bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PD07-05: In Situ Immune Response after Neoadjuvant Chemotherapy for Breast Cancer Predicts Survival
Authors: Ladoire S , Coudert B , Fumoleau P , Arnould L , Ghiringhelli F.
Published: April 2011

Purpose: Accumulating preclinical evidence suggest that anticancer immune responses contribute to the success of chemotherapy. However, the prognostic value of tumor infiltrating lymphocytes after neoadjuvant chemotherapy for breast cancer remains unknown. We hypothesized that the nature of the immune infiltrate following neoadjuvant chemotherapy would predict patient survival.

Patients and Methods: In a series of 111 consecutive HER2 and a series of 51 non HER2 overexpressing breast cancer patients treated by neoadjuvant chemotherapy, we studied by immunohistochemistry tumor infiltration by Foxp3 and CD8 T lymphocytes before and after chemotherapy. Kaplan-Meier analysis and Cox modeling were used to assess relapse-free survival (RFS) and overall survival (OS). A prognostic scoring system using American Joint Committee on Cancer (AJCC) pathologic staging and immunological markers was created.

Results: Association of high CD8 and low Foxp3 cell infiltrates after chemotherapy was significantly associated with improved RFS (p=0.02) and OS (p=0.002), and outperformed classical prognostic factors in multivariate analysis. A combined score associating CD8/Foxp3 ratio and pathological AJCC staging isolated a subgroup of patients with a long-term overall survival of 100%. Importantly, this score also identified patients with favorable prognosis in an independent cohort of HER2 negative breast cancer patients.

Conclusion: Immunological CD8 and Foxp3 cell infiltrate after treatment is a novel independent prognostic factor of survival in breast cancer patients treated with neoadjuvant chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-05.
Abstract PD08-02: The Impact of Patient Reported Outcomes (PRO) on the Evaluation of Therapy Related Side-Effects and the Improvement of Adherence to Endocrine Treatment in Breast Cancer Patients
Authors: Hubalek M , Oberguggenberger A , Meraner V , Giesinger J , Kemmler G , Sperner-Unterweger B , Beer B , Oberacher H , Marth C , Holzner B.
Published: April 2011

Background: Long term treatment regimen with significant side effects may diminish a patient's quality of life (QOL) and consequently undermine adherence. Endocrine treatment for breast cancer causes various side effects, which can lead to early discontinuation of this effective therapy. Current knowledge on patients’ quality of life (QOL) impairments caused by endocrine therapy originates from clinicians’ impressions and expert ratings. This runs the risk of underestimating the effects of endocrine therapy on patients’ quality of life. Patient reported outcome (PRO) may provide higher accuracy and may therefore essentially contribute to medication evaluation and clinical decision making. In this study, we report on the patient reported outcome (PRO) related to endocrine therapy in early breast cancer.

Methods: Pre-and postmenopausal breast cancer outpatients treated with aromatase inhibitors (AIS) or tamoxifen were approached at their routine control appointment with the treating physician. We conducted a comprehensive PRO assessment comprising the following scales: FACT-B/+ES and HADS (high scores indicate high symptoms). In a short, semi-structured interview data on patients’ general medication intake behavior were collected focusing on the intake of complementary and alternative medicine (CAM)

Results: We analyzed PRO data of 240 patients undergoing endocrine treatment. 66.6% received AI therapy, 71.9% were postmenopausal. We found high levels of symptom burden in this study group: 55.9% had moderate to severe bone pain, 47.8% menopausal symptoms and 49.1% loss of sex drive. Postmenopausal women in the AI group had significantly more symptoms on the endocrine subscale (mean 24.25 vs. 16.42, p=0.045), significantly more anxiety (mean 8.8 vs. 5.11, p=0.036) and depression (mean 8.75 vs. 3.86, p=0.011). In the tamoxifen group premenopausal patients scored significantly higher on all scales. Moreover, patients who used complementary substances had a significant lower physical well-being (22.70 vs. 24.39, p=0.007) and more endocrine symptoms (22.63 vs. 16.30, p=0.004).

Conclusion:The results of our study show a significantly higher assessment of physical side-effects and psychosocial burden on part of the patients than implied by clinicians’ reports and expert ratings. PRO data may therefore provide a more accurate measure for symptom burden and contribute to individualized clinical decision making. It is an important tool to detect and effectively treat therapy related side effect to ultimately preserve adherence to endocrine treatment. According to our findings, it appears mandatory to incorporate PRO data in individualized clinical decision making to arrive at a more accurate assessment of symptom burden.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-02.
Abstract PD08-06: Duloxetine for Treatment of Aromatase Inhibitor (AI)-Associated Musculoskeletal Syndrome (AIMSS)
Authors: Henry NL , Banerjee M , Blossom D , Wicha M , Van Poznak C , Smerage JB , Schott AF , Griggs JG , Hayes DF.
Published: April 2011

Background: Approximately 50% of postmenopausal women with hormone receptor positive early stage breast cancer treated with an aromatase inhibitor (AI) develop arthralgias. Standard analgesics are relatively ineffective. Duloxetine is a serotonin and norepinephrine receptor inhibitor with proven efficacy for treatment of multiple chronic pain states. We investigated the hypothesis that duloxetine would be efficacious for treatment of AIMSS.

