bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin effects on cancer adjacent breast preneoplasia in a randomized pre-surgical trial.
Authors: De Censi Andrea , Puntoni Matteo , Pruneri Giancarlo , Cazzaniga Massimiliano , Vingiani Andrea , Serrano Davide , Guerrieri-Gonzaga Aliana , Gentilini Oreste Davide , Johansson Harriet Ann , Aristarco Valentina , Lazzeroni Matteo , Varricchio Clara , Bonanni Bernardo 
Published: March 2020

1517 Background: Metformin has been associated with a significant reduction in cancer incidence and mortality in diabetic patients, including positive results in breast cancer. In a window-of-opportunity trial in 200 non-diabetic women with breast cancer, we showed a heterogeneous effect of metformin on breast cancer proliferation (Ki-67) depending on insulin resistance, with a trend to a decreased proliferation in women with insulin resistance (HOMA>2.8) and an opposite trend in women with normal insulin sensitivity (Bonanni et al. JCO 2012). Here we determined whether metformin has antiproliferative effects on adjacent lobular or ductal intraepithelial neoplasia (LIN or DIN) and on distant ductal hyperplasia and whether these effects are different according to specific host and tumor characteristics. Methods: Baseline core biopsies of tumor tissue and blood samples were obtained at study entry and before surgery for pre/post-treatment comparisons. Patients were randomly assigned to metformin, 850 mg or placebo once daily on day 1-3 followed by two 850 mg tablets from day 4 to 28. At surgery, three to five specimens of adjacent (≤1 cm from the tumor) and distant (>1 cm from the tumor) grossly normal tissue were obtained to assess systematically the prevalence, grade and proliferation of LIN or DIN and ductal hyperplasia. Results: Overall, the prevalence of LIN, DIN and ductal hyperplasia was 4.5% (9/200), 66.5% (133/200) and 35% (69/200), respectively. Ki-67 was positively associated with DIN grade (p-trend<0.001). The median (and IQ range) Ki-67 LI distribution of LIN+DIN was 12% (8-20) and 10% (6-22) on metformin and placebo, respectively (p=0.6). Compared with placebo, metformin exhibited different effects on Ki-67 according to DIN grade (delta=+4.4% in DIN1 vs -27.9% in DIN3, p-interaction=0.09), cancer HER2 status (median 12% vs. 10% in HER2-ve; 28% vs. 35% in HER2+ve, p=0.03), abdominal circumference (p=0.08), and BMI (p=0.17). Conclusions: Metformin had no overall significant effect on breast preneoplasia proliferation but exhibited heterogeneous effects depending upon host and tumor characteristics. The significant reduction of HER2+ve, DIN3 proliferation under metformin warrants further studies. Clinical trial information: 16493703.
Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study.
Authors: Lakoski Susan G. , Barlow Carolyn , Gao Ang , DeFina Laura , Radford Nina , Farrell Steve , Willis Benjamin , Peppercorn Jeffrey M. , Douglas Pamela S. , Berry Jarett , Jones Lee 
Published: March 2020

1520 Background: Few studies have examined the prognostic importance of cardiorespiratory fitness (CRF) to predict cancer incidence or cause-specific mortality following a cancer diagnosis in men. Accordingly, we examined the relationships between baseline CRF and incidence of prostate, lung, or colorectal cancer in men at Medicare age and subsequent cause-specific mortality among men diagnosed with cancer. Methods: The Cooper Center Longitudinal Study (CCLS) is a prospective observational cohort study of participants undergoing a preventive health examination including CRF assessment at the Cooper Clinic in Dallas, Texas. We studied 17,049 men with a complete CCLS medical exam and cardiovascular risk factor assessment at a mean age of 50± 9 years. Cancer incidence was defined using Medicare claims data. Cox proportional models were used to estimate the risk of adjusted primary cancer incidence and cause-specific mortality after cancer according to baseline age-specific CRF quintiles (Q). Results: The mean times from CRF assessment to cancer incidence and death were 20.2 ± 8.2 years and 24.4 ± 8.5 years, respectively. During this period, 2885 men were diagnosed with prostate, lung, or colorectal cancer and 769 died. Compared with men in lowest CRF quintile, the adjusted hazard ratio (HR) for incident lung, colorectal, and prostate cancer incidence among men in the highest CRF quintile was 0.32 (95% CI: 0.20 to 0.51, p<0.001), 0.62 (95% CI: 0.40 to 0.97, p=0.05), 1.13 (95% CI: 0.97 to 1.33, p=0.14), respectively. In men developing cancer, both cancer-specific mortality and cardiovascular-specific mortality declined across increasing CRF quintiles (p’s <0.001). A 1-MET increase in CRF was associated with a 14% reduction in cancer-specific mortality (HR 0.86, 95% CI: 0.81-0.91, p<0.001), and 23% reduction in cardiovascular-specific mortality (HR 0.77, 95% CI: 0.69-0.85, p<0.001). Conclusions: Fitness is a strong independent predictor of incident lung and colorectal cancer and remained a robust predictor of cause-specific mortality in middle-aged and older men diagnosed with lung, prostate, or colorectal cancer.
The relationship between serum vitamin D levels and breast cancer prognosis: A meta-analysis.
Authors: Rose April Ann Nicole , Elser Christine , Goodwin Pamela Jean 
Published: March 2020

1521 Background: Vitamin D (VitD) is a circulating hormone known to regulate gene transcription in breast cancer (BC) cells. The association between VitD and BC risk has been extensively studied. Until recently, however, the role of VitD in BC progression and its association with clinical outcomes among BC patients was poorly understood. To assess these new developments, a systematic review and meta-analysis was performed. Methods: A systematic review and meta-analysis by searching MEDLINE (1982 – 2012), ASCO, and SABCS for abstracts (2009 – 2012), with the following keywords: “breast cancer” and “prognosis” or “survival”, and “vitamin D” or ”calcitriol.” Abstracts were scrutinized for reports correlating serum VitD levels with breast cancer clinical outcomes, including: disease-free survival (DFS) and overall survival (OS). Studies were included if serum VitD samples were taken shortly after diagnosis and survival data were reported. Meta-analyses were performed using an inverse-variance weighted fixed-effects model. Results: We identified 7 studies reporting correlative data between serum VitD levels and BC survival. These data included 4,885 patients evaluated for DFS and 3858 patients evaluated for OS. VitD-deficiency was defined as <30ng/mL, <20ng/mL, and <14ng/mL in 3, 3, and 1 studies, respectively, and was identified in an average of 48.1% of patients (range: 17.9-87.8%). VitD deficiency was associated with a pooled hazard ratio (HR) of 2.13 (CI: 1.64 - 2.78) and 1.76 (CI: 1.35 - 2.30) for DFS and OS, respectively. Conclusions: To our knowledge, this is the first report of a meta-analysis of the relationship between serum VitD and BC prognosis. The prevalence of VitD-deficiency varied widely across studies and may reflect differences in geographic location, race, and rates of supplementation across patient populations. These findings support the hypothesis that VitD-deficient breast cancer patients have poorer clinical outcomes than VitD sufficient patients; but do not establish whether this relationship is causative. Further studies are warranted to investigate the possible protective effects of VitD supplementation on survival among VitD-deficient BC patients.
Changes in early- and late-stage colorectal cancer incidence during the era of screening: 1976-2009.
Authors: Yang Daniel X , Gross Cary Philip , Yu James B. 
Published: March 2020

1522 Background: Ideally, screening detects cancer at a more curable stage, and as a result decreases the incidence of subsequent diagnosis at a late stage. Whereas breast cancer screening is suggested to have led to a substantial increase in the number of early-stage cancers diagnosed in the United States with only marginal reductions in the number of late stage cancers, the impact of colorectal cancer screening on cancer incidence is unknown. Methods: Colorectal cancer incidence data spanning over three decades, 1976—2009, were collected from the Surveillance, Epidemiology, and End Result (SEER) database. Screening utilization data spanning 1986—2010 were collected from the National Health Survey (NHS) progress reports. We examined trends in the incidence of early-stage (in situ, local) and late-stage (regional, distant) colorectal cancer among adults 50 years or older. Results: Over the past three decades, the incidence of late-stage colorectal cancer decreased significantly, from 118 to 74 cases per 100,000 people—a 37% decrease. The incidence of early-stage colorectal cancer also decreased, from 77 to 67 cases per 100,000 people. There was also an associated increase in the utilization rates of screening colonoscopy. From 1987 to 2010—the years for which NHS data were available—the percentage of adults 50 and older who received screening colonoscopy rose from 27% to 63%. After adjusting for trends in cancer incidence in non-screened populations, we estimated that colorectal screening was associated with a reduction of approximately 550,000 cases of colorectal cancer over the past three decades in the United States. Using the most conservative assumption of constant cancer incidence during the past three decades, 235,000 cases of colorectal cancer were prevented. Conclusions: There has been a significant decline in both early and late stage colorectal cancer diagnoses, during a time of increasing rates of increased screening.
APC I1307K polymorphism as a predictive factor for colorectal neoplasia recurrence.
Authors: Boursi Ben , Sella Tal , Liberman Eliezer , Geva Ravit , Shmueli Einat , Kazanov Diana , Kraus Sarah , Arber Nadir 
Published: March 2020

1526 Background: The use of surveillance colonoscopy to detect disease recurrence after initial colorectal neoplasia resection has increased significantly in the past decade. Currently, predictive factors at index colonoscopy include only histo-pathologic characteristics such as adenoma number, size, type and dysplasia. The goal of the current study is to identify additional factors (i.e., genetic markers) that increase the risk of subsequent lesions and may optimize the use of surveillance colonoscopies. Methods: A prospective analysis of 383 consecutive Israeli subjects with an initial neoplastic finding in screening colonoscopy. The participants were followed over a period of 10 years, and underwent up to five surveillance colonoscopies. Clinical data regarding potential risk factors for colorectal cancer as well as blood samples were collected. Genetic polymorphisms were detected using real-time PCR from DNA extracted from peripheral mononuclear cells. Results: The overall prevalence of recurrent Colorectal carcinoma and adenoma was 9.4% (36/383) and 69% (268/383) respectively, with a median of 4.8 years from index colonoscopy. In a univariate analysis, subjects with recurrent lesions had significantly higher number of adenomas at index colonoscopy (3.9 Vs 1.1, p=0.001), increased rate of high grade dysplasia (65.8% Vs 50%, p=0.018), and a non-significant trend for larger adenomas and villous histology. The APC I1307K gene variant was detected in 11.8% of subjects with recurrent lesions compared to 3.8% of subjects with normal follow-up colonoscopies (p=0.03). In a multivariate logistic regression (adjusted to age, sex, family history of CR neoplasia, time to recurrence and number of colonoscopies performed), the I1307K variant and the presence of dysplasia were the only significant predictive factors for recurrent neoplasia with an OR of 3.27 (1-11.02, p=0.05) and 1.72 (1.02-2.89, p=0.04) respectively. Conclusions: The APC I1307K gene variant is an important predictive factor for recurrent colorectal neoplasia after a positive index colonoscopy and should be considered as part of the criteria for high risk subjects among Israeli Jews.
Comparative study of the efficacy of breast cancer neoadjuvant chemotherapy (NAC) in patients (pts) with BRCA1/2 mutation vs sporadic cancer cases versus pts with a family history but no BRCA1/2 mutation.
Authors: Duhoux Francois P. , De Rycke Yann , Falcou Marie-Christine , Bidard Francois-Clement , Kirova Youlia M. , Savignoni Alexia , Alran Severine , Pierga Jean-Yves , Asselain Bernard , Stoppa-Lyonnet Dominique , De La Rochefordiere Anne 
Published: March 2020

1533 Background: During NAC, impaired DNA repair mechanisms may account for the higher response rate of BRCA mutation carriers (group #1) when compared to sporadic cases with no history of breast/ovarian cancer (group #2). In this study, we investigated whether pts with possible BRCAX mutation (i.e. with a family history but no BRCA1/2 mutation, group #3) treated by NAC exhibit a different efficacy (response rate, survival) pattern. Methods: All pts screened for a BRCA1/2 mutation between 1999 and 2010 were selected from the prospectively registered cancer genetics database of Institut Curie. Pts younger than 36 years old were excluded. Pts who received NAC were classified in groups #1 (n=23 mutated pts) or #3 (n=64 non-mutated pts). Group #2 (n=87 sporadic cancer pts) was built to match groups #1 and #3 according to age (+/- 5 years), year of treatment (+/- 2 years), hormone receptor status and taxane or trastuzumab use. Results: Median follow-up was 65 months. Fifty % of pts had cytologically proven axillary nodal involvement before NAC. Taxanes were used in 63% of pts and trastuzumab in 9% of pts. Pathological complete response (pCR) rates were 39.1% in group #1, 17.2% in group #2 and 20.3% in group #3 (p=0.07). For locoregional relapse (LR), the difference between groups was statistically significant (p=0.007). The hazard ratio (HR) for LR was higher in group #1 (HR=7.86, p=0.002) than in group #2. No significant difference was seen between group #3 and group #2 (HR=2.37, p=0.15). The difference between groups was also statistically significant for distant metastasis relapse (DMR) (p=0.009). The HR for DMR was higher in group #1 than in group #2 (HR=4.57, p=0.01) and in group #3 than in group #2 (HR=2.81, p=0.01). Conclusions: While pts with BRCA1/2 mutations have a trend towards higher pCR rates with NAC, they have higher rates of LR and DMR than sporadic cases. Pts with a positive family history but no BRCA1/2 mutation have similar pCR and LR rates than sporadic cases, but they have higher rates of DMR. Whether these differences translate into overall survival differences remains to be studied.
Genome sequencing of multiple primary tumors to reveal underlying germline cancer susceptibility.
Authors: Schrader Kasmintan A. , Stratton Kelly Lynn , Murali Rajmohan , Laitman Yael , Cavallone Luca , Offit Lily , Wen Yong Hannah , Shah Sohela , Rau-Murthy Rohini , Manschreck Christopher , Otegbeye Ebunoluwa , Corines Marina , Kauff Noah D. , Klein Robert J. , Robson Mark E. , Stadler Zsofia Kinga , Friedman Eitan , Foulkes William , Vijai Joseph , Offit Kenneth 
Published: March 2020

1552 Background: Apart from germline mutations in BRCA1 and BRCA2, the basis for genetic susceptibility to breast and ovarian cancer is heterogeneous, and can necessitate sequential or multiplex genetic testing. In addition, examination of germline DNA alone may not be conclusive. Information regarding both primary and secondary genetic events can be obtained from genomic analysis of tumors in conjunction with germline DNA. Methods: To determine the underlying cause of multiple primary malignancies in an Ashkenazi Jewish individual, whole genome sequencing was performed on DNA from the patient’s germline, invasive ductal carcinoma of the breast, and ovarian high-grade serous carcinoma. After identifying a structural variant of interest in this patient, germline DNA of 1846 Ashkenazi Jewish individuals who had a personal history of either breast, pancreatic, or ovarian cancer or a history of both breast and/or ovarian cancer and a similar family history, were screened using a TaqMan copy number assay or a specific PCR breakpoint assay to determine if this structural variant is a founder mutation. Results: A novel germline complex structural variant of PALB2 creating a 3790 base-pair deletion encompassing exon 11 associated with a 68 base-pair insertion was identified and confirmed by Sanger sequencing and a TaqMan copy number assay. The germline deletion was retained in both tumors. In addition, both tumors acquired second hits that led to inactivation of the wild-type allele of PALB2. The germline PALB2 structural variant was not identified in any of the additional 1846 Ashkenazi Jewish individuals genotyped. Conclusions: Whole genome sequencing of multiple primary tumors enabled identification and characterization of a novel germline structural variant in PALB2 as the basis for the individual’s susceptibility to breast and ovarian cancer. The variant does not appear to be a founder mutation in Ashkenazim.
Personalized cancer tests and services on the Internet: A website content analysis.
Authors: Gray Stacy W. , Janeway Katherine A. , Weeks Jane C. 
Published: March 2020

