Survival in Familial Pancreatic Cancer

Survival in Familial Pancreatic Cancer

Original Paper Pancreatology 2008;8:252–256 DOI: 10.1159/000134272 Received: September 12, 2007 Accepted after revision: December 18, 2007 Published ...

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Original Paper Pancreatology 2008;8:252–256 DOI: 10.1159/000134272

Received: September 12, 2007 Accepted after revision: December 18, 2007 Published online: May 22, 2008

Survival in Familial Pancreatic Cancer Jianguang Ji a Asta Försti a, c Jan Sundquist a Per Lenner b Kari Hemminki a, c a

Center for Family and Community Medicine, Karolinska Institute, Huddinge, and b Department of Oncology, Norrlands University Hospital, Umea, Sweden; c Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Key Words Pancreatic cancer ⴢ Survival ⴢ Hazard ratio ⴢ Family history

Abstract Background: Family history has been reported to be associated with an increased risk of pancreatic cancer. However, its possible influence on pancreatic cancer survival has rarely been studied, probably because of the rareness of cases in the same family. Methods: We used the nationwide Swedish Family-Cancer Database to examine the survival differences between familial and sporadic pancreatic cancers. Hazard ratios (HRs) for cause-specific and overall survival in pancreatic cancer were examined. HRs show the probability of death in the study group compared to the reference group. Results: A total of 75 familial pancreatic cancers were noted. HRs were significantly higher among offspring with an affected parent compared to those without an affected parent; for cause-specific and overall survival, the HRs were 1.44 and 1.37, respectively. Reversing the analysis and deriving HRs for parents (offspring as probands) showed that familial pancreatic cancer had a worse prognosis than sporadic cases (HR 1.37 for cause-specific and 1.28 for overall survival). The HRs were close to unity among spouses with concordant pancreatic cancer. Conclusion: The data show that survival in familial pancreatic cancer is worse than that in sporadic disease, which could be explained by genetic factors, if other confounding factors can be excluded. Copyright © 2008 S. Karger AG, Basel and IAP

© 2008 S. Karger AG, Basel and IAP 1424–3903/08/0083–0252$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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Introduction

Worldwide, the incidence of pancreatic cancer ranges between 1 and 10 cases per 100,000 people. The rates in developed countries are in the upper part of this range; in Sweden it is 5 per 100,000 women and marginally higher for men [1]. Pancreatic cancer is the 4th most common cause of cancer deaths in United States and the 6th in Europe. Pancreatic cancer is also one of the most fatal cancers, with 1- and 5-year survival rates of 12–17 and 1–2%, respectively [2, 3], although patients with early pancreatic cancer may have a better chance of survival [4]. There have been no improvements in relative survival in pancreatic cancer during the past 4 decades [5, 6]. Known or suspected risk factors for pancreatic cancer include tobacco smoking, chronic pancreatitis, diabetes, and a diet that is poor in fruit and vegetables, rich in meat and high in calories [7–10]. Family history has been reported to be associated with an increased risk of pancreatic cancer in many previous studies [11–16]. However, the impact of a positive family history on survival has rarely been studied, probably because of the rareness of familial cases. In this study we used the nationwide Swedish Family-Cancer Database to examine the survival differences between familial and sporadic pancreatic cancers. A total of 75 familial pancreatic cancers were noted from the database. The data on family relationships and cancer cases were obtained from registered sources that have practically complete coverage at the national level.

Jianguang Ji Center for Family and Community Medicine, Karolinska Institute Alfred Nobels alle 12 SE–14183 Huddinge (Sweden) Tel. +46 852 488 671, Fax +46 852 488 706, E-Mail [email protected]

Year of diagnosis

Age at diagnosis

1.0

0.8 Survival probability

≥70 60–69 50–59 <49

2000–2004 1990–1999 1980–1989 1970–1979 1961–1969

0.6

0.4

0.2

0

0

6

a

12 18 Survival time (months)

24

30

0

b

6

12 18 Survival time (months)

24

30

Fig. 1. Overall survival among parents with pancreatic cancer. a Year of diagnosis. b Age at diagnosis.

Subjects and Methods The Family-Cancer Database was created by linking information from the Multigeneration Register, national censuses, the Swedish Cancer Registry and death notifications [17, 18]. Data on family relationships were obtained from the Multigeneration Register, in which children born in Sweden from 1932 onwards are registered with their biological parents as families. Thus, the second generation (offspring) had reached a maximum age of 72 years; the ages in the first generation (parents) were not limited. Information retrieved from the various registers was linked at the individual level via the national 10-digit civic registration number that is assigned to each person in Sweden for his or her lifetime. Prior to inclusion in the database (MigMed2), civic registration numbers were replaced by serial numbers to ensure anonymity of all individuals. The Swedish Cancer Registry is based on compulsory reports of diagnosed cases provided by physicians (clinical report) and by pathologists or cytologists (pathology report); the coverage of the cancer register is currently considered to be close to 100%. The Database was updated in 2006 to include cancer cases from 1958–2004 [18]. Only cases classified as primary neoplasms of the exocrine pancreas (International Classification of Diseases, ICD, 7th revision, code 157) were considered in the present study; endocrine pancreatic cancers were recorded with a code of 195, and they were not examined in this study. Analysis was done separately for pancreatic cancer in offspring and parents. A total of 2,513 offspring were diagnosed with pancreatic cancer between 1961 and 2003, of whom 75 had a parent affected with pancreatic cancer. For parental pancreatic cancers, 22,724 cases were noted between 1961 and 2003. However, in order to adjust the median diagnosis

Familial Pancreatic Cancer

year of the sporadic and familial cases, sporadic cases included only those diagnosed before 1995 (16,898 cases). Cases were defined as familial when offspring were diagnosed with pancreatic cancer (75 cases). Family history among siblings was not considered in this study because only a few affected sibling pairs were noted (n = 19). Family size was similar between familial and sporadic cases [14]. To examine the effects of shared environmental factors, survival was also analyzed among spouses with concordant pancreatic cancer. The spouses were defined as the parents of the last child of the couple. A total of 92 spouses were diagnosed with pancreatic cancer. Follow-up for survival began at diagnosis and terminated at death, emigration or the closing date of the study (31 December 2004), whichever came first. Cox’s proportional hazard regression models were used to estimate the hazard ratios (HRs) for disease-specific and overall survival. HR indicates the relative risk of dying in the defined period compared to a reference group; when it is above 1.0, the risk is higher than in the reference group. HRs were adjusted for age at diagnosis, sex, period, socioeconomic status and diagnosis region. For the analysis of disease-specific survival, death as a result of pancreatic cancer (recorded as underlying cause of death) was the primary end point; deaths due to other causes were censored. For the analysis of overall survival, death due to any cause was the end point. The proportional hazard assumption for the covariates was tested by Schoenfeld residuals and by plotting the log of the negative log of the survival function versus the log of time; covariates were stratified in the models if they did not meet the assumption. All statistical analyses were performed using SAS software (version 9.1; SAS Institute, Cary, N.C., USA).

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Table 1. Hazard ratios for cause-specific and overall survival in familial pancreatic cancer Parameter

Cases n

Offspring pancreatic cancer Sporadic cases, reference Parents with pancreatic cancer

Median Median Median survival time age at year of diagnosis diagnosis months

Cause-specific survival deaths, n (%)

Overall survival

HR

95% CI

2,438 75

1998 1999

57 56

5.4 4.0

2,033 (83.4) 68 (90.7)

1.00 1.44b

1.13–1.84

Parental pancreatic cancer 16,898 Sporadic cases, referencea Offspring with pancreatic cancers 75

1982 1982

69 72

2.7 2.2

15,515 (91.8) 74 (98.7)

1.00 1.37b

1.09–1.72

deaths, n (%)

HR

95% CI

1.00 1.37b

1.08–1.73

16,824 (99.6) 1.00 75 (100.0) 1.28b

1.02–1.60

2,275 (93.3) 72 (96.0)

HR = Hazard ratio, adjusted for sex, age, period, region and socioeconomic status. a Parents were diagnosed with pancreatic cancer before 1995. b 95% CI does not include 1.00.

Table 2. Hazard ratios for cause-specific and overall survival in pancreatic cancer among individuals whose spouses were diagnosed with pancreatic cancer Cases n

Median Median Median sur- Cause-specific survival vival time age at year of deaths, n (%) HR 95% CI diagnosis diagnosis months

deaths, n (%)

HR

95% CI

12,462 92

1985 1982

68 67

2.5 2.5

11,236 (90.2) 87 (94.6)

1.00 1.04

0.84–1.28

12,213 (98.0) 92 (100.0)

1.00 1.00

0.81–1.22

Wives Population cases, reference 10,371 Husbands with pancreatic cancer 92

1989 1987

69 69

3.0 2.7

9,429 (90.9) 89 (96.7)

1.00 1.06

0.86–1.31

10,100 (97.4) 91 (98.9)

1.00 1.01

0.82–1.24

Parameter

Husbands Population cases, reference Wives with pancreatic cancer

Overall survival

HR = Hazard ratio, adjusted for age, period, region and socioeconomic status.