Methods: We performed a single-arm, open-label phase II study of duloxetine in 35 postmenopausal women who had been treated with AI therapy for at least 2 weeks and who developed new or worsening pain after starting AI therapy that was rated at least 4 on a 10 point Visual Analog Scale. Enrollment was completed in June 2010. Subjects were treated with duloxetine 30 mg daily for one week, and then 60 mg daily for 3 weeks. Depending on patient-perceived response to therapy, patients had the option of continuing duloxetine 60 mg daily or increasing the dose to 60 mg twice daily for the subsequent 4 weeks. Change in patient-reported pain was assessed. Outcome measures included the Brief Pain Inventory (BPI) and modified Health Assessment Questionnaire (HAQ). Benefit from therapy was defined as a 30% decrease in average pain score from baseline to 8 weeks. Paired t tests were used for statistical analysis.

Results: Of the 35 enrolled subjects, 20 subjects completed the 8-week study period, 6 subjects discontinued therapy early because of duloxetine-associated toxicity, and 9 subjects had been enrolled less than 8 weeks at the time of this analysis and were therefore not evaluable. In an intent-to-treat analysis, 16 of 26 evaluable subjects (61.5%) experienced at least a 30% decrease in average pain, and 14 of 20 subjects (70%) who completed all 8 weeks of protocol-directed treatment chose to continue duloxetine therapy. There were statistically significant reductions in average pain severity (p < 0.0001) and maximum pain severity (p < 0.0001) from baseline to 8 weeks. The mean percent reduction in average pain severity between baseline and 8 weeks was 56.1% (95% CI 37.9%-74.2%) and in maximum pain severity was 55.7% (95% CI 37.3%-74.1%). No grade 3 or 4 adverse events were reported. The most common adverse events were fatigue and drowsiness, xerostomia, nausea, and headache.

Conclusions: Duloxetine appears to be effective and well-tolerated for treatment of AIMSS. Final results from the entire cohort will be presented. Future randomized, placebo-controlled studies are warranted. Clinicaltrials. gov NCT01028352.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-06.
Abstract PD08-07: The Impact of 1-Year Supervised Exercise Training on Physical Performance and Quality of Life of Breast Cancer Patients — A Randomise Prospective Phase III Trial
Authors: Saarto T , Penttinen H , Sievänen H , Kellokumpu-Lehtinen P-L , Blomqvist C , Nikander R , Huovinen R , Hakamies-Blomqvist L , Luoma M-L.
Published: April 2011

The BREX study is the largest randomised prospective study to investigate the effect of physical exercise in rehabilitation of breast cancer survivors shortly after adjuvant treatments.Patients: 537 Finnish breast cancer patients(aged 35-68 years) were enrolled into the 1-year aerobic exercise intervention study (BREX) between 2005 and 2007. Patients were randomly allocated into exercise or control group. Methods: The exercise intervention consisted of weekly supervised step aerobics and home training. The physical performance was tested by a 2-km walking test and figure-8 running. The intensity of physical activity was measured by a two-week diary (METs) and Quality of life (QoL)by the EORTC QLQ-C30 and BR-23, FACIT-F and BDI before the intervention and after 6 and 12 mo's. Results: 500/537 patients were included in the final analyses (263 exercise and 237 control group). Patients participated in the supervised weekly exercise training median 32/52 times, vigorous home training 1.6 and endurance 1.4 times per week. Results are shown in table 1 and 2. Conclusions: Supervised aerobic exercise training improved significantly physical performance, even though physical activity increased in both groups. Physical activity correlated positively to QoL during the intervention irrespectively of the study group. However, the intervention itself did not influence on QoL.

Table 1.

Table 2.

Factors association to QoL change from baseline. Change versus change.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-07.
Abstract PD08-08: Exercise for Health: A Randomised, Controlled Trial of an Exercise Intervention for Women with Breast Cancer — Effect on Upper-Body Function
Authors: Hayes SC , Rye S , Eakin E , Battistutta D.
Published: April 2011

Background: Impairments in upper-body function are common during and following breast cancer and may persist into long-term survivorship. An objective of the Exercise for Health program was to assess the effect participation in an 8 month exercise program (initiated 6 weeks after breast cancer surgery) has on upper-body function and associated symptoms.

Methods: Women residing in an Australian metropolitan city and diagnosed with invasive breast cancer were eligible to participate in this randomised, controlled trial. Consenting women were allocated to either a face-to-face delivered exercise group (FG, n=67), a telephone-delivered exercise group (TG, n=67) or a usual-care group (UG, n=60). At 6 weeks (pre-intervention), 6 months (mid-intervention) and 12 months (postintervention) after surgery upper-body function was assessed via self-report using the Disability of the Arm, Shoulder and Hand questionnaire and clinically using an incremental maximal upper-body strength test. The presence and severity of upper-body symptoms such as pain, weakness and numbness were assessed using a 5-point Likert scale, while lymphoedema was measured clinically using bioimpedance spectroscopy.

Results: Women in the exercise intervention groups reported greater improvements (p=0.02) in perceived upper-body function (indicated by negative scores) between 6 weeks and 6 months post-surgery, (FG, mean=-6.3; TG, mean=-11.9) when compared to changes observed in the UG (mean=-4.2) and maintained these improvements by 12-months PS. Similar findings were observed for clinically measured upper-body function (P<0.01). At 12 months post-surgery, those in the UG were 1.5 times more likely to report at least one moderate to severe upper-body function symptom. The number of lymphoedema cases did not differ between the groups at mid-or post-intervention.

