Chemotherapy For Primary Breast Cancer Research Articles

Abstract P3-06-08: Ki-67 mRNA as a predictor for response to neoadjuvant chemotherapy in primary breast cancer

Abstract Background: Pathologic complete response (pCR, ypT0/is) is one of the strongest prognostic factors for primary breast cancer (PBC) in the setting of neoadjuvant chemotherapy (NAC). Factors predictive for response to NAC can help to stratify for an individualized therapy. As chemotherapeutic agents are most active in highly proliferative tumors, it was the aim of the present study to evaluate the potential of Ki-67 as a single proliferation marker, quantitatively measured on the mRNA or protein level, to predict response of PBC to NAC. Material and methods: Pretreatment core cut biopsies from n=72 patients with PBC treated within a randomized phase II trial (1) of anthracylin/taxane based NAC were examined. Immunohistochemistry was performed for the Ki67 antigen on an automated IHC platform (Dako Techmate 500). Ki-67 were assessed either by visual scoring (vIHC) or by quantitative image analysis (qIHC). For quantitative IHC analysis tumor proliferation was analyzed after tumor stroma segmentation using the Aperio Image Analysis toolbox. RNA was extracted from formalin-fixed, paraffin embedded (FFPE) routine biopsies using a bead-based extraction method (STRATIFYER XTRAKT kits). Ki-67, TOP2A and RACGAP1 as well as CALM2 as a house keeping gene were measured via a multiplex quantitative RT-PCR (qPCR). Kaplan-Meier survival estimates, patitioning test and correlation analyses were performed using the SAS JMP® 9.0.0 software. Results: There was only a moderate correlation between Ki-67 mRNA or Ki-67 measured by immunohistochemistry (IHC) and histologic grade (Spearman r = 0.52 p < 0.0001; r = 0.23 p = 0.033, respectively). Conventional visual scoring and qIHC correlated well (r = 0,78 p < 0,0001), while qPCR and qIHC correlated moderately (r = 0,50 p < 0,0001). For Ki-67 determined by visual scoring of standard IHC there was an optimal discrimination at a cut-off of 20% stained nuclei with regard to chemotherapy response. Yet, the difference between pCR-rates for high and low Ki-67 on IHC was non-significant, with 16.3% and 12.5% pCRs in the IHC Ki-67 high and low group, respectively. For Ki-67 IHC analysed by quantitative image analysis there was optimal cut-off at 35% stained nuclei resulting in 37,5% versus 8,7% pCR rate and 54% of pCRs classified correctly. For qPCR determination, high Ki-67 mRNA expression was associated with a high pCR-rate of 36.4% as opposed to 5.8% in tumors with low Ki-67 mRNA levels and 82% classified correctly. Conclusion: High Ki-67 mRNA expression measured by RT-qPCR was predictive for the achievement of pCR to NAC and in this respect was superior to Ki-67 determined by vIHC or qIHC. This is consistent with data on Ki-67 IHC as a predictor of pCR on larger neoadjuvant cohorts (1). RT-qPCR based measurements of Ki-67 mRNA ensures an objective and highly reproducible quantification of proliferative activity from FFPE tissue from routine core cut biopsies. As such it seems to be more robust and meaningful compared to protein-based determination of Ki-67 by IHC, both by visual scoring or quantitative image analysis. 1) Schneeweiss et al, Ann Oncol 2011 2) Fasching et al., BMC Cancer 2011 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-08.

Abstract P3-06-19: Ki-67 mRNA as a predictor for response to neoadjuvant chemotherapy in primary breast cancer

Abstract Background: Stratification of molecular subtypes is of outmost importance for clinical decision making according to the 12th St Gallen Consensus conference (1). The molecular subtypes were originally identified by genome-wide mRNA analysis of fresh tissue specimen (2). Conventional immunehistochemistry assessment using ER, PR, HER2 and Ki67 approximate these subtypes with ∼ 80% concordance (3). Here we have tested a predefined Single-Sample-Predictor for molecular subtyping based on mRNA assessment of ESR1, PGR, HER2, Ki67 and RACGAP1 in a prospective-retrospective study design. Materials and Methods: Pretreatment core cut biopsies from n=100 patients with PBC treated within a randomized phase II trial (1) of anthracylin/taxane based NAC were examined. Immunohistochemistry was performed for the Ki67 antigen on an automated IHC platform (Dako Techmate 500). Ki-67 were assessed either by visual scoring (vIHC) or by quantitative image analysis (qIHC). RNA from formalin-fixed, paraffin embedded (FFPE) routine biopsies was extracted using a bead-based extraction method (STRATIFYER XTRAKT kits). Fresh tissue samokes were prepared by using Qiagen kits. ESR1, PGR, HER2, Ki-67 and RACGAP1 as well as CALM2 as a house keeping gene were measured via a multiplex quantitative RT-PCR (qPCR). Stratification into molecular subtypes was done by stepwise analysis of singular genes using predefined cut-off values. Kaplan-Meier survival estimates, patitioning test and correlation analyses were performed using the SAS JMP® 9.0.0 software. Results: Concordance between RNA based and IHC-based subtyping into Luminal A, Luminal B, HER2 positive and Triple Negative breast cancer by using ESR1, PGR, HER2, Ki-67 and RACGAP1 was at 85%. mRNA based analysis of fixed tumor specimen performed equally well as fresh tissue analysis. The rate of pathological complete Remission for the predefined molecular subtypes has been for Luminal A 0%, Luminal B 19%, HER2 positive 21% (without Trastuzumab) und Triple Negative Tumors 22%. qPCR from fresh tissue specimen resulted in almost identical classifications. The 5-year overall survival rate was significantly different between subtypes as expected: Luminal A 100%, Luminal B 85%, HER2 positiv 80% und triple negativ 60%. Luminal tumors predominantly metastasized into the bones. Cancer related deaths within the first three years were restricted tot he Triple negative Tumortype. Conclusion: The Single-Sample-Predictor based on assessment of only five mRNA Markers (ESR1, PGR, HER2, Ki-67 and RACGAP1) reliably stratified into molecular subtypes by using either fixed or fresh pretreatment core needle biopsies. The mRNA based assessment enables objective and highly reproducible subtyping for clinical routine diagnostics. 1) Goldhirsch et al., Annals of Oncology 2011 2) Perou et al., Nature 2000 3) Sotiriou&Pusztai, NEJM 2009 4) Schneeweiss et al, Ann Oncol 2011 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-19.

Characterisation of tumour-infiltrating macrophages: impact on response and survival in patients receiving primary chemotherapy for breast cancer

The role of the tumour microenvironment and complex cellular interactions has attracted interest in responses to primary chemotherapy. Of particular interest are tumour-infiltrating T cells and tumour-infiltrating macrophages (TIMs). We evaluated TIMs and their key activation markers in patients with breast cancer undergoing primary chemotherapy related to response and survival. One hundred and ninety nine patients with large or locally advanced breast cancers received primary chemotherapy. Clinical data, histopathological responses to chemotherapy and survival were examined related to infiltrating cells in tumour microenvironments: cluster of differentiation (CD)3 (pan T cell); CD4 (helper T cells); CD8 (cytotoxic T cells); CD25 (activated T cells); CD68, suppressor of cytokine signalling (SOCS)1, SOCS3 (macrophages); and CD11c and CD205 (dendritic). In tumours demonstrating better responses to chemotherapy, there were significantly fewer CD4(+) T-helper cells than a poorer response (p < 0.05). There were increased numbers of SOCS3 expressing macrophages (pro-inflammatory) in tumours with complete pathological responses compared with no response to chemotherapy (p < 0.05). There was no association between SOCS1 expressing macrophages (anti-inflammatory) and tumour response. Multivariate analysis revealed that factors indicating better survival were receiving anthracycline plus docetaxel (ExpB = 1.166; p = 0.006), better pathological chemotherapy response (ExpB = 0.309; p = 0.009) and a low macrophage SOCS1 expression (ExpB = 13.465; p = 0.044). This study highlights the heterogeneity of TIMs and provides further insight into complex interactions within tumours. The results emphasise the importance of characterising activation status of infiltrating macrophages and provides proof of principle for using macrophage SOCS protein expression as a survival predictor. The apparent impact of macrophage subsets on overall survival underlines the therapeutic potential of manipulating macrophage activation in cancer.

Persistent pain, sensory disturbances and functional impairment after adjuvant chemotherapy for breast cancer

