Polypharmacy, over-the-counter medications, and aromatase inhibitor adherence in early-stage breast cancer.

PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation. METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence. RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation. CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.

Exploring breast tissue microbial composition and the association with breast cancer risk factors.

BACKGROUND: Microbial dysbiosis has emerged as an important element in the development and progression of various cancers, including breast cancer. However, the microbial composition of the breast from healthy individuals, even relative to risk of developing breast cancer, remains unclear. Here, we performed a comprehensive analysis of the microbiota of the normal breast tissue, which was analyzed in relation to the microbial composition of the tumor and adjacent normal tissue. METHODS: The study cohorts included 403 cancer-free women (who donated normal breast tissue cores) and 76 breast cancer patients (who donated tumor and/or adjacent normal tissue samples). Microbiome profiling was obtained by sequencing the nine hypervariable regions of the 16S rRNA gene (V1V2, V2V3, V3V4, V4V5, V5V7, and V7V9). Transcriptome analysis was also performed on 190 normal breast tissue samples. Breast cancer risk score was assessed using the Tyrer-Cuzick risk model. RESULTS: The V1V2 amplicon sequencing resulted more suitable for the analysis of the normal breast microbiome and identified Lactobacillaceae (Firmicutes phylum), Acetobacterraceae, and Xanthomonadaceae (both Proteobacteria phylum) as the most abundant families in the normal breast. However, Ralstonia (Proteobacteria phylum) was more abundant in both breast tumors and histologically normal tissues adjacent to malignant tumors. We also conducted a correlation analysis between the microbiome and known breast cancer risk factors. Abundances of the bacterial taxa Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp. were associated with age (p < 0.0001), racial background (p < 0.0001), and parity (p < 0.0001). Finally, transcriptome analysis of normal breast tissues showed an enrichment in metabolism- and immune-related genes in the tissues with abundant Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp., whereas the presence of Ralstonia in the normal tissue was linked to dysregulation of genes involved in the carbohydrate metabolic pathway. CONCLUSIONS: This study defines the microbial features of normal breast tissue, thus providing a basis to understand cancer-related dysbiosis. Moreover, the findings reveal that lifestyle factors can significantly affect the normal breast microbial composition.

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes.

PURPOSE: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. METHODS: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. RESULTS: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. CONCLUSIONS: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.

Breast Cancer Worry in U.S. Female First-degree Relatives: Moderating Role of Daily Spiritual Experiences.

Female first degree relatives of breast cancer patients experience worry because of their own increased breast cancer risk. The aim in the present study was to examine the role of daily spiritual experiences as a potential protective factor against breast cancer worry. We hypothesized that daily spiritual experiences would moderate the relationship between relatives' stage of disease and breast cancer worry. Sixty-three mothers, daughters or sisters of breast cancer survivors completed surveys assessing relative's disease characteristics and their own demographics, fear of breast cancer, and daily spiritual experiences. All participants were living in the midwestern United States. Results showed that daily spiritual experiences moderated the relationship between stage of disease and breast cancer worry. Low scores on daily spiritual experiences were associated with more worry when relatives had advanced disease, and high scores on daily spiritual experiences was associated with less worry when relatives had advanced disease. Findings suggest the need to focus on this population when providing support services to families of patients.

Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence.

BACKGROUND: Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. METHODS: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher's exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models. RESULTS: Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. CONCLUSIONS: Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

Serum hormone levels and normal breast histology among premenopausal women.

PURPOSE: Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations. METHODS: Pathology AI analysis was performed on 316 digital images of H&E-stained sections of normal breast tissues from Komen Tissue Bank donors ages ≤ 45 years to assess 11 quantitative metrics. Associations of circulating factors with AI metrics were assessed using regression analyses, with inclusion of interaction terms to assess effect modification. RESULTS: Higher prolactin levels were related to larger TDLU area (p < 0.001) and increased presence of adipose tissue proximate to TDLUs (p < 0.001), with less significant positive associations for acini counts (p = 0.012), dilated acini (p = 0.043), capillary area (p = 0.014), epithelial area (p = 0.007), and mononuclear cell counts (p = 0.017). Testosterone levels were associated with increased TDLU counts (p < 0.001), irrespective of parity, but associations differed by adipose tissue content. AI data for TDLU counts generally agreed with prior visual assessments. CONCLUSION: Among premenopausal women, serum hormone levels linked to BC risk were also associated with quantitative features of normal breast tissue. These relationships were suggestively modified by parity status and tissue composition. We conclude that the microanatomic features of normal breast tissue may represent a marker of BC risk.

Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.

OBJECTIVE: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations. METHODS: In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk. RESULTS: Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10-8), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts. CONCLUSIONS: Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.

TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer.

BACKGROUND: In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. METHODS: Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. RESULTS: Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. CONCLUSION: In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.

Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10-23), representing a previously unidentified mechanism for HFS. CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

Prospective evaluation of finger two-point discrimination and carpal tunnel syndrome among women with breast cancer receiving adjuvant aromatase inhibitor therapy.

PURPOSE: Aromatase inhibitors (AIs) are associated with musculoskeletal symptoms and risk of developing carpal tunnel syndrome (CTS), which can impair quality of life and prompt treatment discontinuation. The incidence of CTS and clinical utility of diagnostic tests such as 2-point discrimination (2-PD) have not been prospectively examined among women receiving AIs. METHODS: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were enrolled in a randomized clinical trial investigating adjuvant AIs (Exemestane and Letrozole Pharmacogenetics, ELPh) underwent prospective evaluation of 2-PD with the Disc-criminator™ (sliding aesthesiometer) and completed a CTS questionnaire at baseline, 3, 6, and 12 months, following initiation of AI. Changes in mean 2-PD were analyzed with multivariable mixed effects modelling. A p value < 0.05 was considered statistically significant. RESULTS: Of 100 women who underwent baseline 2-PD testing, CTS was identified by questionnaire in 11% at baseline prior to AI initiation. Prevalence of CTS at any time in the first year was 26%. A significant increase in worst 2-PD score was observed from baseline to 3 months (3.7 mm to 3.9 mm, respectively, p = 0.03) when adjusted for age, prior chemotherapy, randomized treatment assignment, and diabetes. There were no significant differences in treatment discontinuation due to CTS between the arms. CONCLUSION: For women receiving adjuvant AI, 2-PD scores were significantly worse at 3 months compared to baseline. Studies are required to assess whether change in 2-PD is an adequate objective assessment for CTS with AI therapy. Early diagnosis of CTS may expedite management, improve AI adherence, and enhance breast cancer outcomes.

Serum insulin-like growth factor (IGF)-I and IGF binding protein-3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: The Susan G. Komen Tissue Bank.

Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay. Hematoxilyn and eosin-stained tissue sections were assessed for numbers of TDLUs ("TDLU count"). Zero-inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p < 0.0001). Postmenopausal IGFBP-3 was inversely associated with TDLU count among AA (RRT3vs.T1 = 0.49, 95% CI = 0.28-0.84, p-trend = 0.04) and Caucasian (RRT3vs.T1 =0.64, 95% CI = 0.42-0.98, p-trend = 0.04) women. In premenopausal women, higher IGF-I:IGFBP-3 ratios were associated with higher TDLU count in Caucasian (RRT3vs.T1 =1.33, 95% CI = 1.02-1.75, p-trend = 0.04), but not in AA (RRT3vs.T1 =0.65, 95% CI = 0.42-1.00, p-trend = 0.05), women. Our data suggest a role of the IGF system, particularly IGFBP-3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women.

Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008.

BACKGROUND: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. METHODS: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. RESULTS: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37-0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. CONCLUSION: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).

A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial.

PURPOSE: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS. METHODS: In the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively. RESULTS: From 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density. CONCLUSIONS: Compared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.

Acceptance and commitment therapy for symptom interference in metastatic breast cancer patients: a pilot randomized trial.

PURPOSE: Breast cancer is the leading cause of cancer mortality in women worldwide. With medical advances, metastatic breast cancer (MBC) patients often live for years with many symptoms that interfere with activities. However, there is a paucity of efficacious interventions to address symptom-related suffering and functional interference. Thus, this study examined the feasibility and preliminary efficacy of telephone-based acceptance and commitment therapy (ACT) for symptom interference with functioning in MBC patients. METHODS: Symptomatic MBC patients (N = 47) were randomly assigned to six telephone sessions of ACT or six telephone sessions of education/support. Patients completed measures of symptom interference and measures assessing the severity of pain, fatigue, sleep disturbance, depressive symptoms, and anxiety. RESULTS: The eligibility screening rate (64%) and high retention (83% at 8 weeks post-baseline) demonstrated feasibility. When examining within-group change, ACT participants showed decreases in symptom interference (i.e., fatigue interference and sleep-related impairment; Cohen's d range = - 0.23 to - 0.31) at 8 and 12 weeks post-baseline, whereas education/support participants showed minimal change in these outcomes (d range = - 0.03 to 0.07). Additionally, at 12 weeks post-baseline, ACT participants showed moderate decreases in fatigue and sleep disturbance (both ds = - 0.43), whereas education/support participants showed small decreases in these outcomes (ds = - 0.24 and - 0.18 for fatigue and sleep disturbance, respectively). Both the ACT and education/support groups showed reductions in depressive symptoms (ds = - 0.27 and - 0.28) at 12 weeks post-baseline. Group differences in all outcomes were not statistically significant. CONCLUSIONS: ACT shows feasibility and promise in improving fatigue and sleep-related outcomes in MBC patients and warrants further investigation.