1553 Background: The Internet may facilitate the use of guideline endorsed “personalized” cancer tests and services by increasing awareness of and access to new technologies; however limited regulation over Internet marketing may also lead to the promotion of tests and services of unproven benefit. Methods: We identified 51 websites that sell personalized cancer medicine (PCM) tests and/or services by searching Google, Bing, and Yahoo (53 search terms per site, 30 results per search term), reviewing the medical literature, and abstracting information from the exhibitor list from a national oncology conference. Two independent coders evaluated website content. Discrepancies were resolved by consensus. Results: Sites most commonly promoted physicians/institutions selling PCM (49%), tumor analysis (47%, e.g., DNA, RNA, or protein analysis) or offered interpretive services (12%, e.g., cloud-based analytical systems to select personalized cancer therapies). Eighty-six percent of sites included information on the benefits of PCM whereas only 24% of the sites included information on the limitations of PCM (McNemar’s chi square =32, p<0.001). Forty-three percent of sites included general cost information; of those sites, 23% provided an exact dollar figure and 24% included information on insurance reimbursement. Commercial sites were more likely to include cost information than educational and organizational sites (56% vs. 23%, chi square = 4.1, p=0.04). Cancer-related germline testing was offered by 27% of sites. Websites marketed guideline endorsed tests such as EGFR and KRAS mutation testing as well as tests that are not guideline endorsed such as in vitro and in-vivo (mouse) chemotherapy sensitivity testing, EMSY, ZNF703, and whole-exome sequencing. Conclusions: The clinical utility of “personalized” cancer tests and services marketed and sold over the Internet is highly variable. Patients and physicians need to evaluate PCM Internet sites with caution given the fact that benefit information is more common than limitation information and that unproven technologies are commonly promoted.
Characterization of colorectal cancer (CRC) in Lynch syndrome (LS) patients with MSH6 or PMS2 mutations.
Authors: Lee Jean Kyung , Shia Jinru , Rau-Murthy Rohini , Corines Marina , Salo-Mullen Erin E. , Markowitz Arnold , Robson Mark E. , Offit Kenneth , Guillem Jose G. , Saltz Leonard , Stadler Zsofia Kinga 
Published: March 2020

1555 Background: The majority of LS patients harbor germline mutations in the MLH1 or MSH2 genes. However, ~10% have MSH6 and ~<5% PMS2 mutations. An attenuated form of LS has been suggested in MSH6/PMS2 carriers with decreased CRC risk and older age of disease onset. As recent guidelines suggest that initiation of CRC screening may be delayed in such patients, we characterized our patients with MSH6/PMS2-associated CRC. Methods: We obtained an IRB waiver to identify all LS patients with CRC, defined as the presence of a deleterious germline mutation in a MMR gene, from the Clinical Genetics database at MSKCC. Clinical, pathologic, and genetic features were extracted from medical records and Progeny software. Results: Of 147 LS patients with CRC, 23 had mutations in the MSH6 (n=16, 11%) or PMS2 (n=7, 5%) genes. Mean age at CRC diagnosis was 48.5 yrs (range 32-70) in MSH6 and 40.7 (range 22-57) in PMS2 carriers. 16 (70%) and 5 (22%) were diagnosed at age ≤50 or ≤35, respectively. 4 (17%) had metachronous and 3 (13%) synchronous primary CRCs, and 5 (22%) had additional LS-associated cancer. Although all 23 LS patients met Revised Bethesda guidelines, only 50% of MSH6 and 0 of the PMS2 carriers met Amsterdam I/II criteria (AC). Of 32 independent primary CRCs, 18 (56%) were stage I/II, 9 (28%) stage III, and 1 (3%) stage IV. 9/9 MSH6 and 4/4 PMS2 CRCs had high-frequency microsatellite instability. In MSH6 carriers, 11/13 had absence of MSH6protein expression only on IHC, 1 had inconclusive MSH6 staining, and 1 had absence of both MSH6 & MSH2 proteins. In PMS2carriers, 7/7 had absence of PMS2 on IHC, 2 also had equivocal/focal MLH1 staining. Right-sided CRC was present in 50% and at least 40% had mucinous features. 26/29 (90%) of tumors underwent segmental resection. 6/11 stage II patients received adjuvant chemotherapy including 2 with pT4N0 tumors. With a mean follow-up of 5.6 yrs to date, 1 patient is known to have developed recurrent CRC. Conclusions: Although the majority of MSH6/PMS2 CRC patients do not meet AC, 70% of CRCs were diagnosed at age ≤50, 22% at age ≤35, and 30% had synchronous/metachronous CRCs. These findings have important implications for CRC surveillance and may not support delaying colonoscopy initiation in MSH6/PMS2 LS families.