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Originally published as JCO Early Release 10.1200/JCO.2009.22.8353 on August 3 2009 © 2009 American Society of Clinical Oncology.
Reply to J. Tinat et alMEDomics Molecular Diagnostic Laboratory, Azusa, CA
Department of Clinical Cancer Genetics, City of Hope, Duarte, CA
MEDomics Molecular Diagnostic Laboratory, Azusa, CA We appreciate the inquiry from Tinat et al1 about our recent report2 on the first large series of clinical TP53 testing for Li-Fraumeni syndrome (LFS) reflective of clinical practice and not biased by specific selection criteria. Surprisingly, a sensitivity of 99% was found when a combination of classic LFS criteria and Chompret criteria were supplemented with choroid plexus carcinoma without regard for family history (Gonzalez criteria). Tinat et al correctly calculated that the sensitivity for the Chompret criteria alone was 92%, highlighting the large contribution of the Chompret criteria to the total sensitivity observed by the Gonzalez criteria. While the combination of classic LFS and choroid plexus carcinoma may have lower sensitivity, the specificity is much higher. Tinat et al1 state that our group was not aware of the Bougeard et al article3 which validates the Chompret criteria for LFS. On the contrary, as per the abstract, tables, and figures, we understood the novelty of the article to be the existence of large deletions in TP53 (5% of their patients with mutations). The authors centrally dealt with the molecular basis of LFS and provided evidence supporting the mechanistically appealing, but still controversial, hypothesis that germline missense mutations are associated with an earlier age of onset of cancer. We did not find that in our cohort (data in preparation). We remain unable to find any data on sensitivity or specificity of the Chompret criteria in the Bougeard et article. Tinat et al state that in the Bougeard article they "could estimate the sensitivity and specificity of the Chompret criteria to 82% and 58%, respectively." The peer-reviewed, published data underlying the above statement would be of value. Bougeard et al2 proposed revised Chompret criteria in the last paragraph of their article. The data for the revision and the rationale for the revision were not provided. Tinat et al1 present unpublished data on TP53 mutations in women with breast cancer before the age of 36 years. We believe a more accurate conclusion would be that, within their sample, the frequency of TP53 mutations is likely to be lower than 9% (95% CI for five of 128 is 1.3% to 8.9%). In addition, the difference in their French and our cohorts (five of 128 v one of 14) is not statistically significant (P = .5, Fisher's exact test, two sided; Appendix Table A2 in Gonzalez et al2). Further, we believe our 7% frequency to be a more accurate reflection of the actual frequency across the world. Our cohort consisted of patients submitted from all across the United States as well as a minority of international patients. The United States represents a genetically diverse and heterogeneous group. Secondly, we believe that Tinat et al's point estimate frequency of 4% would be more similar to our frequency of 7% if the age limit were reduced from 36 to 30, as it was in our data. Third, our data is likely an underestimate for two reasons: we did not include analysis of large rearrangements, which Bougeard et al3 showed to account for 5% of TP53 mutations2 and our cohort was not preselected for BRCA1/2 negative status. Tinat et al1 conclude, "it would be appropriate to avoid TP53 testing in patients with early onset breast cancer without familial history of cancer or multiple primary tumors." We disagree. Given the potential for modification of high risk for new primary breast cancer and possible influence on treatment decisions, the 2009 National Comprehensive Cancer Network guidelines indicate that TP53 testing should be considered for a woman with breast cancer before age 30 years and uninformative BRCA test results.4 Remaining cognizant of the principles of nondirective counseling and patient autonomy, we suggest that genetic testing of TP53 should be offered to patients with breast cancer before the age of 30 years, proper genetic counseling should include an explanation of the likelihood of detecting a mutation as well as the possible distress that genetic testing can cause, and the patient him/herself should ultimately decide whether to proceed with testing. Tinat et al1 also propose another version to the Chompret clinical criteria based on our data as well as their preliminary data (presented in paragraph four). To avoid confusion with the original Chompret criteria, we suggest that this current criteria be named "Tinat." We believe the aggregate data do not support elimination of early-onset breast cancer irrespective of family history. Future validation studies are needed to further optimize criteria for patients who have a likelihood of carrying germline TP53 mutations. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Tinat J, Bougeard G, Beart-Desurmont, et al: 2009 version of the Chompret Criteria for Li Fraumeni syndrome. J Clin Oncol 27:e108–e109, 2009. 2. Gonzalez KD, Noltner KA, Buzin CH, et al: Beyond Li-Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. J Clin Oncol 27:1250–1256, 2009. 3. Bougeard G, Sesboue R, Baert-Desurmont S, et al: Molecular basis of the Li-Fraumeni syndrome: An update from the French LFS families. J Med Genet 45:535–538, 2008. 4. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Genetic/ Familial High-risk assessment: Breast and Ovarian. 2009 http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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