乳癌基因檢測之臨床應用與倫理考量

Clinical Utilization and Ethical Considerations of Breast Cancer Genetic Testing

10.3966/168395442015121503003

陳秋慧(Chiu-Hui Chen)

乳癌易感基因 ； 基因檢測 ； 乳癌風險降低策略 ； BRCA (Breast cancer susceptibility gene) ； Genetic testing ； Breast cancer riskreducing strategies

腫瘤護理雜誌

15卷增訂刊（2015 / 12 / 01）

15 - 30

繁體中文

BRCA 1與BRCA 2具有修補DNA及調控細胞生長週期的重要功能，此二基因的突變帶原者被發現終其一生其罹患乳癌的機會可高達80%以上。BRCA 1/2基因的突變甚少發生於一般人，而是與人種和家族有關。因此，BRCA1/2的基因檢測並不被列於一般常規檢驗項目，而只建議用於乳癌高風險族群。檢測結果的判斷，必須根據被檢者的乳癌風險評估資料；檢測的結果不僅代表著個人罹患乳癌的可能性，更影響著個人及家族未來的健康醫療計畫。結果的告知極可能引發受檢者對罹患乳癌的焦慮與害怕。故基因檢測需要一個嚴謹的、持續性的、多次性的諮詢過程，以達到正確危險因子評估，詳實的訊息告知，並藉此支持被檢者選擇最適合的乳癌風險降低策略。目前被認為有利於降低乳癌風險的策略有四；1.良好的生活型態；2.定期篩檢；3.預防性藥物處置，例如：Tamoxifen或Raloxifene；4.預防性乳房／卵巢手術切除。其中藥物性處置和外科切除手術，已被報告可大幅度減少乳癌發生機率；但是，這些正面效益的報告多不是來自隨機分派臨床試驗。更重要的是，不論是藥物使用或手術的執行皆有可能發生短期的合併症或長期副作用的危險。乳癌基因資訊的揭發和風險降低策略的執行所帶來的利與弊，不僅是醫療處置的討論，更牽涉著對醫療倫理包括良善與不傷害、自主以及隱私權保護原則的挑戰，是身為醫護人員的我們不可忽略的重要臨床議題。

The genes of BRCA 1 and BRCA 2 play an essential role in DNA repair and cell cycle regulation. Mutation of these two genes is associated with an 80% lifetime risk of developing breast cancer. BRCA 1/2 gene mutation rarely occurs in general population, but is race and family related. Thus, genetic testing of BRCA1/2 mutation is not considered as routine test. Instead, it is recommended for high-risk groups for breast cancer. Understanding of the breast cancer risk factors in the particular individual is a crucial basis in the interpretation of testing results, for the results not only disclose the possibility of developing breast cancer, but also the need for future plans of the subject as well as his /her family regarding their healthcare. This information, undoubtedly, can cause a certain degree of anxiety and fear for the subject and the family. Consequently, genetic counseling sessions are needed in order to achieve a comprehensive assessment of risk factors, provision of accurate information, and to support and help the subject to choose the best risk-reducing strategies. Four strategies have been recommended to reduce the risk of developing breast cancer: 1. Life style modification, 2. Screening, 3. Prophylactic pharmacological interventions, e.g.: Tamoxifen or Raloxifen, and 4. Prophylactic surgery. Among these, pharmacological interventions and surgery have been proven to significantly reduce the risk of breast cancer. Nevertheless, majority of the evidences are not reported from randomized controlled trials. Furthermore, both medical and surgical strategies may result in acute complications or long term adverse effects. The pros and cons of uncovering the genetic information and formulating risk-reducing strategies do not just mean a simple discussion of medical treatment, but also post a medical ethics challenge including beneficence and do no harm, respect for autonomy, privacy and so on. As healthcare providers, these issues must be taken into consideration when we encounter patients with breast cancer.

