Citations

BACKGROUNDBreast cancer patients in the MA.27 trial had similar outcomes with steroidal aromatase inhibitor (AI) exemestane and nonsteroidal anastrozole. AIs increase the risk of osteoporosis. This study examined the effects of self‐reported osteoporosis and osteoporosis therapy (OPT) on outcomes.METHODSThe MA.27 phase 3 adjuvant trial enrolled 7576 postmenopausal women. The primary outcome was event‐free survival (EFS), and the secondary outcome was distant disease–free survival (DDFS). Patients were permitted bisphosphonates to prevent or treat osteopenia/osteoporosis. In a multivariate, stratified Cox regression, factors were significant with a 2‐sided Wald test P value ≤ .05.RESULTSOsteoporosis was reported at the baseline by 654 of the 7576 women (8.6%) and in total by 1294 patients. Oral OPT was received at the baseline by 815 of the 7576 women (10.8%) and in total by 2711 patients (36%). With a median follow‐up of 4.1 years, 693 EFS events (9.15%) and 321 DDFS events (4.2%) occurred. Osteoporosis was not associated with EFS or DDFS. Few EFS events occurred before the initiation of OPT, with no substantive evidence of a time‐differing effect on outcomes (nonproportional hazards). OPT (yes vs no) was significantly associated with improved EFS (hazard ratio [HR] for yes vs no, 0.67; 95% confidence interval [CI], 0.57‐0.80; P < .001) and DDFS (HR, 0.57; 95% CI, 0.44‐0.73; P <. 001). Time‐differing (time‐dependent) OPT was not (EFS; P = .45). OPT did not alter the incidence of visceral‐only metastasis (P = .31).CONCLUSIONSOral OPT, administered to postmenopausal breast cancer patients receiving adjuvant AI therapy, was associated with improved EFS and DDFS; the time of OPT initiation (a time‐dependent effect) did not affect the outcome. OPT did not alter the risk of visceral metastasis. Cancer 2017;123:2444–51. © 2017 American Cancer Society.

Abstract BACKGROUND: Based on prospective clinical trials, there is no evidence for differences in efficacy between the 3 aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole. The purpose of this study was to identify germline genetic variants associated with response to AIs and to help identify novel mechanisms associated with drug disease efficacy. METHODS: A genome-wide association study (GWAS) was performed for 624 patients (Steroids 2015;99:32-38) to identify SNPs associated with estrogen level change in women with estrogen receptor (ER) positive breast cancer treated with anastrozole. Replication of associated SNPs was performed in a GWAS from the MA.27 trial that compared adjuvant anastrozole and exemestane treatment of post-menopausal women with ER+ breast cancer. Functional studies were subsequently performed to determine SNP effects and underlying mechanisms. RESULTS: Our initial GWAS identified SNPs within CSMD1 that were associated with changes in estrogen levels during anastrozole therapy. An additional SNP in CSMD1 was also associated with breast cancer events in CCTG MA.27. Functionally, we showed that CSMD1 regulates CYP19 expression in a SNP-, and in an anastrozole- dependent fashion. These phenomena were not observed for either letrozole or exemestane. In MA.27, an anastrozole- specific effect was also seen with the minor allele having a protective effect on time to distant metastasis (HR=0.49, p=0.00259), but this was not the case for exemestane (HR=0.71, p=0.111). Our in vitro functional studies indicated that overexpression of CSMD1 sensitized anastrozole or letrozole resistant cells to anastrozole but not to the other two AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane in lymphoblastoid cell lines (LCLs) homozygous for either WT or variant CSMD1 SNP genotypes. Based on these observations, we explored whether anastrozole has additional mechanisms beyond its function as a CYP19 inhibitor. Utilizing an estrogen response element (ERE) luciferase reporter assay in a CYP19 CRISPR knockout breast cancer T47D cell line and a surface plasmon resonance (SPR) assay, we found that anastrozole can also function as an ERα agonist, and can bind to, and result in, proteasome dependent ERα degradation, especially in the presence of E2. Treatment of these CYP19 CRISPR knockout cells with anastrozole in the presence of increasing concentrations of E2 results in greater sensitivity compared with anastrozole alone, while the addition of E2, as expected, does not improve letrozole or exemestane sensitivity. These same observations were also seen in letrozole and anastrazole resistant cells. CONCLUSIONS: Our findings suggest that anastrozole might be more effective than letrozole or exemestane in patients with the CSMD1 SNP. Furthermore, anastrozole can function as an ERα agonist, binding to ERα and resulting in its degradation, especially in the presence of E2. These findings should help to make it possible to develop precision endocrine therapies for women who are candidates for AIs. Citation Format: Cairns J, Ingle J, Dudenkov T, Kalari K, Buzdar A, Kubo M, Robson M, Ellis M, Goss P, Shepherd L, Goetz M, Weinshilboum R, Wang L. CSMD1 SNPs selectively affect anastrozole response in postmenopausal breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD1-04.

