Association of childhood trauma with fatigue, depression, stress, and inflammation in breast cancer patients undergoing radiotherapy.

BACKGROUND: This pilot study examined whether breast cancer patients with childhood trauma exhibit increased fatigue, depression, and stress in association with inflammation as a result of whole breast radiotherapy (RT). METHODS: Twenty breast cancer patients were enrolled in a prospective, longitudinal study of fatigue, depression, and perceived stress prior to RT, week 6 of RT, and 6 weeks post-RT. Six weeks after RT, subjects completed the childhood trauma questionnaire (CTQ). Patients were also administered the multidimensional fatigue inventory, inventory of depressive symptomatology-self-reported, and perceived stress scale at all three time-points and underwent blood sampling prior to RT for gene expression and inflammatory markers previously associated with childhood trauma and behavioral symptoms in breast cancer patients. RESULTS: Eight subjects (40%) had past childhood trauma (CTQ+). Compared to CTQ- patients, CTQ+ patients had significantly higher fatigue, depression, and stress scores before, during, and after RT (p < 0.05); however, RT did not increase these symptoms in either group. CTQ+ patients also exhibited increased baseline expression of gene transcripts related to inflammatory signaling, and baseline inflammatory markers including c-reactive protein, interleukin (IL)-6, and IL-1 receptor antagonist were positively correlated with depression, fatigue, and stress scores in CTQ+ but not CTQ- patients. CONCLUSIONS: Childhood trauma was prevalent and was associated with increased symptoms of fatigue, depression, and stress irrespective of RT. Increased symptoms in CTQ+ patients were also associated with baseline inflammatory markers. Treatments targeting childhood trauma and related inflammation may improve symptoms in breast cancer patients.

The 21-gene recurrence score and locoregional recurrence in breast cancer patients.

PURPOSE: Although the 21-gene recurrence score (RS) assay has been validated to assess the risk of distant recurrence in hormone receptor-positive breast cancer patients, the relationship between RS and the risk of locoregional recurrence (LRR) remains unclear. The purpose of this study was to determine if RS is associated with LRR in breast cancer patients and whether this relationship varies based on the type of local treatment [mastectomy or breast-conserving therapy (BCT)]. METHODS: 163 consecutive estrogen receptor-positive breast cancer patients at our institution had an RS generated from the primary breast tumor between August 2006 and October 2009. Patients were treated with lumpectomy and radiation (BCT) (n = 110) or mastectomy alone (n = 53). Patients were stratified using a pre-determined RS of 25 and then grouped according to local therapy type. RESULTS: Median follow-up was 68.2 months. Patients who developed an LRR had stage I or IIA disease, >2 mm surgical margins, and received chemotherapy as directed by RS. While an RS > 25 did not predict for a higher rate of LRR, an RS > 24 was associated with LRR in our subjects. Among mastectomy patients, the 5-year LRR rate was 27.3 % in patients with an RS > 24 versus 10.7 % (p = 0.04) in those whose RS was ≤ 24. RS was not associated with LRR in patients who received BCT. CONCLUSIONS: Breast cancer patients treated with mastectomy for tumors that have an RS > 24 are at high risk of LRR and may benefit from post-mastectomy radiation.

Local recurrence patterns in breast cancer patients treated with oncoplastic reduction mammaplasty and radiotherapy.