Abstract Background Persistent pain after breast cancer treatment (PPBCT) is a considerable clinical problem affecting between 25 and 60% of breast cancer survivors [1]. Several risk factors have been proposed, among them nerve damage caused by adjuvant treatment [2]. Taxanes used in adjuvant therapy for breast cancer are neurotoxic, and thereby being a potential risk factor for PPBCT and sensory disturbances. However, the long term influence of taxanes on PPBCT is not well documented. Thus, the aim of this study was therefore to compare a nationwide cohort treated with cyclophosphamide and epirubicin + docetaxel (CE + T) versus a nationwide cohort treated with cyclophosphamide, epirubicin and fluoruracil (CEF), in order to assess differences in reporting of PPBCT, sensory disturbances in surgical area, symmetric peripheral sensory disturbances, and functional impairment. Methods A comparative nationwide cross-sectional questionnaire study on two cohorts treated with CEF respectively CE + T, based on the Danish Breast Cancer Cooperative Groups database. Inclusion criteria were identical i both cohorts: women treated with adjuvant chemotherapy for primary breast cancer, age 18–69 years, without recurrence. Exclusion criteria: bilateral or previous breast surgery, including reconstructive surgery. The same questionnaire [1] was used for both cohorts and contained detailed questions regarding pain intensity and frequency and sensory disturbances in the breast area, side of chest, axilla and arm, bilateral peripheral sensory disturbances in the hands and feet, and questions regarding daily activities. Results 1241 patients treated with CEF in 2005-2006 and 1652 patients treated with CE + T in 2007–2008 were included. 664 (54%) with CEF and 861 (53%) patients with CE+T reported PPBCT. In the multivariate analysis including available risk factors, CE + T did not increase risk of PPBCT, adjusted OR 0.95 (95%C10.81–1.11), p = 0.52, compared to CEF. Patients treated with CE + T had a lower risk of sensory disturbances in the area of surgery compared with CEF, adjusted OR 0.75 (95%C1 0.62–0.90), p = 0.002. More CE+T patients reported peripheral sensory disturbances in the hands, adjusted OR 1.56 (95%C11.27–1.92), p &lt; 0.0001, and in the feet, adjusted OR 2.0 (95%C1 1.66–2.42), p &lt; 0.0001, compared to CEF. There was no difference in functional impairment (p = 0.62). Conclusion Docetaxcel as adjuvant treatment for breast cancer does not increase the risk of PPBCT, sensory disturbances in the surgical area or functional impairment, but increase the risk for peripheral sensory disturbances.

Feasibility of prior administration of cyclophosphamide in TC combination treatment

TC (docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) q3w) combination is used for neoadjuvant/adjuvant chemotherapy in primary breast cancer. The incidence of allergic reaction is reportedly more common in patients who receive docetaxel before cyclophosphamide. This study aims to determine the significance of cyclophosphamide and docetaxel administration sequence. Prospective analysis was performed of 49 consecutive patients treated with TC for stage I-IIB breast cancer from March 2010 to June 2011. Premedication was administered with granisetron, dexamethasone, and chlorpheniramine. Patient charts were reviewed for completion rate and adverse events. Two-tailed Fisher exact test was used to evaluate adverse events between prior cyclophosphamide and prior docetaxel. Of 49 patients, 26 received docetaxel prior to cyclophosphamide and 23 received cyclophosphamide before docetaxel. There were no differences in patient characteristics between the two groups. Completion rates were 95.6 % in the prior cyclophosphamide group, and 100 % in the prior docetaxel group. The relative dose intensities of docetaxel and cyclophosphamide were 94.5 and 94.8 % in the prior cyclophosphamide group, and 98.5 and 98.7 % in the prior docetaxel group (p < 0.01). In the prior cyclophosphamide group, severe neutropenia occurred in 96 % of patients, but in only 46 % of patients in the prior docetaxel group (p < 0.01). Significantly fewer cases of skin eczema (27 versus 61 %), nausea (8 versus 48 %), stomatitis (23 versus 61 %), and diarrhea (4 versus 30 %) were observed in the prior docetaxel group as compared with the prior cyclophosphamide group (p < 0.01). Decreased incidences of fatigue (50 versus 65 %) and edema (19 versus 35 %) were found in the prior docetaxel group (p < 0.05). No difference was observed in allergic reaction or neuropathy between the two groups. Patients receiving cyclophosphamide prior to docetaxel were at increased risk of several toxicities as compared with patients receiving docetaxel prior to cyclophosphamide in TC combination therapy.

Predicting response to neoadjuvant chemotherapy in primary breast cancer using volumetric helical perfusion computed tomography: a preliminary study

To investigate whether CT-derived vascular parameters in primary breast cancer predict complete pathological response (pCR) to neoadjuvant chemotherapy (NAC). Twenty prospective patients with primary breast cancer due for NAC underwent volumetric helical perfusion CT to derive whole tumour regional blood flow (BF), blood volume (BV) and flow extraction product (FE) by deconvolution analysis. A pCR was achieved if no residual invasive cancer was detectable on pathological examination. Relationships between baseline BF, BV, FE, tumour size and volume, and pCR were examined using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was performed to assess the parameter best able to predict response. Intra- and inter-observer variability was assessed using Bland-Altman statistics. Seventeen out of 20 patients completed NAC with four achieving a pCR. Baseline BF and FE were higher in patients who achieved a pCR compared with those who did not (P = 0.032); tumour size and volume were not significantly different (P > 0.05). ROC analysis revealed that BF and FE were able to identify responders effectively (AUC = 0.87; P = 0.03). There was good intra- and inter-observer agreement. Primary breast cancers which exhibited higher levels of perfusion before treatment were more likely to achieve a pCR to NAC.

