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Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery.

ABSTRACT: Persistent pain following breast cancer surgery is a significant problem. Both inherited and acquired mechanisms of inflammation appear to play a role in the development and maintenance of persistent pain. In this longitudinal study, growth mixture modeling was used to identify persistent breast pain phenotypes based on pain assessments obtained prior to and monthly for 6months following breast cancer surgery. Associations between the "no pain" and "mild pain" phenotypes and single nucleotide polymorphisms (SNPs) spanning 15 cytokine genes were evaluated. The methylation status of the CpG sites found in the promoters of genes associated with pain group membership was determined using bisulfite sequencing. In the multivariate analysis, three SNPs (i.e., interleukin 6 (IL6) rs2069840, C-X-C motif chemokine ligand 8 (CXCL8) rs4073, tumor necrosis factor (TNF) rs1800610) and two TNF CpG sites (i.e., c.-350C, c.-344C) were associated with pain group membership. These findings suggest that variations in IL6, CXCL8, and TNF are associated with the development and maintenance of mild persistent breast pain. CpG methylation within the TNF promoter may provide an additional mechanism through which TNF alters the risk for mild persistent breast pain after breast cancer surgery. These genetic and epigenetic variations may help to identify individuals who are predisposed to the development of mild levels of persistent breast pain following breast cancer surgery.

SUBMITTER: Stephens KE

PROVIDER: S-EPMC5675785 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery.

Stephens Kimberly E KE Levine Jon D JD Aouizerat Bradley E BE Paul Steven M SM Abrams Gary G Conley Yvette P YP Miaskowski Christine C

Cytokine 20170729

Persistent pain following breast cancer surgery is a significant problem. Both inherited and acquired mechanisms of inflammation appear to play a role in the development and maintenance of persistent pain. In this longitudinal study, growth mixture modeling was used to identify persistent breast pain phenotypes based on pain assessments obtained prior to and monthly for 6months following breast cancer surgery. Associations between the "no pain" and "mild pain" phenotypes and single nucleotide po ...[more]

PMID: 28764974

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Project description:ImportanceThrough the Choosing Wisely campaign, surgical specialties identified 4 low-value breast cancer operations. Preliminary data suggest varying rates of deimplementation and have identified patient-level and clinician-level determinants of continued overuse. However, little information exists about facility-level variation or determinants of differential deimplementation.ObjectiveTo identify variation and determinants of persistent use of low-value breast cancer surgical care.Design, setting, and participantsRetrospective cohort study in which reliability-adjusted facility rates of each procedure were calculated using random-intercept hierarchical logistic regression before and after evidence demonstrated that each procedure was unnecessary. The National Cancer Database is a prospective cancer registry of patients encompassing approximately 70% of all new cancer diagnoses from more than 1500 facilities in the United States. Data were analyzed from November 2019 to August 2020. The registry included women 18 years and older diagnosed as having breast cancer between 2004 and 2016 and meeting inclusion criteria for each Choosing Wisely recommendation.Main outcomes and measuresRate of each low-value breast cancer procedure based on facility type and breast cancer volume categories before and after the release of data supporting each procedure's omission.ResultsThe total cohort included 920 256 women with a median age of 63 years. Overall, 86% self-identified as White, 10% as Black, 3% as Asian, and 4.5% as Hispanic. Most women in this cohort were insured (51% private and 47% public), were living in a metropolitan or urban area (88% and 11%, respectively), and originated from the top half of income-earning households (65.5%). While there was significant deimplementation of axillary lymph node dissection and lumpectomy reoperation in response to guidelines supporting omission of these procedures, rates of contralateral prophylactic mastectomy and sentinel lymph node biopsy in older women increased during the study period. Academic research programs and high-volume facilities overall demonstrated the greatest reduction in use of these low-value procedures. There was significant interfacility variation for each low-value procedure. Facility-level axillary lymph node dissection rates ranged from 7% to 47%, lumpectomy reoperation rates ranged from 3% to 62%, contralateral prophylactic mastectomy rates ranged from 9% to 67%, and sentinel lymph node biopsy rates ranged from 25% to 97%. Pearson correlation coefficient for each combination of 2 of the 4 procedures was less than 0.11, suggesting that hospitals were not consistent in their deimplementation performance across all 4 procedures. Many were high outliers in one procedure but low outliers in another.Conclusions and relevanceInterfacility variation demonstrates a performance gap and an opportunity for formal deimplementation efforts targeting each procedure. Several facility-level characteristics were associated with differential deimplementation and performance.

Project description:Background: Persistent breast pain (PBP) is prevalent among breast cancer survivors and has powerful negative psychological consequences. The present study provided a first test of the hypothesis that: (a) pain catastrophizing, (b) heightened perceived risk of cancer, and (c) worry that pain indicates cancer may be independent mediating links between breast cancer survivors' experiences of PBP and heightened emotional distress. Methodology: We assessed levels of PBP and psychological factors in breast cancer survivors (Survivor Group: n?=?417; Stages I-IIIA; White = 88.7%; Age M?=?59.4 years) at their first surveillance mammogram post-surgery (6-15 months). A comparison group of women without histories of breast surgery or cancer (Non-cancer Group: n?=?587; White = 78.7%; Age M?=?57.4 years) was similarly assessed at the time of a routine screening mammogram. All women completed measures of breast pain, pain catastrophizing, perceived breast cancer risk, and worry that breast pain indicates cancer, as well as measures of emotional distress (symptoms of anxiety, symptoms of depression, and mammography-specific distress). Analyses included race, age, BMI, education, and menopausal status as covariates, with significance set at 0.05. Results: As expected, PBP prevalence was significantly higher in the Survivor Group than in the Non-cancer Group (50.6% vs. 17.5%). PBP+ survivors also had significantly higher levels of emotional distress, pain catastrophizing, mammography-specific distress, and worry that breast pain indicates cancer, compared to PBP- survivors. Structural equation modeling results were significant for all hypothesized mediational pathways. Interestingly, comparisons of PBP+?to PBP-?women in the Non-cancer Group showed similar results. Conclusion: These findings suggest the importance of (a) pain catastrophizing, (b) perceived breast cancer risk and, (c) worry that breast pain may indicate cancer, as potential targets for interventions aimed at reducing the negative psychological impact of PBP in post-surgery breast cancer survivors, as well as in unaffected women with PBP due to unknown reasons.

Dataset Information

Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery.

Publications

Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery.

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