Risk Breast Cancer Patients Research Articles

Factors associated with low chemotherapy dosing in high risk breast cancer.

e15520 Background: Chemotherapy dose is often reduced or delayed due to adverse effects. However, a low relative dose intensity (RDI) is associated with reduced disease control and survival. There is little data among patients receiving modern breast cancer regimens regarding the risk of low RDI, or factors associated with it. Methods: We used an institutional registry at a large multidisciplinary cancer center to identify subjects with incident invasive, non-metastatic breast cancer diagnosed between 2009-2018. We focused on a subset of high-risk patients for whom chemotherapy is clearly recommended by guidelines: triple negative (estrogen receptor, progesterone receptor and HER2 negative) or HER2-positive subtypes, and either positive lymph node metastases or tumor size > 1.0 cm. We obtained administration dates and doses for the following agents: doxorubicin, cyclophosphamide, paclitaxel, docetaxel, and carboplatin. Our primary outcome was RDI < 85% of guideline-recommended doses of at least one of these agents. Other outcomes included dose of each agent (first cycle dose < 85% or total dose < 85) and timing (delay ≥7 days or early discontinuation). Variables used for analyses included BMI ≥25, race, HER2 status, age ≥55 years, marital status, stage, and Charlson co-morbidity score. Results: More than half of our cohort of high risk breast cancer patients experienced a low RDI of at least one chemotherapy agent. Out of the 237 patients who met our inclusion criteria, 60% had a low RDI, 10% received a low first cycle dose, 38% received a low total dose, and 46% experienced either a dose delay or discontinued treatment. Using logistic regression analyses, we found that being overweight (CI: 1.01-3.54; p = 0.046) and stage 3 breast cancer (CI:1.05-5.96; p = 0.038) were associated with increased odds of having a low RDI. Low total dose was associated with being overweight (p = 0.0181), unmarried (p = 0.0278), and stage 3 (p = 0.0201). HER2-positive status was also associated with a low first cycle dose (p = 0.001) and dose delays or discontinuation (p = 0.0002). Conclusions: Having a BMI ≥25, higher-stage, or being unmarried, which may serve as a proxy for low social support, are factors that may help identify patients who will have guideline-recommended chemotherapy doses reduced.

Assessment of death risk of breast cancer patients with joint frailty models.

Objectives:To investigate the effects of risk factors on recurrence and death in breast cancer patients, taking into account the dependence between recurrence and death as well as the heterogeneity among individuals. The other aim of this study was to make predictions of death risks with a dynamic model that includes patient’s history and different horizons.Methods:The data of 465 patients who had undergone surgery at the Istanbul University Oncology Institute, Istanbul, Turkey, between 2009 and 2016 were used. For data analysis in this retrospective study, the authors applied the joint frailty model, and the predictions were obtained using dynamic prediction methods that consider the patient’s history. The Brier score was used to evaluate the accuracy of the estimations.Results:A positive relationship was found between recurrence and death, and heterogeneity was found among patients (p<0.001, p=1.008, p=2.945). The effects of Cerb-B2, tumor type, remaining lymph nodes, neoadjuvant chemotherapy, and surgery type were statistically significant for death and recurrence (p<0.05, relative risk [death, recurrence] = [2.5, 11.86], [2.065, 2.798], [1.852, 3.113], [4.211, 9.366], [1.521,1.991]). The Brier score values used in the evaluation of the predictions obtained by the dynamic prediction methods were found to be below 0.30.Conclusion:The use of joint frailty models is recommended for the detection of heterogeneity effects and dependence between recurrence and death. Through models in survival analysis, researchers can obtain more accurate parameter estimates. A significant variance of frailty indicates different death risks for the same characteristics.

Investigating the Link between Lynch Syndrome and Breast Cancer.