Efficacy analysis of THP-containing regimens as neoadjuvant and adjuvant chemotherapy for primary breast cancer

To evaluate the effect of anthracycline pirarubicin-based regimen in association with different ways of fluorouracil (5-Fu) as neoadjuvant and adjuvant chemotherapy for primary breast cancer. Two hundred and eighty-nine primary breast cancer patients who were to be operated, two to eight cycles of pirarubicin in association with cyclophosphamide and 5-Fu (CTF or CTFci regimen) were given before operation. The pathological response rate, effect and its relation with the infusion routes of 5-Fu were analyzed. The overall pathological complete remission (pCR) rate was 28.4%. The median follow-up period was 39 months. The 5-year DFS was 87.6% (95% CI:82.1% to 92.7%), 5-year DDFS was 89.9% (95% CI:84.0% to 95.8%), and overall survival was 99.6%. CTFci (5-Fu, continuous infusion) regimen was superior to CTF regimen in pCR rates (32.3% vs. 20.2%, P = 0.037), and 5-year DDFS were 92.9% and 80.1%, respectively (P = 0.015). The pCR group was superior to non-pCR group in 5-year DDFS (92.4% vs. 85.6%, P = 0. 033). The pCR rate of patients with ER/PR-positive tumor was significantly lower than those of ER/PR-negative (P = 0.004). The 5-year DDFS rates of HER-2 (+) and HER-2(-) groups were 75.0% and 91.9%, respectively (P = 0.043). In the ER/PR-positve group, the 5-year DDFS of CTFci regimen was superior to those of CTF regimen, 91.4% vs. 81.4% (P = 0.047). CTF/CTFci regimen as neoadjuvant and adjuvant chemotherapy is effective for primary breast cancer. CTFci regimen is superior to CTF regimen in pathological complete response rate and 5-year DDFS. CTFci regimen may do better to ER/PR (+) patients' benefits compared with CTF regimen.

P4-02-07: Influence of the Progesterone Receptor on the Prognosis of Breast Cancer in Interaction with Other Prognostic Factors.

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

P5-13-20: TOP2A Amplification Have Associated with Response to Anthracycline-Based Preoperative Chemotherapy in Primary Breast Cancer.

Abstract Background: Recent studies have suggested that HER2 gene amplification or overexpression have association with sensitivity of anthracycline-based chemotherapy. Preclinical studies found that TOP2A amplification or deletion only could be detected in HER2 amplification or over-expressive cases. And TOP2A protein is the target of anthracycline. In fact, the value of HER2 for predicting response to anthracycline-based chemotherapy in breast cancer may be more likely related to the concomitant amplification of the TOP2A gene. In this study we studied the association between TOP2A gene amplification and response to anthracycline-based preoperative chemotherapy. Methods: 309 early and local advanced breast cancer cases were enrolled in our study. HER2 proteins were qualitatively analysed by IHC, and TOP2A gene alterations were quantified by real-time polymerase chain reaction (RT-PCR) in primary tumor core biopsies from all HER2 over expressive cases. The enrolled patients received an intense dose dense (IDD) (CE, Cyclophosphamide + Epirubicin) or conventionally (TE, Paclitaxel+Epirubicin) scheduled anthracycline- based preoperative chemotherapy. The tumor was evaluated every two cycles. Median time on study for 309 patients with follow-up was 38 months. Results: The pCR was 14.3%. HER2 overexpression was found in 80/309 (25.9%) breast cancer cases, of which 61/80 cases have been tested for TOP2A status. 19/80 cases have not been tested for TOP2A status because of lacking core biopsies tumor tissue after pathological diagnosis. HER2 overexpression was associated with a significantly higher pCR rate compared to HER2 lower expression (27.5% vs. 9.6%, P&amp;lt;0.001). Further analysis was carried on and found the significantly higher pCR rate in TOP2A co-amplified cases compared to TOP2A deleted or normal cases (56.3% vs. 13.8%, P=0.001). HER2 overexpression was associated with a significantly higher pathologic complete response (pCR) rate only when TOP2A was co-amplified (56.3% vs. 9.6%, P&amp;lt;0.001), but not when deleted or normal (13.8% vs. 9.6%, P=0.183), compared to HER2 lower expression tumors. The interaction between HER2 or TOP2A and anthracycline-based regiment was observed not only in IDD but conventionally scheduled preoperative chemotherapy. Discussion: Previous studies demonstrate that TOP2A gene amplification may define a subtype of HER2−positive breast cancer, This subtype of breast cancer may be highly sensitive to anthracycline-based chemotherapy, which may improve progression in HER2 and TOP2A co-amplification cases. Howerver, this viewpoint needs suppose from preoperative chemotherapy. Using RT-PCR to test TOP2A statue from 61 primary breast cancer tumor tissue, we demonstrate that TOP2A amplification breast cancer have highly sensitive to anthracycline-based preoperative chemotherapy. This finding suggests that TOP2A as a predictive marker in breast cancer should be included in future studies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-20.