Discussion: These results demonstrate that exercise interventions, delivered over the phone or face-to-face, can facilitate improvements in upper-body function during and following breast cancer treatment without adversely increasing risk of developing lymphoedema or other arm-related symptoms. This is particularly important since function is directly associated with a woman's ability to carry out daily tasks and has been shown to predict quality of life.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-08.
Abstract PD10-04: An ERBB2 Gene Dosage Effect Confers Biological Aggressiveness to Breast Cancers and Trastuzumab Sensitivity in Patients with Metastatic Disease
Authors: Fuchs E-M , Köstler WJ , Horvat R , Hudelist G , Kubista E , Zielinski CC , Singer CF.
Published: April 2011

Background: Despite patient selection based on ERBB2 overexpression, response to trastuzumab-based therapy is not always achieved. The reasons for response failure to ERBB2-targeted therapy are still largely unknown. We have investigated whether a gene dosage effect, conferred by an increased number of ERBB2 copies, might provoke increased biological aggressiveness and altered trastuzumab sensitivity. Methods: Vysis PathVysion DNA-based FISH technology was used to measure absolute ERBB2 copy numbers (“CN”) and ERBB2/centromer 17 ratios (“R”) in tumor specimens of 137 patients who had received trastuzumab-based treatment for Her-2/neu over-expressing metastatic breast cancer.

Results: An R of > 2.2 was identified as independent negative predictor for time to first metastasis (TTM). Upon trastuzumab-initiation, progressionfree survival (PFS), albeit not overall survival (OS), was significantly longer in patients with R of ≥2.2 (p=0.006 and p=0.123, respectively). Within the amplified patient population a CN > 13 (“high-amplified”) predicted for a significantly shorter TTM and, upon trastuzumab-initiation, a significant longer PFS and showed a trend towards a higher OS (p= 0.020 and p=0.086, respectively; Log Rank test) compared with the low-amplified (CN ≥13) patient population. Multivariate Cox regression analysis revealed that within our patient population higher CN and R were both associated with improved PFS (p=0.003 and p=0.004, respectively) and OS (p=0.004 and p=0.038, respectively).

Furthermore, Logistic Regression analysis showed that higher CN and R values were associated with improved overall responses (OR: 1.151, 95% CI: 1.034-1.269 and OR: 1.501, 95% CI 1.169-1.964, respectively). Conclusion: In ERBB2 over-expressing FISH-amplified breast cancers CN can discriminate between two groups of breast cancer patients with different prognosis in the adjuvant setting as well as in the metastatic setting under the influence of trastuzumab-based therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-04.
Abstract PD10-05: Do the Results of Metastatic Breast Tumour Biopsies Affect Patient Survival Outcomes? Results from a Large Prospective Trial
Authors: Amir E , Miller N , Geddie W , Maung H , Freedman OC , Oldfield M , Napolskikh J , Kassam F , Simmons C , Clemons M.
Published: April 2011

Background: Differences in receptor status between primary and metastatic breast cancer are well recognized. We have previous demonstrated substantial receptor discordance rates resulting in a change in management in 14% of patients. However, while retrospective studies suggest that discordance can be associated with a worse patient prognosis, there are currently no prospective data assessing the impact of such discordance on survival outcomes.

Methods: A single-center prospective biopsy study was performed. Patients with either recurrent or progressive disease underwent biopsy of their metastases. Subsequent treatment choices were modified according to the results and patients were followed up for progression or death. To account for the differing times at which patients entered the study, progression-free survival (PFS) was calculated as the duration between biopsy and either progression or death. Overall survival (OS) was defined as the duration from diagnosis of metastatic disease to death. A Cox propotional hazards model accounting for duration of metastatic disease and visceral versus non-visceral metastatic disease was utilized.

Results: 121 biopsies were completed and 38% of cases showed discordance between the primary and the recurrence. Survival data were available from 96 patients. After a median follow-up of 11 months, 76 patients (79%) had progressed and 38 (40%) had died. There was no difference in median PFS between concordant and discordance cases (5.9 vs. 6.5 months, HR 0.89, p=0.61). There was a non-significant trend towards worse OS in discordant cases (50.6 vs. 57.8 months, HR 0.77, p=0.47). When compared with the primary tumour a gain of HER2 was associated with a poor survival, while loss of HER2 was associated with improved outcome. Metastatic biopsies showed a trend towards better prediction of response to endocrine therapy with tumors losing progesterone receptor expression between primary and metastatic disease having worse DFS on endocrine therapy. Conclusion: We have previously shown that performing metastatic biopsies is associated with a substantial rate of receptor discordance between primary and metastatic disease. The current analysis demonstrates that this discordance is associated with a trend towards worse OS, but not PFS. Knowledge of the receptor status of metastatic disease allows better prognostication between HER2-postive and HER2-negative disease and also allows for improved prediction of response to endocrine therapy. Metastatic biopsies should therefore be considered in patients with recurrent breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-05.
Abstract S1-4: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of AMG 479 With Exemestane (E) or Fulvestrant (F) in Postmenopausal Women With Hormone-Receptor Positive (HR+) Metastatic (M) or Locally Advanced (LA) Breast Cancer (BC)
Authors: Kaufman PA , Ferrero JM , Bourgeois H , Kennecke H , De Boer R , Jacot W , McGreivy J , Suzuki S , Loh E , Robertson J.
Published: April 2011

Background: AMG 479 is an investigational, fully human monoclonal antibody targeting the type 1 insulin-like growth factor receptor (IGF1R) that blocks binding of IGF-1 and IGF-2. Preclinical data suggest that inhibition of estrogen receptor (ER) and IGF1R signaling in ER+ BC can result in greater suppression of cell proliferation than achieved by blocking either pathway alone. Inhibition of the IGF1R-signaling pathway might enhance sensitivity of 2nd-line hormonal therapy in BC patients (pts). We conducted a 2-arm, double blind, placebo-controlled, randomized study evaluating the addition of AMG 479 to either E or F in M or LA BC pts who had progressed on prior endocrine therapy.

