Jill Hayden

Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast Cancer

PURPOSE Aromatase inhibitors (AIs) are effective for treatment of hormone receptor-positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another. PATIENTS AND METHODS Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period. RESULTS Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months. CONCLUSION Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.

Estrogen Receptor Genotypes Influence Hot Flash Prevalence and Composite Score Before and After Tamoxifen Therapy

PURPOSE Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) alpha and beta (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes. PATIENTS AND METHODS We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency x severity) before and 1, 4, 8, and 12 months after starting tamoxifen. RESULTS Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001). CONCLUSION Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment.

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen‐induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low‐density lipoprotein cholesterol (P<0.0001) by 23.5 mg/dl (13.5–33.5 mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1‐XbaI and ESR2–02 genotypes were associated with tamoxifen‐induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene–dose effect), respectively. In premenopausal women, the ESR1‐XbaI genotypes were associated with tamoxifen‐induced changes in triglycerides (P=0.002; gene–dose effect) and high‐density lipoprotein (P=0.004; gene–dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen.

Comparison of Subjective and Objective Hot Flash Measures Over Time Among Breast Cancer Survivors Initiating Aromatase Inhibitor Therapy

Objective:Hot flashes are valuable indicators of physiological condition and drug effect; however, subjective and objective measures do not always agree. No study has examined both subjective and objective hot flashes in women prescribed aromatase inhibitors. The study (1) compared subjective and objective hot flash measures, (2) examined changes in subjective and objective hot flashes over time, and (3) evaluated predictors of change in hot flashes in aromatase inhibitor-treated women. Methods:Participants (n = 135) were enrolled in a randomized clinical trial comparing exemestane and letrozole for the treatment of breast cancer. Hot flashes were assessed before the start of the drug therapy and 1, 3, and 6 months later. Participants wore a sternal skin conductance monitor for 24 hours or longer at each time point. With each perceived hot flash, women pressed an event button and rated intensity and bother in a paper diary. Results:Participants had a mean age of 60 years and were mainly white (92%). Across time points, monitor hot flashes were (1) significantly more frequent than diary and/or event button flashes (P < 0.05) and (2) moderately correlated with subjective measures (0.35 < r < 0.56). Monitor hot flashes did not significantly change over time with aromatase inhibitor therapy, whereas both diary and event button frequencies significantly varied but in dissimilar patterns (51% nonlinear). No consistent predictors of hot flashes across measures or time points were identified. Conclusions:Findings indicated dissimilarities between subjective and objective measures of hot flashes. Despite statistical significance, there was little clinically meaningful change in hot flashes after initiating aromatase inhibitor therapy.

Association of Aromatase Inhibitor-Associated Musculoskeletal Symptoms with Ultrasonographic Changes at the Wrist.

Background: About 40% of aromatase inhibitor (AI)-treated women develop AI-associated musculoskeletal symptoms (AIMSS) such as arthralgias, but the etiology is unclear. Tendon sheath fluid and tenosynovial changes have been demonstrated by imaging in symptomatic AI-treated patients. It is unclear if these changes correlate with development of AIMSS.Methods: Thirty consecutive patients (pts) initiating therapy with letrozole or exemestane on a prospective clinical trial were enrolled to this substudy. Pts with prior wrist trauma or who declined to provide informed consent were excluded. Pts underwent high resolution ultrasonography (US) of the wrists bilaterally and completed the Health Assessment Questionnaire (HAQ), pain Visual Analog Scale (VAS), and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire at baseline (BL) and after 3 mo of AI. AIMSS was defined as increase in HAQ or pain VAS score during AI therapy that exceeded a predefined cutoff. Analysis of US images was performed in a blinded manner. Imaging abnormalities included the following: presence of fluid, synovitis, and/or hyperemia in the tendon sheath or joint recess. Statistical analysis was performed using univariate chi-square tests and logistic regression analyses.Results: Of the 30 enrolled subjects, 25 completed both BL and 3 mo assessments. Eight of 30 (27%) discontinued therapy because of AIMSS (2 before and 6 after the 3 mo timepoint), and 3 patients discontinued therapy for unrelated reasons. All patients have been followed for at least 6 mo. We observed a significant association between early treatment discontinuation and change in HAQ (Odds Ratio (OR) 1.525, p=0.0006) and VAS (OR 1.307, p=0.0096) but not DASH (OR 1.001, p=0.96) scores between BL and 3 mo. The proportion of pts with abnormalities on US at BL or that developed during therapy is given in tables 1 and 2, respectively. We did not observe a statistically significant correlation between objective abnormalities on US at BL or following initiation of AI therapy and the development of AIMSS or early treatment discontinuation because of AIMSS.Conclusions: Clinically relevant musculoskeletal symptoms develop in AI-treated women, leading to treatment discontinuation in a substantial percentage. However, patient-reported symptoms were not associated with inflammatory changes visible on wrist US in this pilot study. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 802.

