bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of the sequential FEC 100-Taxotere chemotherapy regimen as an adjuvant or neoadjuvant treatment for breast cancer. Experience of a single institution.
Authors: Cousin S , Mailliez A , Servent V , Vanlemmens L , Vennin P , Jacques B
Published: December 2010

Abstract #4110

The sequential treatment of 3 FEC 100- 3 Taxotere is one of the standard treatments in the adjuvant and neoadjuvant settings. However , if the general tolerability of this regimen is acceptable, few studies have been devoted to the hematological toxicity outside of clinical trials and to the need of Granulocyte growth factors (GCSF)  Patients and methods: We studied the incidence of grade 3 and 4 neutropenia observed at D1 of each cycle and of febrile neutropenia induced by the FEC100 -Taxotere regimen in 284 patients (1757 chemotherapy cycles). Side effects were graded according to NCI criteria. The relative dose intensity (RDI) was the ratio between the dose received by each patient and the duration of treatment between the first dose and 3 weeks after the last administration. GCSF were given according to the recommendations, mostly after febrile neutropenia.  Results: 1757 cycles were administered; 23 (1.3%) were deleted mostly because of non hematological toxicities due to Taxotere. A febrile neutropenia (hyperthermia and grade 4 neutropenia) was observed in 0.1% of the FEC100 cycles and in 0,7% after Taxotere. In about 2/3 of the cases febrile neutropenia was observed at the first cycle. Hyperthermia and grade 3 neutropenia was observed in 0,6% of the cycles after FEC100 and 0,2% after Taxotere. A RDI of more than 85% was observed for the overall treatment in 84% of the patients, for FEC100 in 91%, for Taxotere in 76 %. Granulocyte growth factors were used in 76 cycles. The efficacy results according to RDI after neoadjuvant treatment (n= 115) will be presented.  Discussion and Conclusion: This study confirms the results previously published (Debled 2007).The hematological tolerability of the FEC100-Taxotere regimen is acceptable without GCSF. Nevertheless, febrile neutropenia occurs essentially at the first cycle, risk factors should be looked for and this particular patient population might benefit of GCSF. Furthermore, up to 16% of the patients receive less than 85% of the theoretical dose, essentially due to neutropenia and might also benefit of a treatment with GCSF.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4110.
Relative dose intensity reduction in breast cancer adjuvant chemotherapy.
Authors: Faustino C , Afonso N , Sousa B , Espírito Santo J , Rodrigues H
Published: December 2010

Abstract #4111

Introduction  In breast cancer (BC), adjuvant chemotherapy has become a standard therapy, resulting in prolonged survival. This goal might be affected by chemotherapy dose reductions and delays that are not uncommon features.  The aim of this study was to assess relative dose intensity (RDI) reduction risk factors and define predictive factors.  Methods  Data regarding BC patients (pts) under anthracycline based-chemotherapy regimens was collected, retrospectively, from two Portuguese centres, between 1998 and 2007, and combined into a database of 783 individuals. Primary G-CSF prophylaxis was not planned. DIEP® (Dose Intensity Evaluation Programme) software was developed to allow calculation of RDI, and includes demographic data, clinical and treatment characteristics, chemotherapy dose modifications and delays, haematological toxicities and patterns of use of G-CSF.  Univariate and multivariate analysis was performed to identify factors related to RDI ≤ 90% in these patients. A value of P < 0.05 was considered of statistical significance.  Results  Pts distribution according to chemotherapy: doxorubicin/cyclophosphamide (A60 C600) – 31,5%, 5-fluorouracil/epirubicin/cyclophosphamide (F500 E100 C500) – 19,2%, 5-fluorouracil/doxorubicin/cyclophosphamide (F500 A50 C500) – 49,3%. A RDI ≤ 90% was frequent across all chemotherapy regimens, but most common in pts receiving FEC (34,7%) and AC (23,5%) regimens.  According to univariate analysis, factors related to reduction of RDI were: age ≥ 65 years (P = 0,006), node positive (P = 0,037), chemotherapy regimen (P < 0,001), number of pts with at least one G-CSF administration on secondary prophylaxis (P = 0,015), number of pts with at least one G-CSF administration due to neutropenia or febrile neutropenia (P < 0,001 ) and number of pts with at least one hospitalization due to febrile neutropenia (P < 0.001). In multivariate analysis, independent predictors of RDI ≤ 90% were: AC regimen (P = 0,008), FEC regimen (P = 0,002), age ≥ 65 years old (P = 0,018), node positive (P = 0,016) and at least one hospitalization due to febrile neutropenia (P < 0,001).  Conclusion  A considerable number of our BC pts, submitted to anthracycline based-chemotherapy, continue to experience RDI reductions. Most affected pts were more than 65 years old, or under FEC or AC regimens, or had node positive tumors. This data might help to identify a subgroup of BC pts that benefit from primary prophylaxis with G-CSF.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4111.
Phase 2 study of dual VEGF/HER2 blockade with pazopanib + lapatinib in patients with first-line HER2 positive advanced or metastatic (adv/met) breast cancer.
Authors: Slamon DJ , Stemmer SM , Johnston S , Kim S , Durante M , Pandite LN , Roychowdhury DF , Goodman VL
Published: December 2010

