Reducing the Risk of Gynecologic Cancer in the Lynch Syndrome
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《新英格兰医药杂志》
The first description of a kindred with hereditary nonpolyposis colorectal cancer (HNPCC) in 1925 was based on the family history of a woman who later died from endometrial cancer. On the basis of a detailed interview by Michigan pathologist Aldred Scott Warthin with this woman (his seamstress) and with other members of "Family G," Warthin described a large kindred with hereditary colorectal and endometrial cancers.1 Sixty-eight years later, Henry Lynch broadened the spectrum of hereditary cancers in the HNPCC syndrome to include ovarian cancer, transitional-cell cancer of the renal pelvis, and less often, stomach, small-intestine, pancreatic, and other types of cancer.2,3
In this issue of the Journal, Schmeler and colleagues4 report the results of a retrospective study examining the occurrence of endometrial and ovarian cancer in women with the Lynch syndrome and documented germ-line mutations in the mismatch-repair genes MSH2, MLH1, and MSH6 who had undergone prophylactic hysterectomy alone or with bilateral salpingo-oophorectomy, as compared with controls who did not have prophylactic surgery. No endometrial cancers occurred in the 61 women who underwent hysterectomy, whereas endometrial cancers occurred in 69 women of 210 who did not undergo hysterectomy. Similarly, no ovarian or peritoneal cancers were diagnosed in the 47 women who underwent bilateral salpingo-oophorectomy, as compared with ovarian cancers diagnosed in 12 of 223 controls who did not undergo bilateral salpingo-oophorectomy.
Although the evidence to support prophylactic gynecologic surgery in this report appears to be overwhelming — zero endometrial or ovarian cancers observed after risk-reducing surgery — several important caveats must be considered. Because of its retrospective design, the study is vulnerable to important biases. As noted by the authors, 62 percent of the women who underwent risk-reducing surgery had genetic testing for the Lynch syndrome performed after the surgical intervention, and 92 percent of those in the control group with endometrial cancers had genetic testing performed after receiving the diagnosis of endometrial cancer. It is therefore possible that the group who underwent surgery may have preferentially included women with the best outcomes — those who were alive and motivated to seek testing years after surgery. Similarly, control patients may have presented for genetic testing because of the diagnosis of a gynecologic cancer related to the Lynch syndrome. The selective ascertainment in the control group also probably explains why the incidence density of endometrial cancer among the controls was three times greater than previously reported by Lynch and colleagues5 and may lead to an overestimation of the effect of risk-reducing surgery. Similar issues were raised with respect to retrospective studies of risk-reducing surgery for hereditary breast and ovarian cancer published in the Journal and elsewhere.6
As acknowledged by the authors, a decrease in the incidence of endometrial cancer alone may not translate into improved survival, since five-year survival rates are greater than 90 percent for both early-stage sporadic and inherited endometrial cancers.7,8 The documentation of occult (microscopically present but clinically undetected) endometrial cancer in this report (in three patients), and in other case reports,9 may be considered additional evidence to support the use of risk-reducing surgery. However, it could be argued that these occult endometrial cancers might ultimately have been detected at an early stage and therefore surgery was not justified. Indeed, in an overview of more than 25,000 women receiving tamoxifen as part of four trials of breast-cancer chemoprevention, the incidence of endometrial cancer was significantly greater in the group treated with tamoxifen than in controls, but there was no increase in mortality from endometrial cancer among those who received tamoxifen, as compared with controls.10
Another limitation of the study is that the protective effect against ovarian cancer after surgery was not statistically significant, although there was a clear suggestion of benefit. Unlike endometrial cancer, ovarian cancer often is not diagnosed at a curable stage. Although Schmeler and colleagues did not document ovarian cancer in any of the surgical specimens obtained from the women who underwent prophylactic surgery, such cancers may be expected to occur. Indeed, we observed a case of an incidentally diagnosed, stage IA clear-cell carcinoma of the ovary in a woman with a documented MSH2 mutation who was undergoing a therapeutic hysterectomy for a stage IA, grade 2, endometrioid histologic subtype of endometrial cancer (unpublished data). Documentation of other cases of occult ovarian cancer will strengthen the argument for risk-reducing salpingo-oophorectomy in patients with the Lynch syndrome. However, such cases may be quite rare: the incidence of ovarian cancer among women with HNPCC is one third or less of that among women with a BRCA mutation (0.005 per year in patients with HNPCC vs. 0.015 per year at the age of greatest risk in families with a BRCA mutation).11
A striking finding of the present report is that in the control group two thirds of the cases of ovarian cancer and three quarters of those of endometrial cancer were detected at stage I or II. Although the authors did not have information on screening, the favorable stages of the cancers at diagnosis suggest a benefit of close surveillance. This observation is similar to the findings in other large cohorts of HNPCC-mutation carriers.8,12 If gynecologic cancers associated with HNPCC are predominantly at an early stage and curable at the time of detection, the costs of prophylactic surgery (including premature menopause and its sequelae) may outweigh the benefits.