Patients: Eligibility included: HR+ incurable M or LA BC; progression while receiving prior endocrine therapy for MBC or LA or within 12 months of completing adjuvant hormonal therapy; post menopausal; adequate glycemic control. HER2+ tumor status allowed. Study Design: Pts were randomly allocated 2:1 to either AMG 479 or placebo; E or F was per investigator. Pts received AMG 479 12 mg/kg IV or placebo Q2W + either E 25 mg QD PO or F 500 mg IM on day 1, 250 mg IM day 15 and 29, and Q4W thereafter. Eligible pts who progressed on the placebo arm could proceed on open-label AMG 479. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. MRI or CT scans were done every 8 weeks and bone scans every 12 weeks (for pts with bone involvement at screening).

Endpoints: The primary endpoint was progression-free survival (PFS), as measured by modified RECIST v1.0 per investigator review.

Results: 156 pts were randomized between March 2008 and July 2009. Median age, 61 (range 36-88) years; M vs LA BC, 154 (99%) vs 2 (1%). 127 pts (81%) had discontinued treatment as of May 2010. See table for efficacy. For pts receiving AMG 479 or placebo, the incidence of grade ≥3 AE was 42% and 24% and for serious AE, 25% and 18%. The most common grade ≥3 AEs (AMG 479/placebo) were: hyperglycemia (6%/0%), neutropenia (6%/2%), thrombocytopenia (4%/0%), asthenia (4%/2%), and increased AST (4%/0%). There were 5 grade 5 AEs; none were treatment related: 4 in the AMG 479 arm (2 PD, 1 sub occlusive syndrome [progression], and 1 pulmonary embolism [post-operative setting]) and 1 in the placebo arm (alteration of general status). 8% of pts in the AMG 479 arm vs 12% in the placebo arm had AEs that led to discontinuation of any study treatment.

Conclusion: The combination of AMG 479 + E or F did not result in an improvement in PFS in this population of pts with HR+ M or LA BC. There were no unanticipated safety findings.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-4.
Abstract S1-5: Interaction between Goserelin and Tamoxifen in a Controlled Clinical Trial of Adjuvant Endocrine Therapy in Premenopausal Breast Cancer.
Authors: Sverrisdottir A , Johansson H , Johansson U , Bergh J , Rotstein S , Rutqvist LE , Fornander T.
Published: April 2011

Background: Ovarian ablation improves survival in premenopausal women with early breast cancer, but the potential added value by luteinizing hormone-releasing hormone agonists (LHRH-a) to tamoxifen, is still not clear. There has been lack of data reported separately for patients who underwent randomization to both LHRH-a and tamoxifen. Patients and Methods: In Stockholm, 927 patients assigned to the Zoladex in Premenopausal Patients (ZIPP) trial, were included in a 2 x 2 factorial randomization to goserelin (3.6 mg subcutaneously, q 28d), tamoxifen (40 mg daily), the combination of goserelin and tamoxifen or no endocrine therapy for two years, with or without chemo-and/or radiotherapy. The trial was designed to examine the effect of goserelin and the role of interaction between goserelin and tamoxifen in adjuvant therapy of premenopausal breast cancer. We examined as well, the impact of different estrogen receptor (ER) content on treatment effect. The definition of first event was breast cancer recurrence, contra lateral breast cancer or death. The ER content was determined by isoelectric focusing on polyacrylamide gel and receptor values normalized to DNA content.

Results: After a median follow up of 12.3 years, goserelin reduced the risk of first event by 32% (p=0.005) in the absence of tamoxifen and tamoxifen reduced the risk by 27% (p=0.018) in the absence of goserelin. The combined goserelin and tamoxifen treatment reduced the risk by 24% (p=0.021) and there was a significant interaction between goserelin and tamoxifen (p=0.025). In highly ER positive tumours, there were 29% fewer events among goserelin treated (p=0.044) and a trend towards greater risk reduction depending on the level of ER content. The greatest risk reduction from goserelin treatment was observed among those not receiving tamoxifen (HR: 0.52, p=0.007). For tamoxifen, there was not a significant risk reduction at different ER levels, but there was a trend towards interaction between goserelin and tamoxifen effect among the highly ER positive (p=0.076).

Discussion: In this strictly randomized cohort of endocrine responsive premenopausal breast cancer, goserelin as well as tamoxifen, reduces the risk of recurrence. However, the combination of goserelin and tamoxifen is not superior to either modality alone. The effect of goserelin seems to be modified by ER levels, whereas tamoxifen effect is not. Women with strongly estrogen receptor positive tumours may benefit more from goserelin treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-5.
Abstract S1-7: Lack of Correlation between Gene Variants in Tamoxifen Metabolizing Enymes with Primary Endpoints in the ATAC Trial.
Authors: Rae JM , Drury S , Hayes DF , Stearns V , Thibert JN , Haynes BP , Salter J , Pineda S , Cuzick J , Dowsett M.
Published: April 2011

Background. A number of studies have provided widely heterogeneous results for and against the hypothesis that genetic variants in drug metabolizing enzymes can influence patient response to tamoxifen. Most of these studies are confounded by relatively small numbers of patients, lack of comprehensive genotype information, lack of detailed clinical outcome data, and patient selection biases. The ATAC trial was a prospective randomized double-blind placebo-controlled trial designed to compare the adjuvant use of anastrozole versus tamoxifen for 5 years. The trial's detailed efficacy and safety data, long term (10-year) follow-up and high number of events make it an ideal setting for pharmacogenetic analyses. Here we report our initial findings testing for correlations with SNPs in CYP2D6 and UGT2B7, the primary enzymes responsible for the presumed activation and inactivation of tamoxifen, respectively, with clinical outcomes including any disease recurrence, distant recurrence, and overall survival.

