Disease-free Survival HR Research Articles

ERCC1, defective mismatch repair status as predictive biomarkers of survival for stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy

Background:Excision repair cross-complementation group 1 (ERCC1) expression status has been identified as a candidate marker for predicting efficacy of oxaliplatin (OX) treatment for metastatic colorectal cancer (CRC) in several trials. Also, an association between expression of mismatch repair (MMR) genes and favourable postoperative survival in stage II CRC receiving 5-FU chemotherapy has been identified. It is unknown if the expression of ERCC1 protein and MMR status are associated with survival of stage III colon cancer receiving OX-based chemotherapy.Methods:Immunohistochemistry (IHC) analysis of the expression of MMR and ERCC1 was performed on tumour tissue of 255 patients with stage III colon cancer. In all, 95 patients received fluoropyrimidine-based chemotherapy and 160 patients received OX-based chemotherapy. A predictive model for 5-year disease-free survival (DFS) and overall survival (OS) was constructed using Kaplan–Meier analysis, logistic and Cox regression.Results:Patients who were treated with OX-based therapy with positive ERCC1 tumours had lower 5-year DFS (54%) and OS (60%) than those with negative ERCC1 tumours (72% and 78%, respectively; DFS HR: 1.98, 95% confidence interval (CI): 1.19–3.31, P=0.009; OS HR: 2.44, 95% CI: 1.37–4.34, P=0.02). Excision repair cross-complementation group 1 status did not impact DFS or OS in fluorouracil group (DFS HR: 1.16, 95% CI: 0.63–2.14, P=0.62; OS HR: 1.16, 95% CI: 0.63–2.14, P=0.63), whereas MMR status had no impact on DFS or OS in either group.Conclusion:Excision repair cross-complementation group 1 status is highly predictive of which patients will benefit from the addition of OX to 5-FU for stage III colon cancer. Mismatch repair status had no predictive value in this setting.

Abstract S3-2: Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: The CALOR trial (Chemotherapy as Adjuvant for Locally Recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02)

Abstract Introduction Patients with isolated local and regional recurrences (ILRR) of breast cancer (BC) have a high risk of developing distant metastasis and dying from BC. We investigated the impact of chemotherapy (C) on disease-free survival (DFS) and overall survival (OS) after ILRR. Methods Patients with resected ILRR were stratified according to prior chemotherapy (yes vs. no), ER and/or PgR status of the recurrent tumor (both negative vs. either positive), and location of recurrence (breast vs. scar/chest wall vs. lymph nodes). Radiation, hormone and HER2 directed therapies were delineated in the protocol. Participants were randomly assigned to receive C or none. Multidrug C for at least 4 courses was recommended. Drug selection was at the discretion of the investigator. Slow accrual led to premature closure of the trial before achieving the planned sample size of 265. Results The trial accrued 162 patients (C, 85; control, 77) from 2002–2010. The groups were balanced in regard to the characteristics listed in the table below. At a median follow up of 4.9 years, there were 24 (28%) DFS events and 9 (11%) deaths in the C group compared with 34 (44%) DFS events and 21 (27%) deaths in the control group, corresponding to a 5-year DFS of 69% vs. 57%, [DFS HR (C/control) = 0.59, 95% CI (0.35, 0.99)], p =0.046] and a 5-year OS of 88% vs. 76%, [OS HR (C/control) = 0.41, 95% CI (0.19, 0.89)], p =0.02]. The results remained significant for both DFS and OS in multivariable Cox proportional hazards modeling controlling for ILRR location, disease-free interval, ER status and prior adjuvant chemotherapy. Adjuvant C was particularly effective for women with ER-negative ILRR: 5-year DFS 67% vs. 35%, [DFS HR (C/control) = 0.32, 95% CI (0.14, 0.73)], p =0.007] and OS 79% vs. 69%, [OS HR (C/control) = 0.43, 95% CI (0.15, 1.24)], p =0.12]. Results for the ER-positive ILRR cohort were: 5-year DFS 70% vs. 69%, [DFS HR (C/control) = 0.94, 95% CI (0.47, 1.89)], p =0.87] and OS 94% vs. 80%, [OS HR (C/control) = 0.40, 95% CI (0.12, 1.28)], p =0.12]. Conclusion Adjuvant chemotherapy should be recommended for patients with completely resected isolated loco-regional recurrences of breast cancer, in particular, if the recurrence is not sensitive to endocrine therapy. Funding NCI PHS grants U10-CA-37377, -69974, -12027, -69651, CA-75362. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-2.

