Uses and Abuses of Tumor Markers in the Diagnosis, Monitoring, and Treatment of Primary and Metastatic Breast Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139922/1/onco0541.pd

Prediction of Postchemotherapy Ovarian Function Using Markers of Ovarian Reserve

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140040/1/onco0068.pd

Pilot study of duloxetine for treatment of aromatase inhibitor‐associated musculoskeletal symptoms

BACKGROUND: Approximately 50% of postmenopausal women with hormone receptor‐positive early stage breast cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are relatively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of AI‐associated musculoskeletal symptoms. METHODS: The authors performed a single‐arm, open‐label phase 2 study of duloxetine in postmenopausal women with breast cancer who developed new or worsening pain after treatment with an AI for at least 2 weeks. Patients were treated with duloxetine for 8 weeks (30 mg for 7 days, then 60 mg daily). The primary endpoint was a 30% decrease in average pain score over 8 weeks, and secondary outcomes included change in average and worst pain, pain interference, depression, sleep quality, and hot flashes. Statistical analysis was done with t tests for paired data. RESULTS: Twenty‐one of 29 evaluable patients (72.4%) achieved at least a 30% decrease in average pain, and 18 of 23 patients (78.3%) who completed protocol‐directed treatment continued duloxetine. The mean percentage reduction in average pain severity between baseline and 8 weeks was 60.9% (95% confidence interval [CI], 48.6%‐73.1%), and in maximum pain severity it was 59.9% (95% CI, 47.0‐72.7%). The most common adverse events were grade 1 or 2 fatigue, xerostomia, nausea, and headache. CONCLUSIONS: Duloxetine appears to be effective and well tolerated for treatment of AI‐associated musculoskeletal symptoms. Future randomized, placebo‐controlled studies are warranted. Cancer 2011;. © 2011 American Cancer Society. Bothersome musculoskeletal symptoms affect about half of women with early stage breast cancer treated with aromatase inhibitors. In this pilot clinical trial, treatment with duloxetine appeared to significantly improve pain and functioning, and was relatively well tolerated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89530/1/26230_ftp.pd

Whole Genome Amplification of DNA for Genotyping Pharmacogenetics Candidate Genes

Whole genome amplification (WGA) technologies can be used to amplify genomic DNA when only small amounts of DNA are available. The Multiple Displacement Amplification Phi polymerase based amplification has been shown to accurately amplify DNA for a variety of genotyping assays; however, it has not been tested for genotyping many of the clinically relevant genes important for pharmacogenetic studies, such as the cytochrome P450 genes, that are typically difficult to genotype due to multiple pseudogenes, copy number variations, and high similarity to other related genes. We evaluated whole genome amplified samples for Taqman™ genotyping of SNPs in a variety of pharmacogenetic genes. In 24 DNA samples from the Coriell human diversity panel, the call rates, and concordance between amplified (∼200-fold amplification) and unamplified samples was 100% for two SNPs in CYP2D6 and one in ESR1. In samples from a breast cancer clinical trial (Trial 1), we compared the genotyping results in samples before and after WGA for three SNPs in CYP2D6, one SNP in CYP2C19, one SNP in CYP19A1, two SNPs in ESR1, and two SNPs in ESR2. The concordance rates were all >97%. Finally, we compared the allele frequencies of 143 SNPs determined in Trial 1 (whole genome amplified DNA) to the allele frequencies determined in unamplified DNA samples from a separate trial (Trial 2) that enrolled a similar population. The call rates and allele frequencies between the two trials were 98 and 99.7%, respectively. We conclude that the whole genome amplified DNA is suitable for Taqman™ genotyping for a wide variety of pharmacogenetically relevant SNPs

Genotyping concordance in DNA extracted from formalin‐fixed paraffin embedded (FFPE) breast tumor and whole blood for pharmacogenetic analyses

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135708/1/mol22015991868.pd

Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors

PURPOSE: Aromatase inhibitors (AI), which decrease circulating estradiol concentrations in post-menopausal women, are associated with toxicities that limit adherence. Approximately one-third of patients will tolerate a different AI after not tolerating the first. We report the effect of crossover from exemestane to letrozole or vice versa on patient-reported outcomes (PROs) and whether the success of crossover is due to lack of estrogen suppression. METHODS: Post-menopausal women enrolled on a prospective trial initiating AI therapy for early-stage breast cancer were randomized to exemestane or letrozole. Those that discontinued for intolerance were offered protocol-directed crossover to the other AI after a washout period. Changes in PROs, including pain [Visual Analog Scale (VAS)] and functional status [Health Assessment Questionnaire (HAQ)], were compared after 3 months on the first versus the second AI. Estradiol and drug concentrations were measured. RESULTS: Eighty-three patients participated in the crossover protocol, of whom 91.3% reported improvement in symptoms prior to starting the second AI. Functional status worsened less after 3 months with the second AI (HAQ mean change AI #1: 0.2 [SD 0.41] vs. AI #2: -0.05 [SD 0.36]; p = 0.001); change in pain scores was similar between the first and second AI (VAS mean change AI #1: 0.8 [SD 2.7] vs. AI #2: -0.2 [SD 2.8]; p = 0.19). No statistical differences in estradiol or drug concentrations were found between those that continued or discontinued AI after crossover. CONCLUSIONS: Although all AIs act via the same mechanism, a subset of patients intolerant to one AI report improved PROs with a different one. The mechanism of this tolerance remains unknown, but does not appear to be due to non-adherence to, or insufficient estrogen suppression by, the second AI

Association between body mass index and response to duloxetine for aromatase inhibitor‐associated musculoskeletal symptoms in SWOG S1202

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149517/1/cncr32024.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149517/2/cncr32024_am.pd

Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer

PURPOSE: Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI-treated breast cancer patients. METHODS: In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole (n = 241) or exemestane (n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry-based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs. RESULTS: The ranges of baseline estrogen concentrations were <LLOQ-361 pg/mL for E2, <LLOQ-190 pg/mL for E1, and 8.3-4060 pg/mL for E1S. For E2, the frequency of suppression below the LLOQ was not statistically significantly different between AIs (exemestane: 89.0%, letrozole: 86.9%, p = 0.51). However, patients on letrozole were more likely to achieve suppression below the LLOQ of both E1 (exemestane: 80.1%, letrozole: 90.1%, p = 0.005) and E1S (exemestane: 17.4%, letrozole: 54.9%, p = 4.34e-15). After 3 months of AI therapy, the ranges of estrogen concentrations were <LLOQ-63.8 pg/mL, <LLOQ-36.7 pg/mL, and <LLOQ-1090 pg/mL for E2, E1, and E1S, respectively. During treatment, 16 patients had an increased concentration compared to the baseline concentration of at least one estrogen. CONCLUSIONS: Letrozole had greater suppression of plasma E1 and E1S than exemestane, though the response was highly variable among patients. Additional research is required to examine the clinical relevance of differential estrogen suppression