Results

Figure 1 presents the overall survival curves among parents with pancreatic cancer. Survival curves for offspring were not shown because almost no offspring were diagnosed before 1990. Patients diagnosed between 2000 and 2004 had a better survival compared to those diagnosed before 2000. Patients who were diagnosed at a younger age also showed a better survival compared to those diagnosed at older ages. Age and year of diagnosis, as well as socioeconomic status and diagnosis region, were included in the final multivariate Cox models. HRs for cause-specific and overall survival in familial pancreatic cancer are shown in table 1. A total of 75 (3%) offspring were observed with an affected parent. HRs were significantly higher among offspring with a family history compared to those without; for cause-specific and overall survival, the HRs were 1.44 and 1.37, respectively. Among the familial cases, 91% had died of pancreatic 254

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cancer, and the overall mortality was 96%. The median years of diagnosis were 1999 and 1998 for familial and sporadic diseases, respectively; the median survival time was 5.4 months in sporadic cases, and 4.0 months in familial cases. The median ages at diagnosis were 57 and 56 for sporadic and familial cases, respectively. Reversing the analysis and deriving HRs for parents (offspring as probands) showed that familial pancreatic cancer had a worse prognosis than sporadic cases (1.37 for cause-specific and 1.28 for overall survival). Cause-specific mortality was 98% and the overall mortality was 100%. Median survival times were 2.7 and 2.2 months among sporadic and familial cases, respectively. Median diagnosis age was younger in sporadic cases (69 years) compared to familial cases (72 years). To study the impact of shared environmental factors on outcome, we analyzed the survival in spouses with concordant pancreatic cancer (table 2), using the individuals without an affected spouse as reference. A total of 92 Ji /Försti /Sundquist /Lenner /Hemminki

husbands were noted with an affected wife; the HRs were close to unity for cause-specific (1.04) and overall survival (1.00). The median years of diagnosis were 1982 and 1985 for husbands with and without an affected wife, respectively. Similar results were noted for wives with an affected husband.

Discussion

The main observation in this study was that familial pancreatic cancer may have a more aggressive course than sporadic disease. The present study was based on nationwide databases in Sweden that registered family structures, medically verified cancers, underlying causes of death and complete follow-up of cancer patients. Thus, overall, the sources of data can be considered reliable. The results were consistent in showing the survival difference between familial and sporadic cases for both parents and offspring. To our knowledge, the unfavorable survival of familial pancreatic cancer has not been shown before. A similar survival experience among familial and sporadic pancreatic cancer patients was noted by James et al. [19]. However, their study was based on only 30 cases, and their familial cases were diagnosed at earlier ages, which could be related to a better prognosis. In contrast, in the present study diagnostic ages were similar between familial and sporadic cases, and the results were adjusted for many potential confounding factors. An obvious question arising from this finding is whether the worse prognosis among familial cases is due to true biological differences, which may be related to inherited genes, or shared environmental factors, such as smoking. Although smoking may influence the prognosis of pancreatic cancer [20], the contribution to the present results on familial effects should be minor, judged from the poor correlation of pancreatic cancer between spouses [21]. Additionally, it should be considered that shared environmental factors, such as smoking, could be

References

Familial Pancreatic Cancer

more common between spouses than between parents and offspring. Thus, the present HRs close to unity for concordant pancreatic cancer among spouses confirm the above circumstantial argument about the unlikely contribution of environmental factors to the observed survival difference. These data do suggest that there are true biological differences between familial and sporadic pancreatic cancers, which may be best explained by genetic factors. Most current models of metastasis view it as a gradual process whereby cells in the primary tumor acquire a metastatic potential through a number of somatic events, while the possible role of heritable effects has not been delineated [22, 23]. Whether the heritable factors would be expressed in clinical parameters, such as histopathological grade and stage, remains to be seen because these data were unavailable in our database. If there were true biological differences between familial and sporadic pancreatic cancers relating to such clinical factors then adjusting for them might eliminate the observed difference. Another limitation in this study is the lack of information about the treatment, such as operation and palliative care, among pancreatic cancer patients, which could be examined further. In summary, our data show that survival in familial pancreatic cancer is worse than in sporadic disease, which could be explained by genetic factors. Further studies are needed to decipher the underlying molecular determinants for the poor survival in familial pancreatic cancer.

Acknowledgements This study was supported by Deutsche Krebshilfe, the Swedish Cancer Society, the EU, LSHC-CT-2004-503465 and the Swedish Council for Working Life and Social Research. The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.

1 International Agency for Research on Cancer: GLOBOCAN 2000. Cancer Incidence, Mortality and Prevalence Worldwide. Lyon, IARC Press, 2001. 2 Cooperman AM: Pancreatic cancer: the bigger picture. Surg Clin North Am 2001; 81: 557–574. 3 Shi X, Friess H, Kleeff J, Ozawa F, Büchler MW: Pancreatic cancer: factors regulating tumor development, maintenance and metastasis. Pancreatology 2001; 1:517–524.

4 Tsuchiya R, Tajima Y, Matsuzaki S, Onizuka S, Kanematsu T: Early pancreatic cancer. Pancreatology 2001; 1:597–603. 5 Talbäck M, Stenbeck M, Rosén M, Barlow L, Glimelius B: Cancer survival in Sweden 1960–1998 – developments across four decades. Acta Oncol 2003;42:637–659. 6 Singh M, Maitra A: Precursor lesions of pancreatic cancer: molecular pathology and clinical implications. Pancreatology 2007; 7: 9–19.

Pancreatology 2008;8:252–256

255

7 Hamilton S, Aaltonen L (eds): Tumours of the Digestive System. World Health Organization Classification of Tumours. Lyon, IARC, 2000. 8 Fernandez E, La Vecchia C, Porta M, Negri E, d’Avanzo B, Boyle P: Pancreatitis and the risk of pancreatic cancer. Pancreas 1995; 11: 185–189. 9 Weiderpass E, Partanen T, Kaas R, Vainio H, Porta M, Kauppinen T, Ojajärvi A, Boffetta P, Malats N: Occurrence, trends and environmental etiology of pancreatic cancer. Scand J Work Environ Health 1998; 24: 165– 174. 10 World Cancer Research Fund/American Institute for Cancer Research: Nutrition and the Prevention of Cancer: a global perspective. Washington DC, American Institute of Cancer Research, 1997. 11 Klein AP, Hruban RH, Brune KA, Petersen GM, Goggins M: Familial pancreatic cancer. Cancer J 2001;7:266–273.

256

12 Fernandez E, La Vecchia C, D’Avanzo B, Negri E, Franceschi S: Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 1994;3:209–212. 13 Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH: Systematic populationbased assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 1994;86:1600–1608. 14 Hemminki K, Li X: Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden. Int J Cancer 2003;103:525–530. 15 Lynch HT, Deters CA, Lynch JF, Brand RE: Familial pancreatic carcinoma in Jews. Fam Cancer 2004;3:233–240. 16 Rieder H, Bartsch DK: Familial pancreatic cancer. Fam Cancer 2004;3:69–74. 17 Hemminki K, Li X, Plna K, Granström C, Vaittinen P: The nation-wide Swedish family-cancer database: updated structure and familial rates. Acta Oncol 2001;40:772–777. 18 Hemminki K, Granström C, Sundquist J, Lorenzo Bermejo J: The updated Swedish family-cancer database used to assess familial risks of prostate cancer during rapidly increasing incidence. Heredit Cancer Clin Pract 2006;4:186–192.

Pancreatology 2008;8:252–256

19 James TA, Sheldon DG, Rajput A, Kuvshinoff BW, Javle MM, Nava HR, Smith JL, Gibbs JF: Risk factors associated with earlier age of onset in familial pancreatic carcinoma. Cancer 2004;101:2722–2726. 20 Yu GP, Ostroff JS, Zhang ZF, Tang J, Schantz SP: Smoking history and cancer patient survival: a hospital cancer registry study. Cancer Detect Prev 1997;21:497–509. 21 Hemminki K, Jiang Y: Cancer risks among long-standing spouses. Br J Cancer 2002;86: 1737–1740. 22 Nguyen DX, Massague J: Genetic determinants of cancer metastasis. Nat Rev Genet 2007;8:341–352. 23 Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM, Kalyana-Sundaram S, Wei JT, Rubin MA, Pienta KJ, Shah RB, Chinnaiyan AM: Integrative molecular concept modeling of prostate cancer progression. Nat Genet 2007;39:41–51.

Ji /Försti /Sundquist /Lenner /Hemminki