ABSTRACT
Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report provides insights into the formation of a pharmacogenomics consultation service at a safety-net hospital, which predominantly serves low-income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.
Subject(s)
Pharmacogenetics/organization & administration , Safety-net Providers/organization & administration , Vulnerable Populations , Academic Medical Centers/organization & administration , Humans , Medically Uninsured , PovertyABSTRACT
BACKGROUND: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. METHODS: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. RESULTS: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ≥20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. CONCLUSION: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.
Subject(s)
Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast/drug effects , Adult , Aged , Aged, 80 and over , Androstadienes/therapeutic use , Aromatase/genetics , Breast/metabolism , Breast/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chemotherapy, Adjuvant/methods , Estrogens/metabolism , Female , Humans , Letrozole , Mammography/methods , Middle Aged , Nitriles/therapeutic use , Polymorphism, Single Nucleotide , Postmenopause/drug effects , Postmenopause/genetics , Postmenopause/metabolism , Prospective Studies , Triazoles/therapeutic useABSTRACT
BACKGROUND: Tamoxifen, a selective oestrogen receptor (ER) modulator, increases bone mineral density (BMD) in postmenopausal women and decreases BMD in premenopausal women. We hypothesised that inherited variants in candidate genes involved in oestrogen signalling and tamoxifen metabolism might be associated with tamoxifen effects in bone. METHODS: A total of 297 women who were initiating tamoxifen therapy were enrolled in a prospective multicentre clinical trial. Lumbar spine and total hip BMD values were measured using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of tamoxifen therapy. Single-nucleotide polymorphisms (SNPs) in ESR1, ESR2, and CYP2D6 were tested for associations in the context of menopausal status and previous chemotherapy, with a mean percentage change in BMD over 12 months. RESULTS: The percentage increase in BMD was greater in postmenopausal women and in those patients who had been treated with chemotherapy. No significant associations between tested SNPs and either baseline BMD or change in BMD with 1 year of tamoxifen therapy were detected. CONCLUSION: The evaluated SNPs in ESR and CYP2D6 do not seem to influence BMD in tamoxifen-treated subjects.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Bone Density/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Tamoxifen/pharmacology , Absorptiometry, Photon , Adult , Cytochrome P-450 CYP2D6/genetics , Estrogen Receptor beta/genetics , Female , Humans , Middle Aged , Polymorphism, Single Nucleotide , Prospective Studies , RegistriesABSTRACT
The star-allele nomenclature is the result of efforts to standardize genetic polymorphism annotation for the cytochrome P450 genes. As clinical pharmacogenetic testing becomes widespread, it is important that this system effectively communicate a patient's genotype and predicted clinical phenotype. As genomics research expands, it is equally important that the system remain a valuable tool for the wider community of genetic researchers to exploit our ever-improving ability to catalog variability in the human genome.
Subject(s)
Alleles , Genomics/trends , Protein Biosynthesis , Terminology as Topic , Humans , Phenotype , Polymorphism, GeneticSubject(s)
Plasmalogens/chemical synthesis , Plasmalogens/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Humans , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phospholipid Ethers/chemical synthesis , Phospholipid Ethers/pharmacology , Tumor Cells, CulturedABSTRACT
Close spacing of children may be a significant risk factor for subsequent abuse in some families. Twin births are an extreme example of close spacing. Therefore, the authors hypothesized that twin births may predispose to an increased incidence of child abuse. Thirty-eight families with twins were compared with 97 single birth families and matched for birthdate, maternal age, race, and socioeconomic status. Families with twins experienced a significantly higher incidence of child abuse and neglect than did those with single births (p less than .003). A written questionnaire designed to study mothers' feelings and perceptions of support systems showed a significant difference only in greater difficulty in feeding twins as compared with single infants (p less than .001). Mothers of abused children were more likely not to answer the questionnaire at all (p less than .005). Neither mothers of single births nor those of twins felt that health professionals provided adequate education or support following the birth of their infants.
Subject(s)
Child Abuse , Twins , Ethnicity , Female , Humans , Infant , Maternal Age , Mothers/psychology , Pregnancy , Risk , Social Support , Socioeconomic Factors , Surveys and QuestionnairesABSTRACT
Large families and inadequate spacing of children increase the risk of abuse. Twin births incorporate both of these factors, yet the association of twinning with subsequent abuse has not been explored. Forty-eight families with twins from St Vincent Hospital and Medical Center and Nashville General Hospital were compared with 124 single-birth families, matched for hospital of delivery, birth date, maternal age, race, and socioeconomic status. Three control (2.4%) and nine twin (18.7%) families were reported for maltreatment (P less than .001). Mothers of twins experienced greater previous parity than did control subjects (P less than .001). Twins also had significantly longer nursery stays (P less than .001), lower birth weights (P less than .001), and lower Apgar scores at one (P less than .01) and five (P less than .05) minutes. A regression analysis incorporating all of these variables, however, showed that twin status was most predictive of subsequent abuse.