Abstract #4114

Background: Evidence indicates a direct molecular link between HER2 amplification and up-regulation of VEGF in HER2+ breast cancer. Concurrent over-expression of HER2 and VEGF is associated with a poorer clinical outcome than over-expression of either alone. These data provide the rationale for simultaneous blockade of both pathways. Pazopanib (P) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit. Lapatinib (Tykerb®) (L) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2). This study (VEG20007) evaluated the efficacy and safety of dual pathway inhibition in patients (pts) with HER2+ adv/met breast cancer.  Methods: Eligible pts received no prior chemotherapy or HER2-directed therapy for met disease and had measurable disease per RECIST. Pts were enrolled in one of 2 cohorts. In cohort 1 (C1), pts were randomized to P 400 mg/d + L 1000 mg/d or L alone (1500 mg/d). Enrollment to cohort 2 (C2) began after completion of enrollment to C1. In C2 pts received the combination at doses of P 800 mg/d and L 1500 mg/d. Following disease assessment at week (wk) 12, pts with an objective response could continue on study treatment following re-consent; those with stable disease could continue only where trastuzumab was unavailable. The primary endpoint of C1 was progressive disease rate (PDR) at wk 12 in HER2 FISH+ pts. The primary endpoint of C2 is week 12 response rate in HER2 FISH+ pts.  Results: 140 pts were included in the randomized cohort analysis which was previously reported [J Clin Onc 26:2008 (May 20 suppl; abstr 1016)]. Enrollment in C2 has been completed; 40 pts (36 confirmed FISH+) have been enrolled. A preliminary safety analysis has been performed. The most common adverse events of any grade were diarrhea, nausea, fatigue, hypertension, and rash. The most common laboratory abnormalities were ALT and AST increase. Efficacy data will be analyzed when the last pt has completed the week 12 assessment.  Conclusion: This is the first Phase II trial to evaluate the combination of 2 oral targeted agents in first-line Her2+ adv/met breast cancer. The lower dose combination demonstrated improved response rate compared to L monotherapy. Previously unreported efficacy and safety data from the higher dose cohort will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4114.
Activity and safety of sunitinib in combination with trastuzumab for the treatment of metastatic breast cancer: initial results from a phase II study.
Authors: Bachelot T , Lluch A , Gutierrez M , Martin MM , Kozloff MF , Prady C , Tassell V , Kern K , Huang X , Verma S , Blay J
Published: December 2010

Abstract #4115

Background: Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSF-1R, with proven single-agent activity in pts with advanced BC. Trastuzumab (T) is indicated as both monotherapy for second-line treatment and in combination with taxane-based therapies for first-line treatment of metastatic BC. This study investigates the activity and safety/tolerability of SU administered in combination with T in pts with advanced, HER2+ BC.  Materials and methods: Eligible pts have unresectable, locally recurrent or metastatic HER2+ BC. Pts received SU at a starting dose of 37.5 mg/d po continuous daily dosing (CDD). T was administered iv wkly (loading 4 mg/kg then wkly 2 mg/kg) or q3w (loading 8 mg/kg then 6 mg/kg q3w). Due to changes in standard of care, the trial was amended from a randomized, placebo controlled design, to a single-arm study, and eligibility criteria were changed to allow inclusion of pts who had previously received CT in the first-line setting. Previous treatment with T (± lapatinib) was also permitted. The planned sample size is 53 pts and the primary endpoint is ORR.  Results: In this ongoing trial, a total of 49 pts have been enrolled to date (6 pts under the original protocol and 43 under the amendment). All 43 pts enrolled under the amendment were evaluable for safety/tolerability, and antitumor activity, measured by RECIST. As of May 2008, 25 pts continue on study and 18 have discontinued, 4 due to AEs. Pts started a total of 167 cycles of treatment with a median of 4 cycles/pt (range: 1–8). The planned dose of SU (37.5 mg/d) was maintained in 31/43 pts (72%). It was reduced to 25 mg/d in 12/43 pts (28%). One pt achieved a CR and 10 a PR. SD occurred in 20 pts and PD in 6 pts. This translated into an ORR of 26% (95% CI, 13.5–41.2) and a clinical benefit rate of 35% (95% CI, 21.0–50.9). Median PFS was 25.3 wks (95% CI, 19.3–32.0). The most common treatment-related AEs were diarrhea (55.8%), asthenia (48.8%) and hypertension (37.2%) of which most were G1 or 2. The most frequent G3 AEs were neutropenia (14%) and asthenia (11.6%). There were 2 treatment-related G4 events: thrombocytopenia (2.3%) and LVEF decline (2.3%). There was 1 treatment-related G5 AE (cardiogenic shock).  Conclusions: SU 37.5 mg/d on a CDD schedule in combination with T (wkly or q3w) appears to have a manageable safety profile and antitumor activity in pts previously treated for advanced HER2+ BC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4115.
Primary analysis of study MO19391, an open-label safety study of bevacizumab (B) plus taxane-based therapy as 1st-line treatment of patients (pts) with locally recurrent (LR) or metastatic breast cancer (mBC).
Authors: Smith IE , Biganzoli L , Cortés-Funes H , Stroyakovskiy D , Franke FA , Chlistalla A , Pierga J , Thomssen C , Pritchard K
Published: December 2010

Abstract #4118

Background: The addition of B (15mg/kg q3w) to 1st-line taxane therapy significantly improved PFS in pts with LR or mBC in 2 phase III studies, E2100 and AVADO. MO19391 investigated B plus 1st-line taxane-based chemotherapy (CTx) in LR or mBC to obtain safety and efficacy data in a community-based population.  Methods: This open-label, multicentre study has completed enrolment of 2,000 pts with LR or mBC and an ECOG PS of 0–2. Exclusion criteria included prior CTx for LR or mBC and evidence of CNS metastases. The primary endpoint was safety; secondary endpoints included TTP and OS. B was administered at 10mg/kg q2w or 15mg/kg q3w plus the physician's choice of taxane regimen (or investigator's SOC, excluding anthracyclines). Treatment with B continued until disease progression or unacceptable toxicity. As well as AEs, attention was paid to AEs of special interest (hypertension, proteinuria, wound-healing complications, thromboembolic events, CNS bleeding, other haemorrhages, GI perforation, fistulae, RPLS and CHF). The safety population included all pts who received at least one dose of B.  Results: As of March 2008, the safety population consisted of 1,553 pts from 35 countries. The median number of cycles received was 6 for both B (range 1–28) and CTx (range 1–28). Pts received: single-agent taxane 66.2%, taxane combination 13.5%, other single agent 8.5%, other combination 3.3%. Frequently reported AEs are shown below. Grade 3/4 AEs of special interest were reported in 6.3% of pts, most commonly hypertension 2.2%, proteinuria 0.7%, pulmonary embolism 0.5%, epistaxis 0.4%. AEs leading to death during the study phase were reported in 27 pts (1.7%)*.    Conclusions: MO19391 is the largest study population of pts with LR or mBC receiving B plus CTx. Toxicity was low and preliminary results are consistent with previous B safety studies. Final analysis of the primary endpoint and secondary efficacy analyses will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4118.
Tolerability of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2+ advanced breast cancer.
Authors: Cardoso F , Canon J , Amadori D , Dirix L , Villa E , Aldrighetti D , Machiels J , Verkh L , Huang X , Giorgetti C
Published: December 2010

Abstract #4120

Background: Trastuzumab (T) combined with docetaxel (D) is approved for the first-line treatment of HER2+ advanced BC (ABC). Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3 with single-agent activity in pts with previously treated ABC. The tolerability and preliminary antitumor activity of SU combined with D and T was investigated in this exploratory study as a first-line regimen for ABC.  Materials and methods: A target of 25 female pts (≥18 yrs, ECOG PS 0 or 1) with unresectable, locally recurrent or metastatic HER2+ BC are being enrolled. Starting doses for the 3 treatments are listed in the table below. The primary objective is safety. Secondary endpoints are PK and preliminary tumor activity according to RECIST. After discontinuation of D, responsive pts (PR or SD) can continue SU and T until PD.    Results: As of May 2008, 18 pts were enrolled; 11 pts continue on study therapy and 7 have discontinued (5 due to PD; 1 due to pt decision; 1 due to G3 fatigue). Of the 18 pts enrolled, 16 are evaluable for safety and 11 for activity. Pts completed 75/96/98 cycles of D/SU/T, respectively, with a median of 5 cycles/pt for each drug (range: 1-13/1-12/1-13). The planned dose of SU (37.5 mg/d) was reduced to 25 mg/d in 6/16 pts due to G4 neutropenia (1); G3 febrile neutropenia (1); G3 fatigue (1); G2 hyperbilirubinemia (1); G2 hypertension (1); and G2 diarrhea (1). D was reduced in 4 pts due to febrile neutropenia (2) and G4 neutropenia (2). T was given q3w in 12 pts and wkly in 4 pts. T dosing was delayed by ≥4 days in 6 pts, 4 due to D dose delay and 2 due to AEs when D was already discontinued (G2 neutropenia and G3 fatigue). Overall, the most frequent AEs were fatigue (68.8%) and neutropenia (43.8%), consistent with the most common toxicities of D. No GI perforation or bleeding were reported. The most frequently reported severe AEs were neutropenia (1 G3 and 6 G4) and febrile neutropenia (5 G3). G-CSF was administered to 8 pts. Of the 11 pts evaluable for antitumor activity, 1 showed a confirmed CR, 7 a confirmed PR, 2 had PD and 1 was not evaluable.  Conclusions: The combination of SU 37.5 mg/d (Schedule 2/1) with D 75 mg/m2 q3w and T wkly/3-wkly, given as first-line treatment to HER2+ pts with ABC, shows manageable toxicities. The use of G-CSF appears beneficial. Preliminary antitumor activity is encouraging. Enrollment is ongoing.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4120.
Carcinoma of breast in males in Turkey: a Turkish oncology group study.
Authors: Bolukbasi Y , Kucucuk S , Aydin A , Yetmen O , Haydaroglu A
Published: December 2010

