bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-reported pain and other symptoms as prognostic factors for overall survival (OS) in a phase III clinical trial of patients with advanced breast cancer.
Authors: Shen Wei , Wang Ping , Smyth Emily Nash , Bowman Lee , Peterson Patrick , John William J. , Melemed Allen S.
Published: March 2020

1068

Background: The safety and efficacy of gemcitabine plus paclitaxel versus paclitaxel in advanced breast cancer after anthracycline-based adjuvant therapy has been reported previously (Albain et al. 2008). This post-hoc analysis evaluates the prognostic effect of baseline scores of the Brief Pain Inventory short form (BPI-SF) and the Rotterdam Symptom Checklist (RSCL) on OS. Methods: Patients completed theBPI-SF and the RSCL. BPI “worst pain” item and BPI interference subscale scores range from 0 (no pain or interference with daily living) to 10. Four RSCL subscales were transformed to 0-100, with 100 as best score. Univariate Cox models were used to determine the prognostic effect of each measure on OS. Multivariate Cox models were used to determine the prognostic effect of each measure in the presence of 11 demographic/clinical variables, including Karnofsky performance status, age, and estrogen and progesterone receptor status. Kaplan-Meier curves and log-rank tests were used to compare OS among patient groups categorized using clinically meaningful thresholds and the sample median of the BPI and RSCL scores. Results: Randomized patients were evaluable for this analysis (n=529). In the univariate analysis, significant prognostic effects on OS were observed for baseline scores of both BPI measures (worst pain and interference) (HRs, 1.07 for 1-point increase; all p≤0.0042) and three out of four RSCL subscales (activity level, physical distress, quality of life) (HRs, 0.86-0.91 for 10-point increase; all p≤0.0120). In the multivariate Cox models, BPI worst pain remained as a significant prognostic factor (p=0.0245), as did RSCL activity level (p=0.0004). The median OS for patients with BPI worst pain score 0 (no pain) was 23.8 months (mos) versus 17.9 mos and 14.8 mos for scores 1-4 (mild) and 5-10 (moderate/severe) (log-rank p=0.0066). The median OS was 23.8 mos for patients with RSCL activity scores greater than or equal to the sample median (≥95.2) versus 14.6 mos for patients with scores <95.2 (log-rank p<0.0001). Conclusions: This retrospective analysis resulted in strong evidence that BPI-SF and RSCL provide distinct prognostic information for OS.
EEG for evaluation of “chemobrain.”
Authors: Moore Halle C. F. , Parsons Michael W. , Yue Guang H. , Rybicki Lisa A. , Siemionow Vlodek
Published: March 2020

1076

Background: Cognitive impairment is a poorly understood and worrisome potential complication of adjuvant chemotherapy (CT). We sought to evaluate electroencephalography (EEG) as a means to measure neurophysiologic function in women receiving CT for early breast cancer. Methods: Women planning to undergo CT for operable breast cancer and age-similar controls were evaluated at baseline, during CT and at 1 year with neurophysiologic assessments. Testing included a brief fatigue inventory (BFI), brief mental fatigue assessment (BMF), Processing Speed Index (PSI) derived from Digit Symbol Coding and Symbol Search subtests of the Wechsler Adult Intelligence Scale, and a sustained elbow flexion physical task (PT). EEG recordings were obtained at rest and after the cognitive and physical tasks. Data were analyzed using repeated measures of analysis of variance. Results: Eight patient/control pairs completed baseline and on-treatment evaluations; 7 pairs also completed the 1 year assessment (1 pair withdrawn due to a second malignancy). Subjective mental fatigue measured by BMF is similar for patients and controls at baseline but BMF scores increase significantly during CT for patients relative to controls (p=0.033), recovering to no difference at one year. Differences in PSI are not observed between patients and controls or at the different time points. BFI scores are greater in patients at all 3 time points but endurance on the PT is no different from controls. During chemotherapy EEG total spectrum amplitudes in patients are greater than in controls at rest (p=0.05) and following both the cognitive (p<0.001) and physical (p<0.001) tasks. EEG activity prior to chemotherapy and at one year is not different between patients and controls. For patients but not controls EEG readings after the cognitive task demonstrate greater amplitude than pre-task readings during the time of CT treatment only (p=0.012) with a similar trend seen for the physical task (p=0.06). Conclusions: Patient-perceived mental and physical fatigue during chemotherapy correspond to significant changes in EEG brain activity patterns but not to cognitive testing or physical endurance testing. EEG may offer a sensitive means to measure alterations in brain function associated with CT.
Sequential treatment with epirubicin/cyclophosphamide, followed by docetaxel versus FEC120 in the adjuvant treatment of node-positive breast cancer patients: Final survival analysis of the German ADEBAR phase III study.
Authors: Janni Wolfgang , Harbeck Nadia , Sommer Harald Leo , Rack Brigitte Kathrin , Augustin Doris , Simon Wolfgang , Jueckstock Julia Kathrin , Wischnik Arthur , Annecke Katja , Friese Klaus , Kiechle Marion ,   SUCCESS Study Group
Published: March 2020

