Shepherd, Lois E.

Abstract Abstract 39 Three randomized trials have previously reported a progression-free survival (PFS) advantage for patients receiving thalidomide (T) maintenance post ASCT in MM. Two trials reported an overall survival (OS) advantage but the largest trial reported shows no OS advantage and in very high risk MM the use of T was deleterious. Recent trial reports demonstrate a PFS but not yet an OS advantage for patients receiving maintenance lenalidomide. We report results of NCIC CTG MY.10 which compared treatment with T (200 mg daily) and prednisone (50 mg alternate days) (T/P) until progression versus observation alone when used as maintenance therapy following ASCT. Importantly, OS was the 1ry endpoint of this study, 2ry endpoints were PFS, quality of life (QoL), toxicity, and the incidence of venous thromboembolism events (VTE). Eligibility: Patients with MM who had ASCT within 1 year of beginning initial treatment for their disease. Patients were randomized 60–100 days post ASCT and had no other medical condition precluding long term use of T/P. Results: 332 patients were enrolled. Median age was 58 years and the arms were balanced. Patients were stratified by age (<60 or >60), and CR status post transplant. Median follow up is 4 years. Only 14% of patients were in CR post transplant. 111 patients died (50 versus 61 in T/P vs. observation). The median OS was 5 years for observation, and has not yet been reached for T/P, however T/P maintenance therapy did not significantly prolong OS: p = 0.18, HR of maintenance vs. observation 0.77 (95% CI 0.53–1.13). The 4 year survival rate was 68% for T/P and 60% for observation. Age and response to transplant had no significant association with OS (p=0.21), while higher disease stage was associated with shorter OS (p=0.03). The median PFS was 28 months for T/P versus 17 months for observation: p<0.0001, HR of T/P vs. observation 0.56 (95% CI 0.43 – 0.73). The 4 year PFS rate was 32% for T/P treated patients versus 14% for patients on observation. At relapse, treatment by arm (T/P vs observation) included lenalidomide (39 vs 34%), T (13 vs 22%) or bortezomib (50 versus 46%). Non hematologic toxicities were seen in more patients with treatment (Grade 3: 92% T/P vs 49% observation, grade 4: 16% vs 7%). Common toxicities of all grades that were significantly higher in T/P treated patients included hyperglycemia, edema, hypertension, fatigue, Cushingoid appearance, constipation, mouth dryness, dyspepsia, anxiety, memory loss, sensory neuropathy, tremor, blurred vision, depressed consciousness, cataracts, dyspnea and bruising. 7% of patients on maintenance T/P developed a VTE in the absence of prophylaxis versus 0% on observation. NCIC CTG standardized response analysis was use to compare QoL data between the 2 treatment arms. Overall, patients on T/P had worse QoL specifically in physical (p=0.07), role (p=0.08), cognitive (p = 0.01) and global (p=0.06) domains, and worse symptoms with dyspnea (p = 0.0007), constipation (p<0.0001), thirst (p=0.003), swelling in leg (p=0.03), numbness (p=0.02), dry mouth (p<0.0001), and balance problems (p<0.0001). However, patients on T/P reported improvement in appetite (p 0.02), and sleep (p=0.04). Conclusions: T/P maintenance did not improve overall survival, the primary objective of this trial, although a trend in favor of T/P was seen. In contrast, PFS was significantly improved in the T/P arm while toxicity was demonstrably increased and quality of life diminished. Disclosures: Stewart: Millennium: Consultancy; Celgene: Honoraria. Trudel:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Research Funding, Speakers Bureau. White:Celgene: Honoraria, Research Funding. Meyer:Celgene: Honoraria.