Distinct Clinical Course of EGFR-Mutant Resected Lung Cancers: Results of Testing of 1118 Surgical Specimens and Effects of Adjuvant Gefitinib and Erlotinib

EGFR and KRAS mutations are mutually exclusive and predict outcomes with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in patients with stage IV lung cancers. The clinical significance of these mutations in patients with resected stage I-III lung cancers is unclear. At our institution, resection specimens from patients with stage I-III lung adenocarcinomas are tested for the presence of EGFR or KRAS mutations during routine pathology analysis such that the results are available before consideration of adjuvant therapy. In a cohort of 1118 patients tested over 8 years, overall survival was analyzed using multivariate analysis to control for potential confounders, including age, sex, stage, and smoking history. The impact of adjuvant erlotinib or gefitinib was examined in an independent data set of patients exclusively with EGFR mutation, in which date of recurrence was recorded. In the overall population, we identified 227 KRAS (25%) and 222 EGFR (20%) mutations. Patients with EGFR-mutant lung cancers had a lower risk of death compared with those without EGFR mutations, overall survival (OS) HR 0.51 (95% confidence interval [CI]: 0.34-0.76, p < 0.001). Patients with KRAS-mutant lung cancers had similar outcomes compared with individuals with KRAS wild-type tumors, OS HR 1.17 (95% CI: 0.87-1.57, p = 0.30). A separate data set includes only patients with EGFR-mutant lung cancers identified over 10 years (n = 286). In patients with resected lung cancers and EGFR mutation, treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, disease-free survival HR 0.43 (95% CI: 0.26-0.72, p = 0.001), and a trend toward improved OS. Patients with resected stage I-III lung cancers and EGFR mutation have a lower risk of death compared with patients without EGFR mutation. This may be because of treatment with EGFR TKIs. Patients with, and without KRAS mutation have similar OS. These data support reflex testing of resected lung adenocarcinomas for EGFR mutation to provide prognostic information and identify patients for enrollment on prospective clinical trials of adjuvant EGFR TKIs.

LBA5_PR - Phare Trial Results Comparing 6 to 12 Months of Trastuzumab in Adjuvant Early Breast Cancer

ABSTRACT Background Since 2005, One year trastuzumab (T) treatment has been providing survival benefit to patients with early breast cancer and HER2 overexpression. However, the optimal duration of T has been debatable due to concerns forcardiac toxicity and results from the FinHer trial which showed that 9 weeks of T provided a similar magnitude of benefit than the 1-year treatment. The French National Cancer Institute (INCa) initiated an academic randomised non-inferiority trial aiming to compare a shorter T exposure of 6 months versus the standard 12 months. This trial, named PHARE for ‘Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure’ [NCT00381901] was approved by an independent ethics committee with regularly planned IDMC meetings. Patients and methods Patients with HER2 + early breast cancer who received at least 4 cycles of (neo)-adjuvant chemotherapy were eligible. Randomization 1:1 using a minimisation algorithm was stratified on concomitant or sequential T administration with chemotherapy, oestrogen receptors (ER) status and center. The primary objective was to compare disease free survival (DFS). Overall survival (OS) and cardiac toxicity were investigated as secondary aims. An absolute loss of 2% in DFS in the experimental arm was defined as the non-inferiority margin (1.15 in relative terms) and required 3400 patients with alpha = 0.05 and 80% power. Results Between 5/2006 and 7/2010, 3382 patients were randomized to 6 or 12 months of T following the IDMC recommendation for accrual interruption and extended follow-up. Disease and treatment characteristics were well balanced between the 2 arms: median age 55 years (range 21–86), median tumour size 20 mm (0–270), node involvement 45%, SBR grade III 56%, ER positive 58%, radiotherapy 88%; concomitant T administration 58%, anthracyclin and taxane containing chemotherapy 73%. The data-base was locked on July 30th, 2012. Median follow-up is 47.2 months since the start of T treatment. The DFS HR is 1.28 (95% CI: 1.05-1.56). The non inferiority of 6 months of trastuzumab compared to 12 months could not be demonstrated as the lower bound of the 95% CI crosses the prespecified non inferiority margin of 1.15. Disclosure X. Pivot: The study of the abstract has received funding and sponsorship from the French National Cancer Institut (INCa). All authors have declared no conflicts of interest.

