bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized study of capecitabine versus S-1 in women with metastatic or recurrent breast cancer: Japan Breast Cancer Research Network (JBCRN) 05 trial.
Authors: Yamamoto Daigo , Iwase Satoru , Yamamoto Chizuko , Tsubota Yu , Yamaguchi Takuhiro
Published: March 2020

1111

Background: Capecitabine and S-1 are orally administered fluorinated pyrimidines with high-level activity against metastatic breast carcinoma (MBC). Methods: This randomized multicenter phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine and S-1, in breast cancer patients. Patients with MBC were randomly assigned to receive capecitabine at 1,657 mg/m2two times daily on days 1–21 every 4 weeks, or S-1 at 40–60 mg two times daily according to the body surface area on days 1–28 every 6 weeks. Results: One hundred and forty-two patients were enrolled, and 136 patients were randomized to capecitabine (N=71) or S-1 (N=65). The median progression-free survival, the primary end-point, was 1.4 years for capecitabine and 1.3 years for S-1, with a hazard ratio (S-1/ capecitabine) of 0.85 (95%CI: 0.52-1.38) (log-rank p = 0.5). The confirmed ORR for both populations was 24.0% for capecitabine and 23.1% for S-1(p = 0.938). The median OS was 3.5 years for capecitabine and 2.7 years for S-1; the hazard ratio (S-1/ capecitabine) was 1.32 (95% CI: 0.7–2.48) (p = 0.39). Further, the most common treatment-related adverse events were grade 1/2 in intensity. However, there were more adverse events, thrombocytopenia (p = 0.040, S-1: 9.2%, capecitabine: 1.4%), and nausea (p = 0.079, S-1: 26.2%, capecitabine: 14.1%) in the S-1 group. Hand–foot syndrome occurred in the S-1 and capecitabine groups (p = 0.029, S-1: 10.8%, capecitabine: 25.4%). Conclusions: The results of the current study demonstrate that S-1 or capecitabine is an effective and well-tolerated treatment in patients with MBC. In addition, they are convenient and orally administered drugs, which makes them attractive agents for use in outpatient treatment. Clinical trial information: NCT 00438100.
Roles of cMET/ErbB3 activation and overexpression in the development of resistance to EGFR inhibitors in NSCLC patients.
Authors: Ahn Myung-Ju , Park Silvia , Sun Jong-Mu , Ahn Jin Seok , Park Keunchil , Langley Emma J. , Kim Phillip Sangwook , Singh Sharat , Lockton Steve
Published: March 2020

11113

Background: Multifaceted efforts in the molecular and cellular research of lung cancer revealed many critical pathway dysregulations due genetic and epigenetic alterations to alter balances in signal transduction leading to carcinogenesis. Methods: US guided FNAs or pleural fluid were collected from 44 NSCLC patients enrolled in on-going prospective study involving EGFR inhibitors (gefitinib, erlotinib, or afatinib) and evaluated for EGFR as well as other various receptor tyrosine kinases (RTKs, i.e. ErbB2, ErbB3, cMET, IGF1R, ALK, etc) and downstream AKT and MAPK pathway proteins for their level of expression and activation in order to 1) Compare objective response rate according to the expression/activation of RTK and pathway proteins; 2) Evaluate the modulation of the RTK and pathway proteins during the treatment of EGFRi; 3) Correlate between activating EGFR gene mutations and RTK activation in patients treated with EGFRi. Results: Majority of patients over-expressed EGFR. While not overexpressed, varying and significant levels of cMET and ErbB3 were found and quantitated in each patient. A striking difference in PFS was observed with respect to relative levels of cMET to EGFR in pretreatment FNA. Regardless of EGFR mutation status, patients with higher levels of EGFR to cMET (or higher E/M-Index) showed superior PFS. With an increase in cMET involvement (or decrease in E/M-Index; continuous variable), NSCLC patients exhibited worse clinical outcome with reduction in PFS (as shown in the Table). Furthermore, patients with shorter PFS (< 8 months) had significantly higher levels of total and phosphorylated ErbB3 (67% positive) than patients with longer PFS (>8 months, 27% positive). Conclusions: This study clearly demonstrates the critical roles of cMET and ErbB3 in resistance to EGFR inhibitors in NSCLC patients. E/M-Index and activation may serve as predictive markers for treatment selection with EGFRi and cMETi, and should be validated in prospective clinical studies. [Table: see text]
Two lipids based on lipidomics as novel biomarkers for early detection of squamous cell lung cancer.
Authors: Deng Youping , Ai Junmei , Borgia Jeffrey Allen , Chen Hankui , Mahon Brett , Liptay Michael J. , Bonomi Philip , Mulshine James L.
Published: March 2020

11114

Background: Lipids play roles in membrane structure, energy storage, and signal transduction as well as lung cancer. Lipidomics, a new technology aims to measure all the lipids in a cell, has not been applied to diagnostic test development for a variety of cancer types. Here, we adopt lipidomics as a means to identify plasma lipid markers for the early detection of lung cancer and complement CT-based methods for lung cancer screening. Methods: Using mass spectrometry, we profiled 390 individual lipids in a training discovery cohort comprised of cohorts that were either at “high-risk” for lung cancer (n=22) and squamous cell carcinoma at early stages (n=22). Cases had a minimum of two years clinical follow-up and were matched in terms of race, sex, age and smoking status. Gain ratio feature selection and local weighted classification model were employed to find the best training classifier, which was further validated against an additional cohort, including high-risk individuals (n= 20) and squamous cell carcinoma patients (n=17). Results: In the training discovery stage, we found 20 distinct lipids that were significantly distributed between high-risk and cases of squamous cell carcinoma. We further defined a two lipid marker panel had a training accuracy at 95.5% sensitivity, 90.9% specificity and 95.2% AUC (Area under ROC curve). The validation accuracy against the additional cohort is 100.0% sensitivity, 90.0% specificity and 99.0% AUC (Table). The power for sample size we used in both discovery training and validation stages were over 90%. Conclusions: Using lipidomics we identified two lipid markers capable of discerning cases of squamous cell carcinoma from individuals at high risk for lung cancer, with a high sensitivity, specificity and accuracy. The markers maybe further developed as a quick, safe blood test for early diagnosis of squamous cell lung cancer and reduce unnecessary follow-up imaging or invasive procedures. [Table: see text]
Analysis of prognostic factors after 16 years of follow-up in a randomized phase II trial of neoadjuvant FAC compared with CMF in stage III breast cancer.
Authors: Leone Julieta , Leone Jose Pablo , Vallejo Carlos Teodoro , Perez Juan Eduardo , Romero Alberto Omar , Machiavelli Mario Raul , Romero Acuna Luis , Dominguez Maria Ester , Langui Mario , Fasce Hebe Margot , Leone Bernardo Amadeo , Ortiz Eduardo , Iturbe Julian , Zwenger Ariel Osvaldo
Published: March 2020

11118

Background: Neoadjuvant chemotherapy is a standard treatment in stage III breast cancer. Prognostic factors can help to identify patients (pts) with high risk of recurrence. The aim of this study was to assess several prognostic factors after a long follow-up, in stage III breast cancer pts, treated with neoadjuvant chemotherapy. Methods: We evaluated 126 pts with stage III breast cancer that participated in a phase-II randomized trial of neoadjuvant 5-fluorouracil, doxorubicin and cyclophosphamide (FAC every 21 days) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF days 1 and 8 every 28). Chemotherapy was administered for three cycles prior to definitive surgery and radiotherapy, and then for six cycles as adjuvant. Response was assessed by WHO criteria. Results: The median age was 52 years (range 24-75). Median follow-up was 4.5 years (range 0.2-16.4), disease free survival (DFS) 4.8 years and overall survival (OS) 6.4 years. Results of the phase-II study showed no difference in efficacy between groups. Univariate analysis showed that the number of pathologically involved lymph nodes (pLN), pathologic response and estrogen and progesterone receptor status correlated with DFS and OS. Number of pLN was the only prognostic factor with statistical significance in Cox regression test for both, DFS and OS (P=0.0004 and P=0.0006, respectively). In a subgroup analysis of pts with pLN, we found no difference in survival when we compared FAC with CMF. Conclusions: The prolonged follow-up of this study provides a unique opportunity to evaluate factors that predict long-term outcomes. After 16 years of follow-up, the number of pLN remains the most powerful predictor of survival. The subset of pts with pLN had similar survival regardless of the regimen used. Clinical trial information: NCT00002696.
Meta-analysis to determine the clinical effectiveness of axillary lymph node dissection in the treatment of operable primary breast cancer.
Authors: Joyce Doireann , Manning Aidan , Hill Arnold D. , Kell Malcolm R. , Barry Mitchel
Published: March 2020

1112

Background: The optimum surgical management of the axilla is controversial. Guidelines mandate axillary surgery in the setting of positive sentinel nodes. However, recent studies have questioned the oncological benefits of this potentially morbid procedure. Therefore a meta-analysis of relevant randomised trials was performed to clarify this issue. Methods: A comprehensive search of published randomized trials that compared patients with primary operable breast cancer with/without axillary lymph node dissection (ALND) was performed using MEDLINE and available data was cross referenced. Reviews of each study were conducted, and data were extracted. Primary outcomes were overall survival and recurrent axillary disease. Results: A total of 4,759 patients with operable primary breast cancer were identified from 13 randomised controlled trials comparing patients with/without ALND. Overall survival favours patients not having ALND (OR = 1.38 (95% CI = 1.12 TO 1.69, p=0.002)) however patients undergoing ALND had similar disease free survival (OR=1.04 (95% CI= 083-1.31, p=0.7). However, though axillary recurrence was uncommon it was significantly less so following ALND (1% vs. 5 %, p<0.05, ALND vs. No ALND). Conclusions: Based on this meta-analysis, ALND does not appear to positively impact on breast cancer survival. Enhanced and targeted adjuvant treatment strategies may facilitate less aggressive axillary surgery. The management and implications of a positive sentinel node need to be re-evaluated in this regard.
TARGIT-A trial: Updated results for local recurrence and survival for the German centers.
Authors: Wenz Frederik K. , Vaidya Jayant S. , Bulsara Max , Suetterlin Marc , Sperk Elena , Ataseven Beyhan , Pigorsch Steffi , Feyer Petra C. , Blohmer Jens U. , Kaufmann Manfred , Roedel Claus , Friese Klaus , Belka Claus , Solomayer Erich , Fleckenstein Jochen , Park-Simon Tjoung-Won , Bremer Michael , Joseph David John , Tobias Jeffrey S. , Baum Michael
Published: March 2020

1121

Background: In 2010, we reported data on local control and early toxicity for the TARGIT-A trial of intraoperative radiotherapy after lumpectomy for early breast cancer. The updated results and first analysis of survival of the whole cohort (n = 3,451) were presented at San Antonio Breast Cancer Symposium in December 2012. We analysed the German cohort of patients, which was supposed to be more homogeneous (prepathology IORT only, homogeneous treatment in EBRT arm) and lower risk (older, smaller tumors, larger margin) than the international cohort of patients due to legal restrictions for radiotherapy studies in Germany. Methods: TARGIT-A was a randomised trial in patients >=50 years with invasive ductal carcinoma (<= 2cm) undergoing breast conserving surgery comparing standard fractionated whole breast EBRT (56 Gy) with single dose TARGIT (20 Gy) immediately after tumor excision / at the time of the primary operation. The experimental arm mandated additional EBRT (46 Gy, excluding a boost, n = 126) if adverse features were detected on final pathology (EIC, N+, margin < 1 cm) making this a “risk-adapted policy”. Median follow-up was 2 years and 5 months. Results: 734 patients recruited from 7 centres in Germany. Patient’s ages were <=50y 3%, 51-60y 33%, 61-70y 51%, >70y 12%. Tumour sizes were 0-1cm 35%, 1.1-2cm 55% and >2cm 11%. Grade I 29%, II 59%, III 12% and nodes negative 81%, 1-3 nodes 16%, >3 nodes 3%. At 5-years, the absolute number of events in TARGIT vs. EBRT were as follows: Primary outcome: IBR 4 vs. 1, Exploratory outcome: All recurrences (breast +axilla+contralateral+distant recurrence) 11 vs. 7, Secondary outcome: All deaths 6 vs. 12, Breast Cancer deaths 3 vs. 5, Non-Breast Cancer deaths 3 vs. 7. Conclusions: Patients in the TARGIT-A trial have excellent 5 year outcomes (local control > 97%, overall survival >= 94%) in both arms of the trial. Clinical trial information: protocol 99PRT/47.
Propensity-score matched pair comparison of accelerated partial breast irradiation (APBI) and whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS).
Authors: Wilkinson John Ben , Fowler Ashley , Marina Ovidiu , Wallace Michelle , Marvin Kimberly , Grills Inga S. , Brabbins Donald S. , Chen Peter Y
Published: March 2020

1123

Background: DCIS remains a cautionary criterion for APBI by the ASTRO APBI consensus statement. We performed a matched analysis to compare the efficacy of WBI and APBI for patients with DCIS. Methods: Women with DCIS treated with APBI or WBI were reviewed. APBI (n=102) patients with ≥2 y follow-up were matched 1:3 to WBI (n=546) patients with ≥5 y follow-up by age, tumor size, nuclear grade, ER status, margin status, and laterality. Ipsilateral breast tumor recurrence (IBTR), distant metastasis (DM), contralateral breast cancer (CLBC) and cause-specific survival (CSS) were compared by cumulative incidence (Gray’s) and competing risks regression (Fine and Gray’s), and overall survival (OS) and disease-free survival (DFS) by Kaplan-Meier (log-rank test). Results: Median follow-up was 4.6 y (2.0-14.7) for APBI and 9.0 y (5.4-27.0) for WBI. Median (range) or percentages are shown (Table). Patients did not differ by match criteria. There were 17 LR, 1 DM, 19 CLBC, 2 CSS, 22 OS, and 19 DFS events during follow-up. The patient groups had similar rates of cancer-related events including ipsilateral and contralateral breast recurrences at both five and eight years. Treatment type, age, tumor size, nuclear grade, ER status, and hormone therapy (HT) were not prognostic of LR or CLBC on uni- and multi-variate analyses. Conclusions: APBI provides equivalent and exemplary outcomes compared to WBI following breast-conserving surgery for DCIS. These findings support previous reports on the efficacy of APBI in the treatment of noninvasive breast carcinoma. Prospective randomized comparison of APBI to WBI for DCIS is needed. [Table: see text]
PTEN-deficient breast cancer in neoadjuvant treatment.
Authors: de la Haba-Rodriguez Juan , M Cano , Y Rangal , Cristina Morales , E Fuentes , M Montero , I Porras , B Chia , A Rodriguez , Aranda Enrique
Published: March 2020

1125

Background: Loss of function mutations in the tumour suppressor gene PTEN or lack of PTEN expression have both been observed in a wide range of human tumours. PTEN encodes a phosphatase, whose activity antagonizes PI3 kinase signal pathway by dephosphorylation the plasma membrane lipid, phosphoinositide-3,4,5-trisphosphate (PIP3). Loss of PTEN phosphatase activity is thought to foster tumorigenesis, at least in part, by causing downstream constitutive activation of AKT. In addition to this role, PTEN has been suggested to have a nuclear function in maintaining genomic stability[2]. Our proposal is to identify those tumours without expression of PTEN, their characteristics and response to treatment. Methods: We have studied PTEN expression by immunohistochemistry in tumours samples from 86 patients treated with neoadjuvant treatment. Normal breast epithelium or vascular endothelium were used as positive control. PTEN was evaluated by inmunoreactive stain score, taking into account staining intensity and percentage of positive cells, PTEN deficiency (PTEN -) has been stablished by a IRS=0[1]. We analyzed the PTEN localization (nuclear vs citoplasmatic). Results: In our serie, 38 (44.2%) of the tumours samples were PTEN deficient. Taking into account as reference PTEN + tumours, we have found that PTEN deficient tumours are more frequently; ductal carcinoma (94.2% vs 81.8%), G3 (72% vs 48.7%), ER negative (47% vs 30.4%), Triple negative (24.2% vs 15%) and higher Ki67 expression (>20%) in the 100% of PTEN deficient tumours. The pathological rate response was PTEN -:18.4% vs PTEN +:19.1% p:ns, and the recurrence rate was higher in PTEN- (26,3% vs 8,3%) p:0.025. Conclusions: The PTEN deficient breast tumours is associated to more histological aggressive profile, and we have not found relations with the pathological rate response to neoadjuvant treatment.
Referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: A nationwide study based on 240,134 consultations and 134,652 genetic tests.
Authors: Pujol Pascal , Stoppa-Lyonnet Dominique , Frébourg Thierry , Blin Julien , Picot Marie Christine , Lasset Christine , Bonaiti Catherine , Berthet Pascaline , Grandjouan Sophie , Soubrier Florent , Buecher Bruno , Guimbaud Rosine , Lidereau Rosette , Jonveaux Philippe , Olschwang Sylviane , Houdoyer Claude , Bressac Brigitte , Galibert Virginie , Nowak Frederique , Nogues Catherine
Published: March 2020

1528

Background: Patients referral to dedicated consultations for cancer predisposition syndrome has become a standard in clinical practice. Based on nationwide data from the French national cancer institute (NCI), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with a BRCA1/2 or MMR mutation. Methods: All French cancer genetics centres completed annually a survey collecting standardized parameters for the NCI from 2003 to 2011. We report on the analysis of a total of 240,134 consultations and 134,652 genetic tests that enabled to identify 32,494 mutation carriers. Results: From 2003 to 2011, 141,639 (59 %) and 55,698 (23.2 %) patients were referred for a breast or a colorectal cancer predisposition syndrome, respectively. During this period, we found a dramatic and steadily increase in genetic tests performed for the BRCA1/2 genes (from 2095 to 7393 tests/year, P<0.0001) but not for the MMR genes (from 1144 to 1635/year, P=NS). The percentage of deleterious mutations identified in the probands tested was 13.8 % and 20.9 % in BRCA1/2 and Lynch syndromes, respectively. In families with a BRCA1/2 or a MMR identified mutation, there was an average number of 3.03 relatives performing target tested. Conclusions: This nationwide study shows a lack of referral and genetic testing in Lynch syndrome as compared to BRCA1/2 syndrome. Only a third of relatives for a proband identified with a BRCA1/2 or MMR gene mutations performed a genetic targeted test. Enhanced information about validated benefit of genetic testing should be given to clinicians and patients particularly for Lynch syndrome and for relatives of a proband carrying an identified BRCA1/2 or MMR genes mutation.
PROFILE: Broadly based genomic testing for all patients at a major cancer center.
Authors: Rollins Barrett J , MacConaill Laura E. , Wagle Nikhil , Garcia Elizabeth , Kuo Frank C , Longtine Janina A , Garber Judy Ellen , Janeway Katherine A. , Fuchs Charles S. , Bertagnolli Monica M. , Soiffer Robert , Matulonis Ursula , Lin Nancy U. , Hahn William C , Garraway Levi A. , Kantoff Philip W. , Lindeman Neal Ian
Published: March 2020

1531

Background: Genotyping plays an increasingly important role in the management of cancer patients. However, the landscape of genomic abnormalities is unknown for many cancers and the influence of specific genotypes on clinical behavior is often unclear. To address these deficiencies, we developed PROFILE, a project designed to obtain genomic information on all patients who come to our hospitals for cancer-related care. Methods: Clinically acquired specimens were genotyped using a mass spectrometry genotyping test (OncoMap) which assays 471 alleles in 41 cancer-related genes. Because the majority of these alleles currently have no known clinical meaning, we implemented PROFILE as a research test. This required developing an "umbrella" protocol governing PROFILE activity, a highly simplified 2-page consenting brochure, and a centralized consenting process. We created process flows for retrieving clinical specimens and performing OncoMap in a CLIA-certified laboratory. We return results on individual participants to their ordering providers who can use actionable findings to guide management. All results are stored in a database which can be queried using a web-based search tool that returns aggregate results. Approval to link specimen to clinical information can be sought by a streamlined process of User Committee and IRB approval, and linkage is performed by IS acting as honest brokers. Results: From August 2011 through December 2012, we consented 12,980 patients (consent rate >70%). We found that 39% of clinical samples are of sufficient quality to yield OncoMap results. We have reported and stored 3,000 genotyping results. OncoMap mutations were detected in 40% of clinical samples. As expected, mutations in KRAS, PIK3CA, TP53, and BRAF were most commonly observed across all tumor types. However, rarer mutations were also detected in RET, PIK3R1, and ERBB2 among others. Conclusions: Novel operational approaches have permitted enterprise-wide, broadly-based genotyping that serves a combination of research and clinical needs. Early insights from this database will be discussed along with information about their impact on clinical management.
Telomere length and recurrence risk after curative resection in women with adenocarcinoma of the lung: A prospective cohort study.
Authors: Kim Eric S. , Ye Yuanqing , Vaporciyan Ara A. , Xing Jinliang , Huang Maosheng , Gu Jian , Roth Jack A. , Lippman Scott Michael , Wu Xifeng
Published: March 2020

1532

Background: We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small cell lung cancer (NSCLC). Methods: This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative resection at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time PCR. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. Results: Median duration of follow-up was 61 months and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared to those without recurrence (1.13 vs 1.07, P=0.046). A subgroup analysis indicates that women had longer RTL compared to males (1.12 vs 1.06, P=0.025), and the patients with adenocarcinoma demonstrated longer RTL compared to those with other histologic types (1.11 vs 1.05, P=0.042). To determine if longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, gender, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in female (HR=2.25; 95% CI, 1.02-4.96, P=0.044) and adenocarcinoma subgroups (HR=2.19; 95% CI, 1.05-4.55, P=0.036). The increased risk of recurrence due to long RTL was more apparent in females with adenocarcinoma (HR=2.67; 95% CI, 1.19-6.03, P=0.018). Conclusions: This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma appear to be special subgroups in which telomere biology may play an important role. (Supported by NCI CA 111646, CA 55769, and CA 70907.)
Inadequate family history assessment by oncologists as a physician barrier to referral for cancer genetics evaluation.
Authors: Ow Samuel Guan Wei , Yong Yvonne Fong Ling , Chieng Wei Shieng , Phyu Pyar Soe , Lee Soo-Chin
Published: March 2020

1535

Background: Cancer genetics programs have been established in tertiary cancer centers in Asia for more than a decade. However, the proportion of high-risk patients who are referred for genetic evaluation remains low, and may be attributed to physician and patient barriers. Methods: We reviewed 3-generation genograms of 6301 cancer (CA) patients constructed by a trained cancer genetics counselor at our centre between 2001 and 2012, and identified 1092 (17.3%) patients with suspected hereditary cancer syndromes. 618 patients were estimated to have ≥10% chance of carrying a BRCA1/2 mutation. Their case records were reviewed to determine the referral pattern to the cancer genetics clinic. Results: Of the 618 high risk patients, 420 (68%) had young onset CA (age <40), 112 (18.1%) were breast CA families, and 58 (9.4%) were breast and ovarian CA families; only 164 (26.5%) were seen in the cancer genetics clinic. Of the 391 records reviewed so far, 132 cases (33.8%) were referred for genetic evaluation. A good family history (FH), defined by obtaining CA history in 3 consecutive generations, was obtained by the primary oncologist in 52.2%, compared to adequate smoking and drinking history in 64.7% of cases (p<0.001). Taking a good FH increased the likelihood of oncologists suspecting hereditary breast and ovarian CA syndrome (50% vs 32.1%; p<0.001), with 79% (128/162) of physician-suspected cases referred for genetic counseling. Young onset CA was more likely to arouse physician suspicion (46.9%) compared to other indications (30.5%, p=0.002). Of the 259 high-risk cases that were not referred, lack of FH evaluation by the oncologist was the most common reason (41.3 %), followed by lack of suspicion despite taking a FH (34.7 %), patient refusal (8.6%), and planned but no formal action (1.6%). Conclusions: Failure to take a good FH and failure to recognize high-risk CA patients despite taking a FH are important physician barriers that resulted in only a third of high-risk breast or ovarian CA patients being referred for cancer genetics evaluation at a tertiary cancer center in Asia. Systematic FH screening by genetic counselors, clinic-based protocols, and continued physician education may rectify this barrier.
A randomized trial of telephone versus in-person disclosure of BRCA 1/2 results.
Authors: Bradbury Angela R. , Patrick-Miller Linda J. , Egleston Brian , Smith Kyle , Fetzer Dominique , Forman Andrea , Bealin Lisa , Rybak Christina , Rainey Kim , Cherry Carol , Montgomery Susan , Daly Mary Beryl
Published: March 2020

1538

Background: While some providers use telephone to share genetic test results, there is limited data on the efficacy and impact on patient cognitive and emotional responses. Methods: Patients who completed in-person genetic counseling for BRCA 1/2 testing were randomized to telephone (TD) or in-person (IPD) disclosure. Baseline (BL) and post-disclosure (PD) surveys assessed knowledge, satisfaction and psychological factors. We used T-tests and multiple linear regressions. Results: 179 patients (68% of approached),126 (72%) agreed to be randomized; 36 (28%) declined randomization (Self-select IPD). Patient characteristics did not differ between arms. Change in knowledge, satisfaction and psychological factors did not differ between TD and IPD (Table). Self-select IPD participants had greater declines in depression and state anxiety (Table). In multivariable models, history of cancer was associated with greater declines in general anxiety (coef -1.4, p=0.01). BRCA+ results were associated with greater increases in knowledge (coef 3.2, p 0.02) and state anxiety (coef 12.0, p<0.01), and declines in satisfaction (coef -6.6, p<0.01). Having a mutation in the family was associated with greater declines in intrusive thoughts (coef -4.8, p<0.01). Conclusions: In general,telephone disclosure of BRCA1/2 results does not appear to negativelyimpact psychological outcomes but outcomes among carriers (BRCA+) differ. Larger studies are needed to understand the impact among subgroups and more diverse populations. Some patients preferred in-person communication and had different outcomes, suggesting more data is needed before telephone disclose is universally adopted. [Table: see text]
R497K of EGFR and BIM deletion polymorphisms as predictive biomarkers to EGFR TKIs in NSCLCs harboring wild-type EGFR.
Authors: Kang Jin Hyoung , Shin Jung-Young , Kim Jeong-Oh , Oh Ji-Eun , Jeon Eun Kyoung , Hong Sook Hee , Chun Sang Hoon
Published: March 2020

