Family history of breast or ovarian cancer modifies the risk of secondary

leukemia after breast cancer: Results from a population-based study

Helena M. Verkooijen1,2, Gerald Fioretta1, Elisabetta Rapiti1, Georges Vlastos3, Isabelle Neyroud-Caspar1,Pierre O. Chappuis4,5 and Christine Bouchardy1*

1Geneva Cancer Registry, Institute for Social and Preventive Medicine, Geneva University, Geneva, Switzerland2Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore3Senology and Surgical Gynecologic Oncology Unit, Geneva University Hospitals, Geneva, Switzerland4Division of Oncology, Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland5Division of Genetic Medicine, Department of Genetic Medicine and Laboratory, Geneva University Hospitals, Geneva, Switzerland

We evaluated the impact of a family history of breast/ovarian can-cer on the risk of secondary leukemia following breast cancer. Atthe Geneva cancer registry, we identified 4,397 patients diagnosedwith invasive breast cancer between 1990 and 2004. Patients werefollowed up for leukemia until the end of 2005. Family history wascategorized as positive in patients with �1 first- or second-degreerelative with breast/ovarian cancer. We compared leukemia ratesin patients with positive and negative family histories with thoseexpected in the general population, generating standardized inci-dence ratios (SIRs). With Cox regression analysis, we calculatedadjusted risks of secondary leukemia in patients with familialrisks compared to those without it. Breast cancer patients had asignificantly increased risk of secondary acute leukemia (SIR 3.2,95% CI: 1.2–6.9) but not of chronic leukemia (SIR 1.6, 95% CI:0.6–3.5). Among patients with a positive family history (n 5 1.125,25.6%), the SIRs were 5.7 (95% CI: 1.2–16.6) for acute and 5.2(95% CI: 1.4–13.3) for chronic leukemia. Among breast cancerpatients, family history was independently associated with leuke-mia [adjusted hazard ratio (HRadj) of 3.2, 95% CI: 1.1–9.2, amongpatient with vs. without family history]. The effect of family his-tory was stronger for chronic leukemia (HRadj: 11.6, 95% CI 1.3–104.7) than for acute leukemia (HRadj 1.6, 95% CI: 0.4–6.6).Breast cancer patients with a family history of breast/ovarianhave an increased risk of secondary leukemia, both compared tothe general population as well as to breast cancer patients withoutfamily histories. This excess risk is largely due to the increasedrisk of secondary chronic leukemia.' 2007 Wiley-Liss, Inc.

Key words: breast cancer; secondary cancer; leukemia; familyhistory; population-based

The risk of secondary leukemia following treatment for breastcancer has been well established.1–4 Modifiers of this risk includeincreasing age and exposure to radiotherapy as well as certaintypes of chemotherapy.5–7 Most studies reported only increasedrisks of acute myeloid leukemia following breast cancer, but arecent large, population-based study has shown that breast cancerpatients are at increased risk of developing acute lymphoblasticleukemia and chronic myeloid leukemia as well.1

A family history of leukemia or other hematologic malignanciesis not considered as a major risk factor for leukemia,8–10 except forchronic lymphocytic leukemia.11 There have been some reportsof breast cancer and leukemia clustering in families, in particular,in the context of some hereditary cancer syndromes like ataxia-telangiectasia and Li-Fraumeni syndrome.10,12 In addition,Rauscher et al. reported that adults, whose sisters had been diag-nosed with breast cancer, were at 1.8–3.3 times increased risk ofdeveloping acute leukemia.13

Although the excess absolute risk of secondary leukemia fol-lowing breast cancer is rather low—around 9 extra cases per100,000 person years—and the individual risk of developing leu-kemia following breast cancer is decreasing,1 the overall the bur-den of this serious complication may actually rise. The increasingincidence of breast cancer in combination with improving survivalrates leads to increasing numbers of women at risk of leukemiafollowing breast cancer. The aging of the population may also

contribute to increasing numbers of leukemia following breastcancer, since some studies have indicated that the risk of leukemiafollowing breast cancer is highest among women who developedbreast cancer at an older age.2 Finally, the number of patientsmanaged with breast conserving treatment, including lumpectomyand radiotherapy, is still on the rise, leading to increasing numberof patients exposed to ionizing radiation and therefore at increasedrisk of leukemia.

