Original Article
Breast Cancer in Female Survivors of Wilms Tumor: A Report From the National Wilms Tumor Late Effects Study Jane M. Lange, MS1; Janice R. Takashima, BA2; Susan M. Peterson, MBA2; John A. Kalapurakal, MD3; Daniel M. Green, MD4; and Norman E. Breslow, PhD1,2
BACKGROUND: The standard treatment of pulmonary metastases in patients with Wilms tumor (WT) includes 12-gray radiotherapy (RT) to the entire chest. To the authors’ knowledge, the risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported. METHODS: A total of 2492 female participants in National Wilms Tumor Studies 1 through 4 (1969-1995) were followed from age 15 years through the middle of 2013 for incident BC. The median age at the time of last contact was 27.3 years. The authors calculated cumulative risk at age 40 years (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIRs) relative to US population rates, and 95% confidence intervals (95% CIs). RESULTS: The numbers of survivors with invasive BC divided by the numbers at risk were 16 of 369 (CR40, 14.8% [95% CI, 8.7-24.5]) for women who received chest RT for metastatic WT, 10 of 894 (CR40, 3.1% [95% CI, 1.3-7.41]) for those who received only abdominal RT, and 2 of 1229 (CR40, 0.3% [95% CI, 0.0-2.3]) for those who received no RT. The SIRs for these 3 groups were 27.6 (95% CI, 16.1-44.2) based on 5010 person-years (PY) of follow-up, 6.0 (95% CI, 2.9-11.0) based on 13,185 PY of follow-up, and 2.2 (95% CI, 0.3-7.8) based on 13,560 PY of follow-up, respectively. The risk was high regardless of the use of chest RT among women diagnosed with WT at age 10 years, with 9 of 90 women developing BC (CR40, 13.5% [95% CI, 5.6-30.6]; SIR, 23.6 [95% CI, 10.8-44.8] [PY, 1463]). CONCLUSIONS: Female survivors of WT who were treated with chest RT had a high risk of developing early BC, with nearly 15% developing invasive disease by age 40 years. Current guidelines that recommend screening only those survivors who received 20 Gy of RT to the chest might be reevaluated. C 2014 American Cancer Society. Cancer 2014;120:3722-30. V KEYWORDS: cancer survivorship, secondary malignant neoplasms, radiotherapy, doxorubicin, Wilms tumor..
INTRODUCTION Modern treatment of the childhood kidney cancer Wilms tumor (WT) has led to cure rates approaching 90%.1 Survivors have increased rates of developing secondary cancers,2 due in part to the late effects of radiotherapy (RT) and chemotherapy. Among patients with unilateral WT enrolled on the first 3 protocols of the National Wilms Tumor Study (NWTS), approximately 11% had pulmonary metastases at the time of WT diagnosis3 and a further 9% developed them at the time of disease recurrence.4 The majority of such patients received an RT dose of 12 gray (Gy) (the current standard) or 14 Gy to the entire chest.5-7 The Childhood Cancer Survivor Study (CCSS) estimated that survivors of childhood cancer who were treated with and without chest RT had, respectively, 24.7 times and 4.8 times the rates of breast cancer (BC) of the US population.8 Information regarding BC in survivors of childhood cancer mainly comes from patients with Hodgkin lymphoma (HL),9 who comprised 65% of BC cases in the CCSS cohort.10 Chest RT in survivors of HL was associated with a cumulative incidence of BC of 12.9% by age 40 years.8 Patients with HL receive various quantities of RT. Lee et al11 reported a median of 35 Gy and range of 15 Gy to 60 Gy. Unlike whole-lung RT in patients with WT, the radiation fields used for patients with HL may not always include the entire volume of both breasts.12 Current guidelines from the Children’s Oncology Group recommend routine screening for BC in survivors of childhood cancer only if the chest RT dose is 20 Gy,13,14 which would exclude most patients with WT. Information regarding BC in survivors of WT is to the best of our knowledge scarce. The CCSS and British Childhood Cancer Survivor Study reported 3 cases and 8 cases, respectively.8,15 In the current study, we report what to our
Corresponding author: Norman Breslow, PhD, Department of Biostatistics, Box 357232, University of Washington, Seattle, WA 98195-7232; Fax: (206) 616-2724; [email protected] 1 Department of Biostatistics, University of Washington, Seattle, Washington; 2Department of Biostatistics and Bioinformatics, Fred Hutchinson Cancer Research Center, Seattle, Washington; 3Department of Radiation Oncology, Northwestern University, Chicago, Illinois; 4Department of Epidemiology and Cancer Control, St. Jude’s Children’s Research Hospital, Memphis, Tennessee.