Abstract Introduction: In multiple myeloma, randomized trials of maintenance therapy using thalidomide or lenalidomide following autologous transplant (ASCT) demonstrated prolonged progression-free survival (PFS), but overall survival benefit was inconsistent. The MY.10 trial (n=332) demonstrated improved PFS with thalidomide-prednisone maintenance therapy, but quality of life was inferior and overall survival was not improved. As a randomized trial with a no-treatment control arm and biospecimen collection, MY.10 provides a unique opportunity to identify predictors of benefit from therapy that could be used to personalize treatment. Immunomodulatory drug action is mediated in part through binding to cereblon (CRBN) and downregulation of IRF4. Candidate single nucleotide polymorphisms (SNPs) were selected from the CRBN/IRF4 pathway and other genes previously associated with myeloma prognosis, drug response and toxicity from literature review. The aim of this study was to investigate associations between candidate SNPs and benefit from immunomodulatory compound-based maintenance therapy, as well as prognostic impact. Methods: Genomic DNA was extracted from samples preserved in Trizol¨. SNPs were genotyped using TaqMan¨ genotyping assays on the ViiA7 qPCR platform. Analysis was performed on 187 patients with available samples and clinical data (86 in treatment arm; 101 in observation arm). Cox regression models were performed using SAS clinical 2.0 for prognostic impact of a single SNP on PFS, assessed with and without adjusted covariates (age, stage, performance status and response to ASCT). In treatment benefit analysis, PFS was modeled with genotype, treatment assignment and their interaction term. Results: SNPs with significant prognostic impact for PFS in all 187 patients were found in CRBN (rs1672753) (HR 0.59, 95%CI 0.4-0.86; p=0.006) and the following SNPs which had been found to be prognostic in prior studies were validated: CYP1A1 (rs1048943) (HR 1.98, 95%CI 1.19-3.27; p=0.008), CYP1B1 (rs1056836) (HR 0.72, 95%CI 0.52-0.99; p=0.043), and trend toward significance for SNP in CYP1A2 (rs2069514) (HR 2.02, 95%CI 0.98-4.15; p=0.057). Of these, only the CYP1A1 SNP was found to be possibly predictive of greater benefit from maintenance therapy. A SNP in ABCA1 (rs363717), previously associated with thalidomide-induced neuropathy,‎ was prognostic in this study (HR 1.44, 95%CI 1.03-2.02; p=0.033) but not predictive of treatment benefit. Table 1 lists SNPs associated with a differential level of benefit from maintenance therapy, including SNPs in FAM179a and ICAM1 that were possibly associated with harm from maintenance therapy. Table 1. SNPs and treatment interaction with significant impact on PFS. HR represent hazard ratio of treatment versus observation for a given genotype group. Asterisk Indicates trend toward significance. Wildtype Heterozygote & mutant p-value interaction Gene dbSNP ID SNP HR 95% CI HR 95% CI FAM179A rs1053667 T>C 0.46 0.33, 0.66 2.28 0.78, 6.65 0.003 ICAM1 rs1799969 G>A 0.51 0.36, 0.73 1.75 0.83, 3.70 0.007 CASP3 rs1049216 A>G 0.82 0.54, 1.25 0.41 0.25, 0.69 0.029 IRF4 rs12203592 C>T 0.69 0.47, 1.02 0.38 0.21, 0.69 0.062* CYP1A1 rs1048943 A>G 0.62 0.44, 0.87 0.11 0.02, 0.52 0.079* Conclusion: Previously identified SNPs in drug metabolism and drug efflux genes were validated to be prognostic in this cohort. The prognostic but not predictive significance of a SNP in CRBN suggests a possible role for CRBN in multiple myeloma disease biology independent of immunomodulatory therapy. SNPs predictive of differing degrees of benefit from immunomodulatory maintenance were found in genes involved in immunomodulatory activation, drug action and cell adhesion mediated drug resistance; SNPs in FAM179A and ICAM1 were possibly associated with harm from thalidomide maintenance and could potentially be used to identify patients unsuitable for immunomodulatory maintenance therapy. These results may be applicable to lenalidomide and pomalidomide, since immunomodulatory compounds exhibit similar chemical structures and mechanisms of action. Validation of these SNPs in prospective clinical trials involving other immunomodulatory can test this hypothesis. Further studies are needed to confirm our findings. Disclosures Off Label Use: thalidomide and prednisone maintenance for multiple myeloma. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Johnson & Johnson: Research Funding. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Celgene Canada: Honoraria, Research Funding. Chen:Celgene: Consultancy, Honoraria, Research Funding. Seftel:Celgene: Honoraria, Research Funding. Howsen-Jan:Celgene: Honoraria, Research Funding. Reece:Amgen: Honoraria; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Onyx: Consultancy; Millennium Takeda: Research Funding; Lundbeck: Honoraria; Otsuka: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Shepherd:Celgene: Honoraria, Research Funding. Chen:Celgene: Honoraria, Research Funding. Djurfeldt:Celgene: Research Funding. Reiman:Soricimed Biopharma Inc: Consultancy, Other: Scientific Advisory Board for Soricimed.

529 Background: The effect of metformin on sex hormones (SHs) levels that may impact breast cancer (BC) outcome, is unclear. We evaluated the effect of metformin on SHs in a subgroup of women enrolled in the placebo-controlled MA.32 trial, a phase III randomized study of nondiabetic subjects with T1-3, N0-3 BC randomized to receive metformin 850 mg po bid or placebo for 5 years. Methods: Our substudy was conducted on the group of post-menopausal women with estrogen receptor (ER) and progesterone receptor (PR) negative BC and not receiving endocrine treatment enrolled in the trial. Post-menopausal was defined as prior bilateral oophorectomy or > 12 months since last menses without prior hysterectomy. Fasting blood and adherence to study drug at baseline and 6 months was required. Sex hormone binding globulin (SHBG), free testosterone and estradiol serum levels were evaluated using Roche Modular competitive ECLIA (electrochemiluminescense immunoassay). We compared change from baseline to 6 months in estradiol, SHBG and free testosterone between study arms using Wilcoxon sum rank tests and regression models to adjust for baseline BMI and weight change. Results: 304 women were eligible, 135 metformin vs 169 placebo; tumor stage and prior (neo)adjuvant chemotherapy (98% in both arms) and HER2 targeted treatment were well balanced between arms. At baseline mean age was 58.2±6.9 vs 57.6±7.9 years, mean BMI 26.9±4.9 vs 28.6±6.2 Kg/m2, median estradiol 29.82 vs 31.01 pmol/L, SHBG 80.6 vs 73.7 nmol/L and free testosterone 0.02 vs 0.03 nmol/L in metformin vs placebo patients, respectively. In univariable analysis, median estradiol decreased significantly between baseline and 6 months on the metformin vs placebo arm (-4.81 vs 0 pmol/L, p = < 0.0001); this difference remained significant after controlling for baseline BMI (p = 0.0001) and weight change (mean weight change -1.8±3.5 vs 0.4±3.5 Kg, p = < 0.0001 for metformin vs placebo respectively) between baseline and 6 months (p = 0.0007). In contrast, there was no significant change in SHBG or free testosterone (median change SHBG -5.5 vs -5.9 nmol/L, p = 0.33; median change free testosterone 0 vs 0 nmol/L, p = 0.33 for metformin vs placebo respectively). Conclusions: Metformin lowered estradiol levels, independent of weight change in non-diabetic post-menopausal women with ER and PR negative BC enrolled onto MA.32 trial. This observation suggests a new metformin action that has potential relevance to BC management.

Abstract Background Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence. Methods In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor–positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease–free survival (DDFS); and overall survival (OS). All statistical tests were two-sided. Results Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years’ follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non–aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01). Conclusion Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased “all-cause” mortality, presumably because of higher preexisting cardiovascular risks.