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Outcome of Preventive Surgery and Screening for Breast and Ovarian Cancer in BRCA Mutation Carriers

From the Clinical Genetics, Breast Cancer Medicine, and Developmental Chemotherapy Services, Department of Medicine; Breast and Gynecology Services, Department of Surgery; and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Kenneth Offit, MD, MPH, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: offitk{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer.

PATIENTS AND METHODS: Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians.

RESULTS: Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker–based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing.

CONCLUSION: This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
GENETIC TESTING PROVIDES new opportunities for the prevention of hereditary cancers. Assuming a one in 345 frequency in the general population in the United States, and a one in 40 frequency in those of Ashkenazi Jewish background, up to 950,000 individuals in the United States carry mutations of the BRCA1 and BRCA2 tumor suppressor genes.^1,2 Approximately 100,000 breast cancer survivors are at risk for subsequent malignancies because of inherited BRCA mutations.^3,4 For BRCA mutation carriers, the risk for early-onset breast cancers is increased up to 20-fold,⁵ and the lifetime risk for ovarian cancer is increased up to nine-fold.⁶ Breast cancer risk is also increased in males with BRCA mutations.⁷ Counseling of families at hereditary cancer risk has included discussion of the presumed but unproven benefit of radiographic, medical, and surgical options for screening and prevention.⁸

In this study, we provide prospective follow-up of both breast and ovarian cancer outcome in a large cohort of individuals with BRCA mutations who were counseled regarding available options for cancer screening and prevention. Using a multimodality approach of physician and self-examination, radiographic screening, and risk-reducing surgery, a high proportion of early-stage malignancies were detected. These results were achieved despite the limited sensitivity and specificity documented for the individual screening modalities used.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Participants
Included in this report are 251 of 267 BRCA1 or BRCA2 mutation carriers identified from 1,865 patients who received genetic test results at Memorial Sloan-Kettering Cancer Center (MSKCC) from June 1, 1995, until October 31, 2000. Two hundred fifteen (86%) of 251 patients were involved at the outset in two institutional review board–approved protocols (one for those of Ashkenazi origin) that provided specific informed consent for prospective follow-up for 10 years. An additional 36 patients were enrolled on other protocols at a time when such specific consent was not deemed necessary for clinical follow-up; these patients have subsequently been approached for consent for continued follow-up. At the time of initial genetic counseling, all patients were asked to provide detailed information regarding personal and family history of cancer.

In accord with New York State law, all patients provided informed consent, including discussion of the risks and benefits, before genetic testing. Counseling also addressed medical and surgical options for screening and prevention. Individuals received recommendations for surveillance and descriptions of prevention options, including risk-reducing surgery.^8-10 Specific recommendations provided to carriers of BRCA mutations are summarized in Table 1. Of 251 patients shown to carry mutations of BRCA1 or BRCA2, 222 (88%) were contacted by telephone by an MSKCC staff member at a median of 8.8 months after receiving genetic test results. Patients were asked to complete a structured phone questionnaire detailing present medical status, current cancer screening practices, and any risk-reducing operations they underwent. After this initial contact, patients were contacted annually by letter and asked to complete a questionnaire updating follow-up information. For 29 patients who did not respond to phone or mailing and who had provided specific informed consent, their primary physician was contacted and asked to provide follow-up information. Self-reported therapeutic and preventative surgical outcomes were confirmed by chart review and review of pathology reports, including all cases diagnosed with breast or ovarian cancer after genetic testing.

Statistical Analysis
Continuous variables were compared using the independent samples t test, and discrete variables compared using the Fisher’s exact test. Age of testing refers to age at receipt of BRCA test results. The Wilcoxon signed-rank test was used to compare pre- and postcounseling screening frequency. In cases where multiple annual follow-up data were available, screening frequency at last follow-up was used in this analysis. The sign test was used to compare the proportion of patients participating in any screening before and after testing. Person-years of follow-up were calculated using the difference between date of last contact and date of results. Analysis was performed on SPSS software (Version 10.0; SPSS, Inc, Chicago, IL). Cancer incidence rates were calculated using the life-table method.¹³ All reported P values are two sided.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The mean age at testing of the 251 individuals with BRCA mutations was 47.7 years (range, 24.1 to 79.0 years). Two thirds of individuals carried BRCA1 mutations and one third carried BRCA2 mutations. At time of testing, 59.4% of individuals had a personal history of breast cancer (Table 2). Additionally, 12 patients (4.8%) had a history of other malignancies, including uterine (three patients), oral cavity (two patients), vulvar, esophageal, papillary thyroid, renal, cervical, unknown primary, or leukemia. For those with a prior diagnosis of cancer, the median time between the prior cancer diagnosis and genetic testing was 4.8 months (range, 0.1 to 39 months).

Risk-Reducing Surgery
At the time of receiving genetic test results, 194 of 233 women had breast tissue at risk. Twenty (8.6%) of 233 had previously undergone risk-reducing mastectomies (RRM), and 19 of 233 had undergone bilateral mastectomies for breast cancer. Of the remaining 194 women, 29 (14.9%) underwent RRM at a median of 5.3 months (range, 0.1 to 34.8 months) after receiving results. Women electing RRM were younger than those not opting for surgery (mean, 43.0 v 46.8 years; P = .015), and had a greater number of breast and ovarian malignancies in first- and second-degree relatives (mean, 2.7 v 2.1 cancers; P = .046). They were not more likely to have had a personal history of breast cancer. Two women were found to have unsuspected DCIS in their RRM specimens (Table 3). In these two women, mammograms obtained within 9 months of surgery were not considered suspicious.

Outcome of Cancer Surveillance
Women not choosing to undergo RRM were advised to undergo clinical surveillance with monthly breast self-examination, clinical breast examination two to four times a year, and annual mammography. Some women, at the discretion of their physician, also received screening breast ultrasound or magnetic resonance imaging (MRI) examinations. With a mean follow-up of 24.1 months (range, 1.6 to 66.0 months), 12 (7.3%) of 165 women were diagnosed with a new primary breast cancer. In six women (five with BRCA1 mutations, one with BRCA2), breast cancer was detected by radiographic surveillance at a mean of 20.2 months after BRCA results transmission (Table 4). Two noninvasive and three invasive cancers were detected by mammography. One case of DCIS was identified by MRI in a woman with an unremarkable mammogram and ultrasound examination. Of the three invasive cancers, all were less than 2 cm. A single lymph node metastasis was identified in a woman with a negative mammogram 16 months prior.

Of 89 patients with ovarian tissue at risk who did not undergo RRSO, ovarian screening data was available on 84. Of these, 62 (73.8%) received ovarian surveillance. Abnormal transvaginal ultrasonograms or CA-125 measurements were noted in 22 of 62 (35.5%) women. Five (22.7%) of 22 were found to have an ovarian or peritoneal malignancy (Table 4). Five patients with abnormal ultrasound and/or elevated CA-125 had surgery that revealed benign findings. In 12 cases, follow-up ultrasonograms (nine cases) or serial CA-125 determinations (three cases) normalized over time and no interventions were required. Including the two cases diagnosed at the time of RRSO in the setting of normal ultrasound and/or CA-125, the sensitivity of ovarian cancer screening by serial ultrasound and CA-125 determination was 71% (five of seven) and the specificity was 90.9% (50 of 55). There were six other cancers detected during follow-up, including melanoma (two patients), oral cavity, lung, pancreas, and metastatic neuroendocrine carcinoma.

Impact of Counseling and Testing on Screening Behavior
For women who did not undergo risk-reducing surgery before testing and who reported pre- and postcounseling screening frequency, there was an overall increase in mean number of mammograms, clinical breast examinations, ovarian ultrasonograms, and CA-125 determinations performed after genetic testing (Table 6). The effect of genetic testing on breast cancer screening was not statistically significant in the subset with prior breast cancer, attributable in part to a high incidence of baseline screening (data not shown). On average, 15 months after BRCA risk notification, 83% of patients were performing breast self-examination, compared with 77% at the time of initial visit (P = .14). Frequency of transvaginal ultrasound examination increased from one every 24 months to one every 9 months, and CA-125 determination frequency increased from once every 2.8 years to once every 10.1 months. Of 143 women with a history of breast cancer at the time of genetic testing, tamoxifen use was reported in 56 and raloxifene use was reported in 10 women. Of 90 women without a history of breast cancer, six initiated tamoxifen and three started raloxifene after counseling.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The current screening and prevention options for individuals at highest hereditary risk for breast and ovarian cancer have presumed but unproven efficacy.^9,10 Retrospective studies have shown that mammography may detect some early-stage cancers in BRCA mutation carriers,¹⁴ and that prophylactic mastectomy,¹⁵ oophorectomy,¹⁶ and/or hormonal chemoprevention^17,18 may be effective in reducing cancer risk. Recently, prospective reports have also compared the efficacy of radiographic screening and preventive surgery in women at hereditary risk for breast cancer.^19-21

The observed 43% sensitivity of radiographic screening for breast cancer (six breast tumors detected radiographically, of 14 in total) is among the lowest reported in a series of women at increased familial risk.^14,19-21 Annual mammograms did not image breast malignancies in six cases, although in three of these the palpable lesions were able to be visualized on preoperative mammograms performed 3 to 9 months after the normal imaging study. The only node-positive tumor (patient no. 145) detected by mammography occurred in the setting of a 16-month interval from prior mammographic examination. Similarly, four of eight tumors detected in a recent trial combining mammography and MRI occurred between annual screening intervals.¹⁹ Although the findings of this and the prior studies may be explained by varying quality of performance or interpretation of radiographic imaging, these interval cancers may represent "kinetic failures" of screening. Decreasing the interval of radiographic screening (eg, to 6 months) may improve the ability to find early-stage tumors in BRCA mutation carriers. This prediction is also consistent with the higher mitotic rates and growth fraction in age-matched BRCA1-linked tumors.²²

Participants with breast cancers detected by radiographic screening were older than those that presented with cancer between radiographic screening intervals. This supports the observation that mammography is less effective in younger women, whose breasts tend to be denser.²³ In one case where mammography failed to image a breast tumor, MRI succeeded, consistent with recent reports in the literature.^20,21,24 The least well documented of breast cancer screening modalities, breast self-examination, was practiced by greater than 75% of women at the time of genetic testing. The importance of this modality of cancer detection is supported by the observation that self-examination after testing led to the diagnosis of five interval cancers, with four of the five tumors lymph node–negative.

Pure intraductal carcinomas, previously reported to be rare in BRCA mutation carriers,²⁴ constituted half of radiographically detected breast cancers in this series. Two additional cases of DCIS were found in 29 RRM procedures, a rate for pure DCIS higher than reported in RRM specimens from women with familial breast cancer.²⁵ Although pure DCIS may be less frequent in BRCA-associated tumors, the existence of DCIS in association with invasive cancers is not uncommon in previously described cases.²⁴ Interestingly, no intraductal tumors were reported in 76 cases of prophylactic mastectomy or eight tumors detected by surveillance in a recent series.¹⁹ In contrast, the finding of a noninvasive phase in a subset of BRCA-associated breast tumors in this and other recent series^20,21 further supports the rationale for screening approaches.

Prior studies have suggested superior sensitivity and specificity of ultrasound and CA-125 screening for ovarian cancer in high-risk compared with average-risk populations.²⁶ The reported specificity of ovarian cancer screening on the basis of a single abnormal ultrasound examination or CA-125 determination was only 22.7%; however, this improved to 90.9% if persistently abnormal tests were considered. The estimated 71% sensitivity of ovarian screening modalities is an overestimate, because it implies knowledge of the true-positive rate in this cohort. In contrast to the very poor sensitivity of annual ovarian screening reported recently,²⁷ the documentation of five early-stage ovarian or primary peritoneal cancers detected by semiannual ultrasound and CA-125 determinations supports the efficacy of this approach in genetically defined high-risk populations. In five cases, however, false-positive ultrasound examinations and/or CA-125 determinations resulted in unnecessary surgical explorations, confirming the limited specificity of these approaches.

The absence of ovarian cancers presenting between surveillance intervals in this series may have been because of the high uptake of risk-reducing oophorectomy in the cohort studied. The finding of two occult ovarian adenocarcinomas in 90 RRSO procedures performed after BRCA testing is somewhat lower than the incidence of two cancers in 50 operations reported in a previous series of women at hereditary risk for ovarian cancer.²⁸ The detection of early-stage ovarian malignancies in this series is consistent with recent reports of a preinvasive phase of BRCA-associated ovarian neoplasia.²⁹ Elective salpingo-oophorectomy may also result in a reduction of future incidence of ovarian¹⁶ and breast cancer³⁰ in those at hereditary risk, although a small number of peritoneal cancers will continue to occur.³¹

This study constitutes the first prospective report of both breast and ovarian cancer screening and preventive surgery in a large cohort of individuals carrying BRCA mutations. The rate of müllerian cancers detected in this series, 32 per 1,000 WY, is higher than the ovarian cancer rate of five to 16 per 1,000 WY predicted for BRCA carriers from retrospective linkage consortium data.^32,33 Similarly, the 41 per 1,000 WY rate of breast cancer in this series is somewhat higher than the rate of 16 to 26 per 1,000 WY predicted from linkage studies.^33,34 However, the incidence rate for breast cancers observed for BRCA carriers in this series is similar to the rate of 33 per 1,000 WY documented in a smaller retrospective study.¹⁴ One explanation for the higher rates observed in this series is the detection of prevalent early-stage cancers in the first year after testing.

Limitations of the study include the relatively short follow-up, the single-institution setting, and the highly motivated nature of the individuals seeking genetic testing services. It is possible that given the strong personal and/or family history of cancer in the study participants, genetic counseling rather than the specific results of genetic testing motivated the observed changes in screening and preventive practices. In addition, for those with a history of a prior cancer, physician recommendations may have motivated screening behavior. The documented increase in ovarian cancer surveillance, as well as the smaller but significant impact on breast cancer screening behavior, supports the rationale for cancer genetic counseling as one component of a preventive oncologic strategy.

Taking into account all modalities of radiographic screening, breast examination, and preventive surgery, 79% of breast cancers diagnosed after BRCA testing were stage I (or stage 0), 21% were stage II, and 0% were stage III/IV, compared with 37% of BRCA-associated breast cancer cases presenting with stage 0/I disease, 51% with stage II disease, and 12% with stage III/IV disease in seven series of 279 BRCA-associated breast cancer cases.^34-40 The rate of lymph node–positive disease detected at screening in this series is identical to the rate of four (21%) of 19 combining two recent MRI screening trials involving 375 patients at hereditary risk for breast cancer.^20,21 Of the five ovarian or fallopian tube cancer cases staged in this series, none were stage III/IV, compared with 61% to 92% stage III/IV in the Surveillance, Epidemiology, and End-Results registry and in a series of consecutively ascertained BRCA-linked ovarian tumors, respectively.^41,42 The single case of primary peritoneal cancer in this series was stage IIC, the least common as well as earliest stage reported for this tumor type.⁴³

The detection of early-stage tumors in this series was achieved despite a low sensitivity of radiographic breast cancer screening and a limited sensitivity and specificity of ovarian cancer surveillance in this high-risk cohort. More frequent mammographic examination, breast ultrasound, and MRI offer potential options to improve sensitivity of breast cancer screening in genetically predisposed individuals. In addition, our results indicate that both ovarian screening as well as risk-reducing salpingo-oophorectomy may lead to the diagnosis of early-stage ovarian cancers in genetically predisposed individuals. Larger prospective trials comparing frequency and modalities of cancer screening as well as the role of risk-reducing operations are necessary to determine optimal management of patients at hereditary risk for these malignancies.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
We are grateful for the special contribution of Amy Finch who assisted in patient follow-up. We acknowledge the contributions, care, and follow-up provided by Robin Baum, MS, Karen Brown, MS, Emily Glogowski, MS, Bruce Haas, MS, Heather Hampel, MS, Judy Hull, MS, Deborah McDermott, MS, Beth Peshkin, MS, Heather Pierce, MS, PhD, Charlene Schulz, MS, and Beth Siegel, MS. We are indebted to Teresa Gilewski, MD, Alexandra Heerdt, MD, and other physicians and nurses at Memorial Hospital. We are grateful to Alice Schluger, MS, Marco Capasso, Jessica Greene, Sabrina Jhanwar, Helen Huang, Archana Minnal, Peter Herndon, and Khedoudja Nafa, PhD, for technical advice and assistance. Finally, we thank Lucy Hann, MD, and Elizabeth Morris, MD, for their critical reading of the manuscript.

	ACKNOWLEDGMENTS

 
Supported in part by grant nos. ACS RP95-10503, DAMD 17-96-6293 (K.O.), and ACS PRTA-38 (M.R.) and by the Society of Memorial Sloan-Kettering Cancer Center, Koodish Fellowship Fund, Lymphoma Foundation, Danziger Foundation, Frankel Foundation, and Breast Cancer Research Foundation.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted August 20, 2001; accepted November 6, 2001.

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