Abstract #4132

Purpose: Compared to breast carcinoma in women breast carcinoma in males is frequent and information in males is limited. The aim of this multicentric study is to evaluate the treatment results of male patients with breast cancer treated in cancer centers in Turkey.  Methods: Between 1973-2006, 167 male breast cancer patients who were treated, analyzed retrospectively respect to clinical presentation, treatment, survival and prognostic factors. Median age was 61 (range: 32-90), 51.5% were found in right breast. Majority of the tumors were occured in the central(36.5%) and upper outer quadrant (32.9%). Except one patient, all of them underwent mastectomy. Stage distrubution was as follows; Stage I 9%, Stage II 34.7 %, stage III 44.9%, stage IV 4.8% and 11 patients (6.6%) can not be staged due to Tx or Nx status. The most common histologic type was invasive ductal carcinoma (89.8%). Contralateral breast cancer developed in 3 patients. Of the patients 81.4% (136) received adjuvan radiotherapy for the whole breast and also to the periferial lymphatics for patients carrying high risk factors. Median total dose was 50 Gy with a daily fraction dose of 2 Gy. Five patients were treated with radiotherapy due to recurrences, 3 patients were treated for metastases and one patient was treated for curative intent. Radiation therapy was not given to 22 patients. Adjuvant chemotherapy and hormonal therapy were used in 83 and 70 patients, respectively.  Results: During a median follow-up duration of 66 months (range: 1-237 months) . Isolated local-regional recurrence and distant metastases were observed in 13.2% and 34.1% of cases, respectively. Five-years overall survival, disease free survival and local control were, 66.1%, 63.4%, 89%, respectively. The prognostic factors influencing overall survival were presence of positive axillary lymp node (p=0.000), T stage (p=0.000), lymph node ratio (>50%) (p=0.001), AJCC stage (p=0.000), skin invasion (p=0.00), nipple invasion (p=0.027) and blood vessel invasion (0.006) in the univariate analysis. In the multivarian analysis, the only prognostic factor which has impact on overall survival was AJCC stage (p=0.023). No prognostic factor was found to be significant for disease free survival and local control.  Conclusion: In the present study positive axillary lymp node, T stage, Lymph node ratio (>50%), AJCC stage (p=0.000), skin invasion, nipple invasion and blood vessel invasion were the significant prognostic factors for overall survival. In absence of prospective randomised trials, retrospective review data from multi-centre approaches are necessary and this can provide useful guidelines for understanding the biology of breast cancer in males.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4132.
Is there any benefit in routine wound drainage following mastectomy and axillary clearance?.
Authors: Shokuhi S , McArdle K , Rai S , Brown H , Vishwanath L
Published: December 2010

Abstract #4153

Introduction: Seromas are the most frequent complication of breast cancer surgery and are often considered a "necessary evil". Despite limited evidence, suction drains are routinely used to reduce their risk. Drains are an important factor contributing to increased hospital stay as patients are usually reluctant to be discharged before their removal. The aim of this study was to compare the seroma rate post mastectomy and axillary clearance with and without insertion of suction drains.  Methods: All patients undergoing mastectomy and axillary clearance treated under the care of three consultant breast surgeons were studied. Data was collected prospectively and analysed retrospectively. Outcome measures included incidence and volume of postoperative seroma, number of aspirations, length of stay and complication rate. Mann-Whitney U test and difference between proportions was used for statistical analysis.  Results: Between December 2006 and March 2008 a total of 74 women, median age 63 (range 44-88) underwent 78 mastectomy and axillary clearance (4 bilateral). Patients were divided into three groups. Group 1 no drain, Group 2 one drain, Group 3 two drains.    There was no significant difference between the 3 groups in rate of seroma formation. Total volume of seroma and out patient aspirations were significantly higher in group 1 compared with group 3 (P=0.008 and P=0.03 respectively) however there was no significant difference between group 2 and 3. There was no significant difference in complication rates in the three groups. There was a significant reduction in hospital stay in groups 1 and 2 compared to group 3 (P=0.014).  Conclusion: Drains did not prevent seroma formation, and were associated with a longer postoperative stay. There was no benefit in insertion of a second drain in reducing seroma volume and number of aspirations required. Second drain leads to a significantly longer hospital stay. The routine use of suction drains post mastectomy may not be warranted. Insertion of two drains is not justified.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4153.
Cyclin B as a prognostic factor in low-risk node negative breast cancer.
Authors: Koliadi A , Nilsson C , Ahlin C , Fjällskog M
Published: December 2010

Abstract #4161

Background: The cell cycle regulation is a well-controlled mechanism in normal non-transformed cells. Cyclins are important proteins for this regulation. Cyclin B1 plays an essential role as a mitotic cyclin in the entry of mitosis from G2 phase. Previous studies have suggested that cyclin B1 over-expression could be a poor prognostic factor in breast cancer. We wanted to examine cyclin B1 as a prognostic factor in a group of patients with low-risk node negative breast cancer.  Material and Methods: We compared women that died from their breast cancer (n=17) with women free from relapse > 8 years after initial diagnosis (n=24). All women had stage I, low-risk breast cancer. The groups were matched regarding tumour size, receptor status, adjuvant chemotherapy and tumor differentiation. Tumor samples were analyzed regarding cyclin B1 expression using immunohistochemistry with commercial antibodies and optical microscopy.  Results: The mean percentage of cyclin B1 was significantly higher (p=0,00008) in women that died from their breast cancer (13%) compared with women free from relapse (5%). Mortality was significantly higher (p=0,001) in patients with high cyclin B (85%) than with low cyclin B (21%) using 9% as cut-off value.  Conclusion: In our study, we found that low-risk node negative patients with high expression of cyclin B1 had a significantly worse outcome than patients with low expression of cyclin B1. We suggest that cyclin B1 could be a potent prognostic factor in this low-risk patient group. However, further studies are needed to confirm our findings.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4161.
Bone scintigraphy (BS) may no longer be relevant in the era of integrated PET/CT for women undergoing evaluation for suspected metastatic breast cancer (MBC).
Authors: McArthur HL , Lynch C , Morris P , Larson S , Grabski K , Howard J , Patil S , Hudis CA , Dickler MN
Published: December 2010