For this reason, it would be useful to identify additional riskfactors for leukemia after breast cancer, in order to be able to bet-ter predict which women will develop this often highly fatal dis-ease. In this study, we evaluated whether the risk of secondary leu-kemia after breast cancer is modified by family history of breast/ovarian cancer.

Methods

We used information from the population-based Geneva CancerRegistry, which records all incident cancers occurring in the popu-lation of the Geneva canton (�420,000 inhabitants) since 1970. Itcollects information from various sources and is considered accu-rate, as attested by its very low percentage (<2%) of casesrecorded from death certificates only.14 All hospitals, pathologylaboratories and private practitioners in the canton are requestedto report all cancer cases. Trained tumor registrars systematicallyabstract data from medical and laboratory records. Physiciansregularly receive enquiry forms to complete missing clinical andtherapeutic data.

Recorded data include sociodemographic information, tumorcharacteristics coded according to the International Classificationof Diseases for Oncology15 and treatment given during the first 6months after diagnosis. The Registry staff regularly assess sur-vival, taking as reference date the date of confirmation of diagno-sis or the date of hospitalization (if it preceded the diagnosis andwas related to the disease). In addition to passive follow-up (stand-ard examination of death certificates and hospital records), activefollow-up is performed yearly using the files of the Cantonal Pop-ulation Office (office in charge of the registration of the residentpopulation). Cause of death is taken from clinical files.

In the current study, we included resident patients diagnosedwith invasive breast cancer between 1990 and 2004. We limitedour study to this period, since for these years information on fam-ily history of cancer was available. Family history of breast and/orovarian cancer was obtained from the Familial Breast CancerRegistry. This unit of the Geneva Cancer Registry was set up in

Grant sponsor: Swiss National Science Foundation (PROSPER Grant);Grant number: 3233-069350.*Correspondence to: Geneva Cancer Registry, 55 Boulevard de la

CLuse, 1205 Geneva, Switzerland. Fax:141-22-379-4971.E-mail: christine.bouchardymagnin@imsp.unige.chReceived 26 June 2007; Accepted after revision 3 September 2007DOI 10.1002/ijc.23212Published online 31 October 2007 inWiley InterScience (www.interscience.

wiley.com).

Int. J. Cancer: 122, 1114–1117 (2008)' 2007 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

1999, by extending its data set to the detailed family history ofcancer for all women diagnosed with invasive breast cancer in theGeneva population.16 The level of familial risk was classified into3 categories according to the number of relatives diagnosed withbreast or ovarian cancer, their age at diagnosis and their degree ofkinship.17 The low familial risk category included breast cancerpatients with no first- or second-degree relatives with breast orovarian cancer (i.e., sporadic cases). The high familial risk cate-gory included patients who reported 1 of the following family his-tories: (i) �1 first-degree relative with breast or ovarian cancer�50 years; (ii) �2 first-degree relatives with breast or ovariancancer at any age; (iii) �3 cases of breast or ovarian cancer amongfirst- or second-degree relatives. Patients with other types of fam-ily history were classified into the moderate familial risk category.

Other variables of interest were age, stage, family history ofbreast cancer and type of adjuvant treatment. Stage was codedusing the pathologic tumor node metastasis (pTNM) classificationsystem or, when not available, the clinical cTNM classification.18

Adjuvant therapy was categorized as (i) no adjuvant therapy, (ii)radiotherapy, (iii) chemotherapy and (iv) radiotherapy and chemo-therapy. Family history of breast and/or ovarian cancer wasobtained from the Familial Breast Cancer Registry. This unit ofthe Geneva Cancer Registry was set up in 1999, by extending itsdata set to the detailed family history of cancer for all womendiagnosed with invasive breast cancer in the Geneva population.