Lynch syndrome is an inherited genetic disorder associated with a predisposition to early-onset colorectal and endometrial cancers, but breast cancer risk in these patients is debated. The aim of this study is to evaluate breast cancer rates in a cohort of Lynch syndrome patients, as well as to identify women who may be eligible for additional breast cancer specific genetic testing or enhanced breast surveillance (contrast-enhanced magnetic resonance imaging (MRI) screening). Using a hereditary colorectal cancer registry at a single academic institution for identification of patients with Lynch syndrome, a retrospective chart review was performed of 188 women with DNA mismatch repair (MMR) mutations. The Tyrer-Cuzick model was used to estimate breast cancer risk in patients without breast cancer. The prevalence of breast cancer differed based on mutation type (p=0.0043), as 27% of women with a PMS2 mutation were diagnosed with breast cancer, compared to 3%, 4%, and 9% in MLH1, MSH2, and MSH6 patients. The average age at diagnosis for women with a PMS2 mutation was 46.7 years. Additionally, 7.5% of unaffected women had an estimated lifetime risk of breast cancer greater than 20%. 46/188 (24.4%) of patients were eligible for breast specific genetic testing. Our analysis suggests that Lynch syndrome patients with PMS2 mutations may be at higher risk of developing breast cancer. Additionally, the personal and family history of cancer suggests crossover in eligibility for breast specific genetic testing in a significant number of patients (16.5-24.4%). Also, many women are eligible for enhanced breast surveillance (7.5%) which would otherwise not be offered.

Developing a Survivorship Care Transition Model for Rural and Underserved Low Risk Breast and Gynecologic Cancer Patients

Developing a Survivorship Care Transition Model for Rural and Underserved Low Risk Breast and Gynecologic Cancer Patients

Abstract P2-09-06: Genetic counseling and genetic testing for germline BRCA1/2 mutations among high risk breast cancer patients in Jordan: A study of 500 patients

Abstract Introduction: Breast Cancer is the most common cancer worldwide and so in our region. In Jordan, almost 50% of patients are diagnosed before the age of 50. Knowledge of BRCA1/2 mutations has significant clinical impact on the management and prevention of breast cancer. In this study, we evaluate the prevalence of germline mutations in BRCA1/2 among high-risk Jordanian patients selected as per the updated NCCN guidelines. Methods: Jordanian breast cancer patients, stages I-IV, with a selected high-risk profile treated at our institution were invited to participate. Blood samples were obtained for DNA extraction, and BRCA sequencing and dosage analysis were performed at Leeds Cancer Center, Leeds-United Kingdom. BRCA1/2 mutations were classified as pathogenic/likely pathogenic and variant of uncertain significance (VUS). Clinical and pathological data were obtained from patients' medical records and a detailed 3-generation family history was also obtained by a genetic counselor. Results: A total of 517 patients were enrolled, genetic testing and counseling have been completed for all. Median age at diagnosis was 39 (range: 20-78) years. Among the whole group, 72 (13.9%) patients had pathogenic or likely pathogenic BRCA1 (n=24, 4.6%) or BRCA2 (n=48, 9.3%) mutations, while 53 (10.3%) others had VUS. Among 333 younger (≤40 years) patients, pathogenic/likely pathogenic mutations were observed in 44 (13.2%) patients and 36 (10.8%) others had VUS. Among 242 patients who had one or more close relatives with breast cancer, diagnosed at age 50 years or younger, 40 (16.5%) had pathogenic/likely pathogenic mutations (Table). Twenty (35.1%) of the 57 patients with triple-negative (TN) disease had pathogenic/likely pathogenic mutations; 16 (28.1%) were in BRCA1. Rate was significantly higher (55.6%, p &amp;lt;0.0001) among those with two family members with breast cancer at any age (n=9). However, compared to older patients, mutation rates were not higher among 37 TN-patients who were 40 years or younger. Conclusions: BRCA1/2 mutations are not uncommon and may contribute to the pathogenesis of familial breast cancer among Jordanians. Young age, per se, has the weakest association with positive BRCA1/2 mutations while TN-disease, especially when associated with positive family history, has significantly higher mutation rate. The establishment of Clinical Cancer Genetics program made running such culturally-sensitive genetic testing and counseling more acceptable even in societies like ours. Table: Rates of positive BRCA1/2 mutation across different indications for testingVariableTotalPositive BRCA mutations*BRCA1BRCA2BRCA1/2P-ValueAge (years)≤4033315 (4.5%)29 (8.7%)44 (13.2%)0.53&amp;gt;401849 (4.9%)19 (10.3%)28 (15.2%)Age ≤ 50 years with one or more close relative with breast cancer at any ageYes2428 (3.3%)32 (13.2%)40 (16.5%)0.1No27516 (5.8%)16 (5.8%)32 (11.6%)Age ≤ 60 with triple negative diseaseYes5716 (28.1%)4 (7.0%)19 (35.1%)&amp;lt;0.001No4628 (1.7%)44 (9.6%)53 (11.3%)Any age with at least 2 breast cancer primariesYes574 (7.0%)4 (7.0%)8 (14.0%)0.98No46020 (4.3%)44 (9.6%)64 (13.9%)Any age with 2 or more close relatives with breast cancerYes1157 (6.1%)21 (18.3%)28 (24.3%)&amp;lt;0.001No40217 (4.2%)27 (6.7%)44 (10.9%)Any age with one or more close relatives with invasive ovarian cancer diagnosed at any ageYes192 (10.5%)4 (21.1%)6 (31.6%)0.023No49822 (4.4%)44 (8.8%)66 (13.3%)All Patients51724 (4.6%)48 (9.3%)72 (13.9%)*Positive mutations: Pathogenic/Likely Pathogenic Citation Format: Hikmat Abdel-Razeq, Lama Abujamous, Amal Al-Omari, Abdelghani Tbakhi, Dima Jadaan. Genetic counseling and genetic testing for germline BRCA1/2 mutations among high risk breast cancer patients in Jordan: A study of 500 patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-06.

