ARTICLE

Familial Risk of Cancer Shortly After Diagnosis of the First Familial Tumor

J. Lorenzo Bermejo, Kari Hemminki

Affiliations of authors: Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany (JLB, KH); Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden (KH)

Correspondence to: J. Lorenzo Bermejo, PhD, Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany (e-mail: J.Lorenzo{at}dkfz.de).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background: The diagnosis of the first cancer in a family may lead to the medical examination of the patient's relatives and the subsequent identification of additional familial cancers. If detection bias is present, familial risks could be overestimated soon after first diagnosis. Methods: We followed 1 677 722 offspring/siblings of 846 448 probands from the year of diagnosis of the first familial tumor to the diagnosis of first cancer, death, emigration, or December 31, 2002, using the Swedish Family Cancer Database. The risks of cancer among the offspring and siblings of patients with melanoma and cancers of the breast, prostate, colorectum, cervix, and lung were compared with those in the general population. Relative risks (RRs) were determined using Poisson regression, according to the time after first diagnosis. All statistical tests were two-sided. Results: Daughters of women with breast cancer had a statistically significantly higher relative risk of in situ breast cancer during the year of the mother's diagnosis than they did 5 or more years later (RR = 4.78, 95% confidence interval [CI] = 2.16 to 10.6, 26.6 cases per 100 000, versus RR = 1.97, 95% CI = 1.65 to 2.37, 27.2 cases per 100 000; P = .033). Daughters diagnosed the same year as their mothers were younger and were diagnosed earlier in the calendar year than daughters of women diagnosed 5 or more years after their mothers. Similarly, the risk of invasive melanoma among the offspring of individuals with invasive melanoma was higher during the year of the parent's diagnosis than it was 5 or more years afterward (RR = 8.27, 95% CI = 3.82 to 17.9, 57.0 cases per 100 000, versus RR = 3.18, 95% CI = 2.55 to 3.97, 37.6 cases per 100 000; P = .019). Sibling risks of in situ breast cancer, in situ cervical cancer, and invasive prostate cancer also decreased with time after diagnosis of the first familial tumor. Conclusions: Increased surveillance may result in the earlier detection of asymptomatic familial cancers, i.e., in detection bias. The possibility of overestimated familial risks of cancer shortly after diagnosis of the first familial tumor should be considered before a patient's clinical and genetic counseling is implemented.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Accurate estimates of the risk of cancer among relatives of affected patients are essential for genetic counseling (1), and familial risks may also help to identify environmental and heritable factors that are associated with increased risks of specific cancers, leading to cancer prevention strategies (2,3). Familial clustering may be caused not only by shared genetic or environmental factors but also by the availability of screening methods that permit the detection of cancer in the preclinical state, e.g., mammography for breast cancer or prostate-specific antigen (PSA) testing for prostate cancer (4,5).

The diagnosis of cancer in a family raises concern in the patient's relatives, who may seek medical advice. Routine screening of these relatives could result in subsequent detection of asymptomatic tumors. Some of the new cancers would have been undetected if the first familial cancer had not been diagnosed because the individual would have died of other causes prior to the onset of clinical disease. This phenomenon is known as surveillance/detection bias. Better surveillance of individuals with affected relatives could result in overestimated familial relative risks (RRs), especially soon after the diagnosis of the first cancer in the family (610).

The objective of this study was to assess the possible role of surveillance bias in the estimation of familial relative risks of cancer. The Swedish Family Cancer Database was used to explore the pattern of familial risk after diagnosis of the first cancer in the family. The investigation was based on the offspring and siblings of patients affected by melanoma or cancers of the breast, prostate, colorectum, cervix, or lung.


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The Swedish Family Cancer Database was created in the mid-1990s by linking census information, death notifications, and the administrative family register at Statistics Sweden to the Swedish Cancer Registry (11,12). The Family Cancer Database includes all persons who were born in Sweden after 1931 and their biologic parents. The 2004 update of the Family Cancer Database includes more than 10.5 million individuals (13). The Swedish Cancer Registry relies on separate compulsory notifications by the clinicians who diagnosed the neoplasm and by the pathologists or cytologists who reviewed the specimens (14). Neoplasms were coded according to the 7th revision of the International Classification of Diseases (ICD-7) and subsequent ICD classifications (15). In this study, only adenocarcinomas were included as invasive colorectal cancer; anal cancers were excluded. The ICD-7 was also used for classification of in situ tumors.

