bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic algorithm identified in node-negative early breast cancer patients predicts outcome also in node-positive patients treated with adjuvant chemotherapy.
Authors: Kronenwett R , Kalogeras KT , Stropp U , Weber K , Dafni U , Gehrmann M , Pectasides D , von Toerne C , Papakostas P , Wirtz RM , Fountzilas G
Published: December 2010

Abstract #6044

Background: Recently, we identified and validated a prognostic multigene score, which predicted outcome in early node-negative breast cancer patients that did not receive systemic therapy. The aim of this study was to examine the performance of our prognostic multigene algorithm in node-positive patients treated with adjuvant chemotherapy.  Patients and Methods: Patients were treated with adjuvant anthracycline-based chemotherapy in the context of a randomized Phase III study. This was a two-arm trial (E-CMF vs. E-T-CMF) investigating postoperative dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). RNA was isolated from 222 formalin-fixed, paraffin-embedded tumor tissue samples, using a Siemens proprietary automated method based on silica-coated magnetic beads, followed by kinetic one-step RT-PCR for mRNA expression analysis of 9 informative genes and 2 normalization genes. For each patient a risk score was calculated using a linear combination of expression values. Patients were separated into high, intermediate and low risk by applying two thresholds of the score. As used in node-negative patients, distant metastasis-free survival (MFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox analysis for MFS and OS was also performed.  Results: The prognostic score could be calculated for 213 patients (102 E-T-CMF; 111 E-CMF). Looking at all patients independently of type of chemotherapy, the score could classify the patients into three distinct risk groups, which were significantly different in terms of MFS (log-rank test, p=0.004) and OS (p=0.01). The separation of the risk groups was even better when focusing on patients with more than three involved lymph nodes (MFS: p=0.0001; OS: p=0.0015; n=166). The respective analysis of the two treatment arms showed that the separation of the risk groups was only significant in E-CMF-treated patients (E-CMF: p=0.002; E-T-CMF: p=0.37). Interestingly, the subgroup of patients with more than three involved lymph nodes and classified as intermediate or high risk (n=77) had a nearly significant better MFS when treated with E-T-CMF in comparison with E-CMF (p=0.07; HR: 0.53; 95% CI: 0.2685 to 1.060).  Conclusions: Our prognostic algorithm, identified and validated in node-negative patients that had not been systemically treated, predicts outcome also in node-positive chemotherapy-treated patients. Our findings suggest that the prognostic score may also be predictive of benefit from the addition of taxanes to adjuvant chemotherapy. This hypothesis needs to be confirmed in a larger cohort of samples from an independent clinical study.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6044.
Predicting response to alkylating chemotherapy in breast cancer patients using array comparative genomic hybridization.
Authors: Vollebergh MA , Nederlof PM , Wessels LF , Schmidt MK , Joosse SA , van Beers E , Froklage F , Holtkamp M , Schrama JG , Wesseling J , Hauptmann M , de Bruin M , Rodenhuis S , Linn SC
Published: December 2010

Abstract #6050

Background: Breast cancer cells lacking the DNA repair mechanism Homologous Recombination (HR) have recently been shown to be hypersensitive to bifunctional alkylating agents such as carboplatin and poly(ADP-ribose)polymerase(PARP)-inhibitors, a novel class of targeted agents. We have previously reported the construction of an array Comparative Genomic Hybridization (aCGH) classifier that detects the characteristic copy number aberrations of BRCA1-mutated tumors which are thought to be caused by HR deficiency. We hypothesized that metastatic breast cancer patients with tumors harboring such a BRCA1-profile may specifically benefit (longer progression-free survival (PFS)) from intensive treatment with bifunctional alkylating agents compared to patients without this tumor-profile.  Methods: We isolated DNA from formalin-fixed paraffin-embedded primary tumor tissue collected from 3 prior studies carried out in our institute, in which metastatic breast cancer patients received intensive alkylating chemotherapy with carboplatin, thiotepa and cyclophosphamide (CTC). DNA from 40 tumors was tested for the presence of the BRCA1-profile by aCGH. Furthermore, we screened for the majority of BRCA1 and BRCA2 mutations that frequently occur in Dutch BRCA1 and BRCA2 families.  Results: Sixteen patients had a tumor with a BRCA1-profile and had a better response to CTC-treatment, defined by achievement of a complete remission (p=0.01) and longer PFS (p=0.001, figure 1), with a hazard ratio for progression of 0.30 (p=0.002).    All 6 patients who remain in continuous complete remission (56+ to 150+ months) had a tumor with a BRCA1 profile. Two BRCA1 and 2 BRCA2 mutations were found in 4 patients of whom 3 had a BRCA1-profile and a long PFS (> 30months), linking HR deficiency (BRCA1 and BRCA2 mutations) in breast cancer patients to good outcome on platinum-based chemotherapy.  Discussion: Using an aCGH classifier initially constructed to identify BRCA1-mutated tumors we were able to identify a group of metastatic breast cancer patients treated with platinum-based chemotherapy with a high complete remission-rate and long progression free survival. Moreover, this group contained all patients who were apparently cured by intensive alkylating chemotherapy. Our aCGH assay may represent an effective test for BRCA-ness and could be important to select patients with sporadic tumors for therapy targeted at cells deficient in Homologous Recombination.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6050.
Ratio of cyclin-dependent kinase 1 (CDK1) activity to CDK2 activity after ex vivo paclitaxel treatment predicts response to paclitaxel in human breast cancer.
Authors: Kim S , Taguchi T , Tamaki Y , Tsukamoto F , Akazawa K , Ueno NT , Hortobagyi GN , Nakayama S , Torikoshi Y , Gohda K , Ishihara H , Noguchi S
Published: December 2010

