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Risk of New Primary Nonbreast Cancers After Breast Cancer Treatment: A Dutch Population-Based Study

Michael Schaapveld, Otto Visser, Marieke J. Louwman, Elisabeth G.E. de Vries, Pax H.B. Willemse, Renée Otter, Winette T.A. van der Graaf, Jan-Willem W. Coebergh, Flora E. van Leeuwen

From the Comprehensive Cancer Center North-Netherlands; Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen; Comprehensive Cancer Center; Department of Epidemiology, Netherlands Cancer Institute, Amsterdam; Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen; Comprehensive Cancer Center South, Eindhoven; and the Department of Public Health, Erasmus Medical Center, Rotterdam, the Netherlands

Corresponding author: Michael Schaapveld, PhD, Comprehensive Cancer Center North-Netherlands (CCCN), P.O. Box 330, 9700 AH Groningen, The Netherlands; e-mail: m.schaapveld{at}ikn.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To assess the risk of secondary nonbreast cancers (SNBCs) in a recently treated population-based cohort of breast cancer patients focused on the association with treatment and prognostic implications.

Patients and Methods In 58,068 Dutch patients diagnosed with invasive breast cancer between 1989 and 2003, SNBC risk was quantified using standardized incidence ratios (SIRs), cumulative incidence, and Cox regression analysis, adjusted for competing risks.

Results After a median follow-up of 5.4 years, 2,578 SNBCs had occurred. Compared with the Dutch female population at large, in this cohort, the SIR of SNBCs was increased (SIR, 1.22; 95% CI, 1.17 to 1.27). The absolute excess risk was 13.6 (95% CI, 9.7 to 17.6) per 10,000 person-years. SIRs were elevated for cancers of the esophagus, stomach, colon, rectum, lung, uterus, ovary, kidney, and bladder cancers, and for soft tissue sarcomas (STS), melanoma, non-Hodgkin's lymphoma, and acute myeloid leukemia (AML). The 10-year cumulative incidence of SNBCs was 5.4% (95% CI, 5.1% to 5.7%). Among patients younger than 50 years, radiotherapy was associated with an increased lung cancer risk (hazard ratio [HR] = 2.31; 95% CI, 1.15 to 4.60) and chemotherapy with decreased risk for all SNBCs (HR = 0.78; 95% CI, 0.63 to 0.98) and for colon and lung cancer. Among patients age 50 years and older, radiotherapy was associated with raised STS risk (HR = 3.43; 95% CI, 1.46 to 8.04); chemotherapy with increased risks of melanoma, uterine cancer, and AML; and hormonal therapy with all SNBCs combined (HR = 1.10; 95% CI, 1.01 to 1.21) and uterine cancer (HR = 1.78; 95% CI, 1.40 to 2.27). An SNBC worsened survival (HR = 3.98; 95%CI 3.77 to 4.20).

Conclusion Breast cancer patients diagnosed in the 1990s experienced a small but significant excess risk of developing an SNBC.

	INTRODUCTION

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Breast cancer is the most frequent malignancy in women in Western Europe and North America.¹ During the last decades, breast cancer survival has increased considerably,^2,3 largely as a result of earlier diagnosis and increasing use of adjuvant therapies. As the risk of developing cancer increases with age, longer survival is associated with an increased probability of new cancer occurrence. Common hereditary predisposition and etiologic factors, such as overweight, reproductive factors, and smoking, play an important role in the risk of developing new cancers. The increased use of cytotoxic and hormonal drugs and radiotherapy have raised awareness in the medical community of secondary cancers as possible long-term sequels of breast cancer treatment. Breast cancer patients have a two- to three-fold increased risk of developing cancer in the contralateral breast, which comprises 30% to 50% of all second tumors in these patients.^4-9 Previous studies have shown increased risks of cancer of the esophagus,^9,10 lung^7,9,11 and soft tissue sarcoma,^8,12-15 most notably angiosarcoma, with a possible relation with radiotherapy. Furthermore, increased risks for melanoma, uterine and ovarian cancer, and acute myeloid leukemia (AML) have been observed.^4,7-9,12,16 Tamoxifen use is associated with an increased uterine cancer risk.^17-21 The increased AML risk may be associated with radiotherapy and chemotherapy.^{4,9,12,16,22-24}

However, most studies addressing second cancer risk concerned patients treated in the distant past, evaluated risk in selected, often hospital-based, patient groups, or lacked treatment data.^{4,5,7-10,12-14,16,22,23} In addition, adjuvant treatment in particular has changed considerably during recent decades. Therefore, in this study we examined the risk of secondary nonbreast cancers (SNBCs) in a large recently treated cohort of breast cancer patients with near-complete follow-up. We focused on possible associations of SNBC risk with breast cancer treatment and the prognostic implications of SNBCs.

	PATIENTS AND METHODS

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The cohort comprises all women diagnosed with breast cancer in the regions of the Comprehensive Cancer Centers North-Netherlands (Groningen, the Netherlands) and Amsterdam from January 1989 to January 2003. The Comprehensive Cancer Center South (Eindhoven, the Netherlands) provided patients diagnosed from January 1989 to January 2002. Together, these registries cover the northwestern and the southeastern part of the Netherlands with 7.4 million inhabitants, or 46% of the Dutch population.

Data Collection
PALGA, the nationwide Dutch network and registry of histo- and cytopathology submits reports of diagnosed malignancies to the Dutch cancer registries. The national hospital databank, which receives discharge diagnoses of all Dutch hospitals, completes case ascertainment. Registry personnel collect data on diagnosis, stage, and treatment from the medical records using the registration and coding manual of the Dutch Association of Comprehensive Cancer Centers. All Dutch patients are treated in public hospitals. In case of multiple primaries, a new primary tumor is defined as any new tumor that is not a recurrence or direct extension of a known tumor, located at another anatomic site or, if at the same site, belonging to a different histologic subgroup or exhibiting a different behavior (in situ v invasive growth).

Vital status was assessed from the medical record, through linkage of cancer registry data with municipal population registries, or by contacting the patient's general practitioner. Vital status was also checked through record linkage with the National Death Registry. Date of censoring was set at December 31, 2004, for patients from the Comprehensive Cancer Center South and at December 31, 2005, for the other registries.

Second Cancers
The index cases were patients with a first invasive breast carcinoma, with no previous cancer other than nonmelanoma skin cancer. The occurrence of any subsequent cancer was ascertained by means of computerized record linkage. All unknown primary adenocarcinomas were excluded as second cancers. Meningiomas, myelodysplastic syndrome, and polycythemia vera were excluded as second cancers as these entities were only recorded since 1999. Nonmelanoma skin cancer was also excluded, and if a subsequent cancer was diagnosed after nonmelanoma skin cancer, this cancer was included as the first-occurring SNBC. For 2,905 women (synchronous or metachronous) breast cancer was the first new primary cancer. Second breast cancers were not included as an event, but were treated as a competing risk. Sarcomas arising in the breast were classified under soft tissue sarcomas, but phyllodes tumors were excluded.

Treatment
The treatment guidelines during the study period are briefly outlined below. Breast-conserving surgery combined with radiotherapy was advised for tumors smaller than 4 cm. Alternatively a modified radical mastectomy was performed. Locoregional radiotherapy on parasternal, axillary, and infra- and supraclavicular nodes was indicated in case of more than three positive axillary nodes or extranodal growth. Irradiation of the parasternal nodes was indicated for node-positive patients with a medially located tumor. Premenopausal node-positive patients received adjuvant chemotherapy, generally consisting of cyclophosphamide, methotrexate, and fluorouracil (CMF). Anthracycline-based chemotherapy has been used increasingly for high-risk patients since the mid-1990s. Until 1998, postmenopausal node-positive patients received 2 years of treatment with tamoxifen. Since 1998, adjuvant systemic therapy was also administered to node-negative patients with less favorable tumor characteristics (intermediate or poorly differentiated tumors 2 cm in size). Furthermore, since 1998, all hormone-receptor–positive/node-positive and unfavorable node-negative patients were to receive 5-years of treatment with tamoxifen, irrespective of menopausal status. Inoperable and locally advanced cancers received chemotherapy, hormonal therapy, and/or radiotherapy.

Statistical Analysis
SNBC risk was quantified using various risk measures. The standardized incidence ratio (SIR) compares observed with expected numbers of SNBCs based on age- and calendar-year–specific cancer incidence rates for the Dutch female population, derived from the Netherlands Cancer Registry. The 1989, 1990, 1992, 1994, 1996, 1998, 2000, and 2002 incidence rates were used to compute expected SNBC numbers. Time at risk started at index cancer diagnosis and ended at the date of SNBC diagnosis, the date of death, or the predetermined censoring date. SIRs were computed for four time intervals (< 1, 1 to 4, 5 to 9, and 10 to 14 years) since diagnosis and, for three age groups, at diagnosis (< 50, 50 to 69, and 70+ years). A high SIR does not necessarily imply a high disease burden, given that expected incidence of certain cancers may be low, and the SIR is measured on a multiplicative scale. The absolute excess risk (AER), defined as the observed minus the expected number of SNBCs divided by the accumulated person-years and expressed per 10,000 person-years, better estimates excess disease burden, as it measures excess incidence on an additive scale. The 95% CI for SIR and AER were determined assuming a Poisson distribution for the observed SNBC numbers. Tests for homogeneity and trend of SIRs were performed using Poisson regression analysis of collapsed person-time data; tests for trend of AERs were based on Poisson regression analysis of the AERs.

The cumulative incidence of SNBC and its CI were calculated with death and second breast cancer (or another second cancer for site-specific analysis) as competing risks.^25,26 Cox regression analysis, accounting for competing risks, was used to examine the effect of initial treatment on SNBC risk.²⁷ Because there was insufficient overlap between age categories for chemotherapy and hormonal treatment, Cox regression analysis was performed stratified for age (< 50 and 50 years). Initial treatment was entered into the model using three separate binomial variables (yes v no) for radiotherapy, chemotherapy, and hormonal therapy. A Cox model with a time-dependent covariate, allocating follow-up time for each patient to the no-SNBC group until SNBC occurrence, was constructed to compare survival with and without an SNBC. For this analysis, time at risk ended at the date of death or the predetermined censoring date, whichever came first. Model fit was evaluated using residual-based graphical methods and goodness-of-fit test statistics. All P values are two sided; the statistical significance level was set at a P < .05.

	RESULTS

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The study population comprised 58,068 patients. Patient and primary breast cancer characteristics are shown in Table 1. Diagnosis of 295 index cancers was not pathologically confirmed. The median follow-up was 5.4 years (interquartile range, 3.0 to 9.0 years), 20,125 patients (34.7%) were followed for 5 to 9 years, and 11,120 (19.1%) were followed for 10 years or longer. The patients accumulated 362,470 person-years, 231,027 in the 1- to 4-year period, 100,542 in the 5- to 9-year period, and 29,132 in the period of 10 years or longer after index cancer diagnosis.

View this table: [in this window] [in a new window]   Table 2. Observed and Expected Number; SIRs; AERs; and 5-, 10-, and 15-year Cumulative Incidence of Selected SNBCs ( 20 cases observed)

View larger version (23K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Standardized incidence ratios (SIRs) and 95% CIs for selected secondary nonbreast cancers (SNBCs; 20 cases observed and increased SIR overall), according to age at the index cancer diagnosis. NHL, non-Hodgkin's lymphoma; AML, acute myeloid leukemia.

View larger version (23K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Standardized Incidence ratios (SIRs) and 95% CIs for selected secondary nonbreast cancers (SNBCs; 20 cases observed and increased SIR overall), according to follow-up period. NHL, non-Hodgkin's lymphoma; AML, acute myeloid leukemia.

Comparisons of Cancer Risk Within the Cohort
Independent effects of index cancer treatment on the risk of developing selected SNBCs are shown in Table 3. The SNBC risk generally increased with age. Only risks of ovarian cancer, melanoma, bladder cancer, kidney cancer, and AML did not vary with age.

View this table: [in this window] [in a new window]   Table 3. Multivariate Cox Regression Analysis for Association of Breast Cancer Treatment and the Risk of Developing Selected SNBCs ( 20 cases observed and increased SIR overall), Adjusted for Competing Risks

Among patients age 50 years and older, radiotherapy was associated with a strongly increased risk of soft tissue sarcomas (HR = 3.43; 95% CI, 1.46 to 8.04). Fifteen of the 39 sarcomas were hemangiosarcomas, which all occurred after radiotherapy. Radiotherapy was associated with a decreased ovarian cancer risk. Chemotherapy was associated with increased risks of melanoma, uterine cancer, and AML. Hormonal treatment was associated with an increased risk of all SNBCs combined (HR = 1.10; 95% CI, 1.01 to 1.21) and uterine cancer (HR = 1.78; 95% CI, 1.40 to 2.27).

Comparison of Survival Within the Cohort
SNBC occurrence, modeled as a time-dependent covariate, was associated with worse survival compared with patients without SNBCs in multivariate analysis (Table 4). Adjusted for age and stage of the index cancer, SNBCs increased the risk of death four-fold (HR = 3.98; 95% CI, 3.77 to 4.20). The impact of an SNBC on risk of death differed by SNBC type, but even a subgroup of cancers that are generally considered prognostically favorable (including cancers of the lip, major salivary glands, thyroid gland, cervix, and uterus, and melanoma and Hodgkin's disease) increased risk of death 1.82-fold (95% CI, 1.57 to 2.10) compared with patients without an SNBC.

	DISCUSSION

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We observed elevated risks for cancer of the esophagus, stomach, colon, rectum, lung, uterus, ovary, kidney, and bladder, and for soft tissue sarcomas, melanoma, non-Hodgkin's lymphoma, and AML. These findings were also seen with older treatment regimens.^4,7,9,12,16 Several sites for which increased risks were observed share either genetic and/or lifestyle risk factors.^28-37 Diagnostic and, to a lesser extent, follow-up examinations may result in earlier detection of some malignancies and some upward bias of risk estimates, especially in the interval shortly after index cancer diagnosis. The increased melanoma risk has been attributed to increased surveillance. Alternatively, shared genetic and hormonal risk factors may play a role, although several large studies have not found an increased breast cancer risk after melanoma, and an association of melanoma with reproductive and hormonal factors remains inconclusive.^38-41 Treatment may also be associated with melanoma risk. We observed an increased hazard of melanoma associated with chemotherapy among patients 50 years.

A few studies have shown an increased esophagus cancer risk after breast cancer.^9,10 Ahsan et al¹⁰ found an increasing trend for squamous cell esophageal cancer risk with longer follow-up after radiotherapy, with a significantly increased risk only for patients followed for 10 years or longer. We found no association between esophageal cancer and radiotherapy. However, the relative rarity of esophageal cancer in females and relatively short follow-up do not allow firm conclusions.

In agreement with several prior studies^4,7,9,11,16 we observed an increased lung cancer incidence in our cohort, particularly among patients younger than 50 at breast cancer diagnosis.^7,12 In the Surveillance, Epidemiology, and End Results (SEER) database, data lung cancer risk was increased after 10 years only among irradiated compared with nonirradiated patients.¹¹ We did observe an increased hazard associated with irradiation, restricted to patients younger than 50 years at breast cancer diagnosis.

We found an increased risk of soft tissue sarcomas. Soft tissue sarcoma risk was strongly increased after radiotherapy, with 29 sarcomas, including all 15 hemangiosarcomas, occurring in previously irradiated patients. In many population-based studies, risk estimates were greater than unity, but few found a significant excess.^4,7-9,12-16 However, in a large Swedish case-control study, hemangiosarcomas were associated with arm lymph edema and not with radiotherapy.¹⁵

The SIR of uterine cancer was 1.9-fold increased (95% CI, 1.7 to 2.2) in our study. Tamoxifen increases uterine cancer risk, with greater risks after longer use.^17-21 The average tamoxifen use in our population was 2 years, and hormonal therapy use was associated with a 1.8-fold higher risk compared with that in nonusers. However, the SIR of uterine cancer was also increased among nonusers, which is likely a result of shared etiological risk factors for uterine and breast cancer.^27,28

We observed that chemotherapy was associated with a decreased hazard for all SNBCs combined, as well as colon and lung cancer, in patients younger than 50 years at breast cancer diagnosis. We are not aware of other studies showing this association. An explanation might be a protective effect through premature ovarian failure or eradication or delay of the growth of subclinical SNBCs by chemotherapy. Adjuvant chemotherapy frequently comprised fluorouracil, which is also effective in colon cancer treatment. Notably, a large risk reduction was seen for colon cancer. However, particularly for lung cancer, the decreased risk after chemotherapy could also be explained by an increasing tendency toward disqualifying second cancers as metastasis when they were diagnosed after a higher stage breast cancer.

The AML risk was elevated in our cohort. There is conflicting evidence on the association of chemotherapy and AML risk.^22-24,42-45 Cyclophosphamide has leukemogenic potential,^42,43 but the relatively low cumulative cyclophosphamide dose in the standard six-cycle CMF regimen, one of the main adjuvant regimens used in our population, probably conveys only a small AML risk. The Milan group⁴⁴ found no increased leukemia risk in a combined analysis of their CMF-based trials. Doxorubicin has also been associated with AML development.⁴² AML (or myelodysplastic syndrome) risk was increased for more dose-intensive AC (doxorubicin, cyclophosphamide) regimens, and additional radiotherapy further increased AML risk.²³ A slightly increased leukemia risk has been shown for patients treated with FAC (fluorouracil, doxorubicin, cyclophosphamide)-based regimens.²² Although we observed a significant AML risk associated with chemotherapy for patients 50 years, this was based on only eight of 34 AML patients age 50 to 69 years. We observed no association of AML risk with radiotherapy, although excess risk of leukemia after radiotherapy for various malignancies, including breast cancer, has been reported.^23,24,46-50

When interpreting our results, one must consider the strengths and limitations of the study. The cohort includes a large number of unselected patients with a nearly complete follow-up for vital status and, on the basis of cancer registry data, the follow-up for SNBCs is also virtually complete. Therefore this study provides reliable estimates of SNBC risks in the 1990s and early 2000s, and reflects the effects of contemporary treatment policies. However, use of cancer registry data has some limitations. Information on confounders, such as past and present smoking status, body mass index, and alcohol use were not available. Also information on tumor recurrence was not recorded by any of the registries. Although most SNBCs will be new primaries, distinguishing SNBCs from metastases is sometimes difficult, which may have resulted in slightly overestimated SNBC risks. The long-term risk estimates in our study are still based on small numbers, limiting our ability to draw conclusions on long-term effects of therapy.

Our results, covering a 10-year follow-up period, indicate a small but significant excess number of SNBCs in breast cancer survivors. Because for most SNBCs, there was no clear association with previous treatment, SNBC occurrence has no major implications for contemporary treatment strategies. The occurrence of an SNBC did, however, substantially worsen survival. Therefore, physicians should be alert to the occurrence of SNBCs among breast cancers survivors. Follow-up appointments are an important opportunity to stress the importance of health-related behavior such as maintenance of healthy body weight, regular exercise, and, especially for patients who underwent radiotherapy, refraining from smoking. Although screening options for SNBCs are limited, physicians should be alert to gynecologic, digestive, and urinary tract symptoms.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Michael Schaapveld, Elisabeth G.E. de Vries, Pax H.B. Willemse, Renée Otter, Winette T.A. van der Graaf, Jan-Willem W. Coebergh, Flora E. van Leeuwen

Provision of study materials or patients: Michael Schaapveld, Otto Visser, Marieke J. Louwman, Jan-Willem W. Coebergh

Collection and assembly of data: Michael Schaapveld, Otto Visser, Marieke J. Louwman, Jan-Willem W. Coebergh

Data analysis and interpretation: Michael Schaapveld, Otto Visser, Marieke J. Louwman, Elisabeth G.E. de Vries, Pax H.B. Willemse, Renée Otter, Winette T.A. van der Graaf, Jan-Willem W. Coebergh, Flora E. van Leeuwen

Manuscript writing: Michael Schaapveld, Otto Visser, Marieke J. Louwman, Elisabeth G.E. de Vries, Pax H.B. Willemse, Renée Otter, Winette T.A. van der Graaf, Jan-Willem W. Coebergh, Flora E. van Leeuwen

Final approval of manuscript: Michael Schaapveld, Otto Visser, Marieke J. Louwman, Elisabeth G.E. de Vries, Pax H.B. Willemse, Renée Otter, Winette T.A. van der Graaf, Jan-Willem W. Coebergh, Flora E. van Leeuwen

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Absolute excess risks (AERs) and 95% CIs for selected secondary nonbreast cancers (SNBCs; 20 cases observed and increased SIR overall), according to age at the index cancer diagnosis. NHL, non-Hodgkin's lymphoma; AML, acute myeloid leukemia.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Absolute excess risks (AERs) and 95% CIs for selected secondary nonbreast cancers (SNBCs; 20 cases observed and increased SIR overall), according to follow-up period. NHL, non-Hodgkin's lymphoma; AML, acute myeloid leukemia.

	NOTES

 
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 18, 2007; accepted November 20, 2007.

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