The Swedish Family Cancer Database includes 3.6 million families (parents and offspring). Information from the database on women in families with two or more sisters has been used previously to analyze risks for breast cancer among sisters (10). The age of the parents was unlimited, but the maximum age in the second generation was 70 years. The first patient diagnosed with invasive cancer in the family was the proband. Offspring and siblings of the proband were followed from the proband's year of diagnosis to the diagnosis of first cancer, death, emigration, December 31, 2002, or the closing date of the study. The study included 1 677 722 offspring and siblings of 846 448 probands. Relative risks were used to compare the incidence of cancer among relatives of probands with the incidence of cancer in the general population. For breast and cervical cancers, relative risks were estimated for daughters and sisters of affected women; for prostate cancer, only males were considered. Both males and females were included in the calculations for colorectal cancers, lung cancers, and melanoma.

To preserve the anonymity of the participants, national personal identification codes have been deleted from the Family Cancer Database. The Swedish Family Cancer Database has been approved by Statistics Sweden and the ethical board of the Karolinska Institute.

Statistical Analysis

The cases of cancer and the person–years were classified according to the variables of time after first diagnosis, age, sex, and current calendar year. In order to investigate the pattern of the familial risks after first diagnosis, the cutpoints 0, 1, 2, 3, 4, and 5+ years were chosen. The distribution of the number of cases in each group was modelled by Poisson regression, using the logarithm of the number of person–years as the offset (16). Computations were performed using the Genmod procedure of SAS, version 9.1 (17). To take into account the possible overdispersion of the data due to clustered family structure, standard errors and statistical analyses were adjusted using Pearson's chi-square, divided by the degrees of freedom (16,18). The hypothesis that familial risk of cancer was higher soon after first diagnosis than thereafter was assessed using the group of 5 or more years as the referent. To validate the applied methodology, the risk pattern of lung cancer was also analyzed. Screening for early detection of lung cancer is not available to date (19); thus, no trend was expected. All statistical tests were two-sided, and a P of <.05 was considered statistically significant.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The relative risks in offspring of invasive and in situ cancers after the diagnosis of parents with invasive cancer are shown in Table 1. Among the 2491 women with invasive breast cancer and a maternal history of breast cancer, 59 women (2.4%) were diagnosed in the same year as their mothers. The daughter's relative risk of invasive breast cancer was 2.80 (95% confidence interval [CI] = 1.37 to 5.70) during the mother's year of diagnosis, and it decreased thereafter. The relative risk of in situ breast cancer during the mother's year of diagnosis was statistically significantly higher than that 5 or more years after diagnosis (RR = 4.78, 95% CI = 2.16 to 10.6, 26.6 cases per 100 000, versus RR = 1.97, 95% CI = 1.65 to 2.37, 27.2 cases per 100 000; P = .033). Daughters diagnosed the same year as their mothers were younger and were diagnosed earlier in the calendar year than daughters of women diagnosed 5 or more years after their mothers. The risk of prostate cancer in the sons of men with prostate cancer was the highest when they were diagnosed in the same year, as was the risk of invasive colorectal cancer in the offspring of patients with invasive colorectal cancer (Table 1). In contrast, the risk of in situ colorectal cancer for the offspring of patients with invasive colorectal cancer reached its maximum (RR = 5.01, 95% CI = 1.92 to 13.1) 2 years after the parent's diagnosis. The risk of invasive cancer among the offspring of individuals with invasive melanoma was higher during the year of the parent's diagnosis than 5 or more years afterward (RR = 8.27, 95% CI = 3.82 to 17.9, 57.0 cases per 100 000, versus RR = 3.18, 95% CI = 2.55 to 3.97, 37.6 cases per 100 000; P = .019). Daughters of women with invasive cervical cancer had the highest relative risk of invasive cervical cancer 1 year after the mother's diagnosis and the highest relative risk of in situ cervical cancer during the year of the mother's diagnosis (Table 1). The relative risks of lung cancer for the offspring of lung cancer patients did not show statistically significant differences between the diagnostic periods. The offspring of individuals affected by cancer at any site showed the highest relative risk of any invasive or in situ cancer during the year of diagnosis of parents; the risk of invasive cancer for this period was statistically significantly higher than that after 5 or more years (RR = 2.08, 95% CI = 1.48 to 2.91 versus RR = 1.18, 95% CI = 1.10 to 1.27; P = .001; Table 1).