See editorial on pages 3598-601, this issue. DOI: 10.1002/cncr.28908, Received: December 28, 2013; Revised: February 28, 2014; Accepted: March 20, 2014, Published online October 27, 2014 in Wiley Online Library (wileyonlinelibrary.com)
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knowledge is the largest number of BC cases observed in survivors of WT reported to date, focusing on the increased risk due to chest RT with a view toward evaluating the adequacy of current screening guidelines. The associations between BC risk and abdominal RT, use of doxorubicin (which was found to increase the risk of secondary tumors in an earlier study16), and age at onset of WT were also examined. MATERIALS AND METHODS Study Cohort
The study population consisted of 2492 female US and Canadian patients aged birth to 19 years at the time of WT onset who were enrolled on 1 of the first 4 NWTS protocols (1969-1995). All participants survived to age 15 years or 5 years from the onset of WT, whichever came later, and were followed from that time forward until age at time of last contact or death. The closing date for follow-up was June 30, 2013. Consent was provided by parents/guardians for enrollment in the NWTS and patients were reconsented as adults for continuing follow-up at age 18 years. Secondary malignancies were ascertained via clinical records and annual status reports; whenever possible, they were confirmed by medical records review. Radiotherapy
The first protocol (NWTS-1) specified uniform doses of 14 Gy for pulmonary metastasis at the time of WT diagnosis.7 The dose was reduced to 12 Gy during NWTS-2 and remained at 12 Gy on NWTS-3 and NWTS-4.5,6,17 The entire chest, from approximately the clavicle to the L1 vertebra, was included in the treatment volume, regardless of the number and location of visible metastases. These studies lacked specific protocols for pulmonary metastasis at the time of disease recurrence, but most physicians used 12-Gy whole-chest RT for the initial metastasis and lower doses to smaller fields for subsequent ones. There was greater variation in the abdominal doses, with intensified chemotherapy replacing RT in later protocols. Most patients in NWTS-1 received 18 to 40 Gy of RT to the renal fossa (flank), depending on age, with whole-abdomen RT or boosts given for patients with more extensive disease. By the time NWTS-4 was conducted, only a minority of patients at “high risk” of disease recurrence by virtue of stage of disease or histology received any RT to the flank, and then in a standard dose of 10.8 Gy, with additional amounts administered for more extensive disease. Treatment of disease recurrence was largely at the discretion of the local investigator. Figure 1 shows standard fields for chest, whole abdomen, and flank, respectively, for a female patient aged Cancer
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5 years. Actual fields varied with the age of the patient and tumor location. Patients were classified with regard to whether they received chest RT, abdominal RT only, or no RT and by the total dose to any portion of the chest (none, 1-12 Gy, and >12 Gy). Of those patients receiving chest RT, 87% had a single course of treatment to the entire chest. Regression analyses used the highest cumulative RT doses given to the entire or to any portion of the left (L) and right (R) chest and to the L and R flank. Covariates
Covariates included age at the time of WT diagnosis and whether doxorubicin was administered. Statistical Analysis
We calculated cumulative risk of BC as a function of participant age, subtracting the Kaplan-Meier estimate from 1.18,19 Because only 3% of participants died of other causes, this was comparable to cumulative incidence in which death is considered a competing risk.20 Standardized incidence ratios (SIRs), with tests, 95% confidence intervals (95% CIs), and intergroup comparisons based on Poisson statistics,18 compared rates of BC in survivors of WT with age-specific and period-specific US population rates, both in yearly intervals.21 Participants were considered at risk of BC until the end of follow-up, even if a previous BC had occurred. The effects of RT variables and covariates on risk of BC after adjustment for each other were estimated as hazard ratios (HR) using Cox models for age at first BC. To investigate the separate effects of contralateral versus ipsilateral RT, each patient generated 2 records: 1 for the L breast and 1 for the R breast. Participants with bilateral BC, whether synchronous or metachronous, contributed 2 events. Correlation between records for the same patient was accounted for by grouped jackknife (robust) standard errors; influence and tests for nonproportionality were assessed by standard methods.22 All calculations were performed in R statistical software.23 The 95% CIs are shown in parentheses. Imputation of Missing Data
We imputed missing information regarding RT doses as described.24 Two patients missing information on chest RT and 20 patients for whom data were missing regarding flank RT for primary disease were assigned the protocol dose. Multiple imputation was used for missing information on 16 patients who were eligible for chest RT and 3 3723
Original Article
Figure 1. Axial computed tomography (CT) scan and digitally reconstructed radiographs (DRRs) with breast tissue contours are shown in a 5-year-old girl with Wilms tumor. (A) Axial CT scan of the chest is shown. (B) DRR of a standard whole-lung radiation field is shown. (C) DRR of a standard whole-abdomen radiation field is shown. (D) DRR of a standard flank field is shown.
