Deciphering the genetic background in unexplained high-risk breast cancer families : integration of somatic data to unravel heredity

Breast cancer is a heterogeneous disease for which the existence of monogenic and polygenic models of inheritance have been described for decades. Multigene panel testing is useful for the diagnosis of monogenic breast cancer predisposition, allowing to simultaneously sequence a large number of genes of several patients. However, this approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We first performed a systematic review and meta-analysis of studies conducting multigene panel testing on germline DNA of women with familial breast cancer. We found that using current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a pathogenic variant. BRCA1 and BRCA2, the two most extensively studied breast cancer predisposing genes until now, were the only genes presenting the opposite trend. Reclassification of VUS in the other more recently identified genes is therefore required to drastically reduce the number of families for which genetic counselors are not able to draw a conclusion. Using a cohort of 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53 or CHEK2 mutation, we demonstrated that sequencing the matching tumor can help reclassify germline VUS based on second events hitting the same gene and provide clinically relevant information. We then explored the concept of oligogenic inheritance of familial breast cancer, and obtained data suggestive of the pertinence of this model. Analyzing the combined segregation patterns of low-frequency variants in affected familial relatives of 54 of our index patients, we found significantly higher segregation rates of rare variants in cancer-related genes in families in which affected members share a similar breast cancer phenotype, as compared to phenotypically heterogeneous families. Furthermore, cancer genes with disease-cosegregating variants harbored second somatic hits more frequently than those with non-segregating variants. Our investigations demonstrate that new and original studies are required to provide answers to the questions raised out of the exponential access to sequencing technology. In depth study of matched tumor material and the exploration of an oligogenic model of inheritance form approaches that could tackle the issue of missing heritability in familial breast cancer.(MED - Sciences médicales) -- UCL, 201

Acute cerebral toxicity during concurrent anti-HER2 therapy and radiotherapy for breast cancer brain metastases

Patients with HER2-positive advanced breast cancer frequently develop brain metastases. Dual anti-HER2 therapy significantly prolongs survival in previously untreated metastatic disease. However, no safety data exist on the concurrent use of pertuzumab, trastuzumab and brain radiotherapy. We describe two cases of previously untreated HER2-positive breast cancer and brain metastases, that developed acute cerebral toxicity during the concomitant administration of anti-HER2 therapy and whole-brain radiotherapy. Systematic clinical data is warranted to prove the safety of this association

Acute liver failure secondary to metastatic liver infiltration: Case report and review of the literature

We present the case of a patient who died from multiple organ failure due to acute liver failure as a result of malignant hepatic infiltration by an adenocarcinoma. A review of the literature revealed that the clinical picture, laboratory examination, and imaging studies do not contribute to the diagnosis of this rare cause of liver failure. Therefore, liver biopsy should be considered early in the process, as this diagnosis is a contraindication for orthotopic liver transplantation

Rapid and fatal acute heart failure induced by pazopanib

Tyrosine kinase inhibitors, represented by sunitinib, sorafenib, axitinib and pazopanib, are emerging molecules harbouring antitumoural efficacy in multiple neoplasia. We report the case of a 51-year-old woman with right thoracic sarcoma who developed fatal heart failure on pazopanib. The patient had no cardiovascular risk factor, except previous exposure to anthracycline, and her cardiac function was normally controlled before initiating the pazopanib. Despite a rapid tumour response, fatigue rapidly appeared, requiring treatment interruption 2 weeks after pazopanib introduction. After clinical improvement, the pazopanib was reintroduced at reduced dose; however, a few days later, our patient was admitted for worsening dyspnoea and fatigue. Pulmonary embolism was excluded as was pleuropericardial effusion. Brain natriuretic peptide was the only laboratory abnormality, and echocardiography revealed acute and severe heart failure. The patient died despite pazopanib arrest and inotropic support. Copyright 2015 BMJ Publishing Group. All rights reserved

Palmar fasciitis and polyarthritis, a rare paraneoplastic syndrome related to ovarian cancer

Palmar fasciitis and polyarthritis syndrome (PFPAS) is an uncommon disorder characterized by diffuse inflammation of the palmar fascia, tendon sheaths, and joints of the fingers and wrists, which rapidly progresses to flexion contracture of the hands. This paraneoplastic syndrome, originally linked to ovarian carcinoma, has also been associated with multiple different malignancies. As PFPAS usually precedes the detection of cancer, its symptoms should raise the suspicion of an underlying malignancy and should be thoroughly investigated

Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: A systematic review and meta-analysis of gene-panel data.

BACKGROUND: Gene-panels are used to assess predisposition to breast cancer by simultaneous testing of multiple susceptibility genes. This approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We performed a systematic review of published studies to calculate the prevalence of VUS and pathogenic variants (PV) in routinely tested breast cancer susceptibility genes in patients at high risk of breast cancer. METHODS: We comprehensively searched the literature using Medline through May 23, 2017 for studies conducting gene-panel testing on germline DNA of women with familial breast cancer and reporting on both PVs and VUSs. A meta-analysis of the collected data was carried out to obtain pooled VUS and PV prevalence estimates per gene using a generalized linear mixed model with logit link for binomial distribution. RESULTS: Of 602 publications, 4 were eligible and included 1870 patients. The panels encompassed 4-27 considered genes. Overall, the estimated probability per gene of a PV and VUS was 55% (95% confidence interval (CI) 26%-81%) and 91% (95% CI 78%-97%), respectively (p =  0.0066). The estimated probability per patient of a PV and VUS was 8% (95% CI 1%-34%) and 23% (95% CI 7%-52%), respectively (p =  0.0052). The ratio of VUS to PV was highest in the mismatch repair genes MLH1, MSH2, MSH6, PMS2 (18.7), CDH1 (13.4) and ATM (9.5). Amongst the 1468 patients tested for BRCA1 and BRCA2, only these two genes had a VUS to PV ratio of less than one (0.2 and 0.6, respectively). CONCLUSION: With the current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a PV. Better classification of VUSs is therefore critical and requires gene-specific VUS-assessment in every future study of gene-panel testing in patients at high risk of breast cancer

CO2 measurement for the early differential diagnosis of shock at the emergency department: a case series.

Objective: An early differential diagnosis is mandatory when facing a patient with clinical shock of unclear aetiology, in order to guide proper treatment. We assessed if the expired CO2 measurement and alveolar-arterial CO2 calculation could improve the differential diagnosis of shock during its initial presentation, particularly in separating pulmonary embolism from other causes of shock. Methods: We analysed the charts of 12 patients who presented with clinical shock and had end-tidal CO2 (EtCO2) and arterial CO2 partial pressure (PaCO2) measurements. Results: In cases with pulmonary embolism-related shock (n ¼ 3), the gradient between PaCO2 and EtCO2 was increased (37 vs 0.2 mmHg). There was a similar trend for a higher PaCO2 value (60 vs 32.2 mmHg) and a lower EtCO2 value (23 vs 32 mmHg). Conclusion: An initial CO2 measurement might be an easily available tool for the early diagnostic workup of clinical shock

Routine use of gene panel testing in hereditary breast cancer should be performed with caution

Breast cancer is the most frequent cancer occurring in women. Ten percent of these cancers are considered hereditary. Among them, 30% are attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Other genes of lower penetrance are also known, explaining together up to 40% of the hereditary risk of breast cancer. New techniques, such as next-generation sequencing, allow the simultaneous analysis of multiple genes in a cost-effective way. As a logical consequence, gene panel testing is entering clinical practice with the promise of personalized care. We however advocate that gene panel testing is not ready for non-specialist clinical use, as it generates many variants of unknown significance and includes more genes than are presently considered clinically useful. We hereby review the data for each gene that can change the risk management of patients carrying a pathogenic variant