2 Background: The MA.17 trial demonstrated that extended adjuvant endocrine therapy with letrozole after 5-y of tamoxifen markedly reduced the risk of recurrence in women with ER+ early stage breast cancer. This trial provides an opportunity to assess the ability of biomarkers to predict late recurrences in ER+ breast cancer. The Breast Cancer Index (BCI), a continuous risk index based on the combination of HOXB13:IL17BR (H:I) and the molecular grade index (MGI), estimates the individual risk of recurrence in ER+ breast cancer patients. In this study, the prognostic utility of BCI to predict late recurrences was examined. Methods: FFPE tumor blocks were collected from patients who experienced a breast cancer recurrence up to unblinding of MA.17. Controls were matched 2:1 for age, tumor size, nodal status and prior chemotherapy, and were disease free for longer than cases. All cases were reviewed for standard histopathology and evaluated using the real-time RT-PCR BCI assay. Results: Patient characteristics for the case-control study were similar to that from the overall study. Characteristics for cases (N=83) and controls (N=166) were not significantly different except for treatment. A higher percentage of controls compared to cases tended to be categorized as low risk by BCI (58% vs 43%), while a lower percentage of controls than cases tended to be categorized as high risk by BCI (34% vs 24%). In univariate analysis, treatment, BCI, H:I and HOXB13, but not tumor grade or MGI, were significant predictors of late recurrence. After adjusting for standard variables (age, tumor grade and treatment), BCI (OR 2.37; P=0.03), H:I (OR 2.55; P=0.04) and HOXB13 (OR 1.35; P=0.02) remained significant predictors of recurrence. HOXB13 expression at diagnosis predicted patient benefit from extended endocrine therapy with letrozole. Conclusions: In this case-controlled study, the data demonstrate that BCI is a significant predictor of late recurrences in ER+ patients following 5-y of tamoxifen. The prognostic performance of BCI to predict late recurrences was largely dependent on HOXB13 expression. The integration of H:I and MGI within BCI provides prognostic utility for both early and late recurrences.

