bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of a lung cancer growth factor, LASEP1, as a serologic and prognostic biomarker and a therapeutic target.
Authors: Takano Atsushi , Nakamura Yusuke , Daigo Yataro
Published: March 2020

11104

Background: Identification and evaluation of oncoproteins are an effective approaches to develop novel diagnostic/prognostic biomarkers or therapeutic targets. Methods: We established a strategy as follows. i)To identify up-regulated genes in non-small cell lung cancers (NSCLCs) using the cDNA microarray, ii) To verify the candidate genes for their no or low expression in 23 normal tissues by northern-blot, iii)To validate clinicopathological significance of their protein expression by tissue microarray, iv)To verify whether they are essential for the growth of cancer cells by siRNA, and v)To measure their serum protein levels by ELISA. Results: We identified LASEP1 (Lung cancer Associated Serum Protein 1) as a candidate target molecule. Immunohistochemical staining using tumor tissue microarrays consisting of 374 NSCLC confirmed positive staining of LASEP1 was observed in 210 (56.1%) of 374 NSCLC. In addition, a high level of LASEP1 expression was associated with poor prognosis of NSCLC patients. Serum LASEP1 levels were higher in NSCLC than in healthy volunteers. The proportion of serum LASEP1-positive cases was 127 (38.6%) of 329 lung cancers, while 4 (3.9%) of 102 healthy volunteers were falsely diagnosed. Furthermore, treatment of lung cancer cells with siRNAs against LASEP1 suppressed its expression and resulted in growth suppression of the lung cancer cells; on the other hand, induction of exogenous expression of LASEP1 conferred growth-promoting activity in vitro. We found its 50-kDa receptor (LASEPR) which interacts with LASEP1 on lung cancer cell surface. Suppression of LASEPR expression by siRNAs inhibited the growth of cancer cells. The LASEP1-LASEPR interaction promoted the cell growth in an autocrine manner. In addition, the growth activity of the LASEP1-positive cells was neutralized by the addition of originally developed anti-LASEP1 monoclonal antibodies into their culture media. The systemic administration of the anti-LASEP1 antibody to tumor-implanted mice significantly suppressed tumor growth without any adverse events. Conclusions: We have identified LASEP1 as potential targets for development of biomarkers and therapeutic target for lung cancer.
Can BCL2L12 be a promising favorable prognostic biomarker in breast cancer?
Authors: Tzovaras Alexandros , Kladi Athina , Michaelidou Kleita , Tsoukalas Nikolaos , Tsoukalas Grecory , Kountourakis Pantelis , Stamatopoulou Sofia , Oikonomopoulos Georgios , Misitzis Ioannis , Ardavanis Alexandros , Scorilas Andreas
Published: March 2020

11117

Background: Many genes of the BCL2 family were found to be implicated in breast carcinogenesis and to serve as possible prognostic markers. BCL2-like 12 (BCL2L12) is a new member of BCL2 gene family which was discovered and cloned by members of our group and found to be expressed in the mammary gland. The aim of the study was the quantification and the evaluation of the prognostic value of BCL2L12 in breast cancer. Methods: BCL2L12 mRNA levels were determined in 140 samples (81 cancerous and 59 adjacent non-cancerous) of breast tissue using a highly sensitive quantitative real-time polymerase chain reaction (qRT-PCR) method. Relative quantification analysis was conducted using the comparative CT (2-ddCT) method, whereas the association between BCL2L12expression and clinopathological data, disease free survival (DFS) and overall survival (OS) were defined by statistical analysis. Results: Significant relationships between BCL2L12 expression and early TNM stages (P=0.021), absence of metastasis (P<0.001), Estrogen Receptor (ER) positivity (P=0.031) and breast tumors of 2-5cm diameter (P=0.032) were observed. Moreover univariate analysis indicated that BCL2L12 expression is a significant prognostic factor of disease-free survival (DFS) and overall survival (OS), whereas multivariate analysis revealed strong association between BCL2L12 expression and DFS. Conclusions: With regard to breast cancer, patients bearing BCL2L12-positive tumors have significantly longer DFS and OS. These results denote a promising, independent favorable prognostic marker and a significant association of BCL2L12 expression with good outcome.
Prognostic significance of reduction rate of Ki-67 after neoadjuvant chemotherapy in breast cancer patients with non-pCR.
Authors: Matsubara Nobuaki , Mukai Hirofumi , Naito Yoichi , Hosono Ako , Itoh Kuniaki , Fujii Satoshi , Yoneyama Kimiyasu , Wada Noriaki
Published: March 2020

1113

Background: A pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is well established predictive marker for long-term prognosis in patients (pts) with HER2 or triple negative (TN) breast cancer. However, predictive marker has not been established in pts with non-pCR after NAC yet. Reduction of Ki-67 value after NAC has been reported to be associated with a favorable prognosis. However, the association between the reduction rate of Ki-67 and prognosis has not been investigated in detail. This study investigates whether reduction rate of the Ki-67 could indicate a survival advantage in pts with non-pCR. Methods: A total of 450 pts who had received neoadjuvant anthracycline with or without taxane chemotherapy and surgery were analyzed retrospectively. Ki-67, hormone receptor and HER2 status were examined by immunohistochemistry (IHC) in pre-NAC biopsy samples and post-NAC surgical specimens. Pts with non-pCR were subdivided into threesubgroups according to Ki-67 change after NAC: High-reduction (absolute value of Ki-67 was reduced by > 80% compared with that prior to NAC), low-reduction (absolute value of Ki-67 was reduced by from 0% to 80% compared with that prior to NAC), and increase groups (absolute value of Ki-67 was increased compared with that prior to NAC). The relapse-free survival (RFS) rates were compared among subgroups. Results: pCR was observed in 19.5% of pts. In pts with non-pCR, a reduction in Ki-67 was observed in 64% (232/362 pts) and the median reduction rate was 60%. A total of 15% of pts were in the high-reduction, 63% in the low-reduction and 22% in theincrease group. The median follow-up was 64.5 months. The 5-year RFS rates among three groups were significantly different (p<0.0001). Similar positive results were observed in the HER2(p=0.033), TN (p=0.034) and luminal subtype (p=0.001). Pts in the high-reduction group showed comparable RFS to pts with pCR (hazard ratio 1.12 p=0.792). Conclusions: In pts with non-pCR, the reduction rate of Ki-67 after NAC significantly predicted RFS regardless of their tumor subtypes. Pts who are non-pCR but achieve a high reduction of the Ki-67 can be expected to have a favorable prognosis similar to that of pts with pCR.
A phase I-II study of tipifarnib plus weekly paclitaxel (P) followed by dose-dense doxorubicin/cyclophosphamide (AC) in stage IIb-IIIc breast cancer (BC).
Authors: Andreopoulou Eleni , Vigoda Ivette Sara , Valero Vicente , Hershman Dawn L. , Raptis George , Vahdat Linda T. , Han Hyo S. , Wright John Joseph , Pellegrino Christine M. , Alvarez Ricardo H. , Fehn Karen , Fineberg Susan , Sparano Joseph A.
Published: March 2020

1118

Background: Tipifarnib (T) is an orally bioavailable farnesyl transferase inhibitor (FTI) that has activity in metastatic BC (J Clin Oncol 2003; 21:2492-9). We previously showed that adding T (200 mg PO BID days 2-7) to preoperative AC was associated with a higher pathologic complete response (pCR) than expected compared with historical data (Clin Cancer Res. 2009;15;2942-8), and preclinical data suggest that FTIs enhance the antineoplastic effects of P (Cancer Res 2005; 65:3883-93). Methods: Eligible pts with HER2-negative clinical stage IIB-IIIC BC received 12 weekly doses of P (80 mg/m2) followed by AC (60/600 mg/m2 every 2 weeks and pegfilgrastim), plus T 100 mg or 200 mg on days 1-3 of each P dose in cohorts of 3-6 pts in the phase I (and T 200 mg PO BID on days 2-7 each AC cycle in both the phase I and II). Simon two-stage design used for the phase II in two strata generally resistant to neoadjuvant chemotherapy. The trial was powered to detect an improvement in breast pathologic complete response (pCR) from 15% to 35% in each stratum (alpha 0.10, beta 0.10), which required breast pCR in at least 4/19 eligible pts in stage I to proceed to stage II, and at least 8/33 pts in stage I and II to be considered promising. Results: Sixty patients accrued in both the phase I and II. Two patients were non evaluable. There were no DLTs in the first 6 evaluable patients treated at dose level 1 and 2.The recommended phase II dose of T identified in the phase I trial was 200 mg BID.All protocol therapy was completed in 43/55 pts (78%) in the phase II, and one pt died of pneumonitis during therapy of uncertain cause. The prespecified efficacy endpoint was not met for either stratum. Conclusions: The addition of the FTI tipifarnib to neoadjuvant sequential weekly paclitaxel followed by dose-dense AC did not result in a higher breast pCR rate compared with historical data. Clinical trial information: NCT00049114. [Table: see text]
Sentinel lymph nodes before chemotherapy: The Besançon experience.
Authors: Chaigneau Loic , gannard Pechin Elsa , Almotlac Hamidi , Mouillet Guillaume , Bazan Fernando , Villanueva Cristian , Cals Laurent , Montcuquet Philippe , Meneveau Nathalie , Nguyen Thierry , Curtit Elsa , Sautiere Jean-Loup , Maisonnette Yolande , Algros Marie-Paule , Pivot Xavier B.
Published: March 2020

1122

Background: It is debatable whether sentinal lymph node (SLN), before chemotherapy in locally breast cancer (LBC) is feasible. Impact on survival and locoregionally recurrence are unknown. Methods: 256 consecutive patients with LBC treated in Franche Comté (France) between 2004 and 2010 by standard neoadjuvant chemotherapy were retrospectively studied. 177 patients underwent axillary lymph node (ALN) dissection after chemotherapy (cohort A) and 79 patients underwent SLN before chemotherapy (cohort B). The aim of this study was designed to confirm the feasible of SLN before neoadjuvant chemotherapy without negative impact of recurrence and survival. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier method. Differences in OS and DFS according ALN exploration were tested for significance using the Log-Rank test. Results: No statistically significant differences were observed in terms of median age (respectively 59 and 48 years in cohort A and B), tumor size, histological type, grading score, estrogen receptor, progesteron receptor and human epidermal receptor-2 status. No difference of breast conserving surgery was observed between cohort A and B (56.25 vs. 64.56%, p = 0.21). In cohort B, 38 patients (48.10%) of patients underwent SLN alone. For others patients (n = 41, 51.90%), secondary complete axillary lymphadenectomy was performed in the same time of breast surgery. After a median follow up of 57 months (range: 38-105), there was no significant difference in termsof local and axillary recurrences (1.13 vs. 1.27%), metastatic recurrence (11.30 vs. 11.40%). Five-year DFS (76 vs 81%, p = 0.55) and 5-year OS (91 vs. 97%, p = 0.76) did not differ between patients in cohort A and B. Conclusions: SLN before neoadjuvant chemotherapy is feasible and allows to avoid ALN dissection in nearly 50% of patients without impact on recurrence and survival.
Volume-based parameters on FDG-PET/CT as early predictors of disease recurrence in postmastectomy breast cancer patients with one to three positive axillary lymph nodes without adjuvant radiotherapy.
Authors: Nakajima Naomi , Kataoka Masaaki , Nishikawa Atsushi , Sugawara Yoshifumi , Sakai Shinya , Ohsumi Shozo , Kiyoto Sachiko , Mochizuki Teruhito
Published: March 2020

1124

Background: The indication for postmastectomy radiotherapy (PMRT) in patients with 1-3 lymph node metastases in the axilla have been controversial, despite the recommendation that PMRT should be applied. In the current study, we focused our study on volume-based parameters of pretreatment FDG-PET/CT, with the aim of investigating a measurement that could help identify high-risk populations for recurrence. Methods: We retrospectively analyzed 88 patients of breast cancer treated with modified radical mastectomy and were found to have 1-3 metastatic axillary lymph nodes between 2006 and 2010. All of them were studied with FDG-PET/CT for initial staging. We evaluated the relationship between clinicopathologic factors or PET parameters including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and recurrence. MTV and TLG of the primary tumor and metastatic lymph node were measured by using semi-automatically delineated volume of interest (VOI) with an isocontour threshold of 40 % of the SUVmax. The optimal cutoffs of PET parameters were determined by ROC curve analysis. Results: The median follow up duration was 39 months. Median MTV was 21.1and median TLG was 42.7. Recurrence was observed in 10 patients. The area under the ROC curve of MTV and TLG for DFS was 0.82 and 0.85, respectively. In Cox univariate analysis, estrogen receptor status (HR = 6.8, p = 0.003), triple negativity (HR = 10.4, p = 0.0008), SUVmax (HR = 71.1, p = 0.001), MTV (HR = 130.3, p < 0.0001), and TLG (HR = 234.1, p = 0.0001) were significantly related to disease free survival (DFS). The estimated 3-year DFS rates were 96.4 % for the lower MTV group (< 31.8) and 71.4% for the higher MTV group (≥ 31.8, p = 0.0005). The estimated 3-year DFS rates were 95.8 % for the lower TLG group (< 109.6) and 50.0 % for the higher TLG group (≥ 109.6, p < 0.0001). On multivariate analysis, TLG was an independent prognostic factor of DFS (HR = 8.5, p = 0.005). Conclusions: Volume-based parameters on FDG-PET/CT were significant predictors of DFS in postmastectomy breast cancer patients with 1-3 metastatic axillary lymph nodes.
Distinctive lipid profiles of human breast cancer and adjacent normal tissues by desorption electrospray ionization mass spectrometry imaging.
Authors: Caragacianu Diana L. , Liu Xiaohui , Norton Isaiah , Ide Jennifer , Richardson Andrea , Dillon Deborah , Jolesz Ferenc A. , Golshan Mehra , Agar Nathalie Y.R.
Published: March 2020

1132

Background: Routine intra-operative distinction between normal breast tissue and tumor is currently not possible in breast conserving surgery (BCS). This limitation affects the success of surgery, resulting in up to 40% requiring more than one operative procedure. Desorption electrospray ionization mass spectrometry (DESI MS) has been successfully used to discriminate between normal and cancerous human tissues from anatomical sites such as the liver and brain. The aim of this proof of concept study was to determine the feasibility of using DESI MS imaging for tissue identification and differentiation of breast cancer versus normal tissue. Methods: DESI MS imaging was carried out on 14 human invasive breast cancer samples. Breast cancer and adjacent normal paired human tissue sections (margin of tumor, 2cm and 5 cm from tumor) from 14 patients undergoing mastectomy were flash frozen in liquid nitrogen, sectioned, and thaw mounted to glass slides. All samples were imaged using DESI MS at 200 μm imaging resolution. DESI MS images were overlaid and compared with hematoxylin and eosin (H&E) images of the same sections. Results: Discrimination between cancer and adjacent normal tissue was achieved on the basis of the spatial distribution and varying intensities of particular fatty acids and lipid species. Several fatty acids such as oleic acid (m/z 281) and arachidonic acid (m/z 303) displayed much greater signal intensities in the cancer specimen compared to low or undetectable intensities in normal tissue. The cancer margins delineated by the DESI MS images of these molecules were consistent with H and E images of the tumor edge. Cancerous tissue was distinguished from normal tissue based on the qualitative assessment of molecular signatures and the distinction was in agreement with expert histopathology evaluation in 85% of samples. Conclusions: Our findings offer proof of concept that examination and classification of breast normal and cancer tissue by mass spectrometry imaging is highly accurate. The results are encouraging for development of a MS-based method that could be utilized intra-operatively for rapid detection of residual cancer tissue in the lumpectomy bed in BCS.
Breast cancer surveillance in high-risk women with magnetic resonance imaging every 6 months.
Authors: Guindalini Rodrigo Santa Cruz , Huang Yi-Ching , Obeid Elias , Patrick-Miller Linda , Bradbury Angela R. , Verp Marion S. , Hong Susan , Wroblewski Kristen , Abe Hiroyuki , Karczmar Greg S. , Newstead Gillian , Olopade Olufunmilayo I.
Published: March 2020

1506

Background: Surveillance with mammography (MMG) and magnetic resonance imaging (MRI) is recommended for women at high-risk for breast cancer, but there is no consensus on screening strategy. Aim of this study was to evaluate the efficacy of semi-annual MRI in high-risk women. Methods: A multi-modality surveillance program was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years, an additional 5 years of follow-up with yearly MMG and MRI was offered to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, sensitivity, specificity, NPV, and PPV of semi-annual MRI were analyzed. Results: From 2004 to 2012, 226 patients underwent 1467 MRI and 851 MMG with a mean follow-up of 3.6 yrs. Median age at entry was 43 yrs (range 21-73), 48% were mutation carriers (105 BRCA1/2, 2 CDH1, 1 P53) and 19% had personal history of breast cancer. Eleven cancers were screen-detected, of which 6 (55%) were detected only by MRI, 1 (9%) only by MMG, and 4 (36%) by both. Of these tumors, 4 were detected in the first round of MMG/MRI screening and 7 (64%) in mutation carriers (5 BRCA1, 1 BRCA2, 1 CDH1), and 3 tumors (27%) were detected due to the additional MRI during semi-annual screening. No interval cancers occurred. Sensitivity, specificity, PPV and NPV of MRI were 91%, 97%, 18%, 99%, respectively. Of the incident cancers, 3 (27%) were stage 0 (ductal) and 8 (73%) were stage 1 (7 ductal and 1 lobular). Mean size of the invasive cancers was 0.78 cm (range 0.1-1.6; only 2 tumors > 1.0 cm), none had lymph node metastasis, and 75% were high grade and hormone receptor positive. The largest tumor detected was invasive lobular in a 73 year old CDH1mutation carrier. Conclusions: To our knowledge, this is the first surveillance protocol with repeated screening rounds that detected mean size of invasive tumors less than 1 cm. Absence of interval cancers, high sensitivity/specificity, and detection of all tumors in early stages (stages 0 or 1) support this screening strategy as a viable alternative to prophylactic mastectomy. Ongoing work will examine quality of life, cost effectiveness and impact on overall survival of this screening approach. Clinical trial information: NCT00989638.
Comparison of false positive rates for screening breast MRI in high risk women when studies are done stacked versus alternating.
Authors: Othman Edress , Wang Jue , Sprague Brian , Ji Yongli , Herschorn Sally D. , Wood Marie
Published: March 2020

1512

Background: Screening breast MRI added to mammography increases screening sensitivity for high risk women. However, false positive rates are high for MRI and the optimal screening schedule is unclear. In this study we compare rates of false positive MRI when studies were performed on a stacked or alternating schedule. Methods: We reviewed charts for women at increased risk for breast cancer who had screening breast MRI between 2004 - 2012 at the University of Vermont. Eligible women had at least 1 MRI and 1 mammogram performed within one year. Charts were abstracted for clinical, radiological, and biopsy data. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined as MRI result of BI-RADS 3-4-5-0 with additional negative imaging within 12 months or benign biopsy. Results: 143 women had screening which met inclusion criteria; 45 per stacked schedule, 52 alternating, 40 mixed and 6 neither. Women in this study had similar characteristics with respect to age, ethnicity, menopausal status and indications for MRI (i.e. family history, BRCA mutation, biopsy history and prior chest irradiation). 371 MRIs were reviewed (165 stacked and 206 alternating). The overall false positive rate was higher in the stacked group vs. alternating [30(18.2%) vs. 21(10.2%), p=0.0264]. Using only BI-RADS 4-5-0 as a positive result that difference was lost. There were significantly more BI-RADS category 3 interpretations in the stacked vs. alternating MRIs [16(9.7%) vs. 6(2.9%), p=0.006]. The rate of BI-RADS category 4-5-0 was not different between the two groups [16(9.7%) vs. 17(8.3%), p= 0.6272]. A similar number of biopsies were performed in both groups Conclusions: MRI added to mammography for women at increased risk for breast cancer was associated with higher rates of false positive interpretations when studies were done on a stacked compared to alternating schedule. In this study the greater number of BI-RADS 3 interpretations with a stacked schedule accounted for this difference. Further studies are needed to identify the optimal screening schedule when adding MRI to mammography.
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.
Assessment of cancer screening practices after BRCA testing in Michigan.
Authors: Zenger Hain Julie , Mange Sarah , Bach Janice , Duquette Debra , McLosky Jennifer , Dohany Lindsay , Roberson Jacquelyn , Biro Katie , Petrucelli Nancie , Iacoboni Daniela , Ahsan Samira , Merajver Sofia , Milliron Kara J. , Everett Jessica , Zakalik Dana
Published: March 2020

1557

Background: Women who harbor BRCA1/2 mutations are at increased risk for breast and ovarian cancer and are advised to undergo high risk surveillance and/or preventative surgery. The compliance with screening guidelines in these women is not well known. This study aims to evaluate the uptake and screening practices of women with known deleterious BRCA mutations and BRCA true negatives who received genetic counseling in the state of Michigan. Methods: A telephone survey coordinated by the Michigan Department of Community Health was conducted on pts seen at 8 genetics clinics between 10/07 to 10/09. Each center was staffed by board certified genetics professionals who provided pre and post-test genetic counseling. Pts who were found to carry a deleterious BRCA mutation, or to be negative for a known familial mutation, were queried regarding adherence to NCCN guidelines. Results: 138 of 253 (55%) pts responded to the phone survey, with an elapsed time of 1.7 to 4.6 years from post-test counseling session. Among BRCA mutation carriers over age 25 years with no cancer history or mastectomy, 11 of 21 pts (52%) adhered to MRI screening guidelines, 3 pts (14%) reported two MRIs, and 7 (33%) pts had no MRI screening in the preceding year. 18 of 21 pts (86%) reported having a screening mammogram in the preceding year and the remaining 3 had two or more. 8 of 20 (40%) pts had two clinical breast exams. Of the women who had breast cancer and no mastectomy, 5 of 9 (56%) pts did not have MRI screening. Of the BRCA true negatives with no cancer history, CA-125 or transvaginal ultrasound was performed in 7 (19%) and 8 (20%) of 37 pts, respectively. Conclusions: This study reveals sub-optional compliance with screening guidelines in women who were identified to be carriers of BRCA mutations or those who were true negatives, despite pre and post-test genetic counseling and communication of established management guidelines. Some recommended screening measures were under-utilized in BRCA mutation carriers, and some were over-utilized in the true negatives. Additional interventions are needed to improve adherence to evidence-based screening guidelines aimed at promoting early detection, with an emphasis on appropriate utilization of limited healthcare resources.
Occurrence of familial malignant tumors in the first-degree relatives of patients with differentiated (non-medullar) thyroid carcinoma.
Authors: Mindruta-Stratan Rodica , Belev Nicodim F. , Sturgis Erich M. , Xu Li
Published: March 2020

1567

Background: Family aggregation of thyroid cancer and aggregation of a number of "associated" malignant tumors in one family indicates a possible significant genetic predisposition and an increased risk for developing cancer in blood relatives of these families. Methods: Distribution of malignant tumors in first degree relatives of 1135 patients surgically treated for thyroid tumors during 3 years period was studied. These families don’t refer to hereditary syndromes. Patients were distributed in 3 groups: I group - 453 patients with thyroid carcinoma, II group - thyroid carcinoma on adenoma background (222) and III group - thyroid gland adenoma (460 probands). Results: In the I-st group from 2868 first degree relatives 870(64, 5±1.6%) was affected by cancer. From these: 49(3.9±2.8%) had thyroid cancer (TC), 39(3.1±2.8%) - gastric cancer (GC), 36(2.8±2.7%) - colorectal cancer (CRC), 26(2.05±2, 8%) - breast cancer (BC) and 20(1.6±2.8%) - endometrial cancer (EC). Thyroid adenoma was seen in 86(6, 6%) cases. Incidence of the TC was 23, GC- 11, CRC-5, and BC- 4, EC 12 times higher, respectively in compare with general population. From 1414 relatives (II group) 445(66, 1±2.2%) first degree relatives were affected by cancer. From these: 27(4.3±3.9%) - TC, 22(3.5±4.0%) - GC, 21(3.3±3.9%) - CRC, 14(2.2±4.1%) – BC and 5(0.8%) - EC. Thyroid adenoma was seen in 45(6.9±3.7%) cases. In III group - from 2945 investigated first degree relatives 924(66.6±1.5%) relatives were affected by cancer. From these: 44(3.4±2.7%) - TC, 37(2, 8±2.7%) - GC, 27(2.1±2.8%) - CRC, 34(2.6±2.7%) – BC and 19(1.5±2.8%) - EC. Thyroid adenoma represented 116(8, 6±2.6%) cases. Differences between groups are not statistically significant (p <0,05). Conclusions: The results obtained by clinical and genetic research of non-medullar thyroid cancer patients and their first degree relatives are an important reason to direct the monitoring of these families for the risk assessment of hereditary predisposition to cancer, genetic testing, dynamic monitoring and performing of preventive interventions.