Abstract #6065

Background: Increased CDK1 activity and reduced CDK2 activity reflect paclitaxel sensitivity in vitro. We have developed a novel assay that measures CDK1 and CDK2 activity in small tissue samples (“C2P assay”). The aim of this study was to determine whether the CDK1/2 ratio after ex vivo paclitaxel treatment correlates with response to paclitaxel in human breast cancer.  Material and Methods: This study included 38 patients with primary breast cancer. The median age was 50 years. Twenty-five patients (66%) had stage II, 12 (32%) stage III, and 1 (3%) stage IV. Thirty-three patients (87%) had invasive ductal and four (11%) invasive lobular cancer: 1 patient (3%) had mucinous disease. Histologic grade was II in 33 patients (87%) and III in 5 patients (13%). Twenty-one patients (55%) had ER-positive and 11 (29%) HER2-positive disease. All patients received preoperative chemotherapy - paclitaxel (80 mg/m2, weekly for 12 weeks) followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) (500/75/500 mg/m2, every 3 weeks for 4 cycles) in 34 patients (89%) and paclitaxel alone in 4 patients (11%). Tumor tissues obtained by core needle biopsy before chemotherapy were treated ex vivo with paclitaxel (100 nM) for 24 h, and then had CDK1/2 activity measured using the C2P assay. Clinical responses were evaluated with magnetic resonance imaging after paclitaxel treatment, and tumors that showed equal and more than 80 % shrinkage were defined as responders. The cutoff value for distinguishing between high and low CDK1/2 ratio was identified as 5.2 to best separate the responders and non-responders to paclitaxel.  Results: Of the 23 tumors with a high CDK1/2 ratio, 18 responded to paclitaxel. On the other hand, of the 15 tumors with a low CDK1/2 ratio, 10 did not respond to paclitaxel (positive predictive value, 78%; negative predictive value, 67%; p = 0.006). Of the 34 patients who were treated with paclitaxel followed by FEC and underwent surgery, 9 (26%) had a pathologic complete response (pCR). Eight of 21 tumors in the high CDK1/2 ratio group but only 1 of 13 tumors in the low CDK1/2 ratio group had a pCR (positive predictive value, 38%; negative predictive value, 92%; p = 0.05).  Discussion: The CDK1/2 ratio is significantly associated with response to paclitaxel and also with pCR after treatment with paclitaxel followed by FEC. The CDK1/2 ratio after ex vivo paclitaxel treatment might be a useful test to predict paclitaxel sensitivity in breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6065.
Prevalence of fibroadenomas in kidney-transplanted patients using cyclosporine A.
Authors: Machado JN , Vieira Jr. LA , Araujo Neto JT , Kemp C , Facina G , Nazario AC
Published: December 2010

Abstract #6078

Background: Fibroadenoma is the commonest benign tumor of female breast, classified as fibroepithelial neoplasia. It is frequent during reproductive years mainly in the 2nd and 3rd decades of life, coinciding with follicular maturation and steroidogenesis. With the beginning of the era of transplants the use of cyclosporine A was accepted by the medical community as potential lymphocyte T suppressant. In 1980 the first report on multiple breast fibroadenomas in renal transplant patients taking cyclosporine A was published. The imaging standard of fibroadenomas also seems to differ from usually found in asymptomatic patients: diameters are notably larger, lower longitudinal / anteroposterior diameter ratio and are more hyperechogenic.  Objetive: To define the prevalence of breast fibroadenomas in kidney-transplanted patients taking cyclosporine A.  Materials and Methods: Prevalence of breast fibroadenomas was determined in three groups of patients: 50 women with renal transplant taking cyclosporine A (Group 1); 51 women with renal transplant not taking cyclosporine A (Group 2) and 181 women without renal transplant (Control Group). Evaluation was performed by anamnesis, physical examination and breast ultrasonography. In the case of clinical or imaging suspicion of fibroadenoma, the diagnosis was confirmed by core needle biopsy or lumpectomy.  Results: The groups were homogeneous regarding age, menstrual status and former breast cancer family history. Fourteen percent fibroadenomas were found in the renal transplant patient group taking cyclosporine A versus 2.0% in the renal transplant patient group not taking cyclosporine A, and 2.8% in the control group. Prevalence of breast fibroadenomas in renal transplant patients taking cyclosporine A was significantly higher than in those not taking the drug and than in the control group (p=0.001). Frequency of fibroadenomas of the control group and renal transplant patients not taking cyclosporine was similar (p=0.073). Multiplicity, bilaterality and greater nodule dimensions were observed more in renal transplant patients taking cyclosporine A, but there was no statistical significance among the groups.    Conclusion: Breast fibroadenomas are more prevalent in the renal transplant patients taking cyclosporine A.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6078.
Clinicopathological features of the triple-negative tumors in Chinese breast cancer patients.
Authors: Yin W , Di G , Lin Y , Lu J , Liu G , Wu J , Shen Z , Shao Z
Published: December 2010