Bleeding risk in breast cancer patients during concomitant administration of warfarin and tamoxifen: A population-based nested case-control study.

We aimed to investigate whether the concomitant use of tamoxifen with warfarin is associated with higher risk for bleeding among patients with early estrogen-receptor (ER)-positive breast in a population-based nested case-control study. We identified 1787 patients taking warfarin and 92 cases hospitalized for bleeding and found an adjusted odds ratio (OR) of 1.42 (95% confidence interval (CI): 0.84-2.40) for the risk of bleeding in patients treated with warfarin that initiated tamoxifen within the previous 30days. As a result, we could not definitively rule out a potential association between tamoxifen use during warfarin and bleeding risk in patients with breast cancer.

Identification of key molecular targets that correlate with breast cancer through bioinformatic methods.

The present study aimed to identify key molecular targets of breast cancer for targeted treatment and to improve the survival rate. Overlapped difference expression genes in three datasets were identified in a weighted gene co-expression network analysis (WGCNA) module and MetaDE.ES analysis. Combined with the prognosis information [time, death, status and relative survival (RS)] in GSE42568, single-factor Cox regression analysis was used to screen the genes that were significantly related to the prognosis in the target gene set. In total, 13 optimal gene combinations with a significantly correlated prognosis were obtained, including SSPN, NELL2, AGTR1, NRIP3, IKZF2, NAT1, CXCL12, NPY1R, PRAME, PPP1R1B, CRISP3, NMU and GSTP1. In addition, there was a significant correlation between the samples given by the prognostic prediction system and the validation dataset (GSE20685 and TCGA), with p values of 0.0299 in GSE20685 and 1.461 × 10-5 in TCGA, and an area under the receiver operating characteristic of 0.942 and 0.923, respectively. RS-related differentially expressed genes between high- and low-risk groups were significantly related to biological processes such as cell period and the hormone stimulation response, and were also significantly involved in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways such as cell period, the peroxisome proliferator-activated receptor signaling pathway and the cancer pathway. By predicting the survival risk of breast cancer patients based on the 13 optimal genes, high-risk patients would be detected early. Accordingly, this would help in the formulation of an appropriate treatment plan for patients.

AR pathway activity correlates with AR expression in a HER2-dependent manner and serves as a better prognostic factor in breast cancer.

Androgen receptor (AR) antagonists are currently tested in multiple clinical trials for different breast cancer (BC) subtypes, which emphasizes the need for clarifying the role of AR in this type of cancer. Previous studies showed that AR expression was associated with a favorable prognosis in ER-positive BC. However, the true biological effect of AR signaling in BC is not clear. An AR pathway signature was generated to compute AR pathway activity in BCs (n=6439) from 46 microarray datasets. Associations of AR pathway activity and AR expression with BC prognosis were compared by survival analysis. AR pathway activity showed moderate positive and negative correlations with AR expression in HER2-positive and HER2-negative BCs, respectively. AR pathway activity increased while AR expression decreased in ER-negative BCs. Like ER and progesterone receptor (PR) expression, AR expression was also negatively associated with tumor grade, neoadjuvant response, and recurrence risk in BC. By contrast, AR pathway activity was positively, and more significantly, associated with these clinical features. Moreover, the AR pathway, but not AR expression, was significantly associated with recurrence risk in BC patients treated with endocrine therapy. These data suggest that, although AR expression probably reflects well-differentiated states of BC and is thus associated with favorable prognosis in BC, the biological effects of AR signaling confers worse outcomes in BC. Our findings encourage the continued evaluation of AR antagonists for BC treatment and support that AR pathway activity serves as a better prognostic factor than AR expression in BC.

