Colonoscopy use following mutation detection in Lynch syndrome: exploring a role for cancer screening in adaptation.

Lynch syndrome (LS) is the most common inherited form of colorectal cancer. Mutation carriers can reduce the morbidity and mortality associated with colorectal cancer through colonoscopy. Theoretical models suggest that such health-related behaviors might also bring psychological benefits. This study assessed whether colonoscopy following mutation detection was associated with the levels of depressive symptoms. Data were obtained from a prospective family cohort study offering genetic services for LS. Participants completed questionnaires prior to the provision of services and 6 months post-receipt of mutation results. One hundred thirty-four (134) persons were identified to carry a mutation and completed both the questionnaires. Main outcome measures were depressive symptoms 6 months post-receipt of test results. Mutation carriers who did not complete a colonoscopy within the 6 months following receipt of results were six times (p < 0.01; odds ratio = 6.06) more likely to report depressive symptoms at a level of clinical importance post-receipt of test results compared to those who did undergo colonoscopy. Facilitating the expeditious use of colonoscopy following mutation detection may benefit newly identified mutation carriers by addressing the objective risks for cancer and moderating underlying emotional distress responses to genetic risk information. Furthermore, depressive symptoms may interfere with behavioral compliance in some patients, suggesting referral to mental health specialists.

Characterization of two novel BRCA1 germ-line mutations involving splice donor sites.

Deleterious BRCA1 mutations have significant clinical implications for the patients that carry them. Point mutations in critical functional domains and frameshift mutations that lead to early termination of protein translation are associated with a 60-80% risk of breast cancer and a 20-40% risk of ovarian cancer. In contrast, the significance of mutations located in intronic regions of BRCA1, even in the setting of a family history of breast and ovarian cancer, is not always clear. Some of these mutations occur in splice donor/acceptor consensus sites. These mutations can affect heteronuclear RNA (hnRNA) processing, leading to the loss of functional BRCA1 protein and thus may be disease-associated. However, it is important to verify the effect of these mutations, because splicing alterations cannot be predicted from genomic sequence alone. We report here the characterization of two novel BRCA1 mutations identified in families seen in our cancer risk evaluation clinic that alter splice donor sites of BRCA1. We show that both mutations alter transcript splicing and result in truncated BRCA1. IVS17 + 1G --> T leads to inclusion of part of intron 17 after the coding sequence of exon 17, resulting in early termination of BRCA1 protein following codon 1692. 252del5insT abolishes the splice donor site in exon 3, leading to the skipping of exon 5 and BRCA1 protein truncation following codon 45. Thus, both mutations result in loss of BRCA1 function, and carriers of these mutations should be counseled in the same manner as carriers of other truncating BRCA1 mutations.

Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience.

PURPOSE: To determine whether breast conservation and prolonged neoadjuvant chemotherapy have efficacy in locally advanced breast cancer (LABC), as measured by survival and rate of breast conservation. MATERIALS AND METHODS: Eighty-nine patients with stage III disease were enrolled at the University of Michigan (UM) onto a prospective nonrandomized trial. Patients received nine 21-day cycles of neoadjuvant chemohormonal therapy that consisted of doxorubicin 30 mg/m2 and cyclophosphamide 750 mg/m2 intravenously on day 1, conjugated estrogens 0.625 mg orally twice daily on days 6 to 8, methotrexate 40 mg/m2 and fluorouracil 500 mg/m2 intravenously on day 8, and tamoxifen 10 mg orally twice daily on days 9 to 14. Patients with a negative biopsy received radiation only, while those with residual disease underwent mastectomy and postoperative radiotherapy. Eight more cycles of chemohormonal therapy were administered after local-regional therapy. RESULTS: The clinical response rate to neoadjuvant therapy was 97%, 28% of patients had a complete pathologic response evaluated at biopsy. Five-year overall and disease-free survival probabilities were 54% and 44%, respectively. The median disease-free survival time was 2.4 years. The 5-year actuarial rates of local-regional control with local failure as only first failure were 82% and 78% following radiotherapy, and mastectomy and radiotherapy, respectively (P = .99). CONCLUSION: Prolonged neoadjuvant chemohormonal therapy and biopsy-driven local therapy have efficacy in LABC, with 28% of patients being candidates for breast conservation and a 5-year overall survival rate of 54%.

