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USPSTF guidelines will miss BRCA families due to paternal inheritance or a truncated family tree
Submit responseGuidelines such as that by USPTF (1, 2) are important resources for clinicians. However, the published guideline and accompanying text are silent on the possible limitations of a small family tree and/or the potential for missed paternal transmission of BRCA gene mutation. Given the autosomal dominant inheritance of the BRCA genes, hereditary predisposition to breast cancer is equally likely to be paternal or maternal in origin. As most male BRCA carriers are nonpenetrant, a paucity of adult females on the paternal lineage would obscure the pattern of cancers necessary to meet the proposed guidelines for testing. In the setting of a BRCA mutation inherited from the paternal side, each affected paternal relative is automatically one degree of relationship more distant to the proband, highlighting the need to take a more extensive family history including cousins and great aunts. Consider a 35-year old woman as the only case of breast cancer over two generations in her family and a paucity of female relatives on the paternal side. The current USPSTF guideline does not include affected 3rd degree relatives with ovarian or premenopausal breast cancers, and patients may neglect to volunteer such history, despite a plausible genetic predisposition pattern. Other factors may reduce BRCA-associated cancer expression in a pedigree such as surgeries for non-cancer indications (e.g. hysterectomy with bilateral oophorectomy), adoption, and the early death of family members from other causes. Consequently, we promote taking a comprehensive family history where one exists and considering single cases of early onset breast cancer for genetic counseling and BRCA testing, particularly if the family tree is truncated.
Guidelines from the National Comprehensive Cancer Network(3) include footnotes about the potential impact of “limited family structure,” with criteria such as “a single case of early age of onset of breast cancer” as an important indicator for genetic risk assessment. The USPSTF guideline’s focus on unaffected women with multiple affected family members may result in a missed opportunity to alert the at-risk relatives about their potential peril. By dismissing a single case with provocative features (e.g. early onset) we may be missing an opportunity to anticipate and manage risk for new primary cancers. One recent report on 10-year outcomes for BRCA carriers with limited stage breast cancer noted that 25% of the mortality was due to subsequent ovarian cancers.(4) Thus, we advocate guidelines that incorporate single case indicators and allow for the judgment of expert clinicians.
1. USPSTF. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med. 2005;143(5):355-61.
2. 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.
3. Daly MB, Bryant E, Buys S, et al. NCCN Practice Guidelines: Genetic/familial high-risk assessment breast and ovarian. Version 1 ed. Vol. 2005.
4. Metcalfe KA, Lynch HT, Ghadirian P, et al. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol. 2005;96(1):222-6.
Conflict of Interest:
None declared
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Primum non nocere
Submit responseTo the editor:
The US Preventative Services Task Force (USPSTF) recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene (BRCA) testing for women whose family history is not associated with an increased risk for deleterious BRCA 1 or 2 mutations(1). We applaud the authors for their evidence-based review which also helps to address appropriate referral so that limited manpower in genetic counseling is utilized effectively. However, we are concerned that the complexity of these guidelines may be misunderstood by non-cancer genetics professionals.
The authors state, “public interest in testing is growing and physicians are increasingly faced with this issue while providing primary health care”. Our goal in providing guidance to primary care providers should be to make it as straightforward as possible. The 2003 update of the American Society of Clinical Oncology (ASCO) Policy Statement on Genetic Testing for Cancer Susceptibility(2) simply recommends testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition; 2) the test can be adequately interpreted; and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members. The National Comprehensive Cancer Network (NCCN; www.nccn.org) has simplified guidelines for referral to cancer genetic professionals, which are then followed by more stringent guidelines for actual BRCA testing.
The busy clinician, faced with the USPSTF guidelines, would need to search hard to find a paragraph buried within the clinical considerations section to determine if a referral is warranted. Finding these criteria too complicated, he/she may not proceed beyond the summary recommending against referral and testing. More alarmingly, he/she may fail to refer at-risk patients who do not know their family histories or who have few female family members (false negatives). With such guidelines on the Internet, at-risk patients may be discouraged from seeking counseling due to the perceived “harm” described in the summary. Instead, primary care providers and their patients should be encouraged to seek a consultation, which includes genetic counseling, with cancer genetics professionals for guidance. It would be useful to emphasize that this consultation will help the patient (consultand) explore the appropriateness of proceeding to gene testing and further management. The dawn of genomics-based practice of personalized healthcare has arrived. Thus, we should strive harder to ensure ever-evolving guidelines that serve to clarify and not to confuse: the centuries old clinical dictum “Primum non nocere” (‘Above all, do no harm’) continues to apply.
Kevin Zbuk, MD Amy Shealy, MS, CGC Jennifer Stein, MS, CGC Charis Eng, MD, PhD, FACP
Genomic Medicine Institute Cleveland Clinic Foundation Cleveland, OH 44195
1. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med. 2005;143(5):355-61.
2. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21(12):2397-406.
Conflict of Interest:
None declared