Factors affecting adherence to a high-risk surveillance protocol among patients with Li-Fraumeni syndrome.

BACKGROUND: High-risk surveillance for patients with Li-Fraumeni syndrome (LFS) has shown a stage shift and improved overall survival, but is demanding. Our objective was to evaluate surveillance adherence in a population of patients with LFS presenting for high-risk care. METHODS: A retrospective analysis of surveillance adherence of adult patients with LFS at a single institution was performed. Adherence was defined by the duration from initial University of Virginia (UVA) LFS clinic visit to the time of first missed surveillance test. Two-sample t-tests and ANOVA tests were used to identify factors associated with duration of adherence. RESULTS: A total of 42 patients were evaluated in the UVA LFS clinic between 2017 and 2021. Of these, 21 patients met inclusion criteria. At the time of review, 6 patients (29%) were up to date with high-risk surveillance recommendations. The mean duration of adherence was 17 months. Female sex was found to be associated with longer duration of adherence (mean 21 mo vs. 3.5 mo for males, p = 0.02). A personal history or active diagnosis of cancer was also associated with increased adherence (p = 0.02). However, neither age (p = 0.89), geography (p = 0.84), or known family history of LFS (p = 0.08) were associated with duration of adherence. CONCLUSION: Female sex as well as a personal history of cancer were associated with longer duration of adherence to recommended high-risk surveillance among patients with LFS. Identification of barriers to surveillance will be essential moving forward to increase adherence and promote early detection of cancer, thereby reducing the morbidity and mortality of LFS.

Bloom syndrome in a Mexican American family with rhabdomyosarcoma: evidence of a Mexican founder mutation.

Bloom syndrome is a rare autosomal recessive disorder with less than 300 cases reported in the literature. Bloom syndrome is characterized by chromosome instability, physical stigmata, growth deficiency, immunodeficiency, and a predisposition to cancer, most commonly leukemias, although solid tumors are reported as well. Bloom syndrome occurs in multiple ethnic groups with a higher incidence in persons of Ashkenazi Jewish origin. Few patients of Hispanic ethnicity have been reported. We report here a Mexican American family with a BLM pathogenic variant, c.2506_2507delAG, previously reported in a single patient from Mexico. In this family of four siblings, three have phenotypic features of Bloom syndrome, and BLM gene mutation was homozygous in these affected individuals. Our proband developed a rhabdomyosarcoma. Analysis of surrounding markers in the germline DNA revealed a common haplotype, suggesting a previously unrecognized founder mutation in the Hispanic population of Mexican origin.

Mechanisms to increase cascade testing in hereditary breast and ovarian cancer: Impact of introducing standardized communication aids into genetic counseling.

AIM: Precancer identification of women with hereditary breast and ovarian cancer (HBOC) could prevent 20% of these ovarian cancers. The objective was to determine whether standardized Facing Our Risk of Cancer Empowered (FORCE) materials are acceptable, improve knowledge of HBOC and increase disclosure to family members. METHODS: A prospective cohort of women with breast or ovarian cancer was identified prior to genetic testing. Subjects completed a baseline knowledge survey and were provided three communication aids. Knowledge, acceptability and communication to family members were reassessed at 6 months and compared to a retrospective cohort who had undergone genetic testing for breast or ovarian cancer prior to the intervention. The primary outcome was increase in HBOC knowledge, requiring 20 pre- and postknowledge scores to detect a 10% difference. RESULTS: Forty women were enrolled. The median age at cancer diagnosis was 50 years and 55% had a family history of breast or ovarian cancer. Though subjects found the resources acceptable, knowledge scores did not improve after their use. Disclosure rates were of no different between cohorts (83% preintervention vs 77% postintervention, P = 0.26) though there was an increase in deleterious mutation carriers, 0% (0/6) preintervention vs 100% (22/22) postintervention. Rates of subsequent testing in relatives were low in both preintervention and postintervention cohorts (0% vs 4.5%). CONCLUSION: Inclusion of standardized communication tools is acceptable to patients. Knowledge did not improve after their use. In deleterious mutation carriers, disclosure rates increased postintervention.

Evaluation of breast screening strategies in a high risk breast and ovarian cancer clinic.

Recent data suggest that BRCA mutation carriers younger than 40 may not benefit from mammography in addition to MRI. Our objective was to evaluate screening modalities utilized in a high-risk population. Clinicopathologic data were abstracted for patients followed in a high risk clinic from 2007 to 2017. Descriptive statistics were calculated and associations between categorical variables were evaluated using chi-square tests. 631 women comprised the study population; 496 patients had no known mutation (79%), 128 (20%) had a BRCA mutation, and 7 patients had other deleterious mutations. BRCA mutation carriers were more likely to have cancers diagnosed after mammogram callbacks (p = 0.0046) and biopsies (p = 0.0026) compared to non-BRCA mutation carriers. BRCA mutation carriers were also more likely to have cancers diagnosed after biopsies following screening MRI (p = 0.045). 13 BRCA patients were diagnosed with cancer (average age 51). Of the cancers diagnosed after abnormal MRI, 3 were DCIS; all 3 patients had a normal mammogram 4-6 months prior. In those found after abnormal mammogram (n = 6), follow up MRI was performed in 4 cases; all demonstrated the lesion. Three patients were diagnosed younger than 40, 1 on mammogram and 2 on MRI. The patient diagnosed on mammogram had no prior MRI and the lesion was seen on follow-up MRI. Interval screening MRI identified DCIS in BRCA patients with a previous normal mammogram and cancers diagnosed on mammogram were all identified on follow-up MRI. These findings support further evaluation of MRI alone until age 40 in BRCA mutation carriers.