Statistics

Follow-up of breast cancer patients for secondary leukemiaoccurrence started 6 months after breast cancer diagnosis. Follow-up ended on date of leukemia occurrence, date of death, emigra-tion or December 31, 2005. We only considered microscopicallyproven leukemia.

The relative risk of secondary leukemia was expressed as theratio of observed to expected number of cases, i.e. standardizedincidence ratio (SIR).19 To calculate the expected number ofcases, we multiplied the age- and calendar period specific inci-dence rates of leukemia in the background population by corre-spondingly stratified person-years at risk in our breast cancercohort and summing all the products. With Cox regression analy-sis we evaluated whether differences in leukemia risk betweenwomen of high versus low familial risk persisted after adjustmentfor age, disease stage and types of adjuvant treatment.

Results

Between 1990 and 2004, 4,861 women were diagnosed withinvasive breast cancer in Geneva, Switzerland. We excludedpatients diagnosed with in situ or invasive cancer before or within

6 months after breast cancer diagnosis (n 5 445). In addition, weexcluded 19 autopsy cases, leaving us with 4,397 patients with pri-mary invasive breast cancer. After a median follow-up of 61months (mean, 72 months), 14 patients (0.32%) developed second-ary leukemia. The time interval between breast cancer diagnosisand date of leukemia diagnosis varied from 8 months to 7.7 years.

A moderate familial risk was reported for 885 (20%) patients,and 240 (5.5%) patients were classified as having a high familialrisk. For 405 (9.2%) patients, there was no information on pres-ence or absence of breast or ovarian cancer in family members.Patients with a moderate or high familial risk were on average 2years younger at breast cancer diagnosis than those at low familialrisk (58–59 years vs. 61 years respectively; Table I). Stage distri-bution was similar for women at low, moderate and high familialrisk: for all 3 groups, more than 80% of cancers were stage I orstage II at diagnosis. However, women at moderate or high fami-lial risk were more likely to have received some type of adjuvanttreatment: 80% of women at low familial risk received adjuvanttreatment versus 87% of women at moderate or high familial risk(p < 0.001). Women at unknown familial risk were older, hadmore often advanced stage disease, less often adjuvant treat-ment and more often missing information on stage and adjuvanttreatment.

TABLE I – CHARACTERISTICS OF 4,397 BREAST CANCER PATIENTS ACCORDING TO FAMILIAL RISK FACTORS

Familial risk

Low Moderate High Unknown p value (chi square)

N 2,867 (65.2)1 885 (20.1) 240 (5.5) 405 (9.2)Mean age (test with ANOVA) 60.7 [24–100]2 58.1 [25–94] 58.6 [24–97] 69.6 [29–101] <0.0001Stage

I 1110 (39) 340 (38) 93 (39) 109 (27) <0.0001II 1226 (43) 403 (46) 111 (46) 133 (33)III 264 (9) 85 (10) 24 (10) 38 (9)IV 159 (6) 33 (4) 7 (3) 53 (13)Unknown 108 (4) 24 (3) 5 (2) 72 (18)

Adjuvant treatmentNone 577 (20) 115 (13) 30 (13) 229 (57) <0.0001Chemo only 209 (7) 72 (8) 18 (8) 38 (9)RT only 1088 (38) 347 (39) 102 (43) 32 (8)RT and chemo 885 (31) 327 (37) 83 (35) 30 (7)Unknown 108 (4) 24 (3) 7 (3) 76 (19)

RT, radiotherapy; chemo, chemotherapy.1Values given in parentheses indicate percentages.–2Values given in square brackets indicate ranges.