1081

Background: Based on meta-analytic evidence, taxane containing adjuvant chemotherapy has been established as standard treatment in breast cancer (BC). However, in the MA-21 study, adriamycin-cyclophosphamide, followed by paclitaxel was significantly inferior FEC120. We prospectively compared a sequential epirubicin-docetaxel chemotherapy regimen to FEC120. Methods: The ADEBAR study was a multicenter phase III trial (n=1502) to evaluate whether pts with > 3 axillary lymph node metastases BC benefit from a sequential anthracycline-docetaxel regimen (E90C–D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21d followed by 4 cycles docetaxel [D] 100mg/m2 q21d) compared to dose-intensive anthracycline-containing polychemotherapy (FE120C: 6 cycles E 60 mg/m² d 1+8, 5-FU 500mg/m² d 1+8 and C 75 mg/m² d 1-14, q4w). The observation time (median – 95%CI) was 49.5 (47.4 – 51.3) m. Results: Treatment was stopped prematurely in 3.7% of the pts in the E90C–D arm and in 8.0% in the FE120C arm due to toxicity (p=0.0009). Antibiotic treatment was given in 10.4% (E90C–D) vs. 19.7% (FE120C), G-CSF support in 39.2% vs 61.4 % and erythropoietin stimulation in 8.7% vs. 20.0%, respectively (p<0.0001). Haematological toxicity (leucopenia, neutropenic fever, thrombocytopenia, anemia) was significantly higher in the FEC-arm. At the time of the current analysis, 369 events of recurrence, were observed: 166 events in the FE120C group and 193 in the E90C–D group. The unadjusted hazard ratio (HR) was 0.877 (95 percent confidence interval, 0.722 to 1.065; p=0.3819, log-rank test). Overall survival in the two groups was not significantly different: (131 deaths with FEC vs. 134 with E90C–D (HR 0.996, 0.783-1.267, p=0.9691). Subgroup analyses, stratifying for tumor size, lymph node involvement, hormone receptor and HER2-neu status showed no significant difference between the two arms. Conclusions: Different toxicity profiles given, hematological toxicity in the FE120C group was more severe than in the E90C–D. In contrast to AC-P in earlier studies, EC-Doc provides a feasible and effective option to FEC120.
Participation in adjuvant clinical breast cancer trials: Is there a difference in survival compared to guideline adherent adjuvant treatment? A retrospective multicenter cohort study of 5,326 patients.
Authors: Wöckel Achim , Van Ewijk Reyn , Hoffmann Isabell , König Jochem , Kreienberg Rolf , Blettner Maria , Schwentner Lukas ,   BRENDA Study Group
Published: March 2020

1082

Background: Clinical trials (CT) usually compare a standard treatment regime versus innovative new substances or regimens. However participation in CT is available for only few patients and exclusion criteria is usually very strict. Therefore this study tries to answer the following questions: (1) Does participation in adjuvant CT improve survival in breast cancer (BC)? (2) Is there a difference in survival compared to guideline adherence and what is the role of the other treatments surrounding adjuvant breast cancer treatment? Methods: This German multi-center [17 participating hospitals all are certified as breast cancer centers] retrospective cohort study called BRENDA (BRENDA = quality of breast cancer care under evidence-based guidelines) included 5326 patients obtained from 1992 until 2005. The definition of guideline adherence was based on the German national S3 guideline for diagnosis and treatment of breast cancer (2004). Results: 554 (10,4%) patients participated adjuvant clinical trials and 4772 (89,6%) not. There was a trend towards a significantly impaired RFS [p=0.17; HR=0.87 (95% CI: 0.71-1.06)] and OAS [p=0.65; HR=0.84 (95% CI: 0.65-1.09)] when comparing participants (PA) versus non-participants (NPA). When stratifying for guideline adherence (compared to PA-guideline conform in all adjuvant therapies) the outcome was not different in NPA-guideline adherent [RFS: p=0.13; HR=1.25 (95% CI: 0.94-1.67)] [OAS: p=0.83; HR=1.41 (95% CI: 0.96-2.06)]. However survival parameters were significantly impaired in non-guideline conform PA [RFS: p=0.005; HR=1.66 (95% CI: 1.16-2.38)] [OAS: p=0.01; HR=1.83 (95% CI: 1.15-2.92)] and non-guideline conform NPA [RFS: p>0,001; HR=1.70 (95% CI: 1.27-2.26)] [OAS: p=0.002; HR=1.82 (95% CI: 1.24-2.67)]. Conclusions: There is a strong association between guideline adherence in adjuvant treatment in BC and survival. PA in clinical trials trended to an improved survival, but only if guideline adherent treatment was applied. Patients who don`t have access to clinical seem to profit substantially of guideline adherent adjuvant treatment.
Reduction of ovarian reserve in young early breast cancer patients: First data of a prospective cohort trial.
Authors: Sanders Lea , Wenners Antonia Sophie , Koss Juliane , Schem Christian , Bauer Maret , Grambach Jana , Schaefer Fritz Werner , Schulz Ulrike , Jonat Walter , Schmutzler Andreas Gerd , Mundhenke Christoph
Published: March 2020

1084

Background: Breast cancer is the most common malignancy in premenopausal women. Sideeffects of chemotherapy are well known nevertheless the precise effects on ovarian function are inadequately studied by now. Premenopausal women undergoing chemotherapy are at risk for symptoms of sexual hormone deficiency and impaired fertility. Searching for predictive parameters of ovarian reserve after chemotherapy this prospective cohort study has been set up. Methods: 36 young patients with primary breast cancer have been included in this trial after written consent (April 2010 to November 2011) and after the study was approved by the local review board. All women were premenopausal (< 46 years). They all received anthracycline based “A” neo- or adjuvant chemotherapy (as FEC) or combinations with taxanes “T” ( as TAC or FEC/Doc). Before and 6 and 12 months after initiation of chemotherapy age and chemotherapy related changes in hormone (LH, FSH, E2 and Anti-Müllerian hormone) levels, antral follicel count and amenorrhea as parameters of endocrine function and fertility were assessed.The additional impact of parity, BMI and nicotine use on ovarian reserve was also evaluated. Results: There is a correlation of antral follicle count before and 1 year after chemotherapy and a negative correlation of age and follicle count before and after chemotherapy (n.s.). This analysis shows that patients receiving “T” compared to those with “A” have a significant increase of LH (p=0.025) and FSH (mean:24 vs.59 IU/l, p=0.021) between visit 1 and 3. The type of chemotherapy has no influence on antral follicle count and AMH levels within the first 3 visits. BMI is negatively correlated with AMH at all time points (n.s.). BMI, nicotine abuse and age have no influence on the duration of amenorrhea, whereas patients with "T" showed 12 months of amenorrhea instead of 9 months in patients with "A" (n.s.). Conclusions: Our study will contribute to a better understanding and prediction of ovarian reserve of young early breast cancer patients undergoing chemotherapy. The 12 months follow up data suggest to offer fertility preserving measures before chemotherapy especially to patients planned for taxane containing chemotherapy.
Evaluation of overall survival (OS), progression-free survival (PFS), or time to progression (TTP) in systematic review of randomized clinical trials (RCT) in patients with metastatic breast cancer (MBC).
Authors: Mukonje Terence , Santana-Davila Rafael
Published: March 2020

1089

Background: Limited data exists to establish if the introduction of newer agents has been associated with a trend towards an improved OS over time in women with MBC. Methods: Trough a computer-based systematic search of PubMed we identified RCT that treated patients with MBC published between 1980 and 2011. Trials that compared systemic chemotherapy for MBC, and reported a median OS were included. We excluded trials that use concomitant hormonal treatment, investigated only immunotherapy, or if they enrolled only responders to an initial regimen. The data abstracted included: year of publication, number of patients, regimens used, number of patient treated as 1st line vs. refractory patients, median PFS, TTP and OS. Linear regression analysis was used to establish trends. Results: An initial searched revealed 5485 publications, 134 RCT that enrolled 38,090 patients fulfilled our entry criteria and were included. First line therapy was studied in 99 trials and 35 evaluated mostly refractory patients. The use of adjuvant therapy has increased substantially, trials reported in the 1980’s had a mean of 0.07% of patients having had adjuvant chemotherapy compare to a mean of 48% in the last decade. Overall survival has significantly improved; the slope of the fitted line for first line clinical trials was 0.39 (p<0.001), which indicates a 0.39-month increase in median survival time per year. In trials of subsequent lines of therapy this slope was 0.19 (p=0.001). PFS or TTP was reported in 98 trials, interestingly in contrast to OS, this has not significantly changed, the slope for the fitted line has remained almost flat in both first line (0.002, p=0.97) and refractory trials (0.01, P=0.81). Conclusions: Our study is the first of its kind conducted in trials of patients with MBC. It shows that progress has been made in the last 3 decades OS in women affected with MBC, however the lack of change in PFS or TTP appears to indicate that the increase in OS is driven by a combination of newer agents, more subsequent lines of therapy being offered to patients and improved palliative care.
A study of sperm-associated antigen 5 (SPAG5) in predicting response to anthracycline (ATC)/platinum chemotherapies (CT) in breast (BC) and ovarian cancers (OVC).
Authors: Abdel-Fatah Tarek M. A. , Ball Graham , McArdle Stephanie , Johnson Catherine , Moseley Paul , Hosnii Shama , Green Andrew R. , Ellis Ian O. , Chan Stephen
Published: March 2020

1098

Background: Recently TOP2A alteration was found to be a predictor for ATC-CT and our neural network analysis of BC gene expression array (GEA) data has revealed SPAG5 gene as a major hubs in both TOP2A and proliferation pathways. In this study the molecular and clinicopathological functions of SPAG5 was investigated in BC and OVC. Methods: (1) A series of 171 BC was evaluated for SPAG5 gene copy number (using aCGH) and mRNA expression (using GEA) which were validated in 5 independent databases. (2) The expression of SPAG5 protein was evaluated pre-clinically in BC and OVC cell lines and in both 40 normal breast tissues and a series of 1650 primary BC and was correlated to clinicopathological and other biomarkers. (3) The association between SPAG5 and response to CT was investigated in a) 350 ER negative BC treated with adjuvant ATC-CT, b) 250 BC treated with neoadjuvant (NEO-A)-ATC-CT, and c) 200 primary OVC treated with cisplatinum based adjuvant CT. Results: (1) 5% and 15% of the 171 BC showed amplification and gain of SPAG5 locus, respectively, at 17q11.2. SPAG5 mRNA expression displayed a significant correlation with its copy number (p< 0.0001). (2) 30% and 20% of ovarian and BC respectively, showed overexpression of SPAG5 protein (+). In BC, SPAG5+ at both mRNA and protein levels showed a significant association with aggressive phenotypes, high mitosis, ER-, high grade, p53 mutation and epithelial mesenchymal transition phenotypes (ps <0.0001). SPAG5 mRNA (+) was statistically associated with poor survivals (p<0.0001). (3) In ER- BC treated with adjuvant ATC-CT, SPAG5 negative (-)had 7-times higher risk of progression compared with SPRAG+ BC (p<0.0001). SPAG5+ BC received NEO-A-ATC based CT achieved 38% pathological complete response (pCR) vs. 6% of SPAG5- (p<0.0001). After controlling to other predictors for pCR, SPAG5 was an independent predictor (HR; 2.4; p=0.001). Similarly, SPAG5- OVCs were resistant to platinum (p<0.001) and independently associated with poor survival (p<0.001). Conclusions: SPAG5 is an important novel gene implicated in the survival of BC and OVC cells and its protein expression is an independent predictor for anthracycline/ cisplatinum CT.
Radiofrequency ablation (RFA) of breast cancer: A multicenter retrospective analysis.
Authors: Ito Toshikazu , Oura Shoji , Yamamoto Naohito , Nagamine Shinji , Takahashi Masato , Tanino Hirokazu , Yamamichi Noboru , Earashi Mitsuharu , Doihara Hiroyoshi , Imoto Shigeru , Mitsuyama Shoshu , Sonoo Hiroshi , Akazawa Kohei
Published: March 2020

1119

Background: Local ablative therapy of breast cancer represents the next frontier in the minimally invasive breast-conservation treatment. We performed a retrospective study of ultrasound-guided percutaneous radiofrequency ablation (RFA) of breast cancers to determine safety and complication related to this treatment. Methods: Four hundred and ninety-seven patients with core biopsy proven breast carcinoma in 10 institutions of non-surgical ablaton study group underwent RFA without surgical excision were enrolled in this study. Results: Mean patient age was 54 years (range 22 - 92 years). Mean tumor size was 1.6 cm. Four hundred and twenty-five tumors ( 86 %) were ≤ 2 cm. The median follow-up period was 50 months (range 3 – 92 months). The mean required for ablation was 19 minutes (range, 4- 72 minutes), and the average temperature of the tumor after ablation was 91 degrees Celsius. The local recurrence rate after RFA was higher in tumors of negative estrogen receptor (8 of 78, 10%) than in tumors of positive estrogen receptor (17 of 437, 4%; p<0.05), and was higher in tumors of positive HER2/neu than in tumors of negative HER2/neu (14.9% vs. 3.2%; p<0.01). The local recurrence rate after RFA was higher in tumors of positive node than in tumors of negative node (9.8% vs. 3.6%), and was higher in tumors without irradiation than in tumors with irradiation (18.2% vs. 3.2%; p<0.001). The local recurrence rate after RFA was higher in tumors of > 2 cm (13 of 72, 18%) than in tumors of ≤ 2 cm (11 of 425, 3%; p<0.001). RFA-relating adverse events were observed in 17 patients of local pain, 14 patients of skin burn and 4 patients of retraction of nipple. Conclusions: RFA is considered to be a safe and promising minimally invasive treatment of small breast cancer ≤ 2 cm in diameter. Further studies are necessary to optimize the technique and evaluate its future role as local therapy for breast cancer.
Prospective outcomes trial of immediate, implant breast reconstruction using acellular dermal matrix (POBRAD Trial): Pilot series results.
Authors: Westbroek David , Douek Michael
Published: March 2020

1131

Background: Acellular dermal matrices (ADM) are biological meshes of dermal origin (allo- or xenografts) stripped of all cellular components leaving a structurally intact and immunologically inert extracellular matrix. They are currently in use as adjunctive subdermal scaffolding during implant breast reconstruction to optimise aesthetic outcome. Despite current use in clinical practice there is no prospective data on their clinical efficacy, associated complication rates and cost-benefit analysis. These are the endpoints of our pilot cohort series, intended to provide baseline event rates to help power a multi-centre prospective, phase II, outcomes cohort study. Methods: From July 2011 to January 2012 and with our institution review board's approval - 20 consecutive patients undergoing immediate, implant breast reconstruction were prospectively accrued to the study. Primary endpoints: 30-day complication rates; Secondary endpoints: cosmetic outcome and cost-benefit analysis. Indications for mastectomy included therapeutic intent and/or risk reduction. The ADM used in all cases was SurgiMend PRS (TEI Bioscience Inc. Boston, MA). Results: Preliminary 30 day complication rates are in keeping with peer reviewed estimates for implant based breast reconstruction. Sub-set analysis of cosmetic outcome and cost-benefit ratio's are currently pending. In overview, ADM's appear to deliver the aesthetic benefit of autologous- implant cover (eg. latissimus dorsi myocutaneous flap) without the downside of donorsite morbidity and prolonged in-patient admission. Conclusions: This is to our knowledge the only prospectively accrued dataset seeking to critically evaluate the clinical efficacy, cost-benefit value and enhanced aesthetic utillity of ADMs (SurgiMend PRS) in the immediate breast reconstruction setting. The early results provide new evidence in support of the use ADMs in breast reconstruction and validate our intention to extend the study to a multicentre trial.
Estrogen plus progestin (E+P) and breast cancer incidence and mortality.
Authors: Chlebowski Rowan T. , Anderson Garnet L , Kuller Lewis H , Aragaki Aaron K , Manson JoAnn E , Stefanick Marcia L , Johnson Karen , Gass Margery , Lane Dorothy S , Ockene Judith , Sarto Gloria , Wactawski-Wende Jean , Rajkovic Aleksandar , Prentice Ross L ,   Women's Health Initiative
Published: March 2020

1501

Background: In the WHI clinical trial, E+P increased both breast cancer incidence and breast cancer mortality (JAMA 2010;304:1684). In contrast, breast cancers associated with E+P use in most observational studies have a more favorable prognosis. To address differences, a cohort of WHI Observational Study participants with characteristics similar to the WHI clinical trial was identified to examine E+P association with invasive breast cancer incidence and outcome. Methods: 41,449 postmenopausal women with no prior hysterectomy and mammogram negative for breast cancer < 2 years before who either were not hormone users (25,328) or were using E+P (16,121) were identified. Breast cancers were verified by centralized medical record review. Adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). Additional analyses adjusted for breast cancer screening, censoring participants for incidence analyses who had a > 2 year interval without a mammogram. Results: After a mean (SD) follow-up 11.3 (3.1) years, 2,236 breast cancers were diagnosed. Breast cancer incidence was higher in E+P users (0.60% vs 0.42%, annualized rate, respectively: HR 1.55, 95% CI 1.41-1.70, P<0.001). Screening adjusted analyses had stronger breast cancer association (0.63% vs 0.39%, HR 1.72, 95% CI 1.54-1.93; P<0.001). Survival following breast cancer, measured from diagnosis date, was similar in E+P users and non-users (HR 0.95, 95% CI 0.74-1.23). Breast cancer mortality, analyzed from cohort entry date, are shown in the table. Conclusions: E+P use is associated with increased breast cancer incidence. As breast cancer prognosis following diagnosis on E+P is similar to that of nonusers, the higher incidence with E+P leads to increased breast cancer mortality. [Table: see text]
Long-term therapy with thiazolidinediones and the risk of bladder cancer: A cohort study.
Authors: Mamtani Ronac , Haynes Kevin , Bilker Warren B. , Vaughn David J. , Strom Brian L. , Glanz Karen , Lewis James D.
Published: March 2020

1503

Background: The US Food and Drug Administration and other regulatory agencies recently warned prescribers that use of pioglitazone, a thiazolidinedione (TZD), may increase the risk of bladder cancer. France and Germany removed the drug from their markets, although the rest of Europe did not. However, no information was available about the risk from alternative TZDs. We aimed to compare bladder cancer risk over time with use of TZDs relative to sulfonylureas (SUs), and between pioglitazone and rosiglitazone. Methods: We conducted a cohort study of patients with type 2 diabetes who initiated treatment with a TZD or SU using The Health Improvement Network (2000-2010), a UK general practitioner medical record database. Incident cancers within the database were identified. We computed hazard ratios (HRs) of bladder cancer for TZDs in comparison to the reference group of SU users. Results: There were 60 incident diagnoses of bladder cancer in the TZD cohort (n=18,459) and 137 in the SU cohort (n=41,396). There was no significant difference in bladder cancer risk between the cohorts (HR 0·93, [95% CI 0·68-1·29]), but most use was short-term use. In contrast, the risk of bladder cancer increased with increasing time since initiation of TZD versus SU therapy (HRs 1·15, 1·40, and 1·72 for 3-4, 4-5, and ≥ 5 years, respectively; P-trend=0·033). Bladder cancer risk also increased with increasing time since initiation of pioglitazone (P-trend<0·001) and rosiglitazone (P-trend=0·006). Direct comparison of pioglitazone to rosiglitazone did not demonstrate significant differences in cancer risk with increasing time since initiation (P-trend=0·12) or duration of therapy (P-trend=0·75). Conclusions: Long-term TZD therapy is associated with an increased risk of bladder cancer, which appears to be a class effect.
Routine universal screening for Lynch syndrome in colorectal cancer patients in the community setting.
Authors: Goldberg Jeffrey M. , Lewis Andrea L. , Alabek Michelle , Dreher Cara , Brooks Sandra Elane
Published: March 2020

1512

Background: Identification of colorectal cancer (CRC) cases that are due to Lynch Syndrome (LS) is important to prevent secondary malignancies or development of additional malignancies among relatives. Utilization of clinical criteria to select CRC patients for laboratory testing fails to identify a significant proportion of patients whose CRC is due to LS. Therefore, universal screening for LS among CRC patients has been advocated by the Evaluation of Genomic Applications in Practice and Prevention Working Group. However, the feasibility of routine universal screening has not been evaluated in a community-based, non-research setting. We implemented a universal screening protocol for LS as part of routine care of CRC at Norton Healthcare, a multi-institutional community-based healthcare organization. Methods: Beginning in October 2009, all resected CRC tumors automatically underwent immunohistochemistry analysis (IHC) for Lynch Syndrome-associated mismatch repair gene (MMR) expression. Selected patients who underexpressed MLH1 also underwent testing for the BRAF V600E mutation. Patients who had a BRAF V600E mutation were considered to have sporadic CRC. All other patients with abnormal IHC were automatically referred for genetic counseling. We retrospectively reviewed the outcomes of genetic counseling in all patients referred through this universal screening protocol. Results: Between October 2009 and December 2011, 388 patients underwent resection of CRC, all of whom had IHC for MMR expression. Seventy patients were identified as having abnormal IHC. Sixty-two had MLH1/PMS2 underexpression, of which 18 underwent BRAF testing and 13 had a BRAF V600E mutation. Eight had MSH2/MSH6 underexpression. Nine patients have been confirmed to have LS, 31 have been found not to have LS, and 19 are in the process of evaluation. Seven patients declined genetic counseling, and 4 died before they could be adequately evaluated. Conclusions: Universal screening for CRC due to LS, using IHC with select BRAF V600E mutation testing and automated referral for genetic counseling, is feasible in the community setting. Funded in part with federal funds: NCI, NIH, Contract No. HHSN261200800001.
Pathologic findings at risk-reducing salpingo-oophorectomy among women at increased ovarian cancer risk: Results from GOG-199.
Authors: Mai Phuong L. , Sherman Mark E , Piedmonte Marion , Ioffe Olga B. , Ronnett Brigitte M. , Van Le Linda , Mutch David Gardner , Cohn David E. , Thigpen J. Tate , Tewari Krishnansu Sujata , Disilvestro Paul , Kauff Noah D. , Lu Karen H. , Greene Mark H.
Published: March 2020

1519

Background: Although risk-reducing salpingo-oophorectomy (RRSO) is a standard management option for women with BRCA1/2 mutations, the lack of large, prospective cohort studies makes estimating the prevalence of cancer at RRSO problematic. Methods: GOG-199 is a large, non-randomized multi-center trial which enrolled women at high-risk (due to BRCA mutations or strong family history) of ovarian cancer, comparing surgery at enrollment with serial transvaginal ultrasound and CA-125 screening. RRSO specimens were processed according to a standardized tissue processing protocol including 2-3mm sectioning of both ovaries and tubes. Results: 2,605 participants were accrued to GOG-199. Of the 1 030 enrolled in the baseline RRSO cohort, 28 were ineligible and 36 declined surgery after enrollment, resulting in 966 baseline RRSO. Pathology review demonstrated 4 tubal intraepithelial carcinoma and 20 serous pelvic cancers, of which 12 were identified only microscopically. Among the 20 serous cancers, the predominant or exclusive site of involvement was ovary in 10, fallopian tube in 5, and peritoneum in 5 cases. In addition, 6 endometrial cancers (among the 515 undergoing concomitant hysterectomy) and 3 adenocarcinomas suggestive of metastasis were identified. The serous pelvic cancer prevalence was: entire cohort=2.1% (20/966), all BRCA mutation carriers=3.2 (18/558), BRCA1 mutation carriers=3.7% (12/325), BRCA2 mutation carriers=2.6% (6/231), and mutation-negative=0.5% (2/402). Compared to those without cancer, women with serous pelvic cancer were older at surgery (p< .001), and more often menopausal (vs pre-menopausal, p= .002), nulliparous (vs parous, p=.04) and never users of tamoxifen (vs ever users, p= .04). Serous pelvic cancers were more frequent in BRCA mutation carriers (vs no mutation, p= .004), and among carriers, more common in those with BRCA1 mutations (vs BRCA2 mutation, p= .02). Conclusions: The prevalence of serous pelvic cancers in this cohort was 3.2% among carriers vs 0.5% among the mutation-negative but with a strong family history. Our data will be useful when counseling women at increased ovarian cancer risk who are contemplating risk-reducing surgery.
Contribution of TP53 p.R337H mutation to breast cancer prevalence in Brazil.
Authors: Ashton-Prolla Patricia , Osorio Cynthia ABT , Koehler-Santos Patricia , Graudenz Marcia S , Palmero Edenir Inez , Fernandes Gabriela , Micheli Rodrigo , Martel-Planche Ghyslaine , Achatz Maria Isabel , Soares Fernando Augusto , Goldim Jose Roberto , Caleffi Maira , Hainaut Pierre , Camey Suzi Alves , Giacomazzi Juliana
Published: March 2020

1522

Background: The exact contribution of TP53 germline mutations, associated with Li Fraumeni Syndrome, to the overall burden of cancer is still only partially known. Studies in Southern and Southeastern Brazil have shown that a specific germline mutation at codon 337 (c.1010G>A; p.R337H), has incomplete penetrance and may be present in a significant number of subjects (estimated frequency at the populational level of 1:300 individuals). In an exploratory approach, the aim of the study is to assess the frequency of the p.R337H mutation in women from different Brazilian regions, diagnosed with breast cancer (BC) before 46 and after 55 years of age, and unselected for family history of cancer. Methods: Formalin-fixed paraffin-embedded (FFPE) non-tumoral tissue (lymph nodes or normal breast) of women diagnosed with BC between 2000 and 2010 in 3 pathology laboratories from the Brazilian cities of Porto Alegre, São Paulo and Barretos were obtained retrospectively and analyzed after anonimization. Genomic DNA was isolated with standard methods and genotyping performed in duplicates by qPCR (TaqMan assay). Confirmation of all mutation-positive and a sample of mutation-negative cases were done by TP53 exon 10 sequencing or by a second independent qPCR analysis. Results: Analysis of 515 BC-affected women identified the p.R337H mutation in the germline of 70 (8,6%) cases: 49/403 (12,1%) diagnosed before 46 years and 21/412 (5,1%) diagnosed after 55 years. BC occurred earlier in p.R337H mutation carriers than in non-carriers (p=0.001). Conclusions: Preliminary analysis in a sample of women with BC indicates that p.R337H founder mutation is present in a high proportion of cases, especially those diagnosed at a young age. Regional genetic background and recruitment strategies may account for the different mutation frequencies observed in the centers of study. The occurrence of this mutation at such a high frequency in a particular geographic region has important implications for disease management and cancer risk counseling for these patients and families. This mutation likely contributes to a significant proportion of the health burden associated with BC in Brazil. Financial support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith Kline.
Racial disparities in treatment patterns and clinical outcomes in patients (pts) with HER2+ metastatic breast cancer (MBC).
Authors: Brufsky Adam , Yardley Denise Aysel , Ulcickas Yood Marianne , Tripathy Debu , Kaufman Peter Andrew , Mayer Musa , Feng Shibao , Abidoye Oyewale O. , Rugo Hope S.
Published: March 2020

1526

Background: Data examining prognosis and treatment outcomes for black pts with HER2+ MBC are limited. Methods: registHER is a large, observational cohort of pts (N=1,001) with HER2+ MBC diagnosed w/in 6 mos of enrollment and followed until death, disenrollment, or 6/09 (median follow-up 27 mos). Demographics, treatment patterns, and clinical outcomes were described for black (n=126) and white pts (n=793). Progression Free Survival (PFS) and Overall Survival (OS) were examined. Multivariate analyses adjusted for baseline and treatment factors. Results: Black pts were more likely to be obese (BMI ≥ 30), have diabetes, and a history of cardiovascular disease (CVD) than white pts (Table). Black pts were less likely to have estrogen receptor (ER)/progesterone receptor (PR)+ disease and more likely to present with stage IV MBC. In trastuzumab (T)-treated pts, incidence of cardiac safety events (grade ≥3) was higher in black (13/119 [10.9%]) than white pts (59/746 [7.9%]). Unadjusted median OS (mos) was significantly lower (blacks: 27.1, 95%CI 23.2-32.1; whites: 37.3, 95%CI 34.6-41.1) and median PFS (mos) was lower (blacks: 7.0, 95%CI 5.7-9.7; whites: 10.2, 95%CI 9.3-11.2) in black than white pts. The adjusted OS hazard ratio (HR) for black vs. white was 1.32 (95%CI 1.04, 1.69); the adjusted PFS HR was 1.31 (95% CI 1.07, 1.61). Conclusions: These population-based data show poorer prognostic factors and independently worse clinical outcomes in black vs. white pts, and represent the largest database to date with black pts with HER2+ MBC. Further research is needed to explore the basis for the differences noted in this hypothesis-generating analysis. [Table: see text]
Associations between allergies and risk of hematologic malignancies: Results from the Vitamins and Lifestyle (VITAL) cohort study.
Authors: Shadman Mazyar , Walter Roland B. , DeRoos Anneclaire , White Emily
Published: March 2020

