bluuebunny/crossref_metadata_2025 huggingface dataset:
P5-07-06: Effect of Angiotensin-(1-7) and Angiotensin II on T47D Breast Cancer Cells in the Proliferation and cAMP Production.
Authors: da Silva IDCG , Correa-Noronha SSAA , Noronha SMR , Alecrim C , Shimuta SI , Nakaie CR , Gebrim LH , Nazario ACP
Published: June 2012

Angiotensin-(1-7) [Ang(1-7)] is a peptide hormone that produces opposite responses to those of the well-characterized peptide angiotensin II (Ang II). The main actions of Ang(1-7) and AII occur, respectively, via MAS and Angiotensin type 1 receptor (AT1R), respectively. Ang (1-7) has blood pressure and proliferative effects contrary to those of AngII, exhibits significant antiangiogenic activity and may be a novel therapeutic agent for lung cancer treatment targeting a specific AT(1-7) receptor (Soto-Pantoja et al., 2009). Here, our aim was to evaluate T47D breast cancer cell proliferation and cAMP production after treatment with Ang (1-7) and AngII.By means of the cyclic AMP (cAMP) competitive enzymeimmunoassay system we measured cAMP content of T47D cells. Cell proliferation was measured using incorporation of BrdU after Ang (1-7) and AII stimulation. Intracellular cAMP increasing drugs like Forskolin (FK) and isobutylmethylxanthine (IBMX) were also used to stimulate T47D cells.AII inhibited cAMP production (−39%) and A-(1-7) increased its formation (48%). Pattern of cAMP production was not altered when cells were previously incubated with FK. Results were inverted after IBMX incubation. In proliferation, opposite responses were observed for Ang II and Ang (1-7), that is, increasing (7.6 times) and decreasing (7.5 times) proliferation rates respectively. Also both peptides decreased proliferation when cells were stimulated by FK. Exactly the opposite happened after IBMX stimulation, both peptides increased proliferation. These results suggest that Ang (1-7) inhibits growth of T47D cells probably through inhibition of the via RAS/RAF/MAP quinase, what corroboraties previous findings. On the other hand, AngII can induce cell proliferation by an alternative via (CREB/growth factor). Therefore, Ang (1-7) seems to be not only a promising target to develop novel lung cancer therapeutic drugs, but it also might help to prevent the molecular changes that lead the normal breast epithelial cells to cancer initiation.

Financial Support: FAPESP.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-07-06.
P5-11-08: High Concordance of 5 HER2 In Situ Hybridization Methods with Abbott FISH.
Authors: Boers JE , Netjes C , Meeuwissen HC , Prinsen C , Bart J , van der Logt EMJ , Schuuring E
Published: June 2012

Background: HER2 in situ hybridization (ISH) has become a common test in breast cancer. Abbott FISH was used in most clinical studies showing the efficacy of anti-HER2 treatment in HER2 positive carcinomas. Only reports comparing one or two of newly developed ISH assays with Abbott FISH have been published previously. We conducted a comprehensive concordance study of 5 ISH methods with Abbott FISH in a large series of breast carcinomas.

Methods: Tissue Micro Arrays (TMA) were constructed by taking three 0.6 mm tissue cores from formalin-fixed/paraffin-embedded tissue-blocks from 402 primary breast carcinomas diagnosed in 2007 (supported by the Dutch Pathological Society). Up to 384 cases were analyzable in the TMA. ISH was performed after ample experience with 6 ISH assays. Scoring was performed by two independent observers without knowledge of the other ISH data according the ASCO-guidelines for HER2−testing. HER2 and chromosome 17 (Chr17) signals were counted separately, the HER2:Chr17 ratio was calculated and considered positive when the ratio was ≥ 2.0 In cases with a ratio was between 1.8 and 2.2, additional enumeration was performed. The discordant cases were reviewed and scores were reassigned on consensus of opinion. Concordance and Cohen's kappa score were calculated.

Conclusion: Concordance of 5 HER2 ISH assays with Abbott FISH were shown to be 98% or higher. Each of these tests might be used for a reliable assessment of HER2 amplification.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-08.
P5-11-12: Correlation of Ki67 Expression between Initial Biopsy and Surgical Specimen in Untreated Breast Cancer Patients. Does Menstrual Cycle Matter?
Authors: Torrejón D , Rubio I , Sanchez-Olle G , Peg V , Sansano I , Jimenez J , Gomez P , De la Peña L , Di Cosimo S
Published: June 2012

Background: The measure of proliferative index by Ki67 expression is being increasingly used to identify breast cancer subtype and to guide treatment decisions. Findings on initial tumor biopsy are in some cases, such as for primary systemic treatment, the only data available prior to treatment. In addition, results from window studies to develop novel anti-tumor agents depends on initial breast cancer biopsy findings. This study aims to compare the Ki67 expression on initial biopsy with matched primary breast cancer surgical specimens. In addtion, we aimed to explore the possible effect of hormonal levels — as reflected by menstrual cycle phase — on discordant Ki67 cases. Material and Methods: A total of 50 random cases were analyzed by 2 blinded pathologists. Ki67 expression was collected as a continuous variable. Tumors were then classified as high — or low-proliferative according to a Ki67 value of > or = 15% or < 15%, respectively. Sperman Rank test was used to study the correlation between initial and surgical biopsies. Data on menstrual cycle phase at the time of biopsy and surgery were retrived from medical history of all premenopausal patients.