TABLE II – CHARACTERISTICS OF BREAST CANCER PATIENTS WHODEVELOPED SECONDARY LEUKEMIA ACCORDING TO FAMILY HISTORY

OF BREAST OR OVARIAN CANCER

Familial risk

Low(N5 6)

Increased(N 5 7) p value

Mean age at breast cancerdiagnosis (years)

67 66 0.861

Mean age at leukemiadiagnosis (years)

70 71 0.812

Delay between breast cancerand leukemia (months)

27 60 0.007

Stage at diagnosis 0.796*I 3 (50)1 3 (43)II 3 (50) 4 (57)III/IV 0 (0) 0 (0)

Adjuvant treatment 0.657*None 1 (17) 1 (20)Only radiotherapy 3 (50) 5 (60)Radio- and chemotherapy 2 (33) 1 (20)Only chemotherapy 0 (0) 0 (0)

One patient with missing information on familial risk was notincluded in this table.*p values were obtained by Fisher’s exact test.1Values given in parentheses indicate percentages.

1115RISK OF SECONDARY LEUKEMIA AFTER BREAST CANCER

Among the 14 patients who developed leukemia after breastcancer, 6 belonged to low risk families, 7 had an increased fami-lial risk (5 moderate and 2 high familial risks) and for 1 patient thefamily history was missing. There were no major differences interms of age at breast cancer diagnosis, age at leukemia diagnosis,stage at diagnosis and type of adjuvant breast cancer treatmentbetween women at low versus increased familial risk (Table II).Women at low familial risk had on average a significantly shortertime interval between breast cancer diagnosis and onset of second-ary leukemia than those with increased familial risk.

Compared to the general population, breast cancer patients ingeneral were at increased risk of developing leukemia (SIR 2.3,95% CI 1.2–3.8). This excess risk was significant only for acuteleukemia (SIR 3.2, 95% CI 1.2–6.9) but not for chronic leukemia(SIR 1.6, 95% CI 0.6–3.5). After stratification by familial risk, theSIR of leukemia was higher for patients with an increased familialrisk compared to those without (Table III). Breast cancer patientswithout a family history of breast and/or ovarian cancer did nothave an increased risk of secondary leukemia compared to thegeneral population (SIR 1.4, 95% CI 0.5–3.1), but patients with amoderate or high familial risk had a more than 5-fold increasedrisk of leukemia (SIR 5.4, 95% CI 2.2–11.1). After further stratifi-cation into acute and chronic leukemia, the risk of acute leukemiawas almost 3-fold, but not significantly increased for women with-out familial risk (SIR 2.8, 95% CI 0.9–6.9). Breast cancer patientsat increased familial risk had a significantly increased risk of acuteleukemia compared to the general population (SIR 5.7, 95% 1.2–16.6). The risk of chronic leukemia was not increased for breastcancer patients at low familial risk (SIR 0.4, 95% CI 0.01–2.2),but significantly increased for breast cancer patients at increasedfamilial risk (SIR 5.2, 95% CI 1.4–13.3).

Within the group of breast cancer patients, a family history ofbreast/ovarian cancer was associated with a significantly higherrisk of developing chronic leukemia [hazard ratio (HR) 11.0, 95%CI 1.2–98.5], but not of acute leukemia (HR 1.6, 95% CI 0.4–6.5).These risks did not change after adjustment for age, stage and useof adjuvant chemotherapy and/or radiotherapy (multiadjusted HRs11.6, 95% CI 1.3–104.7 for chronic leukemia and 1.6, 95% CI0.4–6.6 for acute leukemia). Also, in subgroup analysis including

patients treated with radiotherapy only, or patients treated withradiotherapy with or without chemotherapy, the excess risk ofpatients at increased familial risk remained elevated (Table IV).