Methods: CYP2D6 genotype data for the 7 most common alleles were used to assign each patient a ‘score’ based on predicted allele activities from 0 (no activity) to 2 (high activity). Patients were also tested for the UGT2B7*2 variant, which has lower enzymatic activity and has been shown to correlate with higher serum endoxifen concentrations. All genotype determinations were made without knowledge of the patient's treatment assignment or outcomes.

Results: Comprehensive CYP2D6 genotype data were obtained on 588 and 615 patients randomized to receive tamoxifen, and anastrozole, respectively. After median 10 years of follow-up, there were 115 recurrences in the tamoxifen cohort. We found no associations between any of the CYP2D6 scores and rates of recurrence in tamoxifen treated patients. A test for trend across CYP2D6 scores was not significant. In the anastrozole cohort, there were 92 recurrences, and there was no evidence of an association between CYP2D6 score with rates of recurrence. Likewise, there was no detectable association in either the tamoxifen or anastrozole group with UGT2B7 genotype alone or in combination with CYP2D6 score. Concomitant SSRI usage was recorded in these patients and is being assessed for possible impact on these results.

Conclusion: These data from a large prospective clinical trial, with detailed outcome data and long-term follow-up do not support the hypothesis that patient with decreased CYP2D6 enzymatic activity receive less benefit from tamoxifen therapy compared to wild-type CYP2D6 patients. Variants in drug targets and estrogen signaling pathways may be the genetic basis for patient variability in anti-estrogen risk versus benefit profiles.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-7.
Abstract S2-1: Obesity at Diagnosis Is Associated with Inferior Outcomes in Hormone Receptor Positive Breast Cancer
Authors: Sparano JA , Wang M , Martino S , Jones V , Perez EA , Saphner T , Wolff AC , Sledge GW , Wood WC , Fetting J , Davidson NE.
Published: April 2011

Background: Obesity has been associated with worse outcomes in operable breast cancer. We evaluated the effect of obesity on outcomes in several adjuvant trials coordinated by the ECOG which included doxorubicin/cyclophosphamide plus other agents, including E1199 (NEJM 2008; 358: 1663), E5188 (JCO 2005; 23: 5973) and E3189 (JCO 10998; 16: 2382). Methods: The relationship between body mass index (BMI in kg/m2) and disease free survival (DFS) and overall survival (OS) was evaluated in multivariate models adjusted for covariates including age, tumor size, nodal status, race (black vs. other), surgery type, prior RT, menopausal status, treatment arm, and treatment adherence. Results are expressed as hazard ratios (HR) from Cox's proportional hazards models (HR > 1 indicates a worse outcome). All p-values are two sided.

Results: The study characteristics and results are shown in the table below. We first evaluated results for the E1199 trial (for the 75% of those with BMI data available) and found a non-significant trend toward inferior DFS (HR 1.10, 95% CI 0.96, 1.26, p=0.18) and OS (HR 1.13, 95% CI 0.96, 1.33, p=0.15) for obese subjects compared with others. When evaluated by breast cancer subtype, however, obese subjects with ER and/or PR-positive/HER2-negative disease had significantly inferior DFS (HR 1.24, p=0.026) and OS (HR 1.42, p=0.003), an effect that was not seen for HER2-positive and triple negative disease. In a model including obesity, ER and/or PR-pos/HER2-neg disease, and their interaction, the interaction term was significant for OS (p=0.017) but not DFS (p=0.21). There was no evidence for differing chemotherapy delivery or endocrine therapy adherence, or differences in toxicity for obese subjects in the E1199 trial. We then evaluated the relationship between obesity and outcomes in two prior ECOG studies which included only premenopausal women with ER positive, node positive breast cancer (E5188) and women of any age with ER/PR negative, node positive disease (E3189), and confirmed a relationship between obesity and poor outcomes only in women with hormone receptor positive disease.

HR-hazard ratio; ER/PR-estrogen/progesterone receptor

Conclusions: Obesity was associated with significantly inferior DFS and OS in hormone receptor positive operable breast cancer treated with adjuvant chemotherapy. These findings suggest that hyperinsulinemia or other factors associated with obesity may predispose to recurrence specifically in hormone receptor positive disease, and requires further evaluation in prospective studies in order to identify modifiable factors contributing to this effect.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-1.
Abstract S2-2: Multivariate Analysis of Obesity and Disease Free Survival in Patients with Nodal Positive Primary Breast Cancer — The ADEBAR Trial
Authors: Hepp PGM , Rack B , Annecke K , Wischnik A , Wolfgang S , Zwingers T , Harbeck N , Sommer HL , Friese K , Kiechle M , Janni W.
Published: April 2011

Background: The prevalence of obesity increases throughout all evolved civilizations. On the other hand several epidemiological studies have shown not only an increase in breast cancer among obese women but also an adverse impact of obesity on survival of breast cancer patients. This analysis focuses on the impact of obesity on patients (pts) treated within the ADEBAR study protocol.

Methods: The ADEBAR Trial compared 4 cycles of EC followed by 4 cycles of Doc vs. 8 cycles of FEC (120) in pts with primary breast cancer (>=4LN). 1500 pts have been accrued from sep/01 through may/05. For this analysis data of 1361 pts has been analyzed about the impact of obesity on disease free survival. Therefore pts have been grouped to either “underweight” (BMI<18.5kg/m2), “normal weight” (BMI18.5-25kg/m2), “overweight” (25kg/m230kg/m2) or “obese” (BMI>30).