Results: Baseline patients characteristics are as follows: median age 48 (35-56 years), premenopausal 27 (54%), postmenopausal 23 (46%), invasive ductal carcinoma 38 (76%). A differential expression of Ki67 was found in 36 patients (72%), 20 pre- and 16 post-menopausal. Spearman's Rank Order correlation did not show any significant difference between biopsy and matched surgical specimen in terms of Ki67 expression. Indeed, there was a strong positive correlation between initial and surgical biopsy, which was statistically significant across all patients (rs = .556, P < 0.001), and regardless the menopausal status. However, 15% of pre-menopausal patients transformed from Ki67 low to high. Therefore, data on pre-menopausal patients were analyzed according to the phase of menstrual cycle at the timing of initial and surgical biopsies. The Spearman's Rank Order gave no correlation among 14 premenopausal patients with differential menstrual cycle phase at the timing of initial biopsy and surgery (rs = .411, P = 0.145).

Conclusions: Initial breast cancer biopsy can be used with high confidence for Ki67 determination. However, it should be noted that menstrual cycle phase could affect Ki67 expression as women with distinct menstrual cycle phase at the time of initial biopsy and final surgery do not show concordant results. Prospective evaluation of Ki67 expression in premenopausal patients is being planned.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-12.
P5-13-13: The Role of Topoisomerase IIa in Predicting Sensitivity to Anthracyclines in Breast Cancer Patients: A Meta-Analysis of Published Literatures.
Authors: Lu J , Du Y , Zhou Q , Yin W , Zhou L , Di G , Shen Z , Shao Z
Published: June 2012

Topoisomerase IIα is not only a proliferation marker of tumor cells but also a target for anthracycline-based chemotherapy. Both in vitro and in vivo studies have shown that there was a relationship between topo IIα and chemosensitivity to anthracyclines, but the predictive role of topo IIα is still controversial in breast cancer patients. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the association between topo IIα and sensitivity to anthracycline-based chemotherapy. A total of 13 eligible studies including 2,633 cases and 2,118 controls were identified. Topo IIα was associated with sensitivity to anthracyclines in locally advanced breast cancer patients who received neoadjuvant chemotherapy (RR = 1.93, 95%CI: 1.27−2.94, P=0.002; RR =1.98, 95%CI: 1.37−2.86, P<0.001). In early breast cancer patients who received anthracycline-based adjuvant chemotherapy compared with non-taxane-based polychemotherapy, amplification(HR = 0.64, 95%CI: 0.49−0.83, P=0.001; HR = 0.59, 95% CI: 0.35−1.01, P=0.056) or deletion (HR = 0.82, 95%CI: 0.67−1.00, P=0.051; HR =0.58, 95%CI: 0.35−0.97, P=0.036) of topo IIα was significantly associated with better RFS and OS. The subgroup analysis in the early breast cancer patients indicated that taxane could be an interference for evaluation of the predictive role of topo IIα. In summary, the present meta-analysis suggests that topo IIα is a predictive factor for breast cancer patients who received anthracycline-based chemotherapy. Larger and well-designed prospective studies are required to further evaluate the predictive role of topo IIα in clinical practice.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-13.
P5-13-15: Proteomic Identification of Predictive Biomarkers of Resistance to Neoadjuvant Chemotherapy in Luminal Breast Cancer: A Possible Role for 14–3-3 and BID?
Authors: Hodgkinson VC , ELFadl D , Agarwal V , Garimella V , Drew PJ , Lind MJ , Cawkwell L
Published: June 2012

Background: Chemotherapy resistance is a major obstacle in effective neoadjuvant treatment for oestrogen receptor (ER)-positive breast cancer. The ability to predict tumour response would allow chemotherapy administration to be directed towards only those patients who would benefit, thus maximising treatment efficiency. We aimed to identify protein biomarkers associated with chemotherapy resistance, using proteomic analysis of fresh ER-positive breast cancer samples, and then to perform pilot clinical validation experiments. Materials and Methods: Chemotherapy resistant and chemotherapy sensitive tumour samples were collected from breast cancer patients who received standard anthracycline-based neoadjuvant therapy consisting of epirubicin with cyclophosphamide followed by docetaxel. Comparative proteomics experiments were performed using invasive ductal carcinomas which demonstrated ER-positivity (luminal subtype). Protein expression was compared between chemotherapy resistant and chemotherapy sensitive tumour samples using 2-dimensional gel electrophoresis (2-DE) with MALDI-TOF/TOF mass spectrometry (MS). In addition the Panorama XPRESS Profiler725 antibody microarray, containing 725 antibodies from a wide variety of cell signalling and apoptosis pathways, was employed in the discovery phase. Differentially expressed proteins (DEPs) were submitted to Ingenuity Pathway Analysis (IPA) to identify any canonical pathway links. A pilot series of archival breast cancer samples, from patients treated with neoadjuvant anthracycline-based chemotherapy, was used for preliminary clinical validation of putative predictive biomarkers.

Results: Five datasets were generated by antibody microarray analysis, revealing 41 targets. Of these, 7 DEPs were identified in at least 2 datasets and these included 14–3-3, BID and Bcl-xL. The top canonical pathway matched in IPA was “ERK5 signaling”, which involved 6 DEPs, including 14–3-3. The “PI3/AKT” pathway also involved 6 DEPs, including 14–3-3 and Bcl-xL. Three datasets were generated using 2-DE with MALDI-TOF/TOF MS, containing over 300 DEPs. These included several isoforms of 14–3-3. Differential expression of 14–3-3, BID and Bcl-xL was confirmed by immunoblotting in samples used for the discovery phase. A pilot clinical validation using immunohistochemical analysis of archival breast cancers revealed 14–3-3 tau and tBID to be significantly associated with chemotherapy resistance.

