bims-lifras 2023-08-20 papers

Radiol Case Rep. 2023 Oct;18(10): 3586-3591

Multimodality local ablative therapy of 23 lung metastases with surgical resection and percutaneous cryoablation in a patient with Li-Fraumeni Syndrome: A case report.

Jonathan A Saenger, Ismail Tahir, Manuela Födinger, Gregory M Cote, Ashok Muniappan, Florian J Fintelmann.

Patients with Li-Fraumeni syndrome (LFS) are prone to develop a variety of malignancies due to insufficient activity of the encoded tumor suppressor protein P53, including adrenocortical carcinoma, breast cancer, lung cancer, pancreatic cancer, and sarcoma. In the setting of LFS, local treatment options for lung metastases are limited to surgery and thermal ablation since radiotherapy and some systemic therapies predispose patients to additional future malignancies. We present the case of a 45-year-old woman with LFS with leiomyosarcoma metastases to both lungs who underwent bilateral wedge resections to treat a total of eight lung metastases followed by six percutaneous cryoablation sessions to treat 15 additional lung metastases over a period of 24 months. Our case demonstrates the option of multimodal local ablative therapies for lung metastases in patients with LFS, including percutaneous cryoablation.

Keywords: Cryoablation; Leiomyosarcoma; Li-Fraumeni syndrome; Lung metastasis; Thermal ablation

DOI: https://doi.org/10.1016/j.radcr.2023.07.047

J Clin Oncol. 2023 Aug 14. 101200JCO2301372

Germline EGFR mutations and familial lung cancer.

BACKGROUND: The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants (PVs).METHODS: The INHERIT study (NCT01754025) enrolled lung cancer patients whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in-person or remotely, providing germline testing and follow-up.
RESULTS: 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon prior genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, consistent with a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver co-mutation. Among 36 germline carriers without a cancer diagnosis, 15 had CT imaging and 9 had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the Southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1 Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago.
CONCLUSIONS: In this first prospective description of familial EGFR-mutant lung cancer, we identify a recent founder germline EGFR T790M variant enriched in the US Southeast. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.

DOI: https://doi.org/10.1200/JCO.23.01372

Eur J Haematol. 2023 Aug 16.

Identifying patients at risk for hereditary myeloid malignancy syndromes incorporating a novel, self-administered questionnaire to an initial screening platform.

Mohammad Faizan Zahid, Kelsey Moriarty, Courtney Dryden, Olga Weinberg, Misha Asif, Ruth Ikpefan, Julia M Anderson, Robert H Collins, Stephen S Chung, Weina Chen, Prapti A Patel, Yazan F Madanat.

INTRODUCTION: Four to 10% of cases of myeloid malignancies are inherited. We report our experience on hereditary myeloid malignancy syndromes (HMMS) incorporating a novel questionnaire in the screening platform for patients with myeloid malignancies and aplastic anemia.METHODS: The questionnaire was sent via electronic patient portal prior to clinic visits. Patients screened positive based on responses to questionnaire items, presence of suspicion disease characteristics (young age, family history, monosomy 7 etc.) and/or presence of signs of HMMS. Those deemed at-risk based on questionnaire responses, clinical features and/or somatic mutation profile were offered germline testing.
RESULTS: A total of 408 patients were screened, 141 (35%) were deemed at-risk. Fifty-four (38%) of at-risk patients were seen in the genetics clinic. Forty-one (76%) of the patients seen agreed to germline testing and 13 declined due to cost or personal decision. Twenty pathogenic (P)/likely-pathogenic (LP) germline mutations were identified in 16 (39%) of the tested patients. Five patients also had a variant of uncertain significance (VUS) and an additional 13 had at least 1 VUS without P/LP mutations (total 29 VUS's were found in 18 (44%) of tested patients). The median age of diagnosis for patients with P/LP mutations was 56 years versus 66 years in the entire cohort.
CONCLUSION: Incorporating an electronic questionnaire is an effective screening method for HMMS. Many patients declined testing due to cost. These results highlight the importance of germline testing in patients with myeloid malignancies, further research in HMMS, and coverage by healthcare plans.

Keywords: germline predisposition; leukemia; myelodysplastic syndromes; myeloid malignancies

DOI: https://doi.org/10.1111/ejh.14084

Eur Urol Oncol. 2023 Aug 12. pii: S2588-9311(23)00150-5. [Epub ahead of print]

Efficacy of National Comprehensive Cancer Network Guidelines in Identifying Pathogenic Germline Variants Among Unselected Patients with Prostate Cancer: The PROCLAIM Trial.

BACKGROUND: Prostate cancer (PCa) patients with pathogenic/likely pathogenic germline variants (PGVs) in cancer predisposition genes may be eligible for U.S. Food and Drug Administration-approved targeted therapies, clinical trials, or enhanced screening. Studies suggest that eligible patients are missing genetics-informed care due to restrictive testing criteria.OBJECTIVE: To establish the prevalence of actionable PGVs among prospectively accrued, unselected PCa patients, stratified by their guideline eligibility.
DESIGN, SETTING, AND PARTICIPANTS: Consecutive, unselected PCa patients were enrolled at 15 sites in the USA from October 2019 to August 2021, and had multigene cancer panel testing.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Correlates between the prevalence of PGVs and clinician-reported demographic and clinical characteristics were examined.
RESULTS AND LIMITATIONS: Among 958 patients (median [quartiles] age at diagnosis 65 [60, 71] yr), 627 (65%) had low- or intermediate-risk disease (grade group 1, 2, or 3). A total of 77 PGVs in 17 genes were identified in 74 patients (7.7%, 95% confidence interval [CI] 6.2-9.6%). No significant difference was found in the prevalence of PGVs among patients who met the 2019 National Comprehensive Cancer Network Prostate criteria (8.8%, 43/486, 95% CI 6.6-12%) versus those who did not (6.6%, 31/472, 95% CI 4.6-9.2%; odds ratio 1.38, 95% CI 0.85-2.23), indicating that these criteria would miss 42% of patients (31/74, 95% CI 31-53%) with PGVs. The criteria were less effective at predicting PGVs in patients from under-represented populations. Most PGVs (81%, 60/74) were potentially clinically actionable. Limitations include the inability to stratify analyses based on individual ethnicity due to low numbers of non-White patients with PGVs.
CONCLUSIONS: Our results indicate that almost half of PCa patients with PGVs are missed by current testing guidelines. Comprehensive germline genetic testing should be offered to all patients with PCa.
PATIENT SUMMARY: One in 13 patients with prostate cancer carries an inherited variant that may be actionable for the patient's current care or prevention of future cancer, and could benefit from expanded testing criteria.

Keywords: Genetic testing; Hereditary cancer risk; Precision medicine; Professional guidelines; Prostate cancer; Racial disparities

DOI: https://doi.org/10.1016/j.euo.2023.07.008