bluuebunny/crossref_metadata_2025 huggingface dataset:
Postmastectomy radiotherapy for patients with one to three positive lymph nodes: Utilization and benefit.
Authors: Huo Dezheng , Hou Ningqi , Jaskowiak Nora T. , Hasan Yasmin , Winchester David J. , Winchester David Porter , Yao Katharine
Published: March 2020

1116

Background: The use of postmastectomy radiotherapy (PMRT) for patients with pT1-2pN1 tumors is controversial and ASCO guidelines indicate that there is insufficient evidence to make recommendation. We hypothesized that the use of PMRT in this patient group was low and has minimal impact on survival. Methods: The study includes 83,742 invasive breast cancer patients from the National Cancer Data Base who underwent mastectomy with pT1-2 and pN1 disease from 1998-2007. Neoadjuvant cases were excluded. We investigated factors related to PMRT use using cross tables and logistic regression. Survival analysis was conducted using Cox models in patients diagnosed from 1998-2002, with a median follow-up of 5.5 years. Results: The proportion of N1 patients undergoing PMRT remained stable from 1998 to 2007, at approximately 20%. PMRT use increased with larger tumor size (15.4% in T1N1 and 24.4% in T2N1), and with increasing positive lymph nodes (14.6%, 23.7%, and 35.2% for patients with one, two, or three positive nodes, respectively). Age was significantly inversely correlated with PMRT use: the proportion of patients receiving PMRT was 31.3% for age <40 years and 8.2% for 80+ years (p<0.001). Asians are more likely to receive PMRT (25.5%), compared to other races (20.3% white, 20.7% black, and 20.6% Hispanic; p<0.001). PMRT also varied considerably by facility location, the highest in the Northeast at 31.3%, and the lowest in the South at 15.8% (p<0.001). There was only minor difference in PMRT use between different types of cancer centers. Insurance status, income and education level were not associated with PMRT use. After adjusting for prognostic factors in the Cox models, PMRT use was associated with a reduced mortality (hazard ratio=0.87, 95% CI: 0.81-0.93; p<0.001). The multivariable-adjusted 5-year death rate was 16.1% in patients receiving PMRT and 18.1% in patients not receiving PMRT. For pT1N1 tumors the absolute benefit was 1.3% compared to 2.7% for pT2N1 tumors. Conclusions: PMRT use varies with facility and clinicopathologic factors, but not socioeconomic factors. The risks of radiation need to be weighed against the 2% absolute survival benefit when deciding on whether to use PMRT for pT1-2N1 patients.
Long-term rates of breast cancer in a population of women with ductal carcinoma in situ treated by breast-conserving surgery.
Authors: Rakovitch Eileen , Nofech-Mozes Sharon , Narod Steven , Hanna Wedad , Saskin Refik , Tuck Alan , Sengupta Sandip , Done Susan , Miller Naomi , Youngson Bruce , Paszat Lawrence Frank
Published: March 2020

1123

Background: Ductal Carcinoma in Situ (DCIS) is a non-invasive form of breast cancer which is often treated by breast-conserving surgery. The addition of radiotherapy to surgery has been shown to reduce the risk of local recurrence (LR), but use of radiotherapy varies. It is not known to what extent women with DCIS are at risk for recurrent cancer due to the omission of radiation therapy. We studied a large provincial cohort of women with DCIS who were treated with breast-conserving surgery for factors which predict local recurrence and estimate the impact of radiotherapy on local recurrence and long-term rates of breast preservation. Methods: All women diagnosed with DCIS in Ontario from 1994 to 2003 were identified. Treatments and outcomes were identified through administrative databases and validated by chart review. Women treated with breast-conserving surgery, alone or with radiotherapy, were included. Survival analyses were used to study local recurrence (DCIS or invasive) in relation to patient characteristics, tumour characteristics and treatment. Results: The cohort included 3975 women who were treated with breast-conserving therapy; of these, 1949 (49%) received radiation. At 10 years median follow-up, 736 developed LR(19%). LR developed in 259 of 1949 women who received radiotherapy (13%) and in 477 of 2026 women who did not (24%;p<0.001). The differences were significant for both invasive LR (7% vs. 14%; p<0.001) and DCIS recurrence (6% vs.9%; p<0.001). The 10-year cumulative rate of mastectomy was 13% for women who received radiotherapy compared to 17% for those who did not (p<0.01).We estimate that 29% (N=214) of all local recurrences diagnosed in Ontario in women treated for DCIS between 1994 and 2003 would be prevented if all patients received radiotherapy. Conclusions: The omission of radiation therapy after breast-conserving surgery in women with DCIS resulted in a substantial number of local recurrences that might have been avoided and lower rates of breast preservation. Improvements in guidelines that facilitate the selection of women in whom radiotherapy can be avoided are needed.
Phase I/II trial of partial breast irradiation (PBI) with various concurrent chemotherapy regimens.
Authors: De Souza Lawrence Lana Maria , Shah Amit , Young Mary Elizabeth , Stearns Vered , Asrari Fariba , Frassica Deborah Anne , Tsangaris Theodore N. , Fetting John H. , Lange Julie R. , Jacobs Lisa K. , Myers Lee , Wolff Antonio C. , Zellars Richard C.
Published: March 2020

1128

Background: Potential benefits of concurrent chemo-radiation include: shorter duration of treatment, smaller interval between surgery and adjuvant therapies, and synergistic effects. We have previously shown that PBI with concurrent dose dense doxorubicin and cyclophosphamide (ddAC) is well tolerated (Zellars JCO 2009). We performed a follow-up feasibility trial of PBI delivered concurrently with other various chemotherapy regimens. Methods: Women with T1-2, N0-1 breast cancer s/p lumpectomy with ≥2 mm margins were eligible. Chemotherapy regimen was at the discretion of the medical oncologist (Table). PBI (40.5 Gy in 15 daily 2.7 Gy fractions) was delivered within the first 2 cycles of chemotherapy. Primary endpoints were hematologic and non-hematologic toxicities graded according to Common Terminology Criteria for Adverse Events manual (v. 3.0). Results: Thirty-four patients enrolled with median f/u of 19.2 mos. (4.0 - 38.6). Mean tumor size was 1.8 cm (+/- 0.7 cm), 71% pN0, 68% HR +, 18% Her2 +. All patients completed concurrent chemo-radiation. Three patients had a 3-8 day delay in chemotherapy (1 grade 2 thrombocytopenia; 1 Grade 2 liver enzymes; 1 T desensitization). There was 1 local (DCIS) and no regional/distant recurrences or deaths. Toxicity: 2 grade 4 neutropenia (ddAC, TCarboH); 1 grade 3 neutropenia (post-AC paclitaxel); 1 Grade 3 hyponatremia and DVT (TC); 1 syncope (TAC). None had > grade 2 radiation dermatitis. Conclusions: PBI and concurrent chemotherapy is associated with minimal toxicity and appears to be well tolerated. These results deserve further investigation. Funded by The Breast Cancer Research Foundation. [Table: see text]
Evaluation of the stage IB designation of the 7th edition of the AJCC Staging System.
Authors: Dallas Nikolaos Andreas , Yi Min , Hunt Kelly , Shah Ruchita R. , Kuerer Henry Mark , Litton Jennifer Keating , Wu Yun , Caudle Abigail Suzanne , Meric-Bernstam Funda , Sahin Aysegul A. , Mittendorf Elizabeth Ann
Published: March 2020

1130

Background: Recent data from large cooperative group trials have questioned the relevance of small volume metastases identified in the sentinel lymph nodes (SLN) of early stage breast cancer patients. The 7th ed. of the AJCC staging system differentiates node negative patients (stage IA) from those with micrometastases (stage IB) or macrometastases (stage II or III). This study was undertaken to determine the utility of the stage IB designation. Methods: Review of a prospectively maintained database identified 3474 patients who underwent SLN biopsy between 1993 and 2007. Clinicopathologic and outcomes data were recorded and patients staged according to the 7th ed. AJCC system. Recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were determined using the Kaplan-Meier method and compared using the log-rank test. Results: AJCC stage distribution included: 2246 (65%) stage IA, 207 (6%) stage IB, 685 (20%) stage IIA, 209 (6%) stage IIB, and 127 (3%) stage III. For patients with stage IB disease, SLN micrometastasis was identified by H&E in 173 (84%) and immunohistochemistry (IHC) in 34 (16%); suggesting that 16% would have been staged IA if enhanced evaluation had not been performed. Median follow-up was 6.1 yrs (range 0-17.2). The 5-yr RFS,DSS and OS rates for patients with stage IB disease were 98.0%, 99.5%, and 95.9% respectively, which did not differ significantly from patients with stage IA disease who had 5-year RFS,DSS and OS rates of (97.5%, p=.9), (98.8%, p=.7) and (96.2%, p=.8). When all stage I patients (IA and IB) were evaluated by ER status or grade (grade 1 vs 2 vs 3), these biologic factors were able to significantly discriminate patients with respect to RFS, DSS and OS. Conclusions: Differentiating patients with micrometastases from node negative patients does not stratify patients with respect to survival. Biologic factors (ER status and grade) are better discriminants of survival than the presence of small volume nodal metastases in patients with early stage disease. These data do not support routine use of IHC or alterations in adjuvant therapy decisions based on identification of SLN micrometastases.
BMI, long-term changes in BMI, and risk of cancer mortality in a large cohort study.
Authors: Taghizadeh Niloofar , Vonk Judith M. , Boezen H. Marike
Published: March 2020

1502

Background: There are indications of an association between Body Mass Index (BMI) and risk of different cancer types. There is dispute whether this association differs between males and females. Methods: We studied the association of BMI at the first survey with risk of mortality from the most common types of cancer (lung, colorectal, breast and prostate cancer) in a large general population-based cohort study (Vlagtwedde-Vlaardingen, 1965-1990) with follow-up on mortality status until 2009. Additionally, we assessed this association based on tertiles of the annual change in BMI (defined as the difference between BMI at last survey and first survey divided by the time between last and first survey). We used 3 categories of BMI (< 25 kg/m2, 25-30 kg/m2, and ≥ 30 kg/m2) and changes in BMI (< 0.02 kg/m2/yr, 0.02-0.2 kg/m2/yr, and > 0.2 kg/m2/yr) in the analyses. The multivariate Cox regression model was adjusted for age, smoking, gender. Analyses were additionally stratified by gender and smoking. Results: Among all 8645 subjects, 1194 died due to cancer (lung cancer: 275; colorectal cancer: 134; breast cancer: 117; prostate cancer: 83). Mortality from all types of cancer was significantly increased in subjects with BMI > 30 kg/m2 (HR (95 % CI)) = 1.22 (1.00-1.48)), especially in females (1.38 (1.06-1.81)) and in never smokers (1.39 (1.02-1.90)). Prostate cancer mortality was significantly increased in males with BMI 25-30 kg/m2 (2.04 (1.90-3.83)) and > 30 kg/m2 (2.61 (1.02-6.67)). This association between prostate cancer mortality and BMI was higher in smokers. Lung cancer mortality risk was decreased in subjects with BMI 25-30 kg/m2 (0.71 (0.54-0.93)) and > 30 kg/m2 (0.82 (0.50-1.32)), especially in males, in smokers, and in smoking males. There were no significant associations between BMI and colorectal or breast cancer mortality nor between change in BMI and mortality from all analyzed types of cancer. Conclusions: We show that an increase in BMI is associated with an increased risk of mortality from all types of cancer in females and with an increased mortality risk from prostate cancer in males but with a decreased lung cancer mortality risk, especially in males. More research is needed into the biological mechanisms that link BMI to cancer.
A multi-institution study of the accuracy of BRCAPRO in predicting BRCA1/BRCA2 mutations in women with ovarian cancer.
Authors: Daniels Molly S , Babb Sheri , King Robin , Urbauer Diana , Amos Christopher I. , Brandt Amanda C. , Buchanan Adam , Mutch David Gardner , Lu Karen H.
Published: March 2020

1520

Background: 10-15% of ovarian cancer patients have a germline BRCA1 or BRCA2 mutation, with significant management implications for both patients and relatives. Genetic testing decisions are guided in part by the estimated likelihood of identifying a mutation. The BRCAPRO model uses personal and family history of breast and ovarian cancer to calculate the likelihood of a BRCA1/2 mutation. This study’s purpose was to assess the ability of BRCAPRO to accurately determine this likelihood. Methods: BRCAPRO scores were calculated using CancerGene v5.1 for 589 ovarian cancer patients referred for genetic counseling at three institutions. The study population was divided into quintiles by BRCAPRO score, with cutpoints chosen such that each quintile represented 20% of the sample. Chi-square goodness-of-fit test was used to compare observed BRCA1/2 mutations to the number predicted. ANOVA models were used to assess factors impacting BRCAPRO accuracy. Results: 180/589 (31%) ovarian cancer patients tested positive for a BRCA1/2 mutation. At BRCAPRO scores under 40%, more mutations were observed than expected (93 observed vs. 34.1 expected, p<0.001). If patients with BRCAPRO scores <10% had not been offered genetic testing, almost one-third of mutations (51/180, 28%) would have been missed. Multivariate analysis demonstrated that BRCAPRO underestimated risk for high grade serous ovarian cancers but overestimated risk for other histologies (p<0.0001), underestimation increased as age at diagnosis decreased (p=0.02), and model performance varied by institution (p=0.02). Conclusions: Ovarian cancer patients classified as low risk by BRCAPRO are more likely to test positive than predicted, therefore the BRCAPRO prediction could falsely reassure patients considering genetic testing. BRCAPRO performance could be improved by incorporating factors such as ovarian cancer histology. Alternatively, given the high prevalence of BRCA1/2 mutations in high grade serous ovarian cancer and the apparent limitations of using family history to predict mutation probability, BRCA1/2 genetic testing could be offered to high grade serous ovarian cancer patients regardless of family history.
Genetic polymorphisms of the OPG gene associated with breast cancer.
Authors: Assmann Gunter , Juhasz-Boess Ingolf , Gruenhage Frank , Graeber Stefan , Wieczorek Stefan , Pfreundschuh Michael , Solomayer Erich-Franz , Ney Jasmin Teresa
Published: March 2020

1523

Background: The receptor activator of NfkappaB (RANK) and osteoprotegerin (OPG) cascade system have been reported to play a role in the pathogenesis of breast cancer (BC). Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are supposed to play a role in the susceptibility of breast cancer. Methods: In the present case-control study genomic DNA was obtained from 307 BC patients (age: median 56) and 396 healthy female controls (healthy blood donors, HC; age median: 45). We studied six single nucleotide polymorphisms (SNPs) in the genes coding for RANK (2 SNPs, rs1805034, rs35211496), OPG (2 SNPs, rs3102735, rs2073618), and RANKL (2 SNPs, rs9533156, rs2277438) using TaqMan assay-guided PCR for the respective SNPs. The genotype and allelic frequencies comparing BC with HC were analyzed with χ2 test for 2x3 and 2x2 tables, respectively. Results: The genotype distributions as well as the allelic frequencies of the SNP rs3102735 in the OPG gene differed significantly (p=0.006 and p=0.019, respectively) between BC patients and HC; the genotypes containing the minor allele were more frequent in BC patients (table). In the OPG SNP rs2073618 the minor allele C was significantly less frequent in BC patients compared to HC (43.8 vs. 49.7%; OR: 0.788; p=0.031). In addition, BC patients carried less frequently the homozygous genotype of the minor allele compared to major allele (18.6 vs. 23.9%, p=0.083). No significant risk was detected for the other SNPs investigated in this study. Conclusions: This is the first study reporting a significant association of the SNP rs3102735 in the OPG gene with the susceptibility to develop BC in the Caucasian population. The minor allele C of OPG SNP rs2073618, however, seems to be protective against BC disease. The impact of the OPG SNP rs3102735 (location: 5`near region, chromosome 8q24) and of the OPG SNP rs2073618 (a missense SNP, leading to amino acid exchanges Leu3Asn) on the pathogenesis of BC are unclear. [Table: see text]
Clinical characteristics and natural history of patients with squamous cell lung carcinoma with FGFR1 amplification.
Authors: Bos Marc Christiaan Allardt , Gardizi Masyar , Heukamp Lukas Carl , Schildhaus Hans-Ulrich , Nogova Lucia , Ko Yon-Dschun , Schlesinger Andreas , Brockmann Michael , Serke Monika Heidi , Gerigk Ulrich , Hekmat Khosro , Stoelben Erich , Reiser Marcel , Engel-Riedel Walburga , Schnell Roland , Schmitz Stephan H. , Frank Konrad , Buettner Reinhard , Wolf Juergen , Zander Thomas
Published: March 2020

1533

Background: FGFR1 amplifications have been described as a promising oncogenic target in squamous cell lung cancer. Here we aimed at describing the clinical characteristics and natural history of FGFR1amplified squamous cell lung cancer patients. Methods: From 01/2011 to 01/2012 we screened 553 squamous cell lung cancer patients in our Network for Molecular Screening of Lung Cancer for the presence of FGFR1 amplifications by FISH analysis in accordance with the local ethics committee. FGFR1 was defined as amplified if the ratio of FGFR1 copies to centromeric copies was above 2 or if more than 50% of tumor cells showed 5 copies or if more than 15% of tumor cells demonstrated clusters of FGFR1. Clinical data were collected by extracting information from medical records, the local cancer registry and by questioning treating physicians and patients. Results: FGFR1FISH analysis could be performed in 95% of the cases and was amplified in 16%. Of the amplified cases 75 % were male and 25% female without significant enrichment for male or female. The median age of the patients at diagnosis was 67 yrs (range 46 - 82). Stage at presentation was: 16% I; 17.3% II; 26.7% IIIa, 40% IIIb/IV. 97,3% of the patients were former or active smokers with a median of 40 pack years. The median progression free survival of patients with stage IIIb/IV disease was 11 months (95% CI 8-14; n=14). The median overall survival was not yet reached after a median follow-up time of 14 months (95% CI 11 - 17; n=24). We further screened for co-existing genetic lesions such as mutations in EGFR, BRAF, KRAS, PIK3CA as well as translocations of ALK and amplifications of ERBB2. Two patients demonstrated co-occurring PIK3CA mutations and one a BRAFmutation. Conclusions: Screening for FGFR1 is feasible under routine clinical conditions. By implementation of a regional molecular screening network the ability to screen for FGFR1 amplification was successfully expanded to non-academic centers and private practices. FGFR1 amplifications in squamous cell cancer of the lung are frequent (16%) and associated with smoking history. Screening for FGFR1 might pave the way for the application of new FGFR1 directed targeted drugs in squamous cell lung cancer.
Molecular epidemiological prospective study of EGFR mutations from Asian patients (pts) with advanced lung adenocarcinoma (PIONEER).
Authors: Yang Pan-Chyr , Shi Yuankai , Au Joseph Siu-kie , Srinivasan Sankar , Cornelio Gerardo H. , Tsai Chun-Ming , Thongprasert Sumitra , Heeroma Dr Karin , Yohji Itoh , Khoa Mai Trong
Published: March 2020

1534

Background: The epidemiological, multicenter prospective study (NCT01185314; PIONEER) assessed EGFR mutation (M) rates in pts from Asia with newly diagnosed advanced lung adenocarcinoma (ADC). Influence of demographic and clinical factors on EGFR M rates was investigated. Methods: Pts were aged ≥20 years, with treatment naïve stage IIIB/IV lung ADC. Tumor sample (biopsy, surgical specimen, cytology) EGFR M status (primary endpoint; positive [M+], negative [M-], undetermined [MU]) was determined using Scorpion ARMS (Therascreen EGFR RGQ kit). EGFR M frequency was calculated and compared between demographic/clinical factor subgroups (chi-square/Fisher’s exact test). Factors with p<0.05 in the univariate analysis were further analyzed by multivariate logistic regression at 1% significance level to take the large dataset into consideration. Results: Of 1482 pts from 7 Asian countries, 43.4% were female, mean age was 60 years (range 17-94), and 52.6% were never-smokers. EGFR M status was evaluated in 1450 patients (32 [2.2%] were MU): 746 (51.4%) were M+, 704 (48.6%) were M-. Country, gender, ethnicity, smoking status, pack years, metastasis, (all p<0.001) and disease stage (p=0.009) correlated significantly with EGFR M status. EGFR M+ rate by country: Vietnam 64.2% (77/120), Taiwan 62.1% (108/174), Thailand 53.8% (63/117), Philippines 52.3% (34/65), China 50.2% (372/741), Hong Kong 47.2% (76/161), India 22.2% (16/72). EGFR M+ rates were 61.1% in females, 44.0% in males, 60.7% in never smokers, and 31.4% in heavy smokers (>50 pack years). EGFR M+ rates were 37.5% in male regular smokers (113/301), 34.8% in female regular smokers (8/23), 56.5% in male never smokers (104/184) and 62.0% in female never smokers (358/577). Ethnic group (p<0.001) and pack years (p<0.001) were identified as important factors by logistic regression; gender was not significant when adjusted for smoking status. Conclusions: The overall EGFR M+ rate in unselected ADC was 51.4%. Ethnicity and pack years were found to have a statistically significant association with EGFR M rates. There was no association between gender and EGFR M rates when adjusted for smoking status.
Correlation of breast cancer risk in European BRCA2 mutation carriers with birth cohort.
Authors: Tea Muy-Kheng Maria , Kroiss Regina , Muhr Daniela , Fuerhauser-Rappaport Christine , Wagner Teresa M. U. , Singer Christian F.
Published: March 2020

1537

Background: Mutations in the Breast Cancer Gene 1 (BRCA1) and Breast Cancer Gene 2 (BRCA2) lead to an elevated risk of developing breast (BC) and ovarian cancer (OC). However, risk estimates vary, depending on the study population. Furthermore, there are indications that birth cohort can influence the cancer risk. We investigated the risks for BC and OC associated with BRCA2 mutations in a cohort of female mutation carriers of a genetically heterogeneous central European population who were identified by molecular genetic testing in our institute. Methods: This study included 171 Caucasian women from Austria who underwent genetic counseling and where molecular genetic analysis identified a mutation in the BRCA2 gene at the Medical University of Vienna, Division of Senology, in Austria. A total of 57 healthy and 114 affected BRCA2-carriers were detected. The risk was estimated using the product limit method. The log rank test was used to compare different strata. Results: The risk of developing cancer to age 70 was found to be 85% for BC (95% CI 77–93%) and 31% for OC (95% CI 16–46%) in our BRCA2 study population. Female BRCA2-carriers born in 1958 or later were at a significantly higher risk of developing BC (p<0.001; 88% vs. 46% to age 40) but not of OC (p is not significant; 0% vs. 2% to age 40) compared to mutation carriers born earlier. Conclusions: We conclude that female BRCA2 mutation carriers should also be counseled about their cohort-dependent cancer risk, especially for breast cancer. Further research about variables that may affect cancer risk like lifestyle-related factors should be considered.
Breast cancer in Irish families with Lynch syndrome.
Authors: Jordan Emmet , Farrell Michael P. , Cadoo Karen Anne , Clarke R. M. , Nolan C. , Kell M. R. , McCaffrey John , Maher Michael A. , Connolly E. M. , Boyle Terence , Kennedy M. John , Morrison P. J. , Muldoon C. , Gallagher David J
Published: March 2020

1543

Background: Breast cancer is not among the recognised malignant manifestations of Lynch Syndrome which include colorectal, endometrial, gastric, ovarian and upper urinary tract tumours. In this study we report the prevalence of breast cancer in Irish Lynch Syndrome families and determine immunohistochemical (IHC) expression of mismatch repair proteins (MMR) in available breast cancer tissue. Methods: Breast cancer prevalence was determined among Lynch Syndrome kindreds from two institutions in Ireland. One kindred was omitted due to a biallelic MMR and BRCA1 mutation.The clinicopathological data that was collected on breast cancer cases included age of onset, morphology, and hormone receptor status, and a genotype phenotype correlation was investigated. Immunohistochemical staining was performed for MLH1, MSH2, MSH6, and PMS2 on all available breast cancer tissue from affected individuals. Results: The distribution of MMR mutations seen in sixteen pedigrees were as follows; MLH1 (n=5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal cancer and 14 cases of endometrial cancer were seen. Seven breast cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of ductal carcinoma in situ were reported in 7 pedigrees. This compared with 4 cases of prostate cancer. Of the 7 LS kindreds containing breast cancer, 6 MSH2 mutations and 1 MSH6 mutations were identified. Median age of breast cancer diagnosis was 49 years (range 38-57). Hormone receptor status is available on 3 breast cancer cases at time of abstract submission; all were ER positive and HER 2 negative. All cases had grade 2 or 3 tumours. 5 samples were available for IHC evaluation. 3 out of 5 cases showed loss of MMR expression, all showed loss of MSH2 and MSH6 expression. One of the two cases with normal IHC expression in breast tissue belonged to a kindred where 3 siblings with colorectal cancer and documented deleterious mutations demonstrated no IHC loss. Conclusions: Breast cancer occurred at an early age and was more common than prostate cancer in Irish Lynch Syndrome pedigrees. All identified breast cancer were in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer screening may be warranted in certain Lynch Syndrome kindreds.
BRCA carrier status as an independent prognostic factor associated with earlier biochemical relapse in local prostate cancer.
Authors: Castro Elena , Olmos David , Goh Chee Leng , Saunders Ed , Leongamornlert Daniel , Tymrakiewicz Malgorzata , Bancroft Elizabeth , Page Elizabeth , Dadaev Tokhir , Govindasami Koveela , Guy Michelle , Sawyer Emma , Wilkinson Rosemary , Ellis Steve , Frost Debra , Peock Susan , Antoniou Antonis C. , Easton Doug , Kote-Jarai Zsofia , Eeles Ros A. ,   UK Genetic Prostate Cancer Study and EMBRACE Collaborators
Published: March 2020

1545

Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter survival. Germline BRCA mutations are associated with worse PCa outcomes. BRCA carriers are currently treated with the same protocols used for non-carriers. We analyzed biochemical-progression free survival (bPFS) after conventional treatment for localized PCa in a cohort of BRCA patients (pts). Methods: In this retrospective case-control study, each BRCA carrier (9 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment , androgen-deprivation therapy (ADT) and year of treatment (±3 yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 172 pts were included. Median follow-up was 76 months (ms). Median age at diagnosis was 58 yrs (43-75). Tumour stages were I 11%, IIA 19%, IIB 28%, III 28%, IV 14%. 80 pts received RT (18 BRCA2, 5 BRCA1, 57NC) and 85% also received ADT (70% for ≥6 months). 92 pts underwent RP (16 BRCA2, 4 BRCA1 and 72 NC), and 9% of them received ADT (<6months). Overall, median bPFS was 71ms. For those treated with RT, median bPFS was 65ms in NC vs 39ms in BRCA carriers (p=0.023). bPFS was not affected by ADT duration. Median bPFS after RP was 65ms in BRCA carriers. No difference was observed in 3yrs-bPFS between BRCA carriers and NC (73% vs 76%). The adjusted MVA confirmed the independent prognostic value of tumour stage (p=0.004) and BRCA status (p=0.032) for bPFS. Among BRCA carriers, the risk was greater when the analysis was limited to BRCA2 pts (p=0.013, HR 2.1,.95%CI 1.2-3.7). Conclusions: Our results suggest that BRCA carriers with PCa have worse local disease control than NC when treated with RT, regardless of ADT duration. No differences in bPFS were observed in pts treated with RP after >6 yrs median follow-up. These results may have implications for tailoring clinical management for these patients.
Public perception of cancer risk.
Authors: Burns Lisa , Kenny Ursula , Healy Laura , Cushen Samantha , O'Reilly Seamus , Ryan Aoife M , Power Derek Gerard
Published: March 2020

1559

Background: The public’s knowledge of cancer risk factors has rarely been studied in Ireland. An understanding of this can help inform cancer prevention programs. Methods: An online surveywas used to assess the public’s perception of cancer risk. Results: 525 people completed the survey. Mean age was 40yrs (range:18-74), 82% were female and 36% had college degrees. 81% were concerned about developing cancer, however 20% believed if cancer was in their family there was nothing they could do about personal cancer risk. 20% did not know that cancer risk increased with age, 27% believed that >50% of cancers are inherited, and 54% believed 10-20% of cancers are inherited. The top 5 risk factors listed by respondents were: smoking 85%, diet 74%, alcohol 44%, genetics 38%, and environment 31%. Only 32% were aware that obesity is a risk factor for cancer and 33% did not think the location of fat was important for cancer prevention. When given a list of potential behaviours relevant to cancer risk 33% believed wearing a tight bra and 49% believed a blow to the breast could increase cancer risk. 87% believed genetics ‘strongly’ increased risk, 85% stress, and 86% believed cell phones increased risk. 12% believed ‘luck’ was important in avoiding cancer, 35% thought ‘detox’ diets and 61% believed organic food reduced risk. Only 33% agreed with the statement that ‘frozen vegetables/fruit are as good as fresh’, 40% were unaware of the link between red meat and cancer. The following foods were thought to increase risk: cheese (29%), soy (9%), milk chocolate (30%), red wine (25%), and eggs (11%). Aerosol use (71%), cleaning agents (73%), smoking (99%), cooking methods (68%), processed meat (86%), food irradiation (77%), and genetically modified foods (81%) were believed to increased risk. The majority were aware that berries, green tea, garlic, brassica vegetables and physical activity of 30 minutes a day can reduce cancer risk. Conclusions: There is a sizable portion of the population who are misinformed about cancer risk. Most are aware of classic risk factors (e.g. smoking, poor diet). Many overestimate risk attributable to genetics, environment, stress, and underestimate age, obesity and sunlight. One in 5 believes lifetime risk of cancer is non-modifiable.
On-line breath analysis of volatile organic compounds as a method for colorectal cancer detection.
Authors: Zambrana Tevar Francisco , Herrero Ana , Vidal-de-Miguel Guillermo , Bailador Gonzalo , Criado Ernesto , Marquina Isabel , Sanchez-Avila Carmen , Sereno Maria , Gomez Raposo Cesar , Lopez-Gomez Miriam , Merino Maria , Aguayo Cristina , Alvarez-Gallego Mario , Erdozain Jose Carlos , Comas Carmen , Mancenido Noemi , Feliu Jaime , Garcia Damian , Casado Enrique
Published: March 2020

1570

Background: Analysis of exhaled volatile organic compounds (VOCs) in breath is an emerging approach for cancer diagnosis, but little is known about its potential use as a biomarker for colorectal cancer (CRC). We investigated whether a combination of VOCs could distinct CRC patients from healthy volunteers. Methods: In a pilot study, we prospectively analyzed breath exhalations of 38 CRC patient and 43 healthy controls all scheduled for colonoscopy, older than 50 in the average-risk category. The samples were ionized and analyzed using a Secondary ElectroSpray Ionization (SESI) coupled with a Time-of-Flight Mass Spectrometer (SESI-MS). After a minimum of 2 hours fasting, volunteers deeply exhaled into the system. Each test requires three soft exhalations and takes less than ten minutes. No breath condensate or collection are required and VOCs masses are detected in real time, also allowing for a spirometric profile to be analyzed along with the VOCs. A new sampling system precludes ambient air from entering the system, so background contamination is reduced by an overall factor of ten. Potential confounding variables from the patient or the environment that could interfere with results were analyzed. Results: 255 VOCs, with masses ranging from 30 to 431 Dalton have been identified in the exhaled breath. Using a classification technique based on the ROC curve for each VOC, a set of 9 biomarkers discriminating the presence of CRC from healthy volunteers was obtained, showing an average recognition rate of 81.94%, a sensitivity of 87.04% and specificity of 76.85%. Conclusions: A combination of cualitative and cuantitative analysis of VOCs in the exhaled breath could be a powerful diagnostic tool for average-risk CRC population. These results should be taken with precaution, as many endogenous or exogenous contaminants could interfere as confounding variables. On-line analysis with SESI-MS is less time-consuming and doesn’t need sample preparation. We are recruiting in a new pilot study including breath cleaning procedures and spirometric analysis incorporated into the postprocessing algorithms, to better control for confounding variables.
Study KBP-2010-CPHG: Characteristics and management of 7,051 new cases of lung cancer managed in French general hospitals in 2010.
Authors: Locher Chrystele , Herman Dominique , De Faverge Geoffroy , Barbieux Hubert , Lemonnier Christine , Hakim Khaldoun , Debieuvre Didier , Gury Jean-Pierre , Marcos Jean-Michel , D Arlhac Michel , Ferrer Lopez Pablo , Hauss Pierre-Alexandre , Raffy Olivier , Paganin Fabrice , Huchot Eric , Auliac Jean-Bernard , Martin Francis , Zureik Mahmoud , Blanchon Francois , Grivaux Michel
Published: March 2020

1574

Background: An initial epidemiologic study was performed in 2000 by the French College of General Hospital Respiratory Physicians (Study KBP-2000-CPHG). Over the last 10 years, lung cancer management changed: new drugs such as targeted therapies appeared; new diagnostic techniques such as exploration for genetic mutations in the tumour have been developed; a new TNM classification has been drawn up. The aims of this study were to describe patient characteristics, first-line management, 1, 4 and 5-year survival rates and to compare the results with those of Study KBP-2000-CPHG. Methods: A prospective multi-centre study included all patients ≥18 years presenting with a new case of primary lung cancer, histologically or cytologically diagnosed between 1 January and 31 December 2010 and managed by one of the participating centers. A standardised form was completed for each patient. A steering committee checked the exhaustivity of data’s collection. Results: 7,610 patients from 119 general hospitals were included between 1 January and 31 December 2010. The main patient characteristics were: mean age 65.5 years (+/-11.3); 24.3% female; 10.9% non-smokers, 39.9% ex-smokers, 49.2% current smokers; 68.9% performance status 0 and 1; 9.1% of patients had lost >10 kg within the previous 3 months. The main tumour characteristics were: 13.7% small-cell lung cancer; 46.2% adenocarcinoma, 26.8% squamous-cell carcinoma; EGFR mutation, explored in 30.5% of cases, were found in 10.5% of cases; 16.4% stage IA to IIB, 13.4% stage IIIA, 10.2% stage IIIB and 60.0% stage IV. First-line treatments were: curative surgery, 16.6%; chemotherapy, 63.4%; radiotherapy alone, 17.8%; combined radio-chemotherapy, 8.8%; and supportive care, 11.1%. Targeted therapy was used in 6.6% of patients treated by chemotherapy. Conclusions: In 10 years, characteristics of lung cancer patients changed with an significantly increase of women, non-smokers, adenocarcinoma histology and stage IV at diagnosis.
The influence of prognostic factors on metastatic breast cancer survival over time.
Authors: Rosenzweig Margaret Quinn , Jung Su Yon , Brufsky Adam
Published: March 2020

1589

Background: Recent evidence suggests that survival in metastatic breast cancer is slowly improving associated with the use of better adjuvant and metastatic chemotherapeutic and targeted agents. Patient and clinical factors such as age, estrogen status, non-white race, Her 2 status, disease free interval and sites of metastatic breast cancer involvement indicate worse clinical outcome after recurrence. This analysis focused on the influence of these factors on metastatic breast cancer survival over time. Methods: Subjects were women with metastatic breast cancer from one large urban practice, of the University of Pittsburgh Cancer Institute Breast Cancer Program followed from 1999 through December, 2008. Patients were dichotomized into two time categories: A) 1999 through 2004 and B) 2005 through 2008. Outliers of long term survivors (n =72) with survival extending beyond 6 years were excluded. Log rank tests were conducted for assessing the relationship between prognostic factors and survival. Results: Cohorts included patients diagnosed with metastatic breast cancer in 1999 through 2004, (n=284) and 2005 through 2008, (n=332). They were followed up to December, 2011. Median survival improved over time (p=0.053). Estrogen negativity remained significant for worse survival across both time periods (p<0.0001). Age, presence of brain metastasis and Her 2 status were not significant for influence on survival at either time interval. Shorter disease free interval (p= 0.02), higher number of metastatic sites (p=.001) and presence of visceral metastasis at diagnosis (p=0.003) became significant for worse survival in the 2005-2008 intervals but had not been in the earlier time period. African American race was highly significant (<0.001) for worse survival in 1999-2004 but lost significance in 2005 through 2008 with dramatic survival increase (median survival - 12.5 months to 35 months). Conclusions: It is important for clinicians to clarify the prognostic features associated with worse outcomes in metastatic breast cancer. With newly emergent therapies and sensitivity toward specific patient factors these features evolve over time.
Effect of sunlight exposure on survival in patients with lymphoma: Results from the prospective Singapore Lymphoma Study.
Authors: Lee Yin Leng , Tay Kevin , Lim Soon Thye , Tan Soo Yong , Tao Miriam , Quek Richard Hong Hui , Tan Leonard , Ha Tam Cam
Published: March 2020

1593

Background: Recently, several studies evaluating the effect of ultraviolet light exposure on the risk of developing lymphoma have yielded conflicting results, in part due to seasonal and latitude variation. Further, most of these studies also lack long term follow up and could not systemically address the influence of sunlight exposure on survival. In this prospective, epidemiological study, we explored the relationship between past sunlight exposure and survival in lymphoma patients in tropical Singapore, where sunlight exposure is constant throughout the year. Methods: Singapore Lymphoma Study was established in 2005. A total of 384 patients with histologically confirmed lymphoma were followed from date of diagnosis through November 2011. Interviewers were trained to conduct in-person interviews to collect detailed information, including every occupational period that lasted at least 1 year and number of hours worked outdoor from 9am to 5pm using a structured questionnaire. Descriptive, multivariate and survival analysis (Kaplan Meier; age, gender, race and education level adjusted) were performed. Results: Among all lymphoma subtypes, the most prevalent was diffuse large B cell lymphoma, 47.7%, followed by Hodgkin lymphoma, 14.6%, follicular lymphoma, 12.2% and T cell lymphoma, 6.5%. 97.1% had black or brown eye color and 49.6% had fair skin. Overall survival of lymphoma and NHL subtype decreased significantly with increasing lifetime occupational hours (ptrend=0.01 and 0.03). Chinese was associated with longer survival with increasing daily sunlight exposure during childhood and adolescent years, whether at school or outdoor leisure (ptrend=0.04) and there were no evidence for non-Chinese (Malays or Indians). Patients with lighter eye color results in shorter survival (HR=2.91, 95% CI: 1.15-7.34, p=0.02). Conclusions: We found leisure sunlight exposure during childhood and adolescent years to be beneficial to the survival of Chinese lymphoma patients and increasing lifetime cumulative occupational exposure is associated with increasing risk of death. This data contributes to the growing research on the effects of sunlight exposure on lymphoma patients.
The evolution of breast cancer screening in the Medicare population: Clinical and economic implications.
Authors: Killelea Brigid K. , Long Jessica B. , Ma Xiaomei , Wang Rong , Chagpar Anees B. , Ross Joseph , Gross Cary P.
Published: March 2020

1595

Background: Breast screening has evolved as newer approaches to mammography, ultrasound, and MRI have diffused into clinical practice. The use of these technologies and their impact on screening-related costs and outcomes remain undefined, particularly among older women. Methods: Using the Surveillance Epidemiology and End Results – Medicare linked database, we identified women aged 66 and older without a diagnosis of breast cancer. We constructed two cohorts (2001 vs. 2006) and followed each for two years. We assessed changes in imaging technology, screening-related costs (defined as costs for screening and subsequent imaging and testing, adjusted to 2009 USD), and stage at diagnosis between the two cohorts. Results: There were 136,845 women in the 2001-2002 (earlier) cohort and 137,733 in the 2006-2007 (later) cohort. The mean age was 76.9 and 77.2 respectively, (p<.001). The proportion of women receiving any screening mammogram was 42.5% in the earlier cohort and 43.4% in the later cohort, (p<.001). The use of digital mammography for screening increased from 2.2% to 15.0%, (p<.001). The use of any computer aided detection (CAD) increased from 3.2% to 29.3% (p<.001). MRI use increased from 0.03% to 0.2%, and ultrasound use from 4.0% to 4.5% (p <.001 for both). Average screening-related cost increased 31%, from $101 to $132 (p<.001). There was no significant difference in early stage at diagnosis over time (58.1% of women were in situ/stage I in early period vs. 57.2% in later period, p=.65). Conclusions: The use of digital mammography and CAD increased substantially between 2001 and 2007, contributing to a 31% increase in screening-related costs for women in the Medicare program. The increased cost of screening and downstream testing must be evaluated in context of an absence of benefit in terms of stage at diagnosis.
A revised RTOG recursive partitioning analysis (RPA) model for glioblastoma based upon multiplatform biomarker profiles.
Authors: Chakravarti Arnab , Wang Meihua , Aldape Kenneth D. , Sulman Erik P. , Bredel Markus , Magliocco Anthony M. , Klimowicz Alexander C. , Hegi Monika , Stupp Roger , Gilbert Mark R. , Curran Walter J. , Werner-Wasik Maria , Mahajan Anita , Schultz Christopher J. , Mehta Minesh P.
Published: March 2020

2001

Background: The Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) model, which relies on clinical variables, has been used worldwide to establish distinct prognostic classes of patients (pts) with malignant glioma as well as eligibility criteria for clinical trials. In the present study, we have updated the RPA to include additional molecular variables, specifically for glioblastoma (GBM) patients treated in the temozolomide (TMZ)-era, to make the model more relevant, contemporary, and discriminatory. Methods: The dataset utilized was from RTOG 0525, a phase III study examining radiation (RT) with concurrent TMZ, followed by adjuvant standard dose vs. dose-dense TMZ in pts with newly-diagnosed GBM. 162 pts from RTOG 0525 had available tissues for profiling of key signaling molecules using the AQUA platform. Results: pAKT, c-met, and MGMT protein were each found to be significantly associated with adverse outcome on multivariate analysis. These variables were combined with clinical and genetic biomarkers (e.g., MGMT promoter methylation, IDH1 mutation, mRNA profiling) previously found to be of significance (MCP model, ASCO, 2011) to generate an even more robust, discriminatory RTOG RPA model. The explained variation for these three classification models was found to be 41.7 (Current RPA), 19 (MCP), and 14.9% (Clinical RPA), respectively, with higher values indicating better separation of prognostic groups (see table). Conclusions: The current RTOG RPA classification model, based upon incorporation of multi-platform biomarker analysis, holds promise for RT+TMZ-treated GBM patients; further validation of this model is planned. Financial Support: NCI grants U10 CA21661, U10 CA37422, U24 CA114734, 1RC2CA148190, 1RC2CA148190, RO1CA108633, and BTFC grant. [Table: see text]
The NFκB pathway as a key mediator of the glioblastoma mesenchymal subtype in glioblastoma stem cells and human tumors.
Authors: Vaillant Brian D. , Bhat Krishna , Sulman Erik P. , Balasubramaniyan Veerakumar , Ezhilarasan Ravesanker , Aldape Kenneth D. , Colman Howard
Published: March 2020

2002

Background: The mesenchymal (MES) subtype of glioblastoma (GBM) is associated with worse prognosis and increased treatment resistance. Several transcription factors driving the MES phenotype have been identified, including STAT3, CEBP-β, and WWTR1/TAZ. However, the key signaling pathways driving this transcriptional program remain unknown. Methods: Expression profiling analyses was performed on multiple GBM stem cell (GSC) lines derived from individual human tumors. Three large GBM tumor gene expression datasets (TCGA, Rembrandt, Erasmus) were also used in the analyses to identify pathways activated in MES tumors and GSCs. Intracranial GSC xenograft models were used for in vivo validation. Results: We found that GSCs with a MES phenotype also demonstrated upregulation of a gene cassette associated with NFκB activation. Analysis of multiple large expression data sets also demonstrated a tight correlation between the MES phenotype and NFκB activation in human tumors. To determine the effect of NFκB activation in GSCs, we stimulated NFκB by addition of the inflammatory cytokine TNFα. This was accompanied by increased expression of the MES transcription factors (STAT3, CEBP-β, TAZ), and MES markers including CD44. Conversely, blockade of NFκB signaling in GSCs by IκB-α was sufficient to prevent TNF-induced MES transition. Investigation of potential source of NFκB activation suggested a role of microglia. Indeed, addition of supernatant from activated microglia was sufficient to activate NFκB and MES transition in GSCs that could be blocked by IκB-α. To test the role of microglia and NFκB activation on treatment resistance in vivo, treatment with minocycline, an inhibitor of microglia activation, led to a reduction of tumor grade and down-regulation of MES markers in intracranial GSC xenografts. Conclusions: NFκB appears to play an important role in induction of the MES phenotype in GBM and GSCs. Furthermore, activation of microglia is a potential source of NFκB activation in these tumors. These data suggest that blockade of NFκB and/or inhibition of microglia activation may be attractive therapeutic approaches for downregulating MES transition and overcoming treatment resistance in GBM.