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2. Sackett DL: Bias in analytic research. J Chronic Dis 32:51-63, 1979 3. Guyatt GH, Sackett DL, Cook DJ: Users guides to the medical literature:II. How to use an article about therapy or preventionB. What were the results and will they help me in caring for my patients? Evidence-Based Medicine Working Group. JAMA 271:59-63, 1994 4. Moher D, Schulz KF, Altman DG, for the CONSORT Group: The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med 134:657-662, 2001 5. Rothwell PM: External validity of randomised controlled trials: To whom do the results of this trial apply? The Lancet 365:82-93, 2005 6. Begg CB, Engstrom PF: Eligibility and extrapolation in cancer clinical trials. J Clin Oncol 5:962-968, 1987 7. Shapiro SH, Weijer C, Freedman B: Reporting the study populations of clinical trials: Clear transmission or static on the line? J Clin Epidemiol 53:973979, 2000 8. Wright JR, Bouma S, Dayes I, et al: The importance of reporting patient recruitment details in phase III trials. J Clin Oncol 24:843-845, 2006 9. Petersen LA, Normand SL, Leape LL, et al: Regionalization and the underuse of angiography in the Veterans Affairs health care system as compared with a fee-for-service system. N Engl J Med 348:2209-2217, 2003

10. Fisher ES, Bynum JP, Skinner JS: Slowing the growth of health care costs: Lessons from regional variation. N Engl J Med 360:849-852, 2009 11. Halm EA, Lee C, Chassin MR: Is volume related to outcome in health care? A systematic review and methodologic critique of the literature. Ann Intern Med 137:511-520, 2002 12. Auerbach AD, Hilton JF, Maselli J, et al: Shop for quality or volume? Volume, quality, and outcomes of coronary artery bypass surgery. Ann Intern Med 150:696-704, 2009 13. Bonell C, Oakley A, Hargreaves J, et al: Assessment of generalisability in trials of health interventions: Suggested framework and systematic review. BMJ 333:346-349, 2006 14. Lamont EB, Landrum MB, Keating NL: Differences in clinical trial patient attributes and outcomes according to enrollment setting. J Clin Oncol 28:215221, 2010 15. Trimble EL, Abrams JS, Meyer RM, et al: Improving cancer outcomes through international collaboration in academic cancer treatment trials. J Clin Oncol 27: 5109-5114, 2009

DOI: 10.1200/JCO.2009.25.8608; published online ahead of print at www.jco.org on November 23, 2009

Weighing Options for Cancer Risk Reduction in Carriers of BRCA1 and BRCA2 Mutations
Zsoa K. Stadler,Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY Noah D. Kauff, Clinical Genetics Service, Department of Medicine, and the Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY See accompanying article on page 222

When BRCA1 and BRCA2 were rst identied in 1994 and 1995, it was not clear that any interventions would alter the risk of cancer associated with inherited defects in these genes.1 In 2001, evidence became available that risk-reducing mastectomy (RRM) could markedly reduce the risk of BRCA-associated breast cancer.2-3 In the subsequent year, risk-reducing salpingo-oophorectomy (RRSO) was shown not only to reduce the risk of BRCA-associated gynecologic (ovarian, fallopian tube, and primary peritoneal) cancers, but if done premenopausally, also reduce the risk of BRCA-associated breast cancer.4-5 Since these initial studies were published, almost a dozen additional studies have examined the impact of risk-reducing surgery on cancer incidence,6,7 However, it has been less clear what the impact of these procedures has been on mortality, with only one early report examining this end point after surgical interventions.8 Simultaneous with the increase in knowledge of the impact of risk-reducing surgical interventions, options for nonsurgical risk reduction in women at inherited risk were also being explored. Advances include evidence that treatment with selective estrogen receptor modulators may reduce the risk of estrogen receptorpositive inherited breast cancer9 and that oral contraceptives appear to decrease the risk of BRCA-associated gynecologic cancer.10-11 Unfortunately, it is less clear what the impact of these interventions has been on mortality, as many BRCA-associated breast cancers are estrogen receptornegative and may not be susceptible to hormone chemoprevention. Similarly, while there is strong evidence that oral contraceptives decrease the risk of BRCA-associated gynecologic cancers, there are several reports that suggest that this protection may come with a concomitant increase in breast cancer risk.12-13 Arguably,
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the most important advance in nonsurgical risk reduction for carriers of BRCA mutations in the past decade has been the advent of magnetic resonance imaging (MRI) breast screening, which appears to detect twice as many cancers as does simultaneously performed mammography and results in interval cancer rates below 10%.14-19 While a reduction in mortality has not yet been demonstrated, when used in conjunction with mammography, MRI appears to result in early breast cancer detection in BRCA-mutation carriers; with 75% to 94% of screen-detected invasive tumors being 2 cm or smaller at diagnosis and 75% to 83% being negative for axillary nodal metastases.14-20 Currently, the most appropriate choice for breast cancer risk reduction in a woman with a BRCA mutation remains a complex and largely personal decision, especially as direct comparisons between intensied breast cancer screening, RRSO, and RRM are not available. To help with decision making under these conditions of uncertainty, considerable attention has been given to decision analysis models that can simulate risk of cancer and benets of risk-reduction strategies in BRCA mutation carriers. Using decision analysis, Schrag et al21 determined the effect of risk-reducing surgery on survival in young women with BRCA mutations, and concluded that a substantial gain in life expectancy of 2.9 to 5.3 years would result from RRM, with a more modest gain of 0.3 to 1.7 years achieved from RRSO, depending on level of cancer risk considered. As this study was conducted before the emergence of breast cancer screening with MRI in addition to mammography, a comparison to RRM was not directly performed. The model also assumed that women undergoing premenopausal RRSO would receive hormone-replacement therapy until the presumed age of natural menopause; thus, the impact of premenopausal
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RRSO on breast cancer risk reduction along with its potential adverse effects were not incorporated into the model. Similar gains in life expectancy were demonstrated by Grann et al22 among young BRCA mutation carriers undergoing risk-reducing surgery; however, when quality-of-life adjustments were incorporated into the model, the benets of RRSO and RRM on quality-adjusted survival were signicantly reduced. A subsequent analysis, focusing exclusively on BRCA1 mutation carriers, incorporated the interaction between oophorectomy and breast cancer risk reduction as well as higher estimates of expected gynecologic cancer risk reduction from RRSO, thereby demonstrating a larger gain in life expectancy for RRSO than previously ascribed.23 In this issue of Journal of Clinical Oncology, Kurian et al24 present the ndings of a decision analysis that was carefully designed to simulate and compare different current strategies for reducing cancer mortality in BRCA1 and BRCA2 mutation carriers. As compared to prior decision analysis in BRCA mutation carriers, the authors assess cancer risk and risk-reducing strategies separately for BRCA1 and BRCA2 mutation carriers and incorporate into their analysis updated recommendations for breast cancer screening with MRI in addition to mammography in this high-risk population. Compared to the 84% survival probability to age 70 in the general US population, without intervention, the overall survival ranged between 48% and 57% in BRCA1 and 62% to 72% in BRCA2 mutation carriers depending on estimates of breast and ovarian cancer risks incorporated into the model. The single most effective intervention for BRCA1 mutation carriers was RRSO at age 40 resulting in an increase in survival from 53% to 68% by age 70. While for BRCA1 mutation carriers, overall survival could be maximized to 79% by RRM at age 25 and RRSO at age 40, the combination of breast cancer screening from age 25 until RRM and RRSO at age 40 yielded a similar overall survival of 77%. Breast cancer screening from age 25 to 69 with RRSO at age 40, a common option chosen by BRCA1 carriers, resulted in only a slightly decreased survival of 74%. In comparison to these relatively minor differences depending on modality of breast cancer risk reduction pursued, delaying RRSO from age 40 to age 50 resulted in a dramatic decrease in survival from 68% to 61%. As this model takes into consideration other causes of mortality after premenopausal oophorectomy including risk of death from cardiovascular disease and deaths related to hip fracture and dementia, the model reinforces the importance of emphasizing RRSO by age 40 or after completion of child bearing for BRCA1 mutation carriers. As the risk of gynecologic cancer in BRCA2 mutation carriers is signicantly lower than in BRCA1 mutation carriers, the decision model has slightly different implications for BRCA2 mutation carriers. Breast cancer screening from age 25 to 69 with RRSO at age 40 resulted in a 9% gain in survival from 71% to 80%. If breast cancer screening was replaced with RRM at age 25 or at age 40, gains in survival were limited to 2% and 3%, respectively. Interestingly, in BRCA2 mutation carriers who undertake breast cancer screening, a delay in RRSO from age 40 to 50 results in a more signicant increase in risk of death from breast cancer (8%) than from ovarian cancer (3%), highlighting the importance of premenopausal RRSO in reducing breast cancer risk in these patients. A limitation of any decision analysis is its dependency on the data used to create the model. As considerable uncertainty exists regarding some of the parameters included in the model, Kurian et al24 performed sensitivity analyses on cancer penetrance in BRCA1 and BRCA2 carriers, breast tumor volume doubling time, sensitivity of
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MRI in cancer detection, impact of oral contraceptive pills on breast and ovarian cancer risk, and impact of premenopausal RRSO on breast cancer and other-cause mortality. Varying breast cancer penetrance from 47% to 85% in BRCA1 and from 40% to 85% in BRCA2 mutations carriers resulted in the most signicant changes with 9% to 10% alterations in overall survival. While the authors did not incorporate into the base model recent evidence suggesting a variation in the amount of benet that premenopausal RRSO provides for breast cancer reduction in BRCA1 versus BRCA2 mutation carriers,25 they did include this parameter in their sensitivity analysis and showed variation in overall survival of 6% in BRCA1 and 3% in BRCA2 mutation carriers. Despite considerable variation included for MRI sensitivity, ranging from 50% to 90%, the impact on survival was small at 2% to 3%. The assumptions incorporated by Kurian et al24 were carefully weighed against a number of other potentially relevant variables. One of the factors that was not included by the authors was the use of chemoprevention with tamoxifen or raloxifene. As discussed earlier, however, there is no denite evidence that chemoprevention with a selective estrogen receptor modulator impacts life expectancy in carriers of a BRCA1 or BRCA2 mutation. Given this uncertainty, excluding this parameter was likelyreasonable.Similarly,whileimpactonperceivedqualityoflifeclearly plays a paramount role in a womans decision to pursue intensied screening versus risk-reducing surgery, the decision by the authors not to include quality of life adjustments is not necessarily a shortcoming of the report. Rather, it allows individual women at inherited risk to weigh the survival impact of varying risk management modalities based on their own preferences and personal biases. In summary, Kurian et al24 provide a well designed, up-to-date decision analysis that incorporates almost all currently accepted risk reduction modalities as well as the majority of variables known to impact breast and ovarian cancer risk in BRCA mutation carriers. The results of this study have the potential to markedly facilitate decision making as women can be provided with BRCA mutationspecic data on the effects of different risk management strategies, undertaken at varying ages, on overall survival as well as on survival from breast and gynecologic cancer. As a future direction, the model likely could be expanded to assess the impact of recently identied genetic modiers of cancer penetrance and age-specic gynecologic and breast cancer risks. In addition, as the risk-benet ratios of various risk-reduction strategies continue to evolve with the emergence of new screening modalities as well as targeted prevention and treatment options, future updates will be needed. In the meantime, especially in the absence of data from randomized trials, this decision analysis will prove to be an important reference for physicians, other genetic professionals, and most importantly, patients with BRCA mutations.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Noah D. Kauff, Wyeth (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: Noah D. Kauff, Wyeth (C) Other Remuneration: None
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AUTHOR CONTRIBUTIONS

Conception and design: Noah D. Kauff Data analysis and interpretation: Zsoa K. Stadler, Noah D. Kauff Manuscript writing: Zsoa K. Stadler, Noah D. Kauff Final approval of manuscript: Zsoa K. Stadler, Noah D. Kauff
REFERENCES
1. Burke W, Daly M, Garber J, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer: II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium: Personalized medicine in the era of genomics. JAMA 277:997-1003, 1997 2. Meijers-Heijboer H, van Geel B, van Putten WL, et al: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345:159-164, 2001 3. Hartmann LC, Sellers TA, Schaid DJ, et al: Efcacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93:1633-1637, 2001 4. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002 5. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616-1622, 2002 6. Guillem JG, Wood WC, Moley JF, et al: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 24:4642-4660, 2006 7. Kauff ND, Barakat RR: Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2. J Clin Oncol 25:2921-2927, 2007 8. Domchek SM, Friebel TM, Neuhausen SL, et al: Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: A prospective cohort study. Lancet Oncol 7:223-229, 2006 9. King MC, Wieand S, Hale K, et al: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention trial. JAMA 286:2251-2256, 2001 10. Narod SA, Risch H, Moslehi R, et al: Oral contraceptives and the risk of hereditary ovarian cancer: Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339:424-428, 1998 11. Whittemore AS, Balise RR, Pharoah PD, et al: Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 91:1911-1915, 2004 12. Narod SA, Dube MP, Klijn J, et al: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94:1773-1779, 2002