533P - Somatic K-Ras Mutation is Predictive in Colorectal Cancer, but is it Prognostic? A Systematic Review and Meta-Analysis

ABSTRACT Background Consistent data from retrospective molecular analysis performed in multiple phase 3 Randomized controlled trials (RCTs) have established that somatic KRAS mutation (K-RAS-mt) is a strong predictor of non-response to anti-epidermal growth factor receptor antibody (anti-EGFR) therapy in colorectal cancer. However, K-RAS's role as a prognostic marker remains undefined. We performed a systematic review and meta-analysis to determine the prognostic significance of somatic K-RAS mutation. Methods We searched MEDLINE, EMBASE, and CENTRAL databases, ESMO and ASCO meeting proceedings for Phase 3 RCTs in colorectal cancer for which retrospective molecular analysis of K-RAS mutation was performed on archival patient samples. Studies were pooled according to setting of treatment (adjuvant, 1st line metastatic, refractory). Meta-analysis was performed using random-effects model. The outcomes of interest were disease-free survival in the adjuvant setting and overall survival (OS) for advanced disease. Results 14 Phase 3 trials which enrolled 18,991 patients were identified, of whom 13,143 had K-RAS status ascertained (69.2% range: 48%-100%) In pooled data of patients who did not receive anti-EGFR therapy and had K-RAS status ascertained, patients with K-RAS-wt patients had better survival outcomes compared to K-RAS-mt patients. In the adjuvant setting (Disease Free Survival HR 0.75 95% CI: 0.66-0.87, p Conclusion Beyond being a predictive marker of non-response to EGFR antibodies, among patients with early stage, 1st line metastatic and refractory colorectal cancer who do not receive anti-EGFR therapy, K-RAS is a negative prognostic marker. Disclosure All authors have declared no conflicts of interest.

524PD - ERCC1, Defective Mismatch Repair Status as Predictive Biomarker of Survival for Stage III Colon Cancer Patients Receiving Oxaliplatin Based Adjuvant Chemotherapy