Abstract #6080

Background: Triple negative breast cancers are defined by a lack of expression of estrogen, progesterone, and Her-2 receptors. A number of studies suggested that the triple-negative phenotype could contribute to an aggressive behavior and a poor prognosis. However, similar data is still not available for Chinese populations. We sought to analyze the clinicopathological features of this subgroup in our hospital in order to get characteristics for Chinese breast cancer.  Methods: We performed a retrospective study of 2028 female unilateral breast cancer patients undergoing surgery in our hospital from February 1991 to December 2003. ER, PR and Her-2 status were assessed using immunohistochemical staining. Survival curves were performed with Kaplan-Meier method and annual recurrence hazard was estimated by hazard function.  Results: According to different combinations of hormone receptor (HR) and Her-2 status, 2028 patients were categorized into the three subgroups as follows: Her-2+ (32.25%), HR+/Her-2- (48.92%) and triple-negative (18.83%). Triple-negative tumors were larger (greater than 2 cm in diameter) than HR+/Her-2- tumors, but smaller than Her-2+ tumors (70.03%, 66.15% and 76.15% respectively, P < 0.001). In addition, 21.99% of patients whose tumors were triple-negative had four or more axillary nodes involved compared with 27.37% of patients with Her-2+ tumors and 22.78% with HR+/Her-2- tumors (P = 0.004). There were statistical differences in the distribution of TP53 mutation and Cathepsin-D status (P < 0.001 for both). In the univariate analysis, we found a statistical significance for recurrence-free survival (RFS) among the three subgroups (P = 0.0036), with the rate of 72.89% for Her-2+ tumors, 78.26% for HR+/Her-2- tumors and 75.61% for triple-negative tumors at the 11th year respectively. When it came to the time of hazard peaks, discrepancies existed in different subgroups. Triple-negative patients showed an early major recurrence surge peaking at the 2.5th year after surgery, followed by a gradual decline until year 6.5 and then a modest increase. As to HR+/Her-2- patients, the hazard plot exhibited a wide initial plateau-like wave covering at least 4 years and a subsequent rise. The hazard rate for Her-2+ patients displayed a tapering sharp at the 1st year and a second rise. Furthermore, the first peak of triple-negative tumors was higher than that of HR+/Her-2- patients, but lower than that of Her-2+ ones.  Conclusions: The recurrence pattern for triple-negative tumors was intermediate between Her-2+ and HR+/Her-2- counterparts.Our findings suggested that biological characteristics and prognosis of Chinese triple-negative breast cancer might be more favorable and somewhat different from those in Western populations.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6080.
Potential economic impact of the 21-gene recurrence score in Brazil.
Authors: Bacchi CE , Saad ED , Carvalho FM , Ojopi EB , Prisco FE
Published: December 2010

Abstract #6102

Objective: The 21-gene recurrence score (RS) may be useful for decisions regarding the use of chemotherapy (CT) in patients with lymph-node-negative (LNN), estrogen-receptor (ER)+ early breast cancer (BC). We investigated the potential impact of using RS in private practice in Brazil, from the perspective of third-party payers, in terms of main direct medical expenses.  Methods: We conducted a web-based survey with 30 (of a total of ∼700) Brazilian medical oncologists, who were stratified by State according to the proportion of patients with BC and private insurance. Such physicians represented States and cities in which approximately 80% of new BC cases are diagnosed each year. The questionnaire evaluated the treatment of first choice for patients with LNN, ER+ BC, regardless of menopausal status. Interviewees were initially invited by telephone and were not aware of the objective of the study. The responses allowed a quantitative assessment of the patterns of care regarding CT regimen according to disease stage (T1b, T1c, T 2-4 cm, T > 4 cm), type of premedication, use of G-CSF and in-hospital treatment for febrile neutropenia (rates taken from the literature). Medication costs were calculated using the manufacturer's recommended prices, and the cost for RS testing, which is currently available in Brazil, was set at BR$ 3,900.00 (US$ 2,294.00). Other direct medical expenses, indirect medical costs, and non-medical costs were not considered. We estimated costs for two hypothetic cohorts of patients (without and with RS), whose stage distribution and RS results followed those reported by Paik et al (NEJM 2004). The model assumed that patients with access to RS testing would receive CT if their RS was intermediate or high, whereas patients with a low RS would receive no CT.  Results: For a hypothetic cohort of 100 patients with no access to RS testing, the survey showed that 84 patients would receive CT (of note, 43% of patients with T1b tumors and adverse features would not receive CT). Reclassifying patient eligibility to CT according to RS would bring this number to 49. For a hypothetic cohort of 100 patients, BR$ 134,958.00 (∼US$ 79,400.00) would be saved in main direct medical expenses.    Conclusion: Considering the current price for the exam, our economic analysis suggests that RS testing is cost-saving in Brazil, from the perspective of third-party payers. Prospective studies are awaited for validating CT decisions based on the RS.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6102.
Docetaxel plus cyclophosphamide is cost-effective compared to doxorubicin plus cyclophosphamide, based on an economic analysis of US oncology trial 9735: additional rationale to avoid anthracyclines in the adjuvant treatment of operable breast cancer?.
Authors: Verma S , Mittmann N , Bernard L , Thompson M , Chan B , Asmar L , Jones S
Published: December 2010

Abstract #6105

Background: Extended 7-year follow-up of the US Oncology Adjuvant Trial 9735 demonstrated that docetaxel plus cyclophosphamide (TC) as adjuvant treatment of operable invasive breast cancer significantly improves disease-free survival (DFS) and overall survival (OS) compared to doxorubicin plus cyclophosphamide (AC). DFS was 81% vs. 75%, respectively (p = 0.033) and OS was 87% vs. 82%, respectively (p = 0.032). A lifetime cost-effectiveness analysis of TC versus AC was conducted from a Canadian (province of Ontario) government payer perspective, based on head-to-head clinical data from Trial 9735. Methods: Survival and monthly risk of disease recurrence of women with early stage breast cancer (base case typifying those entered into the trial) was estimated up to 7 years using OS and DFS data from Trial 9735. Survival was extrapolated to lifetime using life expectancy estimates from the Canadian general population. Canadian resource utilization and unit costs were applied to estimate the costs of chemotherapy (including drug and administration costs), chemotherapy-related toxicities and disease recurrence. Quality of life (utility) weights for health states and events, used in the calculation of quality-adjusted life years (QALYs), were derived from the literature. Total costs, life years and QALYs were calculated for a lifetime horizon. Results: Life years and QALYs were higher for TC patients compared to AC patients, due primarily to longer survival and fewer recurrences for patients receiving TC. The predicted life expectancy of patients receiving TC and AC was 14.64 and 14.02 years, respectively. Mean total lifetime disease-related costs were $12,840 with TC and $8,579 with AC; the difference in costs was driven by higher drug acquisition costs for TC. Cost per life year gained (TC vs. AC) was $6,842 and cost per QALY gained was $8,251, discounting costs and outcomes at 5% per year. Base case results were most sensitive to assumptions regarding time horizon. In a sensitivity analysis conducted with a 7-year time horizon (the time frame of the clinical trial), cost per life year gained was $36,120 and cost per QALY gained was $43,248. In additional one-way sensitivity analyses conducted with a lifetime horizon and alternative assumptions regarding survival extrapolation, utility estimates, costs and discount rate, cost per life year gained remained between $2,982 and $7,538 and cost per QALY gained remained between $3,600 and $9,090. Conclusion: In patients with early stage, operable, invasive breast cancer, adjuvant treatment with TC provides gains in terms of life years and QALYs compared to AC and results in favourable cost-effectiveness ratios that should be acceptable in most jurisdictions.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6105.
Carmustine-methotrexate combination in breast cancer patients presenting with brain metastases.
Authors: Jacot W , Gerlotto-Borne M , Thezenas S , Pouderoux S , About M , Romieu G
Published: December 2010

Abstract #6119

Purpose: There is currently no standard chemotherapy regimen for breast cancer (BC) patients presenting with brain metastases (BM). Since 1999, in our institution, these patients are treated with an association of carmustine (BCNU) and methotrexate (MTX). We report here the efficacy and safety profile of this association. Patients and methods: In this study, BC patients presenting with BM were treated by an association of BCNU 100 mg/m² on day 1 and MTX 600 mg/m² on day 1 and 15 of a 28 days cycle. Treatment was continued until progression or unacceptable toxicity. In order to evaluate this combination, we analyzed activity by recording tumor response rates, progression-free survival (PFS) and overall survival (OS), treatment compliance by analyzing Relative Dose Intensity (RDI) and safety by analyzing clinical and biological toxicities using NCI CTCAE v3.0. Results: Fifty patients were treated between 1999 and 2007, with a median age of 52 years (range 26-77 years). Median time between diagnosis of BC and BM was 37 months (0-180). One patient had synchronous BM. No tumor was recorded to be Scarf, Bloom and Richardson grade I, 40% were hormonal receptor negative and 50% of the 36 tumors analyzed for HER-2 amplification were positive. 94% of the patients presented with concomitant extra-cerebral disease, mainly bone (76%), liver (46%), lung (42%) and lymph node (26%) metastases. The number of previous chemotherapy regimens in the metastatic setting was 2 (1-5). The median number of administered cycles of BCNU-MTX was 3 (1-20). 30% of the patients received up to 6 chemotherapy cycles, with 20% patients continuing the treatment after 6 cycles. There were 11 objective responses (23% [IC95% 12-37]) among 48 evaluable patients, with an additional 29% disease stabilization, for a total 52% of patients with clinical benefit. Median PFS and OS were 4.2 (95%CI: 2.8-5.3) and 6.9 (4.2-10.7) months respectively, with a one-year OS rate of 32% (20-46). There were 2 presumed treatment-related deaths. The median RDI for BCNU and MTX were 0.98 (0.31-1.1) and 0.96 (0.57-1.66) respectively. Treatment was well tolerated, with the most common grade 3-4 toxicities per patients as follow (%pts): anemia (8.4), neutropenia (40.4), thrombocytopenia (21.2), and grade 3 fatigue (10.6). One patient developed febrile neutropenia. Poor prognosis was associated with a poor performance status in a univariate analysis of OS.Conclusion: In this population of heavily pretreated patients affected by BM from BC, the combination of BCNU-MTX appears to be an effective and well tolerated combination in good performance status BC patients presenting with BM.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6119.
Oral combination chemotherapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: phase II study.
Authors: Tanaka M , Tamura K , Anan K , Ohno S , Nishimura R , Yamamoto Y , Masuda N , Mitsuyama S
Published: December 2010

Abstract #6120

Background : Capecitabine and cyclophosphamide(XC) are shown to have a synergistic effect in the preclinical study and can be given orally with non-overlapping toxicities. Phase I study of XC was conducted for metastatic breast cancer patients and the recommended dose was 1657/mg/m2/day of X and 65mg/m2/day of C, respectively, which were to be given daily for 2 weeks at every 3-week schedule. We conducted phase II study with this regimen.  Patients and methods: Women with advanced or metastatic breast cancer who had been treated previously with anthracyclines but not with taxanes, were entered into this trial. Other eligibility criteria included an age from 20 to 74 years, ECOG performance status 0-2, presence of measurable lesions according to the RECIST criteria, HER2-negative tumors, and acceptable major organ functions. One course of XC consisted of the above recommended dose and schedule, and at least 6 courses were to be given unless progression of the disease or unacceptable toxicities occurred. The primary endpoint was response rate and the secondary endpoints were progression free survival (PFS), overall survival (OS) and adverse events. The study was started in July 2005 and ended in December 2007.  Results: Forty-eight patients were registered. The median age was 57 (range: 32 to 72). Thirty-three patients were postmenopausal. Estrogen and progesterone receptor was positive in 30 and 23 patients, negative in 14 and 19, and unknown in 4 and 6 patients, respectively. Three patients never received XC, and 2 patients were withdrawn from the study due to nausea and vomiting during the first course. Two patients were not evaluable for tumor response. Among 43 evaluable patients, there was complete response in 2 patients, partial response in 14, stable disease in 8, and progression of the disease in 19. Thus, an overall response rate was 87%. The response rate of metastatic lesions in each organ was 50% in lungs (6 patients), 65% in liver (17), 80% in lymph nodes (15), and 1.4% in skin (7), respectively. The median PFS and OS was 146 (85 to 942+) days and 672 days with a median follow-up time of 311 (97-1045+) days, respectively. Grade 3 toxicity was encountered for neutropenia with no fever in 5, anorexia in 2, and nausea/vomiting and diarrhea in 1 of each patient. Grade 1 and 2 hand-foot syndrome was experienced in 12 and 2 patients, respectively. One patient with liver metastasis showed grade 3 anemia, thrombocytopenia and elevated serum transaminase levels.  Conclusion: Oral XC combination (1657/mg/m2/day and 65mg/m2/day for 2 weeks at every 3-week schedule) is effective to women with advanced or metastatic breast cancer with acceptable toxicities.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6120.
High dose estrogen as a salvage hormonal strategy for highly refractory metastatic breast cancer (MBC): “back to the future.”.
Authors: Mahtani RL , Stein A , Vogel CL
Published: December 2010

Abstract #6129

High dose estrogens are an efficacious but widely ignored treatment option for patients with MBC. This is due in part to the introduction of tamoxifen, which was shown to be equivalent in efficacy with fewer side effects in the 1970's. After local Institutional Review Board approval we identified 26 patients with MBC treated in our practice with either diethylstilbestrol (15mg/day) or estradiol, generally, at a dosage of 30mg daily. One patient remains too early to evaluate. The median age at initial diagnosis was 46 and median age for patients at the start of high dose estrogen therapy was 59. All but 2 patients had confirmed hormone receptor positive tumors (one with a very long disease free interval and the other, prior response to hormonal therapy). Two of 26 patients were HER-2neu + by FISH analysis. The median # of sites of disease was 2 (range 1-3) and 50% had dominant visceral disease. Patients had received a median of 3 prior chemotherapy regimens (range 0-7), and 4 prior hormonal regimens (range 1-7), for a median of 7 prior systemic therapies (range 0-12). The median distant disease free interval (DFI) was 62 months (range 0 to 264 months). The median time from recurrence to initiation of estrogen therapy was 57 months (range 1 to 132 months). Six of 25 (24%) currently evaluable patients had objective anti-tumor responses, with one having a complete response in liver of 22 months. In addition, 4 of 25 patients (16%) with less clearly measurable disease had prolonged stable disease for ≥ 6months (7, 9, 13, and 14months, respectively). Clinical benefit (defined as CR, PR, and prolonged SD ≥6months) was 40%, with median duration of 9 months (mean of 12). Two patients are in continuing remission at 7 and 14months, respectively. Toxicities included vaginal bleeding in 7 of 25 (6 grade 1 and 1 grade 2), nausea in 4, and fluid retention in 8 (7 grade 1 and 1 grade 2). The patient with grade 2 fluid retention responded to a dose reduction to 6mg daily. Only 3 of 25 of patients discontinued estrogen therapy due to toxicity (1 vaginal bleeding, 1 refused to continue, and 1 nausea). In addition, one of the 3 patients that discontinued due to toxicity had a prolonged estrogen withdrawal response of 12months duration after 9 months of stable disease. Conclusion: Almost all patients with hormone receptor (+) MBC eventually develop resistance to endocrine agents. These data confirm the efficacy of high dose estrogens as yet another option for heavily-treated patients in whom further endocrine manipulation might still be appropriate.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6129.
Fertility and pregnancy in patients below the age of 35 following chemotherapy for breast cancer.
Authors: Katz D , Hamburger T , Divinsky L , Temper M , Ospovat I , Salah A , Galinsky D , Peretz T
Published: December 2010