Metastatic breast cancer patients' expectations and priorities for symptom improvement.

PURPOSE: Little research has examined cancer patients' expectations, goals, and priorities for symptom improvement. Thus, we examined these outcomes in metastatic breast cancer patients to provide patients' perspectives on clinically meaningful symptom improvement and priorities for symptom management. METHODS: Eighty women with metastatic breast cancer participated in a survey with measures of comorbidity, functional status, engagement in roles and activities, distress, quality of life, and the modified Patient-Centered Outcomes Questionnaire that focused on 10 common symptoms in cancer patients. RESULTS: On average, patients reported low to moderate severity across the 10 symptoms and expected symptom treatment to be successful. Patients indicated that a 49% reduction in fatigue, 48% reduction in thinking problems, and 43% reduction in sleep problems would represent successful symptom treatment. Cluster analysis based on ratings of the importance of symptom improvement yielded three clusters of patients: (1) those who rated thinking problems, sleep problems, and fatigue as highly important, (2) those who rated pain as moderately important, and (3) those who rated all symptoms as highly important. The first patient cluster differed from other subgroups in severity of thinking problems and education. CONCLUSIONS: Metastatic breast cancer patients report differing symptom treatment priorities and criteria for treatment success across symptoms. Considering cancer patients' perspectives on clinically meaningful symptom improvement and priorities for symptom management will ensure that treatment is consistent with their values and goals.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

DNA methylation age is elevated in breast tissue of healthy women.

BACKGROUND: Limited evidence suggests that female breast tissue ages faster than other parts of the body according to an epigenetic biomarker of aging known as the "epigenetic clock." However, it is unknown whether breast tissue samples from healthy women show a similar accelerated aging effect relative to other tissues, and what could drive this acceleration. The goal of this study is to validate our initial finding of advanced DNA methylation (DNAm) age in breast tissue, by directly comparing it to that of peripheral blood tissue from the same individuals, and to do a preliminary assessment of hormonal factors that could explain the difference. METHODS: We utilized n = 80 breast and 80 matching blood tissue samples collected from 40 healthy female participants of the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center who donated these samples at two time points spaced at least a year apart. DNA methylation levels (Illumina 450K platform) were used to estimate the DNAm age. RESULTS: DNAm age was highly correlated with chronological age in both peripheral blood (r = 0.94, p < 0.0001) and breast tissues (r = 0.86, p < 0.0001). A measure of epigenetic age acceleration (age-adjusted DNAm Age) was substantially increased in breast relative to peripheral blood tissue (p = 1.6 × 10-11). The difference between DNAm age of breast and blood decreased with advancing chronologic age (r = -0.53, p = 4.4 × 10-4). CONCLUSIONS: Our data clearly demonstrate that female breast tissue has a higher epigenetic age than blood collected from the same subject. We also observe that the degree of elevation in breast diminishes with advancing age. Future larger studies will be needed to examine associations between epigenetic age acceleration and cumulative hormone exposure.

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.

Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

PURPOSE: The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. METHODS: Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. RESULTS: Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). CONCLUSIONS: Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Symptom experiences in metastatic breast cancer patients: relationships to activity engagement, value-based living, and psychological inflexibility.

OBJECTIVE: This study examined symptom-based subgroups of metastatic breast cancer (MBC) patients and the extent to which they differed across key constructs of acceptance and commitment therapy (ACT). METHODS: Eighty women with MBC completed self-report surveys assessing 10 common symptoms and several ACT variables (ie, activity engagement, psychological inflexibility, value obstruction, and value progress) during a single time point. RESULTS: A cluster analysis yielded 3 patient subgroups: low symptoms, low-moderate symptoms, and moderate-high symptoms. Relative to the subgroup with low symptoms, the other subgroups reported less activity engagement. In addition, compared with patients with low symptoms, the subgroup with moderate-high symptoms reported greater psychological inflexibility (ie, avoidance of unwanted internal experiences) and greater difficulty living consistently with their values. CONCLUSIONS: Women with MBC show heterogeneity in their symptom profiles, and those with higher symptom burden are more likely to disengage from valued activities and avoid unwanted experiences (eg, thoughts, feelings, and bodily sensations). Findings are largely consistent with the ACT model and provide strong justification for testing ACT to address symptom interference in MBC patients.