ABSTRACT Background Several trials showed excision repair cross-complementation group 1 (ERCC1) expression status is a candidate marker for predicting efficacy of oxaliplatin (OX) treatment for metastatic colorectal cancer (CRC). Association between the expression of mismatch repair genes (MMR) and favorable postoperative survival in stage II CRC receiving 5-FU chemotherapy has been identified. whether the expression of ERCC1 protein and MMR status are associated with survival of stage IIIB colon cancer receiving OX-based chemotherapy is unclear. Patients and methods We enrolled 255 patients with stage III colon cancer after radical surgery. There were 95 patients receiving full-course Mayo clinic chemotherapy and 160 patients received mFOLFOX6 or XELOX chemotherapy. Immunohistochemistry analysis of the expression of MMR and ERCC1 was performed in tumor tissue. A predictive model for 5-year disease-free survival (DFS) and overall survival (OS) was constructed by using Kaplan-Meier analysis, logistic and Cox regression. Results The patients with positive ERCC1 tumors had lower 5-year DFS (54%) than those with negative ERCC1 tumors (72%) in combined therapy group (HR: 1.98 95%CI: 1.19-3.31 p = 0.009).The OS was also lower in combined therapy group with positive ERCC1 tumors (60%) than those patients with negative ERCC1 tumors (78% HR: 2.44 95%CI: 1.37-4.34 p = 0.02). In multivariate analysis, ERCC1 expression remained an independent significant predictive factor for DFS and OS (DFS HR: 2.33 95%CI: 1.37-3.93 p Conclusion ERCC1 status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of OX to 5-FU for stage IIIB colon cancer. MMR status had no predictive value in this setting. Disclosure All authors have declared no conflicts of interest.

Expression of oestrogen receptor β and prognosis of colorectal cancer

Background:Previous studies suggest that sex steroids influence colorectal cancer (CRC) carcinogenesis. The oestrogen receptor β (ERβ) is the predominantly expressed ER in the colon and loss of ERβ in CRC has been associated with advanced cancer stages.Methods:Information on vital status by the end of 2009 was obtained for 1262 CRC patients recruited between 2003 and 2007. The ERβ expression was immunohistochemically measured and associations of ERβ scores with overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) were evaluated using Cox proportional hazard models adjusted for prognostic factors, such as tumour stage and second primary tumours.Results:Of the 1101 tumour samples with successful measurement, 535 were ERβ negative (48.6%), 381 (34.6%) showed moderate and 185 (16.8%) showed high ERβ expression. Compared with high ERβ expression, lack of ERβ was associated with higher cancer stages as well as greater tumour extent. In multivariate analyses, ERβ negativity was associated with an increased hazard ratio for death (HR=1.61, 95% CI 1.09–2.40, P=0.02), death attributed to CRC (HR=1.54, 95% CI 0.99–2.39, P=0.06) as well as a poorer DFS (DFS HR=1.64, 95% CI 1.23–3.36, P=0.04). The associations were stronger in stage I-III patients (OS HR=2.20, 95% CI 1.28–4.06, P=0.007, DSS HR=2.38, 95% CI 1.20–5.39, P=0.02, respectively).Conclusions:Lack of ERβ expression is associated with advanced cancer stages and independently associated with poor survival.

Adjuvant dendritic cell (DC)-based vaccine therapy of melanoma patients.

2524 Background: Earlier DC vaccine therapy demonstrated clinical benefit in some patients (pts) with advanced melanoma although the effect was seen only in pts with minimal tumor burden (ASCO2007 abstract No: 3077). As there is no effective treatment for high risk resected melanoma we conducted an exploratory trial to assess the effectiveness of DC vaccine in stage III and IV melanoma pts after radical surgery in comparison with observation. Methods: 108 stage III and IV melanoma pts were enrolled in two comparative arms. The arms were well balanced in respect with demographic and prognostic factors. The vaccine was based on mature autologous monocyte-derived DC primed with autologous tumor lysate, administered intradermally every 2-6 weeks until the disease progression. Disease free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier method and compared between the two arms using the log rank test. Safety of DC vaccine was also monitored. Results: The vaccine arm included 56 pts (stage III – 46, stage IV – 10 pts) who were surgically rendered free of disease and treated with DC vaccine. 52 pts were enrolled in the control arm (stage III – 47, stage IV – 5 pts), they were treated surgically and observed afterwards. At a median follow-up of 22 months, the HR (DC vs observation) for DFS was 0.45 (p &lt; 0.05; 95%CI 0.29-0.69) and for OS was 0.71 (p=0.23; 95%CI 0.40-1.25). 60% of pts in the DC arm remained alive at this time point. Risk reduction significantly correlated with the strong delayed type hypersensitivity reaction induced by vaccine in 31 (55%) out of 56 vaccinated pts. The vaccine was safe and well tolerated although vitiligo was registered in 4 cases which was associated with more durable time to progression and OS. Conclusions: The immunotherapy with DC vaccine is safe and significantly improves DFS compared with observation in the adjuvant treatment of stage III and IV melanoma.