Discussion: We have successfully utilised clinical tumour samples for the discovery of putative biomarkers of chemotherapy resistance using two complementary proteomic platforms. We propose a potential role for 14–3-3 tau and BID as predictive biomarkers of chemotherapy resistance in ER-positive tumours and further validation in a larger sample series is now required.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-15.
P5-14-10: Ethnic Differences in the Association between Tumor Size and Lymph Node Status among Breast Cancer Patients in South East Asia.
Authors: Saxena N , Verkooijen HM , Bhoo Pathy N , Siew EL , Iau P , Lee SC , Yip CH , Hartman M
Published: June 2012

Background: South East Asia consists of three major ethnic groups, i.e. Chinese, Malays and Indians. Previous work from our breast cancer research group showed that Malay ethnicity is an independent predictor of poor survival. In this study we evaluate whether (part of) these ethnic survival disparities may be due to ethnic differences in the association of tumor size and lymph node involvement.

Methods: We included all patients diagnosed with breast cancer at the National University Hospital (Singapore) and University of Malaya Medical Center (Kuala Lumpur) between 1990 and 2007, for whom information on tumor size and axillary lymph node status was available (n = 3805). Ethnic differences in the association between tumor size and lymph node involvement were studied and logistic regression analysis was performed to determine the independent effect of ethnicity on the association of tumor size and lymph node involvement.

Results: 1474 patients were categorized as T1 (>0 to 2 cm), 1777 as T2 (2.1 to 5 cm) and 554 as T3 (>5 cm). Within the small tumor size range (>0 to 2 cm) the Malays were significantly more likely to present with node positive disease as compared to the other ethnic groups (36.9% as compared to 24.5% for Chinese and 25.9% for Indians, p value <0.001). Similarly, for tumors measuring 2.1-5 cm, Malays were more likely than Chinese and Indians to have lymph node involvement (59.5%, 50.2% and 52.1%, respectively p value 0.016). After adjustment for age, Progesterone Receptor (PR) status, grade and treatment received, Malay ethnicity was an independent predictor of lymph node involvement, with adjusted Odds Ratio's of 1.4 (95% CI 1.0 to 2.1) for T1 tumors and 1.4 (95% CI 1.1 to 1.9) for T2 tumors compared to Chinese women.

Conclusion: Malay patients are more likely to present with lymph node metastasis especially for the small and midsized tumors as compared to the Chinese and Indians. This could reflect differences in tumor biology between the three ethnic groups with the Malays possibly having more aggressive disease than the others.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-10.
P5-14-17: Stage IV at Presentation – Are HER2 Positive Tumors Overrepresented?
Authors: Woods R , Yerushalmi R , Speers C , Tydesley S , Gelmon K
Published: June 2012

Background: A minority of patients are diagnosed with Stage IV breast cancer at presentation. Recent studies (Dawood 2010) have suggested a better outcome for de novo vs. recurrent Stage IV but they did not account for the variation of molecular subtype. We questioned whether HER2 overexpressing tumors were over-represented in de novo Stage IV disease, and whether this impacted on survival compared to other subtypes. Further, if different subtypes are more likely to present with metastatic disease, then this factor may need to be considered when developing guidelines for staging. With such considerations in mind, the purpose of this study was to determine the breast cancer subtypes according to stage. The main hypothesis was that HER2 positive tumors would be more prevalent in stage IV presentations. Methods: Using the Breast Cancer Outcomes Unit database from the BC Cancer Agency (BCCA), patients referred to the BCCA with a new diagnosis of breast cancer between 2005 and 2010 were selected. Patients with a previous or synchronous contralateral breast cancer, male cases, and patients with referrals for reasons other than new disease were excluded. Four subtypes according to available markers were defined: ER+/HER2−, ER+/HER2+, ER-/HER2+, and ER-/HER2−.

Results: Using these criteria, 485 cases of de novo stage IV disease and 10,723 stages I — III cases were extracted. After excluding cases with missing data, our final cohort consisted of 10,186 stage I-III cases and 425 stage IV cases. Distribution by subtype is presented in the Table below.

Assessment of other patient characteristics for the group of Stage IV de novo patients revealed that age (younger for HER+ subgroups), site of metastases (more visceral vs. non- visceral for ER-/HER2+ and ER-/HER2−) and type of systemic therapy (chemotherapy (CT), hormone therapy (HT), trastuzumab (T) or not) were significant. Surgery rates for both mastectomy and breast-conserving surgery were similar for all subtypes. The ER-/HER2− subtype had the worst overall survival (p < 0.001).

Conclusion: Young age and HER2 overexpression is more common in stage IV de novo presentations (26.6% of stage IV tumors were HER2+ vs. only 16% of stage I-III tumors). This data may be important in considering routine staging guidelines at diagnosis to ensure correct diagnosis and treatment recommendations.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-17.
P5-14-26: Results from a Prospective Clinical Study on the Impact of Oncotype DX on Adjuvant Treatment Decision Making in a Cohort of 142 UK Patients.
Authors: Holt S , Bertelli G , Brinkworth E , Durrani S , Jones S , Khawaja S , Laggner U , Moe M , Pudney D , Pitcher S , Rolles M , Sharaiha Y , Whelan S
Published: June 2012

Objectives: International guidelines support the use of the Oncotype DX derived Recurrence Score (RS) to provide additional prognostic and predictive information in early breast cancer but experience in the UK is limited. In our prospective study we evaluate this test for the NHS and its impact on costs (subject of a separate abstract) and treatment recommendations by UK oncologists.