Cases and evidence for panel testing in cancer genetics: Is site-specific testing dead?

Historically in cancer genetic counseling, when a pathogenic variant is found which explains the cancers in the family, at risk family members are offered site-specific testing to identify whether or not they have the previously identified pathogenic variant. Factors such as turnaround times, cost, and insurance coverage all made site-specific testing the most appropriate testing option; however, as turnaround times and costs have substantially dropped and the recognition of double heterozygous families and families with nontraditional presentations has increased, the utility of site-specific testing should be questioned. We present four cases where ordering site-specific testing would have missed a clinically relevant pathogenic variant which raises the question of whether or not site-specific testing should be regularly used in cancer genetic testing.

Beyond BRCA: Review of Hereditary Syndromes Predisposing to Breast Cancer.

The majority of our hereditary breast cancer genes incur not only an increased risk for breast cancer but for other malignancies as well. Knowing whether an individual carries a pathogenic variant in a hereditary breast cancer gene can affect not only screening for the patient but for his or her family members as well. Identifying and appropriately testing individuals via multigene panels allows for risk reduction and early surveillance in at-risk individuals. Radiologists can serve as first-line identifiers of women who are at risk of having an inherited predisposition to breast cancer because they are interacting with all women receiving routine screening mammograms, and collecting family history suggestive of the presence of a mutation. We outline here the 11 genes associated with high breast cancer risk discussed in the National Comprehensive Cancer Network Genetic/Familial High-Risk: Breast and Ovarian (version 3.2019) as having additional breast cancer screening recommendations outside of annual mammography to serve as a guide for breast cancer screening and risk reduction, as well as recommendations for surveillance of nonbreast cancers.

Universal Lynch Syndrome Screening Should be Performed in All Upper Tract Urothelial Carcinomas.

Lynch syndrome (LS) is defined by germline mutations in DNA mismatch repair (MMR) genes, and affected patients are at high risk for multiple cancers. Reflexive testing for MMR protein loss by immunohistochemistry (IHC) is currently only recommended for colorectal and endometrial cancers, although upper tract urothelial carcinoma (UTUC) is the third-most common malignancy in patients with LS. To study the suitability of universal MMR IHC screening for UTUC, we investigated MMR expression and microsatellite status in UTUC in comparison to bladder UC (BUC), and evaluated the clinicopathologic features of UTUC. We found that 9% of UTUC showed MMR IHC loss (8 MSH6 alone; 1 MSH2 and MSH6; 1 MLH1 and PMS2; n=117) compared with 1% of BUC (1 MSH6 alone; n=160) (P=0.001). Of these, 4/10 (40%) of UTUC (3% overall; 3 MSH6 alone; 1 MLH1 and PMS2) and none (0%) of BUC had high microsatellite instability on molecular testing (P=0.03). The only predictive clinicopathologic feature for MMR loss was a personal history of colorectal cancer (P=0.0003). However, UTUC presents at a similar age to colon carcinoma in LS and thus UTUC may be the sentinel event in some patients. Combining our results with those of other studies suggests that 1% to 3% of all UTUC cases may represent LS-associated carcinoma. LS accounts for 2% to 6% of both colorectal and endometrial cancers. As LS likely accounts for a similar percentage of UTUC, we suggest that reflexive MMR IHC screening followed by microsatellite instability testing be included in diagnostic guidelines for all UTUC.

Current and future role of genetic screening in gynecologic malignancies.

The world of hereditary cancers has seen exponential growth in recent years. While hereditary breast and ovarian cancer and Lynch syndrome account for the majority of mutations encountered by gynecologists, newly identified deleterious genetic mutations continue to be unearthed with their associated risks of malignancies. However, these advances in genetic cancer predispositions then force practitioners and their patients to confront the uncertainties of these less commonly identified mutations and the fact that there is limited evidence to guide them in expected cancer risk and appropriate risk-reduction strategies. Given the speed of information, it is imperative to involve cancer genetics experts when counseling these patients. In addition, coordination of screening and care in conjunction with specialty high-risk clinics, if available, allows for patients to have centralized management for multiple cancer risks under the guidance of physicians with experience counseling these patients. The objective of this review is to present the current literature regarding genetic mutations associated with gynecologic malignancies as well to propose screening and risk-reduction options for these high-risk patients.