P3-14-20: Concomitant Taxane-Anthracyclin Regimen for Neoadjuvant Chemotherapy of Primary Breast Cancer: Experience from a Cohort of 223 Patients Treated in a Single Institution.

Abstract Background: Neoadjuvant chemotherapy (NAC) may be an alternative to mastectomy for localized breast cancer ineligible for breast conservation. The optimal schedule (sequential versus concomitant) remains controversial. Based on encouraging results of a phase 2 study (Luporsi E. et al, ASCO 2000) a concomitant docetaxel (D) and epirubicin (E) neoadjuvant combination is applied in neoadjuvant setting in our institution since 2001 for HER2−negative patients (pts). The results of this combination are presented, with a particular focus on pathological complete response (pCR) and conservation rate. Methods: Between 2001 and 2010, 223 pts received NAC for a T2-T3 breast cancer initially ineligible for conservative surgery, but with hope of breast conservation in case of downstaging by pre-operative medical treatment. Six cycles of D (75mg/m2) and E (75mg/m2) were administered every 3 weeks before surgery, with prophylactic support of G-CSF in order to reduce the risk of febrile neutropenia and to maintain the dose-intensity of the NAC. All patients eligible for breast conservation after NAC underwent lumpectomy, the others were treated by mastectomy. In all cases, an axillary dissection was performed. After lumpectomy all patients received radiation therapy, after mastectomy RT was limited to high risk of loco-regional relapse. Patients with positive hormonal receptors (HR+) received hormonal therapy. Results were analyzed in term of breast conservation rate (BCR), pathologic response rate (pCR defined as no residual invasive tumour in breast and axilla, according to Sataloff's classification) and safety. Results: Mean age of patients was 49,6 years (range: 26–71). Median clinical tumor size was 40mm (range 20–110). Histological subtypes were:78,0 % ductal, 15,3 lobular, 1,8 % ductal/lobular and 4,9 % other types. SBR grading was: grade I: 14,3 %, grade II: 46,2 %, grade III: 33,2 % and 6,3 % unspecified. 77,3 % were HR+, 19,7 % of tumours were triple negative (HER2 unknown for 38 cases). A breast conservation was achievable for 73,5% of patients, the pCR rate was 20,6%. At a median follow up of 48 months, 31 pts relapsed: 9 pts (4%) experienced a local relapse, 5 regional and 28 distant recurrences occured. Additional data about safety and survival will be provided for the meeting. Conclusions: For HER2−negative tumours, 6 cycles of a concomitant taxane-anthracyclin pre-operative combination allowed a 20,6% pCR rate, slightly lower than obtained with 8 cycles of a sequential regimen in several published trials. However breast conservation rate was similar with a low risk of local recurrence. According to these results, concomitant cytotoxic combination is an acceptable option for neoadjuvant treatment of breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-20.

Comparison of Actual Hospital Costs versus DRG Revenues for In-Patient Treatment of Febrile Neutropenia during Adjuvant Anthracycline plus/minus Taxane-Based Chemotherapy for Primary Breast Cancer

Background: In flat-rate reimbursement systems, the hospital’s own costs should not exceed its revenues. In a cohort of primary breast cancer (pBC) patients, costs and reimbursement for febrile neutropenia (FN) were compared to verify cost coverage. Methods: A prospective, observational study in pBC patients receiving adjuvant anthracycline ± taxane-based chemotherapy calculated the costs per in-patient FN episode. The correlating revenues were retrospectively analyzed from diagnosis-related group (DRG) invoices. The actual costs of the therapies were compared to the individual DRG revenues, and the results are presented from the provider’s perspective. Results: In 50 patients, n = 11 patients were treated for FN as in-patients. The hospital’s overall treatment costs were € 18,288, on average (Ø) € 1663 per case (range € 1139–2344); the overall DRG revenues were € 23,593, Ø € 2145 per case (range € 1266–2660). In n = 8 cases, the DRGs were cost covering, and in n = 3 cases, a loss was observed, but overall resulting in a gain of Ø € 482 per case and thus being cost covering for the provider. Inadequate DRG coding (n = 4/11; 36.4%) resulted in a preventable loss of Ø € 1069/case. Conclusions: The costs of FN treatment vary substantially and DRG reimbursements do not necessarily reflect the provider’s costs. Surprisingly, the in-patient treatment of FN here is overall more than cost covering if adequately coded. The main reasons are asymmetrical costs for this FN low-risk pBC group. These results emphasize the importance of correct medical coding to avoid potential losses.

CD24 Ala57Val polymorphism predicts pathologic complete response to sequential anthracycline- and taxane-based neoadjuvant chemotherapy for primary breast cancer

Overexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, we evaluated the clinical relevance of these polymorphisms with respect to their potential to predict a pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC), one of the strongest prognostic factors in this setting. A total of 257 patients were randomized to either doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel (Doc) as NCT for T2-4 N0-2 M0 PBC as part of an international, multicenter, randomized phase II trial. CD24 polymorphisms were analyzed on germ line DNA and correlated with clinicopathologic variables and pCR. No significant associations were found between either of the polymorphisms and any of the clinicopathologic variables. In a multivariate analysis, CD24 Val/Val genotype was the only significant predictor of pCR (OR: 4.97; P = 0.003). The predictive potential was significant in both treatment arms and in the hormone receptor-positive subgroup. There was no correlation between CD24 3'UTR (TG/Del) genotype and pCR. We did not observe any association between CD24 genotype and CD24 protein expression or in vitro chemosensitivity, but there was a significant correlation between CD24 Val/Val and intratumoral lymphocyte aggregates. In conclusion, CD24 Ala/Val SNP is a strong and independent predictor of pCR after NCT for PBC and may affect immune functions rather than tumor characteristics. Further evaluation of the CD24 function and validation of its predictive potential are clearly warranted.

18F-Fluorodeoxyglucose positron emission tomography optimizes neoadjuvant chemotherapy for primary breast cancer to achieve pathological complete response

To assess the usefulness of positron emission tomography combined with computed tomography using (18)F-fluorodeoxyglucose (FDG PET/CT) for optimizing chemotherapy during neoadjuvant chemotherapy for primary breast cancer. One hundred and eight patients (110 tumors) with breast cancer (≥2 cm, stages II and III) received neoadjuvant chemotherapy consisting of an anthracycline-based regimen and taxane. The maximal value of the baseline standardized uptake value (SUV) and the change in SUV after four cycles of an anthracycline-based regimen relative to baseline SUV were assessed for predicting pathological complete response (pCR) after sequential taxane. Tumors with pCR had significantly higher baseline SUV (9.3 ± 3.7 SD) compared to those with non-pCR (7.2 ± 3.8 SD) (p = 0.02), but there was a considerable overlap between two groups. On PET scan after four cycles of chemotherapy, thirty-three patients (33.7%) with a 72.1% or greater reduction in SUV were considered as responders and the performance in predicting pCR had a sensitivity of 88.9% and specificity of 78.7%. The baseline SUV could not be a useful indicator for predicting pCR due to the wide range in sensitivity. On the other hand, a relative change in SUV after completion of an anthracycline-based regimen could be useful for predicting pCR.

Interaction of the progesterone receptor expression with other prognostic factors in primary breast cancer.

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

A longitudinal study of alterations in cognitive function and brain metabolites among women receiving chemotherapy for primary breast cancer.

TPS240 Background: Cancer patients treated with chemotherapy frequently complain of cognitive deficits during treatment and often for some years thereafter. Many cytotoxic drugs commonly used in chemotherapy result in cognitive deficits via direct neurotoxicity to the cerebral parenchyma, neuronal axons, microglia, and/or oligodendrocytes. This chemotherapy-induced neurotoxicity may lead to changes in the levels of various brain metabolites. Previous studies using Magnetic Resonance Spectroscopy (MRS) suggest that cognitive impairment is accompanied by changes in specific brain metabolites such as N-acetyl aspartate (NAA), creatine, choline, and myo-inositol (Jung RE et al; 1999, Ross AJ et al; 2004). Because metabolic changes are likely to precede clinically detectable cognitive dysfunction, MRS may allow early identification of patients who will develop cognitive dysfunction associated with cancer treatments. Methods: The aims of this study are 1. to evaluate cognitive function using neuropsychological testing, 2. to collect MRS data from left thalamus, hippocampus, frontal and parietal lobes, 3. to characterize the temporal relationship between brain metabolite concentrations and cognitive functioning. Fifty newly diagnosed breast cancer patients, who are to receive adjuvant chemotherapy are evaluated with a battery of neuropsychological tests and MRS at three time points: before receiving chemotherapy (baseline), 4-8 weeks after completing their final treatment, and one year later. Patients also complete self-report questionnaires at all three time points. Exclusion criteria include CNS metastasis and depression. Neuropsychological tests are scored by standard procedures with adjustments for age, gender and education, and converted to Z-scores. Concentrations of NAA, creatine, choline, and myo-inositol are calculated from the MRS data for all time points by standard methods, with correction for the cerebrospinal fluid fraction in the voxel. Results of this study could lead to greater understanding of chemotherapy-induced cognitive impairment and improved prevention/treatment strategies in this population of cancer survivors.

