Heidi D. Nelson, MD, MPH; Laurie Hoyt Huffman, MS; Rongwei Fu, PhD; Emily L. Harris, PhD, MPH
Nelson HD, Huffman LH, Fu R, Harris EL. Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Systematic Evidence Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2005;143:362-379. doi: 10.7326/0003-4819-143-5-200509060-00012
Download citation file:
Published: Ann Intern Med. 2005;143(5):362-379.
Clinically significant mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer. Although these mutations are uncommon, public interest in testing for them is growing.
To determine benefits and harms of screening for inherited breast and ovarian cancer susceptibility in the general population of women without cancer presenting for primary health care in the United States.
MEDLINE (1966 to 1 October 2004), Cochrane Library databases, reference lists, reviews, Web sites, and experts.
Eligibility was determined by inclusion criteria specific to key questions about risk assessment, genetic counseling, mutation testing, prevention interventions, and potential adverse effects.
After review of studies, data were extracted, entered into evidence tables, and summarized by using descriptive or statistical methods. Study quality was rated by using predefined criteria.
Tools assessing risks for mutations and referral guidelines have been developed; their accuracy, effectiveness, and adverse effects in primary care settings are unknown. Risk assessment, genetic counseling, and mutation testing did not cause adverse psychological outcomes, and counseling improved distress and risk perception in the highly selected populations studied. Intensive cancer screening studies are inconclusive. Chemoprevention trials indicate risk reduction for breast cancer in women with varying levels of risk, as well as increased adverse effects. Observational studies of prophylactic surgeries report reduced risks for breast and ovarian cancer in mutation carriers.
No data describe the range of risk associated with BRCA mutations, genetic heterogeneity, and moderating factors; studies conducted in highly selected populations contain biases; and information on adverse effects is incomplete.
A primary care approach to screening for inherited breast and ovarian cancer susceptibility has not been evaluated, and evidence is lacking to determine benefits and harms for the general population.
Key question ( ) 1: Do risk assessment and mutation testing lead to a reduction in the incidence of breast and ovarian cancer and cause-specific or all-cause mortality? KQ 2A: How well does risk assessment for cancer susceptibility by a clinician in a primary care setting select candidates for mutation testing? KQ 2B: What are the benefits of genetic counseling before testing? KQ 2C: Among women with family histories predicting an average, moderate, or high risk for a deleterious mutation, how well does mutation testing predict risk for breast and ovarian cancer? KQ 3: What are the adverse effects of risk assessment, genetic counseling, and testing? KQ 4: How well do interventions reduce the incidence and mortality of breast and ovarian cancer in women identified as high risk by history, positive genetic test results, or both? KQ 5: What are the adverse effects of interventions? *Indicates clinically significant mutation of or .
Error bars represent 95% CIs. IBIS = International Breast Cancer Intervention Study.
NNS = number needed to screen. *Based on estimates for mastectomy. †Based on estimates for oophorectomy.
ELSI = ethical, legal, and social implications.
Screening test relevant, available for primary care, adequately described.
Credible reference standard, performed regardless of test results.
Reference standard interpreted independently of screening test.
Indeterminate results handled in a reasonable manner.
Spectrum of patients included in study.
Administration of reliable screening test.
Initial assembly of comparable groups: randomized, controlled trials—adequate randomization, including concealment and statement of whether potential confounders were distributed equally among groups; cohort studies—consideration of potential confounders with either restriction or measurement for adjustment in the analysis; consideration of inception cohorts.
Maintenance of comparable groups (includes attrition, crossovers, adherence, and contamination).
Important differential loss to follow-up or overall high loss to follow-up.
Measurements: equal, reliable, and valid (includes masking of outcome assessment).
Clear definition of interventions.
Important outcomes considered.
Analysis: adjustment for potential confounders for cohort studies, or intention-to-treat analysis for randomized, controlled trials.
Accurate ascertainment of cases.
Nonbiased selection of case-patients and controls, with exclusion criteria applied equally to both.
Diagnostic testing procedures applied equally to each group.
Measurement of exposure accurate and applied equally to each group.
Appropriate attention to potential confounding variable.
The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.
Paoli Calmettes Institute & BC Cancer Agency
October 4, 2005
Equity, Discrimination and Culture
As usual the USPSTF carried out an outstanding and comprehensive assessment of health services(1). However we would like to express three concerns:
First, should the test really be offered only to women whose family history is associated with an increase risk for deleterious mutations in BRCA1 or BRCA2? We claim that whatever criteria, individual or familial, giving us a clue that a women is at risk of being a gene carrier, every women with the same level of risk should be treated in the same way (offered or not offered a test), it's matter of equity. The familial history may be inaccurate with regard to pathological confirmation. Small pedigrees may also downgrade the predictive value of familial history, due to the low birth rate in western countries, many women (above 10%) may experience having her mother as the only female member of first and second degree relatives old enough to be affected with a breast cancer. For all these reasons, using individual characteristics leading to a high probability of being a gene carrier such as age at onset, pathological findings(2), combination of age and pathological findings, or gene profiling of the tumors may be useful. Some of them might not yet reach the level of confidence required by the USPSTF, but some do (a single case before the age of 30).
