Jan 2006

Breast Cancer Screening, Commentary 2

Antonella Surbone, MD, PhD
Virtual Mentor. 2006;8(1):10-15. doi: 10.1001/virtualmentor.2006.8.1.ccas1-0601.

Case

Mr. Jones, a 49-year-old accountant, visited Dr. Seelinn, a urologist, for the first time. Mr. Jones's sister had been treated for ovarian cancer and his mother had a history of breast cancer. While his sister was receiving treatment for her cancer, her physician recommended that the entire family be screened for breast cancer 1 and 2 (BRCA1 and 2) mutations, and Mr. Jones agreed to have this test.

Several weeks after the test, Mr. Jones learned that he tested positive for a mutation and was sent a form letter stating that "men with this mutation have a 6 percent chance of developing breast cancer and a 7 percent chance of developing prostate cancer before age 70." Concerned about his results, he went to see Dr. Seelinn to find out what he should do with this new information. As he handed Dr. Seelinn the letter, Mr. Jones laughed and said, "If I had known the test wasn't going to give me a definite yes or no answer about whether I was going to get cancer, I wouldn't have had it. I don't know anything more than I did before the test."

Dr. Seelinn is also unclear about what this reported risk of prostate cancer means. Does it mean biopsy-proven prostate cancer (which may be unlikely to progress if diagnosed in his late 60s)? Or does it refer to the risk of advanced prostate cancer that would present with symptoms? He's not even sure if this letter means that Mr. Jones is at a higher or lower risk of prostate cancer than men without the mutation.

Seeking to provide Mr. Jones with some guidance and more information, Dr. Seelinn performed a urologic history and a thorough physical exam, including a breast exam and a digital rectal exam (DRE) of the prostate. All of these were normal. Dr. Seelinn also ordered a prostate-specific antigen test (PSA) even though he didn't expect to find anything abnormal in the results.

After Mr. Jones left, Dr. Seelinn wondered whether finding out about his genetic alteration held any benefit for Mr. Jones. Did Mr. Jones really understand what a positive test result would mean? Furthermore, what follow-up schedule is appropriate for Mr. Jones, who appears to be a healthy, 49-year-old man?

Commentary 2

"Future things: not our domain.
But in this today which unravels in front of us,
what shall we do?"
                                    
  —Sophocles, Antigone

The case of Mr. Jones illustrates how the many medical, psychological, ethical, and social dimensions of genetic testing for cancer susceptibility are intertwined. This commentary addresses the controversial medical aspects, summarizes briefly the main ethical considerations raised by breast cancer (BRCA) testing in general, and looks at those concerns as they relate to this case.

BRCA-Associated Risk of Prostate Cancer

Prostate cancer is the most common cancer in men and the second leading cause of cancer mortality in men. In 2003, 220 900 new cases were diagnosed in the US, with 28 900 estimated deaths [1]. Approximately 40 percent of aggressive early onset prostate cancers are linked to inherited factors and 5 percent of them to BRCA germline mutations. BRCA1 and 2 mutations, first identified in association with hereditary breast and ovarian cancer, disrupt DNA repair, which results in increased cancer susceptibility in both women and men [2,3].

Carriers of BRCA2 mutations seem to have a 5-fold increase in the risk of prostate cancer, while BRCA1 carriers seem to have about half that risk [4]. The relative penetrance of different BRCA mutations is still unknown, and contradictory clinical findings have been reported, including a recent suggestion that only BRCA2 mutations are associated with an elevated risk of prostate cancer [5]. Not all studies support the association between early onset prostate cancer and BRCA mutations.

Screening and Follow-Up: Recommendations and Controversies

Despite the high incidence and mortality of prostate cancer and the availability of different screening modalities, the efficacy of screening has been questioned. First, empirical evidence is lacking from prospective randomized studies to prove that screening for the mutation translates into a reduction of mortality from prostate cancer. The morbidity and costs of overdiagnosis and overtreatment of well-differentiated or localized tumors are cause for concern, as are the psychosocial "costs" [6,7].