Abstract #6148

Background  Counseling young breast cancer patients regarding the chances of conception following chemotherapy is a subject of great importance. Previous studies have reported a 50-70% rate of amenorrhea following standard breast cancer chemotherapy and very low rates of pregnancy. However a uniform definition of infertility is lacking and as a result many studies reported results observed in pre-menopausal women as a whole without specific analysis and separation according to age. In this retrospective, single institution study, we examined resumption of menses and pregnancy rates in young breast cancer patients who had received chemotherapy.  Methods  We identified 193 breast cancer patients aged 35 years or younger diagnosed at a single institution between 1996 and 2004. All patients who were treated with adjuvant chemotherapy and had completed at least 1 year of follow-up without evidence of recurrence were included in the study.  Results  Forty seven patients met the eligibility criteria. The mean time of follow-up was 69 months (range, 12-124 mos.). The mean age at diagnosis was 30 years (range, 19-34 yrs). Chemotherapy consisted of Adriamycin based protocols in 29 cases and CMF (Cyclophosphamide, Methotrexate, 5-Fluorouracil) in 18 cases. GnRH agonists were administered to 28 (61%) of patients for at least two years. All patients had regular menses prior to the initiation of chemotherapy. Three patients continued to receive regular injections with a GnRH agonist beyond two years, one patient underwent oophorectomy, two patients developed amenorrhea whilst 35 patients (35/37 95%) resumed menses subsequent to chemotherapy. Information regarding menstruation was lacking for six patients. Sixteen patients (16/37 43%) gave birth to at least one child after menses resumed at a mean age of 35 years (range, 28-41yrs).  Discussion  Standard chemotherapy protocols in breast cancer patients under the age of 35 do not preclude fertility preservation and pregnancy. However, not all young breast cancer survivors wish to become pregnant following treatment and therefore the actual rate of fertility is in fact higher than those recorded. Further prospective studies which incorporate documentation regarding patient's desire for future pregnancies need to be undertaken in order to better advise young patients with respect to their individual chances of conceiving following chemotherapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6148.
Breast cancer after stopping estrogen plus progestin in postmenopausal women in the women's health initiative.
Authors: Chlebowski RT , Kuller L , Anderson G , Mason J , Schenken R , Rajkovic A , Stefanick M , Sarto G , Ravdin P , Prentice R
Published: December 2010

Abstract #64

Background  Following the Women's Health Initiative (WHI) estrogen plus progestin (E+P) trial report (JAMA 2002;288:321), menopausal hormone therapy use decreased dramatically in the United States. Subsequently, breast cancer incidence also dropped substantially, suggesting possible causality (NEJM 2007;16:1680); however, the etiology remains controversial.  Methods  To define effects of stopping E+P on breast cancer incidence more precisely, additional analyses were conducted in the WHI randomized trial of daily conjugated equine estrogens (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) versus placebo. Furthermore, temporal trends for breast cancer diagnoses in the WHI observational study cohort were examined. Breast cancer risk factors, mammography utilization and calendar time-specific breast cancer incidence were assessed relative to E+P use.  Results: The time-specific linear hazard ratio (HR) curves examining E+P influence on breast cancer in the E+P clinical trial (CT), and in the observational study (OS, the later adjusted for E+P use during follow-up) are attached.        In the CT, breast cancer incidence, initially lower in the E+P group, increased with longer duration use but decreased postintervention despite closely comparable mammogram frequency between randomization groups. In the OS, breast cancer incidence was about two-fold higher in E+P users vs non-users (likely reflecting longer duration exposure) but decreased rapidly following year-to-year reductions in E+P use, while differences in mammogram frequency between E+P users and non-users were unchanged.  Conclusion: These findings suggest that cessation of E+P use is associated with a rapid reduction in breast cancer incidence which is not explained by mammography utilization change and support the hypothesis that the recent reduction in breast cancer incidence seen in certain age groups is predominantly related to a decrease in combined menopausal therapy use.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 64.
A meta-analysis of phase III trials evaluating the predictive value of HER2 and topoisomerase II alpha in early breast cancer patients treated with CMF or anthracycline-based adjuvant therapy.
Authors: Di Leo A , Isola J , Piette F , Ejlertsen B , Pritchard KI , Bartlett JM , Desmedt C , Larsimont D , Tanner M , Mouridsen H , O'Malley FP , Twelves C , Cardoso F , Poole CJ , Piccart MJ , Buyse ME
Published: December 2010

Abstract #705

Background: Retrospective studies have suggested that HER2 and topoisomerase II α (TOP2A) might predict sensitivity to anthracyclines (A)  Methods: Four phase III trials comparing A with CMF in early breast cancer (EBC) patients (pts), and with available primary tumor samples, were identified. HER2 and TOP2A genes were evaluated locally by FISH (amplification if ratio ≥ 2). Data were centralized at the statistical office (IDDI, Belgium). On-site visits were performed to check data quality and laboratory procedures. HER2 and TOP2A local scores were validated by submitting randomly selected samples to a central lab (CL) (University of Tampere – Finland), for a 3 color FISH test (HER2, TOP2A, centromere 17, Abbott Labs, IL, USA). Estrogen (ER), progesterone (PgR) receptors, and grade (G) were evaluated locally (no score validation at the CL).  Results: We present the results of the planned interim analysis on 1944 pts. Final results (± 3500 pts) will be presented when tumor sample collection for the UK trial is complete. HER2 local scores were validated at the CL in 137 cases (discordance: 8/137, 5.8%). TOP2A local scores were validated in 123 cases (discordance 38/123, 30.8%). Half of the TOP2A discordant cases were locally deleted-centrally normal or vice versa.    A planned exploratory analysis evaluated the TOP2A predictivity in 4 biologically homogeneous groups: highly or moderately hormone sensitive, HER2+ and ER/PgR negative, triple negative (TN). This analysis did not enhance the TOP2A predictivity in any of the 4 groups. In the TN group (294 pts), the DFS HR was 0.77 (0.54-1.09), suggesting that benefit from A might not be confined to HER2+ pts.  Conclusions: The interim analysis shows that HER2 and TOP2A have a clinically modest and a statistically borderline predictive value. In triple negative disease A may be superior to CMF.  Acknowledgments: Abbott Laboratories, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Pfizer, Scottish BC trials group.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 705.
NSABP B-30: definitive analysis of patient outcome from a randomized trial evaluating different schedules and combinations of adjuvant therapy containing doxorubicin, docetaxel and cyclophosphamide in women with operable, node-positive breast cancer.
Authors: Swain SM , Jeong J , Geyer CE , Costantino JP , Pajon ER , Fehrenbacher L , Atkins JN , Polikoff J , Vogel VG , Erban JK , Livingston RB , Perez EA , Mamounas EP , Ganz PA , Land SR , Wolmark N
Published: December 2010

