Kara J. Milliron

Updates on breast cancer genetics: Clinical implications of detecting syndromes of inherited increased susceptibility to breast cancer

Since the initial discovery that pathogenic germline alterations in BRCA 1/2 increase susceptibility to breast and ovarian cancer, many additional genes have now been discovered that also increase breast cancer risk. Given that several more genes have now been implicated in hereditary breast cancer syndromes, there is increased clinical use of multigene panel testing to evaluate patients with a suspected genetic predisposition to breast cancer. While this is most certainly a cost-effective approach, broader testing strategies have resulted in a higher likelihood of identifying moderate-penetrance genes, for which management guidelines regarding breast cancer risk reduction have not been firmly established. In addition, the testing of more genes has led to increased detection of variants of uncertain significance. We review the current knowledge regarding both high- and moderate-risk hereditary breast cancer syndromes, as well as additional genes implicated in hereditary breast cancer for which there is limited data. Furthermore, strategies for cancer risk reduction in mutation carriers as well as therapeutic implications for those patients who harbor pathogenic germline alterations are discussed.

Differences Between Women Who Pursued Genetic Testing for Hereditary Breast and Ovarian Cancer and Their At-Risk Relatives Who Did Not

PURPOSE/OBJECTIVES To (a) examine differences in appraisals of hereditary breast and ovarian cancer (HBOC), psychological distress, family environment, and decisional conflict between women who pursued genetic testing and their at-risk relatives who did not, and (b) examine correlations among appraisals of HBOC, psychological distress, family environment, and decisional conflict regarding genetic testing in these two cohorts of women. DESIGN Descriptive, cross-sectional cohort study. SETTING Two clinics affiliated with a major research university in the midwestern United States. SAMPLE 372 women aged 18 years and older. 200 pursued genetic testing for BRCA1 and BRCA2 mutations (probands) and 172 of their female relatives who had a greater than 10% prior probability of being a mutation carrier but had not pursued testing. METHODS After providing informed consent, probands and relatives were mailed self-administered questionnaires. MAIN RESEARCH VARIABLES Perceived risk, knowledge of HBOC risk factors and modes of gene inheritance, perceived severity, perceived controllability, psychological distress, family relationships, family communication, and decisional conflict about genetic testing. FINDINGS T tests revealed that probands perceived higher risk and had more psychological distress associated with breast cancer. Probands had more knowledge regarding risk factors and gene inheritance, and greater decisional conflict regarding genetic testing. Relatives reported higher perceived severity and controllability. No differences were observed in family relationships and family communication between probands and relatives. Pearson correlations revealed different patterns in knowledge, perceived controllability, family relationships, and decisional conflict between probands and relatives. CONCLUSIONS Significant differences exist between women who pursue genetic testing and those who do not. The family environment influences adjustment to HBOC and decisions about genetic testing. IMPLICATIONS FOR NURSING Enhancing the family communication process about HBOC can provide informational and emotional support to high-risk women and promote decision making about genetic testing.

Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America

The CHEK2*1100delC mutation has been reported to confer a twofold increased risk of breast cancer among carriers. The frequency of the mutation varies among populations. The highest frequency has been described in Northern and Eastern European countries; the frequency may be much lower in North America. In this study, our aim was to determine the frequency of CHEK2*1100delC in members of breast cancer families who tested negative for a deleterious mutation in BRCA1/2 at the University of Michigan Comprehensive Cancer Center. We genotyped 102 members from 90 families for CHEK2*1100delC. Most of these families had several cases of breast cancer or ovarian cancer (or both), as well as multiple members with other cancer types in a single lineage. No CHEK2*1100delC mutations were detected in any of the 102 individuals, including 51 women diagnosed with breast cancer at an early age (<45 years), 8 women with bilateral breast cancer, 3 men with breast cancer, and 8 women with ovarian cancer. Our data are consistent with the reported very low frequency of CHEK2*1100delC mutations in North American populations (compared with Northern Europe), rendering CHEK2*1100delC such an unlikely culprit in BRCA1/2 negative families that routine testing of these families appears unwarranted.