1. 蔡昌甫, D.F.C.,朱宜康, I. K.,黃天祥(2007)。遺傳檢測與諮詢的倫理議題與職業準則—罹病傾向之遺傳檢測：以BRCA檢驗為例．。醫學教育，11(1)，69-88。
   連結：
2. Altschuler, A.,Nekhlyudov, L.,Rolnick, S. J.,Greene, S. M.,Elmore, J. G.,West, C. N.,Geiger, A. M.(2008).Positive, negative, and disparate-women’s differing long-term psychosocial experiences of bilateral or contralateral prophylactic mastectomy.The Breast Journal,14(1),25-32.
3. Balmana, J.,Diez, O.,Rubio, I. T.,Cardoso F.(2011).BRCA in breast cancer: ESOM clinical practice guidelines.Annals of Oncology,22(supplement 6),v131-v134.
4. Barton, M. B.,West, C. N.,Liu, I. A.,Harris, E. L.,Rolnick, S. J.,Elmore J. G.,Geiger, A. M.(2005).Complications following after bilateral prophylactic mastectomy.Journal of the National Cancer Institute Monographs,35,61-66.
5. Bensam, M.,Hafez, E.,Awad, D.,El-Saadani, M.,Balbaa, M.(2014).Detection of new point mutation of BRCA 1 and BRCA 2 in breast cancer patients.Biochem Genet,52,15-28.
6. Blay, P.,Santamaría, I.,Pitiot, A. S.,Luque, M.,Alvarado, M. G.,Lastra, A.,Balbín, M.(2013).Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain).BMC Cancer,13,243.
7. Chai, X.,Friebel, T. M.,Singer, C. F.,Evans, D. G.,Lynch, H. T.,Issacs, C.,Rebbeck, T. R.(2014).Use of risk reducing surgeries in a prospective cohort of 1.499 BRCA 1 and BRCA 2 mutation carriers.Breast Cancer Treatment,148,397-406.
8. Chen, S.,Parmigiani, G.(2007).Meta-analysis of BRCA 1 and BRCA 2 penetrane.Journal of Clinical Oncology,25,1329-1333.
9. Cohen, J. V.,Chiel, L.,Boghossian, L.,Jones, M.,Stopher, J. E.,Powers, J.,Domchek, S. M.(2012).Non-cancer endopoints in BRCA1/2 carrier after risk –reducing salpingooophorectomy.Familial Cancer,11,69-75.
10. DMedEth, M. T.(2012).Autonomy and reason: Treatment choice in breast cancer.Journal of Evaluation in Clinical Practice,18,1045-1050.
11. Domchek, S. M.,Eisen, A.,Calzone, K.,Stopfer, J.,Blackwood, A.,Weber, B. L.(2003).Application of breast cancer risk prediction models in clinical practice.Journal of Clinical Oncology,21,593-601.
12. Domchek, S. M.,Friebel, T. M.,Singer, C. F.,Evans, D. G.,Lynch, H. T.,Isaacs C.,Rebbeck, T. R.(2010).Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.Journal of American Medical Association,304(9),967-975.
13. Eisen, A.,Lubinski, J.,Klijn, J.,Moller, P.,Lynch, H. T.,Offit, K.,Narod, S. A.(2005).Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation Carriers: An international case-control study.Journal of Clinical Oncology,23(30),7491-7496.
14. Eisinger, F.(2007).Prophylactic mastectomy: Ethical issues.British Medical Bulletin,81 & 82,7-19.
15. Evans, J. P.,Skrzynia, C.,Susswein, L.,Harlan, M.(2006).Genetics and the young woman with breast cancer.Breast Disease,23,17-29.
16. Fackenthal, J. D.,Olopade, O. I.(2007).Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations.Nature Review,7,937-948.
17. Fisher, B.,Constantino, J. P.,Wickerham, D. L.,Redmond, C. K.,Kavanah, M.,Cronin, W. M.,Wolmark, N.(1998).Tamoxifen for prevention of breast cancer: Report of the national surgical adjuvant breast and bowel project P-1 study.Journal of Cancer Institute,90(18),1371-1388.
18. Genetic test queues generated by Angelina Jolie (2014, April). ScienceNordic. Retrieved from http://sciencenordic.com/genetic-test-queuesgenerated-angelina-jolie
19. Gopie, J. P.,Mureau, M. A. M.,Seynaeve, C.,Kuile, M. M.,Menke-Pluymers, M. B. E.,Tibben, A.(2013).Body image issues after bilateral prophylactic mastectomy with breast reconstruction in healthy women at risk for hereditary breast cancer.Familial Cancer,12,479-487.
