Cancer Epidemiol Biomarkers Prev 2008 Lee 2647 55

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2008;17:2647-2655. Published online October 8, 2008.Cancer Epidemiol Biomarkers PrevKuan-Der Lee, Shin-Cheh Chen, Chunghuang Hubert Chan, et al.Population-Based Study in Taiwanwith Breast Cancer Diagnosed at Young Age: AIncreased Risk for Second Primary Malignancies in Women

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Increased Risk for Second Primary Malignancies in Womenwith Breast Cancer Diagnosed at Young Age:A Population-Based Study in Taiwan

Kuan-Der Lee,1,3,4 Shin-Cheh Chen,6 Chunghuang Hubert Chan,1,3,4 Chang-Hsien Lu,1,3,4

Chih-Cheng Chen,1,3,4 Jen-Tsun Lin,1,3,4 Miao-Fen Chen,2,3 Shih-Hao Huang,5

Chun-Ming Yeh,5 and Min-Chi Chen5

1Departments of Hematology and Oncology and 2Radiation Oncology, Chang Gung Memorial Hospital; 3Department of Nursing,Chang Gung Institute of Technology, Chiayi, Taiwan; 4Departments of Medicine and 5Public Health and BiostatisticsConsulting Center, School of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 6Department ofGeneral Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan

Abstract

Studies conducted in Western countries have reportedexcess risks for second primary malignancies afterbreast cancer. However, there is little documentation

of ethnic differences in these excess risks. Asianwomen are characterized by younger age at diagnosisof breast cancer, but very few reports are available onthe incidences and risks for second primary cancersin this region. Using population-based data from theTaiwan National Cancer Registry (TNCR) for theperiod 1979 to 2003, we quantified standardizedincidence ratios and cumulative incidence of secondcancers among 53,783 women with initial diagnosesof breast cancer. Age-specific incidences showed peaksamong women in their 40s, and 1,085 cases (2.02%)developed nonbreast second primary cancers. The riskfor second cancers differs significantly according toage at diagnosis of breast cancer. In comparison with

women diagnosed when z50 years (standardizedincidence ratio, 0.96; 95% confidence interval; 0.89-1.04), there were significantly greater risks for bone,

corpus uterine, ovarian, thyroid, esophageal, kidney andlung cancers, nonmelanoma skin cancer, and leukemiaor lymphoma in women diagnosed when 60 years; refs. 10-12).There is no satisfactory explanation of this disparity inthe age of onset. The age-specific breast cancer incidencerate also differed between African-American and Whitewomen of similar ages in the United States (13, 14),indicating that, in addition to lifestyle and hormone use,other biological factors could contribute to racial orethnic differences in clinical presentation among breastcancer patients.

A 20% to 30% excess risk for a second nonbreastprimary malignancy in female breast cancer patients hasbeen reported, mostly in Europe (10, 15-18) and theUnited States (19-21). The relevance of ethnic diversity tosuch second primary cancers has been much less welldescribed, particularly in Asian countries, so welaunched a large-scale epidemiologic study in Taiwan,an area characterized by early age of breast cancer onset(22, 23). We aimed to define the incidences and patternsof second primary cancers in patients with breast canceraccording to age at onset and time interval since breastcancer diagnosis and to explore the effect of developingsecond cancers on the survival of patients who survived

breast cancer.

Cancer Epidemiol Biomarkers Prev 2008;17(10). October 2008

Received 2/4/08; revised 6/27/08; accepted 7/9/08.

Grant support:National Science Council grants 95-2118-M-182-001 and grantsCMRPD140041 from the Chang Gung Molecular Medicine Research Center, ChangGung University, Taiwan.