Given all these considerations, what is the recommended care for presymptomatic women with documented mutations in the genes MSH2, MLH1, and MSH6 associated with the Lynch syndrome? In addition to colonoscopic screening beginning by the age of 25 years and continuing as frequently as once per year, such persons should be screened for other associated gastrointestinal and genitourinary tract cancers.13 Women should be offered the possibility of either risk-reducing hysterectomy with bilateral salpingo-oophorectomy or gynecologic surveillance consisting of transvaginal ultrasonographic examinations and measurement of serum CA-125 levels once or twice per year, as well as annual endometrial biopsy — a regimen that may detect premalignant lesions as well as endometrial cancers.14 Given that a substantial fraction of HNPCC-associated gynecologic cancers (17 percent of endometrial cancers and 42 percent of ovarian cancers in this report) are diagnosed by the age of 40 years, it seems reasonable to initiate risk-reduction strategies for gynecologic cancers around the age of 30 years. Because young women with the Lynch syndrome (unlike those with a BRCA-associated predisposition to cancer) do not have an increased risk of breast cancer, there may be greater acceptance of short-term estrogen-replacement therapy after oophorectomy as a means to avoid or minimize the potential sequelae of surgically induced menopause. Data from the Women's Health Initiative suggest that estrogen decreases the risk of colon cancer,15 although this has not been studied in young women genetically predisposed to colon cancer.
The report by Schmeler and colleagues provides the first useful estimate of the efficacy of risk-reducing gynecologic surgery in HNPCC. It should, however, be viewed as a starting point, rather than the culmination of studies addressing the relative risks and benefits of risk-reducing surgery in HNPCC. The final judgment regarding the most appropriate methods for gynecologic risk reduction in HNPCC will await the completion of prospective cohort studies assessing the effect of risk-reducing surgery on both cancer incidence and mortality, as compared with gynecologic screening alone. Such a study is currently in development through the Gynecologic Oncology Group. Pending the availability of more data, risk-reducing hysterectomy in patients with the Lynch syndrome should be discussed as one important option for women seeking to learn from the experience of Warthin's Family G.
Dr. Kauff reports having received fees for legal defense work on behalf of Wyeth. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Memorial Sloan-Kettering Cancer Center, New York.
References
Warthin AS. The further study of a cancer family. J Cancer Res 1925;9:279-286.
Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 1993;71:677-685.
Lynch HT, Lynch JF. Lynch syndrome: history and current status. Dis Markers 2004;20:181-198.
Schmeler KM, Lynch HT, Chem L, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354:261-269.
Watson P, Vasen HF, Mecklin JP, Jarvinen H, Lynch HT. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 1994;96:516-520.
Klaren HM, van't Veer LJ, van Leeuwen FE, Rookus MA. Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 2003;95:941-947.
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
Boks DE, Trujillo AP, Voogd AC, Morreau H, Kenter GG, Vasen HF. Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer 2002;102:198-200.
Pistorius S, Nagel M, Kruger S, et al. Combined molecular and clinical approach for decision making for surgery in HNPCC patients: a report on three cases in two families. Int J Colorectal Dis 2001;16:402-407.
Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003;361:296-300.