20. Gronwald, J.,Robidoux, A.,Kim-Sing, C.,Tung, N.,Lynch, H. T.,Foulkes, W. D.,Narod, S. A.(2014).Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.Breast Cancer Research Treatment,146,421-427.
21. Josko, D.(2014).Personalized medicine and ethics.Clinical Laboratory Science,27(3),185-190.
22. Juarez, A., Ramos, J., Leony, D., & Fiscal, A. (2007). Ethical elements in contemporary health care. Retrieved from http://cstep.cs.utep.edu/research/ezine/Ezine-EthicalElementsinContemporaryHealthCare.pdf
23. Kenkhuis, M. J. A.,de Bock, G.,Elferink, P. Q.,Arts, H. J. C.,Oosterwijk, J. C.,Jansenc, L.,Mourits, M. J. E.(2010).Short-term surgical outcome and safety of risk reducing salpingooophorectomy in BRCA1/2 mutation carriers.Maturitas,66,310-314.
24. King, M. C.,Marks, J. H.,Mandel, J. B.(2003).Breast and ovarian cancer risks due to inherited mutation in BRCA 1 and BRCA 2.Science,302,643-646.
25. King, M. C.,Wieand, S.,Hale, K.,Lee, M.,Walsh, T.,Owens, K,Fisher, B.(2001).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.The Journal of American Medical Association,286(18),2251-2256.
26. Knoppers, R. M.(2014).From the right to know to the right not to know.Journal of Law, Medicine, & Ethics,42(1),6-10.
27. Kuo, W. H.,Lin, P. H.,Huang, A. C.,Chien, Y. H.,Liu, T. P.,Lu, Y. S.,Chang, K. J.(2012).Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer.Journal of Human Genetics,57,130-138.
28. Lalloo, F.,Evans, D. G.(2012).Familial breast cancer.Clinical Genetics,82,105-114.
29. Lucas, D. J.,Sabino, J.,Shriver, C. D.,Pawlik, T. M.,Singh, D. P.,Vertrees, A. E.(2015).Doing more: Trends in breast cancer surgery, 2005-2011.The American Surgeon,81,74-80.
30. Mahon, S. M.,Crecelius, M. E.(2013).Practice considerations in providing cancer risk assessment and genetic testing in women’s heath.Journal of Obstetric, Gynecologic, & Neonatal Nursing,42,274-286.
31. Mai, P. L.,Loud, J. T.,Greene, M. H.(2014).A major step forward for BRCA1/2 –related cancer risk management.Journal of Clinical Oncology,32,1531-1533.
32. Meiser, B.,Gaff, C.,Julian-Reynier, C.,Biesecker, B. B.,Esplen, M. J.,Vodermaier, A.,Tibben, A.(2007).International perspectives on genetic counseling and testing for breast cancer risk.Breast Disease,27,109-125.
33. Metcalfe, K.,Lynch, H. T.,Ghadirian, P.,Tung, N.,Olivotto, I.,Warner, E.,Narod, S. A.(2004).Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.Journal of Clinical Oncology,22(12),2328-2335.
34. Mor, P.,Oberle, K.(2008).Ethical issues related to BRCA gene testing in Orthodox Jewish women.Nursing Ethics,15(4),512-522.
35. Moyer, V. A.(2014).Risk assessment, genetic counseling, and genetic testing for BRCArelated cancer in women: U.S. preventive services task force recommendation statement.Annals of Internal Medicine,160(4),271-281.
36. NCCN. (2015). NCCN Guideline version 2.2015, Genetic/Familial high –risk assessment: Breast and ovarian. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf
37. Nelson, H. D.,Pappas, M.,Zakher, B.,Mitchell, J. P.,Okinaka-Hu, L.,Fu, R.(2014).Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: A systematic review to update the U.S. preventive services task force recommendation.Annals of Internal Medicine,160(4),255-266.
38. Olopade, O. I.,Artioli, G.(2004).Efficacy of risk reducing salpingo-oophrectomy in women with BRCA-1 and BRCA-2 mutation.The Breast Journal,10(Supplement 1),S5-S9.
39. Paradiso, A.,Formenti, S.(2011).Hereditary breast cancer: Clinical features and risk reduction strategies.Annals of Oncology,22(Supplement 1),i31-i36.