Discussion

In consistence with previous studies, we observed an increasedrisk of leukemia in women treated for breast cancer.1,2,6 Usually,these increased risks of leukemia are being attributed to exposureto radiotherapy and certain chemotherapeutical agents.1,3,6 Ourresults suggest that familial risk factors may modify the risk ofsecondary leukemia after breast cancer as well. For the first timewe show that breast cancer patients with first or second degreerelatives with breast and/or ovarian cancer have higher risks ofdeveloping secondary leukemia, not only compared to the generalpopulation, but also compared to breast cancer patients withoutfamilial risk factors. This excess risk is chiefly due to an excessrisk of chronic leukemia.

There are several potential explanations for our findings. Firstof all, women at increased familial risk may have received differ-ent adjuvant treatment regimens. In fact, in an earlier study wedemonstrated that young breast cancer patients were more likelyto receive some kind of adjuvant systemic therapy if they are athigh familial risk.20 Also in the present study, women at increasedfamilial risk were more likely to have received some form of adju-vant treatment than women without familial risk. Nevertheless,the design of this study allowed us to adjust for this potentiallyconfounding factor, and we found that the risk estimates of leuke-mia following breast cancer were not modified by adjusting foruse of adjuvant treatment. Nevertheless, we cannot exclude thatthe radiotherapy and chemotherapy regimens of women of highversus low familial risk may have differed in terms of cumulativedoses and intensity, conferring different risks of leukemia.

Women at increased familial risk may have been receivingmore intensive follow-up after their breast cancer than womenwithout affected family members. Although we find this ratherunlikely, we cannot exclude that more intensive follow-up of

TABLE III – STANDARDIZED INCIDENCE RATES (SIRs) OF LEUKEMIA FOLLOWING BREAST CANCER

Familial riskAll leukemia Chronic leukemia Acute leukemia

Observed Expected SIR Observed Expected SIR Observed Expected SIR

Low 6 4.3 1.4 (0.5–3.1)1 1 2.5 0.4 (0.01–2.2) 5 1.8 2.8 (0.9–6.9)Increased 7 1.3 5.4 (2.2–11.1) 4 0.77 5.2 (1.4–13.3) 3 0.53 5.7 (1.2–16.6)Unknown 1 0.68 1.5 (0.04–8.13) 1 0.43 2.4 (0.1–13.1) 0 0.25 NAAll 14 6.2 2.3 (1.2–3.8) 6 3.7 1.6 (0.6–3.5) 8 2.5 3.2 (1.2–6.9)

SIR, standardized incidence ratio; NA, not applicable.1Values given in parentheses indicate 95% CIs.

TABLE IV – RISKS (HAZARD RATIOS) OF SECONDARY LEUKEMIA IN PATIENTS WITH A FAMILY HISTORY OF BREAST OR OVARIAN CANCERCOMPARED TO THOSE WITHOUT

Familial riskAll leukemia Chronic leukemia Acute leukemia

Unadjusted HR Adjusted HR Unadjusted HR Adjusted HR Unadjusted HR Adjusted HR

All patients (4,397)Low 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref)Increased 3.1 (1.0–9.2) 3.2 (1.1–9.5) 11.0 (1.2–98.5) 11.6 (1.3–104.7) 1.6 (0.4–6.5) 1.6 (0.4–6.6)

Patients treated withradiotherapy only (n5 1,537)

Low 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref)Increased 4.4 (1.1–18.5) 4.4 (1.0–18.4) 5.5 (0.5–60.7) 5.5 (0.5–60.3) 3.9 (0.5–60.7) 3.9 (0.6–23.1)

Patients treated with radiotherapy,with or without chemotherapy(n5 2,832)

Low 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref)Increased 2.9 (0.9–9.5) 3.0 (0.9–10.0) 7.5 (0.8–72.0) 7.9 (0.8–75.8) 1.8 (0.8–72.0) 1.9 (0.4–8.3)

HR, hazard ratio; ref, reference category.

1116 VERKOOIJEN ET AL.

patients at increased familial risk may have increased the likeli-hood of being diagnosed with chronic leukemia.

Shared genes may also explain the increased risk of leukemia inbreast cancer patients with a positive family history. Breast cancerand leukemia cluster in families with rare hereditary cancer syn-dromes12 and adult acute leukemia patients are more likely to have afamily history of breast cancer as compared to healthy controls.13 Inaddition, a study by Rudd et al. provided evidence that inherited pre-disposition to chronic lymphocytic leukemia was partly mediatedthough low-penetrance polymorphisms in the ARM-BRCA2-Chek2DNA damage-response axis. Mutations/variations in these samegenes are also associated with increased risk of breast cancer.21

Finally, it has been hypothesized that the presence of a familyhistory of breast cancer modified the effect of certain leukemo-genic risk factors on the risk of developing leukemia.22 Rausscheret al. showed that exposure to smoking, solvents, aromatic hydro-carbon and diagnostic radiation exams doubled the risk of acuteleukemia in the presence of a family history of breast cancer andoften tripled it in case of an affected sibling. Extrapolating thesefindings to our study, we could theorize that exposure to radiother-apy and chemotherapy has a stronger impact in the presence of apositive family history of breast/ovarian cancer. Unfortunately,our study sample was too limited to test for interaction betweenfamilial risk factors and adjuvant treatment.

We recognize that our study has several shortcomings. First ofall, the number of leukemia cases was rather limited, impairing

detailed analyses and tests for interaction. Nevertheless, even withsmall numbers, rather high and statistically significant risk esti-mates were obtained, suggesting that the associations are real andimportant. As mentioned earlier, the Geneva Cancer Registry hasno automated detailed information on types and doses of chemo-therapy and radiotherapy administered, preventing us from evalu-ating dose–response relationships. Since the Familial Breast Can-cer Registry only started in 1990, the follow-up of our populationis rather limited. However, even with relatively short follow-upwe found significantly increased leukemia risks for women atincreased familial risk.

Therefore, we can conclude that the risk of leukemia followingbreast cancer is higher in women with a family history of breast/ovarian cancer. This is particularly true for chronic leukemia.Future research is needed to unravel the underlying reasons forthis association. If our findings were to be confirmed in largerstudies, we may have to rethink the optimal treatment and follow-up strategies for breast cancer patients with an increased familialrisk.

Acknowledgements

Dr. H.M. Verkooijen was financially supported by PROSPERGrant No. 3233-069350 from the Swiss National Science Founda-tion. The Geneva Familial Breast Cancer Registry was set up withfinancial support of the Swiss Cancer League.

References

1. Howard RA, Gilbert ES, Chen BE, Hall P, Storm H, Pukkala E, Lang-mark F, Kaijser M, Andersson M, Joensuu H, Fossa SD, Travis LB.Leukemia following breast cancer: an international population-basedstudy of 376,825 women. Breast Cancer Res Treat 2007;105:359–68.

2. Renella R, Verkooijen HM, Fioretta G, Vlastos G, Kurtz J, SappinoAP, Schafer P, Neyroud-Caspar I, Bouchardy C. Increased risk ofacute myeloid leukaemia after treatment for breast cancer. Breast2006;15:614–19.

3. Curtis RE, Boice JD, Jr, Stovall M, Bernstein L, Greenberg RS,Flannery JT, Schwartz AG, Weyer P, Moloney WC, Hoover RN. Riskof leukemia after chemotherapy and radiation treatment for breastcancer. N Engl J Med 1992;326:1745–51.

4. Rubino C, De Vathaire F, Diallo I, Shamsaldin A, Le MG. Increasedrisk of second cancers following breast cancer: role of the initial treat-ment. Breast Cancer Res Treat 2000;61:183–95.

5. Smith RE, Bryant J, DeCillis A, Anderson S. Acute myeloid leukemiaand myelodysplastic syndrome after doxorubicin-cyclophosphamide ad-juvant therapy for operable breast cancer: the National Surgical Adju-vant Breast and Bowel Project Experience. J Clin Oncol 2003;21:1195–204.