patients who were treated with abdominal RT for disease recurrence.25 Twenty filled-in data sets were generated based on random draws from complete records, and stratified based on prior treatment history and side of disease recurrence. A total of 19 data sets yielded the same classification of subjects by radiation category (none, chest, or abdominal only), the other differing only for a single subject, and a single consensus classification was used for analysis. Results using the quantitative RT variables differed slightly by imputed data set, and standard methods were used to combine them.26 3724
RESULTS Description of Cohort
The 2492 participants had a median age of 27.3 years (interquartile range, 21.5-33.2 years; maximum, 55.2 years) at the time of last follow-up. Twenty-nine cases of invasive BC were ascertained among 28 participants (Table 1). Twenty cases were confirmed by pathology report, 1 by publication, 2 by death certificate, 2 by clinical records, and 4 from detailed annual status report or other patient contact. Patient 1, who was diagnosed with WT at age 7 years, developed a phyllodes tumor in the R breast at Cancer
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Breast Cancer in Survivors of Wilms Tumor/Lange et al
Figure 2. Cumulative risk of breast cancer is shown by radiotherapy (RT) category. Numbers above abscissa are of participants still under observation at ages 20 years, 30 years, and 40 years in each category.
44.2) and the CR40 was 14.8% (Table 2 and Figure 2). Among the patients with BC, RT was administered to the bilateral chest at doses of 12 Gy (9 patients), 14 Gy (3 patients), 15 Gy (1 patient), and 21 Gy (1 patient), respectively (Table 1). Numbers were assigned to patients in Table 1 in order of age at (first) BC diagnosis, and cannot be directly linked to the patient database. Patient 7 received 14 Gy to the bilateral field plus a boost of 26 Gy to the L lung, whereas patient 20 was treated with 12.3 Gy to the R lung only. An RT dose >12 Gy did not appear to increase risk compared with a dose of 12 Gy, but the range of doses was narrow. Among all patients who received chest RT, 4% received a cumulative pulmonary dose of 15 Gy, to the nearest Gy. Most of the higher doses were to a portion of the lung.
age 15 years and a ductal carcinoma in the L breast at age 34 years. The median age at first BC diagnosis was 34.3 years (range, 15.5 years-48.4 years) and the median time from WT diagnosis to first BC diagnosis was 27.1 years (range, 7.9 years-35.7 years). At the time of diagnosis, 15 BC cases were on the L side, 12 were on the R side, and 2 were bilateral. Six patients reported ductal carcinoma in situ (DCIS) without invasive disease, all confirmed by pathology report. These 6 events were included only in a brief sensitivity analysis. They may have been particularly susceptible to detection bias resulting from the more intensive screening of patients who received chest RT. Of the 18 BC cases with information on estrogen receptor (ER) and progesterone receptor (PR), 14 were ER positive and PR positive, 2 were ER positive and PR negative, and 2 were ER negative and PR negative. Three of 16 cases with known human epidermal growth factor 2 receptor status were positive. Eight cases had a known family history of BC. Five died, all due to metastatic BC. The 5-year and 10-year Kaplan-Meier survival probabilities after first BC diagnosis were 91% (95% CI, 67%-98%) and 74% (95% CI, 41%-90%), respectively. Overall, 3.20 cases of BC were expected from US population rates based on 31,755 person-years (PY) of observation (Table 2). The SIR was 9.1 (29 observed (O) vs. 3.20 expected (E); 95% CI, 6.0-13.0) and the estimated cumulative risk at age 40 years (CR40) was 4.5% (95% CI, 2.8%-7.2%).
