Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we ...present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers.
Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies.
Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation.
Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.
•14.3% of patients with rare cancers and/or younger age of onset carried a PGV.•PGVs were highly enriched in certain rare cancer entities, i.e. wild-type GISTs and leiomyosarcomas.•High PGV yields in ATM, BRCA2, or PALB2 in rare cancer entities indicated potentially novel genotype–phenotype associations.•75% of patients with PGVs in cancer predisposition genes were newly diagnosed due to study participation (118/157).•45% of all PGVs supported molecularly informed therapeutic recommendations with a therapeutic benefit in 40% of patients.
Immunosuppressive therapy employing purine analogues is the therapeutic mainstay in patients with chronic active ulcerative colitis. However, despite therapeutic optimization according to ...thiopurine-methyltransferase activity or red blood cell 6-thioguanine levels, a substantial proportion of patients does not tolerate azathioprine or 6-mercaptopurine or relapses during this treatment. In the latter multiple therapeutic regimens comprising 6-thioguanine, cyclosporin or tacrolimus, methotrexate, cyclophosphamide, infliximab, interferons, heparin, leukocyte apheresis, and various other regimens might be considered aiming at long-term remission. Many of these treatment forms have only been evaluated in small mostly uncontrolled trials.
In this review existing treatment modalities and future options for patients with chronic active ulcerative colitis will be discussed focusing on immunomodulating approaches.
Although standard medical therapy in Crohn's disease is efficient in most patients, a substantial proportion of patients suffering from chronic active disease do not adequately respond to standard ...therapy. In these patients, alternative regimens have to be considered. Due to the major advances in understanding the pathogenesis of this complex disease involving genetic, environmental, microbial and immunological factors, various new biological therapies targeting key mechanisms have emerged. In this review, a critical appraisal of modern therapeutical concepts will be presented, focusing on antibody and small inhibitory molecule therapies, including inhibition of TNF-α and other pro-inflammatory cytokines, adhesion molecules and T cell activation, as well as hormonal therapies.
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