1527

Background: Several case-control studies have suggested a reduced risk of hematologic malignancies (HMs) for individuals with allergies, but results have been inconsistent, and prospective cohort studies have not confirmed this association. Herein, we used the large prospective VITAL study to examine this association. Methods: 64,847 men and women, aged 50-76, completed a baseline questionnaire in 2000-2002 and reported on their current allergies and history of physician-diagnosed asthma. Individuals with prior cancer other than non-melanoma skin cancer were excluded from this analysis. Incident HMs were identified through December 2009 by linkage to the SEER registry; those with a diagnosis of a non-HM during follow-up were censored at the time of that diagnosis. Multivariable Cox proportional hazards models were built with adjustment for sex, race/ethnicity, education, smoking, self-rated health, physical activity, history of anemia in the year before baseline, vegetable use and family history of leukemia or lymphoma. Results: Our analysis included 64,839 participants, among whom 681 (1.03%) incident HMs were found (MDS [69], AML (41], myeloproliferative disorders [60], mature B-cell neoplasms [262], chronic lymphocytic leukemia [107], plasma cell disorders [83], Hodgkin lymphoma [23], T-cell/NK-cell neoplasms [22], and others [14]). In multivariable analyses, a history of any allergy was associated with increased risk of HM (HR=1.21; 95% CI 1.02-1.43, p=0.02). This association was seen for current allergies to plants/grass/trees (HR 1.27 [1.06-1.52], p<0.001) but not for allergies to mold/dust, animals, insects, food, or medications. We did not find an association between a history of asthma and incident HMs (HR=0.95 [0.72-1.26]). Conclusions: Our study indicates a moderately increased risk of HMs inindividuals with a history of allergy, especially to plant, grass or trees. While no causality can be inferred, this may suggest a possible carcinogenic role for chronic stimulation of the immune system. However, further mechanistic investigations focusing on the biochemical markers of immune system as well as on possible gene effect modifiers are needed.
Potential risk of asbestos exposure among Japanese general population: Japanese general screening study for asbestos-related diseases (JGSARD).
Authors: Seki Nobuhiko , Yamaguchi Takuhiro , Eguchi Kenji , Kaneko Masahiro , Kusumoto Masahiko ,   JGSARD Study Group
Published: March 2020

1530

Background: The number of patients with pleural mesothelioma and lung cancer associated with asbestos exposure has recently been increasing in Japan. The aim of this study was to evaluate the results of screening for asbestos-related diseases in a group of Japanese general population. Methods: This prospective study was approved by the institutional review board. From 2006 to 2008, 9810 subjects (5283 men and 4527 women; mean age, 57 years) underwent chest radiography and low-dose CT examinations in 26 institutions in Japan. Among them, 6286 (64.1%) subjects underwent subsequent CT examinations after 2 years of interval. Clinical information such as histories of smoking and asbestos exposure was reviewed. Images were interpreted independently by 15 experienced pulmonologists or chest radiologists. Results: The history of asbestos exposure was definitely present in 1253 (12.8%) subjects, possibly present in 2058 (21.0%), and absent in 6499 (66.2%). On chest radiograph, pleural plaque and thickening were seen in 61 (0.6%) and 65 (0.6%) subjects, respectively. On low-dose CT, pleural plaque and thickening were identified in 264 (2.7%) and 245 (2.5%) subjects, respectively, and non-calcified pulmonary nodule/mass was seen in 1003 (10.2%). Furthermore, lung cancer was identified in 29 (0.3%) subjects. The history of asbestos exposure was not confirmed in 77 out of 264 subjects (29.2%) having pleural plaques on low-dose CT. Based on the logistic regression analysis, pleural plaque on low-dose CT was significantly correlated with male, age more than 60 years, smoking, and a history of asbestos exposure. Especially, total residential period in asbestos factory area as well as asbestos exposure work period showed significantly increased relative risk every 10 years. Similarly, lung cancer was significantly correlated with age more than 60 years, a history of asbestos exposure, and presence of pleural plaques. Conclusions: Our results indicate the presence of pleural plaques on low-dose CT among Japanese general population is closely associated with potential risk of asbestos exposure. However, about 30% of such subjects are not aware of a history of asbestos exposure.
Never-smoking women with lung cancer from the Spanish WORLD07 database.
Authors: Isla Dolores , Provencio Mariano , Majem Margarita , Felip Enriqueta , Vinolas Nuria , Campelo Rosario Garcia , de las Penas Ramon , Carcereny Enric , Alberola Vicente , Domine Manuel , Blanco Remei , Dorta Javier , Bernabé Reyes , Guillen Carmen , Vadell Catalina , Maestu Inmaculada , Rodriguez Delvys , Rubio-Viqueira Belen , Figueroa Salvador , Garrido López Pilar ,   ICAPEM Association
Published: March 2020

