Mary-Anne Young

Optimal Selection of Individuals for BRCA Mutation Testing: A Comparison of Available Methods

PURPOSE Several methods have been described that estimate the likelihood that a family history of cancer is a result of a mutation in the BRCA1 or BRCA2 genes. We examined the performance of six different methods with the aim of identifying an optimal strategy for selecting individuals for mutation testing in clinical practice. PATIENTS AND METHODS Two hundred fifty-seven families who had completed BRCA1 and BRCA2 mutation screening were assessed by six models representing the major methodologies used to assess the likelihood of a pathogenic mutation. The performance of each method as a selection criterion was compared with the result of mutation testing to produce sensitivity, specificity, and receiver operating curve data. The impact of incorporating breast cancer pathology data in the assessment was also analyzed. RESULTS The highest accuracy was achieved by the Bayesian probabilistic model (BRCAPRO). The formal probabilistic methods were significantly more accurate than clinical scoring methods. The methods were further improved by the incorporation of information on breast cancer pathology (tumor grade and estrogen receptor/progesterone receptor status). The resulting combined probability figure was highly accurate when selecting individuals for BRCA1 testing. Some BRCA2 mutation carriers were missed by all of the models examined. CONCLUSION Formal probabilistic models provide significantly greater accuracy in the selection of families for gene testing than the use of clinical criteria or scoring methods. The accuracy is further enhanced by incorporating information on the pathology of breast cancers occurring in the families.

Communication and information-giving in high-risk breast cancer consultations: influence on patient outcomes.

This longitudinal study aimed to document (i) the information-giving and patient-communication styles of clinical geneticists and genetic counsellors (consultants) in familial breast cancer clinics and (ii) assess the effect of these styles on womens knowledge, whether their expectations were met, satisfaction, risk perception and psychological status. A total of 158 women from high-risk breast cancer families completed self-report questionnaires at 2 weeks preconsultation and 4 weeks postconsultation. The consultations were audiotaped, transcribed and coded. Multivariate logistic regressions showed that discussing prophylactic mastectomy (P=0.00) and oophorectomy (P=0.01) led to women having significantly more expectations met; discussing genetic testing significantly decreased anxiety (P=0.03) and facilitating understanding significantly decreased depression (P=0.05). Receiving a summary letter of the consultation significantly lowered anxiety (P=0.01) and significantly increased the accuracy of perceived risk (P=0.02). Women whose consultant used more supportive communications experienced significantly more anxiety about breast cancer at the 4 weeks follow-up (P=0.00). These women were not significantly more anxious before genetic counselling. In conclusion, this study found that consultants vary in the amount of information they give and the way they communicate; and this variation can result in better or worse psychosocial outcomes. Greater use of supportive and counselling communications appeared to increase anxiety about breast cancer. Identifying methods to assist consultants to address emotional issues effectively may be helpful.

Women’s preferences and consultants’ communication of risk in consultations about familial breast cancer: impact on patient outcomes

The risk information to be conveyed as part of expert counselling of women at increased risk for breast cancer potentially impacts on decision making about screening, prophylactic strategies, and psychological adjustment. Australian geneticists and genetic counsellors working in cancer genetics nominated risk counselling as the central feature of their work.1 Also, women attending genetic counselling expect to discuss their own and other family members’ risk.2–6 However, studies have consistently reported high levels of inaccurate risk perception in women at high risk, even after counselling, suggesting that risk counselling as currently practised in not optimal.7–10 The information to be conveyed about risk related to breast cancer is exceedingly complex. Statistics commonly presented to patients include population and individual risk, not only for breast cancer, but also for other cancers associated with BRCA1 and BRCA2 mutations, for example, ovarian cancer. Risk may be presented separately for different age groups, for men, and for those with an Ashkenazi Jewish background (which conveys a higher risk). The proportion of population risk attributable to germline mutations may be presented. Risk may be given for an unaffected person’s chance of developing breast cancer, or for an affected person’s chance of developing a second cancer. The risk estimate may apply to the next five years, the next 10 years, or to a lifetime. The probability that a family may have a germline breast cancer susceptibility gene mutation may be raised. Finally, the risk estimates for cancer in proven mutation carriers (and their broad confidence intervals) may be discussed, and the chance of the mutation being found through testing. The multitude of risk statistics possibly presented (sometimes in several formats) has the potential to leave the patient confused and distressed. Although previous studies have identified the type of information women with breast cancer …

Molecular pathologic analysis enhances the diagnosis and management of Muir-Torre syndrome and gives insight into its underlying molecular pathogenesis.

The Muir-Torre syndrome (MTS) is an autosomal dominantly inherited disorder, characterized by visceral malignancies and sebaceous skin lesions. In a subset of MTS families the disease is due to an underlying DNA mismatch-repair defect. We have identified a MTS family whose spectrum of reported neoplasia included adenocarcinomas of numerous gastrointestinal sites, carcinomas of the endometrium, ovary and breast, papillary transitional cell carcinoma of the ureter, a range of cutaneous tumors, as well as keratoacanthomas. All tumors were tested for microsatellite instability and immunohistochemically stained for expression of MLH1 and MSH2 proteins. All tumors were found to be microsatellite unstable and lacking in MSH2 protein expression. The subsequent mutation detection focused on hMSH2, and a germline mutation was identified (CAA→TAA, Gln→STOP, codon 337). This mutation was subsequently found in a family member with a single skin lesion only. We propose that the combination of immunohistologic and microsatellite instability analysis can be exploited to screen individuals with characteristic skin lesions even before development of visceral tumors and to direct the subsequent germline mutation search. The profile of microsatellite instability and the genes rendered dysfunctional differed between tumor samples, suggesting that the molecular pathogenesis varied between lesions, despite a common germline mutation.

Psychological adjustment of women at increased risk of developing hereditary breast cancer

This study aims to describe psychological adjustment in a sample of Australian women at increased risk for hereditary breast cancer and to assess the sociodemographic, personality and appraisal factors which contribute to psychological distress. Psychological adjustment of 355 unaffected women at increased risk of developing hereditary breast cancer who approached familial cancer clinics for advice about their breast cancer risk was assessed in a cross-sectional design, using validated measures of psychological distress. Eight per cent of women showed presence of a significant stress response in relation to being at risk of developing breast cancer. In multiple regression, state anxiety and breast cancer anxiety were both highly correlated with overestimating ones breast cancer risk and having experienced a breast cancer-related event in the family in the past year. State anxiety was strongly associated with a tendency to monitor for threatening information ( t = 3.41, p = 0.001), and breast cancer anxiety was correlated with having had a relative die from breast cancer ( t = 1.49, p = 0.006). Results suggest that women who have experienced a recent breast cancerrelated event in the family and those who have exaggerated risk perceptions are most likely to have high levels of psychological distress. Thus women are likely to benefit from supportive counselling and attempts at correcting inflated risk perceptions. A small group of women was identified who showed a significant stress response to being at risk of developing breast cancer. For these women clear pathways of referral for psychological or psychiatric assistance need to be accessible.

Randomized Controlled Trial of a Telephone-Based Peer-Support Program for Women Carrying a BRCA1 or BRCA2 Mutation: Impact on Psychological Distress

PURPOSE To assess the effectiveness of a telephone-based peer-delivered intervention in reducing distress among women with a BRCA1 or BRCA2 gene mutation. The intervention involved trained peer volunteers contacting women multiple times over a 4-month period to provide informational, emotional, and practical support. METHODS Three hundred thirty-seven participants completed the baseline questionnaire, and those reporting interest in talking to other mutation carriers were randomly assigned to either the usual care group (UCG; n = 102) or the intervention group (IG; n = 105). Participants and researchers were not blinded to group allocation. Two follow-up questionnaires were completed, one at the end of the intervention (4 months after random assignment, time 2) and one 2 months later (time 3). Outcomes included breast cancer distress (primary outcome), unmet information needs, cognitive appraisals about mutation testing, and feelings of isolation. RESULTS There was a greater decrease in breast cancer distress scores in the IG than UCG at time 2 (mean difference, -5.96; 95% CI, -9.80 to -2.12; P = .002) and time 3 (mean difference, -3.94; 95% CI, -7.70 to -0.17; P = .04). There was a greater reduction in unmet information needs in the IG than UCG (P < .01), with unmet needs being lower in the IG than UCG at time 2. There was a greater reduction in Cognitive Appraisals About Genetic Testing stress subscale scores in the IG than UCG (P = .02), with significantly lower scores among the IG than UCG at time 2 (P < .01). CONCLUSION The intervention is effective in reducing distress and unmet information needs for this group of women. Identifying strategies for prolonging intervention effects is warranted.

High Frequency of Germline TP53 Mutations in a Prospective Adult-Onset Sarcoma Cohort

Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-onset sarcoma cases, without regard to family history. The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes. Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired. Of the germline carriers, one appeared to be mosaic, detectable in the tumor and blood, but not epithelial tissues. Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P = 3.0×10−3), and earlier cancer onset (33 vs 48 years, P = 1.19×10−3). The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers. Only 10/17 (59%) pedigrees met classical or Chompret criteria for LFS. In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.

Educating Genetic Counselors in Australia: Developing an International Perspective

The demand for genetic counseling services is increasing worldwide. This paper highlights the Australian experience of genetic counselor education and the history of the profession. The relevance of local factors, including the healthcare system, the education system and the small population in the evolution of the 1-year training programs are considered as an alternative model for emerging programs. The development of the education and training processes compared to that of other countries namely the United States of America (USA), the United Kingdom (UK) and Canada is discussed. The importance of international collaborations between the programs, to facilitate academic discussion and possible curriculum innovations, and to maintain professional understanding between genetic counselors is emphasized. Core genetic counseling competencies have been published for the UK and USA and an Australian set is proposed. In conclusion future directions are considered, including international issues around genetic counseling certification, reciprocity, and the potential for an Australian role in training genetic counselors in South East Asia.

Health Beliefs and Behaviors of Women Who Have Received Genetic Counseling For Breast Cancer

There are both genetic and behavioral risk factors for breast cancer, but the interaction between these factors is not clear. Little is known about the impact of receiving genetic risk information for breast cancer on behaviors such as diet and physical activity. Seven focus groups were conducted with 23 women who had recently received genetic counseling for breast cancer, in order to explore health beliefs and behaviors following genetic counseling. Findings revealed that there was much confusion and uncertainty about the associations between health behaviors and breast cancer risk, and participants reported that receiving genetic counseling had little impact on health protective behaviors. Further research is required to understand variation in response to genetic risk information, and to assess the impact of providing additional information regarding lifestyle factors.

Sociodemographic, psychosocial and clinical factors associated with uptake of genetic counselling for hereditary cancer: a systematic review

Evidence suggests that a significant proportion of individuals referred to cancer genetic counselling (GC) do not attend, and thus may not be engaged in adequate cancer risk management. We aimed to review the literature to better understand barriers to accessing GC and how they may be overcome. We conducted a systematic literature search for articles examining factors influencing cancer GC uptake as well as motivators and barriers to GC attendance. Factors were categorised as sociodemographic, psychosocial or clinical. The literature search identified 1413 citations, 35 of which met the inclusion criteria. GC uptake ranged from 19% to 88%. With the exceptions of education level, socioeconomic status, cancer‐specific distress, personal cancer diagnosis and actual and perceived risk of cancer, support was lacking for most sociodemographic, clinical and psychosocial factors as predictors of GC uptake. Cost and logistical barriers, emotional concerns, family concerns and low perceived personal relevance were reported as important considerations for those declining GC. We conclude that there is poor understanding of GC and a lack of decision support among those referred to GC. Research into ways of providing education and support to referred individuals will be important as the scope and availability of GC and genetic testing broaden.