Ten of 894 patients who received abdominal RT only developed BC. The SIR was 6.0 (10 O vs. 1.67 E; 95% CI, 2.9-11.0 [P1 for ipsilateral and 10 years was 4.6 and highly statistically significant. There was some evidence of nonproportionality (P 5.02); the HR for chest RT decreased with increasing age. Cancer
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TABLE 2. Patient Numbers, Person-Years of Follow-Up, SIRs, and Cumulative Risks of BC at Age 40 Years by Major Risk Categories Subgroup All patients RT group No RT Abdominal RT only Chest RT Chest dosea 0 Gy 1-12 Gy >12 Gy Age at WT diagnosis, y Birth-4 5-9 10-19 Doxorubicin No Yes Current age, y 15-24 25-29 30-35 35-39 40
No. of Patients
PY
SIR
BC Observed
BC Expected
BC Risk at Age 40 Years, %
95% CI
2492
31,755
9.1
29
3.20
4.5
2.8-7.2
1229 894 369
13,560 13,185 5010
2.2 6.0 27.6
2 10 17
0.92 1.67 0.62
0.3 3.1 14.8
0.0-2.3 1.3-7.1 8.7-24.5
2122.9 246.9 122.2
26,746 2857 2153
4.6 46.8 18.9
12 9 8
2.59 0.19 0.42
2.3 14.4 14.2
1.0-5.1 7.6-30.1 7.1-29.3
1856 546 90
22,326 7967 1463
6.0 9.2 23.6
11 9 9
1.84 0.98 0.38
3.1 4.4 13.5
1.5-6.3 2.0-9.1 5.6-30.6
1518 974
19,742 12,013
4.8 19.7
11 18
2.29 0.91
2.6 9.4
1.2-5.4 4.9-17.4
2492 1491 942 477 184
19,979 6086 3527 1580 582
21.3 6.4 11.1 9.6 5.3
3 3 10 9 4
0.14 0.47 0.90 0.94 0.75
NA
NA
Abbreviations: 95% CI, 95% confidence interval; BC, breast cancer; Gy, gray; NA, not applicable; PY, person-years; RT, radiotherapy; SIRs, standardized incidence ratios; WT, Wilms tumor. a Results shown are based on averages over the 20 imputed data sets.
When analysis was restricted to patients who had not received chest RT (model 2), an increase in risk with receipt of flank RT was apparent. The HR associated with older age at onset increased markedly. No individual observation was found to have exceptional influence on the regression coefficients in models 1 and 2, and contributions to their variance from differences between imputed data sets were negligible. Ductal Carcinoma in Situ
A sensitivity analysis included among the BC events the 6 patients with DCIS, 5 of whom received chest RT and 1 of whom received abdominal RT only. This increased the estimated risks by age 40 years to 20.4% for those who received RT to the chest and 4.0% for those receiving abdominal RT. The overall SIR was virtually unchanged at 9.2 (35 O vs. 3.81 E) because DCIS cases from the Surveillance, Epidemiology, and End Results (SEER) program were used in the comparison. The component SIRs were 29.6 (22 O vs. 0.74 E) for chest RT, 5.5 (11 O vs. 2.0 E) for abdominal RT, and 1.9 (2 O vs. 1.1 E) for no RT. DISCUSSION The current study identified 29 cases of invasive BC among survivors of WT, which to the best of our knowledge is the largest number reported to date in a single Cancer
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study. All but 4 cases occurred before age 40 years. Overall, survivors of WT were found to have 9.1 times the rate of BC of similarly aged women in the US population and a CR40 of 4.5%. Patients with WT who were treated for pulmonary metastasis with chest RT had a CR40 of BC of 14.8% and rates that were 27.6 times those of background. These findings are consistent with ranges of SIRs (range, 13.3-55.5) and 40-year to 45-year cumulative incidence (13%-20%) reported in a recent review of studies of BC in survivors of pediatric cancer who received chest RT as part of their primary treatment.14 They were not found to be significantly altered by the inclusion of DCIS among the BC cases. The protocol chest RT dose for patients with pulmonary metastasis was 14 Gy in NWTS-1 but was reduced to 12 Gy in NWTS-2 after unacceptable acute pulmonary toxicity was reported and remained at this level in NWTS-3 and NWTS-4. The vast majority of patients with WT with chest metastases received the protocol dose. The CCSS reported that each additional Gy of radiation increased the excess odds ratio of BC by 0.27.10 Approximating HR by odds ratio, this corresponds to an HR of 4.2 (95% CI, 2.2-9.0) for 12 Gy of chest RT compared with no RT. From Table 3, we estimated a HR of 5.7 (95% CI, 2.6-12.7) for a dose of 12 Gy. These results are remarkably consistent despite differences between 3727
Original Article TABLE 3. Results of Cox Multiple Regression Analyses With the Individual Breast (Right or Left) as the Unit of Analysis and Current Age as Time Model 2a
Model 1 Explanatory Variable
HR
95% CI
P
HR
95% CI
P
log(11chest dose)-ipsilateral log(11flank dose)-ipsilateral Doxorubicin Age at WT diagnosis of 10 y
1.96 1.09 2.24 4.59