Capecitabine plus oxaliplatin (XELOX) versus bolus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for stage III colon cancer: Survival follow-up of study NO16968 (XELOXA).

388 Background: The MOSAIC trial demonstrated that adding oxaliplatin to 5-FU/LV (FOLFOX4) improved 3-year disease-free survival (DFS) compared to infusional and bolus 5-FU/LV as adjuvant therapy in patients (pts) with stage II/III colon cancer [André et al. NEJM 2004]. A significant survival advantage for FOLFOX4 versus 5-FU/LV was not evident until after median duration of follow-up had exceeded 6 years [André et al. JCO 2009]. Study NO16968 demonstrated that XELOX was superior to bolus 5-FU/LV as adjuvant therapy in pts with stage III colon cancer in terms of DFS at 57 months median follow-up (HR 0.80; 95% CI 0.69–0.93; p=0.0045) [Haller et al. JCO 2011]. The difference between treatment groups in overall survival (OS) was not significant at 59 months median follow-up (HR=0.87; p=0.1486). Data from the planned final analysis of NO16968 are presented. Methods: Pts with resected stage III colon cancer were randomized to receive XELOX (8 cycles, 24w) or bolus 5-FU/LV (Mayo Clinic, 6 cycles; 24w or Roswell Park, 4 cycles; 32w). The primary study endpoint was DFS. Secondary endpoints included OS. Results: The ITT population included 1886 pts (XELOX, n=944; 5-FU/LV, n=942). After a median follow-up of 74 months, the HR (XELOX vs 5-FU/LV) for DFS was 0.80 (95% CI 0.69–0.93; p=0.0038). Seven-year DFS rates were 63% for XELOX and 56% for 5-FU/LV. After a median follow-up of 83 months, the HR for OS was 0.83 (95% CI 0.70–0.99; p=0.0367). Absolute 7-year OS rates were 73% with XELOX and 67% with 5-FU/LV. After adjusting for stratification and prognostic variables, HRs remained essentially unchanged for both DFS (0.79; 95% CI 0.68–0.91; p=0.0016) and OS (0.84; 95% CI 0.71–1.00; p=0.0477). Locoregional / systemic treatments after recurrence were given in 230 (24%) XELOX pts and 308 (33%) 5-FU/LV pts. Conclusions: The combination of oxaliplatin and capecitabine improves OS significantly compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer after a median follow-up of 83 months; these data are comparable to those achieved with FOLFOX4 in the MOSAIC trial. XELOX is an effective adjuvant therapy option for pts with resected stage III colon cancer.

Effects on survival of menstrual cycle phase of adjuvant surgical oophorectomy in premenopausal women with breast cancer

Adjuvant surgical oophorectomy is an effective and remarkably cost effective treatment for premenopausal women with hormone receptor positive operable breast cancer. Previously published secondary analyses indicated a survival benefit for patients whose surgery was performed in the luteal phase of the menstrual cycle as opposed to the follicular. This study utilizes additional follow-up and more fully examines this hypothesis and the general implications of long-term follow-up on trial design. Beginning in 1993 we recruited women to a multicenter randomized clinical trial of adjuvant surgical oophorectomy and tamoxifen for 5 years. We recorded the reported day 1 of the patients' last menstrual cycle on the day of their adjuvant surgery. We conducted secondary analyses of the association of history-estimated luteal or follicular phase oophorectomy surgery with disease-free and overall survival. In multivariable Cox analyses, disease-free survival (DFS) exhibited a positive trend and overall survival (OS) showed a significant improvement in patients whose surgery was estimated to have occurred in the luteal phase of the menstrual cycle compared to the follicular (HR for DFS: 0.66, 95% CI: 0.37-1.16; HR for OS: 0.49, 95% CI: 0.27-0.88). From the hazard function plots, it appears that the luteal phase surgery effect on DFS diminishes after 6 years of follow-up. In conclusion, adjuvant surgical oophorectomy during the luteal phase of the menstrual cycle resulted in a reduced hazard of recurrence as compared to oophorectomy in the follicular phase during the first 5.5 years of follow-up. The practical and biological implications of these findings deserve rigorous evaluation in clinical trials.

