Goss, PE

Abstract Background: The third-generation aromatase inhibitors (AIs) are established adjuvant therapy for postmenopausal women with early stage breast cancer. Musculoskeletal adverse events (MS AE) have become increasingly recognized as an issue for many women receiving AIs resulting in decreased quality of life and, in some instances, discontinuation of the AI. MA.27 is an ongoing randomized clinical trial comparing anastrozole with exemestane that accrued 7576 patients (pts), including 6827 from North America, about 79% of whom provided DNA and consent for genetic testing. A review of withdrawals related to adverse events revealed that the most common cause was MS AE. The hypothesis for our study was that a genome-wide association (GWA) case control study would identify single nucleotide polymorphisms (SNPs) associated with MS AE.Methods: Cases were defined as pts with grade 3 or 4 MS AE (NCI CTCAE v3.0) or who went off treatment for any grade MS AE within the first 2 years and were matched to 2 controls based on treatment arm, length of follow-up, prior chemotherapy, age and prior celecoxib (at least 3 months prior to MS AE). The study was restricted to the 94% of pts self-identified as Caucasian. Genotyping was performed with the Illumina Human610-Quad. Genotype quality control prior to analysis required call rates ≥98%. Eigenstrat analyses were performed to control for population stratification.Results: The GWA study included 293 cases and 586 controls with 6 pts (0.7%) (4 cases, 2 controls) excluded for call rates <98%. 551,358 SNPs were used in the analyses after removing 29,439 for a minor allele frequency <1% and 82 with Hardy Weinberg Equilibrium p-values <10-6. Eigenvectors did not impact the results when used as covariates. Four SNPs with the lowest p-values (3.3-8.2 x 10-6, Armitage test), 3 in high LD (r2>.8) on chromosome (ch) 14 (rs7158782, rs7159713, rs2369049) and 1 on the X ch (rs6637820) were identified. The gene closest (4000-7000 bp) to the 3 SNPs on ch 14 was T-Cell Leukemia 1A (TCL1A), encoding a protein known to augment AKT kinase activity. Expression array data from lymphoblastoid cell lines from 300 subjects of 3 ethnicities revealed that all 3 SNPs were associated with decreased TCL1A expression after adjusting for ethnicity using 2 probe sets (p=0.006 to 0.03). Electromobility shift assay (EMSA) showed that 2 of these SNPs (rs7158782, rs7159713) displayed a shift and the former SNP showed substantially less binding for variant than wild type. The gene closest to the X ch SNP was Immunoglobulin Superfamily 1 (IGSF1), but EMSA did not show a shift for this SNP.Conclusions: MS AEs represent a major impediment to optimal use of AIs in women with breast cancer and this GWA study identified SNPs on ch 14 that provide a focus for further research to identify pts at risk for, and means to ameliorate, this adverse event.(Supported in part by NIH grants U01GM61388, U01GM63173, P50CA116201 and U10CA77202) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 15.