Currently, screening is recommended for men beginning at age 50 and consisting of yearly DRE and measurement of serum PSA concentration, followed by biopsy if necessary. These recommendations also apply to known male carriers of BRCA mutations with screening possibly starting, instead, between the ages of 40 and 45 [8,9]. A large ongoing trial known as IMPACT enrolls men aged 45-69 with a known germline BRCA mutation in a screening program. This study aims to identify men with a high risk of aggressive disease [4].

Ethical Considerations Raised by BRCA Testing

The ethical implications of BRCA testing relate to (1) information and informed consent; (2) rights and responsibilities of the individual, the family, the social community, and the scientific community; (3) confidentiality and privacy; (4) possible discrimination in life and health insurance, the work place, the process of adoption, and access to education; (5) prenatal diagnosis and the risk of eugenics; (6) specific ramifications of BRCA testing in minority and underprivileged populations; and (7) justice and fairness in allocation of genetic resources [10,11]. Not all of these concerns come into play in the case of Mr. Jones, but several do.

Information and genetic responsibility
Mr. Jones's sister's physician requested that he undergo BRCA testing, most likely for his and his family's benefit. Mr. Jones agreed to be tested, but subsequently expressed doubts about his perceived lack of personal benefit from the testing, since his risk of developing cancer remained uncertain. Two main ethical problems are involved in this case: it seems that Mr. Jones was not adequately informed of the limited predictive power of BRCA testing, and he did not receive proper counseling before and after testing.

Genetic information is complex and can be difficult to convey in lay terms. High-risk subjects who are anxious and vulnerable may not fully absorb or understand the process of genetic risk assessment in a single encounter and often overestimate the predictive power of genetic testing. Informed consent should be part of an iterative process of communication between the patient and the doctor and the other health care professionals involved. In the case of genetic testing for cancer susceptibility, additional pre- and post-test counseling is needed, given the complex repercussions of any decision and of any result for the patient and his or her family. The literature on BRCA testing shows that subjects who test negative in a high-risk family may suffer significant psychosocial repercussions related to feelings of guilt and isolation that may also require counseling [12].

Mr. Jones's case also raises the question of whether or not the healthy members of a high-risk family should be encouraged to be tested for the good of other family members. Most would agree that members of a high-risk family or community have moral responsibilities toward other members that extend beyond their own personal interest [13]. In clinical practice, we now often see scattered families coming together to face the possible risk of being BRCA carriers, to help other members interested in their family history gain more information, or just to "be there" for each other.

A high-risk individual may, however, refuse to be tested or refuse to reveal genetic information—a shirking of individual genetic responsibility in the eyes of some [14]. Indeed, for almost any person at risk, the decision-making process is extremely complex, and the physician's role is to be nonjudgmental and to facilitate understanding and communication among all family members. The physician's responsibility vis-à-vis genetic testing is, in fact, also expanding beyond duty to the individual patient to include a duty toward his or her extended community. In the clinical setting it is often difficult to strike a balance between the rights of one person and the rights of other community members.

Uncertainty and trust
As Mr. Jones and Dr. Seelinn realized with great concern, genetic testing precedes, in most instances, the development of effective preventive and therapeutic measures. After testing positive for BRCA, Mr. Jones is left with many uncertainties about his future risks and especially about what to do. His physician correctly chooses a strict clinical and laboratory follow-up for Mr. Jones. Yet Dr. Seelinn does so in the face of major medical uncertainties, which he seems to convey honestly to Mr. Jones.

The uncertainty that follows many instances of genetic testing, as well as the concerns related to potential social and ethical abuses of genetic knowledge, can be very challenging for the patient-doctor relationship. This is especially true in the climate of a patient-doctor relationship that has suffered from growing economic and legal pressures and has come to resemble a marketplace exchange between provider and consumer. As a result the role of trust in medicine has come under scrutiny [15,16]. In my clinical experience, persons involved in genetic testing often express a strong need to trust that the experts are being truthful and also that they are willing and able to advocate on their patient's behalf. This need for trust extends beyond individual relationships to institutions, policy makers, and the media [17].

