Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and risk of secondary malignancies across diverse racial groups.

BACKGROUND: Despite significant differences in age of onset and incidence of breast cancer between Caucasian (CA), African-American (AA) and Korean (KO) women, little is known about differences in BRCA1/2 mutations in these populations. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations and the association between BRCA1/2 mutation status and secondary malignancies among young women with breast cancer in these three racially diverse groups. METHODS: Patients presenting to our breast cancer follow-up clinics selected solely on having a known breast cancer diagnosis at a young age (YBC defined as age <45 years at diagnosis) were invited to participate in this study. A total of 333 eligible women, 166 CA, 66 AA and 101 KO underwent complete sequencing of BRCA1/2 genes. Family history (FH) was classified as negative, moderate or strong. BRCA1/2 status was classified as wild type (WT), variant of uncertain significance (VUS) or deleterious (DEL). RESULTS: DEL across these three racially diverse populations of YBC were nearly identical: CA 17%, AA 14% and KO 14%. The type of DEL differed with AA having more frequent mutations in BRCA2, compared with CA and KO. VUS were predominantly in BRCA2 and AA had markedly higher frequency of VUS (38%) compared with CA (10%) and KO (12%). At 10-year follow-up from the time of initial diagnosis of breast cancer, the risk of secondary malignancies was similar among WT (14%) and VUS (16%), but markedly higher among DEL (39%). CONCLUSIONS: In these YBC, the frequency of DEL in BRCA1/2 is remarkably similar among the racially diverse groups at 14%-17%. VUS is more common in AA, but aligns closely with WT in risk of second cancers, age of onset and FH.

Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women.

PURPOSE: To evaluate the frequency and distribution of BRCA1 and BRCA2 mutations in a cohort of young women with breast cancer and to compare the distribution of mutations as a function of race. METHODS: After IRB approved informed consent, 170 white women and 30 African American women with known breast cancer diagnosed at a young age (45 years or less) underwent complete sequencing of the BRCA1 and BRCA2 genes. Each cohort represented approximately 40% of women of the same ethnic background aged 45 years or younger in a breast cancer database. RESULTS: Of the 200 patients tested, 131 (65%) had wild type mutations, 34 (17%) had deleterious mutations, and 35 (18%) had variants of uncertain significance. There were no significant differences between the white and African American cohorts regarding the percentage of deleterious mutations (17% v 17%). However, most African American patients had mutations in BRCA2 (4/5, 80%), while most mutations in the white cohort were in BRCA1 (20/29, 69%). In addition, 46% of the African American women had variants of uncertain significance, compared to only 12% of the white cohort. CONCLUSIONS: Young African American women with breast cancer have a similar frequency of deleterious mutations as white women, but have a significantly higher frequency of variants of uncertain significance. Review of these variants revealed that the majority were unlikely to be associated with disease risk or were likely to be polymorphisms. The implications for genetic testing and counselling in young women with breast cancer are discussed.

Writing Effective Insurance Justification Letters for Cancer Genetic Testing: A Streamlined Approach.

The topic of insurance coverage and justification letters for cancer predisposition testing has been the subject of much discussion on the National Society of Genetic Counselors Cancer Special Interest Group (NSGC Cancer-SIG) listserv. Some counselors have stated that they have had difficulty in obtaining insurance coverage for their patients, while others have indicated that they would appreciate seeing examples of successful letters. The purpose of this paper is to provide practical guidance in writing successful letters of justification and to share insurance success stories in the area of cancer genetic testing.

The breast surgeon's role in BRCA1 and BRCA2 testing.

Five percent to 10% of all women who develop breast cancer carry a hereditary mutation in the genes BRCA1 or BRCA2. Genetic testing is now clinically available, and the results of such testing can dramatically alter a patient's risks for an ipsilateral or contralateral primary breast cancer and ovarian cancer. Therefore, genetic testing will become integral in tailoring surveillance, chemoprevention, and surgical management plans for patients at risk for hereditary cancer syndromes. Such results will also impact the cancer risks for the patient's nuclear and extended family members. Surgeons will play a pivotal role in eliciting personal and family histories from patients, determining which of those histories is suggestive of a germline mutation, facilitating referrals for genetic counseling and testing, and incorporating the results of genetic testing into the patient's short- and long-term management plans.