Abstract Background: Analyses of adjuvant endocrine therapy suggest that the appearance of new vasomotor or joint symptoms within 3 months of initiating either tamoxifen or aromatase inhibitor therapy predict for lower subsequent recurrence. We hypothesized that new vasomotor or joint symptoms may predict outcomes with anastrozole or exemestane in participants in the ongoing NCIC CTG Trial MA.27. We performed a pooled analysis across treatment arms of the MA.27 trial, to examine the effects of early onset new or worsening symptoms on relapse-free survival (RFS).Methods: 7576 postmenopausal women with early breast cancer were accrued to MA.27, a randomized adjuvant trial of exemestane and anastrozole. The second interim analysis data with a 3 year median follow-up was used for this analysis. The trial's primary endpoint is event-free survival, but for this investigational analysis is RFS, which excludes non-breast cancer deaths. All 7118 participants known to be hormone receptor-positive who received trial therapy, and had no relapse in the first 3 months, were included. The association of vasomotor and joint symptoms with patient characteristics was examined with chi-square tests. Stratified log-rank and stratified univariate and multivariate Cox modeling were used to examine the association of early vasomotor and joint symptoms on disease outcomes.Results: Of 4749 women who were asymptomatic at baseline, 230 (5%) experienced vasomotor or joint symptoms at 3 months. The RFS stratified univariate Cox hazard ratio (HR) for vasomotor or joint-related symptoms was 1.184 (95% CI, 0.675-2.079). When all 7118 women were included, 361 (5%) developed new or worsening symptoms at 3 months. RFS was not statistically significant between the women with or without new symptoms (HR 1.129, 95% CI, 0.708-1.800). Higher T stage was the only factor included in the multivariate Cox RFS model that was associated with new or worsening symptoms (p<0.001).Conclusions: In contrast to prior findings, we did not observe a correlation between early emergence of symptoms and improved RFS. Longer follow-up and analysis by treatment arm and at different time points are required. Additional symptoms and time points will be added to the analysis prior to the meeting. Until further data are available, clinicians should not use treatment-emergent symptoms to counsel their patient whether to continue or change their prescribed medication. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 14.

Abstract Abstract #1134 Background: The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of ER+ (but not ER-) invasive breast cancers in healthy women at high risk for developing breast cancer. Aromatase inhibitors (AIs) given as adjuvant therapy to treatment-naïve or post-tamoxifen patients significantly reduce the risk of in-breast recurrences (IBRs) and contralateral breast cancers (CBCs) and are currently in clinical trials for breast cancer prevention (NCIC CTG MAP.3 and IBIS-II). It is hypothesized that SERMS inhibit promotion of ER+ breast cancer whereas AIs may reduce both ER+ and ER- breast cancer by inhibiting both tumor initiation and promotion. Little is known about the characteristics of IBRs and CBCs that arise on AI therapy. We present the ER/PR expression and clinicopathologic features of IBRs and CBCs that occurred on MA.17.
 Methods: We examined ER/PR status of IBRs and CBCs that arose on letrozole vs. placebo among women enrolled in MA.17, a placebo-controlled (PLAC) trial of letrozole (LET) following 5 years of tamoxifen in postmenopausal women with early stage breast cancer.
 Results: Seventy-one patients (pts) developed an IBR and 87 developed a CBC on trial. Consistent with results previously reported, fewer IBRs (LET 20 vs PLAC 51) and CBCs (LET 35 vs PLAC 52) were observed in the LET group. ER and PR status is currently available on 35 women with an IBR and 39 with a CBC. The majority of IBRs were ER+ in both the LET and PLAC groups (10/11 [91%] vs 18/24 [75%], respectively; p=NS) but numbers of both ER+ and – IBRs were less in LET group, suggesting that letrozole may decrease both ER+ and ER- IBRs. CBCs that arose on PLAC were more likely to be ER+ than on LET (16/22 [73%] vs 6/19 pts [32%], respectively; p=0.01), suggesting that letrozole predominantly prevents ER+ CBCs. Discordance in ER expression between primary breast cancer and IBRs among women randomized to LET vs. PLAC was observed in 1/11 [9%] and 6/24 [26%] women respectively (p=NS) and between primary breast cancer and CBCs in 12/18 pts [67%] vs. 6/21 [29%] women respectively (p=0.01). Other clinicopathologic characteristics such as grade, tumor size, PR, HER-2/neu, and nodal status of IBRs and CBCs will be presented at the meeting.
 Conclusion: Extended adjuvant endocrine therapy with letrozole results in fewer IBRs and CBCs compared with placebo as previously reported. Our data suggests that letrozole may decrease both ER+ and ER- IBRs. Letrozole appears to prevent ER+ CBCs but has little or no apparent effect on the development of ER- CBCs. These results need confirmation in the primary prevention trials of AIs.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1134.