6. Chaplain G, Milan C, Sgro C, Carli PM, Bonithon-Kopp C. Increasedrisk of acute leukemia after adjuvant chemotherapy for breast cancer:a population-based study. J Clin Oncol 2000;18:2836–42.

7. Andersen MK, Christiansen DH, Jensen BA, Ernst P, Hauge G,Pedersen-Bjergaard J. Therapy-related acute lymphoblastic leukaemiawith MLL rearrangements following DNA topoisomerase II inhibi-tors, an increasing problem: report on two new cases and review ofthe literature since 1992. Br J Haematol 2001;114:539–43.

8. Sellick GS, Catovsky D, Houlston RS. Familial chronic lymphocyticleukemia. Semin Oncol 2006;33:195–201.

9. Jonsson V, Houlston RS, Catovsky D, Yuille MR, Hilden J, Olsen JH,Fajber M, Brandt B, Sellick G, Allinson R, Wiik A. CLL family ‘Ped-igree 14� revisited: 1947–2004. Leukemia 2005;19:1025–8.

10. Schottenfeld D, Fraumeni JF. Cancer epidemiology and prevention.New York: Oxford University Press, 2006.

11. Yuille MR, Matutes E, Marossy A, Hilditch B, Catovsky D, HoulstonRS. Familial chronic lymphocytic leukaemia: a survey and review ofpublished studies. Br J Haematol 2000;109:794–9.

12. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancersin families with ataxia-telangiectasia. N Engl J Med 1987;316:1289–94.

13. Rauscher GH, Sandler DP, Poole C, Pankow J, Mitchell B, Bloom-field CD, Olshan AF. Family history of cancer and incidence of acuteleukemia in adults. Am J Epidemiol 2002;156:517–26.

14. Bouchardy C. Switzerland, Geneva. In: Parkin DM, Whelan SL,Ferlay J, Raymond L, Young J, eds. Cancer incidence in five conti-nents, Vol. 7. Lyon: International Agency for Research on Cancer,1997. 666–9.

15. World Health Organization (WHO), eds. ICD-O International classifi-cation of diseases for oncology, 1st ed. Geneva: World Health Organi-zation, 1976.

16. Bouchardy C, Verkooijen HM, Chappuis PO, Vlastos G, Sch€afer P,Kurtz J, Benhamou S, Sappino AP. Occurrence and impact of geneticfactors in breast cancer among the female population in Geneva: crea-tion of the Geneva familial breast cancer registry. Bull Suisse Cancer2002;2650:165–8.

17. Hampel H, Sweet K, Westman JA, Offit K, Eng C. Referral for cancergenetics consultation: a review and compilation of risk assessment cri-teria. J Med Genet 2004;41:81–91.

18. Sobin LH, Wittekind Ch, eds. TNM classification of malignanttumours, 6th ed. New York: UICC, 2002.

19. Coleman MP, Hermon C, Douglas A. Person-Years (PYRS). A For-tran program for cohort study analysis. Lyon: International Agencyfor Research on Cancer (IARC), 1989. Report No. 89/006.

20. Verkooijen HM, Chappuis PO, Rapiti E, Vlastos G, Fioretta G, SarpS, Sappino AP, Schubert H, Bouchardy C. Impact of familial risk fac-tors on management and survival of early-onset breast cancer: a popu-lation-based study. Br J Cancer 2006;94:231–8.

21. Rudd MF, Sellick GS, Webb EL, Catovsky D, Houlston RS. Variantsin the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocyticleukemia. Blood 2006;108:638–44.

22. Rauscher GH, Sandler DP, Poole C, Pankow J, Shore D, BloomfieldCD, Olshan AF. Is family history of breast cancer a marker of suscep-tibility to exposures in the incidence of de novo adult acute leukemia?Cancer Epidemiol Biomarkers Prev 2003;12:289–94.

1117RISK OF SECONDARY LEUKEMIA AFTER BREAST CANCER