What would you do? Specialists' perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination.

PURPOSE: To examine what cancer genetics specialists predict they would do personally if they were at 50% risk of carrying a mutation that predisposes to hereditary breast/ovarian cancer (BRCA1/BRCA2) and hereditary nonpolyposis colon cancer (HNPCC). METHODS: Questionnaire survey of the membership of the National Society of Genetic Counselors (NSGC) Special Interest Group (SIG) in Cancer. RESULTS: Of the 296 active members of the NSGC Cancer-SIG surveyed, 163 (55%) responded. Eighty-five percent predicted that if they had a 50% risk of carrying a BRCA1/BRCA2 mutation, they would pursue genetic testing. If they tested positive for a mutation at age 35, 25% predicted they would pursue prophylactic bilateral mastectomies and 68%, prophylactic oophorectomy. Ninety-one percent of respondents believe they would pursue genetic testing for HNPCC, and 17% would elect prophylactic colectomy; 54%, prophylactic hysterectomy; and 52%, prophylactic oophorectomy if they tested positive for a mutation. The majority (68%) would not bill their insurance companies for genetic testing because of fear of discrimination, and 26% would use an alias when undergoing testing. Fifty-seven percent of counselors would seek professional psychologic support to help them cope with the results of testing. CONCLUSION: A large percentage of cancer genetic counseling providers predicted they would opt for prophylactic surgery at a young age if they carried a BRCA or HNPCC mutation, and most would seek professional psychologic assistance when undergoing testing. More than half of respondents would not bill their insurance companies for genetic testing, largely because of fear of genetic discrimination. The vast majority of those providers most familiar with cancer genetic testing and its associated medical, psychologic, and legal implications would still pursue genetic testing.

BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations.

PURPOSE: Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (ipsilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treatment with LRT with respect to IBTR has not been determined. In this study, we estimate the frequency of BRCA1/2 mutations in a study of breast cancer patients with IBTR treated with LRT. PATIENTS AND METHODS: Between 1973 and 1994, there were 52 breast cancer patients treated with LRT who developed an IBTR within the prior irradiated breast and who were willing to participate in the current study. From our database, we also identified 52 control breast cancer patients treated with LRT without IBTR. The control patients were individually matched to the index cases with respect to multiple clinical and pathologic parameters. Lymphocyte DNA specimens from all 52 locally recurrent patients and 15 of the matched control patients under age 40 were used as templates for polymerase chain reaction amplification and dye-primer sequencing of exons 2 to 24 of BRCA1, exons 2 to 27 of BRCA2, and flanking intron sequences. RESULTS: After LRT, eight (15%) of 52 breast cancer patients had IBTR with deleterious BRCA1/2 mutations. By age, there were six (40%) of 15 patients with IBTR under age 40 with BRCA1/2 mutations, one (9.0%) of 11 between ages 40 and 49, and one (3.8%) of 26 older than age 49. In comparison to the six (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mutations, only one (6.6%) of 15 matched control patients without IBTR and had a BRCA1/2 mutation (P =.03). The median time to IBTR for patients with BRCA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P =.03). By clinical and histologic criteria, these relapses represented second primary tumors developing in the conservatively treated breast. All patients with BRCA1/2 mutations and IBTR underwent successful surgical salvage mastectomy at the time of IBTR and remain alive without evidence of local or systemic progression of disease. CONCLUSION: In this study, we found an elevated frequency of deleterious BRCA1/2 mutations in breast cancer patients treated with LRT who developed late IBTR. The relatively long time to IBTR, as well as the histologic and clinical criteria, suggests that these recurrent cancers actually represent new primary breast cancers. Early onset breast cancer patients experiencing IBTR have a disproportionately high frequency of deleterious BRCA1/2 mutations. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast-conserving therapy.

Local recurrence in the conservatively treated breast cancer patient: a correlation with age and family history.