Requests for reprints:Min-Chi Chen, Biostatistics Consulting Center and Departmentof Public Health, School of Medicine, Chang Gung University, 259 Wen-Hwa 1stRoad, Kwei-Shan, Tao-Yuan 333, Taiwan. Phone: 886-3-2118800, ext. 5056;Fax: 886-3-2118700. E-mail: [email protected]

Copyright D 2008 American Association for Cancer Research.

doi:10.1158/1055-9965.EPI-08-0109

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Materials and Methods

Data Sources.We quantified second cancer incidencesamong 59,001 patients with initial diagnoses of breastcancer (International Classification of Diseases, 9thRevision, 174) who were reported to the TNCR7 from

January 1, 1979, to 31 December 2003. The TNCR wasfounded in 1979 and financially supported by theNational Department of Health with the aim of estimat-ing cancer incidence in Taiwan. It is a population-based

cancer registry that covered 22 million people in 2003.Hospitals with >50 beds are obligated to submitinformation on newly diagnosed cancer patients to theTNCR, which reimburses the hospitals on the basis ofnumbers of cases reported to reduce the likelihoodof underreporting. All cancer registry databases in theTNCR have been systemically converted to InternationalClassification of Diseases, 9th Revision, codes (24), andlinked with death certificates from the National DeathDatabase. Persons not identified by this process weretherefore considered to be alive for the purpose of thecurrent study (passive follow-up). Coding of multipleprimaries followed the principles of the InternationalAgency of Cancer Registries and the IARC (25). Thelymphoma and leukemia incidence rates were combined

because they are both classified in the TNCR as cancersof the hematopoietic and reticuloendothelial systems.Informed consent was not required because all registryrecords are anonymous and open to the public.

To assess the age of onset accurately, estimate person-year follow-up and minimize potentially unconfirmedcancer diagnosis in this study cohort, 5,218 patients wereexcluded from analysis because they met one or more ofthe following criteria: (a) missing birth dates (519 cases),(b) missing follow-up date or death status (3,955 cases), or(c ) second cancer diagnosis or death occurring


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290,966 person-years of follow-up (Table 1). Overall, breastcancer was diagnosed at mean the age of 50.35 years(median, 49 years). The mean age at diagnosis of secondprimaries was 60.56 years. The average follow-up time was

5.41 years, including 46,709 cases (87%) followed up for atleast 1 year, 13,140 (24%) for 5 to 10 years, and 9,024 (17%)for >10 years. The average interval between first andsecond cancers was 5.99 years with an SD of 4.81 years.

Table 2. Observed and expected numbers of all and selected second primary cancers, and standardized incidenceratios with 95% CIs in 53,783 breast cancer patients by age at diagnosis of breast cancer

Second primary cancer site (ICD-9 code) O E SIR (O/E) 95% CI

Bone (170) All 9 1.98 4.55 2.70-8.63


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Risk for Second Primary Cancers Stratified by Siteand Age at Diagnosis of Breast Cancer. Standardized

incidence ratios and corresponding 95% CIs for secondprimary cancers at all sites except breast were calculatedand stratified by the age at diagnosis of breast cancer(10 7 5.83 1.20 0.48-2.47Leu or lym (169,196) V5 13 1.62 8.02 4.27-13.72

6-10 0 1.97 0 NA>10 1 2.87 0.35 0.00-1.94

Kidney and other urinary organs (189) V5 4 1.26 3.17 0.85-8.136-10 4 1.72 2.33 0.63-5.95

>10 5 3.17 1.58 0.51-3.68Lung (162) V5 17 4.94 3.44 2.00-5.51

6-10 18 6.64 2.71 1.61-4.28

>10 9 11.20 0.80 0.37-1.53Corpus uteri (182) V5 11 3.89 2.83 1.41-5.06

6-10 8 4.77 1.68 0.72-3.30>10 9 6.00 1.50 0.68-2.85

Thyroid (193) V5 18 5.32 3.38 2.00-5.356-10 10 5.70 1.75 0.84-3.23

>10 4 6.09 0.66 0.18-1.68Age z50 yCorpus uteri (182) V5 28 5.86 4.78 3.17-6.91

6-10 19 5.16 3.68 2.22-5.75>10 9 4.90 1.84 0.84-3.49

Ovary (183) V5 13 5.63 2.31 1.23-3.956-10 11 5.39 2.04 1.02-3.65

>10 4 6.13 0.65 0.18-1.67

Abbreviation: NA: not assessable.

