bims-lifras 2024-01-07 papers

Issue of 2024–01–07
three papers selected by
Joanna Zawacka, Karolinska Institutet

J Clin Oncol. 2024 Jan 04. JCO2302225

Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline.

Isabelle Bedrosian, Mark R Somerfield, Maria Isabel Achatz, Judy C Boughey, Giuseppe Curigliano, Sue Friedman, Wendy K Kohlmann, Allison W Kurian, Christine Laronga, Filipa Lynce, Barbara S Norquist, Jennifer K Plichta, Patricia Rodriguez, Payal D Shah, Marc Tischkowitz, Marie Wood, Siddhartha Yadav, Katherine Yao, Mark E Robson.

PURPOSE: To develop recommendations for germline mutation testing for patients with breast cancer.
METHODS: An ASCO-Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process.
RESULTS: Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations.
RECOMMENDATIONS: BRCA1/2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing, regardless of family history. BRCA1/2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history.Additional information is available at www.asco.org/breast-cancer-guidelines.

DOI: https://doi.org/10.1200/JCO.23.02225

Am J Med Genet A. 2024 Jan 02.

Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor.

Fabienne Meier-Abt, Dennis Kraemer, Nils Braun, Michael Reinehr, Eveline Stutz-Grunder, Katharina Steindl, Anita Rauch.

Somatic variants in the NOTCH pathway regulator FBXW7 are frequently seen in a variety of malignancies. Heterozygous loss-of-function germline variants in FBXW7 have recently been described as causative for a neurodevelopmental syndrome. Independently, FBXW7 was also considered as a susceptibility gene for Wilms tumor due to a few observations of heterozygous germline variants in patients with Wilms tumor. Whether the same FBXW7 variants are implicated in both, neurodevelopmental delay and Wilms tumor formation, remained unclear. By clinical testing, we now observed a patient with neurodevelopmental delay due to a de novo constitutional mosaic FBXW7 splice site pathogenic variant who developed Wilms tumor. In the tumor, we identified a second hit frameshift variant in FBXW7. Immunohistochemical staining was consistent with mosaic loss of FBXW7 protein expression in the tumor. Our data support the role of constitutional FBXW7 pathogenic variants in both, neurodevelopmental disorder and the etiology of Wilms tumor. Therefore, Wilms tumor screening should be considered in individuals with constitutional or germline pathogenic variants in FBXW7 and associated neurodevelopmental syndrome.

Keywords: FBXW7; Wilms tumor; cancer predisposition; constitutional mosaic variant; neurodevelopmental syndrome

DOI: https://doi.org/10.1002/ajmg.a.63528

Semin Oncol. 2023 Nov 24. pii: S0093-7754(23)00081-7. [Epub ahead of print]

Beyond BRCA: Diagnosis and management of homologous recombination repair deficient pancreatic cancer.

Meredith LaRose, Gulam A Manji, Susan E Bates.

Approximately 4%-7% of patients diagnosed with pancreatic adenocarcinoma (PDAC) are found to harbor deleterious germline mutations in BRCA1 and/or BRCA2. Loss of function of BRCA1 and/or BRCA2 results in deficiency in homologous recombination repair (HRR), a critical DNA repair pathway, and confers sensitivity to certain DNA damaging agents, including platinum chemotherapy and PARP inhibitors. The PARP inhibitor olaparib is food and drug administration (FDA) approved for use in pancreatic cancer based on the POLO trial, which found that maintenance olaparib significantly prolonged progression free survival compared to placebo among patients with germline BRCA1 or BRCA2 mutations and metastatic PDAC that had not progressed following frontline platinum-based chemotherapy. Recently, there has been considerable interest in identifying patients without BRCA inactivation whose tumors also exhibit properties of HRR deficiency and thus may be susceptible to therapies with proven benefit in cancers harboring BRCA mutations. Here, we discuss methods for identification of HRR-deficiency and review the management of HRR-deficient cancers with a focus on HRR-deficient PDAC.

Keywords: BRCA; BRCAness; Homologous recombination repair; Pancreatic cancer

DOI: https://doi.org/10.1053/j.seminoncol.2023.11.001