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ABSTRACT Background Multiplex genetic testing is recommended when treating nonsmall cell lung cancer. A certain percentage of test failures in RNA assays owing to poor surgical specimen quality have been documented, and fixation failure is a possible cause. At our institution, sheet‐like fixation is performed to reduce fixation time. This study aimed to compare the quality of RNA from resected lung cancer specimens following different fixation methods. Methods Sheet‐like fixation specimens (n = 15), conventional fixation specimens of the same resected lungs (n = 15), and other lung cancer specimens collected for conventional fixation and subjected to multiplex gene‐panel testing (n = 22) were retrospectively examined. RNA was extracted from each specimen. RNA quality and quantity were compared, and the success rate of multiplex gene‐panel testing was determined. Results The DV200 value was significantly higher in RNA extracted from sheet‐like fixation samples (median 47.5%, interquartile range [IQR]:40.3–51.5) compared with RNA extracted from conventionally fixed samples or conventionally fixed samples of other patient specimens (median 21%, IQR:5.3–29.8 and median 16.3%, IQR:9.5–27.1, respectively). No significant difference was observed in nucleic acid concentration. The multiplex genetic analysis success rate was 95% with conventional methods (one failure); however, it was 100% with the sheet‐like fixation method. Conclusion Sheet‐like fixation preserved RNA extracted from lung cancer specimens, resulting in lesser degradation than with conventional fixation. This study aimed to assess the quality of RNA obtained from sheet‐like fixation lung cancer samples. The quality and concentration of RNA in histopathological samples obtained using sheet‐like and conventional fixation methods, in addition to the success rate of genetic testing, were compared. The DV200 value of RNA extracted from sheet‐like fixation samples was significantly higher than that extracted from conventional fixation samples, and there was no failure in multiplex gene‐panel testing.

The impacts of the Association for Molecular Pathology vs. Myriad Supreme Court decision regarding patenting DNA segments and multi-gene testing on cancer genetic counseling practice have not been well described. We aimed to assess genetic counselors’ perceptions of how their genetic testing-related practices for hereditary breast and/or ovarian cancer (HBOC) changed after these events. One-hundred fifty-two genetic counselors from the National Society of Genetic Counselors Cancer Special Interest Group completed an anonymous, online, mixed-methods survey in November 2013. The survey presented four hypothetical patients and asked about changes in testing practice. Across the vignettes, a majority of participants reported specific changes in testing decisions following Association for Molecular Pathology vs. Myriad and availability of multi-gene testing. Ninety-three percent of participants reported changing the types of first- and second-line tests they order for HBOC; the degree of change varied geographically. Qualitative analysis indicated that some counselors have altered the counseling session content, trading depth of information for breadth and spending more time counseling about uncertainty. This study shows that cancer genetic counselors are adapting quickly to genetic testing changes, but with wide variability. Findings suggest future research to elucidate clinicians’ and patients’ preferences for guidance on the clinical implementation of next-generation sequencing.

Metastatic inflammatory myofibroblastic tumor (IMT) is very rare and detailed reports on diagnosis and treatment are limited. Here, we report a case of metastatic IMT with ALK rearrangement. A 73‐year‐old woman was diagnosed with IMT involving a brain metastasis. Next generation sequencing (NGS) panel testing with Oncomine dx target test revealed that her tumor was positive for EML4‐ALK. Treatment with alectinib was initiated, resulting in remarkable shrinkage of both the primary tumor and the brain metastasis. This report is the first to identify ALK rearrangement in IMT using a commercially available NGS panel testing, followed by treatment with alectinib. This case suggests that NGS panel testing may be useful in the diagnosis and treatment of patients with metastatic IMT. We here report a case of metastatic inflammatory myofibroblastic tumor (IMT) with ALK rearrangement. A 73‐year‐old woman was diagnosed with IMT with a brain metastasis by transbronchial lung biopsy. Next generation sequencing (NGS) panel testing with Oncomine dx Target Test revealed that her tumor was positive for EML4‐ALK. Treatment with alectinib was initiated, resulting in remarkable shrinkage of both the primary tumor and the brain metastasis.

Genetic testing for inherited cancer risk has recently improved through the advent of multi-gene panels and the addition of deletion and duplication analysis of the BRCA genes. The primary aim of this study was to determine which factors influence the intent of individuals with a personal history of breast and/or ovarian cancer and negative or uncertain BRCA1 and BRCA2 testing to return to a hereditary cancer program for additional genetic risk assessment, counseling, and testing. Surveys were sent to 1197 individuals and 257 were returned. Of those participants who were planning to return to clinic, most cited having family members who could benefit from the test result as the primary motivation to return. Many participants who were not planning to return to clinic cited the cost of testing as a barrier to return. Cost of testing and concerns about insurance coverage were the most commonly cited barriers for the group of participants who were undecided about returning to clinic. Results from this study may be used to guide re-contact efforts by clinicians to increase patient uptake to return to clinic for up-to-date genetic risk assessment, counseling, and testing.