Potential biologic causes of the racial survival disparity in adjuvant trials of ER-positive breast cancer.

511 Background: An analysis of SWOG adjuvant breast cancer clinical trials (n = 6,676) found African American (AA) patients (pts, n = 662) had significantly worse survival than others (adjusting for treatment, tumor factors, BMI and SES) overall and in ER-positive (ER+) and ER-negative cohorts separately (JNCI 2009; 101:984). As triple negativity could not fully explain the disparity, we analyzed the ER+ S8814 phase III study to assess if level of ER-positivity or expression of single genes within the 21-gene Recurrence Score (RS) assay might inform this critical issue. Methods: S8814 (ER+, node+, postmenopausal: tamoxifen vs. CAF plus tam; Lancet 2009; 374:2055) was analyzed for disease-free survival (DFS) and overall survival (OS) for AA vs. others, adjusting for other factors. Within the subset available for RS analysis of prognosis/prediction of CAF benefit (Lancet Oncol 2010; 11:55), outcome of AA vs. others was assessed overall; and by ER level, the composite RS, and each of the genes analyzed by RT-PCR. Results: Of 1,477 pts, 139 (9%) were AA, who derived similar benefit from CAF as did others. However, outcomes were worse for AA after adjusting for treatment and other prognostic factors: DFS AA vs. others HR = 1.44 and for OS = 1.70. 27 of 367 pts in the RS sample were AA, for whom DFS was also worse (logrank p = 0.073; adjusted HR 1.65; 5-year DFS 67% AA, 79% others). There was no significant difference in RS by race, although fewer AA had low RS (33% vs. 40%) and more had high RS (41% vs. 32%). There was no significant difference by race in ER level by Allred IHC score or by RT-PCR for each of the 4 ER genes. However, all 5 genes in the proliferation group by RT-PCR had higher quantitative gene expression in AA vs others (p < 0.05 for CCNB1, MKI17, MYBL2, BIRC5; p = 0.051 for AURKA). While Cox regression models that adjusted for nodes, CAF and RS made a marginal impact on the DFS HR by race (1.60), the HR decreased substantially to 1.23 upon adjustment for proliferation. Conclusions: AA on ER+ early breast cancer trials have worse survival than others, due in large part to tumors with higher proliferation and not to differences in degree of endocrine responsiveness. If confirmed in other studies, this finding might impact choice of adjuvant therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health Genomic Health Agendia, Genomic Health

Outcome of Patients With Early-Stage Breast Cancer Treated With Doxorubicin-Based Adjuvant Chemotherapy As a Function of HER2 and TOP2A Status

Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C). TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533). An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio > or = 4.0). Survival was not associated with low-level HER2 amplification (ratio > or = 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio > or = 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size. In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.

