed an acneiform rash as a common observed side effect of Cetuximab therapy. The median survival time from the beginning of the Cetuximab therapy was 8.6 months. CONCLUSION: No advantage could be found in the treatment with Cetuximab monotherapy in patients with advanced cervical cancer in this study. Further studies are necessary to evaluate the significance of Cetuximab in the treatment of advanced cervical cancer.

Dynamic breast MRI in the course of neoadjuvant chemotherapy: standardized evaluation of tumor size and enhancement parameters in correlation to different histopathologic characteristics.

RATIONALE AND OBJECTIVES: Basic exploratory data analysis to evaluate enhancement and tumor size (SIZE) in contrast-enhanced breast magnetic resonance imaging (CE-MRI) during chemotherapy. Correlation with histopathology (human epidermal growth factor receptor (HER2/neu) status and estrogen receptor (ER) score). MATERIALS AND METHODS: Sixty-five women (mean age 47 +/- 10 years) with locally advanced breast cancer (mean SIZE 25 mL) had CE-MRI (three-dimensional fast low angle shot (FLASH); repetition time = 9.1 ms, echo time = 4.8 ms, flip angle (FA) 25 degrees, matrix size 256 x 256 pixels, field of view 350 mm, slice thickness 2 mm, number of slices = 32, one precontrast and five postcontrast series) before and after chemotherapy. Lesion segmentation and subsequent SIZE and enhancement analysis including maximum enhancement (MAX), area under the curve (AUC), time-to-peak (TTP), and maximum upslope (MUS) were performed. Correlation with histopathology (ER score and HER2/neu status). RESULTS: SIZE reduced significantly during therapy (25 mL vs. 5 mL, P < .0001). AUC, MAX, MUS decreased (P < .0001), TTP increased (P < .0001). SIZE and MAX were independent parameters (r(2) = .22). No correlation (P > .01) in any of the parameters with either ER score or HER2/neu status was found. HER2/neu score equal 2+pos. or 3+ showed significantly stronger changes in SIZE (P < .01), MAX (P < .01) and AUC (P < .05) compared to lower HER2/neu score (0 to 2+neg.). CONCLUSIONS: From routine MRI protocol and semiquantitative analysis of signal enhancement curves, information about size, and hemodynamic status of tumors under treatment may be extracted. Reduction in size and maximum enhancement were complementary parameters. In the course of therapy, size and enhancement may develop differently in clinically relevant histopathological subgroups.

Peripartum bilateral uterine rupture in a patient with mixed connective tissue disease with favorable outcome for the severely asphyctic newborn after hypothermia.

PURPOSE: Information about fetal and maternal outcome in pregnant women with mixed connective tissue disease (MCTD) is rare and in part contradictory. The purpose of this study is to review published literature about MCTD in pregnancy in the context of a rare case of peripartum bilateral uterine rupture in a patient with MCTD with favorable outcome for the severely asphyctic newborn after hypothermia. METHOD: The study included a selective literature review based on a PubMed search using the search terms MCTD, Sharp syndrome, uterine rupture and hypothermia, and a detailed report of our case with regard to the MCTD of the patient. RESULTS: Rupture to the backside of the uterus during delivery, independent of prior cesarean section, was unpredictable and its cause remains unclear. The clinical outcome of the newborn was surprisingly favorable and there were no signs of neurodevelopmental sequelae in spite of the fact that the newborn was asphyctic and had a large excess of acids in the umbilical cord blood gas analysis. The favorable outcome is due to treatment with whole body hypothermia. CONCLUSIONS: Any type of prior surgery of the uterus puts the patient at risk during delivery. MCTD might be a risk factor during birth. These patients should be followed closely during pregnancy and should deliver at a center, which provides all options for immediate surgical and neonatological intervention.

Monitoring primary systemic therapy of large and locally advanced breast cancer by using sequential positron emission tomography imaging with [18F]fluorodeoxyglucose.

PURPOSE: To evaluate positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) for prediction of histopathologic response early during primary systemic therapy of large or locally advanced breast cancer. PATIENTS AND METHODS: In a prospective multicenter trial, 272 FDG-PET scans were performed in 104 patients at baseline (n = 104) and after the first (n = 87) and second cycle (n = 81) of chemotherapy. The level and relative changes in standardized uptake value (SUV) of FDG uptake were assessed regarding their ability to predict histopathologic response. All patients underwent surgery after chemotherapy, and histopathologic response defined as minimal residual disease or gross residual disease served as the reference standard. RESULTS: Seventeen (16%) of 104 patients were histopathologic responders and 87 were (84%) nonresponders. All patients for whom baseline SUV was less than 3.0 (n = 24) did not achieve a histopathologic response. SUV decreased by 51% +/- 18% after the first cycle of chemotherapy in histopathologic responders (n = 15), compared with 37% +/- 21% in nonresponders (n = 54; P = .01). A threshold of 45% decrease in SUV correctly identified 11 of 15 responders, and histopathologic nonresponders were identified with a negative predictive value of 90%. Similar results were found after the second cycle when using a threshold of 55% relative decrease in SUV. CONCLUSION: FDG-PET allows for prediction of treatment response by the level of FDG uptake in terms of SUV at baseline and after each cycle of chemotherapy. Moreover, relative changes in SUV after the first and second cycle are a strong predictor of response. Thus, FDG-PET may be helpful for individual treatment stratification in breast cancer patients.

Phyllodes tumour of the breast: clinical follow-up of 33 cases of this rare disease.