Methods: 150 tests were made available to consecutive patients with ER+, pN0, pN1itc or pN1mic early breast cancer who had no contraindication to adjuvant chemotherapy (CT) and who would accept CT + hormone therapy (HT) if recommended. CT recommendations of oncologists based on Adjuvant! Online figures were recorded at an initial consultation. Eligible patients were consented to Oncotype DX testing and review arranged once the result was available. After a second consultation a final decision on adjuvant therapy was recorded.

Results: Analysis is based on 142 patients. (150 tests performed, 3 failed to give a result, 3 repeated tests giving a result on the second block, one bilateral and one test stopped because the patient withdrew from the study). Initial treatment recommendations changed in 38 (26.8%) cases. Of the patients initially recommended CT + HT (total 57 patients), 26 (45.6%) patients were spared chemotherapy after review with the RS. Of the 85 patients initially recommended HT only 12 (14.1%) were changed to HT + CT.

Further analysis shows that Grade, estrogen receptor status by immunohistochemistry (ER by IHC) and progesterone receptor by immunohistochemistry (PR by IHC) are correlated to RS but in our cohort age, size and node status were not. (Spearman rank correlation for grade is 0.05, 95%, Cl 0.36 to 0.61; for ER by IHC is −0.36, Cl −0.49 to −0.20; and for PR by IHC is −0.49, 95%, Cl −0.60 to −0.35). Apart from HER2 positive patients who are already recognized to return a high RS, further analysis of our series shows no clear combination of currently available prognostic factors that would predict RS and therefore reliably avoid testing of any subset of patients.

Conclusion: The results of our study suggest that Oncotype DX is applicable and feasible to perform in UK patients with a reduction in the use of adjuvant chemotherapy consistent with findings of reported studies. RS added prognostic information beyond information provided by Adjuvant!

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-26.
P5-17-02: Associations between Breast Cancer Patients' Satisfaction with Nursing Staff and Hospital Characteristics, Results of a German Multicenter Study.
Authors: Wuerstlein R , Kowalski C , Diener S , Krebs S , Pfaff H , Harbeck N
Published: June 2012

Background

Only few studies have investigated the association between breast center characteristics such as teaching status, number of patients, whether clinical trials are conducted, or whether breast care nurses are employed and patients’ perceptions of care.

Objective: The aim of the study was to determine whether or not the satisfaction of newly-diagnosed breast cancer patients with nursing staff correlates with hospital characteristics after adjusting for relevant patient characteristics. The study is part of a national process-identifying project focusing on breast cancer of the MAGS NRW (Ministry of work, health and social affairs, North Rhine Westfalia, Germany).

Methods: Multilevel regression analysis was applied combining data from newly-diagnosed breast cancer patients (n= 3733) on patient characteristics and satisfaction with nursing staff and data on characteristics of the hospitals (n= 93 breast centers in Germany) in which patients were treated. Patients’ perspectives were measured for six month using the Cologne Patient Questionnaire for Breast Cancer (CPQ-BC), the other informations and hospital characteristics were collected by medical personnel.

Results: Full data of 2945 patients from 81 hospitals were analysed in the multilevel logistic regression model. The odds for patients being satisfied with nursing staff were significantly higher in hospitals which employed breast care nurses at the time of the survey. At the patient level, patients were significantly more likely to be satisfied with nursing staff if they were native speakers, and with higher self-rated health. Cross-level interaction analysis suggested that higher patient satisfaction resulting from employing breast care nurses was largely limited to native speaking patients. Other hospital characteristics were not significantly associated with the perception of nursing staff (teaching hospital, required number of surgeries, clinical trial participation).

Conclusions: The results demonstrate that patient satisfaction with nursing staff is higher if breast care nurses are employed in the treating hospital. Further work will focus on the description of the breast care nurses work as it is interpreted individually in every breast center. However, only the satisfaction of native speakers was significantly higher when breast care nurses were employed.

Implications for Practice: Findings suggest that hospitals should invest in employing specialist nurses. Special attention should be paid to the care of non-native speaking patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-17-02.
P5-18-02: A Population Level Assessment of Emergency Room Visits and Hospitalizations for Women Undergoing Adjuvant Chemotherapy for Early Breast Cancer.
Authors: Enright KA , Trudeau M , Yun L , Grunfeld E , Krzyzanowska M
Published: June 2012

Background: Adjuvant chemotherapy is considered the standard of care for women with lymph node positive and high risk lymph node negative breast cancer. While the acute toxicities of chemotherapy are well documented in clinical trials, the frequency of serious treatment related toxicities of adjuvant chemotherapy in the general population is not well described. We undertook a population based assessment of the frequency of serious treatment related toxicity in women undergoing adjuvant chemotherapy for early breast cancer (EBC). Methods: All incident EBC patients diagnosed between January 2007 and December 2008 in Ontario, Canada were identified from the Ontario Cancer Registry. Patient records were linked deterministically to multiple provincial administrative health care databases to provide comprehensive medical follow-up. Exclusion criteria were set to exclude patients on chemotherapy for advanced breast cancer. Any patient with who received at least 1 cycle of adjuvant chemotherapy was included in the analysis. Serious toxicities resulting in emergency room (ER) visits or hospitalizations occurring between the start date of chemotherapy and 30 days after the last dose of chemotherapy were identified. Logistic regression models were used to identify the impact of chemotherapy regimen, age, comorbidity and duration on therapy on the likelihood of experiencing serious toxicity.