Establishing a cancer risk evaluation program.

PURPOSE: Presymptomatic genetic testing for cancer susceptibility is a new practice arena that raises many complex issues. This article presents one model of a cancer risk evaluation program that specifically addresses the unique issues associated with genetic testing for cancer risk. DESCRIPTION OF PROGRAM: The Cancer Risk Evaluation Program is designed to care for any individual concerned about his or her risk for cancer, offering predisposition genetic testing if appropriate. The program includes clinical and psychosocial assessment, education, cancer risk analysis, and genetic counseling; it offers long-term screening and surveillance and provides a forum for ongoing genetic and clinical research. RESULTS: Program evaluations from participants have shown that the program is successfully meeting the needs of the participants. This program also ensures that the University of Pennsylvania Cancer Center is delivering cancer genetic services consistent with the existing position statements on genetic testing for cancer susceptibility, which have included guidelines and indications for predisposition genetic testing and informed consent. CLINICAL IMPLICATIONS: Researchers anticipate a substantial demand for predisposition genetic testing for cancer susceptibility. However, not all individuals interested in testing are eligible or willing to undergo direct gene analysis because of the potential risks. Therefore, clinical programs must address the complex issues surrounding presymptomatic genetic testing and incorporate cancer risk assessment strategies. Additionally, healthcare providers in this new practice arena should be fully informed and current in the state of the knowledge regarding cancer risk assessment; predisposition genetic testing; and the ethical, legal, and social issues pertaining to cancer risk assessment and management.

Genetic predisposition testing: clinical implications for oncology nurses.

PURPOSE/OBJECTIVES: To describe for oncology nurses the clinical implications of genetic predisposition testing for alterations in cancer susceptibility genes. DATA SOURCES: Published research and educational manuscripts, books, conference proceedings, and personal experiences. DATA SYNTHESIS: Genetic predisposition testing for inherited cancer risk has profound clinical implications that eventually will affect all areas of nursing practice. The provision of genetic information raises issues about cancer risk management, psychosocial sequelae, and legal and professional liability. CONCLUSION: Most healthcare professionals, including nurses, are not adequately prepared to manage the issues resulting from genetic predisposition testing. Furthermore, little data are available to guide practice. Unique educational strategies are needed to prepare providers in this practice arena. IMPLICATIONS FOR NURSING PRACTICE: Genetic predisposition testing is becoming more common in general oncology and primary care communities. Nurses will play a major role in the support, counseling, education, informed consent, and follow-up care of individuals who are considering undergoing or who have undergone testing. To meet the needs of patients and their families, oncology nurses must prepare themselves for this new area of practice.

Predisposition testing for breast and ovarian cancer susceptibility.

OBJECTIVES: To provide an overview of breast cancer predisposition syndromes and the breast and Ovarian cancer susceptibility genes identified to date. To describe the clinical implications of genetic testing for breast and ovarian cancer susceptibility. DATA SOURCES: Published research and educational manuscripts, books, conference proceedings, and personal experiences. CONCLUSION: Nurses must become knowledgeable of predisposition genetic testing for inherited breast cancer risk including: understanding of the gene being analyzed and associated cancer risks, indications for testing, the limitations of the test, the management options for mutation carriers, risks and benefits of testing, and the long-term psychosocial sequelae. IMPLICATIONS FOR NURSING PRACTICE: Predisposition testing for alterations in breast cancer susceptibility genes is rapidly moving into the general oncology and primary care community where nurses will play a major role in the provision of genetic services. The role of nursing in cancer genetics includes practice and education, nursing research, and policy initiatives.

Germline BRCA1 mutations and loss of the wild-type allele in tumors from families with early onset breast and ovarian cancer.