BACKGROUND: The purpose of this study was to describe the incidence and location of ipsilateral breast tumor recurrence (IBTR) among breast cancer patients treated with oncoplastic reduction mammoplasty (ORM) and radiotherapy (RT). METHODS: The medical records of 86 consecutive women with ductal carcinoma in situ (DCIS) (n = 11) or invasive carcinoma of the breast (n = 75) treated with ORM at Emory University between January 1994 and December 2010 were reviewed. RESULTS: Following ORM, prolonged wound healing or surgical complications led to delay of adjuvant chemotherapy or RT in 11 patients. Surgical clips were found outside the primary tumor breast quadrant in 43 % of the patients with available RT planning CT images. When the clips were found outside the primary tumor quadrant, the RT boost was more frequently delivered outside versus inside the primary tumor quadrant (67 vs. 33 %, p < 0.001). After a median follow-up period of 4.5 years (range 0.1-17.9), 6 patients developed an IBTR and only 1 IBTR occurred outside the primary tumor quadrant. The 5-year ipsilateral breast tumor control rates were 91 % (95 % CI 0.82-0.99) and 93 % (95 % CI 0.90-0.97) for patients with DCIS and invasive carcinoma, respectively. CONCLUSIONS: The use of ORM yields acceptable rates of IBTR. ORM may displace breast tissue and surgical clips to breast quadrants outside of the original tumor location, but the majority of IBTRs still occur in the original tumor quadrant. This area remains at highest risk of in-breast recurrence in women treated with ORM irrespective of surgical clip location.

Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy.

Inflammation has been associated with fatigue during and after various types of breast cancer treatments. We examined whether prior chemotherapy was associated with DNA methylation patterns that could explain persisting inflammation and/or fatigue in women treated for breast cancer. Prior to breast radiation therapy, DNA was extracted from peripheral blood mononuclear cells (PBMCs) of 61 Stage 0-IIIA breast cancer patients who had received partial mastectomy with or without chemotherapy. DNA methylation was assessed at >485,000 CpG sites across the genome along with fatigue and plasma inflammatory markers previously associated with fatigue. Compared to non-chemotherapy-treated, women who had received chemotherapy exhibited significantly decreased methylation at eight CpG sites (p<1.03×10(-7)) including four in exon 11 of transmembrane protein 49 (TMEM49), which demonstrated the largest decreases in methylation. Lower methylation at each identified CpG site was associated with increased plasma soluble tumor necrosis factor receptor 2 (sTNFR2) and interleukin (IL)-6 and mediated the relationship between chemotherapy and increases in these inflammatory biomarkers adjusting for multiple clinical and treatment characteristics. sTNFR2, but not CpG methylation status, was correlated with fatigue. Six months after breast radiation therapy, DNA methylation, inflammatory biomarkers and fatigue assessments were repeated in a subset of subjects (N=39). Reduced methylation in 4 of the 8 identified CpG sites was still observed in chemotherapy versus non-chemotherapy-treated patients, albeit with some decay indicating the dynamic and potentially reversible nature of the changes. Reduced methylation in these 4 CpG sites also continued to correlate with either increased sTNFR2 or IL-6, but not fatigue. In conclusion, prior chemotherapy treatment was associated with decreased methylation of CpG sites in DNA from PBMCs of breast cancer patients, which correlated with increased inflammatory markers prior to and 6months after radiation therapy. Persisting epigenetic changes secondary to chemotherapy may be one factor that contributes to inflammation and its consequences including cancer-related fatigue in vulnerable breast cancer patients.

Predictors of depression in breast cancer patients treated with radiation: role of prior chemotherapy and nuclear factor kappa B.

BACKGROUND: Depression is common during and after breast cancer treatment. However, the role of specific therapeutic modalities and related biologic mechanisms remains unclear. Radiation is an essential component of breast-conserving therapy and may contribute to depression in patients with breast cancer through the activation of inflammatory pathways. METHODS: Depressive symptoms and inflammatory mediators, including nuclear factor kappa B (NF-κB), were assessed at baseline (before radiation), during radiation, and 6 weeks after radiation in 64 women who had stage 0 through IIIA breast cancer. RESULTS: No significant increases in depressive symptoms occurred during or after radiation, although a number of patients exhibited moderate-to-severe depression throughout the study. Multivariate analyses of baseline factors predictive of depression revealed that educational status, perceived stress, prior chemotherapy, and peripheral blood NF-κB DNA binding all were independent predictors of persistent depressive symptoms after radiation (all P < .05). Of these factors, only prior chemotherapy was associated with inflammatory mediators, including NF-κB DNA binding, soluble tumor necrosis factor-alpha receptor 2, and interleukin-6, which, in univariate analyses predicted depressive symptoms after radiation (all P < .05). Chemotherapy-treated patients also exhibited an over-representation of gene transcripts regulated by NF-κB. CONCLUSIONS: Radiation was not associated with increased depressive symptoms in the current study, but of disease and treatment-related factors, prior chemotherapy predicted significant depression after radiation. Longitudinal studies are warranted to investigate the relationship among prior chemotherapy, inflammation, and persistent depression after breast cancer treatment.

CDK9 Expression Shows Role as a Potential Prognostic Biomarker in Breast Cancer Patients Who Fail to Achieve Pathologic Complete Response after Neoadjuvant Chemotherapy.

Failure to achieve pathologic complete response is associated with poor prognosis in breast cancer patients following neoadjuvant chemotherapy (NACT). However, prognostic biomarkers for clinical outcome are unclear in this patient population. Cyclin-dependent kinase 9 (CDK9) is often dysregulated in breast cancer, and its deficiency results in genomic instability. We reviewed the records of 84 breast cancer patients from Emory University's Winship Cancer Institute who had undergone surgical resection after NACT and had tissue available for tissue microarray analysis (TMA). Data recorded included disease presentation, treatment, pathologic response, overall survival (OS), locoregional recurrence free survival (LRRFS), distant-failure free survival (DFFS), recurrence-free survival (RFS), and event-free survival (EFS). Immunohistochemistry was performed on patient samples to determine CDK9 expression levels after NACT. Protein expression was linked with clinical data to determine significance. In a Cox proportional hazards model, using a time-dependent covariate to evaluate the risk of death between groups beyond 3 years, high CDK9 expression was significantly associated with an increase in OS (HR: 0.26, 95% CI: 0.07-0.98, p=0.046). However, Kaplan-Meier curves for OS, LRRFS, DFFS, RFS, and EFS did not reach statistical significance. The results of this study indicate that CDK9 may have a potential role as a prognostic biomarker in patients with breast cancer following NACT. However, further validation studies with increased sample sizes are needed to help elucidate the prognostic role for CDK9 in the management of these patients.

A prospective study of quality of life in breast cancer patients undergoing radiation therapy.

PURPOSE/OBJECTIVE: The purpose of this study was to examine the impact of radiotherapy on quality of life (QOL) of breast cancer patients during and until 1 year post radiotherapy treatment. METHODS AND MATERIALS: Thirty-nine breast cancer patients treated with breast conserving surgery were enrolled in a prospective study prior to whole breast radiotherapy (50 Gy plus a 10 Gy boost). No patient received chemotherapy. Data were collected before, at week 6 of radiotherapy, 6 weeks, and 1 year post-radiotherapy. The primary outcome variable was quality of life (QOL), measured by Medical Outcomes Study 36-Item Short Form Version 2 (SF-36) (SF-36). Risk factors potentially associated with total SF-36 scores and its physical and mental health component summary scores were also examined including age, race, marital status, smoking history, menopausal status, endocrine treatment, cancer stage, sleep abnormalities (assessed by the Pittsburgh Sleep Quality Index) and perceived stress levels (assessed by Perceived Stress Scale). Mixed effect modeling was utilized to observe QOL changes during and after radiotherapy. RESULTS: Total SF-36 scores did not change significantly during and up to 1 year after radiotherapy compared to baseline measures. Nevertheless, increased BMI and increased perceived stress were predictive of reduced total SF-36 scores over time (p=0.0064, and p<0.0001, respectively). In addition, increased BMI was predictive of reduced physical component summary scores of the SF-36 (p=0.0011), while increased perceived stress was predictive of worse mental component summary scores (p<0.0001). Other proposed potential risk factors including skin toxicity from radiotherapy were not significant. CONCLUSIONS: Radiotherapy did not worsen QOL in breast cancer patients. However, pre-radiotherapy patient characteristics including BMI and perceived stress may be used to identify women who may experience decreased physical and mental function during and up to 1 year post-radiotherapy.

The Impact of Axillary Lymph Node Surgery on Breast Skin Thickening During and After Radiation Therapy for Breast Cancer.

PURPOSE: This prospective study was conducted to determine predictors of epidermal thickening during and after whole-breast radiation therapy (XRT) using objective measurements acquired with ultrasound. METHODS AND MATERIALS: After breast-conserving surgery, 70 women received a definitive course of whole-breast XRT (50 Gy plus boost). Prior to XRT, at week 6 of XRT, and 6 weeks after XRT, patients underwent objective ultrasound measurements of epidermal thickness over the lumpectomy cavity and all 4 quadrants of the treated breast. A skin thickness ratio (STRA) was then generated normalizing for corresponding measurements taken of the untreated breast. RESULTS: Baseline measurements indicated that 87% of patients had skin thickening in the treated versus untreated breast (mean increase, 27%; SD, 0.29) prior to XRT. The STRA increased significantly by week 6 of XRT (mean, 25%; SD, 0.46) and continued to increase significantly 6 weeks after XRT (mean, 33%; SD, 0.46) above baseline measurements (P<.001 for both time points). On multivariate analysis, breast volume (P=.003) and surgical evaluation of the axilla with full lymph node dissection (P<.05) predicted for more severe changes in the STRA 6 weeks after XRT compared with baseline. STRA measurements correlated with physician ratings of skin toxicity according to Radiation Therapy Oncology Group grading criteria. CONCLUSIONS: This is one of the first studies to objectively document that lymph node surgery affects XRT-induced skin thickening in patients with breast cancer. Surgical evaluation of the axilla with complete lymph node dissection was associated with the most severe XRT-induced skin changes after XRT completion. These results may inform future studies aimed at minimizing side effects of XRT and surgery, particularly when surgical lymph node assessments may not alter breast cancer management or outcome.

Locoregional and Distant Recurrence Patterns in Young versus Elderly Women Treated for Breast Cancer.

Objective. This study examined recurrence patterns in breast cancer patients younger than age of 40 and older than age of 75, two groups that are underrepresented in clinical trials and not routinely screened by mammography. Methods. The records of 230 breast cancer patients (n = 125 less than 40 and n = 105 greater than 75) who presented to the Emory University Department of Radiation Oncology for curative treatment between 1997 and 2010 were reviewed. Data recorded included disease presentation, treatment, and areas of locoregional recurrence. Results. Women less than 40 years of age had higher rates of locoregional recurrence (20% versus 7%, P = 0.004) and distant recurrence (18% versus 5%, P = 0.003) than patients above 75 years of age. On multivariate analysis, patient age less than 40 was the only significant predictor of locoregional recurrence (P = 0.018). In a univariate analysis of each age group, receptor status and postlumpectomy radiation were significant predictors of locoregional recurrence-free survival in younger women while mammography screening predicted for distant recurrence-free survival in older patients. Conclusion. The factors identified in our age-stratified analysis highlight patients who are at high risk of locoregional and distant recurrence. Future studies aimed at enhancing therapies in young patients are warranted.

Locoregional Recurrence Risk in Breast Cancer Patients with Estrogen Receptor Positive Tumors and Residual Nodal Disease following Neoadjuvant Chemotherapy and Mastectomy without Radiation Therapy.

Among breast cancer patients treated with neoadjuvant chemotherapy (NAC) and mastectomy, locoregional recurrence (LRR) rates are unclear in women with ER+ tumors treated with adjuvant endocrine therapy without postmastectomy radiation (PMRT). To determine if PMRT is needed in these patients, we compared LRR rates of patients with ER+ tumors (treated with adjuvant endocrine therapy) with women who have non-ER+ tumors. 85 consecutive breast cancer patients (87 breast tumors) treated with NAC and mastectomy without PMRT were reviewed. Patients were divided by residual nodal disease (ypN) status (ypN+ versus ypN0) and then stratified by receptor subtype. Among ypN+ patients (n = 35), five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 5%, 33%, and 37%, respectively (p = 0.02). Among ypN+/ER+ patients, lymphovascular invasion and grade three disease increased the five-year LRR risk to 13% and 11%, respectively. Among ypN0 patients (n = 52), five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 7%, 22%, and 6%, respectively (p = 0.71). In women with ER+ tumors and residual nodal disease, endocrine therapy may be sufficient adjuvant treatment, except in patients with lymphovascular invasion or grade three tumors where PMRT may still be indicated.

Radiation field design and patterns of locoregional recurrence following definitive radiotherapy for breast cancer.

PURPOSE: Locoregional control is associated with breast cancer-specific and overall survival in select women with breast cancer. Although several patient, tumor, and treatment characteristics have been shown to contribute to locoregional recurrence (LRR), studies evaluating factors related to radiotherapy (XRT) technique have been limited. We investigated the relationship between LRR location and XRT fields and dose delivered to the primary breast cancer in women experiencing subsequent locoregional relapse. METHODS AND MATERIALS: We identified 21 women who were previously treated definitively with surgery and XRT for breast cancer. All patients developed biopsy-result proven LRR and presented to Emory University Hospital between 2004 and 2010 for treatment. Computed tomography (CT) simulation scans with XRT dose files for the initial breast cancer were fused with (18)F-labeled fluorodeoxyglucose positron emission tomography (FDG PET)/CT images in DICOM (Digital Imaging and Communications in Medicine) format identifying the LRR. Each LRR was categorized as in-field, defined as ≥95% of the LRR volume receiving ≥95% of the prescribed whole-breast dose; marginal, defined as LRR at the field edge and/or not receiving ≥95% of the prescribed dose to ≥95% of the volume; or out-of-field, that is, LRR intentionally not treated with the original XRT plan. RESULTS: Of the 24 identified LRRs (3 patients experienced two LRRs), 3 were in-field, 9 were marginal, and 12 were out-of-field. Two of the 3 in-field LRRs were marginal misses of the additional boost XRT dose. Out-of-field LRRs consisted of six supraclavicular and six internal mammary nodal recurrences. CONCLUSIONS: Most LRRs in our study occurred in areas not fully covered by the prescribed XRT dose or were purposely excluded from the original XRT fields. Our data suggest that XRT technique, field design, and dose play a critical role in preventing LRR in women with breast cancer.

Neoadjuvant Hormonal Therapy is Associated with Comparable Outcomes to Neoadjuvant Chemotherapy in Post-Menopausal Women with Estrogen Receptor-Positive Breast Cancer.

OBJECTIVES: We compared outcomes in post-menopausal estrogen receptor-positive (ER+) breast cancer patients treated with neoadjuvant hormonal therapy (NAHT) or neoadjuvant chemotherapy (NACT). METHODS: We retrospectively identified post-menopausal women who received either NAHT or NACT for non-metastatic, non-inflammatory, ER+, Her2neu negative breast cancer from 2004 to 2011. We compared long-term rates of locoregional relapse free survival (LRFS), distant metastasis free survival (DMFS), and overall survival (OS) using the Kaplan-Meier method. The Cox proportional hazards model was used to identify patient and disease factors significantly associated with these endpoints. RESULTS: We identified 99 patients in our study, including 27 who received NAHT and 72 who received NACT. There were no differences in 4-year LRFS, DMFS, or OS between groups. On Cox proportional hazards modeling, the type of systemic therapy (NAHT versus NACT) was not associated with OS. However, patients with progesterone receptor (PR) positive disease had a 92% lower risk of death compared to patients with PR negative disease. CONCLUSION: Our data suggest that outcomes are not adversely affected by NAHT in post-menopausal women with ER+ breast cancer. Therefore, NAHT is a viable and potentially less toxic option than NACT in appropriately selected patients. Furthermore, although PR negative disease appears to be associated with poor prognosis, intensification of systemic treatment with chemotherapy may not be associated with improvement of disease-related outcomes in this patient population.