Teprotumumab for Thyroid-Associated Ophthalmopathy

BACKGROUND: Thyroid-associated ophthalmopathy, a condition commonly associated with Graves’ disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. / METHODS: We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves’ ophthalmopathy–specific quality-of-life questionnaire. Adverse events were assessed. / RESULTS: In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. / CONCLUSIONS: In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997.

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Background: Most $\textit{BRCA1}$ or $\textit{BRCA2}$ mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both $\textit{BRCA1}$ and $\textit{BRCA2}$ are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female $\textit{BRCA1/2}$ mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at $\textit{BRCA1}$ (SH1) or $\textit{BRCA2}$ (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; $p$ = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 ($p$ = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 ($p$ = 0.231), but was on average 4.5 years younger in TH than in SH2 ($p$ < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive ($p$ = 0.010) or progesterone receptor (PR) positive ($p$ = 0.013) than in SH1, but less likely to be ER positive ($p$ < 0.001) or PR positive ($p$ = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for $\textit{BRCA1}$ or $\textit{BRCA2}$ in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.ACA and the CIMBA data management are funded by Cancer Research UK (C12292/A20861 and C12292/A11174). TRR was supported by R01-CA083855, R01-CA102776, and P50-CA083638. KLN, TMF, and SMD are supported by the Basser Research Center at the University of Pennsylvania. BP is supported by R01-CA112520. Cancer Research UK provided financial support for this work. ACA is a Senior Cancer Research UK Cancer Research Fellow. DFE is Cancer Research UK Principal Research Fellow. Tumor analysis was funded by STOP CANCER (to SJR). Study-specific acknowledgements are as provided in the manuscript

Evaluation of models to predict BRCA germline mutations

The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66–2.67) for Penn, 1.74 (95% CI 1.48–2.04) for Myriad, 1.35 (95% CI 1.19–1.53) for Manchester and 1.68 (95% CI 1.39–2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study

Selecting a BRCA risk assessment model for use in a familial cancer clinic

<p>Abstract</p> <p>Background</p> <p>Risk models are used to calculate the likelihood of carrying a <it>BRCA1 </it>or <it>BRCA2 </it>mutation. We evaluated the performances of currently-used risk models among patients from a large familial program using the criteria of high sensitivity, simple data collection and entry and <it>BRCA </it>score reporting.</p> <p>Methods</p> <p>Risk calculations were performed by applying the BRCAPRO, Manchester, Penn II, Myriad II, FHAT, IBIS and BOADICEA models to 200 non-<it>BRCA </it>carriers and 100 <it>BRCA </it>carriers, consecutively tested between August 1995 and March 2006. Areas under the receiver operating characteristic curves (AUCs) were determined and sensitivity and specificity were calculated at the conventional testing thresholds. In addition, subset analyses were performed for low and high risk probands.</p> <p>Results</p> <p>The BRCAPRO, Penn II, Myriad II, FHAT and BOADICEA models all have similar AUCs of approximately 0.75 for <it>BRCA </it>status. The Manchester and IBIS models have lower AUCs (0. and 0.47 respectively). At the conventional testing thresholds, the sensitivities and specificities for a <it>BRCA </it>mutation were, respectively, as follows: BRCAPRO (0.75, 0.62), Manchester (0.58,0.71), Penn II (0.93,0.31), Myriad II (0.71,0.63), FHAT (0.70,0.63), IBIS (0.20,0.74), BOADICEA (0.70, 0.65).</p> <p>Conclusion</p> <p>The Penn II model most closely met the criteria we established and this supports the use of this model for identifying individuals appropriate for genetic testing at our facility. These data are applicable to other familial clinics provided that variations in sample populations are taken into consideration.</p

High frequency of pathogenic non-founder germline mutations in BRCA1 and BRCA2 in families with breast and ovarian cancer in a founder population

Funding Information: This work was supported by State Research Program “Biomedicine for the public health (BIOMEDICINE)” project 5 “Personalised cancer diagnostics and treatment effectiveness evaluation”. Publisher Copyright: © 2018 The Author(s).Background: Pathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population. Methods: Fifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations. Results: In 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations. Conclusion: A relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.publishersversionPeer reviewe

Efficiency of BRCAPRO and Myriad II mutation probability thresholds versus cancer history criteria alone for BRCA1/2 mutation detection

Considerable differences exist amongst countries in the mutation probability methods and thresholds used to select patients for BRCA1/2 genetic screening. In order to assess the added value of mutation probability methods, we have retrospectively calculated the BRCAPRO and Myriad II probabilities in 306 probands who had previously been selected for DNA-analysis according to criteria based on familial history of cancer. DNA-analysis identified 52 mutations (16.9%) and 11 unclassified variants (UVs, 3.6%). Compared to cancer history, a threshold ≥10% with BRCAPRO or with Myriad II excluded about 40% of the patients from analysis, including four with a mutation and probabilities <10% with both programs. All four probands had a BRCA2 mutation. BRCAPRO and Myriad II showed similar specificity at 10% threshold, overall BRCAPRO was more sensitive than Myriad II for the detection of mutations. Only two of the probands with an UV had probabilities >20% with BRCAPRO and Myriad II. In summary, BRCAPRO and Myriad II are more efficient than cancer history alone to exclude patients without a mutation. BRCAPRO performs better for the detection of BRCA1 mutations than of BRCA2 mutations. The Myriad II scores provided no additional information than the BRCAPRO scores alone for the detection of patients with a mutation. The use of thresholds excluded from analysis the majority of patients carrying an UV

Subjective versus objective risk in genetic counseling for hereditary breast and/or ovarian cancers

Background. Despite the fact that genetic counseling in oncology provides information regarding objective risks, it can be found a contrast between the subjective and objective risk. The aims of this study were to evaluate the accuracy of the perceived risk compared to the objective risk estimated by the BRCApro computer model and to evaluate any associations between medical, demographic and psychological variables and the accuracy of risk perception. Methods. 130 subjects were given medical-demographic file, Cancer and Genetic Risk Perception, Hospital Anxiety-Depression Scale. It was also computed an objective evaluation of the risk by the BRCApro model. Results. The subjective risk was significantly higher than objective risk. The risk of tumour was overestimated by 56%, and the genetic risk by 67%. The subjects with less cancer affected relatives significantly overestimated their risk of being mutation carriers and made a more innacurate estimation than high risk subjects. Conclusion. The description of this sample shows: general overestimation of the risk, inaccurate perception compared to BRCApro calculation and a more accurate estimation in those subjects with more cancer affected relatives (high risk subjects). No correlation was found between the levels of perception of risk and anxiety and depression. Based on our findings, it is worth pursuing improved communication strategies about the actual cancer and genetic risk, especially for subjects at "intermediate and slightly increased risk" of developing an hereditary breast and/or ovarian cancer or of being mutation carrier