1540

Background: Activating EGFR mutations are strongly predictive of EGFR tyrosine kinase inhibitor (TKI) activity in NSCLCs, however, some patients having wild type EGFRdo not infrequently show clinically favorable outcome to EGFR TKIs. The key proapoptotic proteins have been reported to be involved in TKI-induced cell death. The up-regulation of BIM, a pro-apoptotic protein of BCL2 family, is required for TKIs to induce apoptosis in cancers. Methods: For 150 advanced or metastatic NSCLC pts. receiving gefitinib or erlotinib, we assayed mutation status of EGFR in paraffin embedded tumor tissue using PNA clamping (PANAGENE, Korea) and direct sequencing. Six different genetic variants of EGFR (-191C>A, -216 G>T, CA repeat number, R497K, 2607G>A, and D994D) and BIMdeletion in genomic DNA extracted from peripheral blood were analyzed. Results: M:F ratio was 72:78 and median age was 63 (35~82). Histological subtypes are as follows: 131 adenocarcinoma (87.3%), 16 squamous cell ca. (10.7%) and 3 large cell ca. (1.3%). Objective tumor response (CR+PR) was observed in 60 pts. (40.0%) and SD in 44 pts. (29.3%). Median PFS and OS were 4.3 (0.4~67.4) and 18.6 (0.9~78.1) months, respectively. Of 129 pts. in whom EGFR mutation could be analyzed, 41 pts. (31.8%) had activating EGFR mutation. In univariate analysis, only gender was associated with objective response to EGFR TKI in activating EGFR mutant group (P=0.048). In wild type EGFR group (n=88), R497K (P=0.04) and BIM (P=0.04) as well as gender (P=0.05) were significantly correlated with objective response. In addition, multivariate analysis demonstrated that gender, R497K and BIM were associated with objective response to EGFR TKIs in wild type EGFR group with statistical significance (P=0.023, 0.027 and 0.018, repectively). Neither six EGFR polymorphisms nor BIM was correlated with PFS and OS in activating EGFR mutant group. Meanwhile, in wild type EGFR group, R497K was significantly associated with OS (P=0.028). Conclusions: Taken together, our data suggest that R497K of EGFR and BIM deletion polymorphisms are useful pharmacogenetic biomarkers to predict objective tumor response for EGFR TKIs in advanced NSCLC pts. harboing wild type EGFR.
Unique genetic characteristics of BRCA mutation carriers in a cohort of Arab American women.
Authors: Shatavi Seerin Viviane , Dohany Lindsay , Chisti Mohammad Muhsin , Jaiyesimi Ishmael A. , Zakalik Dana
Published: March 2020

1541

Background: Worldwide ethnic variations in the distribution of BRCA1 and BRCA2 mutations of breast cancer patients have been recently recognized. This has led to investigations of the epidemiology, genetics and clinical characteristics of BRCA positive individuals within specific populations. This study aims to describe the findings of BRCA genetic testing in a cohort of Arab American women. Methods: A total of 73 women of Arab ancestry were evaluated in the Beaumont Cancer Genetics Program from Jan 2008 to Jan 2013. Criteria for genetic testing included a personal or family history suggestive of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Patients underwent comprehensive genetic counseling, followed by full sequence analysis for germline mutations in BRCA1 and BRCA2. Results: 63 women of Arab ancestry underwent genetic testing for BRCA1 and BRCA2. 13 (21%) patients were found to be mutation carriers, of whom 10 (16%) of the 63 had deleterious mutations (7 in BRCA2, and 3 in BRCA1), and 3 (5%) had variants of undetermined significance (VUS) in BRCA2. Of the 10 patients with deleterious mutations, 4 (40%) unrelated individuals had the same mutation, 5804del4, in exon 11 of BRCA2. The remaining patients had deleterious mutations in exon 2, exon 20, and exon 13 of BRCA2; one patient had a BRCA1 and BRCA2 mutation (exon 18). 7 of 10 patients with deleterious mutations had a cancer diagnosis, of which 5 had breast cancer, 1 had ovarian cancer, 1 had pancreatic cancer, and 3 were unaffected. Conclusions: This study demonstrates that BRCA mutations (predominantly in BRCA2) were seen in a significant proportion of Arab American women undergoing genetic testing for HBOC. A mutation in BRCA2, 5804del4, was seen in nearly half (4/10) of the carriers of deleterious mutations. This mutation, in exon 11, has not previously been associated with Arab ethnicity and may represent a founder mutation. Knowledge of the genetic spectrum, frequency, and clinical characteristics of BRCA mutation carriers will lead to greater understanding of hereditary cancer in Arab American women.
BRCA1/2 mutation prevalence among triple-negative breast cancer patients from a large commercial testing cohort.
Authors: Zonno Kristilyn Dillman , Kaldate Rajesh R. , Arnell Christopher , Saam Jennifer , Abbott Brian , Hartman Anne-Renee
Published: March 2020

1544

Background: BRCA1/2 deleterious mutation identification among triple-negative breast cancer (TNBC) patients has gained importance due to cancer-risk management implications for patients and their relatives, and also has an emerging role in guiding treatment selection for therapies such as PARP inhibitors. The National Comprehensive Cancer Network (NCCN) currently recommends BRCA1/2 testing for TNBC patients diagnosed at age <60. Mutation prevalence among TNBC patients has previously been studied only in small regionalized cohorts. A recent study in unselected patients using the updated definitive criteria for TNBC reported mutation prevalence as 10.6%. Methods: Following the 2011 NCCN Hereditary Breast and Ovarian Cancer (HBOC) Testing Criteria update, serial cohorts of > 5,000 Ashkenazi Jewish and > 65,000 non-Ashkenazi Jewish breast cancer patients undergoing commercial BRCA1/2 testing were analyzed. Age at diagnosis, ethnicity, and provider-reported TN status were obtained from test requisition forms completed by ordering providers, and correlated with test results. Neither the accuracy nor definitive criteria used for TN status reported was independently verified. Results: Incidence of TNBC was reported as 9.7% among non-Ashkenazi patients and 16.5% within the subset with African ancestry. Incidence of TNBC was reported as 4.5% among Ashkenazi patients, but this is likely affected by test ordering for this population. The Table displays the BRCA1/2mutation rates classified by ethnicity and age-group. Conclusions: This study provides the most robust estimate to date of BRCA1/2 mutation prevalence among TNBC patients of all ages. The mutation rates seen among TNBC patients diagnosed after age 60 also illustrate the importance of testing such patients who may not meet the current NCCN HBOC testing criteria. [Table: see text]
Risk of hospital-related morbidity among survivors of breast cancer in British Columbia, Canada.
Authors: Simmons Christine E. , Wai Elaine , Tyldesley Scott , Lorenzi Maria , Li Dongdong , McBride Mary L
Published: March 2020