Abstract 4828: Circulating tumor cells (CTCs) isolated from patients with metastatic breast cancer utilizing a sensitive microfluidic graphene oxide (GO) nanosheet device express markers of cancer stem cells

Breast cancers are driven by a subset of cells that display stem cell properties. These “cancer stem cells” (CSCs) mediate metastasis and contribute to treatment resistance. Many current CTC isolation technologies are limited in their sensitivity and are particularly inefficient at capturing cells which display an epithelial mesenchymal transition (EMT) phenotype which has been associated with CSCs. We have developed a sensitive microfluidic device using functionalized graphene oxide (GO) nanosheets to identify and isolate CTCs from patients with metastatic breast cancer. Unlike other CTC capture devices with microposts, the effective functionalized surface created by GO allows the device to be two-dimensional. The GO nanosheets were adsorbed onto the patterned gold surface and then chemically functionalized. Blood samples were collected into EDTA and AdnaGen tubes from patients with metastatic breast cancer and analyzed within 24 hours of blood sampling. Isolated CTCs were studied for expression of genes using a multiplex TaqMan-based qRT-PCR method. CTC preparations were checked for white blood cells (WBCs) contamination by examining CD45 expression and verifying that there was no or extremely low levels of CD45 expression in all of the processed samples. The majority of isolated CTCs showed mRNA expression of EMT markers including TGFβ and Vimentin at different levels among tested samples. In addition, markers of breast CSCs including CD44+/CD24- and ALDH1+ were observed in CTCs isolated from patients across the molecular subtypes of breast cancer. Interestingly, HER2+ CTCs were isolated from patients with HER2/neu- primary tumors. This is consistent with recent work from our group that demonstrated selective expression of HER2 in the CSC-like populations of luminal breast cancers occur independent of HER2 gene amplification. These studies demonstrate the feasibility of utilizing GO nanosheet microfluidic devices to isolate and molecularly characterize CTCs from metastatic breast cancer patients. Such liquid biopsies may be of particular value for following CSC populations for patients on therapeutic clinical trials. Citation Format: Shamileh Fouladdel, Hyeun Joong Yoon, Tae Hyun Kim, An Shi, Tahra Luther, Jill Hayden, Shawn G. Clouthier, Yadwinder S. Deol, Monika L. Burness, Daniel F. Hayes, Sunitha Nagrath, Ebrahim Azizi, Max S. Wicha. Circulating tumor cells (CTCs) isolated from patients with metastatic breast cancer utilizing a sensitive microfluidic graphene oxide (GO) nanosheet device express markers of cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4828. doi:10.1158/1538-7445.AM2014-4828

PD04-01: Predictors of Recovery of Ovarian Function during Aromatase Inhibitor (AI) Therapy.