1.45-2.69 0.88-1.35 0.80-6.22 1.88-11.2
Breast Cancer in Female Survivors of Wilms Tumor: A Report From the National Wilms Tumor Late Effects Study Jane M. Lange, MS1; Janice R. Takashima, BA2; Susan M. Peterson, MBA2; John A. Kalapurakal, MD3; Daniel M. Green, MD4; and Norman E. Breslow, PhD1,2
BACKGROUND: The standard treatment of pulmonary metastases in patients with Wilms tumor (WT) includes 12-gray radiotherapy (RT) to the entire chest. To the authors’ knowledge, the risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported. METHODS: A total of 2492 female participants in National Wilms Tumor Studies 1 through 4 (1969-1995) were followed from age 15 years through the middle of 2013 for incident BC. The median age at the time of last contact was 27.3 years. The authors calculated cumulative risk at age 40 years (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIRs) relative to US population rates, and 95% confidence intervals (95% CIs). RESULTS: The numbers of survivors with invasive BC divided by the numbers at risk were 16 of 369 (CR40, 14.8% [95% CI, 8.7-24.5]) for women who received chest RT for metastatic WT, 10 of 894 (CR40, 3.1% [95% CI, 1.3-7.41]) for those who received only abdominal RT, and 2 of 1229 (CR40, 0.3% [95% CI, 0.0-2.3]) for those who received no RT. The SIRs for these 3 groups were 27.6 (95% CI, 16.1-44.2) based on 5010 person-years (PY) of follow-up, 6.0 (95% CI, 2.9-11.0) based on 13,185 PY of follow-up, and 2.2 (95% CI, 0.3-7.8) based on 13,560 PY of follow-up, respectively. The risk was high regardless of the use of chest RT among women diagnosed with WT at age 10 years, with 9 of 90 women developing BC (CR40, 13.5% [95% CI, 5.6-30.6]; SIR, 23.6 [95% CI, 10.8-44.8] [PY, 1463]). CONCLUSIONS: Female survivors of WT who were treated with chest RT had a high risk of developing early BC, with nearly 15% developing invasive disease by age 40 years. Current guidelines that recommend screening only those survivors who received 20 Gy of RT to the chest might be reevaluated. C 2014 American Cancer Society. Cancer 2014;120:3722-30. V KEYWORDS: cancer survivorship, secondary malignant neoplasms, radiotherapy, doxorubicin, Wilms tumor..
INTRODUCTION Modern treatment of the childhood kidney cancer Wilms tumor (WT) has led to cure rates approaching 90%.1 Survivors have increased rates of developing secondary cancers,2 due in part to the late effects of radiotherapy (RT) and chemotherapy. Among patients with unilateral WT enrolled on the first 3 protocols of the National Wilms Tumor Study (NWTS), approximately 11% had pulmonary metastases at the time of WT diagnosis3 and a further 9% developed them at the time of disease recurrence.4 The majority of such patients received an RT dose of 12 gray (Gy) (the current standard) or 14 Gy to the entire chest.5-7 The Childhood Cancer Survivor Study (CCSS) estimated that survivors of childhood cancer who were treated with and without chest RT had, respectively, 24.7 times and 4.8 times the rates of breast cancer (BC) of the US population.8 Information regarding BC in survivors of childhood cancer mainly comes from patients with Hodgkin lymphoma (HL),9 who comprised 65% of BC cases in the CCSS cohort.10 Chest RT in survivors of HL was associated with a cumulative incidence of BC of 12.9% by age 40 years.8 Patients with HL receive various quantities of RT. Lee et al11 reported a median of 35 Gy and range of 15 Gy to 60 Gy. Unlike whole-lung RT in patients with WT, the radiation fields used for patients with HL may not always include the entire volume of both breasts.12 Current guidelines from the Children’s Oncology Group recommend routine screening for BC in survivors of childhood cancer only if the chest RT dose is 20 Gy,13,14 which would exclude most patients with WT. Information regarding BC in survivors of WT is to the best of our knowledge scarce. The CCSS and British Childhood Cancer Survivor Study reported 3 cases and 8 cases, respectively.8,15 In the current study, we report what to our
Corresponding author: Norman Breslow, PhD, Department of Biostatistics, Box 357232, University of Washington, Seattle, WA 98195-7232; Fax: (206) 616-2724; [email protected] 1 Department of Biostatistics, University of Washington, Seattle, Washington; 2Department of Biostatistics and Bioinformatics, Fred Hutchinson Cancer Research Center, Seattle, Washington; 3Department of Radiation Oncology, Northwestern University, Chicago, Illinois; 4Department of Epidemiology and Cancer Control, St. Jude’s Children’s Research Hospital, Memphis, Tennessee.