Robson ME, Boyd J, Borgen PI, Cody HS III. Hereditary breast cancer. Curr Probl Surg 2001;38:387-480.
Watson P, Butzow R, Lynch HT, et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2001;82:223-228.
Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919-932.
Rijcken FE, Mourits MJ, Kleibeuker JH, Hollema H, van der Zee AG. Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2003;91:74-80.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.(Kenneth Offit, M.D., M.P.)
In this issue of the Journal, Schmeler and colleagues4 report the results of a retrospective study examining the occurrence of endometrial and ovarian cancer in women with the Lynch syndrome and documented germ-line mutations in the mismatch-repair genes MSH2, MLH1, and MSH6 who had undergone prophylactic hysterectomy alone or with bilateral salpingo-oophorectomy, as compared with controls who did not have prophylactic surgery. No endometrial cancers occurred in the 61 women who underwent hysterectomy, whereas endometrial cancers occurred in 69 women of 210 who did not undergo hysterectomy. Similarly, no ovarian or peritoneal cancers were diagnosed in the 47 women who underwent bilateral salpingo-oophorectomy, as compared with ovarian cancers diagnosed in 12 of 223 controls who did not undergo bilateral salpingo-oophorectomy.
Although the evidence to support prophylactic gynecologic surgery in this report appears to be overwhelming — zero endometrial or ovarian cancers observed after risk-reducing surgery — several important caveats must be considered. Because of its retrospective design, the study is vulnerable to important biases. As noted by the authors, 62 percent of the women who underwent risk-reducing surgery had genetic testing for the Lynch syndrome performed after the surgical intervention, and 92 percent of those in the control group with endometrial cancers had genetic testing performed after receiving the diagnosis of endometrial cancer. It is therefore possible that the group who underwent surgery may have preferentially included women with the best outcomes — those who were alive and motivated to seek testing years after surgery. Similarly, control patients may have presented for genetic testing because of the diagnosis of a gynecologic cancer related to the Lynch syndrome. The selective ascertainment in the control group also probably explains why the incidence density of endometrial cancer among the controls was three times greater than previously reported by Lynch and colleagues5 and may lead to an overestimation of the effect of risk-reducing surgery. Similar issues were raised with respect to retrospective studies of risk-reducing surgery for hereditary breast and ovarian cancer published in the Journal and elsewhere.6
As acknowledged by the authors, a decrease in the incidence of endometrial cancer alone may not translate into improved survival, since five-year survival rates are greater than 90 percent for both early-stage sporadic and inherited endometrial cancers.7,8 The documentation of occult (microscopically present but clinically undetected) endometrial cancer in this report (in three patients), and in other case reports,9 may be considered additional evidence to support the use of risk-reducing surgery. However, it could be argued that these occult endometrial cancers might ultimately have been detected at an early stage and therefore surgery was not justified. Indeed, in an overview of more than 25,000 women receiving tamoxifen as part of four trials of breast-cancer chemoprevention, the incidence of endometrial cancer was significantly greater in the group treated with tamoxifen than in controls, but there was no increase in mortality from endometrial cancer among those who received tamoxifen, as compared with controls.10
Another limitation of the study is that the protective effect against ovarian cancer after surgery was not statistically significant, although there was a clear suggestion of benefit. Unlike endometrial cancer, ovarian cancer often is not diagnosed at a curable stage. Although Schmeler and colleagues did not document ovarian cancer in any of the surgical specimens obtained from the women who underwent prophylactic surgery, such cancers may be expected to occur. Indeed, we observed a case of an incidentally diagnosed, stage IA clear-cell carcinoma of the ovary in a woman with a documented MSH2 mutation who was undergoing a therapeutic hysterectomy for a stage IA, grade 2, endometrioid histologic subtype of endometrial cancer (unpublished data). Documentation of other cases of occult ovarian cancer will strengthen the argument for risk-reducing salpingo-oophorectomy in patients with the Lynch syndrome. However, such cases may be quite rare: the incidence of ovarian cancer among women with HNPCC is one third or less of that among women with a BRCA mutation (0.005 per year in patients with HNPCC vs. 0.015 per year at the age of greatest risk in families with a BRCA mutation).11
A striking finding of the present report is that in the control group two thirds of the cases of ovarian cancer and three quarters of those of endometrial cancer were detected at stage I or II. Although the authors did not have information on screening, the favorable stages of the cancers at diagnosis suggest a benefit of close surveillance. This observation is similar to the findings in other large cohorts of HNPCC-mutation carriers.8,12 If gynecologic cancers associated with HNPCC are predominantly at an early stage and curable at the time of detection, the costs of prophylactic surgery (including premature menopause and its sequelae) may outweigh the benefits.
