Identification and Management of TP53 Gene Carriers Detected Through Multigene Panel Testing.

OBJECTIVES: The increasing use of multigene panel tests may reveal an unexpected pathogenic variant in the tumor protein p53 (TP53) gene among individuals who do not meet clinical criteria for Li-Fraumeni syndrome (LFS). Among a registry-based sample of individuals with a pathogenic (P) or likely pathogenic (LP) variant in TP53, we sought to characterize the original clinical context in which genetic testing was performed, the personal and family history and whether they met clinical LFS criteria, and the follow-up care following diagnosis among those in whom this information was available. METHODS: Among individuals with multigene panel testing (inclusive of the TP53 gene) who were part of either the Inherited Cancer Registry or the Vanderbilt Hereditary Cancer Registry protocols and were confirmed to have a P/LP variant in TP53, pedigree was reviewed to characterize personal and family history, including original clinical context for genetic testing and whether they met clinical diagnostic criteria for TP53. Subsequent cancer risk management options were documented through information collected in the study questionnaire and medical records. RESULTS: Among the 10 participants enrolled in one of the two registries with a germline TP53 P/LP variant detected through a multigene panel test, the most frequent clinical contexts for testing were genetic risk recognized in the survivorship care setting (50%) and a newly diagnosed breast cancer (40%). No participants met classic LFS diagnostic criteria and 6 of 10 met Chompret criteria (60%) at the time of testing. Among the seven participants in whom results of total body magnetic resonance imaging were available, only three had completely negative findings. The remaining four had findings, three of which were likely benign/incidental requiring additional follow-up, and one was consistent with metastatic disease in the vertebrae. CONCLUSIONS: Our findings suggest that individuals identified with a germline P/LP variant in TP53 through multigene panel tests have substantial variations in clinical phenotypes not previously recognized when only those with striking family histories suggestive of LFS were tested through targeted TP53 testing. The expansion of the clinical phenotype among carriers of a P/LP in TP53 in the era of multigene testing should be considered when making cancer risk management recommendations, which were developed based on patients with classic LFS.

Cognitive and psychological impact of BRCA genetic counseling in before and after definitive surgery breast cancer patients.

PURPOSE: To examine changes in cancer-related knowledge, distress, and decisional conflict from pre- to post-genetic counseling (GC) in before (BDS) and after (ADS) definitive surgery breast cancer (BC) patients. METHODS: Sociodemographic and clinical characteristics were collected at baseline; primary outcome data were collected before (T1) and after (T2) pretest GC. Within group changes for cancer-related knowledge, distress, and decisional conflict over genetic testing were compared by Wilcoxon signed-rank tests. RESULTS: Of 103 BC patients, 87 were ADS and 16 were BDS. Analyses revealed that both groups reported significant increases in knowledge between T1 and T2 (median change 4.2, p = 0.004, and 2.7, p < 0.001, for BDS and ADS patients, respectively). Overall cancer-related distress showed a downward trend between T1 and T2 for both groups and was significant for BDS patients (p = 0.041). Reports of BDS patients trended toward overall and subscale-specific increases in decisional conflict, with the exception of the uncertainty which trended downward, but did not reach significance. Overall decisional conflict decreased in ADS patients, approaching marginal significance (p = 0.056), with significant improvements in informed decision making (median change -12.6, p < 0.001; i.e., pretest GC yielded improved knowledge of benefits, risks, and side effects of available options). CONCLUSIONS: These pilot data suggest that pretest GC increases cancer-related knowledge for both BDS and ADS patients, decreases distress in BDS patients, and improves informed decision making in ADS patients. Future studies with larger sample sizes are needed to replicate these results.

Satisfaction with physician recommendation for and information about genetic counseling among breast cancer patients.

To evaluate satisfaction with (a) the timing and strength of provider recommendation for and (b) information received prior to and during genetic counseling (GC) among breast cancer patients who attended GC before definitive surgery (BDS) or after definitive surgery (ADS). Satisfaction with provider recommendation for and information received about GC was evaluated among breast cancer patients who attended GC as part of their clinical care (n=51). There were no significant differences among breast cancer patients who attended GC BDS or ADS in satisfaction with when the physician referred them for GC, the strength of recommendation for GC, the amount of information provided about the GC, and the information received in GC. From a clinical perspective, the optimal time for attending GC may be BDS. Nevertheless, breast cancer patients appear satisfied with physician recommendation of and information related to GC, regardless of when they attend.

Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis.

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.

Recall of and reactions to a surgeon referral letter for BRCA genetic counseling among high-risk breast cancer patients.

BACKGROUND: The oncology care setting represents an important opportunity to identify and refer women at increased risk for hereditary breast and ovarian cancer. However, little is known about the effectiveness of provider approaches to inform patients of hereditary cancer risk or patient uptake of genetic counseling (GC). This qualitative study examined the impact of a surgeon referral letter on recently diagnosed breast cancer patients' uptake of BRCA GC. METHODS: Qualitative open-ended, in-depth interviews were conducted with 26 high-risk breast cancer patients sent a referral letter for BRCA GC by their surgeon. Data were analyzed by a grounded theory approach. RESULTS: Most women (approximately 80%) recalled receiving the letter, and 62% of all (n = 16) women pursued GC. Recall of the letter did not seem to be associated with uptake of GC (P = .49, Fisher's exact test). The results highlight key areas for improvement that may help increase the impact of the letter. Half of the women in this sample believed that the letter was sent to all breast cancer patients, rather than those with specific risk factors. Few women mentioned any implications for the information obtained during GC or testing regarding their current breast cancer diagnosis or treatment. Of the women who did not attend, many perceived that dealing with the GC and testing process in the midst of a cancer diagnosis and treatment was overwhelming. Among the women who had chosen not to attend GC, most stated they would reconsider after completing their treatment. CONCLUSIONS: Patient recall of a surgeon referral letter does not seem to increase the number of high-risk women who attend GC after a breast cancer diagnosis. The letter approach in its current format does not seem to be a wholly effective means of communicating with some patients who may be overwhelmed by their cancer diagnosis or unaware that GC and testing may have implications for their current treatment decisions, possibly resulting in a missed opportunity to engage in informed decision making.

Experiences of genetic counseling for BRCA1/2 among recently diagnosed breast cancer patients: a qualitative inquiry.

For newly diagnosed breast cancer patients, BRCA1/2 genetic counseling (GC) and/or testing has the greatest potential to affect treatment choices if it occurs prior to definitive surgery. This qualitative study sought to examine recently diagnosed breast cancer patients' experiences with pretest GC (n = 9). Study results show the primary reason most women attended GC was due to a family history of cancer. Most women expressed high levels of satisfaction with timing of GC regardless of whether they were referred prior to or after definitive surgical treatment. In this study, newly diagnosed breast cancer patients, particularly those who have already completed definitive surgery, may not be fully informed about the purpose and implications of BRCA1/2 GC and/or testing for treatment decisions had they been referred prior to definitive surgery for their breast cancer diagnosis. Thus, many women felt the information provided during GC had little utility with respect to their current breast cancer diagnosis.

Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.

Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with <45% of wild-type activity can be classified as deleterious whereas variants with >50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability.