bluuebunny/crossref_metadata_2025 huggingface dataset:
Nomogram for predicting breast-conservation surgery after neoadjuvant chemotherapy.
Authors: Kim Min Kyoon , Han Wonshik , Moon Hyeong-Gon , Kim Jisun , Ahn Soo Kyung , Lee Jun Woo , Noh Dong Young , Kim Taeryung , Kim Ju yeon
Published: March 2020

1128

Background: The indications for neoadjuvant systemic treatment (NST) have broadened to early breast cancer patients and more patients can undergo breast conservation with results in better cosmetic outcomes. However, a significant number of patients with operable breast cancer still require mastectomy after NST with a small number of patients experiencing disease progression which may hinder complete surgical resection. Therefore, accurate prediction of each patient’s likelihood of achieving breast conservation after NST is important for establishing a treatment plan for patients with operable breast cancers. Methods: We identified 534 women from the Seoul National University Hospital Breast Care Center, who were stage II and III, and treated with neoadjuvant chemotherapy and surgery from Jan. 2001 to Dec. 2010. Breast conservation surgery (BCS) and tumor size reduction to less than 3cm were clinical outcome variables for nomograms, and we analyzed the various clinicopathologic factors best predicting these outcomes. To develop well-calibrated and exportable nomograms for BCS and for residual tumor size, we built each model in a training cohort and validated it in an independent validation cohort. Results: Of the 513 patients, pCR was observed in 10.5% and BCS was performed in 50.1%. The nomogram for predicting BCS and tumor size reduction to less than 3cm were constructed using logistic regressing model. Initial tumor size(p<0.001), the distance between the lesion and the nipple (p < 0.001), the presence of suspicious calcifications in the mammography (p = 0.0127) and multicentricity (p = 0.0146) were independently associated with breast conservation surgery. ER status (p = 0.001), initial tumor size (p < 0.001), histologic type (p = 0.012) were independently associated with a residual tumor size <3cm. Mastectomy rate in the larger than 3cm tumors were 72.7%, and breast conservation surgery in smaller than 3cm tumors were 63.2%. (p < 0.001). Conclusions: In conclusion, we have established a new model to predict BCS and residual tumor size after NST. The model showed the outperformed prediction accuracy compared with previous similar models with reflecting novel factors impacting on surgical decision making.
Influence of guideline-concordant adjuvant therapy on all-cause and disease-specific survival among breast cancer patients in rural Georgia.
Authors: Guy Gery P. , Gillespie Theresa Wicklin , Goodman Michael , Richardson Lisa Carolyn , Ward Kevin C. , Lipscomb Joseph
Published: March 2020

1130

Background: This study examines whether receipt of chemo-, radiation, and hormonal therapy regimens that are jointly guideline concordant improve survival outcomes among women diagnosed with breast cancer in a rural region of the United States. Methods: All women identified by the state cancer registry residing in rural southwest Georgia diagnosed with early stage breast cancer during 2001-2003 were included. Medical chart abstraction and registry data were used to determine treatment concordance with the 2000 NIH consensus development conference guidelines on breast cancer treatment. Patients were Concordant versus Non-Concordant according to whether their receipt (or non-receipt) of each adjuvant therapy type was according to guidelines. To examine the effects of concordance on all-cause and breast cancer-specific survival, Cox models were developed that used both propensity score weighting and 2-stage residual inclusion instrumental variable techniques to adjust for patient selection effects. Results: In all-cause analyses, Concordance versus Non-Concordance was associated with significantly better survival (hazard ratios (HRs) 0.41 (95% CI: 0.24-0.72) to 0.54 (95% CI: 0.33-0.87). Similar findings emerged in breast cancer-specific survival analyses, with HRs significantly less than 1.0 in most cases. Diagnosis at older age or later disease stage strongly predicted poorer survival outcome; being not married was significant in all-cause but not breast cancer-specific models. Survival was not generally associated with surgical treatment delay, insurance status, socioeconomic status, rural/urban status, comorbidities, tumor grade, or hormonal status. HR for black women versus white was greater than 1.0 across models but never significant (p=0.05). Conclusions: Breast cancer patients in rural Georgia who received guideline-concordant adjuvant therapy had significantly better all-cause and breast cancer-specific survival, based on Cox model analyses that attempted to control for multiple clinical and demographic factors, as well as selection effects. These findings extend the evidence that guideline bundles of care improve outcomes.
Breast cancer risk prediction using the novel germ-line signatures in epigenome regulatory pathways.
Authors: Adaniel Christina , Rendleman Justin , Smith Julia Anne , Klein Robert J. , Schnabel Freya Ruth , Shao Yongzhao , Offit Kenneth , Kirchhoff Tomas
Published: March 2020

1500

Background: Epigenetic regulatory pathways are intensely studied for their involvement in breast tumorigenesis, however little is currently known about the genetic variation in epigenome components contributing to the risk and/or prognosis of breast cancer. In this study we have tested how the novel germline genetic signatures identified in epigenetic regulatory genes (ERGs) may potentially contribute to clinical prediction of breast cancer risk. Methods: We have genotyped 711 SNPs tagging 87 ERGs in 1985 breast cancer cases and 1609 controls, using Sequenom i-Plex. The samples were of white European origin with the fraction of Ashkenazi Jewish (AJ) ancestry (n=1642). The association of SNPs with breast cancer risk was assessed using logistic regression, adjusted by age, AJ status and estrogen-receptor (ER) status. The predictive ability of SNP signatures was tested by ROC curves using logistic regression fitting the SNP/clinical covariate models, and the area under the curve (AUC) was used to assess their utility in the classification of breast cancer risk. Results: We have identified the signature of 20 SNPs tagging 13 ERGs, significantly associated with breast cancer risk. The strongest association has been observed for RUNX1 (rs7280097, OR=0.83, CI 95%: 0.71-0.94, p=0.006) and PRDM16 (rs12135987, OR=1.22, CI 95%: 1.06-1.42, p=0.007). The inclusion of predictor variables (age, AJ status, ER status) and 20 associated SNPs in logistic regression ROC curve analysis yielded in best fitting model involving 10 SNPs tagging 8 ERGs with AUC of 0.723, compared to 0.660 with predictor variables alone (p=0.003). Conclusions: We have identified a signature of 20 SNPs in epigenetic regulatory genes (20-SNP-ERG) significantly associated with breast cancer risk. In addition, the incorporation of 10 SNPs from 20-SNP-ERG into risk prediction model increases the ability to classify breast cancer risk in addition to other clinical and demographic covariates. The results suggest the promising clinical potential of 20-SNP-ERG signature in identification of high-risk individuals in the population, and point to possible biological implication of germline patterns in epigenetic enzymes in breast tumorigenesis.
Impact of bilateral oophorectomy on contralateral breast cancer risk in BRCA negative women from site-specific hereditary breast cancer kindreds.
Authors: Long Kara C , Pike Malcolm C , Otegbeye Ebunoluwa , Arnold Angela G. , Stadler Zsofia Kinga , Robson Mark E. , Barakat Richard R. , Offit Kenneth , Chi Dennis , Kauff Noah D.
Published: March 2020

1511

Background: BRCA negative (BRCAneg) women from site-specific hereditary breast cancer (SSB) kindreds have been shown to have an increased risk of breast cancer (BC), but not ovarian cancer (OC). It is hypothesized that, as in women with BRCA mutations, bilateral salpingo-oophorectomy (BSO) will decrease the risk of developing future BCs in women from these BRCAneg SSB kindreds. Methods: Since 5/1995, all women undergoing genetic counseling and testing for BRCA mutations at our institution were offered participation in an IRB-approved prospective cohort study. This sub-study examines the impact of BSO on contralateral BC risk in BRCAneg SSB kindreds. Inclusion criteria were: a personal history of unilateral invasive BC ≤ age 60, at least one 1st or 2nd degree female relative with BC ≤ age 60, testing BRCAneg between 1/1/2002 and 2/28/2011. Exclusion criteria were: bilateral mastectomy (BM) or BSO prior to genetic testing, family history of OC, <6 months of followup (F/U). Demographic data and pedigrees were collected at the start of F/U, which was defined as the date of genetic testing. F/U data was obtained via mailed questionnaire and medical record review. Participants were censored at the time of BM, OC, or last F/U. Data were analyzed using a Cox proportional-hazards model with time from genetic testing as the time variable and BSO as the time dependent covariate. Results: 328 living participants met the inclusion criteria and F/U was obtained on 301 (208 via questionnaire, 93 via record review). Median age at genetic testing was 49.0 years (27.4-73.2 years). Median F/U time was 5.1 years (0.5-10.5 years). During the course of F/U, 43 women underwent BSO and 21 women underwent BM. There were 12 contralateral BCs (8 invasive, 4 DCIS) identified: 3 in the BSO group and 9 in the no-BSO group. After controlling for age, parity, prior hormone use, and estrogen receptor status of the original BC, the risk of contralateral BCs was not decreased in women who underwent BSO vs those who did not (HR 2.07, 95% CI 0.51 – 8.35, P=0.31). Conclusions: In BRCAneg women from SSB kindreds with a personal history of early onset BC, BSO does not decrease the risk of developing contralateral BC.
The role of statins for primary prevention in non-elderly colorectal cancer patients.
Authors: Sehdev Amikar , Shih Ya-Chen T. , Vekhter Benjamin , Lyttle Christopher , Polite Blase N.
Published: March 2020

1513

Background: There is conflicting evidence for the effect of statins in primary prevention of colorectal cancer (CRC). We conducted a case control study (N=357,702) in non-elderly adult US population (age 18-64 years) to investigate the role of statins in primary prevention of CRC. Methods: We used MarketScan claims database to identify patients with CRC using ICD-9 codes. A case was defined as having an incident diagnosis of CRC. Up to ten controls (matched for age, sex, and geographical region) were selected per case. Statins exposure was assessed from prescriptions in the 12 months prior to the earliest date of CRC diagnosis. The primary objective was to assess the incidence of CRC in statin users and nonusers. Conditional logistic regression was used to adjust for multiple potential confounders and calculate adjusted odds ratios (AOR). Results: The mean age of CRC patients was 54 years, 52% were males.Statins were prescribed to 19.1% (68,461/357,702) patients.A total of 8.3% (5,704/68,461) patients developed CRC in statin exposed group compared to 9.3% (26,912/289,241) patients in non-statin exposed group. In a multivariate model, any statin use was associated with 25% reduced risk of CRC (AOR 0.75, 95% CI, 0.73-0.78, p<0.001). An age-stratified analysis showed more benefit in patients aged 55 years or less than those above age 56 years (AOR 0.68 and AOR 0.79 respectively; p<0.001 for interaction between age group and statin exposure). Variables associated with increased incidence of CRC in the multivariate model were obesity (AOR 1.3, 95% CI, 1.2-1.4, p<0.001); DM (AOR 1.2, 95% CI, 1.1-1.2, p<0.001); IBD (AOR 3.1, 95% CI, 2.8-3.5, p<0.001); use of insulin (AOR 1.2, 95% CI, 1.1-1.3, p<0.001) and sulfonylureas (AOR 1.2, 95% CI, 1.1-1.3, p<0.001). Prescribed NSAIDs showed modest reduction in CRC incidence (AOR 0.94, 95% CI, 0.91-0.97, p=0.002). There was no significant relationship between CRC incidence and other oral hypoglycemic drugs. Conclusions: Statins appears to reduce the incidence of CRC in non-elderly adult US population. A randomized controlled trial is needed to validate this finding.
Variation in the efficacy of low-dose computed tomographic lung screening based on risk of lung cancer mortality in the National Lung Screening Trial.
Authors: Katki Hormuzd A. , Kovalchik Stephanie A , Tammemagi Martin , Berg Christine D. , Caporaso Neil , Riley Tom , Korch Mary , Silvestri Gerard A. , Chaturvedi Anil
Published: March 2020

1523

Background: Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the National Lung Screening Trial (NLST). The efficacy of LDCT screening could be improved by targeting smokers at highest risk of lung cancer death, provided that the efficacy of LDCT screening increases with lung cancer mortality risk. Methods: We evaluated the efficacy of LDCT screening as compared to chest radiography in the NLST across groups defined by participants’ 5-year risk of lung cancer mortality at randomization, which was estimated using a validated prediction model. Across quintiles of 5-year lung cancer mortality risk [Q1: 0.15%-0.55%, Q2: 0.56%-0.84%, Q3: 0.85%-1.24%, Q4: 1.24%-2.0%, Q5: >2.0%], we estimated the number of participants with false positive screens, the number of prevented lung cancer deaths, and their ratio. Results: The number of prevented lung cancer deaths due to LDCT screening increased in tandem with lung cancer mortality risk (Q1=0.2, Q2=3.5, Q3=5.1, Q4=11.0, Q5=12.0 per 10,000 person-years; P-trend=0.01). The number of participants with false positive screens per lung cancer death prevented, a measure of screening efficiency, significantly decreased with increasing risk (Q1=1,648, Q2=181, Q3=147, Q4=64, Q5=65, P-trend<0.001). The 60% of participants at highest 5-year lung cancer mortality risk (0.85% or greater) accounted for 88% of LDCT-preventable lung cancer deaths and included only 64% of participants with a false positive screen. The 20% of participants at lowest lung cancer mortality risk (0.15%-0.55%) accounted for only 1% of LDCT-preventable lung cancer deaths. Conclusions: In the NLST, LDCT screening prevented the most lung cancer mortality among those at highest lung cancer mortality risk and prevented almost no mortality among those at lowest risk, providing empirical support for risk-based targeting of smokers to improve the efficacy of LDCT screening.
Smoking and estrogen plus progestin (E+P) and lung cancer incidence and mortality.
Authors: Chlebowski Rowan T. , Wakelee Heather A. , Rohan Thomas E , Liu Jingmin , Simon Michael S. , Tindle Hilary , Messina Catherine R , Wactawski-Wende Jean , Johnson Karen , Schwartz Ann G. , Gass Margery
Published: March 2020

1524

Background: In the Women’s Health Initiative (WHI) randomized, placebo-controlled clinical trial, E+P increased deaths from lung cancer (those cancer-attributed) and after lung cancer (regardless of cause) (Lancet 2009:374:1243). To examine smoking status influence on this process, a cohort combining WHI clinical trial (CT) and observational study (OS) participants, the latter meeting criteria as in the CT, was identified to examine E+P associations with lung cancer incidence and outcome. Methods: 31,966 postmenopausal women (12,299 CT, 19,668 OS) with no prior hysterectomy and no prior hormone therapy use were classified at baseline as not hormone users or E+P users and as current or never smokers. Lung cancers were verified by medical record review. Multi-variant adjusted Cox proportional hazards regression, including pack-year use, calculated hazard ratios (HRs, 95% confidence intervals [CI]) for groups defined by smoking status and E+P use for lung cancer incidence, deaths from lung cancer and deaths after lung cancer. Results: After 12 years mean follow-up, 664 lung cancers were diagnosed with 444 deaths from lung cancer and 513 deaths after lung cancer. Analyzed from cohort entry; see Table. In nonusers of E+P, lung cancer incidence, deaths from lung cancer, and deaths after lung cancer were significantly and substantially greater in current smokers vs never smokers (p< .0001 for all comparisons). In current smokers, lung cancer incidence, deaths from lung cancer and deaths after lung cancer were significantly and substantially greater in E+P users vs non-users (p=.0021, .0005 and .0002, respectively). Conclusions: E+P use in current smokers nearly doubles their already high risk of death from and after lung cancer. Based on this risk, current smokers should not use E+P. [Table: see text]
Cancer risks and mutation spectrum of mismatch repair genes in African American families with Lynch syndrome.
Authors: Kupfer Sonia , Guindalini Rodrigo Santa Cruz , Gulden Cassandra , Ukaegbu Chinedu I , Koeppe Erika , Conrad Peggy , Hampel Heather , Stoffel Elena Martinez , Syngal Sapna , Olopade Olufunmilayo I.
Published: March 2020

1530

Background: Although African Americans (AA) have the highest colorectal cancer (CRC) incidence and mortality of all populations in the United States, no studies have determined cancer risk and mismatch repair (MMR) genes mutation spectrum in LS patients of AA ancestry and the contribution of this syndrome to cancer disparities. Thus, the aims of this study are: (1) to describe LS cancers in AAs; (2) to investigate the mismatch repair (MMR) gene mutation spectrum in AA families with LS; (3) to determine how Amsterdam II criteria, revised Bethesda guideline, and PREMM(1,2,6) model perform for predicting MMR gene mutations in this population. Methods: Pedigrees of AA families with deleterious mutation or suspected deleterious mutation in MMR genes from five US referral centers were analyzed for personal and familial clinical cancer histories. Results: Twenty-four AA families were identified, of which 22 had deleterious mutations (15 MLH1, 4 MSH2, 2 MSH6, 1 PMS2) and 2 had suspected deleterious mutations (1 MLH1, 1 MSH2). Three recurrent mutation were found in MLH1(677G>A, IVS1-2A>G, IVS4-1G>A), accounting for 25% of all mutations. Of 24 probands, 58% were female and 96% had personal history of cancer. The median age at first primary tumor was 42yrs (range 28-57) and 50% developed more than 1 primary tumor. The majority of probands (79%) had CRC (median age of onset – 42yrs [range 31-61]), of which 26% had at least 2 CRC primaries. Endometrial cancer developed in 50% of the women (median age of onset – 51yrs [range 32-57]). Amsterdam II and Bethesda criteria were met in 63% and 88% of the individuals, respectively. Median score by PREMM(1,2,6) model was 54% (range 12.9-99.8). Conclusions: To our knowledge, this is the largest series of AA families with LS reported to date. Earlier age of onset for CRC at 42yrs (previously reported ~45 yrs) is suggested. The majority of mutations were found in MLH1 (67%), including three recurrent mutations. A 10% cutoff for PREMM(1,2,6) predictive model identified all mutation carriers. Larger studies are warranted to confirm the differences observed in age of CRC onset in this population.
A prospective comparison study on EGFR mutations by direct sequencing and ARMS in completely resected Chinese non-small cell lung cancer with adenocarcinoma histology (ICAN).
Authors: Zhang Xuchao , Wu Yi Long , Wang Jun , Chu Xiang-Yang , Liu Zhi-Dong , Shen Yi , Ma Haitao , Fu Xiang-Ning , HU Jian , Zhou Nai-Kang , Liu Yongyu , Zhou Xinming , Wang Jian-Jun , Yang Kang , Xu Lin , Li Jian , Wang Si-Yu , Wang Qun , Liu Lun-Xu , Xu Shun
Published: March 2020

1547

Background: ICAN study investigated EGFR mutation (M) status, clinical outcomes and recurrent risk factors in Chinese lung adenocarcinoma (ADC) patients (pts) after complete resection. Here we report analysis results for the overall EGFR M rate and the consistency between two EGFR M detecting methods, ARMS and PCR+direct sequencing (Seq). Methods: Pts were aged ≥18 years, with histological diagnosed lung ADC, and received surgical complete resection. Tumor sample EGFR M status (primary endpoint; positive [M+]) was determined according to clinical routine practice by whatever methods, including ARMS, Seq, liquid chip and mutant-enriched PCR. For the pts whose tissue was adequate after EGFR M testing by single method of either ARMS or Seq, the other method was applied. Results: Of 571 pts from 26 sites, 315 (55.2%) pts were EGFR M+. 420 pts’ tissues were tested by both ARMS and Seq. EGFR M+ rates were 58.1% and 54.5% respectively without statistical significance (p=0.0548). The total consistent rate (both M status and M types) between two methods was 76.7%. The following Table showed individual EGFR M types by two methods. Conclusions: The overall EGFR M+ rate in operable Chinese ADC was 55.2%. For resection samples, two common methods, ARMS and Seq, didn’t show statistical significance on EGFR M+ rate. Regarding EGFR M types, Seq found some rare mutations which ARMS kit could not detect, while ARMS seemed more sensitive for exon 20 and 21 mutations, especially for S768I and L861Q. Clinical trial information: NCT01106781. [Table: see text]
Decreased TGFBR1 signaling and breast cancer.
Authors: Henegan Clark , Moore-Smith Lakisha , Yi Nengjun , Ahsan Habibul , Whittemore Alice S , Pasche Boris
Published: March 2020

1548

Background: We previously identified TGFBR1*6A (rs11466445), a hypomorphic TGF-beta type 1 receptor variant that is associated with cancer risk, has impaired TGF-beta signaling capability, and enhances the migration and invasion of breast cancer cells (Cancer Res 2008, 68:1319). Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of breast cancer (Mol Biol Rep 2010 37:3227; PLoS One 2012,7(8). Rs7034462 is a single nucleotide polymorphism (SNP) in a noncoding region more than 9 kilobases upstream of TGFBR1 exon 1, which has been shown to be associated with decreased TGFBR1 expression similar to TGFBR1*6A (J Exp Clin Cancer Res 2010, 29:57). In this study we tested the hypothesis that rs7034462 may be associated with breast cancer risk. Methods: rs7034462 was genotyped in DNA obtained from patients with breast cancer and their unaffected sisters recruited by the Breast Cancer Family Registry (B-CFR). Results: The median age of cases and controls was 48.8 and 47.6 years, respectively. Using a simple case-control genetic association analysis for this family-matched population, rs7034462 was found to be associated with breast cancer risk. Conclusions: TGFBR1 rs7034462 is emerging as a low penetrance breast cancer susceptibility allele suggesting that two distinct TGFBR1 SNPs, each associated with decreased TGFBR1 expression, may modulate breast cancer risk. [Table: see text]
The first 10 years experience with genetic testing (GT) for BRCA1/2 mutations in a publicly funded program at a tertiary care teaching hospital in Ontario, Canada.
Authors: Ruste Sherry Athena Doroja , Eisen Andrea , Pritchard Kathleen I.
Published: March 2020