Overexpression of an Immune Checkpoint (CD155) in Breast Cancer Associated with Prognostic Significance and Exhausted Tumor-Infiltrating Lymphocytes: A Cohort Study.

Purpose The immune checkpoint inhibitor is approved for breast cancer treatment, but the low expression of PD-L1 limits the immunotherapy. CD155 is another immune checkpoint protein in cancers and interacts with ligands to regulate immune microenvironment. This study is aimed at investigating the expression of CD155 and the association with prognosis and pathological features of breast cancer. Methods 126 patients were recruited this cohort study consecutively, and CD155 expression on tumor cells was detected by immunohistochemistry. The Kaplan-Meier survival curve and Cox hazard regression model were used to estimate the association. Results 38.1% patients had an overexpression of CD155, and the proportion of tumor cells with CD155 overexpression was 17%, 39%, 37%, and 62% among Luminal A, Luminal B, HER2-positive, and triple negative breast cancer cases, respectively (p < 0.05). Patients with CD155 overexpression had the Ki-67 index significantly higher than that of patients with low expression (42% vs. 26%). Though the number of tumor-infiltrating lymphocytes was higher among patients with CD155 overexpression (144/HPF vs. 95/HPF), the number of PD-1+ lymphocytes was significantly higher (52/HPF vs. 25/HPF, p < 0.05). Patients of CD155 overexpression had the disease-free and overall survival decreased by 13 months and 9 months, respectively (p < 0.05). CD155 overexpression was associated with an increased relapse (HR = 13.93, 95% CI 2.82, 68.91) and death risk for breast cancer patients (HR = 5.47, 1.42, 20.99). Conclusions Overexpression of CD155 was correlated with more proliferative cancer cells and a dysfunctional immune microenvironment. CD155 overexpression introduced a worse relapse-free and overall survival and might be a potential immunotherapy target for breast cancer.

Long non-coding RNAE330013P06 promotes progression of breast cancer with type 2 diabetes.

BackgroundIn previous research, we found diabetes rather than obesity was an independent risk factor of breast cancer. However, why diabetes could lead to increased risk of breast cancer patients remains elusive. Long non‐coding RNAE330013P06 has been shown to be upregulated in diabetes, and long non‐coding RNAs generally promote progression of cancer.MethodsAbout 200 specimens of breast patients were obtained in previous clinical trial; 34 samples diagnosed as type 2 diabetes in breast cancer patient were enrolled in this research. Blood samples from 36 patients diagnosed as breast cancer without diabetes; 35 diabetic patients and 35 healthy peoples were obtained as control. All blood samples were measured by quantitative real‐time PCR (qRT‐PCR). Invasion and migration were tested by Transwell assay. Cell proliferation assay was tested by CCK‐8. Protein analysis was determined by Western blot.ResultsCompared with breast cancer patients without diabetes, diabetic patients without breast cancer and healthy peoples, LncRNAE330013P06 was upregulated in breast cancer patient with diabetes. Furthermore, of 34 breast patients, high LncRNAE330013P06 expression was significantly associated with family history, tumor‐node‐metastasis stage and lymph node metastasis. E33 promoted cancer cell growth in vitro via downregulation of P53.ConclusionUpregulation of LncRNAE330013P06 driven by type 2 diabetes is one of the factors which promoted progression of breast cancer.

Intraoperative ketorolac in high-risk breast cancer patients. A prospective, randomized, placebo-controlled clinical trial.

BackgroundKetorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.MethodsThe KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.FindingsBetween February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years.At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65–2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34–3.51).ConclusionsA single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.Trial registrationClinicalTrials.gov NCT01806259.

Increased Fracture Risk in Women Treated With Aromatase Inhibitors Versus Tamoxifen: Beneficial Effect of Bisphosphonates.

