Risk factors for subsequent endocrine-related cancer in childhood cancer survivors

in Endocrine-Related Cancer
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  • 1 Department of Pediatric Oncology/Hematology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, the Netherlands
  • 2 Department of Medicine, Section Endocrinology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 3 Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
  • 4 Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, the Netherlands

Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower-dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen–progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk-modifying effects of environmental and lifestyle factors are lacking. Risk-modifying effects of premature ovarian insufficiency and estrogen–progestin replacement therapy on radiation-induced breast cancer require further study.

Abstract

Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower-dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen–progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk-modifying effects of environmental and lifestyle factors are lacking. Risk-modifying effects of premature ovarian insufficiency and estrogen–progestin replacement therapy on radiation-induced breast cancer require further study.

Introduction

Childhood cancer survival has increased substantially over the past five decades due to advances in therapy, risk-based treatment stratification, and supportive care (Hudson et al. 2014). To date, approximately 80% of children and adolescents survive at least 5 years following a diagnosis of childhood cancer (Gatta et al. 2014, Howlader et al. 2015), and are thereby subsequently considered childhood cancer survivors. This percentage is anticipated to grow due to further improvements in childhood cancer care (Hudson et al. 2014), and a slow increase in childhood cancer incidence as reported by some investigators (Siegel et al. 2014, Steliarova-Foucher et al. 2004). Accordingly, awareness of and insight in side effects and long-term consequences of childhood cancer treatment have become increasingly important (Hewitt et al. 2003, Oeffinger et al. 2006, Geenen et al. 2007, Armstrong et al. 2009, Hudson et al. 2013, Hjorth et al. 2015). At an attained age of 45 years, approximately 95% of childhood cancer survivors suffer from at least one chronic health condition related to their former cancer treatment; in approximately 75%, this concerns a serious/disabling or life-threatening condition (Hudson et al. 2013). Over the past decades, childhood cancer treatment protocols have been modified, aiming to reduce the occurrence and severity of long-term treatment-related complications. Recently, Armstrong and coworkers demonstrated that these efforts resulted in improved long-term survival (Armstrong et al. 2016).

Secondary neoplasms are among the most serious long-term adverse health conditions in childhood cancer survivors, and can be defined as histologically distinct tumors developing after primary cancer therapy. They have been estimated to affect approximately 21% of childhood cancer survivors after 30 years of follow-up since primary cancer diagnosis (Friedman et al. 2010). This estimation includes both benign and malignant secondary neoplasms. The 30-year cumulative incidence of secondary malignant neoplasms solely is approximately 8%, and represents a six-fold increased risk in comparison with the general population (Friedman et al. 2010). The increased risk for secondary malignancies in childhood cancer survivors seems to persist even after 40 years of follow-up since primary cancer diagnosis (Olsen et al. 2009). At an attained survivor’s age of 60 years, the cumulative incidence of secondary malignant neoplasms varies between 14 and 18% (Olsen et al. 2009, Reulen et al. 2011). The risk for secondary malignant neoplasms in older ­childhood cancer survivors remains unknown. Although most secondary malignant neoplasms are diagnosed during the first 10–20 years following childhood cancer treatment (Friedman et al. 2010, Choi et al. 2014), they may present within months to decades following the completion of former cancer therapy (Choi et al. 2014). Risk factors for the development of secondary malignancies in childhood cancer survivors include host factors, primary cancer diagnosis, types and timing of primary cancer treatment, environmental factors, and lifestyle factors (Ng et al. 2010). Secondary malignant neoplasms appear to be an important cause of death in childhood cancer survivors. Recent cohort studies demonstrated that 12–19% of mortality in individuals who survived at least 5 years following a diagnosis of childhood cancer was attributable to secondary malignancies (Mertens et al. 2008, Reulen et al. 2010, Garwicz et al. 2012). After 25 years of follow-up since primary cancer diagnosis, secondary malignant neoplasms even become the most important cause of death in survivors of childhood cancer (Mertens et al. 2008, Reulen et al. 2010). Although mortality attributable to secondary malignancies in childhood cancer survivors declined over the past treatment eras (Armstrong et al. 2016), the risk for developing a solid secondary malignant neoplasm did not (Schaapveld et al. 2015). Endocrine-related cancers are among the most common secondary malignancies in childhood cancer survivors (Inskip & Curtis 2007, Olsen et al. 2009, Friedman et al. 2010, Reulen et al. 2011). In the Childhood Cancer Survivor Study, they represent 40% of the invasive secondary malignant neoplasms observed (Fig. 1A) (Friedman et al. 2010).

Figure 1
Figure 1

Distribution of secondary malignant neoplasms and primary cancer diagnoses among childhood cancer survivors who developed a secondary neoplasm as observed in the Childhood Cancer Survivor Study by Friedman et al. (2010). (A) Secondary malignant neoplasms (nonmelanoma skin cancers excluded). (B) Primary cancer diagnoses. CNS, central nervous system; SMN, secondary malignant neoplasm.