Results: 13 pts (1.0%) were “underweight”, 557 pts (40.9%) were normal weight, 491 pts (36.1%) were overweight, 300 pts (22.0%) were obese at the time of study enrollment. After a follow up period of 60 months 87.5% of the underweight group, 70.4% of the normal weight group, 70.7% of the overweight group and 58.6% of the obese group were alive with no signs of recurrent disease. This difference was significant (Chi-square=9.355; p< 0.0249). The tumor size at clinical diagnosis was strongly associated to the patient's weight (< 0.0001). There was no significant difference in the number of positive lymph nodes (p = 0.2890), tumor histology (p = 0.9750), grading (p = 0.9520), ER and PR hormone receptors (ER p = 0.9708, PR p = 0.7785) and the expression of HER2 (p = 0.1710) regarding underweight, normal, overweight and obese patients. In a multivariate analysis obesity was an independent prognostic factor with a hazard ratio of 1,007 per 1kg/m2 increase (P<0,0167).

Conclusion: This analysis strongly implicates an impact of obesity on disease free survival in patients with early stage node positive breast cancer in the prospectively randomized ADEBAR multicenter trial. It is therefore in line with earlier findings in epidemiological research and raises the question whether a weight reduction might be an additional approach on breast cancer therapy. Figures available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-2.
Abstract S2-3: The Impact of Body Mass Index (BMI) on the Efficacy of Adjuvant Endocrine Therapy in Postmenopausal Hormone Sensitive Breast Cancer (BC) Patients; Exploratory Analysis from the TEAM Study
Authors: Seynaeve C , Hille E , Hasenburg A , Rea D , Markopoulos C , Hozumi Y , Putter H , Nortier H , van Nes J , Dirix L , van de Velde C.
Published: April 2011

Background: Obesity is associated with an increased risk of breast cancer (BC) recurrence and decreased survival, also in case of adjuvant endocrine therapy. It is still not clear whether the activity of aromatase inhibitors and tamoxifen (T) given as adjuvant therapy is affected by body mass index (BMI), although both drugs are widely prescribed. In this analysis, we explored the outcome of TEAM patients (pts) treated with exemestane (E) versus T (2.75 yrs), and with E versus T followed by E (T/E) (5 yrs) in relation to BMI.

Patients and Methods: The TEAM trial is a randomized, international phase III study in postmenopausal hormone sensitive early BC pts comparing the activity and safety of adjuvant E (25 mg daily) or the sequence of T (20 mg daily) followed by E (T/E), both regimens given for five years. WHO BMI definitions were used: normal 18.5-24.9 kg/m2, overweight 25-30 kg/m2, obese >30 kg/m2. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method; results were compared by using the log-rank test and Cox proportional hazard modelling adjusted for country.

Results: Weight and height was known in 4741 pts. Mean BMI was 26.9 kg/m2 (SD 4.9); 39% had a normal BMI, 36.9% overweight, and 23.3% of pts was obese. Underweight pts (n=41, 0.9%) were excluded from further analysis. At 2.75 yrs (E vs T) disease relapse in normal weight, overweight and obese pts using E was observed in 8.1%, 6.8% and 7.5% respectively (p=0.57), and in 9.1%, 8.8%, and 12.5%, respectively (p=0.06) of pts using T. The hazard ratio (HR for risk of relapse on E vs T) in the three subgroups was 0.91 (95%CI 0.66-1.24), 0.78 (95%CI 0.55-1.089), and 0.57 (95%CI 0.39-0.84, p=0.004), respectively. At a median follow-up of 5.1 years, disease relapse in normal weight, overweight and obese pts using E occurred in 14.8%, 15.1% and 15.1%, respectively; and in pts using T in 17.0%, 16.9%, and 18.3%, respectively. Regarding DFS, the HR in normal weight, overweight, and obese pts was 0.87 (95%CI 0.69-1.10), 0.88 (95%CI 0.70-1.11), and 0.75 (95%CI 0.56-1.01, p=0.058), respectively, and with respect to OS 0.87 (95%CI 0.65-1.15, p= 0.32), 0.89 (95%CI 0.67-1.18, p= 0.43), and 0.71 (95% CI 0.51-1.01, p= 0.053), respectively.

Conclusions: After 2.75 years more disease events were observed in obese women using tamoxifen, which was not seen in obese exemestane users, whereas at 5 years these differences in disease recurrences disappeared in this group. In contrast to recent reports, there seems to be a difference regarding the influence of a high BMI on recurrence rate between tamoxifen and the aromatase inhibitor exemestane. Further research on this topic is warranted.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-3.
Abstract S2-7: Toxicity of Adjuvant Endocrine Therapy in Postmenopausal Breast Cancer Patients
Authors: Amir E , Ocaña A , Niraula S , Carlsson L , Seruga B.
Published: April 2011

Purpose: To determine differences in serious adverse events (AEs) associated with aromatase inhibitors (AIs) compared with tamoxifen, and to explore whether these AEs might be ameliorated by switching to AIs after 2-3 years of tamoxifen.

Materials and Methods: Published data from trials contributing to the Aromatase Inhibitor Overview Group were included in a meta-analysis. Odds ratios (OR), 95% confidence intervals (CI) and absolute risks (number needed to treat [NNT] associated with one AE) were computed for serious AEs

Results: Any duration of AIs was associated with a higher probability of developing cardiovascular disease (OR 1.20, p=0.01; NNT 143) and bone fractures (OR 1.48, P<0.00001; NNT 34), but a reduced probability of venous thrombosis (OR 0.53, P<0.00001; NNT 67) and endometrial carcinoma (OR 0.32, P<0.00001; NNT 200). The risks of individual serious AEs were similar for upfront AIs and for switching to AIs after tamoxifen. However, compared with 5 years of tamoxifen, there was a non-significant trend towards increased death without recurrence with upfront AIs (OR 1.12, p=0.16), but lower with switching to AIs after tamoxifen (OR 0.74, p=0.03).