See editorial on pages 3598-601, this issue. DOI: 10.1002/cncr.28908, Received: December 28, 2013; Revised: February 28, 2014; Accepted: March 20, 2014, Published online October 27, 2014 in Wiley Online Library (wileyonlinelibrary.com)
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knowledge is the largest number of BC cases observed in survivors of WT reported to date, focusing on the increased risk due to chest RT with a view toward evaluating the adequacy of current screening guidelines. The associations between BC risk and abdominal RT, use of doxorubicin (which was found to increase the risk of secondary tumors in an earlier study16), and age at onset of WT were also examined. MATERIALS AND METHODS Study Cohort
The study population consisted of 2492 female US and Canadian patients aged birth to 19 years at the time of WT onset who were enrolled on 1 of the first 4 NWTS protocols (1969-1995). All participants survived to age 15 years or 5 years from the onset of WT, whichever came later, and were followed from that time forward until age at time of last contact or death. The closing date for follow-up was June 30, 2013. Consent was provided by parents/guardians for enrollment in the NWTS and patients were reconsented as adults for continuing follow-up at age 18 years. Secondary malignancies were ascertained via clinical records and annual status reports; whenever possible, they were confirmed by medical records review. Radiotherapy
The first protocol (NWTS-1) specified uniform doses of 14 Gy for pulmonary metastasis at the time of WT diagnosis.7 The dose was reduced to 12 Gy during NWTS-2 and remained at 12 Gy on NWTS-3 and NWTS-4.5,6,17 The entire chest, from approximately the clavicle to the L1 vertebra, was included in the treatment volume, regardless of the number and location of visible metastases. These studies lacked specific protocols for pulmonary metastasis at the time of disease recurrence, but most physicians used 12-Gy whole-chest RT for the initial metastasis and lower doses to smaller fields for subsequent ones. There was greater variation in the abdominal doses, with intensified chemotherapy replacing RT in later protocols. Most patients in NWTS-1 received 18 to 40 Gy of RT to the renal fossa (flank), depending on age, with whole-abdomen RT or boosts given for patients with more extensive disease. By the time NWTS-4 was conducted, only a minority of patients at “high risk” of disease recurrence by virtue of stage of disease or histology received any RT to the flank, and then in a standard dose of 10.8 Gy, with additional amounts administered for more extensive disease. Treatment of disease recurrence was largely at the discretion of the local investigator. Figure 1 shows standard fields for chest, whole abdomen, and flank, respectively, for a female patient aged Cancer
December 1, 2014
5 years. Actual fields varied with the age of the patient and tumor location. Patients were classified with regard to whether they received chest RT, abdominal RT only, or no RT and by the total dose to any portion of the chest (none, 1-12 Gy, and >12 Gy). Of those patients receiving chest RT, 87% had a single course of treatment to the entire chest. Regression analyses used the highest cumulative RT doses given to the entire or to any portion of the left (L) and right (R) chest and to the L and R flank. Covariates
Covariates included age at the time of WT diagnosis and whether doxorubicin was administered. Statistical Analysis
We calculated cumulative risk of BC as a function of participant age, subtracting the Kaplan-Meier estimate from 1.18,19 Because only 3% of participants died of other causes, this was comparable to cumulative incidence in which death is considered a competing risk.20 Standardized incidence ratios (SIRs), with tests, 95% confidence intervals (95% CIs), and intergroup comparisons based on Poisson statistics,18 compared rates of BC in survivors of WT with age-specific and period-specific US population rates, both in yearly intervals.21 Participants were considered at risk of BC until the end of follow-up, even if a previous BC had occurred. The effects of RT variables and covariates on risk of BC after adjustment for each other were estimated as hazard ratios (HR) using Cox models for age at first BC. To investigate the separate effects of contralateral versus ipsilateral RT, each patient generated 2 records: 1 for the L breast and 1 for the R breast. Participants with bilateral BC, whether synchronous or metachronous, contributed 2 events. Correlation between records for the same patient was accounted for by grouped jackknife (robust) standard errors; influence and tests for nonproportionality were assessed by standard methods.22 All calculations were performed in R statistical software.23 The 95% CIs are shown in parentheses. Imputation of Missing Data
We imputed missing information regarding RT doses as described.24 Two patients missing information on chest RT and 20 patients for whom data were missing regarding flank RT for primary disease were assigned the protocol dose. Multiple imputation was used for missing information on 16 patients who were eligible for chest RT and 3 3723
Original Article
Figure 1. Axial computed tomography (CT) scan and digitally reconstructed radiographs (DRRs) with breast tissue contours are shown in a 5-year-old girl with Wilms tumor. (A) Axial CT scan of the chest is shown. (B) DRR of a standard whole-lung radiation field is shown. (C) DRR of a standard whole-abdomen radiation field is shown. (D) DRR of a standard flank field is shown.