Results: Of the 3090 women identified in our cohort, 1440 (46.6%) experienced at least 1 serious toxicity resulting in an ER visit during their adjuvant treatment. Of the ER visits, the majority (1107, 87%) were attributable to treatment related toxicities. Febrile neutropenia (FN) was the most common treatment related toxicity occurring in 27.1% of patients in the cohort. Docetaxel containing regimens were associated with a significantly higher rate of ER visits and FN (54.6%, 34.6%) compared with paclitaxel (38.0%, 17.9%), or anthracycline alone (epirubicin 45.8%, 23.8%; doxorubicin 32.8%, 15.4%). Table 1 displays the impact of clinical and patient factors on multivariable analysis.

Conclusion: Serious toxicities are a common in women undergoing adjuvant chemotherapy for EBC and result in significant acute health care utilization.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-02.
P5-18-11: Incidence of Chemotherapy Dose Reductions and Dose Delays, and Reduced Chemotherapy Dose Intensity in Early Stage Breast Cancer.
Authors: Weycker D , Edelsberg J , Kartashov A , Barron R , Lyman G
Published: June 2012

Background: Chemotherapy is widely used to treat early stage breast cancer (ESBC). Dose reductions and dose delays–e.g., due to advanced age or severe/febrile neutropenia–are generally believed to increase risk of disease progression and reduce survival. Little is known about incidence of chemotherapy dose reductions and dose delays among women with ESBC in clinical practice.

Methods: This study employed a retrospective cohort design and electronic medical records from over 60 community oncology clinics in more than 20 states (2004-2010). Study population included adult women who received myelosuppressive chemotherapy for ESBC (stages I-IIIA). For each such woman, each unique cycle of chemotherapy within their first observed course was identified. Incidences of chemotherapy dose delays (≥7 days for any drug in ≥1 cycles), chemotherapy dose reductions (≥15% for any drug in ≥1 cycles), and low relative chemotherapy dose intensity (<85% over the course) – relative to physician-reported planned chemotherapy administration – were descriptively analyzed for the seven most frequently observed regimens among subjects.

Results: 2,350 women received seven most frequently observed regimens (80% of study population); mean age – across regimens – ranged from 51–56 years, and 31–94% received primary prophylaxis against severe/febrile neutropenia with a colony-stimulating factor. Incidence of dose reductions ranged from 17–48%, and dose delays, from 24–45%. Overall mean relative dose intensity (RDI) ranged from 80%-99%, and 17–50% of subjects received RDI <85%; mean RDI among those with low RDI ranged from 40%-67%.

Discussion: Chemotherapy dose delays and dose reductions are common in ESBC, among those receiving dose-dense as well as conventional regimens.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-11.
P5-19-03: Albumin-Bound Paclitaxel (ab-pac) Versus Docetaxel for First-Line Treatment of Metastatic Breast Cancer (MBC): Overall Survival and Safety Analysis of a Randomized Phase II Trial.
Authors: Gradishar WJ , Krasnojon D , Cheporov S , Makhson AN , Manikhas GM , Clawson A , Bhar P
Published: June 2012

Background

We previously reported the results of a phase II study evaluating the efficacy and safety of 3 different dosing regimens of ab-pac and docetaxel for the first-line treatment (Tx) of MBC (Gradishar et al. J Clin Oncol. 2009;27:3611–3619). Here, we report final overall survival (OS) and an analysis of safety and associated dose reductions (DRs).

Methods: Patients (pts; N = 300) with previously untreated MBC were randomized to 1 of 4 Tx arms (table). A step-down statistical approach was used for pairwise comparisons of Tx arms. The trial was powered for antitumor activity and safety.

Results: Tx arm C produced the longest OS (33.8 months) with an 11.6-month longer median OS vs arm B (HR 0.575; P = .008) and a 7.2-month longer median OS vs arm D (HR 0.688; P not statistically significant). OS data were consistent with previously reported investigator assessment of overall response rates and progression-free survival. Grade (gr) 4 neutropenia (np) was significantly less frequent in the ab-pac arms vs. the docetaxel arm (5-9% vs. 75%; P < .001). Febrile np occurred in 1% of each ab-pac arm vs 8% in the docetaxel arm. Rates of gr 3 sensory neuropathy (SN) were 21%, 9%, 22% and 12%, respectively, in arms A-D (P = .083). No gr 4 SN occurred. Median time to improvement to ≤ gr 2 SN was 20–22 days in the ab-pac arms vs 41 days in the docetaxel arm. Gr 3 fatigue occurred in 5, 0, 4, and 19% of pts in arms A-D, respectively. In arm C, best response was observed at cycle 2, whereas DRs due to toxicity occurred later, at cycle 4 (table). The percentage of pts dose reduced due to ≥ 1 Tx-related toxicity were 18%, 17%, 47%, and 28% in arms A-D. The median cycles at which DRs occurred were 7, 5, 4, and 3, respectively. Np and SN were the most common toxicities leading to DRs.