LBA7005 Background: In meta-analyses, platinum-based adjuvant (adj) chemotherapy (CT) in completely resected NSCLC increased cure rate by ∼5%. At BR.19 initiation, adj study results with third-generation agents were unavailable. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, showed activity in monotherapy trials. We report a trial of adj gefitinib versus placebo after complete resection of NSCLC. Methods: Patients (pts) with stage IB-IIIA NSCLC were stratified by sex, stage, histology, post-op radiation, and after Jan 2003, adj CT. Pts were randomized to gefitinib 250 mg or placebo daily x 2 years. Study endpoints included overall survival (OS), disease free survival (DFS), toxicity, preplanned correlative studies. Study closed prematurely in Apr. 2005. Trial committee and NCIC CTG staff remained blinded to study drug. Results: 503 pts randomized (Sep 2002-Apr 2005); median age 67, males 54%, PS 0 54%; stage IB 49%, II 38%, III 13%; adenocarcinoma 59%, squamous 28%; ever smokers 89%; adj CT 17%; lobectomy 82%. Commonest grade 3/4 toxicities = fatigue 5%, rash 4% and diarrhea 5%. grade 3+ pneumonitis in 7 (1.4%) pts and led to death in 1. Median follow-up is 4.7 yrs; median treatment time is 4.8 mos. For gefitinib versus placebo, median DFS is 4.2 yrs versus not yet reached (NYR) HR1.22 (95% C.I. 0.93-1.61), p=0.15 and median OS 5.1 yrs versus NYR HR 1.24 (95% C.I. 0.94-1.64), p=0.14. In multivariate analysis, tumor size >4cm was predictive of poor DFS (p<0.0001) and never smoking for better OS with gefitinib (p=0.02). Results for KRAS and EGFR copy are available on 350 and 348 pts respectively. KRAS mutations were neither prognostic HR 1.12 (95% C.I. 0.67-1.86), p=0.66 nor predictive of gefitinib benefit (p = 0.16) on OS. EGFRcopy whether low/high polysomy or amplification was neither prognostic (p=0.77) nor predictive of OS benefit from gefitinib. Conclusions: Adjuvant gefitinib after complete resection of early stage NSCLC did not confer DFS or OS advantage in overall population. KRAS and EGFR copy were neither prognostic nor predictive of benefit from gefitinib. EGFR mutational analysis will be presented. [Table: see text]

LBA504 Background: Limited efficacy and serious toxicities have limited uptake of tamoxifen or raloxifene as preventatives of breast cancer. Aromatase inhibitors (AIs) prevent contralateral breast cancers more than tamoxifen in adjuvant trials and have fewer serious side effects. This is the first report of an AI used in primary prevention. Methods: NCIC CTG MAP.3 is a randomized trial designed to detect a 65% reduction in annual incidence of invasive breast cancer (IBC) on exemestane (E) versus placebo (P). Eligible postmenopausal women had ≥ one of the following risk factors: Gail score >1.66%, prior ADH, ALH, LCIS or DCIS with mastectomy, age over 60. Health-related and menopause-specific quality of life (QOL) were assessed by SF-36 and MENQOL questionnaires. Results: From 2004-2010, 4,560 women were randomized: age 62.5 yrs (37-90); Gail Score 2.3 % (0.6-21); BMI 28.0 kg/m2 (15.9-65.4). Risk factors included: age >60 yrs (49%); Gail score >1.66 (40%); and prior ADH, ALH, LCIS or DCIS with mastectomy (11%). At median follow-up of 35 months there were 11 IBCs on E and 32 on P (annual incidence 0.19% vs 0.55%; HR= 0.35, 95% CI 0.18-0.70, p = 0.002); ductal (10E/27P), lobular (1E/5P). Most tumors were ER positive (7E/27P); Her2/neu negative (10E/26P); TNM stage T1 (8E/28P), N0 (7E/22P), M0 (11E/30P). E was superior in all subgroups: by Gail score, age, BMI, prior LCIS and DCIS. The annual incidence rate of IBC or DCIS was 0.35% E and 0.77% P (HR=0.47;95% CI 0.27-0.79; p = 0.004) based on 64 IBCs or DCISs (20E/44P). Clinical bone fractures, osteoporosis, hypercholesterolemia or cardiovascular events were equal in both arms. No clinically meaningful differences in QOL were detected. Conclusions: Exemestane significantly reduced invasive and pre-invasive breast cancers in postmenopausal women at increased risk for breast cancer with no serious toxicities. Exemestane should be considered a new option for primary prevention of breast cancer. Supported by the Canadian Cancer Society; Pfizer Inc. PEG supported in part by Avon Foundation.

Abstract Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ∼40% or ∼63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy. Cancer Res; 76(23); 7012–23. ©2016 AACR.

Abstract We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion.