Risk of second cancer among women with breast cancer

Risk of second cancer among women with breast cancer

Lene Mellemkjær1*, Søren Friis

1, Jørgen H. Olsen

1, Ghislaine Sc�elo2, Kari Hemminki

3,4, Elizabeth Tracey

5, Aage Andersen

6,

David H. Brewster7, Eero Pukkala8, Mary L. McBride9, Erich V. Kliewer10,11, Jon M. Tonita12, Chia Kee-Seng13,Vera Pompe-Kirn14, Carmen Martos15, Jon G. Jonasson16,17, Paolo Boffetta2 and Paul Brennan2

1Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark2Gene-Environment Epidemiology Group, Genetics and Epidemiology Cluster, International Agency for Research on Cancer (IARC),Lyon, France3Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany4Department of Biosciences at Novum, Karolinska Institute, Hudinge, Sweden5New South Wales Cancer Registry, Eveleigh, NSW, Australia6Institute of Population-Based Cancer Research, Oslo, Norway7Scottish Cancer Registry Information Services, NHS National Services Scotland, Edinburgh, Scotland8Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland9Cancer Control Research Programme, British Columbia Cancer Agency, Vancouver, BC, Canada10Epidemiology and Cancer Registry, CancerCare Manitoba, Winnipeg, MB, Canada11Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada12Program Evaluation and Surveillance, Saskatchewan Cancer Agency, Regina, SK, Canada13Center for Molecular Epidemiology, Singapore14Cancer Registry of Slovenia, Institute of Oncology, Ljubljana, Slovenia15Cancer Registry of Zaragoza, Health Department of Aragon Government, Zaragoza, Spain16Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland17The Medical Faculty, University of Iceland, Reykjavik, Iceland

A large number of women survive a diagnosis of breast cancer.Knowledge of their risk of developing a new primary cancer isimportant not only in relation to potential side effects of their can-cer treatment, but also in relation to the possibility of shared etiol-ogy with other types of cancer. A cohort of 525,527 women withprimary breast cancer was identified from 13 population-basedcancer registries in Europe, Canada, Australia and Singapore,and followed for second primary cancers within the period 1943–2000. We used cancer incidence rates of first primary cancer forthe calculation of standardized incidence ratios (SIRs) of secondprimary cancer. Risk of second primary breast cancer after vari-ous types of nonbreast cancer was also computed. For all secondcancer sites combined, except contralateral breast cancer, wefound a SIR of 1.25 (95% CI 5 1.24–1.26) on the basis of 31,399observed cases after first primary breast cancer. The overall riskincreased with increasing time since breast cancer diagnosis anddecreased by increasing age at breast cancer diagnosis. Therewere significant excesses of many different cancer sites; amongthese the excess was larger than 150 cases for stomach (SIR 51.35), colorectal (SIR 5 1.22), lung (SIR 5 1.24), soft tissue sar-coma (SIR 5 2.25), melanoma (SIR 5 1.29), non-melanoma skin(SIR 5 1.58), endometrium (SIR 5 1.52), ovary (SIR 5 1.48), kid-ney (SIR 5 1.27), thyroid gland (SIR 5 1.62) and leukaemia (SIR 51.52). The excess of cancer after a breast cancer diagnosis is likely tobe explained by treatment for breast cancer and by shared geneticor environmental risk factors, although the general excess of cancersuggests that there may be additional explanations such as increasedsurveillance and general cancer susceptibility.' 2005 Wiley-Liss, Inc.

Key words: female breast cancer; second primary cancer; multi-centre cohort study

Breast cancer is the most common cancer among women indeveloped countries. The 5-year relative survival was 77% amongwomen diagnosed with breast cancer in the period 1990–1994 in22 European countries included in EUROCARE-3,1 and a consid-erable number of women are thus at long-term risk of developinga second primary cancer after breast cancer.

A large number of cancer registry-based studies on the risk ofsecond primary cancer after breast cancer have been published,2–15

with most studies coming from Europe and a few from the United

States12,14 and Japan.3,10 The number of breast cancer cases investi-gated ranged from a few thousands up to about 150,000, while theperiod of breast cancer diagnoses ranged from 1943 to 1998 andlength of follow-up from 8 to 48 years. Most studies reported anoverall excess of 20–30% for second primary cancer not includingcontralateral breast cancer. Excesses of various cancer sites havebeen shown, with the most consistent findings for cancer of theendometrium,2,4,6,7,11–13,15 ovary,3,4,6,7,9,11–13 thyroid gland3,7,10–12

and lung,4,7,11–13 as well as soft tissue sarcomas2,4,6,12,13 and leukae-mia.4,6,11,13,14 Excesses of melanoma,6,7,12,13 stomach4,10,15 andcolon cancer10–12 have also been reported. There is a general ten-dency in many studies towards higher risks of second malignanciesamong younger women with breast cancer compared to olderwomen.4,6–8,11,12 A positive association between a first primarybreast cancer and second primaries at other sites may be a result ofshared risk factors, i.e., genetic, hormonal or environmental factors,or a result of the treatment for breast cancer, such as radiotherapy,chemotherapy and hormonal therapy.

The present investigation is a multicentre study including can-cer data from 13 population-based cancer registries in Europe,Australia, Canada and Singapore. The data were used to assess theincidence of second primary cancer among 525,527 women diag-nosed with a first primary breast cancer between 1943 and 2000.In addition, we assessed the risk of second primary breast cancerafter a first primary nonbreast cancer of various types to determinewhether associations are likely to be caused by shared risk factorsor treatment. The large dataset gave us the possibility to assessrisks quite accurately without much influence from random varia-tion, even when looking at rare cancer types and/or stratificationsof the dataset, e.g., by latency and age.

Grant sponsor: National Cancer Institute; Grant number: R03CA101442-02.*Correspondence to: Institute of Cancer Epidemiology, Danish Cancer

Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark.Fax:145-35-25-77-31/145-35-25-77-34. E-mail: [email protected] 23 November 2004; Accepted after revision 22 August 2005DOI 10.1002/ijc.21651Published online 8 December 2005 in Wiley InterScience (www.

interscience.wiley.com).

Int. J. Cancer: 118, 2285–2292 (2006)' 2005 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

Material and methods

This study is part of an international multicentre study of sec-ond primary cancers coordinated by the International Agency forResearch on Cancer, including data from 13 non-United Statescancer registries that have been in operation for at least 25 years.The registries include New South Wales in Australia, BritishColumbia, Manitoba and Saskatchewan in Canada, Denmark, Fin-land, Iceland, Norway, Scotland, Singapore, Slovenia, Swedenand Zaragoza in Spain. These registries have cancer data coveringdifferent time periods within the period 1943–2000. DifferentICD-classifications have been used, but for the purpose of ourstudy, all cancer codes have systematically been converted intoICD-9. Coding of multiple primaries in the cancer registries hasfollowed a common set of rules proposed by the InternationalAssociation of Cancer Registries (IACR) and the InternationalAgency for Research on Cancer (IARC).16 This was possible asall participating cancer registries currently use the IARC/IACRrules or a local set of more extensive or detailed rules. Accordingto the rules, a primary cancer is one that originates in a primarysite or tissue and is thus neither an extension, nor a recurrence nora metastasis. Only 1 tumor shall be recognized as arising in anorgan or pair of organs or tissue (as defined by the three-charactercategory of the ICD or the topography of the ICD-O) unless thehistology is different.

Cancer of brain and nervous system, bladder cancer and non-melanoma skin cancer have been registered differently in the vari-ous registries. In the present study, we followed the same rules asapplied in Cancer in five Continents,17 so the category brain andnervous system only included malignant tumors, while the cate-gory bladder cancer included papillomas (although not all regis-tries included papillomas). Regarding non-melanoma skin cancer,some registries include all types, others include only squamouscell carcinoma, while others have no data on non-melanoma skincancer. In the category of non-melanoma skin cancer, we includedall cases that were recorded in the individual registers. Risk forcontralateral breast cancer could not be assessed, since the IARC/

IACR rules do not permit coding of more than 1 tumor in pairedorgans if the histology is identical. Also, risk of contralateralbreast cancer of different histology could not be investigated,since data on second breast cancers lacked specifications onwhether the second breast cancer occurred in the same breast asthe first primary breast cancer or was a contralateral breast cancer.

Variables included in each of the 13 datasets were a uniquestudy number, date of birth, sex, date of diagnosis of first primarycancer, diagnosis of first primary cancer (ICD-9), date of exit fromthe cohort, reason for exit, diagnosis of second primary cancer(ICD-9) and date of second primary cancer, if any. The data fromthe 13 cancer registries were checked carefully for inconsistenciesand missing information, with verification provided by the localregistry when required. A small proportion of subjects (0.06%)were excluded because of remaining missing or inconsistent infor-mation. Furthermore, patients for whom the first primary cancerdiagnosis and death were recorded at the same time or who had 2first primary cancers recorded simultaneously (same dates of diag-nosis) were excluded (8%). After these exclusions, there were525,527 women with a first primary breast cancer (ICD-95 174).

All cases of first primary breast cancer in females were fol-lowed up for second primary cancer from date of first breast can-cer diagnosis (1943–2000) to date of second primary cancer(1943–2000), date of death, date of migration or end of follow-up(1992–2000). The number of second primary cancer observed wascompared to an expected number of cancers calculated from accu-mulated person-years and rates among females of first primarycancer specific for each registry and 5-year age and calendar-peri-ods. In parallel, cases of various types of first primary nonbreastcancer were followed up for second primary breast cancer, withentry and exit dates, and the calculation of an expected number ofbreast cancer cases as described earlier. This analysis was carriedout to help determine whether associations are likely to be causedby treatment for breast cancer or shared risk factors. If there is noreverse association between breast cancer and another type of can-cer, and if the risk of this type of cancer after breast cancer

TABLE I – DESCRIPTION OF FIRST PRIMARY BREAST CANCER CASES FROM 13 CANCER REGISTRIES

Characteristic Number of first primarybreast cancer cases (%)

Person-yearsof follow-up

Age at first breast cancer (years)Premenopausal

<41 38,681 (7) 356,90941–45 43,839 (8) 423,590

Perimenopausal46–55 121,629 (23) 1,057,565

Postmenopausal56–65 124,118 (24) 917,57266–74 103,117 (20) 643,600751 94,143 (18) 385,424

Year of first breast cancer<1975 119,999 (23) 1,253,8841975–1983 124,171 (24) 1,167,5351984–1990 123,874 (24) 870,94219911 157,483 (30) 492,299

Cancer Registry (time period)Australia, New South Wales (1972–1997) 56,076 (11) 370,313Europe

Denmark (1943–1997) 100,078 (19) 740,136Finland (1953–1998) 68,944 (13) 494,208Iceland (1955–2000) 3,298 (1) 25,309Norway (1953–1999) 66,468 (13) 524,259Slovenia (1961–1998) 13,269 (3) 97,304Spain, Zaragoza (1978–1998) 5,344 (1) 31,993Sweden (1961–1998) 90,634 (17) 722,205Scotland (1960–1996) 51,910 (10) 279,065

North AmericaCanada, British Columbia (1970–1998) 40,299 (8) 295,459Canada, Manitoba (1970–1999) 12,834 (2) 86,324Canada, Saskatchewan (1967–1998) 9,716 (2) 85,086

Asia, Singapore (1968–1992) 6,657 (1) 32,999

2286 MELLEMKJÆR ET AL.

increases with time since breast cancer, then the association ismost likely explained by treatment for breast cancer. On the otherhand, if a reverse association exists, and there is no increase in riskby latency, then shared risk factors are more likely to explain theassociation.

We did not have information on menopausal status of thewomen at diagnosis of breast cancer, and so age at cancer wasused as a surrogate for menopausal status (age � 45 years, preme-nopausal women; 46 � age � 55 years, perimenopausal women;age � 56, postmenopausal women). Since long-term follow-up isparticularly interesting in relation to treatment-induced cancer,we performed an analysis including 133,414 women who werefollowed for more than 10 years after the first primary breastcancer, with stratification on age at breast cancer and calendar-year(Table V). Only cancer sites with a priori expectations as being treat-ment induced were included, i.e., for radiotherapy this is organs closeto the breast such as esophagus, lung, thyroid gland, stomach, softtissue sarcomas of thorax and upper limb as well as leukaemia, forchemotherapy myeloid leukaemia and for hormonal therapy endome-trial cancer.

Results

Second primary cancer after first primary breast cancer

The study population of 525,527 women with a first primarybreast cancer contributed with 3,784,660 person-years of follow-up (mean, 7.2 years; range >0–55 years). At the time of the breastcancer diagnosis, 82,520 (15%) women were premenopausal and321,378 (61%) women were postmenopausal according to the def-inition given earlier (Table I). There were 119,999 (23%) womenwho were diagnosed before 1975, 248,045 (47%) diagnosed between1975 and 1990 and 157,483 (30%) diagnosed after 1990. The major-ity of cases were from Europe (76%), while a smaller number werefrom Canada (12%), Australia (11%) and Singapore (1%).

The risk of all second primary cancer sites combined after a firstprimary breast cancer was 1.25 (95% CI 5 1.24–1.26) (Fig. 1).Significantly elevated risks were seen for numerous cancer siteswith standardized incidence ratios (SIRs) ranging from 1.10 forpancreatic cancer to 2.25 for soft tissue sarcoma. For soft tissuesarcoma located in the thorax or upper limb including shoulder,the SIR was even higher (N 5 114; SIR 5 5.97; 95% CI 5 4.93–7.18). A significantly decreased risk was seen for a few sites,including liver (SIR 5 0.75; 95% CI 5 0.64–0.86), cervix (SIR 50.94; 95% CI 5 0.88–1.00), brain and nervous system (SIR 50.83; 95% CI 5 0.75–0.93) and multiple myeloma (SIR 5 0.90;95% CI 5 0.82–0.99). The risk for all second malignancies wassignificantly increased for all cancer registries except for Zara-goza in Spain (SIR 5 0.95; 95% CI 5 0.80–1.12) and Singapore(SIR 5 0.90; 95% CI 5 0.74–1.07), but these registries contrib-uted with less than 2 percent of the person-years. The cancer pat-tern was remarkably consistent for all cancer registries with ele-vated risks for various cancer sites and reduced risks for the fewsites mentioned above. Bone cancer was an exception, since theincreased risk for this cancer site was mainly due to excesses seenin the Australian, Danish and Norwegian materials. Omittingresults for these registries reduced the number of observed bonecancers to 25 (SIR 5 1.12; 95% CI5 0.72–1.65).

For all sites combined, the risk increased with the length of timesince breast cancer diagnosis, from a slightly increased SIR of1.04 within 1 year of diagnosis to a SIR of 1.20 during 1–9 yearsand 1.42 after 10 or more years (Table II). The overall incidencerate differences were 2.6/10,000 person-years less than 1 year afterbreast cancer, 12.6/10,000 person-years 1–9 years after breast can-cer and 33.1/10,000 person-years after 10 or more years. The riskincreased with increasing time since first primary breast cancer forcancer of the oral cavity and pharynx (p-value for trend 5 0.01),esophagus (p < 0.01), stomach (p < 0.01), colorectum (p < 0.01),pancreas (p < 0.01), lung (p < 0.01), non-melanoma skin cancer(p < 0.01), ovary (p < 0.01), bladder cancer (p < 0.01), soft tissue

sarcoma (p < 0.01), non-Hodgkin’s lymphoma (p < 0.01) andmyeloid leukaemia (p 5 0.10). For melanoma, endometrial can-cer, thyroid cancer and total leukaemia, the risk was quite constantthroughout follow-up, while for kidney cancer the risk was mostpronounced within the first year of follow-up.

For most cancer sites, the risk decreased with increasing age atfirst primary breast cancer (Table III). Exceptions were cancer ofthe endometrium for which the risk among postmenopausalwomen (age � 56 years) were higher than for premenopausalwomen (age � 45 years), and oral cavity and pharynx, melanomaand kidney for which there were little difference between riskamong premenopausal and postmenopausal women. Among pre-menopausal women, SIRs above 2.5 were seen for soft tissue sar-coma of the thorax and upper limb, including the shoulder (SIR 513.70), bone cancer (SIR 5 4.04), ovarian cancer (SIR 5 2.84)and myeloid leukaemia (SIR 5 3.02).

The overall risk of second malignancies decreased with increas-ing calendar-time, but the SIR was still significantly elevated for

FIGURE 1 – SIRs and 95% CIs for second primary cancer among525,527 women with a first primary breast cancer.

2287SECOND CANCER AFTER FEMALE BREAST CANCER

women diagnosed with breast cancer after 1990 (Table IV).Decreasing risks by calendar-time were seen for cancer of the oralcavity and pharynx, colorectum, pancreas, lung, bone, ovary andbladder, as well as for soft tissue sarcoma and non-Hodgkin’s lym-phoma. For cancer of pancreas, lung, bone and bladder and non-Hodgkin’s lymphoma, the increase in risk disappeared in the mostrecent period(s), whereas the risk for soft tissue sarcoma was stillmarkedly increased. A reverse pattern with increasing risk by cal-endar-time was seen for stomach and endometrium cancer,whereas the risk was quite constant for myeloid leukaemia.

Table V presents risks by age and calendar-time at breast cancerdiagnosis for possibly treatment-induced cancer sites for 133,414women with first primary breast cancer who were followed for 10

or more years. For sites suspected to be related to radiotherapy,there was a tendency towards higher risks among the youngest andamong those with breast cancer before 1975. For the main chemo-therapy-induced site, myeloid leukaemia, the risk did not differmuch by age, but there was a tendency towards higher risk incases diagnosed during 1984–1990. For endometrial cancer, ahigher risk was found among older women and in cases diagnosedduring 1984–1990.

Second primary breast cancer after selected types of firstprimary cancer

The risk of second primary breast cancer after various types offirst primary cancer is presented in Table VI. The risk for second

TABLE II – OBSERVED (Obs) AND SIR FOR SECOND PRIMARY CANCER AMONG 525,527 WOMEN WITH A FIRST PRIMARY BREAST CANCER BYTIME SINCE FIRST PRIMARY BREAST CANCER

Second primary cancer site<1 year after breast cancer 1–9 years after breast cancer 101 years after breast cancer

Obs SIR 95% CI Obs SIR 95% CI Obs SIR 95% CI

All sites 2,929 1.04 1.01–1.08 17,489 1.20 1.18–1.22 10,981 1.42 1.39–1.44Oral cavity and pharynx 56 1.02 0.77–1.33 328 1.16 1.04–1.29 201 1.40 1.21–1.61Esophagus 28 0.76 0.50–1.09 234 1.27 1.11–1.44 185 2.09 1.80–2.42Stomach 193 1.09 0.94–1.25 1,124 1.34 1.26–1.42 606 1.49 1.38–1.62Small intestine 14 1.33 0.72–2.22 83 1.47 1.17–1.82 42 1.33 0.96–1.80Colorectal 493 1.00 0.92–1.10 3,154 1.22 1.18–1.26 1,880 1.30 1.24–1.36Liver 23 0.90 0.57–1.34 95 0.68 0.55–0.84 67 0.81 0.63–1.03Pancreas 81 0.69 0.55–0.86 659 1.06 0.98–1.14 475 1.32 1.20–1.44Larynx 11 1.25 0.63–2.24 67 1.49 1.15–1.89 26 1.19 0.78–1.74Lung 235 0.93 0.81–1.05 1,471 1.08 1.02–1.13 1,198 1.68 1.59–1.78Bone 2 0.43 0.05–1.56 33 1.50 1.03–2.11 26 2.66 1.73–3.89Soft tissue sarcoma1 2 0.89 0.11–3.21 54 4.73 3.55–6.17 58 10.75 8.16–13.89Melanoma 135 1.33 1.11–1.57 648 1.24 1.15–1.34 352 1.39 1.25–1.54Non-melanoma skin cancer 283 1.23 1.10–1.39 1,856 1.55 1.48–1.62 1,216 1.77 1.67–1.87Corpus uteri 257 1.31 1.16–1.49 1,679 1.62 1.55–1.70 758 1.40 1.30–1.50Ovary 234 1.32 1.15–1.50 1,255 1.38 1.31–1.46 788 1.75 1.63–1.88Bladder 80 0.91 0.72–1.14 540 1.16 1.06–1.26 347 1.30 1.17–1.45Kidney 146 1.72 1.46–2.03 540 1.19 1.09–1.30 326 1.27 1.14–1.42Brain and nervous system 22 0.50 0.31–0.75 179 0.79 0.68–0.91 120 1.06 0.88–1.27Thyroid gland 62 1.75 1.34–2.24 260 1.48 1.31–1.68 149 1.86 1.57–2.19Non-Hodgkin’s lymphoma 96 1.01 0.82–1.23 537 1.03 0.95–1.13 397 1.39 1.26–1.54Leukemia 109 1.42 1.16–1.71 639 1.58 1.46–1.71 317 1.43 1.28–1.60Myeloid leukaemia 34 1.28 0.89–1.79 306 2.28 2.03–2.55 140 2.11 1.78–2.49

1Soft tissue sarcoma of the thorax and upper limb including shoulder.

TABLE III – OBSERVED (Obs) AND SIR FOR SECOND PRIMARY CANCER AMONG 525,527 WOMEN WITH A FIRST PRIMARY BREAST CANCER BYAGE AT BREAST CANCER DIAGNOSIS

Second primary sitePremenopausal breast cancer

(�45 years)Perimenopausal breast cancer

(46–55 years)Postmenopausal breast cancer

(561 years)

Obs SIR 95% CI Obs SIR 95% CI Obs SIR 95% CI

All sites 3,682 1.68 1.63–1.73 7,035 1.36 1.33–1.40 20,682 1.16 1.15–1.18Oral cavity and pharynx 50 1.13 0.84–1.49 127 1.23 1.03–1.47 408 1.22 1.11–1.35Esophagus 29 2.22 1.48–3.18 96 2.17 1.76–2.65 322 1.27 1.14–1.42Stomach 148 2.00 1.69–2.35 381 1.84 1.66–2.03 1,394 1.22 1.16–1.29Small intestine 13 1.52 0.81–2.60 23 1.10 0.70–1.65 103 1.49 1.22–1.81Colorectal 424 1.44 1.30–1.58 994 1.23 1.16–1.31 4,109 1.20 1.17–1.24Liver 16 1.03 0.59–1.68 39 0.89 0.63–1.22 130 0.69 0.58–0.82Pancreas 107 1.75 1.43–2.11 255 1.39 1.23–1.57 853 1.00 0.93–1.07Larynx 10 1.25 0.60–2.30 26 1.25 0.82–1.83 68 1.45 1.13–1.84Lung 404 2.12 1.92–2.33 795 1.53 1.42–1.64 1,705 1.05 1.00–1.10Bone 19 4.04 2.43–6.31 16 1.95 1.11–3.17 26 1.10 0.72–1.62Soft tissue sarcoma1 30 13.70 9.24–19.56 26 6.27 4.09–9.18 58 4.55 3.45–5.88Melanoma 195 1.28 1.10–1.47 318 1.37 1.22–1.52 622 1.26 1.17–1.37Non-melanoma skin 347 2.08 1.87–2.31 637 1.68 1.55–1.82 2,371 1.51 1.45–1.57Corpus uteri 269 1.40 1.23–1.57 612 1.22 1.12–1.32 1,813 1.68 1.61–1.76Ovary 559 2.84 2.61–3.09 684 1.64 1.52–1.77 1,034 1.12 1.06–1.19Bladder 88 1.70 1.36–2.10 178 1.20 1.03–1.39 701 1.13 1.05–1.21Kidney 86 1.33 1.06–1.64 218 1.27 1.10–1.45 708 1.27 1.18–1.37Brain and nervous system 55 1.04 0.78–1.35 86 0.82 0.66–1.01 180 0.79 0.68–0.92Thyroid gland 105 2.00 1.64–2.42 160 2.11 1.80–2.47 206 1.27 1.10–1.45Non-Hodgkin’s lymphoma 87 1.12 0.90–1.39 233 1.27 1.11–1.44 710 1.11 1.03–1.20Leukemia 113 2.16 1.78–2.59 232 1.82 1.59–2.07 720 1.38 1.28–1.48Myeloid leukaemia 64 3.02 2.32–3.85 114 2.60 2.15–3.13 302 1.86 1.66–2.08



primary breast cancer was significantly elevated after a diagnosisof oral cavity and pharynx cancer, colorectal cancer, laryngealcancer, melanoma and non-melanoma skin cancer, endometrialcancer, ovarian cancer, bladder cancer, kidney cancer and thyroidcancer. The risk for second primary breast cancer was significantlyreduced for pancreatic cancer and myeloid leukemia. For mostsites where an excess of second breast cancer was seen, there wasno clear increase in risk by latency with the exception of laryng-eal, kidney and thyroid cancer (Table VI).

Discussion

Our study showed that women with a first primary breast cancerhad a 25% increase in the risk of developing a new primary non-breast cancer in comparison with women without cancer. Therewere excesses of many different types of cancer, including cancersites likely to be associated with treatment modalities for breastcancer, shared genetic predisposition or shared environmental riskfactors. Approximately 33 extra cases of cancer per 10,000 womenper year occurred among women who survived and had no secondcancer during the first 10 years after the breast cancer diagnosis.

Radiation has been used to treat breast cancer since the begin-ning of the 20th century.18 The cancer types of concern in respectto radiotherapy are those in organs close to the breast, such asesophagus, lung, thyroid gland, stomach, soft tissue sarcomas ofthorax and upper limb and leukaemia. Our observation of increas-ing risks by latency and lack of reverse associations supported thatthe excesses of cancers of the esophagus, lung, stomach and softtissue may at least partly be a consequence of treatment for breastcancer. With the exception of esophageal cancer, these types ofcancer have also been found in excess in other studies2,4,6,7,10–13,15

and risks of esophageal cancer, lung cancer and soft tissue sar-coma have been found to be higher, in particular during long-termfollow-up, among patients treated with radiotherapy compared tothose not treated in some studies.12,19–22 The risk estimates forthese cancers among those followed for 10 or more years tendedto be lower after 1975. This pattern may reflect the reduction inexposure of normal tissue with modern radiation techniques,although the lack of long-term follow-up for the most recent casesis a limitation. The 2-fold increase in the risk of soft tissue sarco-mas supports estimates given in some of the previous stud-

ies,2,4,12,13 but none of the earlier studies reported risk of soft tis-sue sarcomas located to the thorax and upper limb. We found a6-fold increase in the risk of sarcomas in the thorax and upperlimb, which indicates that these cancers may indeed be related toradiotherapy.

Thyroid cancer is regarded as a radiation inducible cancer.23

However, even though we found an increased risk for thyroid can-cer, our data do not support the hypothesis that the excess of can-cer of the thyroid is treatment induced, because the risk of thyroidcancer did not increase by latency, and the risk of breast cancerwas increased after thyroid cancer. This is supported by studiesshowing that the risk of thyroid cancer was not higher amongbreast cancer patients treated with radiotherapy compared to thosenot treated with radiotherapy.3,10,12,24 Previous studies reportingthat thyroid cancer can be induced by radiation mainly includedsubjects who were exposed during childhood.23 Therefore, the dis-crepancy between these studies and studies on women treated forbreast cancer may be due to a difference in age at exposure, so thathaving radiotherapy in adulthood may not affect the risk of thyroidcancer to any great extent. Our results are more compatible withshared risk factors as the explanation for the excess of thyroid can-cer. Hormonal factors have been suspected to be involved withthyroid cancer because of the 3:1 female-to-male ratio and find-ings of estrogen receptors in thyroid tumors25; however, a pooledanalysis only found weak associations between menstrual andreproductive factors and thyroid cancer, and not all factors were inthe same direction as those for breast cancer.26

In the early 1970s, cytotoxic chemotherapy was introduced totreat operable stage I and II breast cancer, while metastatic breastcancer has been treated with chemotherapy since the 1950s. Dif-ferent regimens have been used over time. The cancer type of con-cern in relation to chemotherapy is mainly acute myeloid leukae-mia. Two distinct types of acute myeloid leukaemia have beendescribed after exposure to alkylating agents such as cyclophos-phamide and topoisomerase II inhibitors such as epirubicin.27 Theobserved risk pattern in our study for myeloid leukaemia fits wellwith this being a therapy induced cancer, since there was noreverse association and no increase within the first year of follow-up time. The risk was approximately the same during 1–9 and101 years of follow-up, which corresponds well with previousobservations that leukaemia may present within a few years after

TABLE IV – OBSERVED (Obs) AND SIR FOR SECOND PRIMARY CANCER AMONG 525,527 WOMEN WITH A FIRST PRIMARY BREAST CANCER BYCALENDAR-YEAR OF FIRST PRIMARY BREAST CANCER DIAGNOSIS

Second primary siteBefore 1975 1975–1983 1984–1990 19911

Obs SIR 95% CI Obs SIR 95% CI Obs SIR 95% CI Obs SIR 95% CI

All sites 10,563 1.32 1.30–1.35 9,691 1.22 1.20–1.25 7,292 1.23 1.20–1.26 3,853 1.18 1.14–1.22Oral cavity and pharynx 194 1.33 1.15–1.53 185 1.20 1.03–1.38 138 1.19 1.00–1.41 68 1.05 0.82–1.33Esophagus 159 1.67 1.42–1.95 140 1.34 1.12–1.58 98 1.33 1.08–1.62 50 1.36 1.01–1.79Stomach 846 1.27 1.18–1.36 539 1.34 1.23–1.45 369 1.51 1.36–1.67 169 1.54 1.32–1.79Small intestine 34 1.06 0.73–1.48 38 1.27 0.90–1.74 43 1.88 1.36–2.53 24 1.77 1.13–2.63Colorectal 1,872 1.28 1.22–1.34 1,776 1.22 1.17–1.28 1,260 1.21 1.14–1.28 619 1.10 1.02–1.19Liver 67 0.84 0.65–1.06 50 0.63 0.47–0.83 46 0.80 0.59–1.07 22 0.72 0.45–1.10Pancreas 477 1.29 1.18–1.41 355 1.01 0.90–1.12 265 1.06 0.94–1.20 118 0.92 0.76–1.11Larynx 26 1.30 0.85–1.90 41 1.57 1.13–2.13 25 1.30 0.84–1.92 12 1.16 0.60–2.03Lung 838 1.64 1.54–1.76 981 1.23 1.15–1.31 718 1.10 1.02–1.19 367 0.98 0.88–1.08Bone 31 2.20 1.49–3.12 23 2.11 1.34–3.17 5 0.67 0.22–1.56 2 0.50 0.06–1.81Soft tissue sarcoma1 52 8.83 6.59–11.58 38 6.16 4.36–8.45 14 3.18 1.73–5.33 10 3.83 1.84–7.05Melanoma 295 1.44 1.28–1.62 360 1.27 1.14–1.41 291 1.21 1.08–1.36 189 1.27 1.09–1.46Non-melanoma skin 1,052 1.84 1.73–1.95 992 1.45 1.36–1.55 864 1.56 1.45–1.66 447 1.46 1.32–1.60Corpus uteri 737 1.26 1.17–1.35 778 1.45 1.35–1.55 756 1.86 1.73–2.00 423 1.74 1.58–1.92Ovary 825 1.55 1.45–1.66 697 1.50 1.39–1.61 509 1.49 1.36–1.63 246 1.26 1.11–1.43Bladder 325 1.27 1.13–1.41 319 1.19 1.06–1.32 214 1.11 0.97–1.27 109 1.06 0.87–1.27Kidney 329 1.26 1.12–1.40 283 1.15 1.02–1.30 244 1.31 1.15–1.49 156 1.55 1.32–1.81Brain and nervous system 97 0.85 0.69–1.04 111 0.90 0.74–1.08 74 0.80 0.63–1.01 39 0.71 0.50–0.97Thyroid gland 182 1.91 1.64–2.21 120 1.38 1.15–1.66 100 1.49 1.21–1.81 69 1.65 1.28–2.08Non-Hodgkin’s lymphoma 295 1.32 1.17–1.47 325 1.12 1.00–1.25 256 1.06 0.94–1.20 154 1.07 0.91–1.26Leukemia 370 1.56 1.41–1.73 336 1.50 1.35–1.67 222 1.39 1.22–1.59 137 1.64 1.38–1.94Myeloid leukaemia 161 2.17 1.85–2.53 152 2.03 1.72–2.38 107 2.07 1.70–2.51 60 2.26 1.73–2.91



TABLE

V–OBSERVED

(Obs)

AND

SIR

FOR

SELECTED

SECOND

PRIM

ARY

CANCER

SITES

AMONG

133,414WOMEN

WITH

AFIRST

PRIM

ARY

BREAST

CANCER

FOLLOWED

FOR

MORE

THAN

10YEARS

BY

AGE

AT

BREAST

CANCER

DIA

GNOSIS

AND

CALENDAR-Y

EAR

Possibly

treatm

ent-induced

cancersites

Ageatfirstprimarybreastcancer

Calendar-yearforfirstprimarybreastcancer

�45yrs

46–55yrs

561

yrs

<1975

1975–1983

1984–1990

Obs

SIR

95%

CI

Obs

SIR

95%

CI

Obs

SIR

95%

CI

Obs

SIR

95%CI

Obs

SIR

95%

CI

Obs

SIR

95%

CI

Radiotherapy

Esophagus

23

2.3

1.5–3.5

63

2.5

1.9–3.2

99

1.9

1.5–2.3

109

2.4

2.0–2.9

66

1.8

1.4–2.3

10

1.7

0.8–3.0

Stomach

84

1.8

1.4–2.2

196

1.7

1.4–1.9

326

1.4

1.2–1.5

427

1.6

1.4–1.7

152

1.3

1.1–1.6

27

1.3

0.9–2.0

Lung

289

2.2

1.9–2.5

477

1.8

1.6–1.9

432

1.4

1.3–1.5

606

1.9

1.7–2.0

480

1.5

1.4–1.6

112

1.8

1.5–2.2

Softtissuesarcoma1

17

17.7

10.3–28.4

16

9.3

5.3–15.1

25

9.2

5.9–13.6

38

13.0

9.2–17.8

17

8.4

4.9–13.5

36.8

1.4–19.9

Thyroid

gland

35

1.7

1.2–2.4

64

2.3

1.8–2.9

50

1.6

1.2–2.1

100

2.2

1.8–2.6

37

1.3

0.9–1.9

12

1.9

1.0–3.4

Leukem

ia50

1.6

1.2–2.1

104

1.5

1.2–1.8

163

1.4

1.2–1.6

191

1.5

1.3–1.7

108

1.4

1.1–1.7

18

1.2

0.7–1.9

Chem

otherapy

Myeloid

leukaemia

22

2.0

1.3–3.1

43

2.0

1.5–2.7

75

2.2

1.7–2.7

86

2.3

1.8–2.8

42

1.7

1.2–2.3

12

2.8

1.5–4.9

Horm

onaltherapy

Corpusuteri

159

1.2

1.0–1.4

247

1.1

1.0–1.3

352

1.8

1.6–2.0

384

1.3

1.1–1.4

284

1.5

1.3–1.6

90

2.1

1.7–2.6

1Softtissuesarcomaofthethoraxandupper

limbincludingshoulder.

TABLE

VI–OBSERVED

(Obs)

AND

SIR

FOR

SECOND

PRIM

ARY

BREAST

CANCER

AMONG

WOMEN

WITH

SELECTED

FIRST

PRIM

ARY

CANCER

SITES

Firstprimarycancersite

Allsecondprimarybreastcancers

Tim

efrom

firstprimarycancerto

secondprimarybreastcancer

<1year

1–9years

101

years

Obs

SIR

95%

CI

Obs

SIR

95%

CI

Obs

SIR

95%

CI

Obs

SIR

95%

CI

Allfirstprimarycancersites

18,121

1.17

1.15–1.19

2,328

1.12

1.07–1.16

9,856

1.18

1.16–1.21

5,937

1.17

1.14–1.20

Oralcavityandpharynx

452

1.18

1.07–1.30

67

1.32

1.02–1.68

243

1.13

0.99–1.28

142

1.22

1.03–1.44

Esophagus

49

0.91

0.67–1.20

14

0.66

0.36–1.11

27

1.04

0.69–1.52

81.16

0.50–2.29

Stomach

352

0.95

0.85–1.05

83

0.90

0.71–1.11

181

0.93

0.80–1.07

88

1.04

0.84–1.29

Smallintestine

50

1.11

0.83–1.47

60.81

0.30–1.77

29

1.09

0.73–1.57

15

1.37

0.77–2.26

Colorectal

3,034

1.21

1.17–1.25

457

1.15

1.05–1.26

1,766

1.19

1.14–1.25

811

1.29

1.20–1.38

Liver

13

0.84

0.45–1.44

40.58

0.16–1.48

91.39

0.63–2.64

0–

0.00–1.88

Pancreas

51

0.71

0.53–0.93

23

0.58

0.37–0.87

22

0.89

0.56–1.35

60.78

0.29–1.70

Larynx

81

1.26

1.00–1.57

91.09

0.50–2.08

43

1.13

0.81–1.52

29

1.63

1.09–2.34

Lung

388

1.05

0.95–1.16

120

0.92

0.76–1.10

217

1.15

1.01–1.32

51

1.01

0.75–1.32

Bone

52

1.30

0.97–1.70

61.57

0.58–3.42

16

0.91

0.52–1.47

30

1.61

1.09–2.30

Softtissuesarcoma1

32

1.29

0.88–1.82

31.44

0.30–4.20

17

1.51

0.88–2.42

12

1.05

0.54–1.83

Melanoma

1,353

1.19

1.13–1.26

146

1.40

1.18–1.65

761

1.22

1.13–1.31

446

1.10

1.00–1.21

Non-m

elanomaskin

cancer

2,743

1.33

1.28–1.38

317

1.29

1.15–1.44

1,711

1.34

1.28–1.41

715

1.33

1.24–1.43

Corpusuteri

2,877

1.35

1.30–1.40

294

1.55

1.37–1.73

1,551

1.40

1.33–1.47

1,032

1.24

1.17–1.32

Ovary

1,137

1.20

1.14–1.28

148

1.07

0.91–1.26

572

1.22

1.12–1.32

417

1.24

1.12–1.36

Bladder

644

1.17

1.08–1.26

93

1.20

0.97–1.48

397

1.18

1.06–1.30

154

1.13

0.96–1.32

Kidney

468

1.19

1.09–1.31

57

0.94

0.71–1.22

273

1.17

1.04–1.32

138

1.40

1.17–1.65

Brain

andnervoussystem

152

1.01

0.86–1.19

15

0.62

0.35–1.03

69

1.07

0.84–1.36

68

1.11

0.86–1.40

Thyroid

gland

552

1.31

1.21–1.43

36

1.17

0.82–1.62

247

1.23

1.08–1.39

269

1.43

1.27–1.62

Non-H

odgkin’slymphoma

430

0.97

0.88–1.07

61

0.81

0.62–1.04

270

0.97

0.86–1.09

99

1.14

0.92–1.38

Leukem

ia265

1.03

0.91–1.16

54

1.05

0.79–1.37

156

0.93

0.79–1.08

55

1.47

1.11–1.92

Myeloid

leukaemia

37

0.72

0.51–1.00

14

0.94

0.51–1.57

18

0.58

0.34–0.91

51.00

0.32–2.33

1Softtissuesarcomaofthethoraxandupper

limbincludingshoulder.


the breast cancer diagnosis.28 The observation of approximatelythe same risk before and after 1975, however, is not compatiblewith the fact that chemotherapy has been given to a larger propor-tion of breast cancer patients during later periods.

Hormonal therapy with tamoxifen has been used to treat estro-gen-receptor positive breast cancer during the past, that is, morethan 20 years. An increased risk of endometrial cancer has beenfound in prevention and adjuvant trials of tamoxifen29 as well asin observational studies.30–32 Our data suggest that the excess ofendometrial cancer is not entirely caused by tamoxifen, since therisk was already increased within 1 year of the breast cancer diag-nosis, the risk was increased before 1975 when tamoxifen wasrarely used, and an increased risk of breast cancer was also seenafter endometrial cancer. Thus, common risk factors such asreproductive and genetic factors, obesity33,34 and/or some un-known factors are likely to lie behind some of the excess. Theeffect of tamoxifen was perhaps most clearly demonstrated in theanalysis by calendar-period, where the risk was most pronouncedamong women diagnosed after 1984 when tamoxifen has beenused most extensively.

Alcohol consumption is a common risk factor for cancer of theoral cavity and pharynx, liver, esophagus, larynx and breast, butour data does not consistently indicate that shared risk factors havecaused the observed excess of cancer of the oral cavity and phar-ynx, esophagus and larynx. Alcohol as a shared risk factor forliver and breast cancers does not seem to be important, since therewas a reduced risk of liver cancer. Obesity is a shared risk factorfor colorectal cancer, kidney cancer and postmenopausal breastcancer. However for colorectal cancer, the pattern is not consis-tently pointing at shared risk factor as the underlying cause for theoverall excess, since the risk increased with the follow-up time.The association should also be most pronounced for postmeno-pausal women, but women who had premenopausal breast cancerwere at greatest risk for developing colorectal cancer. The excessof kidney cancer is more likely to be caused by obesity as a com-mon risk factor, since risk was increased throughout follow-up,although the pronounced risk during the first year also suggestssome effect of detection bias. The overall increase in risk of sec-ond breast cancer after kidney cancer also seems to favour pres-ence of shared risk factors; however, our finding of an increasedbreast cancer risk with increasing time since kidney cancer diag-nosis somewhat contradicts this explanation. In addition, preme-nopausal women had higher risk of kidney cancer than the post-menopausal women.

Breast and ovarian cancers share a genetic predisposition, sincegermline mutations in the tumor suppressor genes BRCA1 andBRCA2 increase the risk of both types of cancer.35 In accordancewith this, we found an excess of ovarian cancer already within 1year of the breast cancer diagnosis, (although the risk tended toincrease by the follow-up time) and the risk of breast cancer wasincreased after ovarian cancer. Furthermore, women who hadbreast cancer below the age 45 had a much more pronounced riskof second ovarian cancer, which could be expected since BRCAmutations typically lead to breast cancer at young age. Bilateraloophorectomy used in the treatment of breast cancer would tendto reduce risk of ovarian cancer in all latency periods, but mayalso have caused some of the early excess if ovarian cancer wasan incidental finding at oophorectomy. Breast and ovarian cancersalso share hormonal risk factors,33,36 and so some of the excessrisk of ovarian cancer could be explained by such factors.

BRCA2 mutations have also been associated with possibleincreased risks for melanoma.37 Mutations in the susceptibilitygene CDKN2A for melanoma have also been linked to breast can-cer.38 Our data suggest that shared risk factors could be the under-

lying explanation for the excess of melanoma after breast cancer,but the lack of a particularly high risk among the youngest womenare not in line with genetic factors as the main explanation, and soother shared risk factors may play a role. Female hormones havebeen linked to increase in risk of melanomas, but the evidence isnot consistent.39 Melanoma and breast cancers are both most fre-quent among higher social classes.40 An excess of melanoma hasalso been seen in some of the previous studies of second cancerfollowing breast cancer.6,7,12,13,41

Many of the results obtained in our study are given with a highlevel of precision due to the large number of first and second pri-mary cases. Since we had data from various Cancer Registries, wehad the opportunity to explore if the pattern of second cancer afterbreast cancer was consistent between populations. Even thoughtreatment of breast cancer and follow-up care program for breastcancer patients may have varied somewhat between centers, thisdid not seem to have a major impact on the overall pattern of sec-ond cancer that was very similar. Unlike most prior studies usingmultiple cancer rates, we used rates of first primary cancer to cal-culate the expected number of cancers, and so we estimated therisk of cancer among women with a first primary breast cancercompared to women without any prior cancer diagnoses. Possiblemisclassification of metastases as new primary cancers does notseem to have been any particular problem, since we observedreduced risk estimates for sites that are frequently metastatic inbreast cancer, such as liver and brain. On the contrary, misclassifi-cation of some new primary cancers as metastases may be morelikely, e.g., some cases of multiple myeloma may have been mis-diagnosed as bone metastases from breast cancer. The overallexcess of bone cancer was not a result of a general excess of bonecancers in all populations, but was seen in 3 populations only. Thelack of information on treatment meant that we were unable toestimate the risk of a second primary cancer associated with typeof treatment, but the different analyses gave indirect evidence ofwhether a specific kind of cancer was likely to be treatmentinduced. The results of our study concerns women diagnosed withbreast cancer over a long time period when treatment has variedgreatly with consequences for survival, and so the observed pat-tern of second cancer may not correspond to that of women whoare currently diagnosed with breast cancer. In addition, womenwith an early calendar year of diagnosis are likely to show a longtime since first primary breast cancer and are also more likely tobe young at breast cancer diagnosis. Cases diagnosed mostrecently after 1990 do not have long-term follow-up, which wouldbe most informative in respect to treatment related second cancer.There is partial overlap between the material included here andless updated material previously published in separate papers fromsome of the registries such as the Swedish,5,15 Danish,13 Finnish11

and Slovenian.7

The overall impression from this very large study is that a breastcancer diagnosis has an effect on subsequent cancer risk in gen-eral, since so many cancer sites were seen to occur in excess ofwhat was expected. The known effects of treatment and commonrisk factors do not seem to fully explain the excesses. Futureknowledge about the impact of such factors may add furtherexplanations in addition to potential influences from increased sur-veillance and general cancer susceptibility.

Acknowledgements

G. Sc�elo worked on this study during the tenure of a SpecialTraining Award from the International Agency for Research onCancer. We acknowledge the work of Didier Colin, IARC, for ini-tial preparation of the dataset.

References

1. Sant M, Aareleid T, Berrino F, Bielska LM, Carli PM, Faivre J, Gro-sclaude P, Hedelin G, Matsuda T, Moller H, Moller T, Verdecchia A,

et al. EUROCARE-3: survival of cancer patients diagnosed 1990–94—results and commentary. Ann Oncol 2003;14(Suppl 5):v61–v118.


2. Levi F, Te V-C, Randimbison L, La Vecchia C. Cancer risk in womenwith previous breast cancer. Ann Oncol 2003;14:71–3.

3. Tanaka H, Tsukuma H, Koyama H, Kinoshita Y, Kinoshita N, OshimaA. Second primary cancers following breast cancer in the Japanesefemale population. Jpn J Cancer Res 2001;92:1–8.

4. Evans HS, Lewis CM, Robinson D, Bell C, Møller H, Hodgson SV.Incidence of multiple primary cancers in a cohort of women diag-nosed with breast cancer in southeast England. Br J Cancer 2001;84:435–40.

5. Dong C, Hemminki K. Second primary neoplasms in 633,964 cancerpatients in Sweden 1958–1996. Int J Cancer 2001;93:155–61.

6. 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.

7. Volk N, Pompe-Kirn V. Second primary cancers in breast cancerpatients in Slovenia. Cancer Causes Control 1997;8:764–70.

8. Buiatti E, Crocetti E, Acciai S, Gafa L, Falcini F, Milandri C, La RosaM. Incidence of second primary cancers in three Italian population-based Cancer Registries. Eur J Cancer 1997;33:1829–34.