Use of Cancer Genetics Services in African-American Young Breast Cancer Survivors

INTRODUCTION African-American women have higher rates of early-onset breast cancer compared with their Caucasian counterparts; yet, when diagnosed with breast cancer at a young age, they underuse genetic counseling and testing to manage their risk of developing future cancers. METHODS Self-reported baseline data were collected between September 2012 and January 2013 and analyzed in 2014 from a subpopulation of 340 African-American young breast cancer survivors (YBCSs) enrolled in an RCT. YBCSs were diagnosed with invasive breast cancer or ductal carcinoma in situ between ages 20 and 45 years and were randomly selected from a statewide cancer registry. Logistic regression examined predictors of using cancer genetics services. RESULTS Overall, 28% of the sample reported having genetic counseling and 21% reported having genetic testing, which were significantly lower (p≤0.005) compared with white/other YBCSs participating in the parent study. In a multivariate analysis, income was positively associated with counseling (B=0.254, p≤0.01) and testing (B=0.297, p≤0.01), whereas higher education levels (B=-0.328, p≤0.05) and lack of access to healthcare services owing to cost (B=-1.10, p≤0.03) were negatively associated with genetic counseling. Lower income and lack of care because of high out-of-pocket costs were commonly reported barriers. CONCLUSIONS Despite national recommendations for genetic evaluation among women with early-onset breast cancer, few African-American YBCSs reported undergoing genetic counseling and testing. Most reported that their healthcare provider did not recommend these services. Interventions addressing patient, provider, and structural healthcare system barriers to using genetic counseling and testing in this population are needed.

Recruiting families at risk for hereditary breast and ovarian cancer from a statewide cancer registry: a methodological study

PurposeCancer genetic services (counseling/testing) are recommended for women diagnosed with breast cancer younger than 45 years old (young breast cancer survivors—YBCS) and at-risk relatives. We present recruitment of YBCS, identification and recruitment of at-risk relatives, and YBCS willingness to contact their cancer-free, female relatives.MethodsA random sample of 3,000 YBCS, stratified by race (Black vs. White/Other), was identified through a population-based cancer registry and recruited in a randomized trial designed to increase use of cancer genetic services. Baseline demographic, clinical, and family characteristics, and variables associated with the Theory of Planned Behavior (TPB) were assessed as predictors of YBCS’ willingness to contact at-risk relatives.ResultsThe 883 YBCS (33.2% response rate; 40% Black) who returned a survey had 1,875 at-risk relatives and were willing to contact 1,360 (72.5%). From 853 invited at-risk relatives (up to two relatives per YBCS), 442 responded (51.6% response rate). YBCS with larger families, with a previous diagnosis of depression, and motivated to comply with recommendations from family members were likely to contact a greater number of relatives. Black YBCS were more likely to contact younger relatives and those living further than 50 miles compared to White/Other YBCS.ConclusionIt is feasible to recruit diverse families at risk for hereditary cancer from a population-based cancer registry. This recruitment approach can be used as a paradigm for harmonizing processes and increasing internal and external validity of large-scale public health genomic initiatives in the era of precision medicine.

The role of cognitive appraisal and worry in BRCA1/2 testing decisions among a clinic population

Previous studies examining decision making in the context of genetic testing for BRCA1/2 gene mutations have been limited in their reliance on cross-sectional designs, lack of theoretical guidance, and focus on measures of intention rather than actual behavior. Informed by the Health Belief Model and other theories of self-regulation, the present study set out to examine the role of cognitive appraisal and worry in BRCA1/2 testing decisions. A total of 205 women completed baseline questionnaires prior to their genetic counselling appointment. Medical charts were audited to determine testing decisions. Bivariate analyses indicated that perceived severity of being a carrier and perceived benefits and barriers to testing were significantly associated with testing decisions. Perceived benefits remained significant in multivariate analyses. Moreover, multivariate analyses revealed a significant three-way interaction between perceived susceptibility, perceived severity, and worry about being a mutation carrier and testing decisions. Among women high in baseline worry, those high in perceived susceptibility but low in perceived severity were significantly more likely to undergo genetic testing than all other susceptibility/severity combinations (80% vs. 36.2–42.9% range; Wald test = 8.79, p < 0.01). These results support the need for researchers and practitioners to consider how interactions between cognition and worry may influence genetic testing decisions.

Development of a Web-based Family Intervention for BRCA Carriers and Their Biological Relatives: Acceptability, Feasibility, and Usability Study

Background Carriers of breast cancer gene (BRCA) mutations are asked to communicate genetic test results to their biological relatives to increase awareness of cancer risk and promote use of genetic services. This process is highly variable from family to family. Interventions that support communication of genetic test results, coping, and offer decision support in families harboring a pathogenic variant may contribute to effective management of hereditary cancer. Objective The aim of this paper was to describe the development of the Family Gene Toolkit, a Web-based intervention targeting BRCA carriers and untested blood relatives, designed to enhance coping, family communication, and decision making. Methods We present findings from focus groups regarding intervention acceptability and participant satisfaction and from a pre-post pilot study with random allocation to a wait-listed control group regarding intervention feasibility and usability. Results The Family Gene Toolkit was developed by a multidisciplinary team as a psycho-educational and skills-building intervention. It includes two live webinar sessions and a follow-up phone call guided by a certified genetic counselor and a master’s prepared oncology nurse. Each live webinar includes two modules (total four modules) presenting information about BRCA mutations, a decision aid for genetic testing, and two skill-building modules for effective coping and family communication. Participants in focus groups (n=11) were highly satisfied with the intervention, reporting it to be useful and describing clearly the important issues. From the 12 dyads recruited in the pre-post pilot study (response rate 12/52, 23%), completion rate was 71% (10/14) for intervention and 40% (4/10) for wait-listed control groups. Conclusions Acceptability and satisfaction with the Family Gene Toolkit is high. On the basis of the findings from usability and feasibility testing, modifications on timing, delivery mode, and recruitment methods have been implemented. Trial Registration ClinicalTrials.gov NCT02154633; https://clinicaltrials.gov/ct2/show/NCT02154633 (Archived by WebCite at http://www.webcitation.org/6yYNvLPjv)

Evaluating and improving the implementation of a community-based hereditary cancer screening program

Healthcare disparities exist in the provision of cancer genetic services including genetic counseling and testing related to BRCA1/2 mutations. To address this in a community health setting a screening tool was created to identify high-risk women. This study evaluates the implementation of the tool and identifies opportunities for improved cancer genetic screening, including regular clinician education. A mixed-method approach was used to evaluate clinician utilization of the screening tool at Planned Parenthood affiliates. Novel surveys that evaluated acceptance and implementation were administered to clinicians (n = 14) and semi-structured interviews (n = 6) were used to explore clinicians’ perspectives and identify gaps in its utilization. Educational modules that addressed gaps were developed, implemented, and evaluated using a post-education survey (n = 8). Clinicians reported confidence in administering and interpreting the screening tool, but reported less confidence in their knowledge of cancer genetics and ability to connect clients with genetic counseling and testing (p = .003). Educational modules resulted in significant gains in clinician knowledge on genetic topics (p < .05) and increased self-reported confidence in connecting clients with genetic services. The modules reinforced the belief that genetic testing is beneficial for patients at increased risk (p = .001) and is important to inform subsequent medical management (p = .027). While building community clinicians’ capacity to connect clients with genetic services is crucial, it is challenged by knowledge and confidence gaps in discussions of genetic services with clients. Consistent genetic-focused education with non-genetic clinicians can improve confidence and knowledge, enabling a more effective screening program in community health settings.