1551

Background: Long-term consequences of cancer diagnosis and treatment are of increasing concern, as therapeutic interventions improve survival. Various survivorship programs exist; few address the importance of bridging oncology and primary care. This study assesses risk of late hospital-related morbidity among a population-based cohort of 39,436 3-year survivors of female breast cancer in British Columbia, Canada and compares the risk of morbidity to a similarly-aged comparison group. Methods: Demographic and clinical records of breast cancer survivors diagnosed between 1986 and 2005 were linked to inpatient records from provincial administrative databases. A comparison group from the provincial health insurance plan registry, frequency-matched by birth cohort was identified. Morbidity was ascertained from diagnosis codes listed on hospital records, and categorized by organ system. Poisson regression was used to assess the relative risk of morbidity, adjusting for sociodemographic factors. Results: Compared to controls, non-relapsed survivors diagnosed age 18-39 (N=1158) had more than twice the risk of morbidity (RR 2.57, 95%CI 2.21-2.98); those with a relapse (N=580) had eight times the risk (95% CI 6.78-9.44). Among those diagnosed age ≥40, non-relapsed survivors (N=20473) had a 62% increase in risk RR 1.62, 95% CI 1.57-1.68; relapsed survivors (N=5223) had triple the risk of morbidity (RR 2.89, 95% CI 2.78-3.01). In both cohorts, excess risks were statistically significant for most types of non-neoplastic morbidity, with highest rates seen for disorders of the blood, endocrine, skin and circulatory systems. Among survivors, those diagnosed with a higher stage cancer had increased risk of morbidity. Type of treatment received did not correlate with increased risk of morbidity (RR 1.05, 95% CI 1.00–1.11 for combination of surgery, radiation and systemic therapy vs surgery alone); majority of the risk increase is likely related to the impacts of cancer itself rather than treatment. Conclusions: Survivors of breast cancer are at an increased risk of a wide range of morbidities years after diagnosis. This underscores calls for improved models of survivorship care and continued survivorship research.
Increasing dietary rice bran consumption for colorectal cancer prevention and control.
Authors: Borresen Erica , Weir Tiffany , Doyle-Gundlach Kerry , Wdowik Melissa , Brown Regina J. , Marschke Robert Frederick , Dickson Erica , O'Malia Joanne , Bazan Marlon , Ryan Elizabeth
Published: March 2020

1558

Background: Emerging evidence supports that dietary rice bran (RB) exhibits colorectal cancer (CRC) control and prevention activity, yet a significant knowledge gap exists for feasibility of increased RB intake in humans. BENEFIT (Bran Enriching Nutritional Eating For Intestinal health Trial), is a community-academic partnership for dietary chemoprevention research. Our main objectives were to pilot the feasibility of increased RB consumption in healthy adults, with and without a history of CRC, and to examine changes in gut microflora and fecal metabolite profiles following RB consumption. Methods: Seven meals and six snacks were developed for inclusion of dietary RB (30g/day). A total of 15 adults (7 non-cancer and 8 CRC survivors) completed the randomized-controlled, dietary intervention trial. Participants were blinded to their study group (placebo-control or RB) and consumed one study meal and snack daily for 28 days. Blood, urine, saliva and stool samples were collected at baseline, 2-week, and 4-week timepoints for metabolomic and microbiome analyses. Participants recorded weekly 3-day dietary food logs. Results: Adding RB (30g) into prepared foods provided 4-8% daily caloric intake with 95.5% intervention compliance. Inclusion of RB or control diet intervention in our non-cancer cohort did not result in a major shift of the fecal microbiome after 2- and 4-weeks. For CRC survivors, we observed that 19% of the total variation in the fecal microbiome was due to the rice bran intervention. At the genus level, we saw changes in Bacteroides, Bifidobacterium, and Ruminococcus. Principal Components Analyses of fecal metabolome detected using liquid-chromatography mass spectrometry revealed 16% variation between time points and 8% variation when comparing RB and control groups at 4 weeks. Candidate metabolites from ~50 features will be determined by spectral libraries and database matches. Conclusions: The accessibility, affordability, and availability of RB support the global public health impact potential for novel RB “phytochemical teamwork” based CRC control and prevention strategies. These findings warrant further evaluation of increased RB intake in a larger cohort for CRC control and prevention.
Addressing tobacco use and cessation in cancer patients: Practices, perceptions, and barriers reported by oncology providers.
Authors: Warren Graham Walter , Marshall James Roger , Cummings K. Michael , Toll Benjamin A , Gritz Ellen R. , Hutson Alan , Dibaj Shiva , Herbst Roy S. , Mulshine James L. , Hanna Nasser H. , Dresler Carolyn
Published: March 2020