40. Pena-Salcedo, J. A,Soto-Miranda, M. A.,LopezSalguero, J. F.(2012).Prophylactice mastectomy: Is it worth it?.Aesthetic Plastic Surgery,36,140-148.
41. Phillips, K. A.,Milne, R. R.,Rookus, M. A.,Daly, M. B.,Antoniou, A. C.,Peock, S.,Hopper, J. L.(2013).Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.Journal of Clinical Oncology,31(25),3091-3099.
42. Rebbeck, T. R.,Friebel, T.,Lynch, H. T.,Neuhausen, S. L.,Veer L,Garber, J. E.,Weber, B. L.(2004).Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group.Journal of Clinical Oncology,22(6),1055-1066.
43. Salhab, M.,Bismohun, S.,Mokbel, K.(2010).Risk-reducing strategies for women carrying brca1/2 mutation with a focus on prophylactic surgery.BMC Women’s Health,10(28),1-10.
44. Stan, D. L.,Shuster, L. T.,Wick, M. J.,Swanson, C. L.,Pruthi, S.,Bakkum-Gamez, J. N.(2013).Challenging and complex decision in the management of the BRCA mutation carrier.Journal of Women’s Health,22(10),825-833.
45. Surbone, A.(2011).Social and ethical implications of BRCA test.Annals of Oncology,22(Supplement 1),i60-i66.
46. Tirona, M. T.(2013).Breast cancer screening update.American Family Physician,87(4),274-278.
47. Tirona, M. T.,Sehgal, R.,Ballester, O.(2010).Prevention of breast cancer (part II): Risk reduction strategies.Cancer Investigation,28,1070-1077.
48. Tirona, M. T.,Sehgal, R.,Ballester, O.(2010).Prevention of breast cancer (part I): Epidemiology, risk factors, and risk assessment tools.Cancer Investigation,28,743-750.
49. Trentham-Dietz, A.,Sprague, B. L.,Hampton, J. M.,Miglioretti, D. L.,Nelson, H. D.,Titus, L. J.,Newcomb, P. A.(2014).Modification of breast cancer risk according to age and menopausal status: A combined analysis of five population-based case–control studies.Breast Cancer Research Treatment,145,165-175.
50. Turner, N.,Tutt A.,Ashworth, A.(2004).Hallmarks of ‘BRCAness’ in sporadic cancers.Nature Reviews,4,1-6.
51. Valachis, A.,Nearchou, A. D.,Lind, P.(2014).Surgical management of breast cancer in BRCA-mutation carriers: A systemic review and meta-analysis.Breast Cancer Research Treatment,144,443-455.
52. Vig, H. S.,Wang, C.(2012).The evolution of personalized cancer genetic counseling in the era of personalized medicine.Familial Cancer,11,539-544.
53. Visvanathan, K.,Hurley, P.,Bantug, E.,Brown, P.,Col, N. F.,Cuzick, J.,Lippman, S. M.(2013).Use of pharmacologic interventions for breast cancer risk reduction: American society of clinical oncology clinical practice guide.Journal of Clinical Oncology,31,1-22.
54. Vogel, V. G.,Costantino, J. P.,Wickerham, D. L.,Cronin, W. M.,Cecchini, R. S.,Atkins, J. N.,Pajon, E. R.(2010).Update of he national surgical adjuvant breast and bowel project study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer.Cancer Prevention Research,3(6),696-706.
55. World Health Organization. (2015). Medium center: Cancer. Retrieved from http://www.who.int/mediacentre/factsheets/fs297/en/
56. Yip, C. H.,Taib, N. A.,Choo, W. Y.,Rampal, S.,Thong, M. K.,Teo, S. H.(2009).Clinical and pathologic differences between BRCA1-, BRCA2-, and Non-BRCA-associated breast cancers in a multiracial developing country.World Journal of Surgery,33,2077-2081.
57. Zagouri, F.,Chrysikos, D. T.,Sergentanis, T. N.,Giannakopoulou, G.,Zografos, C. G.,Papadimitriou, C. A.,Zografos, G. C.(2013).Prophylactic mastectomy: An appraisal.The American Surgeon,79(2),205-212.
58. 吳啟明,黃燦龍,謝玲玲(2003)。BRCA 1 及BRCA 2與乳癌。當代醫學，30(1)，63-65。
59. 衛生福利部（2015 年，2 月 ）．乳癌高峰約在45-69歲早發現早治療存活率9成以上104年衛生福利部新聞．取自http://www.mohw.gov.tw/cht/ministry/DM2_P.aspx?f_list_no=7&fod_list_no=5309&doc_no=48411