Given all these considerations, what is the recommended care for presymptomatic women with documented mutations in the genes MSH2, MLH1, and MSH6 associated with the Lynch syndrome? In addition to colonoscopic screening beginning by the age of 25 years and continuing as frequently as once per year, such persons should be screened for other associated gastrointestinal and genitourinary tract cancers.13 Women should be offered the possibility of either risk-reducing hysterectomy with bilateral salpingo-oophorectomy or gynecologic surveillance consisting of transvaginal ultrasonographic examinations and measurement of serum CA-125 levels once or twice per year, as well as annual endometrial biopsy — a regimen that may detect premalignant lesions as well as endometrial cancers.14 Given that a substantial fraction of HNPCC-associated gynecologic cancers (17 percent of endometrial cancers and 42 percent of ovarian cancers in this report) are diagnosed by the age of 40 years, it seems reasonable to initiate risk-reduction strategies for gynecologic cancers around the age of 30 years. Because young women with the Lynch syndrome (unlike those with a BRCA-associated predisposition to cancer) do not have an increased risk of breast cancer, there may be greater acceptance of short-term estrogen-replacement therapy after oophorectomy as a means to avoid or minimize the potential sequelae of surgically induced menopause. Data from the Women's Health Initiative suggest that estrogen decreases the risk of colon cancer,15 although this has not been studied in young women genetically predisposed to colon cancer.
The report by Schmeler and colleagues provides the first useful estimate of the efficacy of risk-reducing gynecologic surgery in HNPCC. It should, however, be viewed as a starting point, rather than the culmination of studies addressing the relative risks and benefits of risk-reducing surgery in HNPCC. The final judgment regarding the most appropriate methods for gynecologic risk reduction in HNPCC will await the completion of prospective cohort studies assessing the effect of risk-reducing surgery on both cancer incidence and mortality, as compared with gynecologic screening alone. Such a study is currently in development through the Gynecologic Oncology Group. Pending the availability of more data, risk-reducing hysterectomy in patients with the Lynch syndrome should be discussed as one important option for women seeking to learn from the experience of Warthin's Family G.
Dr. Kauff reports having received fees for legal defense work on behalf of Wyeth. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Memorial Sloan-Kettering Cancer Center, New York.
References
Warthin AS. The further study of a cancer family. J Cancer Res 1925;9:279-286.
Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 1993;71:677-685.
Lynch HT, Lynch JF. Lynch syndrome: history and current status. Dis Markers 2004;20:181-198.
Schmeler KM, Lynch HT, Chem L, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354:261-269.
Watson P, Vasen HF, Mecklin JP, Jarvinen H, Lynch HT. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 1994;96:516-520.
Klaren HM, van't Veer LJ, van Leeuwen FE, Rookus MA. Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 2003;95:941-947.
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
Boks DE, Trujillo AP, Voogd AC, Morreau H, Kenter GG, Vasen HF. Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer 2002;102:198-200.
Pistorius S, Nagel M, Kruger S, et al. Combined molecular and clinical approach for decision making for surgery in HNPCC patients: a report on three cases in two families. Int J Colorectal Dis 2001;16:402-407.
Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003;361:296-300.
Robson ME, Boyd J, Borgen PI, Cody HS III. Hereditary breast cancer. Curr Probl Surg 2001;38:387-480.
Watson P, Butzow R, Lynch HT, et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2001;82:223-228.
Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919-932.
Rijcken FE, Mourits MJ, Kleibeuker JH, Hollema H, van der Zee AG. Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2003;91:74-80.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.(Kenneth Offit, M.D., M.P.)