Aromatase inhibitors have been associated with accelerated bone loss and an increased risk of osteoporotic fractures. Currently, bisphosphonates are recommended to reduce fracture risk in these patients. The aim of this study is to evaluate the fracture risk in breast cancer patients receiving aromatase inhibitors, compared to tamoxifen users, and to assess the effectiveness of oral bisphosphonates in reducing fracture risk. We performed an observational cohort study up to 10 years of follow-up. Data were extracted from primary care records in a population database. Women diagnosed with breast cancer between 2006 and 2015 and treated with tamoxifen or aromatase inhibitors (n = 36,472) were stratified according to low (without osteoporosis diagnosis nor bisphosphonates exposure) or high (with osteoporosis and/or treated with bisphosphonates) fracture risk. Cox models were used to calculate hazard ratios (HR [95% CI]) of fracture from the propensity score-matched patients. Sensitivity analyses account for competing risk of death were performed (subdistribution hazard ratio [SHR] [95% CI]). In postmenopausal women, fracture risk in aromatase inhibitor users showed an HR 1.40 [95% CI,1.05 to 1.87] and SHR 1.48 [95% CI, 1.11 to 1.98], compared to tamoxifen. Observing aromatase inhibitors patients at high risk of fracture, bisphosphonate-treated patients had an HR 0.73 [95% CI, 0.51 to 1.04] and SHR 0.69 [95% CI, 0.48 to 0.98] compared to nontreated. In conclusion, fracture risk in postmenopausal women during aromatase inhibitor treatment, in real-life conditions, was >40% compared to tamoxifen, corroborating previous randomized controlled trials results. In high-risk patients, bisphosphonate users had lower significant fracture incidence during aromatase inhibitor therapy than nonbisphosphonate users. Monitoring fracture risk and related risk factors in aromatase inhibitor patients is advisable. © 2019 American Society for Bone and Mineral Research.

1816P - Prophylaxis with lipegfilgrastim in patients with primary breast cancer receiving dose dense chemotherapy: Results from the German NIS NADENS

BackgroundOnly limited data are available on the impact of primary prophylactic use of G-CSF in high risk breast cancer (BC) patients (pts) treated with dose dense (dd) chemotherapy (CTx) protocols in standard clinical practice. Lipegfilgrastim (LF) is a glyco-pegylated long-acting G-CSF indicated to reduce the duration of neutropenia and the incidence of febrile neutropenia (FN). MethodsNADENS was a multi-center, prospective, non-interventional study (NIS) in Germany on the primary prophylactic LF administration for BC pts treated with dd two-weekly CTx. 328 pts were enrolled at 68 sites (27 hospitals with 143 pts, 41 private practices with 185 pts, Safety Set (SAF)). Due to protocol violations 46 pts were excluded from analysis set (282 pts). ResultsSevere neutropenia (SN, grade 3/4) occurred in 131 pts (46.5%) at least once during max. 4 observed cycles. Incidences in cycles 1/2/3/4 were 33.3%/22.1%/22.9%/19.8%, respectively. 6 pts (2.1%) experienced a FN, (incidence per cycle 1.1%/0.4%/1.4%/0.4%). Altogether 275 SN and 9 FN events were documented for the 1,121 observed CTx cycles. CTx had to be modified in 74 pts (26.2%). 96 pts (34.0%) received anti-infectives. 35 pts were hospitalized (12.4%) with 51 single hospitalizations. Reasons included FN (4 events), other neutropenic complications (5) and infections (7). No stay on ICU was reported. AEs were observed for 119 pts (36.3% of SAF, 342 events) and SAEs for 23 pts (7.0%, 30 events). No AE was fatal, 12 AEs (3.6%) were rated as grade 4. 89 AEs (in 61 pts) were classified as probable or possible drug related. For 280 pts (99.3%) treatment with LF was rated as ‘beneficial’ by the treating physician. Tolerability of LF treatment was assessed mostly as ’very good’ (152 pts, 53.9%) or ’good’ (120 pts, 42.6%), ’moderate’ was documented for 8 pts (2.8%), ’bad’ for 2 pts (0.7%). ConclusionsNADENS provides a realistic picture about the use and efficacy of LF for this defined patient group in daily clinical care in Germany. LF was found to be effective and safe and results fall in the range of those observed in RCTs. No new safety signal was detected. The known limitations of non-interventional studies have to be considered. Clinical trial identificationXM22-ONC-40115 (BfArM NIS No 7038). Legal entity responsible for the studyTeva GmbH, Ulm, Germany. FundingTeva GmbH, Ulm, Germany. DisclosureM. Kiechle: Advisory / Consultancy: Teva GmbH. C. Schem: Advisory / Consultancy, Speaker Bureau / Expert testimony: Teva GmbH. D. Lüftner: Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Teva GmbH; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Amgen; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: AstraZeneca; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Celgene; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Lilly; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Loreal; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: MSD; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Mundipharma; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Mylan; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Novartis; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Pfizer; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Roche; Non-remunerated activity/ies, Honoraria for Advisory Board activities and/or oral presentations: Tesaro. X. Hamann: Full / Part-time employment: Teva GmbH. R. Jünemann: Full / Part-time employment: Teva GmbH. M. Tölg: Honoraria (institution), CRO for reported study: Teva GmbH. U. Köhler: Advisory / Consultancy: Teva GmbH.