13. Brohet RM, Goldgar DE, Easton DF, et al: Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: A report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 25:3831-3836, 2007 14. Kriege M, Brekelmans CT, Boetes C, et al: Efcacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351:427-437, 2004 15. Warner E, Plewes DB, Hill KA, et al: Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 292:1317-1325, 2004 16. Kuhl CK, Schrading S, Leutner CC, et al: Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. J Clin Oncol 23:8469-8476, 2005 17. Leach MO, Boggis CR, Dixon AK, et al: Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: A prospective multicentre cohort study (MARIBS). Lancet. 365: 1769-1778, 2005 18. Lehman CD, Blume JD, Weatherall P, et al: Screening women at high risk for breast cancer with mammography and magnetic resonance imaging. Cancer 103:1898-1905, 2005 19. Sardanelli F, Podo F, DAgnolo G, et al: Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study): Interim results. Radiology 242:698-715, 2007 20. Robson M, Oft K: Clinical practice: Management of an inherited predisposition to breast cancer. N Engl J Med 357:154-162, 2007 21. Schrag D, Kuntz KM, Garber JE, et al: Decision analysis effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 336:1465-1471, 1997 22. Grann VR, Panageas KS, Whang W, et al: Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. J Clin Oncol 16:979-985, 1998 23. van Roosmalen MS, Verhoef LC, Stalmeier PF, et al: Decision analysis of prophylactic surgery or screening for BRCA1 mutation carriers: A more prominent role for oophorectomy. J Clin Oncol 20:2092-2100, 2002 24. Kurian AW, Sigal BM, Plevritis SK: Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol 28:222-231, 2010 25. Kauff ND, Domchek SM, Friebel TM, et al: Risk-reducing salpingooophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: A multicenter, prospective study. J Clin Oncol 26:1331-1337, 2008

DOI: 10.1200/JCO.2009.25.6875; published online ahead of print at www.jco.org on December 7, 2009

Living With Imperfection

Tony S.K. Mok, State Key Laboratory of Southern China, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China See accompanying article on page 357

A denition serves the purpose of dening a medical phenomenon, assures mutual understanding of a biologic process and, hopefully, helps to unify therapy. For an illness, such as pneumonia, which biologically and pathophysiologically is well understood, the denition could be straightforward. However, when the biologic process is poorly understood, formulation of a denition could prove to be a challenge. Jackman et al1 have made an excellent attempt at dening acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in nonsmall-cell lung cancer (NSCLC). The authorship list represents the celebrity list for EGFR mutation. These are the researchers who discovered the EGFR mutation2,3 and described the resistance mechanism.4 Their proposal of four simple and largely clinical criteria is user-friendly and highly relevant to clinicians in their day-to-day practice and to researchers in
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their design of studies. As EGFR TKIs are now established as standard rst-line therapy for patients with lung cancer with EGFR mutation,5,6 we expect to see more patients with acquired resistance. This denition may prove to become another milestone. However, as perfect beauty does not exist, neither does a perfect denition. Criteria 1 and 2(1) previously received treatment with a single-agent EGFR TKI (eg, getinib or erlotinib) and (2) either or both of the following: a tumor which harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benet from treatment with an EGFR TKIare almost beyond argument (Table 1). One cannot acquire resistance without exposure to EGFR TKIs and beneting from them. The only imperfection is the rst part of criterion 2. Harboring an EGFR mutation known to be associated with drug sensitivity alone does not guarantee tumor response to
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