Katherine A. Schneider

Anticipated Versus Actual Emotional Reactions to Disclosure of Results of Genetic Tests for Cancer Susceptibility: Findings From p53 and BRCA1 Testing Programs

PURPOSE We examined the ability of individuals undergoing genetic testing for cancer susceptibility in two structured research protocols to accurately anticipate emotional reactions to disclosure of their test result. We explored whether accuracy of emotional anticipation was associated with postdisclosure psychologic adjustment. METHODS Data from 65 individuals were analyzed; 24 members of Li-Fraumeni cancer syndrome families were tested for p53 mutations (all 24 were unaffected), and 41 subjects with hereditary breast-ovarian cancer susceptibility were tested for BRCA1 mutations (34 were unaffected and seven were affected). Subjects were from families in which a germline mutation had been previously identified. At the pretest session, subjects rated the extent to which they anticipated feeling each of six emotional states (relief, happiness, sadness, guilt, anger, and worry) after disclosure that they did or did not carry the familial mutation. After receiving their test result, they rated their feelings on the same scale of emotions for the appropriate condition. Extent of accuracy and association with psychologic distress at 6 months, as assessed with standardized measures, were evaluated. RESULTS Overall, mean levels of emotional reactions after receiving test results were not different from those anticipated before result disclosure. However, affected BRCA1 carriers experienced higher levels of anger and worry than they had anticipated. Underestimation of subsequent distress emotions related to test result was associated with a significant increase in general psychologic distress at 6 months. CONCLUSION Unaffected individuals in cancer-predisposition testing programs are generally accurate in anticipating emotional reactions to test results. However, cancer patients may underestimate their distress after disclosure of positive results and could benefit from intervention strategies.

Sharing BRCA1/2 Test Results With First-Degree Relatives: Factors Predicting Who Women Tell

PURPOSE Patient communication with relatives about cancer genetic test results is the primary means for alerting those who may benefit from identification of hereditary risk. This study identifies factors predicting patterns of disclosure of BRCA1/2 test results to first-degree relatives (FDRs) among women tested in a clinical protocol. PATIENTS AND METHODS A total of 273 women completed a family communication measure 4 months after BRCA1/2 result disclosure. chi2 analyses and logistic regression models identified factors predicting sharing of the test result. RESULTS Most FDRs were informed of the participants test result by 4 months; female relatives were more likely to be informed than males. Tested women conveyed inconclusive results (variant or negative without known familial mutation) less frequently to their sisters than conclusive (positive/true negative) results (P = .03). Twenty-three percent of participants did not inform their father. Informing brothers was more likely when BRCA1/2 was inherited through paternal lineage (P = .04), but 29% of brothers were not informed. Women older than age 40 were less likely to share their result with their parents (P = .03) than were women < or = 40. Childrens ages influenced communication to offspring; most children were told. CONCLUSION Demographic, health-, and test-related factors predicted genetic test result communication to FDRs. Additional research investigating the full spectrum of discussion within families and motives for incomplete sharing of genetic test results with relatives may suggest strategies for providers and targeted educational interventions for patients to enhance family communication.

F18-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Screening in Li-Fraumeni Syndrome

CONTEXT Individuals with Li-Fraumeni syndrome (LFS) have an inherited cancer predisposition to a diverse array of malignancies beginning early in life; survivors of one cancer have a markedly elevated risk of additional primary tumors. The underlying genetic defect in the majority of the families is a germline mutation in the TP53 tumor suppressor gene. The diversity of tumors and rarity of families have contributed to the difficulty in devising effective screening recommendations for members of LFS kindreds. OBJECTIVE To gather preliminary data with which to evaluate F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging as a potential surveillance modality to detect early malignancies in asymptomatic members of LFS kindreds. DESIGN, SETTING, AND PARTICIPANTS Members of LFS families with documented germline TP53 mutations or obligate carrier status, no history of cancer within 5 years of enrollment, and no symptoms of cancer or ill-health were offered FDG-PET/CT scanning as a screening test in a comprehensive US cancer center from 2006 to 2007. Scans were initially reviewed clinically, then centrally reviewed by an expert radiologist. MAIN OUTCOME MEASURE The primary outcome was the detection of new primary cancers using FDG-PET/CT scanning. RESULTS Of 15 individuals, baseline FDG-PET/CT scan identified asymptomatic cancers in 3 (20%). Two individuals had papillary thyroid cancers (stage II and stage III) and one individual had stage II esophageal adenocarcinoma. CONCLUSIONS These preliminary data provide the first evidence for a potential cancer surveillance strategy that may be worthy of further investigation for patients with LFS. Concerns about radiation exposure and other challenges inherent in screening high-risk patients will require further consideration.