Background: AIs may cause a paradoxical rise in estrogen levels due to re-activation of ovarian function in women with chemotherapy-induced ovarian failure (CIOF). Therefore, identification of residual ovarian estradiol production is critical if such women are treated with adjuvant AI therapy rather than tamoxifen. We performed a prospective registry trial to identify predictors of recovery of ovarian function during AI therapy. Methods: Women with hormone receptor (HR) positive breast cancer who were pre- or peri-menopausal at diagnosis and who remained amenorrheic for ≥8 weeks after cyclophosphamide-containing adjuvant chemotherapy were enrolled in a multi-institutional, open-label clinical trial of anastrozole (1 mg/day). Following confirmation that serum estradiol (E2) levels were Results: Sixty-nine women were enrolled; current status is given in Table 1. Median age at initiation of chemotherapy was 47.2 yrs (range 37–55), median time since chemotherapy was 0.8 yrs (range 0.3–6.4), and median age at enrollment was 49.8 yrs (range 40–58). Thirty-six had received tamoxifen. We observed elevated E2 concentrations or return of menses during AI therapy in 21 subjects after a median 2.0 mo (range 0.6-17); for that cohort, median age at chemotherapy was 43.8 yrs (range 37–51) and median age at AI initiation was 45.8 yrs (range 40–56). In contrast, for the 15 subjects who had postmenopausal E2 levels for at least 48 wks, median age at chemotherapy was 49.2 yrs (range 44–52) and median age at AI initiation was 50.7 yrs (range 44–55). Age at chemotherapy (p=0.0006) and age at AI initiation (p=0.001) were statistically significant different between the 2 cohorts. On multivariable analysis, age at chemotherapy and age at AI initiation remained significant when each was adjusted for menopausal status, BMI, and baseline E2 (odds ratio (OR) 1.64, p=0.0102 and OR 1.47, p=0.015, respectively). Conclusions: A significant proportion of women who develop CIOF recover ovarian function during AI therapy. Although recovery is usually rapid, it can occur at least one year following initiation of AI therapy. Younger age was the strongest predictor of recovery of ovarian function, although 2 of 21 women who developed elevated E2 levels or return of menses were older than 50 yrs at the time of chemotherapy. Tamoxifen remains the standard of care for women with CIOF; if use of an AI is necessary, patients should be monitored frequently with high-quality E2 assays for recurrent ovarian function. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-01.

Abstract P2-14-09: Prospective Evaluation of Change in 2-Point Discrimination of Index Finger as a Potential Early Predictive Marker for Carpal Tunnel Syndrome among Women Receiving Adjuvant Aromatase Inhibitor Therapy for Postmenospausal Breast Cancer in the Exemestane and Letrozole Pharmacogenomics (ELPh) Trial

Introduction: Third generation aromatase inhibitors (AIs) represent an integral part of hormonal therapy in postmenopausal women with hormone receptor (HR)-positive breast cancer. AIs are associated with musculoskeletal symptoms in up to 50% of women. Post-hoc analyses of adjuvant AI trials (ATAC and IES) have suggested that AIs might be associated with carpal tunnel syndrome (CTS), a pressure-induced neuropathy disorder caused by compression on the median nerve. The clinical diagnosis of CTS is made with typical symptoms of pain, weakness, and paresthesias in affected arm. A variety of tests, including change in 2-point discrimination (2PD) can be used to aid in diagnosis. However, the actual incidence of CTS and clinical utility of diagnostic tests such as 2PD have not been prospectively examined among women receiving AIs. Methods: Postmenopausal women with stage 0-III HR-positive breast cancer, who had completed local therapy and, if indicated, adjuvant chemotherapy, and who were enrolled in the multi-center Exemestane and Letrozole Pharmacogenetics (ELPh) trial underwent prospective evaluation of 2PD with the Disc-criminator™ (sliding aesthesiometer) at baseline, and 3 months, following initiation of the AI. The end of the Disc-criminator™ was applied at the two points at same time to the skin on the volar tip pulp of the index fingers, and the threshold value (in mm) was determined as the shortest distance between the two points a woman was able to differentiate. The exercise was repeated thrice at each point. Abnormal 2PD thresholds were defined using standard criteria (outside 95 percentile for age). The differences in mean 2PD from baseline to 3 months were analyzed using a multivariate mixed effects model where the correlations from repeated measures were accounted for by assuming an unstructured covariance structure. A p value Results: A total of 104 women underwent baseline 2PD testing. The mean age was 59 years, 55.8% had stage I disease, and 42.3% received adjuvant chemotherapy. We observed abnormal 2PD thresholds in 1.9% and 3.5% of women at baseline and 3 months respectively. There was a significant worsening in the adjusted mean 2PD from baseline (3.4 mm) to 3 months (4 mm, p=0.01). The increase in mean 2PD following 3 months of AI therapy was higher among women with age > 55 (p=0.02), BMI > 25 (p=0.002), African Americans (p=0.02), and those who received adjuvant chemotherapy (p=0.05), as compared to their counterparts. Conclusion: Adjuvant AI therapy was associated with a significant worsening of 2PD at 3 months, particularly among older women, overweight women, and those receiving adjuvant chemotherapy. Correlation with CTS symptoms and need for surgical release will be presented at the meeting. Our results suggest that 2PD is a non-invasive method that may potentially allow for early detection of CTS. If confirmed, change in 2PD could serve as an objective early predictor for subsequent CTS in postmenopausal women with breast cancer initiating AI therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-09.