Reduction of toxicity by reversing the order of infusion in docetaxel and cyclophosphamide (TC).

2576 Background: Although TC (docetaxel 75mg/m2 and cyclophosphamide 600mg/m2, q3w) combination is among the most widely used neoadjuvant/adjuvant chemotherapy for primary breast cancer, allergic reactions including rash and edema are occasionally met. This study aimed to determine whether adverse events (AEs) particularly allergic reactions were more common in TC, docetaxel infused prior to cyclophosphamide compared to reverse TC (rTC), cyclophosphamide infused prior to docetaxel. Methods: Retrospective analysis was done at a single institution in consecutive 85 patients treated with TC or rTC for stage 1-3 breast cancer from 2007 to 2010. TC was used in former 2.5 years and rTC in latter 1.5 years. Dexamethasone was administered to prevent allergic reaction in both. Two tailed Fisher Exact test was used to evaluate the significance of proportional differences in AEs between two regimens according to CTCAE ver.4. Results: Among 85 patients, 50 were in TC and 35 in rTC. Baseline characteristics of two groups were not different. Significant decreases in fatigue (11% vs. 72%), edema (11% vs. 48%), neuropathy (14% vs. 66%), and myalgia (6% vs. 48%) were observed in rTC as compared with TC. There were also decreased incidences of grade 3 and 4 edema (0% vs. 2%), neuropathy (3% vs. 10%), myalgia (0% vs. 2%), and rash (6% vs. 10%) in rTC. All 2 cases who did not complete their treatments were in TC due to rash. Hematologic AEs were not different in 2 regimens. Conclusions: Patients receiving cyclophosphamide infused prior to docetaxel were decreased risk for several toxicities as compared with docetaxel infused prior to cyclophosphamide. The immunosuppressive effects of cyclophosphamide may reduce hypersensitivity reactions with docetaxel by reversing order of infusion.

Sentinel Node Biopsy After Primary Chemotherapy in Breast Cancer: A Note of Caution from Results of ABCSG-14

Over the past years, experience has been increasing with lymphatic mapping and sentinel node biopsy (SNB) after preoperative chemotherapy for breast cancer, with a wide range of results reported in the literature and final conclusions on the diagnostic value and clinical consequences of this sequential approach still missing. Between 1999 and 2002, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) conducted a prospective randomized multicenter trial comparing three versus six preoperative cycles of epirubicin/docetaxel + granulocyte colony-stimulating factor for operable breast cancer. Of the 292 patients recruited to the trial overall, 111 were enrolled in a prospective subprotocol for performing LM and SNB in addition to obligatory axillary lymph node dissection (ALND) after PC. SNB after PC identified at least one sentinel node in 100 of 111 patients (identification rate 90%). In six cases, a false-negative SN was identified, resulting in a false-negative rate of 13% (6 of 47). We only found little correlation between patients and tumor characteristics and the identification rate or false-negative rate. Lymphatic mapping and SNB after primary chemotherapy failed to predict histologic infiltration of the sentinel node with sufficient sensitivity. The routine use of SNB after primary chemotherapy should therefore be discouraged.

The assessment of breast cancer response to neoadjuvant chemotherapy: comparison of magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography

Neoadjuvant chemotherapy for locally advanced breast cancer is a widely accepted treatment. For assessment of the tumor response after chemotherapy, both magnetic resonance imaging (MRI) and (18)F-fluorodeoxyglucose positron emission tomography (PET) are promising methods. To retrospectively compare MRI and PET in the assessment of tumor response to neoadjuvant chemotherapy for primary breast cancer with the pathologic response as the reference standard. Between August 2006 and May 2008, 32 women with breast cancer underwent concurrent MRI and PET before and after neoadjuvant chemotherapy. For response assessment, we calculated the changes in the maximum diameters of the tumor (ΔD(max)) on MRI, and the changes in the standard uptake values (ΔSUV) on PET. The correlation between the ΔD(max) and ΔSUV was analyzed using Pearson's correlation coefficient. The correspondence rates between each imaging modality and pathologic assessment were calculated. For prediction of the pathologic complete response (pCR), the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were analyzed using the McNemar test. The pathologic assessment of tumor response to neoadjuvant chemotherapy identified eight complete responses (25.0%), 10 partial responses (31.2%), and 14 non-responses (43.8%). The change in size on MRI was moderately correlated with the change in SUV on PET (r=0.574, p=0.001). The correspondence rate of response assessment was 75.0% (24/32) between MRI and pathologic response and 53.1% (17/32) between PET and pathologic response. For the pCR, specificity (95.8% vs. 62.5%) and PPV (83.3% vs. 47.1%) were statistically higher on MRI than PET (p < 0.05), while sensitivity (100.0% vs. 62.5%) and NPV (100.0% vs. 88.5%) on PET tended to be higher than MRI. Before and after neoadjuvant chemotherapy for breast cancer, the ΔD(max) of MRI correlated moderately with the ΔSUV on PET. For prediction of the pCR, MRI proved to be a more specific modality than PET.