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Table 1.  Offspring risk of invasive and in situ cancer at the same site as the parental probands, according to time after the parents' diagnosis with invasive cancer*

 
The pattern of the cancer risk for siblings of cancer patients is shown in Table 2. No temporal trend was observed for the relative risk of invasive breast cancer. In contrast, among the 98 sisters of women with invasive breast cancer who were affected by in situ breast cancer, 15 women (15.3%) were diagnosed the same year as their sisters (RR = 5.22, 95% CI = 1.99 to 13.7; Table 2). The relative risks of invasive prostate cancer were also highest during the year of diagnosis in the first brother and 2 years thereafter. The relative risk of invasive colorectal cancer for siblings of probands with invasive colorectal cancer reached its maximum 3 years after the first diagnosis. Sisters of probands with invasive cervical cancer had the highest relative risk of in situ cervical cancer in the same year. The relative risks of lung cancer for siblings of lung cancer patients did not show statistically significant differences between the diagnostic periods.


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Table 2.  Risk of invasive and in situ cancer in siblings at the same site as the proband, according to the time after diagnosis of the proband with invasive cancer*

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The present study explored the change of the familial relative risks of melanoma and cancers of the breast, prostate, colorectum, cervix, and lung with time after diagnosis of the first family member in a large database of familial cancers. The results indicate that the diagnosis of the first invasive cancer in the family leads to the detection of additional tumors. Daughters of women with breast cancer showed the highest relative risk of in situ breast cancer during the year of the mother's diagnosis. The risk of invasive cancer among the offspring of individuals with invasive melanoma was highest during the year of the parent's diagnosis. The sibling risks of in situ breast cancer, in situ cervical cancer, and invasive prostate cancer also decreased with time after diagnosis of the first familial tumor. No pattern was expected for lung cancer, and none was found. Because almost all of the neoplasms considered were histologically verified, false diagnoses were unlikely (20). The most likely reason for the detection of familial cancers close in time is that the first diagnosis leads to the earlier detection of some asymptomatic tumors by increased surveillance in relatives. The implementation of cancer screening in Sweden is probably closely related to our findings: frequent screening and high screening rates should minimize the effect of detection bias, as has been noted for invasive breast cancer among sisters using the Swedish Family Cancer Database; however, without considering the potential for increased incidence due to familial clustering (10).

Pilot studies on mammographic screening were started in Sweden in the mid-1970s, and in the course of 23 years, a nationwide mammographic screening program was implemented; 81% of the eligible women have participated and the screening intervals have varied from 18 to 24 months (21). The detection of breast cancer in a family may result nevertheless in increased surveillance for daughters and sisters of the patient, e.g., by more frequent or more careful mammographies. We found that the relative risks of invasive and in situ breast cancer were highest during the year of the mother's diagnosis. The proportion of mother–daughter pairs who were diagnosed with invasive breast cancer in the same year was small, however, and those cases have a minor weight (2.4%; Table 1) on the estimation of the overall relative risks. Because 15.3% of the sisters of women with invasive breast cancer who were affected by in situ breast cancer were diagnosed the same year (Table 2), the effect of surveillance bias on the estimation of the relative risk of in situ breast cancer for sisters of women with invasive breast cancer may be more important than that for invasive cancer. The result for breast cancer in situ is in agreement with the detection of increasing numbers of carcinomas in situ by mammography, which has raised concerns about overdiagnosis (22).

Opportunistic screening with PSA testing became common in Sweden in the early 1990s, and the subsequent increase in incidence of prostate cancer in Sweden was probably due to the application of this test (23). In a recent study, Staples et al. (4) investigated the familial risk of prostate cancer during the establishment of PSA testing in Australia. They found that prostate cancer screening did not substantially alter familial risks of prostate cancer diagnosis, although familial effects for brothers were inflated. The present study shows that the relative risk of prostate cancer was highest during the father's year of diagnosis but that this relative risk was not statistically significantly different from that at 5 or more years after the father's diagnosis. Because only 1.2% of the sons were diagnosed in the same year as their fathers, detection bias should have little effect, if any, on the estimation of the father–son risks. In contrast, 61.9% of the fraternal cases of prostate cancer were detected within 3 years of each other, and the data suggested some overestimation of the relative risk during this period. However, considering the age truncation of the fraternal population to 70 years and the increasing incidence trends, some caution is needed in the interpretation of these results.