Conclusion: Ab-Pac 150 mg/m2 qw3/4 resulted in a 33.8-month OS, a longer OS than historically achieved with taxane monotherapy in MBC. Within the 150 mg/m2 ab-pac arm, best response occurred at cycle 2, whereas DRs due to toxicities occurred at later cycles. These data indicate that dosing ab-pac at 150 mg/m2 on a qw3/4 schedule may allow pts to achieve a clinical response before emergence of dose-limiting adverse events.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-03.
P5-19-07: The Effects of ABCC2 and SLCO1B3 Single Nucleotide Polymorphisms on Docetaxel-Induced Leukopenia in Breast Cancer Patients.
Authors: Chen J , Wu LJ , Shen P , Yu LF , Huang S
Published: June 2012

Purpose Docetaxel-based combination treatment has known to be effective for breast cancer. Genotyping of ABCC2 and SLCO1B3 were demonstrated determining the risk of docetaxel-induced leucopenia in other ethnic. We designed this phase II trial to evaluate single nucleotide polymorphisms (SNPs) of the two genes association with docetaxel haematological toxicity in chemonaive breast cancer patients of chinese population.

Patients and Methods We selected 45 breast cancer patients who received docetaxel combination chemotherapy, Genomic DNA was isolated from peripheral blood and detected polymorphisms in ABCC2 and SLCO1B3.

Results All patients were evaluated for toxicity. 28 patients developed with grade 3 or 4 leukopenia, and 17 with grade 1 or 2 in nadir leukocyte from cycle 1 baseline. The combined analysis indicated a significant association of 9383C/G in ABCC2 (P = 0.002) and 5676A/G in SLCO1B3 (P = 0.005) with docetaxel induced ***leukopenia. Patients homozygous for the variant allele (GG) of SLCO1B3 5676A/G had significantly higher leukopenia compared to patients with AA/AG ***genotypes(P <0.05). Similar trend was observed for ABCC2 (9383C/G) with heterozygotes (CG) having the highest percentage decrease compared to those with CC/GG genotypes(P = 0.06).

Conclusion The study indicating that SNPs in ABCC2 and SLCO1B3 may predict the risk of leukopenia induced by docetaxel chemotherapy in china breast cancer patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-07.
P5-19-14: Platinum-Based Chemotherapy in Triple-Negative Breast Cancer.
Authors: Villarreal-Garza C , Bouganim N , Khalaf D , Clemons M , Kassam F , Enright K , Verma S , Myers J , Dent R
Published: June 2012

Background: There is increasing evidence that DNA repair defects characteristic of BRCA1-related cancers and triple negative breast cancer (TNBC) confer sensitivity to certain chemotherapeutic agents, such as platinums. However, prospective and retrospective studies comparing the efficacy of these agents versus conventional treatment in TNBC are lacking. The aim of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) in metastatic TNBC in terms of median duration of treatment and overall-survival (OS) and compare it to patients treated with conventional chemotherapy. Methods: We performed a retrospective chart review of patients with metastatic TNBC who received PBC from January 2007 to June 2010 treated at the Sunnybrook Odette Cancer Center and the Ottawa Hospital Cancer Centre. This cohort was compared to a control group that included metastatic TNBC treated with conventional agents that included anthracyclines, taxanes, capecitabine, and vinorelbine.

Results: A total of 166 metastatic TNBC patients were analyzed: 60 treated with PBC and 106 managed with conventional treatment. Median age at diagnosis was 48 years and distant disease-free interval was 26 months (m) for both groups. Patients on both groups had multiple sites of metastases at diagnosis of recurrence than a single site of metastasis (69% for both groups). Of the 60 patients treated with PBC, 90% received a combination regimen, most commonly weekly cisplatin plus gemcitabine in 37% of patients and cisplatin plus vinorelbine in 17% of patients. The median number of cycles delivered was 4 (1-24). 33% received the PBC as first-line treatment, 38% as second-line, 18% as third-line, 7% as fourth line, and 3% as fifth-line. Only 8 patients (5%) discontinued PBC secondary to toxicity. The median time on treatment in first, second and third-line therapy was longer for the PBC group compared to the conventional group (5 vs. 2 m, p=0.108; 5 vs. 2 m, p=0.01; and 4 vs. 1 m, p=0.026). Patients treated with PBC had a longer OS compared to those managed conventionally (16 vs. 10 m, p=0.039).

Conclusions: PBC appears to improve clinical outcomes in patients with metastatic TNBC compared to those treated with conventional chemotherapy regimens. Although this is a retrospective study with its obvious limitations, it adds to the growing body of literature, suggesting the benefit of PBC in TNBC. Prospective trials are needed to confirm its benefit in order to integrate it as part of the routine management of these patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-14.
P5-20-06: Survival in Women with Breast Cancer Who Used or Did Not Use Scalp Cooling in the Neoadjuvant/Adjuvant Setting.
Authors: Lemieux J , Perron L , Provencher L , Brisson J , Amireault C , Blanchette C , Maunsell E
Published: June 2012

Background

Scalp cooling can prevent chemotherapy-induced alopecia. Success varies according to the type of chemotherapy. A controversy exists regarding the use of scalp cooling because of the lack of safety data. No data are available regarding the impact on survival.

Purpose: To compare overall survival in women who used or did not use scalp cooling in the neoadjuvant/adjuvant setting.

Method: The survival of women treated in a specialized breast cancer centre (the Centre des Maladies du Sein Deschěnes-Fabia) in Quebec City who all used scalp cooling was compared to that of a population-based random sample of women treated in other regions of the province of Quebec (Canada) where scalp cooling is not available. Cox proportional hazard models were used.