Conclusion: Treatment with AIs is associated with a statistically significant increase in cardiovascular risk, which is of similar magnitude to the risk of venous thrombosis and endometrial cancer with 5-years of tamoxifen. While switching to AIs does not appear to reduce the risk for the development of serious AEs when compared to upfront use of AIs, fewer deaths unrelated to breast cancer occur with switching than with upfront strategies.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-7.
Abstract S3-1: Lapatinib vs Trastuzumab in Combination with Neoadjuvant Anthracycline-Taxane-Based Chemotherapy: Primary Efficacy Endpoint Analysis of the GEPARQUINTO STUDY (GBG 44)
Authors: Untch M , Loibl S , Bischoff J , Eidtmann H , Kaufmann M , Blohmer J-U , Hilfrich J , Strumberg D , Fasching PA , Kreienberg R , Tesch H , Hanusch C , Gerber B , Rezai M , Jackisch C , Huober J , Kuehn T , Nekljudova V , von Minckwitz G.
Published: April 2011

Background: The tyrosine-kinase inhibitor lapatinib (L) has shown to improve efficacy of cytotoxic and endocrine treatment in HER2-positive metastatic breast cancer (BC). Improved pathological complete response (pCR) rates were demonstrated by adding trastuzumab (T) to neoadjuvant chemotherapy. However, so far no head-to-head comparison of the two anti-HER2-agents is available. One primary aim of the GeparQuinto study was to improve the pCR rate by adding L instead of T to anthracycline-taxane-based neoadjuvant chemotherapy. We previously reported interim safety data of this study showing more diarrhea, skin changes, and hot flushes, but no cardiac events with L compared to T (von Minckwitz G et al, Ann Oncol 2010 in press).

Patients and Methods: Patients (P) with untreated HER2-positive BC were eligible if they had cT3/4a-d; or estrogen (ER) and progesterone (PgR) receptor-negative; or ER/PgR-positive tumors with clinically N+ (for cT2) or pNSLN+ (for cT1) disease, and no increased cardiac risks. P were randomized to receive 4 cycles epirubicin/cyclophosphamide (EC) (90/600 mg/m2) q3w followed by 4 cycles docetaxel (D) (100mg/m2) given in combination with either T 6 (loading dose 8) mg/kg every 3 weeks or L 1000-1250 mg/d throughout all cycles. pCR was defined as no invasive or non-invasive tumor residuals in breast and nodes. We assumed a pCR rate of 26% with ECT-DT (based on GeparQuattro) and expected a pCR of 37% for ECL-DL (odds ratio 1.67). A two-sided Pearson's Chi2 with α=0.05 and β=0.20 calculated a sample size of 613 P.

Results: Between May ‘07 and June ‘10 597 P were randomized to ECT-DT (N=299) and ECL-DL (N=298). Median tumor size was 40/40 [T/L] mm (clinically) and 28/29 mm (sonographically); 4.7%/4.3% had T4a-c, 14.8%/14.2% T4d, 2.9%/1.8% bilateral, 17.0%/17.7% multifocal, and 9.0%/12.1% multicentric disease, 96.7%/97.9% had non-lobular, 45.6%/48.9% grade 3, 70.0%/67.7% node-positive, and 56.5%/56.0% ER and PgR-negative disease. Baseline characteristics were well balanced between the treatment arms. The last randomized P will have surgery early Dec'10. Final results on histological response and surgical outcome will be reported.

Conclusion: The GeparQuinto trial will provide for the first time randomized phase III efficacy data on the comparison of L and H in combination to chemotherapy for patients with early breast cancer. As pCR has been confirmed as being a surrogate marker for long-term outcome after T treatment, this result will give insight on the overall efficacy of L in patients with early breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-1.
Abstract S3-3: First Results of the NeoALTTO Trial (BIG 01-06/EGF 106903): A Phase III, Randomized, Open Label, Neoadjuvant Study of Lapatinib, Trastuzumab, and Their Combination Plus Paclitaxel in Women with HER2-Positive Primary Breast Cancer
Authors: Baselga J , Bradbury I , Eidtmann H , Di Cosimo S , Aura C , De Azambuja E , Gomez H , Dinh P , Fauria K , Van Dooren V , Paoletti P , Goldhirsch A , Chang T-W , Lang I , Untch M , Gelber RD , Piccart-Gebhart M
Published: April 2011