Current screening for colorectal cancer includes fecal occult-blood testing (FOBT), flexible sigmoidoscopy, colonoscopy, and double-contrast barium enema (24). Although colorectal cancer is the fourth most common incident cancer in Sweden and effective screening is available to reduce mortality, screening remains rare. Even in the United States, where organized efforts to increase colorectal cancer screening have been in place for almost 20 years, only 32% of adults over age 50 years underwent FOBT in 2003 or 2004, and only 34% say they have ever had either a sigmoidoscopy or colonoscopy (25). In 2000, the European Union began recommending the use of FOBT for population screening (26). The American College of Gastroenterology recommends colonoscopy every 5 years for individuals who have a family history of colorectal cancer diagnosed before age 60 years. The detection of colorectal cancer in a family may result in increased surveillance for relatives of the patient, e.g., by the increased likelihood of screening by colonoscopy. However, we found no strong evidence of biased familial risks for colorectal cancer in the present study.

Little is known about the ability of family doctors to diagnose and refer pigmented skin lesions to dermatologic clinics (27). A recent study found an increased 5-year survival among Swedish patients with malignant melanoma during 1990–1999 compared with previous population-based studies from Sweden; the authors postulate that the data may reflect an improved knowledge and awareness among the Swedish population and Swedish health care professionals (28). The diagnosis of invasive melanoma in a family may raise concern among family members. The present study demonstrates that the relative risk of malignant melanoma was considerably higher during the parent's year of diagnosis than 5 or more years later (Table 1). This initially high relative risk was followed by a constant lower risk, and no smooth trend of subsequent decline was observed, suggesting that the effect of detection bias on the relative risk of malignant melanoma is limited to a short period after the first diagnosis in the family. Similar data were found for siblings of melanoma patients, but the number of affected sibling pairs was small, and the differences among periods were not statistically significant.

Pap smear screening has greatly reduced mortality from cervical cancer. An international study conducted by the International Agency for Research on Cancer, based mainly on Scandinavian and Canadian women aged 25–64 years, estimated that cervical smears every 3 years can prevent 91% of cervical cancers, given 100% program sensitivity and adequate follow-up of all detected lesions (29). Population-based screening programs were introduced in most Swedish counties between 1967 and 1973. When Pap smear screening was fully implemented in Sweden, only about 25% of the smears were performed as part of the organized screening programs, whereas the remaining 75% represented opportunistic screening; i.e., Pap smears were performed at hospitals, maternal health care units, and other outpatient clinics (30). In our study, we found an increased relative risk of in situ cervical cancer among sisters shortly after diagnosis of the first familial invasive cancer. Similar results were observed after the diagnosis of the first familial in situ cervical cancer (data not shown), probably reflecting the concern and the better surveillance among these women.

The study has several potential limitations. The maximum age of individuals in the second generation (70 years) prevented the analysis of the possible effect of surveillance bias on the diagnosis of cancer after this age. Unfortunately, stage data are missing from the Swedish Cancer Registry, and the relationship between time after first diagnosis and tumor stage could not be investigated.

In conclusion, increased surveillance and the availability of screening methods may result in overestimated familial relative risks of cancers shortly after the first diagnosis of a variety of different cancers. The contribution of parent–offspring cancers diagnosed within the same year to the familial clustering of cancer was small. Caution is advised in the estimation and interpretation of the relative risk of invasive prostate cancer for brothers of affected men and of the relative risks of in situ breast and cervical cancers for sisters of affected women. Moreover, in counseling of family members with synchronous cancers, the lead time bias should be considered for a realistic evaluation of the familial risk and explained to the patients to comfort them.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Supported by Deutsche Krebshilfe and the Swedish Cancer Society. The Family Cancer Database was created by linking registers maintained by Statistics Sweden and the Swedish Cancer Registry.


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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Manuscript received March 15, 2005; revised August 19, 2005; accepted September 12, 2005.


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