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Originally published as JCO Early Release 10.1200/JCO.2004.02.994 on April 5 2004 © 2004 American Society of Clinical Oncology.
Tailoring Breast Cancer Treatment to Genetic Status: The Challenges AheadFox Chase Cancer Center, Philadelphia, PA Launched more than a decade ago, the Human Genome Project set out to map the entire human genome, as well as that of other candidate species, to improve our understanding of the genetic contribution to human diseases and to develop rational strategies to reduce disease burden.1 One of the notable outcomes of this research was the discovery of the tumor suppressor genes, BRCA1 and BRCA2, which, when mutated, are associated with significantly increased risks for breast and ovarian cancer.2 In the decade since their discovery, the field of genetic counseling, which had been traditionally concentrated in the neonatal setting, has expanded to encompass the growing list of germline mutations associated with adult onset disorders. As a result, clinical genetic testing for cancer susceptibility genes has become available for individuals with a hereditary pattern of cancer. Much of the literature concerning testing for BRCA1/2 to date has focused on the psychological and ethical concerns surrounding the receipt of genetic test results. Despite initial fears, however, there is a growing consensus that—when accompanied by adequate education, counseling, and support—the long-term adverse psychological effects of undergoing genetic testing are minimal and that evidence for discrimination based on genetic status is largely unsubstantiated.3–5 Recent studies documenting a reduction in both breast and ovarian cancer incidence following prophylactic surgeries6–8 have focused attention on the potential benefits of genetic testing and have served to encourage individuals with a hereditary pattern of breast and ovarian cancer to consider genetic testing for guidance in choosing surveillance and preventive options. Genetic test results have, on the other hand, had little impact on the actual management of these cancers. Although the histopathologic features of BRCA1-related breast cancers clearly demonstrate a more aggressive pattern, there is no conclusive evidence that their prognosis is worse.9 And despite concern that the underlying genomic instability associated with germline BRCA1/2 mutations may have an adverse effect on response to adjuvant radiation therapy, genetic status has not been shown to alter either short-term toxicity or 5-year local recurrence rates in women treated with lumpectomy and radiation therapy.10 What has clearly emerged is a risk for subsequent contralateral breast cancer, which approaches 60% in some series among mutation carriers following a diagnosis of primary breast cancer.11,12 This risk, which persists for at least 10 years following the primary diagnosis, introduces the option of bilateral mastectomy at the time of original diagnosis as an alternative to breast-conserving therapy. The article by Schwartz et al13 in this issue of the Journal of Clinical Oncology addresses the impact of genetic testing and counseling on treatment decisions in the setting of newly-diagnosed breast cancer. The design is a case series of women who were self-referred to a genetic risk assessment and testing study at the time of initial diagnosis of breast cancer. Eligibility was determined by personal and family history reflecting a minimum 10% prior probability of being a BRCA1/2 mutation carrier. Participants underwent a 1.5- to 2-hour pretest education and counseling session before submitting a blood sample for genetic testing for BRCA1/2. Test results were available within approximately 2 weeks and were provided by a 1-hour telephone disclosure session. Subsequent treatment decisions were obtained from the genetic counselors' records. Forty-eight percent of women found to carry a deleterious BRCA1/2 mutation chose bilateral mastectomy as their primary treatment, compared with 24% of those in whom no mutation or a mutation of unknown significance was found and 4% of those who declined testing. Twenty-three percent of women tested made definitive treatment decisions prior to receipt of test results. The other independent predictors of choosing bilateral mastectomy were a strong family history of breast or ovarian cancer and physician recommendation for genetic testing or prophylactic surgery. The relatively high selection (24%) for bilateral mastectomy among women with negative results was attributed by the authors to the existence of other medical and psychosocial factors. This finding is consistent with data indicating that, in general, test uptake is higher among women who experience higher levels of general breast cancer distress and worry14 and who thus may be more likely to pursue prophylactic surgery, even in the absence of a documented BRCA1/2 mutation. The authors conclude that presurgical genetic testing for BRCA1/2 is technically feasible among women newly diagnosed with breast cancer and that this testing will significantly affect their surgical decisions. The select nature of the sample and the unique resources of the study site, however, limit the generalizability of this study. Global feasibility issues reflect both provider and patient constraints. With the recent advent of direct-to-consumer marketing of genetic testing, physicians will increasingly find themselves confronted with requests for BRCA1/2 testing by their patients, but without necessarily having the expertise or resources to make appropriate counseling or referrals. The majority of practicing oncologists lack formal training in the identification of appropriate candidates for genetic testing, the interpretation of test results, and evidence-based clinical management strategies. Furthermore, the provision of genetic risk assessment and testing services requires the availability of trained genetic counselors, often together with nurses trained in cancer genetics, a luxury most oncology practices cannot afford in the current reimbursement climate. Counseling services are particularly important in this context where complex and emotionally charged genetic information is being provided simultaneously with a new diagnosis of breast cancer. In the Schwartz et al study, for example, counselors spent close to 3 hours with each patient in preparation for the receipt of their genetic test results. From the patient's perspective, women newly diagnosed with breast cancer often express both a sense of urgency to initiate treatment and an intolerance of prolonged delays. The average turnaround time for commercial testing is 1 to 3 months, including insurance approval and actual testing. A rapid testing option provides genetic test results within 10 days, but with a price of over $4,000, a cost not routinely reimbursed by insurers. Even when the cost of the actual genetic testing is covered, the accompanying counseling is generally not covered—a situation that threatens to make timely access to genetic testing, to make informative breast cancer therapy choices, an option for the privileged few. And finally, from a philosophic standpoint, surgeons have been slow to accept prophylactic surgery in a disease whose recent triumphs include the adoption of breast-conserving therapy. Many questions are left unanswered by this study, including the long-term consequences of breast cancer treatment choices based on genetic probability. However, despite its limitations, it provides compelling evidence that, when given access to genetic risk counseling and testing services with no financial restraints, women who perceive themselves to be at increased risk for hereditary cancer will be willing to undergo genetic testing and will incorporate the test information into their primary treatment decisions. Given the high rates of contralateral breast cancer in BRCA1/2 mutation carriers, the choice to undergo bilateral mastectomy rather than breast-conserving surgery could ultimately translate into improved survival for this population of patients. The fiscal and institutional impediments to widespread availability of genetic counseling and testing for all appropriate candidates should not deter the oncology community from its uptake but, rather, should commit us to the elimination of these barriers. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Collins FS: Shattuck lecture: Medical and societal consequences of the Human Genome Project. N Engl J Med 341:28–37, 1999
2. Streuwing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401–1408, 1997 3. Croyle RT, Achilles JS, Lerman C: Psychologic aspects of cancer genetic testing. Cancer 80:569–575, 1997[CrossRef][Medline] 4. Randall J, Butow P, Kirk J, et al: Psychological impact of genetic counseling and testing in women previously diagnosed with breast cancer. Intern Med J 31:397–405, 2001[CrossRef][Medline]
5. Schwartz MD, Peshkin BN, Hughes C, et al: Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample. J Clin Oncol 20:514–520, 2002
6. Hartmann LC, Sellers TA, Schaid DJ, et al: Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 93:1633–1637, 2001
7. 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
8. Kauf 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
9. Verhoog LC, Brekelmans CT, Seynaeve C, et al: Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol 17:3653–3663, 1999
10. Pierce LJ, Strawderman M, Narod SA, et al: Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18:3360–3369, 2000
11. Robson M, Levin D, Federici M, et al: Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA founder mutations. J Natl Cancer Inst 91:2112–2117, 1999 12. Greene MH: Genetics of breast cancer. Mayo Clin Proc 72:54–65, 1997[Abstract]
13. Schwartz MD, Lerman C, Brogan B, et al: Impact of BRCA1/BRCA2 counseling and testing in newly diagnosed breast cancer patients. J Clin Oncol 22:1823–1829, 2004 14. Lerman C, Schwartz M, Lin T, et al: The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol 65:414–420, 1997[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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