Results: Overall, survival was comparable (and possibly better although not at a conventionally statistically significant level: HR = 0.80, 95 % CI: 0.63−1.01, p=0.06) among the 553 women who used scalp cooling compared to the 817 who did not. An interaction was found between scalp cooling and treatment in the adjuvant vs. neoadjuvant setting (p-interaction=0.015). In the adjuvant setting (n=485 scalp cooling and 740 no scalp cooling), the crude HR (in favour of scalp cooling) was 0.66 (95% CI: 0.50−0.87, p=0.003). In the neoadjuvant setting (n=68 scalp cooling and 77 no scalp cooling), the HR was 1.40 (95% CI: 0.84−2.33, p=0.2). No interaction was found with stage.

Conclusion: This is the first study to compare survival of women who used scalp cooling to that of women who did not. Scalp cooling to prevent chemotherapy-induced alopecia had no negative effect on survival in women with breast cancer who used it.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-20-06.
P5-20-07: Estimation of Febrile Neutropenia in Women Receiving Docetaxel Plus Cyclophosphamide as Adjuvant Therapy for Early Stage Breast Cancer: A Retrospective Analysis.
Authors: Bordoni RE , Haislip ST , Gilmore JW , Sharpe J , Abella E , Choi MR
Published: June 2012

Background: US Oncology Trial 9735 (Jones S, et al. JCO. 2006;24:5381–5387) established the docetaxel plus cyclophosphamide (TC) regimen as an effective adjuvant therapy for early stage breast cancer (ESBC). This trial did not specifically evaluate the incidence of febrile neutropenia (FN) as a study endpoint, but rates of 4%-8% were reported. Prophylactic granulocyte colony-stimulating factor (G-CSF) support was not allowed; reactive G-CSF support overall was not reported. Subsequent reports in the community setting have indicated FN rates of 25%-50% without G-CSF support and 0%-6.3% with G-CSF support (Table 1). To better determine the incidence of FN among ESBC patients treated with TC, we performed a retrospective clinical data review from the electronic medical record (EMR) database of Georgia Cancer Specialists, a large community oncology practice.

Methods: EMR data were captured between January 2006 and March 2010. Eligibility included women ≥ 18 years old with ESBC (stage I-IIIA) who completed ≥ 1 cycle of TC. The study time period was from the first dose of chemotherapy (CTX) to 6 weeks after the last dose of CTX, death, or loss to follow-up. The primary endpoint was the incidence of FN. Other endpoints included the incidence of severe (grade 3/4) neutropenia, neutropenia-related hospitalizations, G-CSF use, relative dose intensity (RDI), and dose delays and reductions. Results: Data from 662 patients were included in the analysis. Median age was 55 (range: 25–81) years. 40% of patients were white. The median number of CTX cycles received was 4 (range: 1–6). Most patients (91%) received G-CSF support; 73% as primary prophylaxis. See Table 2 for additional results.

Conclusions: This is the largest retrospective, community-based study to evaluate the incidence of FN in ESBC patients treated with TC. The observed FN rate of 5% (with 91% of patients receiving G-CSF) is consistent with other published reports using TC (Table 1). Our results suggest that TC is a taxane regimen with clinically significant myelosuppression (similar to other commonly used regimens in ESBC, such as TAC [NCCN Guidelines v2.2011]) and that the use of G-CSF support should always be considered.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-20-07.
PD03-02: Prognostic and Predictive Predictors for Triple Negative Breast Cancer.
Authors: Karn T , Pusztai L , Ruckhäberle E , Liedtke C , Schmidt M , Müller V , Gätje R , Hanker L , Ahr A , Holtrich U , Rody A , Kaufmann M
Published: June 2012

Background: Both the prognosis and the therapeutic options in triple negative breast cancer (TNBC) are rather limited. Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. The identification of prognostic gene signatures from TNBC cohorts in previous studies was hindered due to relatively small sample sizes.

Materials and Methods: All currently available TNBC gene expression datasets generated on Affymetrix U133 gene chips were assembled. To minimize inter-laboratory variation we analyzed only highly comparable arrays and data set-biased genes were filtered. Supervised analysis was applied to identify a prognostic signature from a finding cohort of 394 TNBC and validation was performed in an independent cohort of 261 TNBC. The genes from the prognostic predictor were analyzed for their correlation to known molecular phenotypes among TNBC.

Results: Two supervised prognostic signatures consisting of 264 and 26 probesets, respectively, were obtained when applying different cutoffs for false discovery rates of 25% and < 3.5% in the finding cohort. In multivariate analysis in the independent validation cohort hazard ratios of 4.03 (95% CI 1.71−9.48; P=0.001) and 4.08 (95% CI 1.79−9.28; P=0.001), respectively, were obtained for the two signatures. When compared to 16 metagenes for previously described molecular phenotypes in TNBC the prognostic signatures displayed highest correlation to metagenes for IL-8/inflammation, VEGF/angiogenesis, and Histones. A subset of genes in the 264-probeset signature was inversely associated with a poor prognosis (29/264=11.0%). Most of these “good prognosis” genes are correlated with immune cell metagenes (21/29=72.4%). In contrast both identified supervised prognostic signatures did not correlate to previously published prognostic signatures (recurrence score, genomic grade index, Amsterdam signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature). Regarding the response of TNBC to neoadjuvant chemotherapy the predictive value of the B-cell metagene was superior to the 264- and 26-probeset signatures. However combination of the B-cell metagene and the signatures increased the AUC in ROC-analysis from 0.606 to 0.656. Conclusions: The use datasets consisting only of TNBC allows identification supervised prognostic signatures for TNBC which are unrelated to previously known prognostic signatures.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD03-02.
PD05-01: Trans-CHER-Lob: A Biomarker Analysis of the Randomized Phase II Study of Neoadjuvant Chemotherapy Plus Trastuzumab, Lapatinib or Combined Trastuzumab and Lapatinib in HER2 Positive Operable Breast Cancer.
Authors: Guarneri V , Frassoldati A , Ficarra G , Maiorana A , Bettelli S , Bottini A , Cagossi K , Bisagni G , Ravaioli A , Amadori D , Musolino A , Cavanna L , Orlando L , Giardina G , Piacentini F , Bagnalasta M , Conte P
Published: June 2012

Introduction: The CHER-Lob study is a randomized phase II trial of preoperative sequential taxanes-anthracyclines in combination with trastuzumab, lapatinib, or combined trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. A translational program to evaluate predictors of response as well as treatment effects on tissue biomarkers was pre-planned.