Abstract P2-09-05: Risk Group Selection in Primary Breast Cancer According to ASCO Recommended Biomarkers Onkotype DX and uPA/PAI-1: First Experience from Prospective Multicenter WSG Plan B Trial

Abstract Background: Both the Oncotype DX multi-gene assay and invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy in primary breast cancer (BC). Material and Methods: The West German Study Group (WSG) Plan B trial (planned n=2,448) is evaluating anthracyline-free adjuvant chemotherapy (6x TC) vs. standard 4xEC-4xDOC in HER2- negative BC with 0-3 positive lymph nodes, Oncotype DX is used as selection criterion where pts with RS&amp;gt; 11 are randomized to one of the two chemotherapy arms and pts with RS ≥11 treated with hormonal therapy alone. uPA/PAI-1 (both low vs. either/both high), measured by ELISA, is obtained as an optional risk factor. Results: By June 2010, 1064 patients had been randomized in Plan B (96 recruiting centers). In 153 patients (27 centers), uPA and PAI-1 had been measured; for 131 (84 N0, 47 N+) of these, Oncotype DX Recurrence Score® (RS) results were also available. When considered as continuous variables, RS was weakly positively correlated (Spearman's coefficient) with uPA (rs=0.18, p=0.04) and with PAI-1 (rs=0.23, p=0.01). When considered as risk categories/(Table 1), there was a weak concordance between RS and uPA/PAI-1, using either the standard RS cutoff points (18 and 30) or the TAILORx trial cutoff points (11 and 25). Table T: Association between RS and uPA/PAI-1 categories Assignment of high risk was most strongly concordant between uPA/PAI-1 and RS (RS &amp;gt; 25: 22/25 patients had high uPA/PAI-1; RS &amp;gt;30: 14/15 patients had high uPA/PAI-1). This high-risk concordance extends to N0 patients (RS&amp;gt;25: 17/19 N0 pts had high uPA/PAI-1; RS&amp;gt;30: 11/12 pts had high uPA/PAI-1). Discussion: For the first time, risk groups in primary breast cancer according to both Oncotype DX and uPA/PAI-1 have been compared. These preliminary data show that the high RS group seems highly concordant with the prospectively assessed invasion markers uPA/PAI-1. However, within low and intermediate RS, uPA/PAI-1 could still identify a substantial collective at risk; low uPA/PAI-1 could define a clinically relevant low-risk collective within risk groups that would be classified as “intermediate” according to the multigene assay Oncotype DX. Additional recruitment and outcome assessment of the ongoing multicenter WSG Plan B trial will address the clinical significance of these findings. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-05.

A Marker of Homologous Recombination Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy in Primary Breast Cancer

To assess the prevalence of defective homologous recombination (HR)-based DNA repair in sporadic primary breast cancers, examine the clincopathologic features that correlate with defective HR and the relationship with neoadjuvant chemotherapy response. We examined a cohort of 68 patients with sporadic primary breast cancer who received neoadjuvant anthracylcine-based chemotherapy, with core biopsies taken 24 hours after the first cycle of chemotherapy. We assessed RAD51 focus formation, a marker of HR competence, by immunofluorescence in postchemotherapy biopsies along with geminin as a marker of proliferative cells. We assessed the RAD51 score as the proportion of proliferative cells with RAD51 foci. A low RAD51 score was present in 26% of cases (15/57, 95% CI: 15%-40%). Low RAD51 score correlated with high histologic grade (P = 0.031) and high baseline Ki67 (P = 0.005). Low RAD51 score was more frequent in triple-negative breast cancers than in ER- and/or HER2-positive breast cancer (67% vs. 19% respectively; P = 0.0036). Low RAD51 score was strongly predictive of pathologic complete response (pathCR) to chemotherapy, with 33% low RAD51 score cancers achieving pathCR compared with 3% of other cancers (P = 0.011). Our results suggest that defective HR, as indicated by low RAD51 score, may be one of the factors that underlie sensitivity to anthracycline-based chemotherapy. Defective HR is frequent in triple-negative breast cancer, but it is also present in a subset of other subtypes, identifying breast cancers that may benefit from therapies that target defective HR such as PARP inhibitors.