Abstract #75

Background: The primary aims of this study were to determine 1) if a concurrent regimen of therapy containing cyclophosphamide compared to a sequential regimen containing cyclophosphamide would prolong disease-free survival (DFS) and overall survival (OS) and 2) if a regimen without cyclophosphamide was at least as efficacious as the two regimens containing cyclophosphamide. The secondary aims were to compare toxicities among the three regimens and to compare differences in amenorrhea in premenopausal women in each arm and its relationship to outcome.  Materials and Methods: 5351 pts with cT1-3, N0-1, M0 were enrolled from 3/1/99 to 3/31/2004. 1783 pts were randomized to Group 1 [doxorubicin (A) 60 mg/m2 and C 600 mg/m2 q 3 weeks (wks) x 4 followed by docetaxel (T) 100 mg/m2 q 3 wks x 4], 1784 pts to Group 2 [A 50 mg/m2 and T 75 mg/m2 q 3 wks x 4], and 1784 to Group 3 [A 50 mg/m2 T 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 q 3 wks x 4]. All patients with ER-positive tumors received hormonal therapy after completing chemotherapy. The protocol specifies that 800 deaths are required for the definitive analysis. This is expected to occur by Fall 2008.  Results: Mean time on study is currently 79 months. At entry, 46% of pts were < 49 yrs; 54% were > 50 yrs. 82% were white, 10% black, 4% Hispanic. 66% had 1-3 positive nodes, 26% had 4-9, and 8% had 10+. 75% of pts were ER pos. 49% had lumpectomy, 51% mastectomy, and 24% local/regional radiotherapy. Mean tumor size was 2.5 cm. The presentation will include the first results of DFS, OS, and relevant toxicities from the trial.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 75.
Lymph node micro-architecture can be imaged using optical coherence tomography.
Authors: McLaughlin RA , Scolaro L , Klyen BR , Hamza S , Robbins P , Saunders C , Sampson DD
Published: December 2010

Abstract #804

Background: Histological assessment is the gold standard technique for identification of lymph node involvement in breast cancer. However, this may only be performed ex vivo and will often result in the unnecessary excision of healthy lymph nodes. In axillary clearance, this will result in lymphedema in approximately 26% of patients. Optical Coherence Tomography (OCT) is a real-time imaging modality with the potential to perform in vivo optical biopsy of lymph nodes. We undertook ex vivo imaging of excised lymph nodes to identify which aspects of the lymph node micro-architecture could be imaged using OCT, and to identify differences between cancerous and normal nodes.  Materials and Methods: 18 lymph nodes were taken from 13 patients undergoing axillary clearance or sentinel lymph node biopsy. Fresh excised lymph tissue was dissected into 2mm slices. A 3D-OCT scan was acquired, with a resolution of ∼11μm in both axial and lateral dimensions. Each sample underwent subsequent histological analysis using Haematoxylin and Eosin (H&E) staining and matched against the 3D-OCT data sets.  Results: OCT images demonstrated differentiation of the three major tissue types found in the lymph node: adipose, lymph cortex and lymph capsule. Adipocytes demonstrated a characteristic honeycomb structure that was also visible in H&E stained histology. The cortex, containing a high concentration of lymphocytes, was found to give a strong level of optical backscatter in the OCT image. The capsule, consisting of less dense stroma tissue, could generally be differentiated from the cortex. Small blood vessels in the stroma and cortex presented as areas of low backscatter. Sinuses were identified as contributing to variation in intensity within the cortex. Germinal centers could be distinguished from resting lymphoid tissue by a characteristic circular structure apparent in both OCT and histology. Cancerous regions were found to be devoid of these characteristic micro-architectural structures, as the malignant cells replaced normal lymph tissue. Figure 1 shows the H&E histology image and corresponding OCT scan of a normal lymph node. Adipose, cortex, stroma and small blood vessels are all apparent in this sample.  Discussion: These results demonstrate that OCT is able to differentiate relevant structures within lymph nodes. Our findings suggest that lymph node metastasis is evident by the lack of these structures. This corresponds well with histological findings. This work forms a basis for future in vivo studies aimed at assessing lymph node involvement prior to excision.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 804.
Significant improvement in recurrence-free survival (RFS) when capecitabine (X) is integrated into docetaxel (T) → 5-FU + epirubicin + cyclophosphamide (CEF) adjuvant therapy for high-risk early breast cancer (BC): interim analysis of the FinXX-trial.
Authors: Joensuu H , Kellokumpu-Lehtinen P , Huovinen R , Jukkola-Vuorinen A , Asola R , Kokko R , Ahlgren J , Bono P , Tanner M , Lindman H , Group for The Finnish Breast Cancer
Published: December 2010

