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© 2001 American Society for Clinical Oncology Effectiveness of Breast Cancer Surveillance in BRCA1/2 Gene Mutation Carriers and Women With High Familial RiskFrom the Family Cancer Clinic (Departments of Medical Oncology, Radiology, and Surgical Oncology), Dr Daniel den Hoed Cancer Center/University Hospital, and Department of Clinical Genetics, Erasmus University, Rotterdam, the Netherlands. Address reprint requests to C.T.M. Brekelmans, MD, PhD, Rotterdam Family Cancer Clinic, Department of Medical Oncology, Dr Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, the Netherlands; email: brekelmans{at}onch.azr.nl
PURPOSE: Women with a high breast cancer risk due to a familial predisposition may choose between preventive surgery and regular surveillance. The effectiveness of surveillance in high-risk women and especially BRCA1/2 mutation carriers is unknown. We present first results from a single large family cancer clinic. PATIENTS AND METHODS: Women with breast cancer risk over 15% were examined by physical examination every 6 months and mammography every year. Detection rates and screening parameters were calculated for the total group and separately for different age and genetic risk groups. RESULTS: At least one examination was performed in 1,198 women: 449 moderate and 621 high-risk women and 128 BRCA1/2 mutation carriers. Within a median follow-up of 3 years, 35 breast cancers were detected (four ductal carcinoma-in-situ; 31 invasive tumors); the average detection rate was 9.7 per 1,000. Detection rates (95% confidence interval) for moderate and high-risk women and BRCA1/2 carriers were 3.3 (1.1 to 8.6), 8.4 (5.4 to 13.2), and 33 (17 to 63) per 1,000 person-years, respectively. The ratio of observed cases versus breast cancers expected in an average-risk population of comparable age was 2.7, 7.0 and 23.7 respectively. Overall, node negativity was 65%; 34% of primary tumors were less than 10 mm; sensitivity was 74%. Results with respect to tumor stage and sensitivity were less favorable in BRCA1/2 carriers and in women under the age of 40. CONCLUSION: It is possible to identify young women at high risk for breast cancer. The number of cancers detected was significantly greater than expected in an age-matched average-risk population and related to the risk category. Overall, screening parameters were comparable to population screening data, with less favorable results in the youngest age group (< 40) and BRCA1/2 carriers.
RANDOMIZED TRIALS and population-based programs have provided evidence that breast cancer screening can be cost effective in women between 50 and 70 years of age.1-4 Although results in women between 40 and 50 are more controversial, it was recently found that screening in this age group can also significantly reduce breast cancer mortality.5 However, in view of the lower incidence of breast cancer and the larger negative screening effects in young women,6 there is no consensus on the cost effectiveness and the desirability of introducing population-based screening programs for women under the age of 50. It might be more efficient to limit screening in women under age 50 to selected groups of high-risk women, such as women with a positive family history of breast cancer.7 The identification of the BRCA1 and BRCA2 genes and the possibility of gene mutation testing has caused an increasing demand from high-risk women for genetic testing and counseling about strategies to reduce their risk of breast cancer death. One of the options is intensive surveillance. Because for ethical reasons no randomized trials in genetically susceptible women are to be expected, the effects of surveillance in these women must be evaluated by means of observational studies. To date, a limited number of studies describing experiences and preliminary results of surveillance in women with a family history of breast cancer have been published.8-11 In this combined retrospective and prospective follow-up study, we describe the first results of surveillance in proven BRCA1/2 gene mutation carriers in addition to women with a family history of breast cancer at the Rotterdam Family Cancer Clinic. Our study sample was large enough to allow subgroup analyses for age and genetic risk group: BRCA1/2 gene mutation carriers and women with high or moderate familial risk. To our knowledge, thus far, no separate screening results for proven BRCA1/2 carriers have been published before. A range of screening parameters was calculated and compared with characteristics of breast screening programs and cancer registry data.