BACKGROUND: The purpose of this study was to evaluate the relationships among young age at diagnosis, family history status, and local recurrence in breast cancer patients treated with lumpectomy and radiation therapy. METHODS: Between January 1970 and December 1990, 984 early-stage breast cancer patients were treated with conservative surgery and radiation therapy at Yale-New Haven Hospital. All patient data, including demographics, staging information, treatment, and outcome variables were entered into a computerized database. The current study focused on the relationships between young age, family history, and local relapse. A group of 52 patients who experienced a local recurrence in the conservatively treated breast and 52 matched control patients who had not experienced a local recurrence were asked to participate in a study to determine whether local recurrence was associated with family history. Detailed family history interviews were conducted, and pedigrees were analyzed by a genetic counselor who was blind to the clinical history of the patients. RESULTS: As of September 1997, with a median follow-up of 12.3 years for the 984 patients in the database, the overall actuarial 10-year survival is 73%, and the 10-year distant metastasis-free survival is 78%. Of the 984 patients, 112 have experienced a local relapse in the conservatively treated breast, resulting in a 10-year actuarial breast relapse rate of 15%. The 10-year survival after breast relapse is 69%. Patient age tested as a continuous variable correlated strongly with ipsilateral breast tumor relapse. Using age 40 as a cutpoint, patients aged 40 years or less had a significantly higher local relapse rate than patients older than 40 years (P < 0.001). Although the relationship between local relapse and young age was strong, no association was found between family history and local relapse in the detailed family history study. CONCLUSIONS: Young age at diagnosis was a significant prognostic factor for local relapse. In a detailed family history study using a case-control design, no significant differences in family history status were found between patients who had experienced a local relapse and patients who had not.

The impact of genetic screening on surgical decision-making in breast cancer.

For centuries, clinicians have recognized that a segment of their patient population is at increased risk to develop breast cancer based on their family history of the disease. Due to the absence of molecular information, it was not uncommon for women and their surgeons to make decisions regarding management of prophylactic surgery based solely on their family history, without specific information about the patient's personal risk to develop the disease. It has been only within the past 7 years that linkage for the breast cancer (BRCA) susceptibility genes has been established, and within the past 3 years that the genes have been cloned. Although clinical testing for the BRCA genes has been available for less than 2 years, it is already apparent that the implications for surgeons and their patients are significant.

Generations Lost: A Cancer Genetics Case Report.

The process of cancer genetic counseling can unearth issues that, sometimes unbeknownst to the counselor, are emotionally and psychologically significant to the patient. The following case report illustrates how the precounseling process of obtaining a medical chart on a deceased parent affected two sister counselees. This medical chart helped these sisters to reconnect with the mother they lost as children and to better understand her struggle with breast cancer. This case also chronicles the counselor's professional growth and discovery during this process.

Framework for a proactive parent support group: the Syracuse cystic fibrosis model.

Many support groups are organized and run according to goals and by-laws set by facilitators. This article introduces a model in which all goals and by-laws are created by the parents based on their group's specific needs. It also describes a "proactive" approach in which the group members identify projects or problems in their community and collectively form a plan in an attempt to improve these situations. This model is based on the real-life experience of a cystic fibrosis parent support group in Syracuse, New York. Lessons learned from this model can be applied to other parent support groups.

Practice variability in prenatal genetic counseling.

This study demonstrated that the content of prenatal genetic counseling sessions varied from counselor to counselor and from center to center. The study was designed to examine which specific issues were included by genetic counselors in prenatal genetic counseling sessions, and to determine which factors led genetic counselors to include or exclude this information from such sessions. Data were collected by randomly surveying 200 full, master degree members of the National Society of Genetic Counselors (NSGC). Respondents provided information by deciding which of 45 specific issues they would include in a standard prenatal genetic counseling session, and which one factor from a bank of 11 factors most accurately described the reason for this decision. The results indicated that the issues included/excluded from sessions varied widely among genetic counselors. The results also indicated that Patient Education/Informed Decision Making (34.5%) played the largest role in decision making overall, with Standard at Center/Departmental Policy (17.6%), Personal Experience/Preference (12.4%), and Applicability (10.9%) serving as the next three most important reasons for including or excluding issues from prenatal genetic counseling sessions.