Key Clinical Message We used a multi‐gene panel testing to identify the germline variants in a mother‐daughter pair with early‐onset breast cancer, and detected one pathogenic protein‐truncating variant in BRCA2. Our results highlight the importance of genetic testing in identifying the pathogenic mutation running in cancer families. We used a multi‐gene panel testing to identify the germline variants in a mother‐daughter pair with early onset breast cancer, and detected one pathogenic protein‐truncating variant in BRCA2. Our results highlight the importance of genetic testing in identifying the pathogenic mutation running in cancer families.

Purpose We examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk. Methods We collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015. Results Asians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P  = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P  = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P  = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity. Conclusion In this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.

PurposeThis review describes the prevalence of germline TP53 mutations, the risk of breast cancer and other cancers in mutation carriers and management implications for women with breast cancer and unaffected women.MethodsLiterature review of English language papers available through PubMed.ResultsWomen who carry germline mutations in the TP53 gene have a very high risk of breast cancer of up to 85% by age 60 years. Most of these breast cancers are early onset with a median age at diagnosis of 34 years. Approximately 5–8% of women presenting with breast cancer under 30 years old have a germline TP53 gene mutation. Breast cancers in women with TP53 mutations are more likely to be hormone receptor positive and/or Her2 positive. Mastectomy is recommended over lumpectomy in TP53 mutation carriers who have breast cancer so that adjuvant breast radiotherapy can be avoided. Risk-reducing surgery should be considered due to the high contralateral breast cancer risk. Mutation carriers are at high risk of various childhood and adult-onset cancers with a very lifetime risk of malignancy, the commonest malignancies being breast cancer and soft tissue sarcoma. In unaffected female mutation carriers, MRI breast screening or risk-reducing surgery is recommended. The optimal surveillance for other cancers is currently unclear and should ideally be performed as part of a clinical trial.ConclusionsIdentifying a TP53 mutation in a gene panel test is a challenging result for the patient and clinician due to the high risk of second primaries and the lack of consensus about surveillance.

Purpose Genetic predisposition to male breast cancer (MBC) is not well understood. The aim of this study was to better define the predisposition genes contributing to MBC and the utility of germline multi-gene panel testing (MGPT) for explaining the etiology of MBCs. Methods Clinical histories and molecular results were retrospectively reviewed for 715 MBC patients who underwent MGPT from March 2012 to June 2016. Results The detection rate of MGPT was 18.1% for patients tested for variants in 16 breast cancer susceptibility genes and with no prior BRCA1/2 testing. BRCA2 and CHEK2 were the most frequently mutated genes (11.0 and 4.1% of patients with no prior BRCA1/2 testing, respectively). Pathogenic variants in BRCA2 [odds ratio (OR) = 13.9; p  = 1.92 × 10 −16 ], CHEK2 (OR = 3.7; p  = 6.24 × 10 −24 ), and PALB2 (OR = 6.6, p  = 0.01) were associated with significantly increased risks of MBC. The average age at diagnosis of MBC was similar for patients with (64 years) and without (62 years) pathogenic variants. CHEK2 1100delC carriers had a significantly lower average age of diagnosis ( n  = 7; 54 years) than all others with pathogenic variants ( p  = 0.03). No significant differences were observed between history of additional primary cancers (non-breast) and family history of male breast cancer for patients with and without pathogenic variants. However, patients with pathogenic variants in BRCA2 were more likely to have a history of multiple primary breast cancers. Conclusion These data suggest that all MBC patients regardless of age of diagnosis, history of multiple primary cancers, or family history of MBC should be offered MGPT.

Purpose Pharmacogenomics (PGx) studies how inherited genetic variations in individuals affect drug absorption, distribution, and metabolism. PGx panel testing can potentially help improve efficiency and accuracy in individualizing therapy. This study compared the cost-effectiveness between preemptive PGx panel testing, reactive PGx panel testing and usual care (no testing) in cardiovascular disease management. Methods We developed a decision analytic model from the US payer’s perspective for a hypothetical cohort of 10,000 patients ≥45 years old, using a short-term decision tree and long-term Markov model. The testing panel included the following gene–drug pairs: CYP2C19 –clopidogrel, CYP2C9/VKORC1– warfarin, and SLCO1B1 –statins with 30 test-return days. Costs were reported in 2019 US dollars and effectiveness was measured in quality-adjusted life years (QALYs). The primary outcome was incremental cost-effectiveness ratio (ICER = ΔCost/ΔQALY), assuming 3% discount rate for costs and QALYs. Scenario and probabilistic sensitivity analyses were performed to assess the impact of demographics, risk level, and follow-up timeframe. Results Preemptive testing was found to be cost-effective compared with usual care (ICER $86,227/QALY) at the willingness-to-pay threshold of $100,000/QALY while reactive testing was not (ICER $148,726/QALY). Sensitivity analyses suggested that our cost-effectiveness results were sensitive to longer follow-up, and the age group 45–64 years. Conclusion Compared with usual care, preemptive PGx panel testing was cost-effective in cardiovascular disease management.