Abstract #5007

Background:   The accurate detection of osseous metastases frequently has significant prognostic and therapeutic implications at metastatic breast cancer (MBC) diagnosis. However, the ideal paradigm for accurate detection of osseous metastases has not yet been determined. In this retrospective, single-institution study, we compare the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) versus bone scintigraphy (BS) for women undergoing extent-of-disease (EOD) evaluation for suspected MBC.  Methods:  Women undergoing EOD evaluation for suspected MBC with integrated PET/CT and bone scintigraphy (BS) between January 1, 2005 and Dec 31, 2007 were identified through institutional databases. Patients with PET/CT and BS imaging completed within 30-days of each other were included. Women with a prior history of MBC or an active second malignancy were excluded. Electronic medical record (EMR) reports were reviewed and classified as positive, negative or equivocal for detecting osseous metastases. All EMR reports deemed potentially equivocal were reviewed by 2 investigators and consensus reached regarding the final classification. Bone biopsy data, where available, was also recorded.  Results:  The median age of the 62 eligible women was 54y (33-90y). Overall, PET/CT and BS demonstrated a high degree of concordance. Of the 41 concordant studies, 13 (21%) and 28 (45%) were reported as positive and negative for osseous metastases, respectively. No studies were classified as equivocal by both modalities. Ten positive PET/CT studies were negative by BS, but no PET/CT-negative studies were positive by BS. Of the 10 patients with PET/CT-positive, BS-negative studies, 4 had subsequent bone biopsies, all of which confirmed osseous metastases.    Conclusions:  This study supports the diagnostic performance of integrated PET/CT in detecting osseous metastases when EOD evaluation for suspected MBC is considered. Whether PET/CT may supplant BS entirely in this setting has not yet been determined.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5007.
A novel breast tissue feature strongly associated with risk of breast cancer.
Authors: McKian KP , Reynolds CA , Anderson S , Vierkant RA , Visscher DW , Frost MH , Pankratz VS , Nassar A , Hartmann LC
Published: December 2010

Abstract #5008

Background: Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features, such as the terminal duct lobular unit (TDLU), may help to stratify women into different risk levels as breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. Regression, however, does not occur in all women.  Materials and Methods: We have quantified the extent of lobule regression on a benign breast biopsy in 85 breast cancer cases and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini/lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women.  Results: There is a step-wise increase in breast cancer risk with increasing numbers of acini/lobule (p=0.0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association.    Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (p=0.03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c-statistic was 0.60 (95% CI; 0.50-0.70); the acinar count c-statistic was 0.65 (95% CI; 0.54-0.75). Combining acinar count and lobular area, the c-statistic was 0.68 (95% GI; 0.58-0.78). Adding the Gail model to these did not improve the c-statistic.    Discussion: Novel, tissue-based features that reflect the status of a woman's normal breast lobules are strongly associated with breast cancer risk. These features appear to provide more accurate risk assessment than the currently used Gail model.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5008.
A prospective evaluation of the utility of clinical breast examination.
Authors: Goodson III WH , Hunt Jr. TK , Plotnik J , Moore II DH
Published: December 2010

Abstract #5012

Emphasis on mammography, and to a lesser extent MRI, for breast cancer screening, is temporally associated with decreased practice of clinical breast examination (CBE). To assess the role of CBE in current practice, we prospectively evaluated CBE in a community, primary care practice. Because CBE is a low yield procedure, we embedded in this study a test of whether an attention focusing intervention would increase the so-called “call rate” for screening CBE. METHODS: With IRB approval, over an 18 month period, we prospectively asked clinicians in a community, primary care practice to record findings from screening CBE for 1522 routine visits. Clinicians were randomized to use one of two forms: 1. a short form that collected brief historical information about the patient and asked the clinician to mark any areas of abnormality on a graphic of the breasts; or 2. a long form that, in addition to the information on the short form, asked the clinician to record several descriptors of the patient's breasts in general. For historical controls, we retrospectively abstracted the same information as in the short form from charts of 300 women seen for routine care in year before the study. To assess the success in finding cancer, we compared the cancer identification rate to the cancers expected on the basis of age adjusted SEER data. RESULTS: There were no statistically significant differences between the two prospective groups in terms of age, presence of a mass prior to CBE according to the patient, or abnormal mammogram before the examination. The call rate for CBE was the same in both study groups for all CBE, CBE when the patient did not think a mass was present, and for CBE when the patient did not think a mass was present and there was not an abnormal mammogram. The call rate for the prospective study patients (8.3%) was, however, significantly higher than the call rate in the preceding year (4.7%; p=0.032) suggesting that the collection of data on separate forms had a Hawthorne Effect in which the conditions of data collection functions as an independent variable. SEER data predicted 3.7 cancers in the 1822 women. We found 4. CONCLUSIONS: Because a simple form as an intervention to focus attention on CBE successfully improved the call rate of CBE and because we found the number of cancers SEER data would anticipate, we question enthusiasm for training in special techniques for CBE and legislative efforts to require separate CPT codes for CBE. We conclude that focusing attention is as successful as special CBE choreography, so that in lieu of training in special techniques, quality efforts should encourage implementation of simple ways to focus clinician attention during CBE.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5012.
Development of a blood based breast cancer test for Indian population.
Authors: Tobin D , Bårdsen K , Lindahl T , Kauczynska M , Punia D , Kumar Y , Desai C , Shroff C , Børresen-Dale A , Sharma P
Published: December 2010

Abstract #5013

Background: The incidence of breast cancer (BC) in India is increasing as the society becomes more westernized. No national screening program exists and there is a high mortality rate which may be linked to the late detection of the disease. Here we report the development of a gene expression based blood test to detect BC. We have previously presented data from European/US cohort with accuracies ranging between 75% - 82% suggesting that test can be developed to early detect breast cancer. We now report the findings from a multi-centre study initiated to test the efficacy of the test for early detection of breast cancer (BC) in an Indian population.  Methods: A multicentre-study was initiated where blood samples were collected from women recruited in 5 different groups 1) early stage BC, 2) late stage BC, 3) women at high risk - without BC, 4) benign breast lesions, 5) without abnormal mammographic findings. The women recruited in group 3 is a part of ongoing prospective study. Recruitment was balanced between pre- and post-menopausal women among the remaining groups. Samples were collected in PAXgene tubes and shipped to a central laboratory where RNA extraction and quality control. Gene expression analysis was performed using TaqMan® low density arrays (LDA's) containing a BC-specific gene signature in a 96-gene assay format. A total of 442 samples from groups 1, 2, 4 and 5 were used to develop the India model and estimate its prediction efficacy. The 442 samples were divided between a training cohort (N=292) and a test cohort (N=150). Gene expression data of the training cohort were used to develop the breast cancer specific diagnostic model and its performance was determined by predicting the class of the independent test cohort.  Results: The developed model correctly predicted the class of 110/150 test samples, resulting in an overall accuracy of 73%. Prediction performance was similar for early and late stage cancer and for benign and healthy (no mammographic findings). No significant difference in diagnostic performance was seen between pre- (57/75 correctly predicted) and post-menopausal (53/75 correctly predicted) women indicating the clinical value of our test in younger women.  Conclusion: The Indian multi-centre study demonstrates the utility of the BC-specific 96 assay signature in detecting BC in an Indian population with similar diagnostic performance seen between women with late stage (stage 2+) and early stage BC. We have previously presented data from European and US cohorts with similar diagnostic performance suggesting the broad applicability of our test. The Breast Cancer test showed the same high level of accuracy in pre-menopausal as in post-menopausal women indicating its clinical applicability in younger women where mammography is of less value due to dense breast tissue.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5013.
Minimal residual disease detection in peripheral blood of primary breast cancer patients – translational research in the SUCCESS-study.
Authors: Jenderek C , Jückstock J , Schindlbeck C , Rack B , Fuchs R , Noeding S , Krabisch P , Ebner F , Lichtenegger W , Beckmann MW , Friese K , Sommer H , Janni W
Published: December 2010

Abstract #5019

Background: The detection of occult tumor cells in the bone marrow of patients with breast cancer has been shown to be an independent predictive and prognostic factor for early disease recurrence and decreased overall survival. However, it is more feasible to monitor treatment efficacy by sampling peripheral blood. The translational research program of the German SUCCESS-trial evaluates Minimal Residual Disease (MRD) in peripheral blood during adjuvant treatment of breast cancer patients. Follow-up results of the detection of MRD at primary diagnosis and after adjuvant chemotherapy (CT) are presented.  Patients and Methods: Cells were separated by Oncoquick® (Greiner-bio one, Frickenhausen, Germany) followed by labeling of epithelial cells with an anti-cytokeratine-antibody (directed against cytokeratins 8, 18 and 19) and immunocytochemical staining. Every preparation was screened by two independent persons. MRD was defined as one or more cytokeratine-positive cell.  Results: 1237 breast cancer patients were analyzed at primary diagnosis. After completion of adjuvant CT 655 patients returned for a second blood sampling. The majority of the tumors was small (40.1% pT1, 52.7% pT2, 5.9% pT3, 1.1% pT4) but mostly of intermediate or unfavorable grade, (G1 4.6%, G2 48.9%, G3 46.2%). 65% of the patients were node-positive (35% pN0, 45.6% pN1, 13.8% pN2, 5.7% pN3) and a positive hormone receptor status was seen in 69.1%. In 25.4% the Her2 status was positive. In 20.3% of all patients MRD was found at primary diagnosis. After CT MRD was observed in 15,7%. The mean number of detected cells was 2.3 (range: 1-25) before and 2.1 (range 1-23) after chemotherapy. Neither tumor size (p=0.48, p=0.47), lymph node metastases (p=0.34, p=0.81), histopathological grading (p=0.83, p=0.85) nor hormone receptor status (p=0.72, p=0.65) of the primary tumor correlated with the presence of MRD before or after CT respectively. The Her2/neu status of the primary tumor did not correlate before, but after CT with the presence of the MRD (p=0.63, p=0.08).  Conclusion: The detection of MRD in peripheral blood can be widely used and is suitable for repeated measurements. Further follow-up of the SUCCESS trial will show this method´s validity for risk stratification and monitoring of treatment efficacy in breast cancer patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5019.
HER2+ circulating tumor cells (CTCs): a more sensitive and specific marker for CTCs positivity than total CTCs count in early breast cancer.
Authors: Ignatiadis M , Durbecq V , Markowicz S , Chaboteaux C , Rouas G , Mounia B , Benjamin B , Liebens F , Georgoulias V , Mavrudis D , Piccart M , Sotiriou C
Published: December 2010

Abstract #5023

Background: CTCs have been detected using the CellSearch System in early and metastatic breast cancer (BC). However, no studies have been reported for the detection of HER2+ CTCs using the CellSearch System. In this study we aimed to analyze CTCs for HER2 expression in different stages of BC progression from ductal/lobular carcinoma in situ (DCIS/LCIS) to early and metastatic BC. Patients and Methods: 20ml of peripheral blood per woman was analyzed from healthy women, DCIS/LCIS or early BC patients, whereas 7.5ml of blood was analyzed from metastatic BC patients. The presence of CTCs as well as HER2 expression was assessed with the CellSearchSystem (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labeled with anti-cytokeratin (8,18,19), anti-HER2 and anti-CD45 antibodies. CTCs were defined as Cytokeratin-positive/CD45-negative cells, whereas HER2+ CTCs were defined as Cytokeratin-positive/CD45-negative/HER2-positive cells. Results: The presence of CTCs and HER2+ CTCs in healthy women, DCIS/LCIS, early and metastatic BC is depicted in table.    Since 1 and 2 CTCs were detected in 7 (14.8%) and 4 (8.5%) of 47 healthy women, respectively, >1CTC or >2CTCs were selected as cutoffs for further analysis. Using the above cutoffs, 7 (18.9%) and 5 (13.5%) of 37 patients with early BC were considered CTC-positive, respectively. Since no HER2+ CTCs were detected in any of the 47 healthy women, a cutoff of ≥1 HER2+ CTCs was chosen. With this cutoff, more women with early BC [11 (29.7%) of 37 women] were considered CTC-positive. Conclusion: HER2+ CTCs seems to be a more sensitive and specific marker for CTCs' positivity than total CTCs counts in early breast cancer. Clinical relevance of the above cutoff for CTCs positivity using HER2+ CTCs detection will be performed in ongoing clinical trials of HER2 positive early breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5023.
Metastatic potential of Her2/neu positive and Her2/neu negative circulating epithelial tumor cells (CETC) released during primary systemic chemotherapy.
Authors: Pachmann K , Camara O , Gajda M , Rabenstein C , Pachmann U , Runnebaum IB
Published: December 2010

Abstract #5031

Background: Most tumor patients do not die from the primary tumor but from metastases in vital organs. To form metastases, cells must exit from the original tumor and reach these organs mainly via blood before they can settle and grow. Peripheral blood can be regarded as a transport system for CETC. Here we report on the influence of trastuzumab on the number of CETC and the impact on metastasis formation.  Material and Methods: Tumor cells were quantified with an automated microscope (Laser Scanning Cytometer®, Icis or ScanR) from anticoagulated blood drawn before each new therapy cycle from patients treated with primary systemic chemotherapy and before and after surgery and subsequent maintenance therapy. After red blood cell lysis leucocytes were stained with PE-anti-CD45 and tumor cells with FITC-anti-EpCAM and changes registered as % increase or decrease. The response of CETC to therapy was correlated to outcome.  Results: All breast cancer patients scheduled for primary systemic treatment had CETC before therapy. The number correlated with tumor size. The variable initial decrease in cell numbers highly correlated with the final tumor size reduction in her2/neu negative patients predicting for relapse free survival. All patients responded to the subsequent taxane therapy with an increase in CETC. In her2/neu positive patients who received combined taxane/trastuzumab there was only a modest increase in CETCs whereas patients with her2/neu positive disease who received taxane only showed a steep increase in CETC. 4 her2/neu positive patients who did never receive trastuzumab all had increasing CETC numbers during the postoperative observation time and all have suffered relapse. 6/6 patients who received trastuzumab only after surgery all had decreasing CETC numbers and all are in sustained complete remission after up to 4 years. 6/15 patients showed no change or an increase in CETC in spite of trastuzumab treatment and of these 4 have suffered relapse. Most relapses occurred 1-2 years after stopping trastuzumab.  Discussion: Monitoring CETC will not only provide the earliest and most reliable indicator of successful neoadjuvant treatment and spare patients unnecessary treatment. In patients with the highly aggressive her2/neu positive tumors such cells may have an increased potential to settle and re-grow. This warrants further therapy studies to control what patients may benefit from additional or modified therapy already before metastases appear.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5031.
Overexpression of LMW cyclin E results in faster M phase progression via Cdc25C interaction leading to chromosome missegragation in breast cancer cells.
Authors: Bagheri-Yarmand R , Keyomarsi K
Published: December 2010

Abstract #5032

Cyclin E is a G (1) cyclin essential for S-phase entry and has a profound role in oncogenesis. Cyclin E is overexpressed and present in low-molecular-weight (LMW) isoforms in breast cancer cells and tumor tissues compared to normal cells and tissues. Such alteration of cyclin E is linked to poor patient outcome. We have previously shown that ectopic expression of low molecular weight of Cyclin E (LMW-E) in breast cancer cell lines induces genomic instability by promoting aneuploidy and the formation of structural chromosomal lesion. To determine the mechanism of induction of genomic instability by ectopic expression of LMW-E, we generated the MCF-7 cells inducibly expressing either the full length (EL) or low molecular weight (LMW-E) form of cyclin E. We observed 5.5 fold higher number of cells with centrosome defects in LMW-E induced versus EL induced cells. Notably, elevated levels of LMW-E led to a significant increase in fragmented nuclei and multinucleated cells. Immunofluorescence analysis also showed a 4-5 fold increase in the number of cells containing lagging chromosomes and anaphase bridges. Karyotype analysis for gross chromosomal aberrations metaphase preparation of the uninduced and EL and LMW induced cells showed a significantly higher percentage of chromosomal defects including dicentric chromosome and chromosomal breaks associated with LMW-E overexpression. We also show that while overexpression of EL leads to accumulation of cells in S and G2/M phases of the cell cycle, the overexpression of LMW of cyclin E causes a faster M phase progression. As a consequence, LMW-cyclin E overexpressing cells are resistant to nocodazole-induced M phase arrest. Using biochemical assays, we show that EL and LMW-E interact with the phosphatase Cdc25C and when either EL or LMW are in complex with CDK2 that they phosphorylate Cdc25C. Such association of LMW-E with Cdc25C results premature inactivation of cyclin B/CDK1 upon treatment of these cells with nocodazole. Additionally, continued induction of LMW-E results in premature inactivation of PLK1 in mitotic cells and deregulated localization of PLK1 such that it is no longer associated to central spindles during anaphase and telophase. Collectively, these results suggest that overexpression of LMW-E interferes with the activation of CDK1 during mitosis. The relatively low activity of CDK1 during the passage through prophase, prometaphase, and metaphase interferes with the regulation of the spindle checkpoint and facilitates the premature transition of dividing cells from metaphase to anaphase resulting in chromosomal instability and aneuploidy. This is the first observation of how mechanistically the overexpression of a proto-oncogene can lead to genomic instability in breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5032.
Amplication of the estrogen receptor 1 (ESR1) gene in mastopathy predicts development of breast cancer.
Authors: Kilic E , Rufle A , Holst F , Ihnen M , Simon R , Zlobec I , Terracciano LM , Sauter G
Published: December 2010

Abstract #5037

Background: Mastopathy is a disease with fibrocystic changes (FCC) of the breast tissue commonly seen between the ages 30-50, but rare in postmenopausal women, and therefore suggestive of an association with estrogen stimulation. Whether FCC bears an elevated breast cancer risk is unclear. The role of ESR1 amplification in FCC has not previously been investigated. Material and Methods: Paraffin embedded tissues from 59 women with invasive breast cancer (BrCa) were analyzed. For all women, tissues with FCC taken at least 1.5 years before first diagnosis of BrCa (termed here “FCC old”) were also available. Average latency between FCC and BrCa was 6years (range1.5-17y). Immunohistochemistry (IHC) with antibody against estrogen receptor alpha (ER) and FISH-analyses with a probe for ESR1 (Zytovision, Bremerhafen/Germany) were performed. As a control, tissues from 19 women with FCC without a diagnosis of in situ or invasive breast carcinoma in the observed time frame (12-18y) were taken. Clinical-pathological data, such as histological subtype, tumour stage, tumour diameter, BRE-grade, patient's age and others, were available for statistical analysis. Results: After FISH analyses, 9 of 59 (15%) BrCa were amplified for ESR1. All ESR1-amplified BrCa were strongly positive for ER with IHC (at least 80% of tumour cells labelled). Tumour type or stage and BRE-grade did not correlate with ESR1-status. In all cases of ESR1 amplification in BrCa areas of amplification in FCC adjacent to the tumour were identified. Interestingly, in women with ESR1 amplification in BrCa, an amplification detectable in tissues with FCC prior to the first diagnosis of BrCa (“FCC old”) was noted but was absent in tissues from women with FCC who did not develop BrCa in the observed time frame. Non-neoplastic ESR1 amplified cells within FCC were strongly positive for ER with IHC. In unaltered mammary glands ESR1 amplification was not observed. Discussion: In this pre-selected collective of women with BrCa and history of FCC we found amplification of the ESR1 gene in 15% of BrCa. In these women, ESR1 amplification was also detectable in tissue with FCC taken prior to the first diagnosis of BrCa. This investigation shows that ESR1 amplification is an early event in breast pathology and its occurrence in FCC predicts development of BrCa.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5037.