1550

Background: Publicly funded testing for BRCA1/2 mutations in Ontario has been available for high-risk individuals since 2000. The criteria are based on personal and/or family cancer history and ethnicity. We reviewed the results of the first 10 yrs of testing at our institution, a regional cancer centre in an academic, tertiary care teaching hospital. Methods: This REB-approved, retrospective study included individuals who had GT from 2001-2011. Sociodemographic, clinical, and GT results were collected. Results: 2,305 individuals met criteria and underwent GT between Jan. 2001and Dec. 2011. Of all tested subjects, 93% were female, median age was 55 yrs., 23% were of Ashkenazi Jewish (AJ) ancestry and 80% lived in an area with family income $50-100K/yr. BRCA1/2 mutations were present in 16%, 8% had unclassified variant (UCV), 76% had normal sequence. We excluded 460 individuals who had predictive GT for a familial mutation, and results are shown in the Table. For each carrier, an average of four additional relatives had GT. The most common criteria for GT was at least three cases of ovarian or breast cancer at any age on the same side of the family. BRCA mutations were most common among those AJ, Italian, Asian Oriental and English ancestry. Wait time for GT result improved from 107 wks. in 2001 to 8 wks. in 2011. Conclusions: In our tested population, the prevalenceof BRCA1/2 mutations was high. Over time wait times improved and more relatives were tested. [Table: see text]
Differences in outcome between colorectal cancer (CRC) patients (pts) with Lynch syndrome (LS) versus MLH1 hypermethylation (MLH1 HM).
Authors: Haraldsdottir Sigurdis , Wu Christina Sing-Ying , Pan Xueliang Jeff , Hampel Heather , Goldberg Richard M. , Bekaii-Saab Tanios S.
Published: March 2020

1556

Background: In ~15% of CRC tumors mismatch repair deficiency (dMMR) is observed and is usually caused by LS (germline mutations in MLH1, MSH2, MSH6 or PMS2) or sporadic inactivation of MLH1 (hypermethylation [HM] of MLH1 gene promoter). The objective of this study was to retrospectively compare clinical factors and outcomes in pts with dMMR with LS to those without LS. Methods: This cohort includes pts with CRC diagnosed between 5/98 and 5/12 with dMMR on immunohistochemistry (IHC) staining. Prior to 2006 pts came from the Columbus area HNPCC study. After 2006, we included all CRC pts at OSU as universal IHC was initiated. Chi-square was used to compare nominal parameters and log-rank to compare overall survival (OS). Results: A total of 189 pts had dMMR per IHC staining (see characteristics in table). In 36 pts (19.0%) a diagnosis of LS was made after germline testing, in 59 pts (31.2%) a diagnosis of MLH1 HM was made with methylation or BRAF testing, in 65 pts (34.4%) a LS or MLH1 HM diagnosis was assumed based on clinical criteria. Median OS was 159 mos in the LS group and 49 mos in the MLH1MH group (p=0.003) and OS was significantly longer in the LS group across all 4 stages (p=0.002) (see Table). Conclusions: Pts with LS-associated CRC had longer OS than pts with MLH1 HM-associated CRC, even in the setting of a higher incidence of other cancers (44.1% vs. 28%). This is likely related to younger age in the LS group. The MLH1HM group was older at diagnosis and more often female. There are a number of limitations to our study including the potential for survivorship bias and lack of a definitive diagnosis in ~50% of patients despite using clinical criteria to define these pts. [Table: see text]
Prostate cancer screening: Rise and fall?
Authors: Eisinger François , Morere Jean Francois , Touboul Chantal , Pivot Xavier B. , Coscas Yvan , Blay Jean-Yves , Lhomel Christine , Viguier Jérôme
Published: March 2020

1562

Background: Our previously published data showed a fast increasing rate of prostate cancer screening in men aged 50-74 from 36% in 2005 to 48% in 2008. According to their expressed wish either to continue to be tested annually or to start prostate cancer screening, the rate of testing was expected to rise to 70% in 2011. We report here the actual rate of prostate cancer screening. Methods: Three nationwide observational surveys (EDIFICE opinion polls) were carried out by telephone (2005, 2008, and 2011). The target was a representative sample of more than 1,500 subjects living in France and aged 40-74. Precision of results for the samples was + 3.2% with a 95% confidence interval (CI). Results: In this survey population (men aged 50-74), the rate of screening reported remained stable between 2008 and 2011 (48% and 49% respectively). However, there were some differences according to age with a decreasing rate for men aged 50 to 59 years: 44% in 2008 vs 37% in 2011 (p=0.11) and an increasing rate for men aged 60 to 74 years: 53% in 2008 vs 62% in 2011 (p=0.04). Comparing privileged versus underserved populations, significant differences were found with a relative decrease in attendance of those of higher professional status (p=0.034) and from higher income groups (p=0.015); the difference was not significant for educational attainment (p=0.147). For household with a monthly income above 2500 €, the screening rate decreased from 61% in 2008 to 51% in 2011, while for an income below 2500 €, the rate increased from 36% in 2008 to 44% in 2011. Conclusions: A plateau or even reduction in prostate cancer screening is observed, possibly due to a progressive recognition of the controversy on prostate cancer screening by the population, which previously engaged only the experts. After previously being more likely to take up prostate cancer screening, the backlash is mainly observed in the younger, wealthier groups. This “fall”, according to many health agencies should not be seen as a health threat. Health institutions and medical practitioners should, however, be aware of this trend, to avoid general mistrust of cancer screening as a whole.
Racial differences in perceived risk in participants enrolled in the American College of Radiology (ACRIN-6654) arm of the National Lung Screening Trial (NLST).
Authors: Lathan Christopher , Kumar Pallavi , Gareen Ilana F , Gorelick Jeremy , Sicks JoRean , Hyland Kelly , Park Elyse R.
Published: March 2020

1563

Background: Blacks in the U.S. have higher incidence and mortality rates of lung cancer (LC) compared to whites. Previous work in small studies suggests that blacks have lower perceived risk of LC which may influence smoking cessation behavior. However, racial disparities in risk perceptions (RP) of LC and smoking related diseases (SRD) in heavy smokers have not been studied. We examined LC and SRD risk perceptions among black and white ACRIN NLST participants. Methods: The 10-item Smoking Risk Perceptions Scale (SRPS) for LC and SRD was administered to NLST participants, from 4 ACRIN sites, with a minimum 30 pack-year smoking history at 1 year following baseline screening chest x-ray or low dose computerized tomography (LDCT). We 1) validated the SRPS in black and white participants separately using exploratory and confirmatory factor analyses, 2) used 2-way ANOVAs to compare RP of black and white participants and 3) used multivariable linear regression models to identify factors associated with RP. Results: Among 1742 white and 194 black participants, the 10 SRPS items loaded onto two factors (absolute and relative risk; Cronbach’s alpha=0.92 and 0.95 for white and black participants, respectively). Black participants had significantly lower RP compared to white participants (SRPS range= 10-50, mean diff. 3.48, 95% CI 2.29-4.68, p<0.01). Factors significantly associated with lower RP in a multivariate linear regression were black race (β=4.59, p < 0.001), former smoking status (β=3.82, p<0.001), male gender (β=1.35, p<0.001), lower education (β=1.16, p =0.010), and older age (years, β = 0.15, p<0.001). Conclusions: We validated the SRPS in black and white ACRIN-6654/NLST participants. Blacks had significantly lower perceptions of LC and SRD risk compared to whites, even after adjusting for study arm, sociodemographics, and smoking status. Sociodemographic factors and smoking status were independently associated with lower RP. These findings confirm that black current and former smokers are at risk of underestimating their smoking-related risk, which may contribute to lower rates of adherence to screening and smoking cessation recommendations.
Insulin analogues to stimulate cell growth in human cancer initiating cells (CICs).
Authors: Holgado Esther , Cortes Semperes Maria , Pernia Olga , Arrizabalaga Olatz , Ibañez de Cáceres Inmaculada , Hitt Ricardo , De Castro Javier , Ayuso Sacido Angel , Perona Rosario , Belda-Iniesta Cristobal
Published: March 2020

1575

Background: Conflicting epidemiologic studies have suggested insulin and their analogues currently used in the management of type 2 diabetes to be involved in tumor progression and development. Surprisingly, time of exposure to insulin analogs reported in those retrospective studies is too short for be a carcinogen. We hypothesized that differential affinity that insulin analogs display for insulin receptor and IGF-1R at CICs may account for this possibility. [AspB10]insulin (X10) is a long-acting insulin analog that displays greater affinity for IGF1R than either the long-acting insulin analog GLA or human insulin (HI) in vitro. X10 is tumorigenic in animal models whereas GLA is not. GLA is rapidly metabolized to the metabolites, M1 and M2 that exhibit metabolic and mitogenic profiles similar to that of HI in vitro. CICs are cancer cells with self-renewing, stem cell-like properties with the ability to proliferate and differentiate into specific cells found in tumor types and thus they are able to maintain tumor bulk. Many cancers are thought to be initiated by CICs, and there is evidence that they cause cancer recurrence, metastatic progression and resistance to therapies. Our aim was to compare the mitogenic activity of HI, GLA, X10, M1 and M2 on human CICs in vitro. Methods: CICs derived from 10 human cell lines including glioma, lung, breast, colon, and prostatic cancers were isolated and grown in defined growth medium (no serum) with either HI, GLA, X10, M1 or M2. Growth was estimated using the MTS colorimetric assay. Results: HI, GLA and X10 stimulated CIC growth to a similar extend, whereas M1 and M2 had growth promoting activity similar to medium without HI. Similar results were obtained when measuring diametric sphere growth. Additionally, AKT phosphorylation levels were increased 2-fold after stimulation with HI, GLA or X10, whereas stimulation with M1 or M2 did not produce a significant increase. Conclusions: This is the first study that has explored the biology of CICs treated with insulin analogs. The data show that GLA displays a mitogenic profile comparable to that of human insulin for all CIC lines tested, whereas M1, has even less growth promoting activity.
Survival rates in patients with primary metastatic breast cancer over a 10-year period: A retrospective analysis based on individual patient data from a multicenter data bank.
Authors: Barinoff Jana , Harter Philipp , Heitz Florian , Dittmer Christine , Kuemmel Sherko , Hils Rita , Lorenz-Salehi Fatemeh , Traut Alexander , du Bois Andreas
Published: March 2020

1577

Background: Approximately 6% of patients with breast cancer have distant metastases at the time of the initial diagnosis. The aim of this analysis was to examine the overall survival rate over time and to investigate the effect of new therapy options. Methods: This retrospective analysis was performed based on the data bank of the Clinic for Gynaecological Oncology/ Dr. Horst Schmidt Klinik, Wiesbaden and the Clinic for Gynaecological Oncology and Senology/ Kliniken Essen Mitte, Essen. The patients with primary metastatic breast cancer (pmBC) who were diagnosed and treated at the accredited breast cancer centres of these clinics were enrolled between 1998 and 2007. The date of diagnosis was used to define 2 specifically chosen 5-year periods: 1998–2002 and 2003–2007. The follow-up time was on average 76 months. The Breslow Test was used to evaluate changes in the median survival time and to detect factors associated with the increase in survival rates. Results: Two hundred sixteen patients with complete baselines were analysed. Ninety patients were diagnosed between 1998 and 2002, and 126 patients received their diagnosis of pmBC between 2003 and 2007. The tumour-biological factors were the same in both groups, whereas the therapeutic concepts were different—the later group (2003–2007) received more aromatase inhibitors, taxane-based chemotherapy and trastuzumab. This finding resulted in an increased median survival time from 31 months in the years 1998–2002 to 44 months in the group with the first diagnosis between 2003 and 2007. Conclusions: Primary metastatic breast cancer occurred at constant rates over last 10 years. The tumour findings did not change in the time between the two examined groups; however, the treatment options in the 2003–2007 group included newly approved therapies. The time period of the first diagnosis was detected as a risk factor for overall survival. Those patients diagnosed in the more recent time frame had a significantly improved survival rate. The establishment of new therapy options may explain this finding.
Survival outcomes for patients with equivocal 18FDG-PET CT scan for extrahepatic disease prior to liver resection for metastatic colorectal cancer.
Authors: Kumar Rajiv , Beeke Carol , Ullah Shahid , Price Timothy Jay , Padbury Rob , Roder David , Karapetis Christos Stelios
Published: March 2020

1581

Background: Patients considered for liver resection (LR) for hepatic metastases from metastatic colorectal cancer (mCRC) have an 18FDG-PET CT scan (PET) to exclude extrahepatic disease (EHD). The prognostic significance of an equivocal PET on overall survival (OS) for patients who proceed to LR is not entirely clear. The aim of the study is to compare OS for patients with equivocal PET prior to LR to those with a PET negative for EHD. Methods: The South Australian Metastatic Colorectal Cancer Registry collects data for mCRC patients diagnosed after February 1, 2006. Patients were included if they had LR and a PET prior to LR. PETs were coded as no EHD and possible EHD. The Cox proportional hazard model was applied to analyse the outcome of patients with an equivocal PET for EHD on OS, adjusting for possible confounders. Results: Of the 2,480 patients on the registry, 273 had had LR. Of these, 183 (67.0%) had a PET prior to LR, with 137 having no EHD and 46 having possible EHD. The no EHD and possible EHD groups were well balanced for patient, tumour and treatment characteristics – mean age: 66.7 yrs-vs-68.4 yrs, male gender: 61.3%-vs-63.0%, KRAS wildtype: 11.0%-vs-16.3%, stage IV disease at initial diagnosis: 49.6%-vs-54.3%, colonic primary: 74.4%-vs-65.2%, one LR: 82.5%-vs-89.1%, one line of chemotherapy: 52.4%-vs-48.6% and well-moderate tumour differentiation: 85.7%-vs-86.4%. The median follow-up was 32.9 months for no EHD and 33.6 months for possible EHD (P-value = 0.84). The OS for no EHD compared with possible EHD at 1-year was 98.5%-vs-93.5%, at 2-years was 87.6%-vs-88.0%, and at 5-years was 61.5%-vs-59.4%. The unadjusted hazard ratio for OS was 1.22 (95% CI 0.64–2.34, P-value = 0.54) for possible EHD. On adjustment for age, gender, stage at diagnosis, primary site, number of LRs, lines of chemotherapy and tumour differentiation, the hazard ratio remained non-significant; however lower (HR=0.76 (95% CI 0.37–1.59, P-value = 0.47)), for possible EHD. Conclusions: A PET was only performed in 67.0% of patients who had LR for mCRC. There was no difference in OS between patients with no EHD and possible EHD on PET who proceed to LR.
Influence of physical activity on recurrence and survival of colorectal cancer patients: A meta-analysis.
Authors: Des Guetz Gaetan , Bouillet Thierry , Uzzan Bernard , Chouahnia Kader , Nicolas Patrick , Zelek Laurent H. , Morere Jean F.
Published: March 2020

1583

Background: Colorectal cancer (CRC) predominates in developed countries among sedentary populations. A meta-analysis (MA) showed that physical activity (PA) decreased the incidence of new cases of CRC. The impact of PA on recurrence and mortality of non-metastatic CRC patients is still controversial. Methods: We performed a literature-based meta-analysis of all published observational studies, using the following keywords (colorectal cancer, physical activity, survival) in PubMed and EMBASE. We searched for a dedicated MA in the Cochrane Library (none found). We cross-checked all references. Pre- and post-diagnostic PA levels were assessed with MET (Metabolic Equivalent Task). Usually, high PA levels corresponded to > 17 MET hours/week. Overall survival (OS) and cancer-specific survival (CSS) were assessed by means of Hazard Ratios (HRs) with their 95 % Confidence Interval (CI). We pooled adjusted HRs since the variables of adjustment were almost identical between studies (age, sex, BMI, tobacco use, alcohol and red meat consumptions ). By convention, when higher PA levels were associated to an improved survival compared with lower PA levels, HRs for detrimental events were < 1. We used EasyMA software. We used fixed effect model whenever possible and random effect model only in case of between-study heterogeneity. Results: Eight studies (11298 participants) published from 2006 to 2013 met the inclusion criteria, representing 3110 males and 3710 females, 3072 colon and 1318 rectum cancers. Mean age was 67 years (range 21-82 years). HR CSS for post-diagnostic PA (higher PA level vs. lower) was 0.61 (CI: 0.44-0.86; random effect model). The corresponding HR for OS was 0.62 (CI: 0.54-0.71). HR CSS for pre-diagnostic PA was 0.80 (CI: 0.69-0.92). The corresponding HR for OS was 0.74 (CI: 0.63-0.86). Conclusions: This MA is the first to show that higher PA levels are associated with a better CSS, suggesting that sustained PA should be advised for non-metastatic CRC patients. OS also significantly improved, not surprisingly since PA should reduce risk of cardio-vascular events. These findings should be tempered by the rather small number of studies included.
Breast cancer subtype variation by ethnicity in a population-based cohort in British Columbia.
Authors: Wan Dante , Villa Diego , Woods Ryan , Yerushalmi Rinat , Gelmon Karen A.
Published: March 2020

1585

Background: Reports suggest breast cancer subtypes (BCS) are different in developing countries, often attributed to ethnicity. We assessed BCS in our multiethnic population with access to screening mammography and universal health care. Methods: The Breast Cancer Outcomes Unit database was used to identify women diagnosed with invasive breast cancer in 2006 and referred to the BCCA. Ethnicity was abstracted by chart review from a patient questionnaire completed by all new referrals. Ethnicities were grouped into: Caucasian (CA), East Asian (EA), Aboriginal (A), South Asian (SA), South-East Asian (SEA) and Other (O). BCS were grouped as: ER/PR+ HER2-, ER/PR+ HER2+, ER/PR- HER2+, ER/PR- HER2-. Rates of ER and HER2 positivity and BCS were compared by ethnicity using the Chi-square test; age at diagnosis was compared by ethnicity using the Kruskal-Wallis test. Results: 2,222 women were eligible with 2072 having completed questionnaires. Median age was 59 years. The distribution of ethnicities: 73% CA, 8% EA, 4% A, 3% SA, 3% SEA and 9% O. T stage was T1 57%, T2 34%, T3 8% and Tx 1%. N stage was N0 55%, N1 25%, N2 9%, N3 3% and NX 9%. 4.5% were Stage IV at diagnosis. HER2 positivity was significant by ethnicity; 14% CA, 18% EA, 25% A, 29% SA, 26 % SEA, 17% O (p = 0.0008). Age varied significantly (p<0.0001); mean age in SEA was 53 compared to 60 years in CA. Conclusions: Although the subsets are small there appear to be differences in the rates of ER and HER2 positivity by ethnicities. ER negative disease was more frequent in Aboriginal and South Asians. These groups and SE Asians had more HER2 + disease. Validation on larger populations is pending. Genomics analysis may provide epidemiologic information. Differences in BCS may impact screening and prevention strategies. [Table: see text]
Frequency of oncogenic alterations in five driver genes in Chinese female lung adenocarcinoma.
Authors: Xu Ren , Ma Jie , Xie Li-Qun , Tao Hui-Qing , Wei Bing , Guo Yong-Jun , Bao Wen-Jing , Tong Guang-Quan , Ding Lu , Zhan Min-Ning , Yong Ma Zhi
Published: March 2020

1588

Background: Currently, 5 driver genes (EGFR, K-RAS, B-RAF, ALK, RET) have been widely explored and become new targets of NSCLC, however no report has been found in Chinese female lung adenocarcinoma, who were prone to EGFR mutations and therefore, are the targets for TKIs therapy. Methods: FFPE-tissues from 310 female lung adenocarcinoma adopted in Hunan or Henan province between 2000 and 2012 were investigated. Oncogenic alterations in newly found 5 driver genes were analyzed. ARMS was used to study EGFR, K-RAS and B-RAF mutation. The reverse transcription and real-time PCR were performed to detect either ALK and RET fusions or ALK and RET gene expression. Sequencing was further applied to confirm the subtypes of fusions. Results: Among 310 samples, 149 (48.1%) EGFR mutations, 16 (5.2%) KRAS mutations, 0 (0%) BRAF mutations, 23 (7.4%) ALK fusions and 5 (1.6%) RET fusions were detected. Only EML4-ALK fusion but no other ALK fusions were found. Further research showed that cases (22, 95.6%) with high ALK expression were often accompanied by EML4-ALK fusion and poorly differentiated adenocarcinoma. Two RET fusions, KIF5B-RET and CCDC6-RET were found, with 2 cases and 3 cases, respectively. The ratio of RET/ABL mRNA levels was significantly higher in CCDC6-RET samples with poorly differentiated adenocarcinoma. However, with KIF5B-RET fusion, relatively high RET/ABL mRNA expression was detected in one KIF5B-RET sample with moderately differentiated adenocarcinoma, while no RET expression was detected in other two KIF5B-RET samples with highly differentiated adenocarcinoma. Conclusions: This is the first research about the oncogenic alterations of 5 important driver genes in Chinese female lung adenocarcinoma, as well as the correlation between ALK fusion and ALK expression or between RET fusion and RET expression, thus laying good foundation for understanding the genetic mutation spectrum in female lung adenocarcinoma.
Rapid online feedback to improve clinical trial accrual: CODEL anaplastic glioma (AG) (NCCTG/Alliance N0577) as a model.
Authors: Massett Holly , Jaeckle Kurt A. , Dilts David M. , Denicoff Andrea , Souhan Erin , Hopkins Jenny R , Mann Bhupinder Singh
Published: March 2020

1596

Background: Structured feedback from community oncologists regarding trial design rarely occurs. Survey templates were created to assess trial feasibility, design and scientific interest from the community, with the aim of improving accrual. We report results from a survey regarding redesign of the Phase III CODEL trial for newly diagnosed 1p/19q codeleted AG, which employed this approach. Methods: A field-tested, online survey template was tailored for CODEL and emailed to U.S. and international oncologists. The survey assessed (a) practice changes resulting from ASCO 2012 data from RTOG 9402 (abstract # 2008b) and EORTC 26951 (abstract # 2); (b) scientific interest in a redesigned trial; and (c) potential accrual issues. Respondents reviewed a brief trial concept and answered 15 questions anonymously via a web-based system. Results: 173 oncologists completed the survey over 2 weeks in Sept 2012(48% US, 52% Int’l; 35% med oncs, 31% rad oncs, 29% neuro-oncs). Results from the 2 prior studies substantially influenced clinicians’ treatment decisions for patients with newly diagnosed 1p19q codeleted AG--from only 9% recommending RT+PCV prior to the ASCO reports, to 46% after the results were presented. Previously, 25% recommended RT alone, and after ASCO, no one did. Most indicated strong interest in the revised CODEL research questions, trial design, randomization arms, and in re-opening the revised trial. The most interesting schema was a 3-arm design (selected by 45% of respondents): (RT + procarbazine, CCNU and vincristine chemotherapy [PCV]) vs. (RT + Temozolomide [TMZ]) vs. (TMZ alone), with neuro-oncs (49%) preferring it most, and rad oncs least (36%). The second most interesting choice (27%) was RT+PCV vs. RT+TMZ; the third choice (20%) was RT+TMZ vs. TMZ alone. Most (61%) felt patients would accept any arm. Respondents encountered eligible patients frequently enough to meet projected CODEL accrual goals. Conclusions: Survey findings significantly influenced decisions on how best to redesign the CODEL trial. Rapid, web-based surveys of community oncologists can provide important feedback regarding level of interest, which might facilitate timely accrual and trial completion.