patients who were treated with abdominal RT for disease recurrence.25 Twenty filled-in data sets were generated based on random draws from complete records, and stratified based on prior treatment history and side of disease recurrence. A total of 19 data sets yielded the same classification of subjects by radiation category (none, chest, or abdominal only), the other differing only for a single subject, and a single consensus classification was used for analysis. Results using the quantitative RT variables differed slightly by imputed data set, and standard methods were used to combine them.26 3724
RESULTS Description of Cohort
The 2492 participants had a median age of 27.3 years (interquartile range, 21.5-33.2 years; maximum, 55.2 years) at the time of last follow-up. Twenty-nine cases of invasive BC were ascertained among 28 participants (Table 1). Twenty cases were confirmed by pathology report, 1 by publication, 2 by death certificate, 2 by clinical records, and 4 from detailed annual status report or other patient contact. Patient 1, who was diagnosed with WT at age 7 years, developed a phyllodes tumor in the R breast at Cancer
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Breast Cancer in Survivors of Wilms Tumor/Lange et al
Figure 2. Cumulative risk of breast cancer is shown by radiotherapy (RT) category. Numbers above abscissa are of participants still under observation at ages 20 years, 30 years, and 40 years in each category.
44.2) and the CR40 was 14.8% (Table 2 and Figure 2). Among the patients with BC, RT was administered to the bilateral chest at doses of 12 Gy (9 patients), 14 Gy (3 patients), 15 Gy (1 patient), and 21 Gy (1 patient), respectively (Table 1). Numbers were assigned to patients in Table 1 in order of age at (first) BC diagnosis, and cannot be directly linked to the patient database. Patient 7 received 14 Gy to the bilateral field plus a boost of 26 Gy to the L lung, whereas patient 20 was treated with 12.3 Gy to the R lung only. An RT dose >12 Gy did not appear to increase risk compared with a dose of 12 Gy, but the range of doses was narrow. Among all patients who received chest RT, 4% received a cumulative pulmonary dose of 15 Gy, to the nearest Gy. Most of the higher doses were to a portion of the lung.
age 15 years and a ductal carcinoma in the L breast at age 34 years. The median age at first BC diagnosis was 34.3 years (range, 15.5 years-48.4 years) and the median time from WT diagnosis to first BC diagnosis was 27.1 years (range, 7.9 years-35.7 years). At the time of diagnosis, 15 BC cases were on the L side, 12 were on the R side, and 2 were bilateral. Six patients reported ductal carcinoma in situ (DCIS) without invasive disease, all confirmed by pathology report. These 6 events were included only in a brief sensitivity analysis. They may have been particularly susceptible to detection bias resulting from the more intensive screening of patients who received chest RT. Of the 18 BC cases with information on estrogen receptor (ER) and progesterone receptor (PR), 14 were ER positive and PR positive, 2 were ER positive and PR negative, and 2 were ER negative and PR negative. Three of 16 cases with known human epidermal growth factor 2 receptor status were positive. Eight cases had a known family history of BC. Five died, all due to metastatic BC. The 5-year and 10-year Kaplan-Meier survival probabilities after first BC diagnosis were 91% (95% CI, 67%-98%) and 74% (95% CI, 41%-90%), respectively. Overall, 3.20 cases of BC were expected from US population rates based on 31,755 person-years (PY) of observation (Table 2). The SIR was 9.1 (29 observed (O) vs. 3.20 expected (E); 95% CI, 6.0-13.0) and the estimated cumulative risk at age 40 years (CR40) was 4.5% (95% CI, 2.8%-7.2%).