Table 2. Observed and expected numbers of all and selected second primary cancers, and standardized incidenceratios with 95% CIs in 53,783 breast cancer patients by age at diagnosis of breast cancer (Contd)

Second primary cancer site (ICD-9 code) O E SIR (O/E) 95% CI

Brain (191) All 8 8.85 0.90 0.39-1.78


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For all patients, risks for the following second cancersshowed statistically significant increases over the popu-lation: bone (standardized incidence ratio, 4.55; 95% CI,2.70-8.63), corpus uteri (standardized incidence ratio,2.75; 95% CI, 2.19-3.40), ovary (standardized incidenceratio, 2.09; 95% CI, 1.62-2.65), skin (nonmelanoma;standardized incidence ratio, 1.52; 95% CI, 1.15-1.96),and thyroid (standardized incidence ratio, 1.42; 95% CI,1.04-1.90). For patients


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and kidney cancers were not significant at any follow-upperiod, perhaps because only limited numbers wereobserved. For those with initial diagnosis at the age ofz50 years, risks for corpus uteri and ovarian cancerswere significant during the first 10 years.

Age Trends of the Secondary Corpus Uteri andOvarian Cancers.To study the trend of two most relatedsecond cancers (corpus uteri and ovary) with age, westratified their standardized incidence ratios according to4 age groups (


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have been rigorously studied; however, the etiologicfactors remain obscure. Exploring the pathogenesis ofsecond primary cancers might provide some insight into

breast cancer etiologies in this region.We found that the second cancer risk is substantially

greater among female patients with initial diagnosis ofbreast cancer at the age of 50 years old showed excess risks only at two sites,corpus uteri and ovary. The mean follow-up of ourcohort was relatively short (5.41 years); the magnitude ofrisk (as measured by standardized incidence ratio andcumulative incidence) might increase with longer follow-up. During the past 25 years, the clinical practice and

breast cancer treatment, including surgery, chemothera-py, tamoxifen, and radiation therapy were similar toWestern countries. Although the trend toward that therisk for second malignancies was higher among youngerpatients was consistent with Western patients (17, 38, 39),various cancer sites at excess risks have been less

consistent except for ovary and corpus uteri. Forexample, bone, skin (nonmelanoma), thyroid, esophagus,kidney, and lung cancers, and leukemia or lymphomawere the concordant sites as compared with Westernstudies (38, 40); however, the excess risks for soft tissuesarcoma, salivary gland, stomach, colon, and rectumcancer from previous reports (10, 16, 29, 41) were notobserved in our cohort. Therefore, second cancerscreening for Western patients cannot be uniformlyapplied to Asian population, probably affected bydifferent genetic or lifestyle factor.

It is always a concern in population-based studiesabout misclassification of metastases in some anatomicsites such as bone, liver, and lung as new primary

cancers. Among 53,783 of breast cancer patients in ourcohort, there were only 10 bone cancers, 109 liver cancers(Taiwan is an endemic area for hepatocellular carcino-ma), and 122 lung cancers. Considering the incidences ofprimary breast cancer metastasizing to these distant sitesshould be far higher than these numbers, we speculatethat possible misclassification of metastases as newsecond primaries does not seem to have been a particularproblem in TNCR. However, subsequent breast cancerswere excluded because the data of the registry did notspecify whether the second breast cancer occurredipsilaterally or contralaterally to the first primary. It isdifficult to discriminate whether they are truly secondprimary breast cancers or recurrences if the histology isidentical. Our cohort assesses only the risk for secondarynonbreast cancers.

Many cancer sites are likely to be associated withtreatment modalities for breast cancer. For example,organs close to the breast such as esophagus (42), lung(43), thyroid (44), and bone (45) are likely to be affected

by radiotherapy. However, our data do not support thehypothesis that the excess cancer rates at these sites aretherapy induced because their risks did not increase bylatency. Moreover, the magnitude of risk at these siteswas very low in breast cancer patients diagnosed at the

age of >50 years, suggesting that other factors such asshared genetic predisposition or shared environmentalrisk factors could be involved. The differential risks

between patients


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the risk for which was higher among women z50 yearsat breast cancer diagnosis (standardized incidence ratio,3.52; 95% CI, 2.66-4.57) than those


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