1561

Background: Tobacco use is associated with adverse outcomes in cancer patients, but there are limited data on tobacco cessation support by oncology providers. Methods: Duplicate surveys were sent to the membership of the International Association for the Study of Lung Cancer (IASLC) and the American Society of Clinical Oncology (ASCO) asking about tobacco assessment and cessation practices, perceptions of tobacco use by cancer patients, and barriers to implementing tobacco cessation. The results of 1,507 responses from IASLC and 1,197 responses from ASCO are reported. Results: At initial consult, most respondents asked about tobacco use (90% in both surveys), asked if smokers would quit tobacco use (79-80%), advised patients to stop smoking (81-82%). Most respondents felt that tobacco affects cancer outcomes (87-92%) and that tobacco cessation should be a standard part of clinical care (86-90%). However, few discussed medication options (40-44%) or actively provided smoking cessation assistance (39% in both surveys). Fewer respondents asked about tobacco use at follow-up and few reported adequate tobacco cessation training (29-33%). Dominant barriers to providing cessation interventions included patient resistance to cessation treatment (67-74%) and inability to get patients to quit tobacco use (58-72%), but very few believed tobacco cessation was a waste of time (8-12%). Lack of time, reimbursement, lack of training, and lack of resources were reported as barriers in less than 50% of respondents. Conclusions: Oncology providers feel tobacco affects cancer outcomes and cessation should be a standard part of clinical care. Most assess tobacco use, but few discuss medication options or provide active cessation support. Efforts are needed to improve cessation methods in cancer patients and to improve access to tobacco cessation support for cancer patients.
Patients’ reactions to a decision aid about lung cancer screening with low-dose spiral computed tomography: An uncontrolled trial.
Authors: Volk Robert J. , Linder Suzanne K. , Leal Viola , Rabius Vance A. , Cinciripini Paul M. , Kamath Geetanjali R. , Munden Reginald F. , Bevers Therese Bartholomew
Published: March 2020

1564

Background: Results from the National Lung Screening Trial (NLST) and a recent ASCO-supported systematic review concluded that screening with low-dose spiral computed tomography (LDCT) reduces lung cancer deaths among selected heavy smokers. Yet, this mortality benefit must be weighed against the potential harms of screening (e.g., high false positive rate). In anticipation of LDCT screening becoming a reimbursable preventive health service, we developed and evaluated a brief, video-based patient decision aid designed for use in clinical settings. Methods: Patients from a tobacco treatment program who were 45 to 75 years of age and had no history of lung cancer participated in the study. Measures of acceptability and ratings of the aid were included. We assessed effectiveness of the aid via knowledge about lung cancer and the benefits and risks of screening, and clarity of values using the Decisional Conflict Scale. Results: Fifty-two patients completed the study (mean age=58.5 years; mean average years smoking=34.8 years). Over 94% of patients watched the entire video, would recommend it to others, felt it held their interest, rated the content favorably, and wanted to view similar video-based aids. Acceptability was high, although 23.3% wanted more information about the NLST findings and evidence base. After viewing the aid, knowledge about lung cancer screening increased significantly (before viewing aid, 25.5% of questions answered correctly; after viewing aid, 74.8%; P<.01). The majority of patients continued to have difficulty with the question about whether all current and former smokers should be screened for lung cancer (23.1% answered correctly). Patients reported being clear about which benefits and harms of screening mattered most to them (94.1% and 86.5% were clear, respectively). Conclusions: Our decision aid was rated favorably by tobacco treatment patients. Large gains in knowledge about lung cancer screening were observed, highlighting the important informational function of the aid. Additional features under consideration for the aid include screening eligibility assessment and information about the evidence behind the screening recommendations.
Increasing access to tobacco cessation support for cancer patients: Results of an institution-wide screening and referral program in an NCI-designated comprehensive cancer center.
Authors: Reid Mary E. , Dobson Amato Katharine , Zevon Michael , Reed Robert , Hysert Pat , Hysert Robert , Segal Stephanie , Mahoney Martin , Nwogu Chukwumere E. , Hyland Andrew , Marshall James Roger , Cummings K. Michael , Warren Graham Walter
Published: March 2020

1566

Background: Guidelines from ASCO and other national organizations recommend assessment of tobacco use and structured tobacco cessation support for cancer patients. However, most oncology providers fail to provide cessation assistance to cancer patients who use tobacco. Reported are results of a systematic approach to assessing tobacco use and delivering cessation support for cancer patients in a comprehensive cancer center. Methods: A standard set of evidence based tobacco assessment questions were incorporated into an automated electronic medical record based system delivered by nursing at initial consult and follow-up. Patients eligible for tobacco cessation support (i.e. patients self-reporting tobacco use within 30 days) were automatically referred to a dedicated tobacco cessation service providing primarily phone based cessation support. Results: Of approximately 11,900 patients screened over 26 months, 2,978 patients were automatically triaged for cessation support. Contact priority was given to newly diagnosed patients in tobacco related disease sites. Using 1.25 full time cessation specialists, 1,531 received only a standard tobacco cessation mailing and no further contacts were attempted by the cessation service. In 1447 patients with attempted phone contact by the cessation service, 1189 (82.2%) were reached within 5 contact attempts. In 1,189 patients contacted, 52 (4.4%) were inappropriate referrals, 245 (20.6%) were in an active quitting phase, 465 (39.1%) were willing to prepare, and only 24 (2.0%) refused any intervention at initial contact. At the most recent follow-up, 44 patients (3.7%) requested no further contact and 90 additional patients (7.6%) were lost to follow-up. In the 1,045 remaining patients, 338 (32.3%) reported quitting tobacco use. Notably, in the 1,531 patients with no phone contact by the cessation service, only 14 proactively contacted the cessation service for assistance. Conclusions: An institution wide program to automate the delivery of tobacco cessation services was feasible with high patient contact rates, low patient refusal, and moderately high tobacco cessation rates.