1531

Background: Gender differences in lung cancer (LC) have been reported, but with many unresolved issues yet. Tobacco causes the majority of women lung cancer (WLC), although the rate of never-smoking WLC is higher than in men. Several factors may play etiologic roles, and an in-depth understanding is needed. Methods: WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. In order to improve the knowledge on never-smoking WLC, information has been extracted from WORLD07 database. Results: From October/2007 to October/2011, 1371 newly diagnosed WLC were included in an e-database from 32 centers, 539 (39.3%) never-smoking. Patient (p) characteristics: median age 71.1 years(y); median age of menarche 13y.; motherhood 91.2% (median 2.3 children, median age at first child 26.4y); oral contraceptive use 11.9%; postmenopausal 88.9% (median age of menopause 49y); HRT 5.2%; second-hand smokers 40% (work-exposure 17.1%, home-exposure 88.8%); obesity 16.3%; familiar history of cancer 39.9% (LC 29.8%); previous history of cancer 13% (breast/lung/cervix: 41.4/5.7/2.9%); current LC histology(%): adenocarcinoma/SqCC/LCC/SCLC: 83.4/6.2/5.5/3.9; EGFR mut+ (268 p analyzed): 55.5% (exon 19/20/21(%): 61.1/7.4/36.9); TNM NSCLC I/II/III/IV(%): 14/3.3/19.8/60.3. Treatment: EGFR-TKI in p EGFR mut+, stage IV(1st-/2nd-line)(%): 51.7/15.4; stage IV NSCLC (1st-line/2nd-line): platinum-based CT 42.5%, EGFR-TKI 33.5%, combinations with bevacizumab 2.9% / EGFR-TKI 15.8%. Overall survival: median 27 months(m), 1/2-y(%) 74.8/55.2; stage IV NSCLC: median 20.5m, 1/2-y(%) 67/46; EGFR-mut+ p: median 27.3m, 1/2-y(%) 75/54.3. Conclusions: According to our e-database, WLC showed high rates of never-smokers (39.3%), and of relatives diagnosed with malignant tumours (39.9%, ≅1/3 LC). Adenocarcinoma was the most frequent histology (76.1%), and more than half of the cases analyzed harboured EGFR mutations. Although 40% were second-hand smokers, further investigations are warranted. Survival outcomes remain satisfactory, as expected from this selected subgroup of p. Additional epidemiologic and treatment data will be presented.
Clinical characteristics of patients with malignant pleural mesothelioma (MPM) harboring somatic BAP1 mutations.
Authors: Zauderer Marjorie Glass , Bott Matthew Joseph , McMillan Robert , Sima Camelia S. , Rusch Valerie W. , Krug Lee M. , Ladanyi Marc
Published: March 2020

1541

Background: Efforts to elucidate tumorigenic mutations in MPM are essential to advance therapy. We reported a 23% incidence of somatic mutations in BRCA1-associated protein-1 (BAP1) in 53 patients with MPM (Bott et al. Nat Genet 2011). Germline BAP1 mutations were also reported in two families with a predisposition to mesothelioma and uveal melanoma (Testa et al. Nat Genet 2011). While BAP1 somatic mutations are more common in poor prognosis uveal melanoma (84% class 2, 4% class 1; Harbour et al. Science 2010), the significance of these mutations in MPM is unknown. Therefore, we analyzed the clinical characteristics of patients with somatic BAP1 mutations in order to describe this newly identified subpopulation. Methods: We reviewed the charts of 121 patients with tumors tested for somatic BAP1 mutations. Results: Patient characteristics are in the Table. Twenty percent harbored somatic BAP1 mutations. Other than the percent of current or former smokers (75% BAP1 mutations, 42% BAP1 wild-type, p=0.006), no other clinical feature was significantly different among those with and without BAP1 mutations. Among 53 samples analyzed for NF2 mutation and p16 deletion, no correlation was seen with BAP1 mutation. Conclusions: Somatic BAP1 mutations occur in about 20% of MPM tumors. Aside from smoking history, no other differences in clinical characteristics or outcomes were noted in the BAP1 mutated cases. Similar efforts are needed to describe the features of germline mutations in order to define this new cancer predisposition syndrome. We are planning a prospective trial to further evaluate the prevalence of germline BAP1 mutations, and we are also exploring the therapeutic implications. [Table: see text]
Why do breast cancer programs fail to refer patients to genetic counseling upon obtaining family history?
Authors: Trosman Julia R. , Weldon Christine B. , Dupuy Danielle , Roggenkamp Betty , Ganschow Pamela , Schink Julian C. , Murphy Anne Marie
Published: March 2020

1553

Background: Women with personal or family history suggestive of susceptibility to hereditary breast or ovarian cancer should be referred to genetic counseling (US Preventive Services Task Force, Ann Intern Med. 2005). Our goal is to examine whether this guideline is followed by breast cancer programs providing screening and treatment in a large urban area; and if not followed, why. Funded by Susan G. Komen for the Cure. Methods: Using the framework approach of qualitative research, we conducted interviews with 130 providers of breast cancer screening and treatment at 26 institutions in Chicago (18 community, 4 academic and 4 public hospitals). We interviewed radiologists, mammography technologists, nurses, surgeons, oncologists, internists, and patient navigators. Interviews were transcribed and coded; theme analysis was conducted; simple frequencies and Fisher's exact test were calculated. Results: While all 26 programs collect patient personal and family history, only one program has both a protocol for referral to genetic counseling and a genetic counseling service. All six interviewees from that program (6/130, 5%) report referring appropriate patients to genetic counseling, compared to none from other programs (p<0.0001). 90% of interviewees (118/130) did not perceive any role in raising patient awareness or referring them to genetic counseling. Among the 124 interviewees not referring to genetic counseling, 51 (41%) have genetic counseling available, but only 12% (6/51) of them view referring or making patients aware of genetic services as their responsibility; while none of the interviewees without genetic counseling services view this their responsibility (p<0.0001). None of the interviewees noted reimbursement of genetic counseling as a barrier to referral. Conclusions: The lack of accountability by care providers is a barrier to referring patients with personal or family history of breast or ovarian cancer to genetic counseling, even when the service is available. A comprehensive approach addressing access to genetic counseling, adoption of referral protocols and clear assignment of referral responsibilities is needed to ensure that women appropriately receive genetic assessment.