A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08

LBA4 Background: The primary aim of this two-arm randomized prospective study was to determine whether mFOLFOX6 plus bevacizumab (mFF6+B) would prolong disease-free survival (DFS) compared to mFOLFOX6 (mFF6) alone. Methods: Between September 2004 and October 2006, 2,672 patients with follow-up (1,338 and 1,334 in respective arms) with stage II (24.9%) or III carcinoma of the colon were randomized to receive either mFF6 (oxaliplatin 85 mg/m2 IV d1, leucovorin 400 mg/m2 IV d1, 5-FU 400 mg/m2 IV bolus d1, and 5-FU 2400 mg/ m2 CI over 46 hrs (d1+2) q14d × 12 cycles) or mFF6+B (same mFF6 regimen + bevacizumab 5 mg/kg IV q 2 wks × 1 yr). The primary end point was DFS. Events were defined as first recurrence, second primary cancer, or death. Results: The median follow-up for patients still alive was 36 months. The hazard ratio (HR: FF6+B vs. mFF6) was 0.89; 95% CI (0.76=1.04); p=0.15. Data censored at intervals disclosed an initial benefit for bevacizumab that diminished over time: The smoothed estimate of the DFS HR over time indicated that bevacizumab significantly reduced the risk of a DFS event during the interval from 0.5 to 1.0 year. There was no evidence that patients receiving bevacizumab had a worse DFS compared to those receiving mFF6 alone following treatment. Conclusions: The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS. There was a transient benefit in DFS during the one-year interval that bevacizumab was utilized. Consideration may be given to clinical trials assessing longer duration of bevacizumab administration. Supported by PHS grants U10CA-12027, -69974, -37377, and -69651 from the NCI and a grant from Genentech, Inc. [Table: see text] No significant financial relationships to disclose.

A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08

LBA4 Background: The primary aim of this two-arm randomized prospective study was to determine whether mFOLFOX6 plus bevacizumab (mFF6+B) would prolong disease-free survival (DFS) compared to mFOLFOX6 (mFF6) alone. Methods: Between September 2004 and October 2006, 2,672 patients with follow-up (1,338 and 1,334 in respective arms) with stage II (24.9%) or III carcinoma of the colon were randomized to receive either mFF6 (oxaliplatin 85 mg/m2 IV d1, leucovorin 400 mg/m2 IV d1, 5-FU 400 mg/m2 IV bolus d1, and 5-FU 2400 mg/ m2 CI over 46 hrs (d1+2) q14d × 12 cycles) or mFF6+B (same mFF6 regimen + bevacizumab 5 mg/kg IV q 2 wks × 1 yr). The primary end point was DFS. Events were defined as first recurrence, second primary cancer, or death. Results: The median follow-up for patients still alive was 36 months. The hazard ratio (HR: FF6+B vs. mFF6) was 0.89; 95% CI (0.76=1.04); p=0.15. Data censored at intervals disclosed an initial benefit for bevacizumab that diminished over time: The smoothed estimate of the DFS HR over time indicated that bevacizumab significantly reduced the risk of a DFS event during the interval from 0.5 to 1.0 year. There was no evidence that patients receiving bevacizumab had a worse DFS compared to those receiving mFF6 alone following treatment. Conclusions: The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS. There was a transient benefit in DFS during the one-year interval that bevacizumab was utilized. Consideration may be given to clinical trials assessing longer duration of bevacizumab administration. Supported by PHS grants U10CA-12027, -69974, -37377, and -69651 from the NCI and a grant from Genentech, Inc. N Ev 3yDFS P Yr 1 1.5 2 2.5 3 mFF6 1338 312 75.5 HR 0.60 0.74 0.81 0.85 0.87 mFF6+B 1334 291 77.4 0.15 P 0.0004 0.004 0.02 0.05 0.08 No significant financial relationships to disclose.

“Dwarf” Estrogen Receptor in Breast Cancer and Resistance to Tamoxifen

“Dwarf” Estrogen Receptor in Breast Cancer and Resistance to Tamoxifen

Randomized phase III trial comparing infused 5-fluorouracil/folinic acid (LV5FU) versus LV5FU+irinotecan (LV5FU+IRI) as adjuvant treatment after complete resection of liver metastases from colorectal cancer (LMCRC). (CPT-GMA-301)

LBA4013 Background: 5FU regimens have been suggested to be effective in the adjuvant setting after LMCRC. Irinotecan (IRI) combined with infused 5FU regimens showed improvement in outcome of advanced colorectal cancer. The aim of this international, randomized trial was to compare the adjunction of IRI to FUFA in this setting. Methods: Main inclusion criteria: complete surgical resection (R0) of exclusively liver metastases with no prior treatment for metastatic disease. Patients were randomized to either: arm A, FA 400mg/m2/2h iv, 5FU 400mg/m2/2h bolus, followed by 2400 mg/m2/46h continuous infusion q2w for 12 cycles, or arm B, FUFA+IRI 180mg/m2/d1. The primary endpoint is disease-free survival (DFS). The analysis was planned after at least 147 events were observed and a minimum of 1 year of follow up in order to detect a hazard ratio of 0.64 (alpha=5%, power=85%). Secondary endpoints include safety and overall survival. Results: Between 12/2001 and 7/2006, 321 pts from 15 countries were randomized. The 2 arms were well balanced (Arms A/B): number treated 153/153, median age 61/63 years, male 65%/59%, and for the stratification factors, only 1 liver metastasis 64%/64%, prior adjuvant chemotherapy 35%/40%, and diagnosis of liver metastasis more than 1 year after resection of primary tumor 37%/39%. Median follow-up was 42 months for both groups. The overall HR for DFS adjusted for the stratification factors was 0.89 (95%CI: 0.66–1.19, log-rank p=0.47). Median DFS was 21.6 for FUFA vs 24.7 months for FOLFIRI. No significant treatment effect was observed for any level of the stratification factors. However, there was a tendency for improved DFS for patients treated with FOLFIRI within 42 days after surgery. Grade 3/4 toxicities (%) in Arms A/B were respectively: any toxicity 34/51, neutropenia 7/23, diarrhea 8/14, vomiting 3/5, nausea 3/3. Conclusions: These results indicate that there was no overall advantage in terms of DFS for the addition of IRI to FUFA. However, we cannot exclude a benefit for patients starting chemotherapy before 6 weeks after surgery. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer

Tamoxifen (T) compared to placebo (P), after adjuvant chemotherapy (CT), in premenopausal women with early breast cancer (EBC): Interim results of NCIC-CTG MA.12

547 Background: In the early 1990’s, the role of adjuvant T in premenopausal women with EBC had not been clearly established. The efficacy of adjuvant T in hormone receptor (H) negative EBC was unclear. Methods: Eligible premenopausal women with node (N) +ve/high risk N -ve EBC, any H status, post surgery, received standard adjuvant CT (AC ×4, CMF ×6, CEF x6) then were randomized to T (20 mg/day) or P for 5 yrs. Overall survival (OS), disease-free survival (DFS) and toxicity/compliance were evaluated. Original sample size was 800 pts but based on slow accrual was reduced to 660. Mortality rate is lower than anticipated, and Data Safety Monitoring Committee approved reporting results after second interim analysis (152 deaths). Results: 1993–2000, 672 women randomized, median follow-up 8.4 yrs. For T vs P, 5 yr OS 87% vs 82% [Hazard Ratio HR 0.81 (95% CI 0.58–1.12), p = 0.19] and 5 yr DFS 78% vs 71% [HR 0.79 (95% CI 0.61–1.03), p = 0.09]. HR for OS (0.87 vs 0.78, p = 0.71) and DFS (0.79 vs 0.77, p = 0.87) were not significantly different for H +ve and H -ve tumors respectively. Compliance with T/P was suboptimal, 29% women stopping treatment within 2 yrs, and only 53% completing 5 yrs. Conclusions: Current results show only a trend towards improved DFS for premenopausal women with EBC who receive T after adjuvant CT. Other studies of similar design have shown improved DFS, but not OS, and meta-analysis may be more informative. Issues affecting results (slow accrual, improved outcomes for EBC, poor compliance, additional therapies) will be discussed. [Table: see text] [Table: see text]