Abstract #82

Background: Adding X to T extends survival in patients (pts) with metastatic BC. The primary objective of the FinXX-trial is to compare RFS with XT→CEX vs. T→CEF as adjuvant therapy in pts with early BC. Secondary objectives are comparison of overall survival, distant RFS and safety. Methods: Between Jan 2004 and May 2007, 1500 pts were randomized to receive T x 3 → CEF x 3 (T 80mg/m² d1 → C 600mg/m² d1, E 75mg/m² d1, F 600mg/m² d1, q3 wks) or XT x 3 → CEX x 3 (T 60mg/m² d1 + X 900mg/m² bid d1–15 → C 600mg/m² d1, E 75mg/m² d1, X 900mg/m² bid d115, q3 wks). Results: 1496 pts were included in the ITT analysis (two pts withdrew consent, two had metastatic disease). The study population represented a high-risk group (90% node positive, 19% HER2 positive, 88% poorly or moderately differentiated tumors). The baseline characteristics were well balanced in the two treatment arms. After median follow-up of 3 years, there have been 134 events (deaths, distant or local relapses; Table). The significantly improved RFS rate was achieved despite a higher number of study treatment discontinuations in the X-containing arm (178 vs. 23 pts in the control arm; when XT was discontinued, the remaining XT cycles were replaced with an equal number of T cycles, and CEX cycles with CEF cycles). 75% of pts in the X-containing arm received all six planned cycles of therapy compared with 96% in the control arm. The adverse effect profiles of XT→CEX and T→CEF were in part different (Gr. 3/4 neutropenic fever/infection 10.0% vs. 20.2%, hand-foot syndrome 11.1% vs. 0.3%, diarrhea 6.2% vs. 3.4%, stomatitis 4.2% vs. 1.6%, myalgia 1.9% vs. 8.0%, respectively).    Conclusions: The primary endpoint of this trial, to demonstrate a significant improvement in RFS, was achieved after median follow-up of 3 years. The hazard ratio of 0.66 (95% CI 0.47–0.94; p=0.020) for RFS translates into a 34% reduction in the rate of recurrences or deaths in pts receiving XT→CEX. This significant benefit was seen using an X dose of 900 mg/m² bid, and with a lower T dose in the XT arm than with T monotherapy. Overall survival data are not yet mature but a trend towards improvement (hazard ratio 0.66 [95% CI 0.401.07]; p=0.089) can be seen in the XT→CEX arm. The results suggest that the risk of breast cancer recurrence can be reduced substantially with integration of capecitabine into a taxane-/anthracycline-based regimen.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 82.
The correlation of tumor vascularity as imaged by near-infrared technology with tissue distribution of angiogenic and growth promoters.
Authors: Tannenbaum SH , Phoenix K , Hegde P , Claffey KP
Published: December 2010

Abstract #907

Background: Angiogenesis is necessary for solid tumors to grow. Rapidly growing tissues, increased metabolic demands as well as the presence of hypoxia and ischemia promote angiogenesis by stimulation of factors like vascular endothelial cell growth factor (VEGF), a key angiogenic factor. Many studies have found that angiogenesis is an independent prognostic factor in both node positive and node negative breast cancer. We have developed a novel technique, ultrasound guided optical tomography in the near-infrared wavelength (NIR-US), that accurately localizes tumor lesion with ultrasound and then images tumor angiogenesis. We have now collected images and tissue from 12 patients treated with preoperative chemotherapy. These tumors are large and heterogeneous with respect to vascular images. We have begun to correlate the tissue expression of a variety of pro-angiogenic proteins with the extent, distribution and pattern of vascularity demonstrated by our NIR-US. Methods: Using NIR-US images, the quantification of vascular content was performed by measuring the total hemoglobin content X volume of distribution of that hemoglobin content. This measure is termed the Blood Volume Index (BVI). In 12 patients studied, the level of tumor vascularity as measured by the initial BVI did not correlate with tumor grade, mitotic index, or estrogen receptor status or most importantly with response to treatment. We analyzed tissue specimens already collected with known patterns of vascular distribution on NIR-US and with known MVD to understand what might be driving the vascular response. Histologic sections were prepared and stained for; endothelial adhesion marker PECAM/CD31, VEGF, the activated stress response kinase P-AMPK, the cell proliferation marker Ki67, and SMA (smooth muscle actin) a marker of vasculature support cells and glucose transporter-1. Each case was quantified using at least 5 40X fields and pixel-by-pixel summation using Image Pro Plus software (Media cybernetics, Inc.) represented as average +/- SD. Results: The tumor BVI as defined by NIR-US did not correlate with either CD31 or SMA expression and was inversely correlated with VEGF levels. The higher VEGF, the lower the BVI. Of particular interest, the highest CD31 signals correlated with high VEGF levels in two, HER-2 positive patients, but not with BVI. Proliferation rate (Ki67), glucose transporter-1 and P-AMPK expression did not correlate with vascular content as measured by NIR-US.  Conclusion: Study of the above growth promoters in tissue imaged by NIR-US did not reveal an association between their expression and the vascular content of the tissue. Of interest, VEGF expression varied greatly within the tumor specimens and showed no correlation to BVI.  Financial support provided by a Research Grant from the CT Breast Health Initiative.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 907.