Tailoring breast cancer treatment to genetic status: the challenges ahead.

Abstract

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. 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. 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. Recent studies documenting a reduction in both breast and ovarian cancer incidence following prophylactic surgeries 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. 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. 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. 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 al 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 1.5to 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 10 MAY 15 2004