The BRCA1 gene on human chromosome 17q21 is responsible for an autosomal dominant syndrome of inherited early onset breast/ovarian cancer. It is estimated that women harboring a germline BRCA1 mutation incur an 85% lifetime risk of breast cancer and a greatly elevated risk of ovarian cancer. The BRCA1 gene has recently been isolated and mutations have been found in the germline of affected individuals in linked families. Previous studies of loss of heterozygosity (LOH) in breast tumors have been carried out on sporadic tumors derived from individuals without known linkage to BRCA1 and on tumors from linked families. Loss of large regions of chromosome 17 has been observed, but these LOH events could not be unequivocally ascribed to BRCA1. We have studied 28 breast and 6 ovarian tumors from families with strong evidence for linkage between breast cancer and genetic markers flanking BRCA1. These tumors were examined for LOH using genetic markers flanking and within BRCA1, including THRA1, D17S856, EDH17B1, EDH17B2, and D17S183. Forty-six percent (16/34) of tumors exhibit LOH which includes BRCA1. In 8 of 16 tumors the parental origin of the deleted allele could be determined by evaluation of haplotypes of associated family members; in 100% of these cases, the wild-type allele was lost. In some of these families germline mutations in BRCA1 have been determined; analyses of tumors with LOH at BRCA1 have revealed that only the disease-related allele of BRCA1 was present. These data strongly support the hypothesis that BRCA1 is a tumor suppressor gene.

Assessment and counseling for women with a family history of breast cancer. A guide for clinicians.

More women in all risk categories are seeking information regarding their individual breast cancer risk, and there is a need for their primary care clinicians to be able to assess familial risk factors for breast cancer, provide individualized risk information, and offer surveillance recommendations. Estimates of the number of women with a family history of breast cancer range from approximately 5% to 20%, depending on the population surveyed. Many of these women will not have a family history that suggests the presence of a highly penetrant breast cancer susceptibility gene. However, a small subset of such women will come from families with a striking incidence of breast and other cancers often associated with inherited mutations. The development and refinement of risk prediction models provide an epidemiologic basis for counseling women with a family history that does not appear related to a dominant susceptibility gene. contrast, the recent isolation of BRCA1, the localization of BRCA2, and the acknowledgement that additional breast cancer susceptibility genes must exist provide a molecular basis for counseling some high-risk women. We present a guide for primary care clinicians that may be helpful in defining families as moderate or high risk, in determining individual risk in women with a family history of breast cancer based on this distinction, and for counseling women in a setting where the data necessary to design surveillance and prevention strategies are lacking. We include criteria for selecting women who may be candidates for detection of inherited mutations in breast cancer susceptibility genes.

Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring.

PURPOSE: Recent innovations allow the integration of microelectronics into drug packaging, providing a continuous record of the interactions of the patient with the drug package. We hypothesized that adherence to oral tamoxifen, as measured by a pressure-activated microelectronic monitoring device, would be significantly discrepant from traditional measures of patient adherence, ie, patient self-report (SR) and pill counts (PCs). PATIENTS AND METHODS: Twenty-six patients receiving oral tamoxifen therapy were assessed by patient SR, PCs, and Medication Event Monitoring System (MEMS; Aprex Corp, Fremont, CA) microelectronic monitoring. A microprocessor in the MEMS cap recorded each opening as a presumptive dose, listing the date, time, and duration of opening for later retrieval on a microcomputer. Patients were not informed that their adherence was to be monitored electronically or that PCs would be performed. RESULTS: A total of 2,102 days (70.1 months) of tamoxifen therapy were monitored; patients were monitored for a mean of 2.92 months of tamoxifen therapy. SR adherence to oral tamoxifen was significantly higher than that suggested by either PCs (SR missed doses only v PC, P = .008) or MEMS adherence monitoring (SR missed doses only v MEMS missed doses only, P = .005; SR dosing-interval errors only v MEMS dosing-interval errors only, P < .0001; SR all dosing errors v MEMS all dosing errors, P < .0005). PC data also suggested significantly higher adherence rates than MEMS monitoring. CONCLUSION: Microelectronic adherence monitoring provides both confirmatory and complimentary data regarding adherence behavior, while also allowing for the evaluation of patterns of nonadherence. Patient SRs and PCs likely overestimate the degree to which patients adhere to their tamoxifen regimen.