The second point is about discrimination: "social consequences, such as insurance and employment discrimination; these issues should be discussed". The Annals of Internal Medicine is amongst the most prestigious quoted and read International Journal. US scientists are obviously providers of "good" science that deserves wide diffusion. The editors should, however, be cautious about a kind of Trojan horse phenomena with culture and social values conveyed hidden within science. Genetic-based health insurance discrimination is a threat in countries in which premiums are risk-based (like in the US), but not in other countries in which "premiums" are income-based.
Lastly we question the relevance of breast self-examination (not clinical breast examination that is useful) that was mentioned in the table 1 "Prevention and Detection recommendations" with a monthly rate beginning by age 18"“21 years, despite evidence about the lack of efficacy in general population, evidence of harm(3) in high risk population and recommendations against(4). Despite the fact that USPSTF uses stringent criteria to make their recommendations, cultural factors may still be at work(5).
1. Nelson HD, Huffman LH, Fu R, Harris EL. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2005;143(5):362-79.
2. Eisinger F, Jacquemier J, Charpin C, et al. Mutations at BRCA1 : The Medullary Breast Carcinoma Revisited. Cancer Res 1998;58:1588-92.
3. van Dooren S, Rijnsburger AJ, Seynaeve C, et al. Psychological distress and breast self-examination frequency in women at increased risk for hereditary or familial breast cancer. Community Genet 2003;6(4):235- 41.
4. Kosters JP, Gotzsche PC. Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database Syst Rev 2003(2):CD003373.
5. Eisinger F, Geller G, Burke W, Holtzman N. Cultural Basis for Differences Between US and French Clinical Recommendations for Women at Increased Risk of Breast and Ovarian Cancer. Lancet 1999;353:919-20.
Kelly E. Ormond
Northwestern University and Immediate Past President of the National Society of Genetic Counselors
December 13, 2005
Response to Annals Patient Summary on BRCA Genetic Risk Assessment
The National Society of Genetic Counselors (NSGC) Familial Cancer Risk Counseling Special Interest Group has reviewed the USPSTF recommendations1 regarding BRCA genetic risk assessment and commends the Annals efforts to create a patient summary on this topic. The NSGC would like to emphasize that the USPSTF recommendations highlight the importance of genetic counseling to the risk assessment process, and that genetic counseling facilitates informed decision-making about genetic testing and management, and in and of itself has not been associated with increased anxiety or other adverse outcomes. Cancer genetic professionals include genetic counselors, medical geneticists, and advanced practice oncology nurses with special training in genetics. These individuals can be located via the NCI website (www.cancer.gov/search/geneticsservices/ ) or the NSGC website (www.nsgc.org).
The following are key points that we feel are either omitted or misleading in the summary2 as written when compared to the published USPSTF guidelines:
1) Although the Task Force did not address genetic counseling and testing for men, they discuss the importance of recognizing cases of male breast cancer and therefore the inclusion of male relatives such as brothers, fathers, grandfathers, and nephews in any family history is necessary.
2) The patient summary implies a substantial likelihood of anxiety, insurance problems or unnecessary procedures, none of which have been found in actual practice.
3) The definition of high risk women of Ashkenazi (Eastern European) Jewish heritage should be stated. ""¦"¦. these include any first-degree relative with breast or ovarian cancer at any age OR (not and) at least 2 second degree relatives on the same side of the family with breast or ovarian cancer at any age."
4) While the USPTF recommendations were directed towards a population without breast or ovarian cancer, it is very important that women affected with these cancers, especially those with a known family member with a BRCA mutation, be provided access to cancer genetic risk assessment and counseling. Such individuals stand to potentially benefit to an even greater extent from genetic risk assessment and BRCA testing.
Finally, we strongly encourage the Annals to consider developing an alternative version of the patient summary incorporating these concerns in collaboration with recognized leaders in the field of cancer genetics.
1. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Annals of Internal Medicine. 143(5):355-61, 2005 Sep 6.
2. Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: U.S. Preventive Services Task Force Recommendations. Annals of Internal Medicine. 143 (5): I-47. 2005 Sept 6.
Editors at Annals
Annals of Internal Medicine
December 16, 2005
A response from the editors
The Editors appreciate The National Society of Genetic Counselors (NSGC) Familial Cancer Risk Counseling Special Interest Group's comments, but we respectfully disagree that a revision of the patient summary accompanying the USPSTF recommendation is warranted. The intent of the summary is to reflect the content of the recommendation statement. The NSGC's first and fourth comments pertain to genetic counseling of men and counseling of women with a personal history of breast or ovarian cancer. These issues are beyond the scope of the USPSTF recommendation. While the NSGC believes that the summary is misleading with respect to the potential harms of screening, the editors believe that the summary is accurate when it states, "...since not all women who have a BRCA mutation develop cancer, identification of mutations may also needlessly expose women to anxiety, insurance problems, or unnecessary procedures." With respect to the third comment, the summary as currently written does use "or" not "and" to describe the characteristics of high risk women of Ashkenazi Jewish heritage.
Results provided by:
Copyright © 2017 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Conditions of Use
This PDF is available to Subscribers Only