Ten of 894 patients who received abdominal RT only developed BC. The SIR was 6.0 (10 O vs. 1.67 E; 95% CI, 2.9-11.0 [P1 for ipsilateral and 10 years was 4.6 and highly statistically significant. There was some evidence of nonproportionality (P 5.02); the HR for chest RT decreased with increasing age. Cancer
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Breast Cancer in Survivors of Wilms Tumor/Lange et al
TABLE 2. Patient Numbers, Person-Years of Follow-Up, SIRs, and Cumulative Risks of BC at Age 40 Years by Major Risk Categories Subgroup All patients RT group No RT Abdominal RT only Chest RT Chest dosea 0 Gy 1-12 Gy >12 Gy Age at WT diagnosis, y Birth-4 5-9 10-19 Doxorubicin No Yes Current age, y 15-24 25-29 30-35 35-39 40
No. of Patients
PY
SIR
BC Observed
BC Expected
BC Risk at Age 40 Years, %
95% CI
2492
31,755
9.1
29
3.20
4.5
2.8-7.2
1229 894 369
13,560 13,185 5010
2.2 6.0 27.6
2 10 17
0.92 1.67 0.62
0.3 3.1 14.8
0.0-2.3 1.3-7.1 8.7-24.5
2122.9 246.9 122.2
26,746 2857 2153
4.6 46.8 18.9
12 9 8
2.59 0.19 0.42
2.3 14.4 14.2
1.0-5.1 7.6-30.1 7.1-29.3
1856 546 90
22,326 7967 1463
6.0 9.2 23.6
11 9 9
1.84 0.98 0.38
3.1 4.4 13.5
1.5-6.3 2.0-9.1 5.6-30.6
1518 974
19,742 12,013
4.8 19.7
11 18
2.29 0.91
2.6 9.4
1.2-5.4 4.9-17.4
2492 1491 942 477 184
19,979 6086 3527 1580 582
21.3 6.4 11.1 9.6 5.3
3 3 10 9 4
0.14 0.47 0.90 0.94 0.75
NA
NA
Abbreviations: 95% CI, 95% confidence interval; BC, breast cancer; Gy, gray; NA, not applicable; PY, person-years; RT, radiotherapy; SIRs, standardized incidence ratios; WT, Wilms tumor. a Results shown are based on averages over the 20 imputed data sets.
When analysis was restricted to patients who had not received chest RT (model 2), an increase in risk with receipt of flank RT was apparent. The HR associated with older age at onset increased markedly. No individual observation was found to have exceptional influence on the regression coefficients in models 1 and 2, and contributions to their variance from differences between imputed data sets were negligible. Ductal Carcinoma in Situ
A sensitivity analysis included among the BC events the 6 patients with DCIS, 5 of whom received chest RT and 1 of whom received abdominal RT only. This increased the estimated risks by age 40 years to 20.4% for those who received RT to the chest and 4.0% for those receiving abdominal RT. The overall SIR was virtually unchanged at 9.2 (35 O vs. 3.81 E) because DCIS cases from the Surveillance, Epidemiology, and End Results (SEER) program were used in the comparison. The component SIRs were 29.6 (22 O vs. 0.74 E) for chest RT, 5.5 (11 O vs. 2.0 E) for abdominal RT, and 1.9 (2 O vs. 1.1 E) for no RT. DISCUSSION The current study identified 29 cases of invasive BC among survivors of WT, which to the best of our knowledge is the largest number reported to date in a single Cancer
December 1, 2014
study. All but 4 cases occurred before age 40 years. Overall, survivors of WT were found to have 9.1 times the rate of BC of similarly aged women in the US population and a CR40 of 4.5%. Patients with WT who were treated for pulmonary metastasis with chest RT had a CR40 of BC of 14.8% and rates that were 27.6 times those of background. These findings are consistent with ranges of SIRs (range, 13.3-55.5) and 40-year to 45-year cumulative incidence (13%-20%) reported in a recent review of studies of BC in survivors of pediatric cancer who received chest RT as part of their primary treatment.14 They were not found to be significantly altered by the inclusion of DCIS among the BC cases. The protocol chest RT dose for patients with pulmonary metastasis was 14 Gy in NWTS-1 but was reduced to 12 Gy in NWTS-2 after unacceptable acute pulmonary toxicity was reported and remained at this level in NWTS-3 and NWTS-4. The vast majority of patients with WT with chest metastases received the protocol dose. The CCSS reported that each additional Gy of radiation increased the excess odds ratio of BC by 0.27.10 Approximating HR by odds ratio, this corresponds to an HR of 4.2 (95% CI, 2.2-9.0) for 12 Gy of chest RT compared with no RT. From Table 3, we estimated a HR of 5.7 (95% CI, 2.6-12.7) for a dose of 12 Gy. These results are remarkably consistent despite differences between 3727
Original Article TABLE 3. Results of Cox Multiple Regression Analyses With the Individual Breast (Right or Left) as the Unit of Analysis and Current Age as Time Model 2a
Model 1 Explanatory Variable
HR
95% CI
P
HR
95% CI
P
log(11chest dose)-ipsilateral log(11flank dose)-ipsilateral Doxorubicin Age at WT diagnosis of 10 y
1.96 1.09 2.24 4.59
1.45-2.69 0.88-1.35 0.80-6.22 1.88-11.2
