Citations

Abstract Breast cancer is the most common type of cancer, and has a strong heritable component, with approximately 15 percent of new cases having family history of breast cancer. Genetic panel testing for patients with a family history of breast cancer has become a popular clinical resource. However, the risk of breast cancer associated with inactivating mutations in the predisposition genes is largely undefined, creating critical limitations in the interpretations of the results from panel testing and subsequent medical management. The Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS) consortium was established to determine the risk of cancers associated with truncating mutations in the known predisposition genes and to extend these studies to the clinical classification of variants of uncertain significance (VUS) in the relevant genes. CARRIERS involves screening of approximately 30,000 population-based breast cancer cases and 30,000 study matched controls for mutations in 28 established or proposed breast cancer predisposition genes. Population-based risks for breast cancer associated with mutations in each gene will be estimated. In parallel, 10,000 breast cancer cases from moderate and high-risk breast cancer families will be similarly screened for mutations and the penetrance of the mutations in high-risk families will be estimated. Furthermore, VUS identified by mutation screening will be characterized by functional and family-based studies and models for classification of the clinical relevance of VUS in each gene will be developed. These data are expected to lead to improvements in cancer risk assessment and improved management of patients found to carry mutations or VUS in breast cancer predisposition. Citation Format: Jenna Lilyquist, Peter Kraft, Steven N. Hart, Emily J. Hallberg, Chunling Hu, Raymond Moore, Rohan Gnanaolivu, Susan M. Domchek, Jeffrey N. Weitzel, Katherine L. Nathanson, David E. Goldgar, Fergus J. Couch. The CARRIERS consortium: Establishing refined breast cancer risk estimates in known predisposition genes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 810.

Abstract Background: Known gene mutations account for approximately 50% of the risk for breast cancer. However, a considerable fraction of heritable risk remains unexplained. Fifteen percent of the risk is accounted for by BRCA1/2 and another 3% by TP53, PTEN, LKB1 and CDH1. CHEK2, ATM, PALB2, BRIP1, RAD51C, RAD51D and BARD1 account for 4%, while SNPs discovered from large multicenter genome-wide association studies explain another 14% of the heritable risk. Founder mutations in the DNA repair pathway genes such as BRCA1 and BRCA2 account for the majority of AJ breast cancer mutations. Methods: We performed exome sequencing of 49 early onset (age <35) breast cancer cases, and 85 BRCA wild type familial breast cancer cases, all of Ashkenazi Jewish (AJ) from the New York City area. A recurrent truncating mutation was then analyzed in 3131 breast cancer cases and 2716 unaffected women of Ashkenazi ancestry from New York and Israel. Using CRISPR and overexpression systems on the human mammary epithelial cell line HMLE, transcript and protein levels were assayed for the mutant and compared to wild-type. Treatment with IlludinS and UVC were performed to assess DNA damage response. Finally, clonogenic survival assay was also performed. Results: Amongst the DNA repair pathway genes, exome sequencing revealed a heterozygous recurrent truncating mutation in ERCC3 (R109X) in 2 of 49 early onset breast cancer cases of AJ ancestry and 4 familial AJ probands. Taqman genotyping in a case control setting from New York and Israel revealed 54 mutation carriers in 3131 cases and 32 in the 2716 controls. In total, there were 60 heterozygotes detected in 3209 cases and 32 in 2716 controls [OR 1.59 (95% CI 1.01-2.50)]; p = 0.02 Fisher one- tailed). Functional studies using CRISPR and overexpression systems on human mammary epithelial cells, show that the mutation results in lower transcript levels and this reduction is effected by nonsense mediated decay of the mutant transcript. Western blotting showed that the mutation resulted in a smaller protein (∼12kDa). Clonogenic assays showed similar survival rate of mutant and wildtype under UVC exposure, however the mutant cell line showed significantly smaller colony size demonstrating a growth disadvantage that was further increased upon DNA damage. Treatment with fungal sesquiterpene IlludinS, a known sensitizer to mutant ERCC3 cell lines, showed drastically reduced survival when compared to the wild type human mammary epithelial cells. Conclusions: We demonstrate that ERCC3 is a moderate risk gene for breast cancer in individuals of Ashkenazi ancestry. ERCC3 is somatically mutated in multiple cancers including breast, ovarian and pancreatic cancers, however its role as a cancer susceptibility gene requires further elucidation. Additional functional and population genetic studies to further characterize this novel ERCC3 variant are underway. Citation Format: Joseph Vijai, Sabine Topka, Kara Maxwell, Vignesh Ravichandran, Tinu Thomas, Danylo Villano, Ann Maria, Pragna Gaddam, Anne Lincoln, Steven Hart, Susan Neuhausen, Mark Robson, Jeffrey Weitzel, Mark Daly, Katherine Nathanson, Fergus Couch, Gadi Rennert, Kenneth Offit. ERCC3 R109X is a moderate risk breast cancer risk variant in Ashkenazi Jews. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 796.

Abstract Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG designated reportable cancer and non-cancer genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole exome sequencing in 404 individuals in 257 families and classified 1640 variants from these genes. Potentially clinically actionable (likely-pathogenic/pathogenic, LP/P) versus nonactionable (VUS/likely-benign/benign) calls were 92% and 88% concordant with locus specific databases and Clinvar, respectively. LP/P mutations were identified in 11 of 25 breast cancer susceptibility genes in 27 BRCA1/2 negative families (11%). Evaluation of 84 additional autosomal dominant cancer susceptibility genes identified LP/P mutations in only four additional families (1.7%), suggesting they do not influence risk in this cohort. However, individuals from nine of 257 families (3.5%) had incidental LP/P mutations in 32 non-cancer disease genes, and 7% of individuals were monoallelic carriers of an LP/P mutation in 39 autosomal recessive cancer syndrome genes. Furthermore, 90% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant classification guidelines. In addition, evaluation of extended panels of cancer genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results. Citation Format: Kara N. Maxwell, Steven N. Hart, Joseph Vijai, Kasmintan A. Schrader, Tinu Thomas, Bradley Wubbenhorst, Vignesh Ravichandran, Raymond M. Moore, Chunling Hu, Lucia Guidugli, Brandon Wenz, Thomas P. Slavin, Susan M. Domchek, Mark E. Robson, Csilla Szabo, Susan L. Neuhausen, Jeffrey N. Weitzel, Kenneth Offit, Fergus J. Couch, Katherine L. Nathanson. Evaluation of ACMG guideline classified variants in 180 cancer and incidental non-cancer genes in families with breast/ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5220.

Rare Tumors is an international peer-reviewed medical journal established in 2009. The journal is focused on rare cancers and aims to expand upon current knowledge on their presentation, diagnosis, management, and outcomes. We reviewed the 335 case reports published from 2009 to 2015. We found great diversity in both the country of origin as well as specialty of first authors. Outside of the United States (US) and European Union (EU), there were 20 countries with contributions to the journal. Similarly, there was representation from twelve medical specialties with first authorship of reports. Rare Tumors continues to encourage involvement from physicians across the globe and from all medical disciplines.

Background/aims: Some of the most promising avenues of cancer clinical investigation center on immunotherapeutic approaches. These approaches have provided notable gains in cancer therapeutics with recent Food and Drug Administration approvals of agents of this class in several types of cancers, although gains for ovarian cancer lag behind. This study examined perceptions of therapeutic trials including immunotherapy and virotherapy among ovarian cancer patients and their family members. Methods: A total of 72 semi-structured qualitative interviews were conducted with 33 patients and 39 family members at two National Cancer Institute–designated comprehensive cancer centers. Eligible patients were diagnosed with epithelial ovarian, primary peritoneal, or fallopian tube carcinoma and had experience with clinical trial conversations; family members were nominated by patients and interviewed separately. Applied thematic analysis was used to understand and interpret the data. Results: More participants were aware of vaccine trials than virus trials, although more than half had heard of at least one of them. Initial reactions to vaccine trials were generally favorable. For many, childhood experience with vaccines lent a familiar frame of reference. Virus trials elicited more negative initial reactions, including the use of adjectives such as “scary” and “dreadful.” Viruses seemed contagious or difficult to control. Increased receptivity to these trials occurred in the context of limited therapeutic options and cancer recurrence. Most participants, including those not immediately drawn to these types of trials, indicated openness to learning more. Conclusion: Although vaccine and viral trials are both immunologically based therapeutic approaches, patients who are offered these trials may perceive their potential benefit and safety quite differently. There is a need to consider terminology, solicit and address “gut reactions,” and provide information that enables patients and their family members to better understand the science behind these trials.

Abstract Background: Palliative care guidelines recommend plain radiographs to assess constipation based on the presumption that visible fecal shadowing represents stool retention. Despite this, using plain radiographs in this way is not well validated. Objectives: This work's main aim was to compare clinicians' reports of fecal loading on radiographs. This study also compares clinicians' assessments with radio-opaque marker transit studies and patients' self-reported constipation symptoms. Methods: This study was conducted in a sample of 30 constipated palliative care patients taking laxatives who had all undergone colon transit studies and contemporaneous assessment of constipation symptoms with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire. Four separate clinicians independently reported their opinions of fecal loading using a previously developed fecal loading scale. Participant details were summarized and pair-wise inter-rater agreement among all four raters were examined using the Bland-Altman approach. For the comparisons of the clinician-assigned fecal loading score between the radiographic assessment of the normal and slow colon transit time, the nonparametric approach of Mann-Whitney U tests were applied. Spearman's correlation analyses were employed to investigate the association between the clinician-assigned fecal loading score and the patient self-reported PAC-SYM score. Results: The results of this study are very similar to other studies conducted in functional constipation, highlighting systematic disagreement between observers. Further poor correlations were noted between fecal loading scores and colon transit times and with patient self-reported symptoms. Conclusion: These results, when considered with other work in chronic constipation, question the ongoing use of radiographs in the diagnosis of constipation.

Abstract Fusion transcript 24analysis by five groups, each using "in house" analytical workflow to analyze RNA-seq data from 813 breast tumors from The Cancer Genome Atlas project detected 2514 high confidence RNA fusions (2 or more junction spanning reads detected by 2 or more groups). A subset of tumors with fusions were evaluated for chromosomal rearrangement using whole genome sequence data (WGS), and about half of the high confidence fusions could be validated, with the remainder likely subclonal and therefore below the limits of detection by WGS at the relatively low depth of coverage (30X) available. The majority of tumors contained one or more fusion transcript (range 0-24 fusions/tumor), but recurrence of specific chimaeric transcripts was low. Only ESR1->CCDC170, C20orf3->ACSS1, and USP22->MYH10 fusions were detected in 10 or more tumors. Additional ESR1 fusions were detected with AKAP12, BNC2, C6orf211, GNAS, POLH, USP25, and UTRN, within 19 tumors, primarily of the Luminal B subtype. RARA was the second most common 5' fusion partner with 17 tumors, predominately of the HER2-enriched subtype, expressing out of frame RARA fusions to 19 different 3' fusion partners. Other common 5' fusion partners included FBXL20, USP22, USP32, BCAS3, MED1, BPTF, ERBB2, MED24, and PPF1A1 (expressed in 10 or more tumors each). The most common 3' fusion partners were ERBB2, CCDC170, PITPNC1, ACSS1, MYH10, IKZF3, and RAB6A (10 or more tumors each). HER2-enriched tumors expressed significantly more fusions than other subtypes (4.9 fusions/tumor vs 3.3 for Basal-like, 1.3 for LumA, and 3.2 for LumB). Almost all HER2-enriched tumors expressed fusions (97%), whereas 85% of Basal-like tumors and 79% of Luminal B tumors expressed one or more fusions. Among Luminal A tumors, only 48% expressed one or more fusion transcript. Those Luminal A tumors with multiple fusion transcripts contained significantly more copy number aberrations and were enriched for expression of mitotic cell cycle genes (p=3.07E-18), characteristic of the recently described high risk CNH subclass of Luminal A tumors. We conclude that, consistent with other observations, breast tumors generally exhibit a high level of genomic instability, associated with multiple copy number alterations and multiple fusion transcripts. However, recurrence of specific fusion transcripts is low. About half of Luminal A tumors express fusion transcripts; and these tumors exhibit multiple copy number events, consistent with high level genomic instability, as well as enriched expression of mitotic cell cycle genes. These tumors appear to be related to the relatively high risk Luminal A CNH subclass, and express high levels of aurora kinases and polo-like kinases, which might be considered as therapeutic targets. Given the increasing emphasis on transcript profiling of clinical samples and the clinical significance of high risk Luminal A tumors, it may be timely to consider inclusion of fusion transcripts in such analyses as surrogate markers of genomic instability and potential therapeutic and/or prognostic indicators. Citation Format: Thompson EA, Asmann YW, Su X, Ellis MJ, Shao J, Hu Y, White KP, Cherniack AD, Hoadley KA, Serie DJ, Perez EA, Perou CM. A comprehensive analysis of fusion transcripts in breast cancer reveals associations between number of fusion transcripts, copy number events, gene expression profiles, and potentially clinical outcome. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S4-02.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Abstract Background: Blood-based testing can be used as a noninvasive method to recover and analyze circulating tumor-derived cells for clinical use. Circulating cancer-associated macrophage-like cells (CAML) are specialized myeloid cells found in peripheral blood and associated with the presence of solid malignancies. We measured CAMLs prospectively in peripheral blood to ascertain their prevalence, specificity, and sensitivity in relation to breast disease status at clinical presentation. Methods: We report on two related but separate studies: 1) CellSieve microfilters were used to isolate CAMLs from blood samples of patients with known malignant disease (n = 41). Prevalence and specificity was compared against healthy volunteers (n = 16). 2) A follow-up double-blind pilot study was conducted on women (n = 41) undergoing core-needle biopsy to diagnose suspicious breast masses. Results: CAMLs were found in 93% of known malignant patients (n = 38/41), averaging 19.4 cells per sample, but none in the healthy controls. In subjects undergoing core biopsy for initial diagnosis, CAMLs were found in 88% of subjects with invasive carcinoma (n = 15/17) and 26% with benign breast conditions (n = 5/19). Conclusion: These preliminary pilot studies suggest that the presence of CAMLs may differentiate patients with malignant disease, benign breast conditions, and healthy individuals. Impact: We supply evidence that this previously unidentified circulating stromal cell may have utility as a screening tool to detect breast cancer in various malignancies, irrespective of disease stage. Cancer Epidemiol Biomarkers Prev; 25(7); 1037–42. ©2016 AACR.

Purpose: To examine the association of obesity with in-hospital mortality and complications during critical illness. Methods: We performed a retrospective analysis of a multiethnic cohort of 699 patients admitted to medical intensive care unit between January 2010 and May 2011 at Mount Sinai St. Luke’s and Mount Sinai West Hospitals, tertiary care centers in New York City. Multivariate logistic regression analysis was used to evaluate the association between obesity (body mass index [BMI] ≥ 30] and in-hospital mortality. Subgroup analysis was performed in elderly patients (age ≥65 years). Results: Compared to normal BMI, obese patients had lower in-hospital mortality (24.4% vs 17.6%, P = .04). On multivariate analysis, obesity was independently associated with lower in-hospital mortality (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.27-0.89, P = .018). There was no significant difference in rates of mechanical ventilation, reintubation, and vasopressor requirement across BMI categories. In subgroup analysis, elderly obese patients did not display lower in-hospital mortality (adjusted OR: 0.85, 95% CI: 0.40-1.82, P = .68). Conclusion: Our study supports the hypothesis that obesity is associated with decreased mortality during critical illness. However, this finding was not observed among elderly obese patients. Further studies should explore the interaction between age, obesity, and outcomes in critical illness.