Background: The addition of trastuzumab to neoadjuvant chemotherapy has significantly improved pathological complete response (pCR) in patients with HER2-positive early breast cancer (BC). Lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor, combined with chemotherapy has significantly improved progression free survival in patients with metastatic HER2-positive BC. Additionally, lapatinib combined with trastuzumab improved disease-free and overall survival in patients with metastatic HER2-positive BC. The NeoALTTO trial is testing the efficacy of lapatinib, trastuzumab or their combination together with paclitaxel when given as neoadjuvant therapy in patients with HER2-positive BC. Material and Methods: NeoALTTO is an international, multicenter, randomized study comparing the efficacy of lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment in HER2- positive primary BC. From January, 2008, to December, 2009, 455 patients were randomized from 99 participating sites. Patients were randomized to receive either lapatinib 1500 mg/d (154 pts), or trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly (149 pts), or lapatinib 1000 mg/d with trastuzumab for a total of 6 weeks (152 pts). After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/m2 for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). After surgery, patients received 3 cycles of adjuvant FEC followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy). The primary objective of the study is to evaluate and compare among the three arms the rate of pCR, defined as the absence of invasive cancer in the breast at the time of surgery. Secondary objectives include objective response rate, safety, pathologic node-negative status, rate of conversion to breast conservation, disease-free survival and overall survival. All patients underwent tumor biopsies for comparative pharmacodynamic analyses before beginning therapy and on day 15 of the biological therapy window. A subset of patients also participated in PET/CT and circulating tumor cells substudies. Results: The last breast surgery was performed in May 2010. Data cleaning and analysis will be complete by November 2010 and results for safety and the primary objective (pCR) of this important phase III trial will be presented at the meeting.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-3.
Abstract S3-5: Discordance in Hormone Receptor and HER2 Status in Breast Cancer during Tumor Progression
Authors: Lindstrom LS , Karlsson E , Wilking U , Bergh J.
Published: April 2011

Background: In the metastatic situation therapy management is routinely based on primary tumor estrogen receptor (ER), progesterone receptor (PR) and HER2 status. Alterations in these therapy predictive factors may lead to altered management.

Methods: Breast cancer patients in the Stockholm health care region who relapsed from 1997 through 2007 were included and intra-individual primary tumor and relapse ER status, PR status and HER2 status accessed. Biochemical, immunohistochemical (IHC) or immunocytochemical (ICC) methods were used for determination of ER and PR (cut-off value of 0.05 fmol/µg DNA and 10%), respectively. For HER2, primary tumors were investigated using IHC with two or three monoclonal antibodies, confirmed by Fluorescence In Situ Hybridization (FISH) for IHC 2+ and 3+ and recurrences using ICC or FISH. The pathology laboratory at Karolinska University Hospital have continuously participated in quality assurance programs for hormonal receptor and HER2 analysis.

Results: In 477, 447, and 108 patients, ER, PR and HER2 information was assessed from both primary tumor and relapse. Intra-individual primary tumor and relapse information for ER, PR and HER2 was available in 68 patients. ER and PR status changed in 26% and 35% from positive in primary tumor to negative in relapse tumor, and 7% and 6% changed from negative to positive, respectively. In 11 (10%) patients, tumors changed HER2 status, seven patients (7%) changed from HER2 positive to HER2 negative and 4 patients (4%) from HER2 negative to HER2 positive. Univariate analyses showed a significantly (log rank P<0.0005) differential survival in women related to intra-individual primary and relapse ER and PR status, respectively. In addition, a significant two-fold increased risk of dying in ER positive women changing to ER negative, compared to stable ER positive women, was noted using a multivariable proportional hazard model.

Conclusions: More than every third patient changed ER and PR status and one patient in ten changed HER2 status during tumor progression. Intra-individual primary and relapse ER and PR status was significantly associated with differential survival in women. In addition, patients loosing ER had an almost two-fold increased risk of dying compared to concordant ER positive patients. Thus, altered management through tumor progression may improve survival and implies the need for hormonal receptor and HER2 investigations in metastatic lesions.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-5.
Abstract S4-3: Ten-Year Follow-Up Analysis of the BICRG 001 Trial Confirms Superior DFS and OS Benefit of Adjuvant TAC (Docetaxel, Doxorubicin, Cyclophosphamide) over FAC (fluorouracil, Doxorubicin, Cyclophosphamide) in Women with Operable Node-Positive Breast Cancer
Authors: Martin M , Mackey J , Pienkowski T , Rolski J , Guastalla J-P , Sami A , Glaspy J , Juhos E , Wardley A , Fornander T , Hainsworth J , Coleman R , Modiano M , Vinholes J , Pinter T , Childs B , Roessner M , Wilson V , Rupin M , Vogel C
Published: April 2011

Background: The second interim analysis of the BCIRG001 trial at a median follow up of 55 months showed that adjuvant chemotherapy with TAC improves disease-free survival (DFS: HR 0.72; P=0.001) and overall survival (OS: HR 0.70; P=0.008) compared with FAC in women with operable node-positive breast cancer (N Engl J Med 2005;352:2302-13). We now report the final analysis of DFS, OS, and long-term safety after 10 years of follow-up.

Patients and Methods: Women with node-positive breast cancer were randomized to adjuvant treatment with either TAC or FAC every 3 weeks for 6 cycles. The primary end point was DFS. Secondary end points included OS and safety.

Results: Between June 1997 and June 1999, 1491 women (TAC N=745; FAC=746) from 20 countries were enrolled. Median follow up was 120 months. As of the cut-off date for this analysis (11 March 2010), there were a total of 620 DFS events (287 events with TAC; 333 with FAC). Ten-year DFS rates were 62% with TAC and 55% with FAC. TAC improved DFS irrespective of nodal status, hormone receptor status, and HER2/neu status. There have been 429 deaths (188 deaths with TAC; 241 with FAC) and 10-year OS rates were 76% with TAC and 69% with FAC. There was no statistically significant difference in rates of grade 3-4 congestive heart failure (CHF): TAC 3.5% vs FAC 2.3%, P=0.18. Deaths due to CHF have occurred in 2 patients in the TAC group and 4 patients in the FAC group. Rates of asymptomatic left ventricular dysfunction will be presented. A total of 6 patients have developed acute myeloid leukemia (TAC N=4; FAC N=2).

table 1

ITT, intention-to-treat

Conclusion: Ten-year follow up analysis of the BCIRG 001 trial confirmed that TAC significantly improves DFS and OS compared with FAC in women with node-positive early breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-3.