In several specialized centers in the Netherlands, women with a more than two times increased breast cancer risk because of a family history are offered regular surveillance. At our institution, a small group of women with familial risk have been screened since 1978, with rapidly increasing numbers in the 1990s. The screening procedure consists of instructions for monthly breast self-examination, yearly mammography, and clinical breast examination (CBE). This last procedure is generally performed every 6 months except in some moderate-risk women who had a yearly screening interval in the early days of the program. Since 1995, magnetic resonance imaging (MRI) is optionally included in the surveillance program in case of dense mammographic breast tissue and/or BRCA1/2 gene mutation carriership. When indicated, additional investigation by ultrasound with or without fine-needle aspiration is performed. The minimum age of entry onto the surveillance program is generally 25 years, or younger in women from families with a young age at onset. The general protocol was approved by the medical ethical committee (project DDHK 91-17).
Data Collection and Statistics We calculated detection rates of cancers found at the first or subsequent examination as well as the rates of cancers occurring in the interval between two examination rounds, so-called interval cancers. Person-years of risk were calculated from the date of the first examination to the end point of interest: the date of detection of breast cancer (at surveillance or in the interval between two examinations), date of bilateral preventive mastectomy (occurred in 65 women, of whom 52 were proven carriers), or the end of the study period (January 1, 2000). 95% Confidence intervals were computed assuming a Poisson distribution. Observed numbers of invasive breast cancer were compared with expected numbers based on National Cancer Registry data12; detection rates and stage distribution were compared with national and international breast screening programs. Sensitivity of the screening test was calculated as the ratio of breast cancers detected by surveillance divided by the total number of breast cancers (screen-detected plus interval cancers).13,14
Population and Screening Characteristics At least one examination was performed at the Dr Daniel den Hoed Cancer Center in 1,198 women with high familial risk, their mean age at first surveillance being 38 years (age range, 21 to 70 years). For 399 women, it was the first examination; for 386 women, screening was done previously in another hospital; and for 413 women, information regarding previous screening examinations elsewhere was missing. By means of DNA testing or genetic-epidemiologic tables,15 three genetic risk groups were defined: 128 carriers of a BRCA1- (n = 113) or BRCA2- (n = 15) gene mutation (group 1) and women with a high (group 2; n = 621) or moderate (group 3; n = 449) lifetime risk of breast cancer. In Table 1, inclusion criteria and mean age at the first visit for the three subgroups are shown.
With a median follow-up period of 3.0 years (range, 0 to 22 years), 35 breast tumors (including four ductal carcinomas-in-situ [DCIS]) were detected. With the total number of follow-up years being 3,607, the average breast cancer detection rate (invasive breast cancer and DCIS) was 9.7 per 1,000; excluding DCIS, it was 8.6 per 1,000 person-years. Twenty-six of the 35 tumors were detected at screening (three at the first examination and 23 at a subsequent examination), making the rate of screen-detected cancers 7.2 per 1,000. Nine cancers were detected in the interval between screens (interval cancer rate 2.5 per 1,000). The time interval from the last negative screen until diagnosis ranged from 8 weeks to 10 months. Four cancers, diagnosed at the time of the scheduled surveillance visit, were already symptomatic: these women had experienced symptoms for several weeks or months without calling in for an earlier check-up, as had been advised to them. The mode of diagnosis of the 26 screen-detected cancers was as follows: 12 cancers were not palpable at the time of detection and found by mammography (n = 9) or MRI (n = 3): in one case, MRI was used as a screening modality instead of mammography because of dense breast tissue; in the two other cases (proven BRCA1 carriers), MRI was alternated with mammography (every 6 months). Twelve cases were detected by CBE and mammography, one case by CBE and MRI (a BRCA1 carrier), and one by clinical examination only.