9. Brenner H, Siegle S, Stegmaier C, Ziegler H. Second primary neo-plasms following breast cancer in Saarland, Germany, 1968–1987.Eur J Cancer 1993;29A:1410–4.

10. Murakami H, Hiyama T, Hanai A, Fujimoto I. Second primary can-cers following female breast cancer in Osaka, Japan—a population-based cohort study. Jpn J Clin Oncol 1987;17:293–302.

11. Teppo L, Pukkala E, Sax�en E. Multiple cancer—an epidemiologicexercise in Finland. J Natl Cancer Inst 1985;75:207–17.

12. Harvey EB, Brinton LA. Second cancer following cancer of the breastin Connecticut, 1935–82. Natl Cancer Inst Monogr 1985;68:99–112.

13. Ewertz M, Mouridsen HT. Second cancer following cancer of the femalebreast in Denmark, 1943–80. Natl Cancer Inst Monogr 1985; 68:325–9.

14. Curtis RE, Hankey BF, Myers MH, Young JL, Jr. The risk of leuke-mia associated with the first course of cancer treatment: an analysis ofthe surveillance, epidemiology and end results program experience.J Natl Cancer Inst 1984;72:531–44.

15. Adami H-O, Bergkvist L, Krusemo U, Persson I. Breast cancer as arisk factor for other primary malignant diseases. A nation-wide cohortstudy. J Natl Cancer Inst 1984;73:1049–55.

16. Muir CS, Percy C. Classification and coding for neoplasms. In: JensenOM, Parkin DM, MacLennan R, Muir CS, Skeet RG, eds. Cancerregistration: principles and methods. IARC Scientific publicationno. 95. Lyon: IARC, 1991;64–81.

17. Whelan SL. Classification and coding. In: Parkin DM, Whelan SL,Ferlay J, Teppo L, Thomas DB, eds. Cancer incidence in five conti-nents, vol. VIII. Lyon: IARC, 2003. 35–41.

18. Mansfield CM, Krishnan L, Komarnicky L, Ayyangar KM, KramerCA. A review of the role of radiation therapy in the treatment ofpatients with breast cancer. Sem Oncol 1991;18:525–35.

19. Roychoudhuri R, Evans H, Robinson D, Moller H. Radiation-inducedmalignancies following radiotherapy for breast cancer. Br J Cancer2004;91:868–72.

20. Neugut AI, Robinson E, Lee WC, Murray T, Karwoski K, KutcherGJ. Lung cancer after radiation therapy for breast cancer. Cancer1993;71:3054–7.

21. Karlsson P, Holmberg E, Samuelsson A, Johansson KA, Wallgren A.Soft tissue sarcoma after treatment for breast cancer—a Swedish pop-ulation-based study. Eur J Cancer 1998;34:2068–75.

22. Yap J, Chuba PJ, Thomas R, Aref A, Lucas D, Severson RK, HamreM. Sarcoma as a second malignancy after treatment for breast cancer.Int J Radiat Oncol Biol Phys 2002;52:1231–7.

23. Boice JD, Jr, Land CE, Preston DL. Ionizing radiation. In: Schotten-feld D, Fraumeni JF, Jr, eds. Cancer epidemiology and prevention,2nd ed. New York: Oxford University Press, 1996.319–54.

24. Huang J, Walker R, Groome PG, Shelley W, Mackillop WJ. Risk ofthyroid carcinoma in a female population after radiotherapy for breastcarcinoma. Cancer 2001;92:1411–8.

25. Ron E. Thyroid cancer. In: Schottenfeld D, Fraumeni JF, Jr, eds. Can-cer epidemiology and prevention, 2nd ed. New York: Oxford Univer-sity Press, 1996.1000–21.

26. Negri E, Dal Maso L, Ron E, La Vecchia C, Mark SD, Preston-MartinS, McTiernan A, Kolonel L, Yoshimoto Y, Jin F, Wingren G, RosariaGM. A pooled analysis of case–control studies of thyroid cancer. II.Menstrual and reproductive factors. Cancer Causes Control 1999;10:143–55.

27. Matesich SM, Shapiro CL. Second cancers after breast cancer treat-ment. Semin Oncol 2003;30:740–8.

28. 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.

29. Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S,Boyle P. Overview of the main outcomes in breast-cancer preventiontrials. Lancet 2003;361:296–300.

30. Peters-Engl C, Frank W, Danmayr E, Friedl HP, Leodolter S, MedlM. Association between endometrial cancer and tamoxifen treatmentof breast cancer. Breast Cancer Res Treat 1999;54:255–60.

31. Matsuyama Y, Tominaga T, Nomura Y, Koyama H, Kimura M, SanoM, Miura S, Takashima S, Mitsuyama S, Ueo H, Ohashi Y. Secondcancers after adjuvant tamoxifen therapy for breast cancer in Japan.Ann Oncol 2000;11:1537–43.

32. Robinson DC, Bloss JD, Schiano MA. A retrospective study oftamoxifen and endometrial cancer in breast cancer patients. GynecolOncol 1995;59:186–90.

33. Bernstein L. Epidemiology of endocrine-related risk factors for breastcancer. J Mammary Gland Biol Neoplasia 2002;7:3–15.

34. Grady D, Ernster VL. Endometrial cancer. In: Schottenfeld D, Frau-meni JF, Jr. Cancer epidemiology and prevention, 2nd ed. New York:Oxford University Press, 1996. 1058–9.

35. Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breastand ovarian cancer. Hum Mol Genet 2001;10:705–13.

36. Weiss NS, Cook LS, Farrow DC, Rosenblatt KA. Ovarian cancer. In:Schottenfeld D, Fraumeni JF, Jr. Cancer epidemiology and preven-tion, 2nd ed. New York: Oxford University Press, 1996. 1040–57.

37. Cancer risks in BRCA2 mutation carriers. The Breast Cancer LinkageConsortium. J Natl Cancer Inst 1999;91:1310–6.

38. Borg A, Sandberg T, Nilsson K, Johannsson O, Klinker M,Masback A, Westerdahl J, Olsson H, Ingvar C. High frequency ofmultiple melanomas and breast and pancreas carcinomas inCDKN2A mutation-positive melanoma families. J Natl Cancer Inst2000;92:1260–6.

39. Armstrong BK, English DR. Cutaneous malignant melanoma. In:Schottenfeld D, Fraumeni JF, Jr. Cancer epidemiology and pre-vention, 2nd ed. New York: Oxford University Press, 1996. 1282–1312.

40. Faggiano F, Partanen T, Kogevinas M, Bofetta P. Socioeconomic dif-ferences in cancer incidence and mortality. In: Kogevinas M, PearceN, Susser M, Bofetta P, eds. Social inequalities and cancer. Lyon:International Agency for Research on Cancer, 1997.65–176.

41. Goggins W, Gao W, Tsao H. Association between female breast can-cer and cutaneous melanoma. Int J Cancer 2004;111:792–4.


Documents

Risk of second cancer among women with breast cancer