Gastric cancer in individuals with Li-Fraumeni syndrome

Purpose: Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome.Methods: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens.Results: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24–74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies.Conclusions: Early-onset gastric cancer seems to be a component of Li-Fraumeni syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer.

Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium

Li-Fraumeni syndrome (LFS) is a rare dominantly inherited cancer predisposition syndrome that was first described in 1969. In most families, it is caused by germline mutations in the TP53 gene and is characterized by early onset of multiple specific cancers and very high lifetime cumulative cancer risk. Despite significant progress in understanding the molecular biology of TP53, the optimal clinical management of this syndrome is poorly defined. We convened a workshop on November 2, 2010, at the National Institutes of Health in Bethesda, Maryland, bringing together clinicians and scientists, as well as individuals from families with LFS, to review the state of the science, address clinical management issues, stimulate collaborative research, and engage the LFS family community. This workshop also led to the creation of the Li-Fraumeni Exploration (LiFE) Research Consortium.

Acceptance of invitations for p53 and BRCA1 predisposition testing: Factors influencing potential utilization of cancer genetic testing

Data on uptake of two cancer predisposition testing programs is presented as the basis for discussion of factors contributing to the acceptance and refusal of genetic testing. Eighty percent (n = 29) of the 36 members of 2 BRCA1 families invited for BRCA1 predisposition testing and counseling accepted, while only 39% (n = 22) of the 57 Li‐Fraumeni syndrome family members invited for p53 predisposition testing and counseling enrolled and 14% (n = 8) postponed enrollment. Factors that may influence utilization of cancer genetic testing programs include programmatic demands, nature and immediacy of cancer risk, demographic factors, perceived lethality of the cancers involved, clarity of surveillance recommendations and perceived efficacy of screening, ego‐strength, and family experience with cancer. Further research is needed to determine the relative weight of these factors and to define how acceptors and decliners of genetic cancer predisposition testing differ. One implication of the hypothesis that individuals seeking testing are psychologically different than those who decline is that more severe psychiatric sequelae of testing might be expected if individuals are tested who have not themselves freely chosen testing. Such subjects might in the future include children whose parents decide about testing or adults tested as a prerequisite to being employed or insured. Further research on decliners and continued psychological evaluation of the impact of cancer predisposition testing is recommended.

Cancer screening recommendations for individuals with Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited condition caused by germline mutations of the TP53 tumor suppressor gene encoding p53, a transcription factor triggered as a protective cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the “Toronto protocol” that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS. Clin Cancer Res; 23(11); e38–e45. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

PTEN, DICER1, FH , and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76–e82. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Cancer Risk Counseling: How Is It Different?

Fifty-six of 80 (70%) full members of the National Society of Genetic Counselors with interest in cancer genetics responded to a 1994 survey regarding their cancer risk counseling practices. This study was undertaken to describe cancer risk counselors and the services they provide and to identify possible differences from general genetic counseling that warrant further study. Of 56 respondents, 41 (75%) were providing CRC. The components of CRC programs are described. Our results found significant differences between CRC and general genetic counseling in terms of training and experience of genetic counselors providing CRC and length and number of counseling sessions per consultand. 51% of respondents had 1–2 years of working in CRC, compared to 17% with 1–2 years experience in genetic counseling (p<0.05). Over one-third had 10 or more years genetic counseling experience. Counselors were more likely to see individuals at risk for cancer for longer counseling sessions (p<0.05) and for additional sessions (p<0.05).

Role of Parenting Relationship Quality in Communicating about Maternal BRCA1/2 Genetic Test Results with Children

It is known that many mothers rapidly share the results of their BRCA1/2 genetic testing with their children, especially adolescent children. What is less known is the extent to which these mothers may engage fathers in a discussion concerning genetic counseling and the anticipated disclosure of genetic test results to children, or seek shared decision making in this context. This short communication addresses this issue by first examining mothers’ and fathers’ discussions concerning a research study of family communication. In our view, this conversation likely served as a precursor to, and proxy indicator of, maternal receptivity to partner input regarding the genetic counseling/testing-results disclosure process. We further evaluated how the quality of the parenting relationship is associated with mothers’ decisions to include or not include the child’s father in this study. Finally, this report addresses potential ways in which the genetic counselor may be able to facilitate parental communication regarding the evolving process of disclosure of genetic information to children and adolescents.