Relationship With Risk and Age Categories
In Table 3, observed and expected numbers of invasive breast cancer are presented per age category. Detection rates varied from 3.6 (1.9 to 7.2) per 1,000 in women under the age of 40 years to 11.8 (6.6 to 21.1) per 1,000 in the age group 40 to 49 years and 26.1 (15.1 to 45.7) per 1,000 in women older than 50 years of age: a clear trend of an increasing detection rate with age, due to the rising incidence of breast cancer with age. Again, 95% confidence intervals partly overlapped. The ratio of observed versus expected breast cancer cases was 5.6 (0.9 to 33.4) in women under the age of 40, 6.2 (1.3 to 29.7) in the age group 40 to 49 years, and 9.8 (1.5 to 62.2) in women over the age of 50.
Tumor Characteristics at Diagnosis and Sensitivity In Tables 4 and 5, tumor and screening characteristics are described for the total group and separately per risk group (Table 4) and age group ( Table 5). Overall, four (11%) of the 35 breast tumors were DCIS. All cases of DCIS were detected in women over the age of 50, being part of the high-risk subgroup. Histology of the 31 invasive tumors was as follows: 28 were ductal, two were lobular invasive, and one was medullary. Ten (34%) of 29 invasive tumors with known tumor size were smaller than 10 mm, eight (28%) were between 10 and 15 mm, and 11 (38%) were greater than 15 mm (range, 16 to 40 mm). The size of two invasive tumors was missing because of multifocality (one case) or ill-defined border (one case).
Twenty (65%) of 31 invasive tumors were node-negative and 11 (35%) were node-positive. Two (66%) out of three cancers detected at the prevalent screen were node-positive, but this was 31% (six of 19) of the incident screen-detected and 33% (three of nine) of the interval cancers, respectively. Risk group– and age-specific results showed high node positivity, especially in proven carriers and the youngest age group: 56% (five out of nine) of the invasive tumors in carriers already node-positive and 62% (five out of eight) of the tumors in women under the age of 40. Differences between the subgroups were not significant. The overall sensitivity of the screening test was 74% (26 of 35), including the four symptomatic screen-detected tumors in the numerator, or 63% (22 of 35) excluding these four tumors from the numerator. Although insignificant, a remarkable difference in sensitivity between risk groups was seen, as interval cancers were detected especially in proven carriers, rendering a low sensitivity (56%) in this subgroup. This might not (only) be due to their young age: although age-specific results showed, as expected, an increasing sensitivity with age of 63% in the youngest age group, 73% in the age group 40 to 49, and 81% in the oldest age group (Table 5), sensitivity in the youngest age group increased to 100% (four of four cases) when proven carriers in this age group were excluded (results not shown because of small numbers).
Follow-Up
Nowadays, a number of countries, including the Netherlands, offer the opportunity of selective breast cancer surveillance to women with a family history of breast cancer. The current policy in 16 European Family Cancer Clinics was recently reviewed by Vasen et al.16 Current surveillance modalities are breast self-examination, clinical examination, and mammography. MRI is performed only in research settings. Most clinics recommend a mammographic examination every year instead of every 2 years, as the growth rate is higher and the mammographic visibility of breast tumors lower in younger women.17,18 There is no consensus on the minimum age at entry: mammography generally is performed for the first time at age 25 to 35 or 5 to 10 years younger than the youngest affected relative in case of young age at onset (< 30 to 35 years). In Tables 6 and 7, characteristics and first preliminary results of published surveillance projects in genetically susceptible women in different countries are presented. Although inclusion criteria and minimum age at entry vary between countries and centers, detection rates are uniformly similar or even higher than in population screening programs aimed at women aged 50 to 70.8-11,19-21
Our results and those of others thus show that it is clearly possible to identify young women at high familial risk: the number of breast cancers detected in our population was on average seven times greater than expected in an average-risk population of comparable age. Our study sample was large enough and the follow-up period long enough to calculate age-specific screening parameters and results for three separate genetic risk groups: proven BRCA1/2 carriers and women with a high or moderate familial risk of breast cancer. With respect to detection rates, we found, as expected, clear trends with age and genetic risk groups. The overall sensitivity found in our study was 74%, which is comparable to the results of the Dutch Breast Screening Programme.22 As expected, a