Conclusion

Genetic knowledge may increase the sense of control over one's life, but it may also shed a dim light on one's future, thus paralyzing the decision-making process. This is the real quandary of genetic testing. We should listen to and respect our patients' different perceptions of whether genetic information provides empowering knowledge or is accepted as a sign of predestination [17].

The influence of genetics on our lives is likely to be much more limited than we tend to believe [18]. Yet, knowing that one is a carrier of a genetic predisposition to cancer involves risks that have a dramatic impact on a person's life. Genetic risk, in fact, entails not only the possibility of developing a future serious illness but also of being forever "asymptomatically ill" in the absence of disease [19]. Mr. Jones, for example, will be subjected from now on to medical tests and possible interventions that may carry substantial economic and emotional costs for him and for the community. He may also experience the psychological and social consequences of being a BRCA mutation carrier that may deeply affect the dynamics of his relationships.

The fundamental question posed by genetic testing is thus whether some degree of knowledge about possible future events helps us or limits us. Genetic information does not come at present with clear answers about what we should do. The worth of genetic testing needs to be evaluated at the individual and community levels and to be balanced against broader medical, psychological, social, and ethical considerations.

References

  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53(1):5-26.
  2. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66-71.
  3. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265(5181):2088-2090.
  4. Edwards SM, Eeles RA. Unravelling the genetics of prostate cancer. Am J Med Genet C Semin Med Genet. 2004;129C(1):65-73.
  5. Kirchhoff T, Kauff ND, Mitra N, et al. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res. 2004;10(9):2918-2921.
  6. Brawley OW. Prostate cancer screening: clinical applications and challenges. Urol Oncol. 2004;22(4):353-357.
  7. Murphy AM, McKiernan JM, Olsson CA. Controversies in prostate cancer screening. J Urol. 2004;172(5 Pt 1):1822-1824.
  8. 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 Genetic Studies Consortium. JAMA. 1997;277(12):997-1003.
  9. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22(4):735-742.
  10. Surbone A. Ethical implications of genetic screening for breast cancer susceptibility. Crit Rev Oncol Hematol. 2001;40(2):149-157.
  11. Harris M, Winship I, Spriggs M. Controversies and ethical issues in cancer-genetics clinics. Lancet Oncol. 2005;6(5):301-310.
  12. The American Society of Clinical Oncology. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility. J Clinic Oncol. 1996;14(5):1730-1736.

  13. Mahowald MB. Genes, Women, Equality. New York, NY: Oxford University Press; 2000.

  14. Rhodes R. Genetic links, family ties, and social bonds: rights and responsibilities in the face of genetic knowledge. J Med Phil. 1998;23(1):10-30.
  15. Surbone A, Lowenstein J. Exploring asymmetry in the relationship between patients and physicians. J Clin Ethics. 2003;14(3):183-188.
  16. Pellegrino ED, Thomasma DC. For the Patient's Good. The Restoration of Beneficence in Health Care. New York, NY: Oxford University Press; 1988.

  17. Surbone A. Balance between science and morality. In: Paradiso A, Surbone A, Muggia F. Controversies in genetic testing predisposition for breast and ovarian cancer screening. Ann Oncol. 2004;15(Suppl):i60-i64.

  18. Murray TH. Genetic exceptionalism and "future diaries": is genetic information different from other medical information? In Genetic Secrets: Protecting Privacy and Confidentiality in the Genetic Era. Rothstein MA, ed. New Haven, Conn: Yale University Press; 1997:60-77.

  19. Billings PR, Kohn MA, de Cuevas M, Beckwith J, Alper JS, Natowicz MR. Discrimination as a consequence of genetic testing. Am J Hum Genet. 1992;50(3):476-482.

Citation

Virtual Mentor. 2006;8(1):10-15.

DOI

10.1001/virtualmentor.2006.8.1.ccas1-0601.

The people and events in this case are fictional. Resemblance to real events or to names of people, living or dead, is entirely coincidental. The viewpoints expressed in this article are those of the author(s) and do not necessarily reflect the views and policies of the AMA.