OBJECTIVE: The "cystosarcoma phyllodes" of the breast is a rare entity which accounts for 0.5% of all breast neoplasms. The aim of our study was to analyse the clinical management with respect to patient outcome. STUDY DESIGN: The data of 5270 patients with primary breast neoplasms treated in our department between 1984 and 2005 were retrospectively analysed for the histopathologic diagnosis of a cystosarcoma phyllodes. The clinical data was analysed with respect to tumour grading and size, treatment and prognosis. RESULTS: Retrospective analysis of 5270 patients with primary breast neoplasms revealed 33 patients. In the histopathological analysis, tumour grade was classified as benign in 40%, borderline in 27% and malignant in 33% of patients. Breast conserving surgery was conducted in 58% of the patients, mastectomy in 42%. Only one patient was treated with adjuvant radiotherapy after primary surgery. Mean tumour size was 6.9 cm, and no lymph node infiltration was found in the 10 patients who received axillary lymph node dissection. Local recurrence occurred in eight patients (26%). The local recurrence rate was 50% in malignant, 20% in borderline and only 8% in benign tumours. Distant metastases were seen in three patients (9%) with malignant phyllodes tumours. Neither regarding age at primary diagnosis nor in tumour size there was a significant difference between patients with local recurrence or metastatic spread and those without (p=0.284 tumour size; p=0.739 for age; Mann-Whitney U-test). CONCLUSION: Histopathological classification appears to be the strongest prognostic factor in this disease.

The risk of non-sentinel metastases in primary breast cancer.

BACKGROUND: Sentinel node biopsy (SNB) has been established as standard of surgical care in primary breast cancer. If the sentinel node (SN) is negative, axillary dissection (ALND) is not necessary, but if the SN is positive ALND is warranted. This analysis evaluated associated risk factors for non-sentinel metastases in the case of a positive SN. PATIENTS AND METHODS: A retrospective analysis of all SNB performed between 10/1999 and 07/2005 was carried out. RESULTS: A total of 406 patients were included: 214 patients (51%) had SNB with ALND while 197 patients (49%) had SNB only. In 41 of 109 nodal-positive patients, the SN was the only nodal metastasis. In the multivariate analysis, the number of positive SN and the presence of lymphatic vessel infiltration were significant risk factors for additional non-sentinel metastases (p = 0.05 and 0.047, respectively). The risk for non-sentinel metastases was 25.9% without and 59.2% with these risk factors, respectively. CONCLUSION: If the SN is positive, ALND remains obligatory.

Importance of CEA and CA 15-3 during disease progression in metastatic breast cancer patients.

UNLABELLED: The aim of this study analysis was to determine the correlation between elevation of CEA and/or CA 15-3 and disease progression of metastatic breast cancer. MATERIALS AND METHODS: We investigated 119 breast cancer patients who had metachronous metastases. We evaluated levels of CEA and CA 15-3 at the time of first recurrence and at every further disease progression (PD). RESULTS: Increasing value levels of CEA as well as CA 15-3 were found in correlation to the number of PD with a continuously increasing sensitivity in the detection of metastatic disease for each marker alone and especially in combination. At the first time of distant metastasis, CEA and CA 15-3 were above the 95th percentile of healthy individuals in 53.5% and 71.8%, respectively. During disease progression the sensitivities were: 1st PD for CEA/ CA 15-3 54.1%/ 70.6%, 2nd PD 63.5%/ 81.2% and 3rd PD 68.6%/ 90%. CONCLUSION: There is a correlation between elevation of CEA and/or CA 15-3 and disease progression, in breast cancer patients.

Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer.

PURPOSE: Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with selective binding to activatory Fcgamma type I/III receptors, resulting in the formation of a tri-cell complex between tumor cells, T cells, and accessory cells. Patients with metastatic breast cancer were enrolled into a multicenter phase I dose-escalating trial. EXPERIMENTAL DESIGN: Three ascending doses of ertumaxomab (10-200 microg) were administered i.v. on day 1, 7 +/- 1, and 13 +/- 1. Safety and tolerability were the primary objectives. Secondary objectives were antitumor activity and different immunologic variables. RESULTS: Fifteen out of 17 enrolled patients completed the study. One hundred micrograms was identified as the maximal tolerable single dose. Most drug-related adverse events were mild and transient including fever (94%), rigors (47%), headache (35%), nausea (29%), vomiting (29%). Grades 3 and 4 (Common Toxicity Criteria) were lymphocytopenia (76%) and elevation of liver enzymes (47%). One patient (200 mug dose) developed severe hypotension and respiratory distress syndrome, another patient (150 mug dose) developed a systemic inflammatory response syndrome and acute renal failure. Aggravation of congestive heart failure was seen in one patient with preexisting ventricular dysfunction after administration of the third dose (200 microg). All adverse events were fully reversible. Antitumor response was seen in 5 out of 15 evaluable patients (one with a complete response, two with partial responses, two with stable disease) at dose levels of > or = 100 microg. Measurements of cytokines (interleukin-6, interleukin-2, tumor necrosis factor-alpha, and IFN-gamma) suggest a strong T helper cell type 1-associated immune response. The induction of human anti-mouse/anti-rat antibodies was detected in 5 out of 16 (31%) patients. DISCUSSION: Treatment with triple infusions of ertumaxomab yields a strong immunologic response. Doses up to 100 microg can be safely infused with close monitoring of patients. The observed clinical responses are encouraging and indicate antitumor efficacy.