trend of increasing sensitivity with age was seen. With respect to risk group, a low sensitivity was found in the group of proven BRCA1/2 carriers: four out of nine cases detected in this group were interval cancers. Although this result is based on small numbers and awaits confirmation by others, it might be that this reflects a true characteristic of BRCA-associated tumors. Although the true sensitivity of screening (the number of missed cases) is a theoretical parameter that cannot be measured, there are several methods to approximate this.13,14 In our study, "sensitivity" was estimated by the number of cancers appearing between screens. This group of so-called interval cancers consists not only of missed cancers, caused for instance by poor mammographic visibility, but also of incident tumors with a high tumor growth rate. In BRCA1 carriers, there are indications for both possibilities: mammographic visibility might be lower in these women,23 and histopathologic studies have found a consistently higher proliferation rate, a marker for growth rate, in BRCA1 carriers.24,25 Nevertheless, we found no differences in disease-free and overall survival between women with BRCA1/2-associated and sporadic tumors matched for age and year of diagnosis.26,27 The percentage of DCIS found in our study (11%) was also comparable to that of the Dutch Breast Screening Programme. Most "high-risk" surveillance studies find a higher percentage of DCIS, which is to be expected, as DCIS is generally found more often in younger women,18 with the possible exception of proven carriers of a BRCA1 mutation.28 This last observation might explain why in our study no cases of DCIS were found in women under the age of 50, an age group that includes a high percentage of BRCA1/2 carriers. The overall percentage of tumors with positive lymph nodes was 35% (11 of 31), whereas this was 31% (six of 19) in cancers detected at an incident screening round. This last percentage is comparable to the Dutch National Breast Screening Programme4 and within the acceptable level suggested for population screening programs in women over the age of 50.29 Although it is important to use population-based standards to monitor surveillance results in women with a positive family history, for a valid comparison it is also useful to compare screening results, such as node positivity to symptomatic tumors in familial breast cancer patients, as it might be that the natural history and tumor characteristics differ from those of sporadic breast cancer patients.30,31 Kollias et al9 found no differences between screened and symptomatic women (matched for age and family history) with respect to invasive tumor size, grade, or lymph node stage, whereas Tilanus-Linthorst et al21 found a more favorable tumor stage in "high-risk" women screened within a breast clinic as compared with a symptomatic group of comparable age and a positive family history. Especially with respect to lymph node status, other surveillance studies of high-risk women show a large variability, ranging from 10% to 45% node positivity ( Table 7). Reasons for these varying results might be different population characteristics, such as age range and percentage of genetically susceptible women, or screening schemes and modalities (Table 6).
Although the average node-positivity rate in our study was 35%, there were differences between the three risk categories and age groups: in the groups of proven carriers and women under the age of 40 (categories that partly overlapped), 56% and 62%, respectively, already were node-positive. There are indications from other studies that breast cancer in young patients might be more aggressive than in older patients.32,33 For instance, in a population of 136 clinically diagnosed patients from Nijmegen, 42% of the cases under the age of 50 with a tumor smaller than 1 cm already had positive lymph nodes, whereas this was 15% in patients in the age group 50 to 69.33 It seems, therefore, that to reduce breast cancer mortality in these young women, a substantial proportion of small cancers has to be detected. In conclusion, in BRCA1/2 mutation carriers, the highest cancer detection rates and observed-expected ratio were found, as well as the lowest sensitivity in addition to a relatively unfavorable tumor stage at diagnosis. Especially in this group and in women under the age of 40, a more intensive screening scheme might be warranted. Alternatively, the current screening methods, such as mammography and CBE, might be insufficiently effective in preventing death of breast cancer. New technologies, such as MRI, might offer better possibilities. In several countries, including the Netherlands, studies were recently started that will evaluate the value of MRI in the early detection of breast cancer in high-risk women.34,35
Supported by grant no. DDHK 95-953 from the Dutch Cancer Society.
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ABSTRACT
INTRODUCTION