Patient-friendly pathology reports for patients with breast atypias

Breast atypias include atypical ductal hyperplasia (ADH), lobular neoplasia (LN), flat epithelial atypia (FEA), and apocrine atypia (AA). Diagnostic criteria for ADH and LN were established by Page et al, who noted a 4-5-fold increased risk of breast cancer with long-term followup. Similarly, Hartmann et al found 30% of patients with isolated ADH or LN developed breast cancer (invasive carcinoma or ductal carcinoma in situ [DCIS]) at 25-year follow-up. Breast cancer risk for isolated FEA and AA is less clear; however, these lesions have been noted to be associated with ADH and LN. When diagnosed on core biopsy, ADH is upgraded to cancer on excision in 20-30% of cases, whereas other atypias are upgraded ≤10% of the time. Although data are emerging that may allow some patients with breast atypias to be followed clinically, many institutions recommend excision, regardless of atypia type, when diagnosed on core biopsy. Since breast atypias are risk markers of cancer, but not cancer themselves, patients may wait longer for next steps in care. This can lead to patient anxiety and feelings of neglect. We aimed to provide patients with comprehensible information about their breast atypia diagnoses in an attempt to ease anxiety. Patients with first diagnoses of breast atypia on core biopsy (7/ 2015-1/2017) were mailed a copy of their pathology report along with a 1-page information sheet on their diagnosis. The contents of the information sheets were created by a multi-disciplinary team (SPR, SH, JCP, KJM, AVN, JMJ) and outlined basic diagnostic criteria, future risk of cancer, and likely next steps in care (Figure 1). A cover letter with contact information was also included in case the patient desired to speak with a breast pathologist (JMJ). Patients were given a survey at their first clinic visit to assess receipt of mailing, value of information, and patient comprehension. All patient materials complied with institutional standards for ease in reading, including fonts (Arial, Lucida), font size (12+ point), and formatting. Forty patients had first diagnoses of atypia which included 21 (52.5%) ADH, 8 (20%) LN, 6 (15%) FEA, 1 (2.5%) AA, 2 (5%) ADH and LN, 1 (2.5%) LN and FEA, and 1 (2.5%) ADH and FEA. Mean time from diagnosis to first appointment was 29 days (range 6-121). Two (5%) spoke with a pathologist via phone prior to first appointment. The majority (38/40; 95%) received surveys at first appointment (one declined an appointment and one was seen 6 days after diagnosis, prior to clinic notification of need for survey). About 47.4% (18/38) of patients returned surveys. Of the 17 who reported to have received the mailing, the majority (16/17; 88.9%) reported that the information was helpful and understandable. Most (14/17; 77.8%) reported that they “did not have breast cancer”; one patient did not answer this question and wrote “don’t know” in the margin and 1 patient checked both “I have” and “I do not have” breast cancer boxes for this question. Of note, 1 patient reported that the mailing had been received but did not complete the remainder of the survey. The majority (38/40; 95%) of patients underwent subsequent excision with mean time from diagnosis to surgery of 66 days (range 21-140). Pathology reports provide critical information which guides patient care. However, they can be detailed and complex, and therefore difficult to interpret. In recent years, much attention has been given to the use of standardized, synoptic pathology reporting to ensure that important diagnostic and staging elements are present and readily identifiable by treating clinicians. These efforts have been well-received by clinicians. Additional efforts have also been undertaken to help understand and improve clinician comprehension of pathology reports. However, many patients are become increasing active in their care, and also desire access to their pathology reports. Received: 12 June 2017 | Revised: 15 June 2017 | Accepted: 21 June 2017 DOI: 10.1111/tbj.13061

DCIS and Hereditary Susceptibility for Breast Cancer

Ductal carcinoma in situ (DCIS) is a noninvasive, transformed, neoplastic lesion with a significant likelihood, but without certainty, of progressing to invasive breast cancer, although there are molecular and cellular features that have some predictive power for the development of invasive disease. In women who carry deleterious mutations in the BRCA or other genes, detection of DCIS is paramount, as these women are believed to be at much higher risk than sporadic cases for progressing to invasive cancer. Here, we discuss the state of knowledge of DCIS in the context of hereditary cancer syndromes and emphasize current recommendations for risk management.