Quantifying the Impact of Regional Lymph Node Irradiation on Lymphedema Risk in Breast Cancer Patients Treated with SLNB or ALND: Long-Term Results from a Prospective Screening Trial

Quantifying the Impact of Regional Lymph Node Irradiation on Lymphedema Risk in Breast Cancer Patients Treated with SLNB or ALND: Long-Term Results from a Prospective Screening Trial

The Impact of Post-Mastectomy Chest-Wall Radiation on Overall Survival for Intermediate-Risk Breast Cancer Patients: A National Cancer Data Base Analysis

The recommendation of post-mastectomy radiation therapy (PMRT) to breast cancer women with intermediate risk disease still requires a great deal of clinical judgment without a single, validated formula. We aimed to assess the impact of PMRT on overall survival (OS) among patients with breast cancer considered intermediate risk for local recurrence by querying the National Cancer Data Base (NCDB) 2004-2014 for breast cancer. We replicated the SUPREMO phase III clinical trial by including patients (age >=18) with pT1-2N1 (or pT2N0 with either histologic Grade = 3 or presence of LVI) who underwent total mastectomy and did not receive neoadjuvant therapy. PMRT had a total radiation dose 40-70 Gy and was given within 6 months after surgery. OS was defined as months from the date of surgery. Logistic regression was applied to assess the pattern of PMRT utilization. Cox proportional hazard model was used for the association with OS. Propensity score (PS) overlap weighting was implemented to balance all observed baseline characteristics and to eliminate the selection bias. The effect of PMRT in the subgroups was estimated through the multivariable model (MVA) with interactions. We obtained 35,244 eligible subjects with a median follow up of 65.5 months. The median age was 57, 82.6% were white, 55.6% had 1 positive lymph node (PLN), 43.7% of tumors were pT1, the median tumor size was 2.2 cm, 38.4% had Grade III-IV, 96.2% had a negative surgical margin, and 68.3% received adjuvant chemotherapy. 4841 (13.7%) received PMRT while 30,403 (86.3%) received no radiation (NR). There was a clearly increasing trend of PMRT utilization over the years. In MVA by logistic regression, the factors associated with a higher probability of PMRT usage include PLN =2-3, present of LVI, pT2, and younger age. The 10-year survival rate was 72.1% (PMRT) vs. 68.7% (NR) by KM method. In MVA with OS by controlling for baseline demographic and disease characteristics, the hazard ratio (HR) for PMRT vs. NR was 0.81 (95%CI: 0.74-0.89), and it was 0.84 (95%CI: 0.74-0.95) by the PS weighting approach. In the subgroups, the HR was 0.75 (95%CI: 0.64-0.88) among patients with PLN = 3, 0.69 (95%CI: 0.59-0.81) among women not receiving adjuvant chemotherapy, 0.68 (95%CI: 0.60-0.77) among women with age > 60, and 0.72 (95%CI: 0.58-0.90) among patients whose tumors exhibited LVI. In this large retrospective study based on NCDB, on average, PMRT provided significant long-term survival benefit among intermediate risk breast cancer patients, with a larger survival benefits noted amongst patients with 3 PLN, age > 60, or the presence of LVI. More informative guidance for the utilization of PMRT may require additional information such as disease specific survival or recurrence (which is unavailable in NCDB), and we are looking forward to the results from the SUPREMO trial.