Methods: The CHER-Lob translational program includes the central evaluation of HER2, p95HER2, PTEN, pAKT, Ki67 on pre and post-therapy samples. All these biomarkers have been evaluated by immunohistochemistry. FISH analysis was performed in case of HER2 IHC 2+, and in all the discordant cases between central and local laboratories. Biomarkers change from baseline to surgery has been evaluated with the Wilcoxon signed-ranks matched-pair test.

Results: 121 patients have been randomized. The pathologic complete response rate (breast and axillary lymphnodes) was 26% in Arm A (chemotherapy + trastuzumab), 28% in arm B (chemotherapy + lapatinib) and 44% in arm C (chemotherapy + trastuzumab and lapatinib). The concordance between central and local HER2 assessment on pre-treatment biopsy was 97%.

The mean (min;max) PTEN expression pre- and post-therapy were 66% (0;100) and 68.4% (0;100) respectively.

The mean (min;max) pAKT expression pre- and post-therapy were 23.3% (0;100) and 8.8% (0;90) respectively. A significant decrease was observed in the overall samples (p=0.01). When analyzing the lapatinib alone arm, the difference was no longer significant (p=0.06), while it maintained significance when evaluating the two trastuzumab containing arms (p=0.0013). The mean (min;max) ki67 expression pre- and post-therapy were 29.5% (4;90) and 16.6% (1;50) respectively. A significant decrease was observed when looking at the whole population (p<0.0001). A significantly higher ki67 inhibition was observed in the dual vs single anti-Her2 therapy (p= 0.003).

Conclusions: The central HER2 retesting showed a high concordance with local laboratories. Treatment induced a suppression in pAKT expression, that was higher in patients receiving trastuzumab. The dual anti-HER2 blockade induced a higher KI67 inhibition as compared to single anti-Her2 blockade. The evaluation of the predictive and prognostic role of these biomarkers is ongoing. Supported by GlaxoSmithKline

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-01.
PD05-03: Impact of Quantitative Measurement of HER2, HER3, HER4, EGFR, ER and PTEN Protein Expression on Benefit to Adjuvant Trastuzumab in Early-Stage HER2+ Breast Cancer Patients in NCCTG N9831.
Authors: Perez EA , Ballman KV , Reinholz MM , Dueck AC , Cheng H , Jenkins RB , McCullough AE , Chen B , Davidson NE , Martino S , Kaufman PA , Kutteh LA , Sledge GW , Geiger XJ , Ingle JN , Tenner KS , Harris LN , Gralow JR , Rimm DL
Published: June 2012

Background: Prediction of benefit from trastuzumab in patients (pts) with HER2+ breast cancer remains an important goal. We sought to investigate the predictive value of quantitative measurement of HER2, HER3, HER4, EGFR, ER and PTEN protein expression on the benefit of trastuzumab in the phase III HER2+ adjuvant N9831 study for pts randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C).

Methods: For each marker, we evaluated quantitative expression, relationship with demographic data, and association with disease-free survival (DFS) of pts. Freshly cut tissue microarray slides with up to three-fold redundancy per specimen from the N9831 cohort were treated identically using the AQUA (Camp, et al; Nat Med 2002, JCO 2008) method of quantitative immunofluorescence for each marker. HER2 was tested with CB11 (mouse monoclonal, Biocare, Inc.) and preliminary results were available for 698 of nearly 1400 pt specimens to be tested. The minimum value per pt was used in statistical analysis. Specimens were classified with high versus low expression based on a median value cutpoint for each marker. Median follow-up was 7.0 yrs.

Results: Quantitative HER2 was compared with centrally performed HER2 testing by IHC and FISH. Median quantitative HER2 via AQUA was 10,017 units for the HER2 IHC 3+ group (n=607) versus 1058, 831, and 970 for the HER2 IHC 2+ (n=68), 1+ (n=11), and 0 (n=11) groups, respectively. The Spearman correlation between quantitative HER2 and FISH HER2/CEP17 ratio was 0.32 (p<0.001). High quantitative HER2 was associated with lower percentage of hormone receptor positivity (48% vs 59%, chi-sq p=0.003) but not associated with age, race, nodal positivity, tumor histology, grade, or size. High HER2 did not impact DFS in any arm of the study (See Table). Data for additional HER2 testing, HER3, HER4, EGFR, ER and PTEN are in process and will be ready by September, 2011.

Conclusions: Similar to results based on standard HER2 testing by IHC and FISH in N9831, quantitative HER2 did not impact benefit from adjuvant trastuzumab. Results for additional markers will be presented. Our complete quantitative results for a second epitope on HER2, HER3, HER4, ER and EGFR will be the first report of these markers in a large patient cohort in the adjuvant setting.

Disease Free Survival

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-03.