High-Resolution Bisulfite-Sequencing of Peripheral Blood DNA Methylation in Early-Onset and Familial Risk Breast Cancer Patients.

Understanding and explaining hereditary predisposition to cancer has focused on the genetic etiology of the disease. However, mutations in known genes associated with breast cancer, such as BRCA1 and BRCA2, account for less than 25% of familial cases of breast cancer. Recently, specific epigenetic modifications at BRCA1 have been shown to promote hereditary breast cancer, but the broader potential for epigenetic contribution to hereditary breast cancer is not yet well understood. We examined DNA methylation through deep bisulfite sequencing of CpG islands and known promoter or regulatory regions in peripheral blood DNA from 99 patients with familial or early-onset breast or ovarian cancer, 6 unaffected BRCA mutation carriers, and 49 unaffected controls. In 9% of patients, we observed altered methylation in the promoter regions of genes known to be involved in cancer, including hypermethylation at the tumor suppressor PTEN and hypomethylation at the proto-oncogene TEX14. These alterations occur in the form of allelic methylation that span up to hundreds of base pairs in length. Our observations suggest a broader role for DNA methylation in early-onset, familial risk breast cancer. Further studies are warranted to clarify these mechanisms and the benefits of DNA methylation screening for early risk prediction of familial cancers.

Conjugated Linoleic Acid Isomers Affect Profile of Lipid Compounds and Intensity of Their Oxidation in Heart of Rats with Chemically-Induced Mammary Tumors-Preliminary Study.

Breast cancer and cardiovascular diseases (CVD) have shared risk factors and mechanisms of pathogenicity, as proven by increased cardiac risk in breast cancer patients receiving anticancerogenic therapies and in cancer survivors. A growing mammary tumor may cause heart injury in cancer patients who have not yet been treated. This study aimed to evaluate the effect of conjugated linoleic acid (CLA) supplementation of female rats with 7,12-dimethylbenz(a)anthracene (DMBA)-induced cancerogenesis on fatty acids (FAs), conjugated FAs (CFAs), malondialdehyde (MDA), cholesterol and oxysterols content in cardiac tissue. FAs, cholesterol and oxysterols contents were determined by gas chromatography coupled with mass spectrometry, while the contents of CFAs and MDA were determined by high performance liquid chromatography with photodiode detection. Our results indicate that both CLA supplementation and the presence of tumors influence the lipid biomarkers of CVD. A significant interaction of both experimental factors was observed in the content of polyunsaturated FAs (PUFAs), n-6 PUFAs and CFAs. CLA supplementation significantly inhibited PUFA oxidation, as evidenced by the lower content of MDA in rats’ hearts, while the cancerous process intensified the oxidation of cholesterol, as confirmed by the elevated levels of 7-ketocholesterol in DMBA-treated rats. These results may significantly expand knowledge about CLA properties in terms of the prevention of co-existing non-communicable diseases.

Radiotherapy after skin-sparing mastectomy with immediate breast reconstruction in intermediate-risk breast cancer : Indication and technical considerations.

Skin-sparing (SSME) and nipple-sparing mastectomy (NSME) were developed to improve the cosmetic results for breast cancer (BC) patients, both allowing for immediate breast reconstruction. Recommendations for post-mastectomy radiotherapy (PMRT) are primarily derived from trials where patients were treated by standard mastectomies. Due to their more conservative character, SSME and especially NSME potentially leave more glandular tissue at risk for subclinical disease. Rates and sites of locoregional failures following SSME and NSME plus/minus reconstruction were analyzed regarding tumor stage and biological risk factors. In particular, the role of PMRT in "intermediate"-risk and early stage high-risk breast cancer patients was revisited. Implications on targeting and dose delivery of PMRT were critically reviewed. The value of PMRT in stageIII BC remains undisputed. For node-negative BC patients, the majority of reports classify clinical and biological features such as tumor size, close surgical margins, premenopausal status, multicentricity, lymphangiosis, triple-negativity, HER2-overexpression, and poor tumor grading as associated with higher rates of locoregional relapse, thus, building an "intermediate" risk group. Surveys revealed that the majority of radiation oncologists use risk-adaptive models also considering the number of coinciding factors for the estimation of recurrence probability following SSME and NSME. Constellations with a10-year locoregional recurrence risk of >10% are usually triggering the indication for PMRT. There was no common belief that the amount of residual tissue, e.g., tissue thickness over flaps, serves as additional decision aid. Modern treatment planning can ensure optimal dose distribution for PMRT in almost all patients with SSME. There are no reliable data supporting areduction of the treatment volume from the CTV chest wall, e.g., to the nipple-areola complex, to the dorsal aspect behind the implant volume, the pectoralis muscle, nor the regional interpectoral, axillary, or complete regional lymph nodes only. The omission of askin bolus in intermediate-risk BC does not compromise oncological safety. For intermediate-risk as well as early stage high-risk BC patients, the DEGRO Breast Cancer Expert Panel recommends the use of PMRT following SSME and NSME when a10-year locoregional recurrence risk is likely to be greater than 10%, as estimated by clinical and biological risk factors. Subvolume-only radiation is discouraged outside of trials. The impact of adequate systemic treatment and the value of radiotherapy on optimal locoregional tumor control, with the goal of less than 5% LRR at 10-years follow-up, has to be verified in prospective trials.

A genetic variant rs13293512 in the promoter of let-7 is associated with an increased risk of breast cancer in Chinese women

Growing evidence has demonstrated that single-nucleotide polymorphisms (SNPs) in the promoter of miRNA may influence individuals’ susceptibility to human diseases. We examined two SNPs rs10877887 and rs13293512 in the promoters of let-7 family to determine if the two SNPs were related to the occurrence of breast cancer (BC). Genotyping of the two SNPs was performed by PCR and restriction fragment length polymorphism analysis or TaqMan assay in 301 BC patients and 310 age matched controls. We found a higher frequency of rs13293512 CC genotype and rs13293512 C allele amongst BC patients (CC vs TT: adjusted odds ratio (OR) = 1.78; 95% CI: 1.14–2.80; P=0.012; C vs T: adjusted OR = 1.33; 95% CI: 1.06–1.67; P=0.013). Stratification analysis showed that rs13293512 CC genotype was associated with an increased risk of BC in patients with negative estrogen receptor (adjusted OR = 2.39; 95% CI: 1.32–4.30; P=0.004), patients with negative progesterone receptor (adjusted OR = 1.92; 95% CI: 1.11–3.33; P=0.02), patients with T1-2 stage cancer (adjusted OR = 1.77; 95% CI: 1.07–2.93; P=0.03), and patients with N1-3 stage cancer (adjusted OR = 1.89; 95% CI: 1.13–3.17; P=0.015). These findings suggest that rs13293512 in the promoter of let-7a-1/let-7f-1/let-7d cluster may be a possible biomarker for the development of BC in Chinese women.

Clinical significance of pathogenic variants in germline BRCA wild type patients at risk for hereditary breast cancer.

e13127 Background: Approximately, 10% of breast cancer (BC) are related to inherited germline mutations. BRCA1/2, the most recognized and tested genes, are responsible for 50% of hereditary BC. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing. Methods: NGS-based germline BRCA status assessment was performed on 209 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset ( &lt; -45), with a family history of BC, bilateral BC and male BC. Multigene-panel testing was subsequently offered to patients with at least 2 of the risk factors and WT germline BRCA. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 53 hereditary cancer-related genes, spanning 229kb of human genome. Results: Among the 209 patients screened, only 12 patients had pathogenic BRCA1/2 mutation. Next, we investigated the prevalence of non- BRCA pathogenic germline pathogenic mutations in patients with at least 2 risk factors. Thirty-seven patients met the criteria and only 23 patients had sufficient WBC DNA for sequencing. This cohort had a median age of 42, with a majority carrying infiltrating ductal carcinoma. Except for one bilateral BC patient who had stage IV disease, all other patients had early stage disease. We identified 5 pathogenic mutations from 5 patients spanning 4 genes: PALB2, PTEN, ATM and WRN, resulting in a prevalence rate of 20% for pathogenic germline mutations in high risk germline BRCA WT BC patients. Two patients carried mutations in PALB2, one with a frameshift and another with a splice mutation. Mutation types for PTEN, ATM and WRN were splice mutation, stop gain mutation and frameshift mutation, respectively. All 5 patients were diagnosed with BC before the age of 40. Three of them had bilateral BC; one had triple negative BC and another patient had a family history of BC. Conclusions: Our study confirms the clinical significance of testing non- BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC. Such approach increases the identification of hereditary BC, thus impacting clinical decision-making.