Citation: Endocrine-Related Cancer 23, 6; 10.1530/ERC-16-0113

In this review, we will discuss risk factors for secondary endocrine-related malignant neoplasms in childhood cancer survivors. A special focus will be on breast and thyroid cancer, since these are the most common secondary endocrine-related malignancies in survivors of childhood cancer (Olsen et al. 2009, Friedman et al. 2010, Reulen et al. 2011).

Search strategy

We systematically searched the MEDLINE-database (United States National Library of Medicine, Washington, DC, USA) until January 2016 for relevant articles on secondary cancer risk in survivors of pediatric malignancies. The keywords ‘childhood cancer survivors’, ‘second malignant neoplasms’, ‘secondary malignant neoplasms’, ‘subsequent neoplasms’, ‘endocrine cancers’, ‘breast cancer’, ‘thyroid cancer’, ‘risk factors’, ‘radiotherapy’, ‘radiation’, ‘irradiation’, ‘chemotherapy’, ‘stem cell transplantation’, ‘total body irradiation’, ‘conformal radiotherapy’, ‘intensity-modulated radiation therapy’ and ‘proton-beam therapy’ were used. Only articles written in English were included in the review. Reference lists of included articles were checked for additional relevant publications. In case two or more articles described the same patient cohort, the most recent or relevant article was included.

Risk factors for secondary malignant neoplasms in childhood cancer survivors

In the Childhood Cancer Survivor Study, host-, disease- and treatment-related risk factors for the development of secondary neoplasms in childhood cancer survivors have been identified (Friedman et al. 2010). The Childhood Cancer Survivor Study is a multi-institutional study conducted in the United States and Canada, and involves 14,363 individuals treated for cancer <21 years of age (Robison et al. 2002). Female gender and older age at initial cancer diagnosis were associated with an increased risk for secondary malignant neoplasms after childhood cancer (relative risk (RR) 1.4 (95% confidence interval (CI): 1.2–1.6) for females vs males; RR 1.5 (95% CI: 1.2–1.9) for age at diagnosis ≥15 years vs 0–4 years) (Friedman et al. 2010). The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI) of the United States could not demonstrate this sex difference in the risk for secondary malignant neoplasms. However, it found a somewhat higher risk for secondary malignancies in black vs white people (standardized incidence ratio (SIR) 8.9 vs SIR 5.5; excess absolute risk (EAR) 18.4 vs 15.0 per 10,000 person-years) (Inskip & Curtis 2007). Genetic susceptibility might contribute to the development of secondary neoplasms in childhood cancer survivors, which is illustrated by high-penetrance genetic cancer predisposition syndromes (Table 1) (Strahm & Malkin 2006, Pilarski & Nagy 2012, Foulkes et al. 2014, Shiovitz & Korde 2015). However, germline mutations in known moderate- to high-penetrance cancer susceptibility genes are only found in 8.5% of pediatric and adolescent cancer patients (Zhang et al. 2015). Data from the Swedish general population suggest that less pathogenic low-penetrance familial cancer predisposition might be more important in the development of malignancies than high-penetrance genetic cancer susceptibility genes (Frank et al. 2015). This is illustrated by Friedman and coworkers, who observed an increased cancer risk in siblings of childhood cancer survivors in comparison with the general population (SIR 1.5 (95% CI: 1.3–1.7)), even after exclusion of families with suspected high-penetrance genetic cancer predisposition syndromes (SIR 1.3 (95% CI: 1.2–1.5)) (Friedman et al. 2005). In their study, siblings and offspring of childhood cancer survivors who developed a secondary malignant neoplasm were even at higher risk of developing cancer in comparison with relatives of childhood cancer survivors who did not develop a secondary malignancy (SIR 2.4 (95% CI: 1.5–3.7) for siblings; SIR 15.0 (95% CI: 5.3–42.9) for offspring) (Friedman et al. 2005).

Table 1

High-penetrance genetic cancer predisposition syndromes associated with endocrine-related malignancies.

NameGenesAssociated cancersReferences
Hereditary breast and ovarian cancer syndromeBRCA1Breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, biliary cancer, melanomaShiovitz & Korde (2015)
BRCA2
Cowden syndrome (also known as multiple hamartoma syndrome)PTENBreast cancer, nonmedullary thyroid cancer, endometrial cancer, genitourinary tumorsPilarski & Nagy (2012), Shiovitz & Korde (2015)
Li–Fraumeni syndrome (LFS)TP53Breast cancer, sarcoma, brain tumor, ­adrenocortical tumor, leukemia, lung cancerShiovitz & Korde (2015)
Hereditary diffuse gastric cancerCDH1Breast cancer, gastric cancer, colorectal cancerShiovitz & Korde (2015)
Peutz–Jeghers syndromeSTK11Gastro-intestinal cancer, breast cancer, ovarian cancer, pancreatic cancerShiovitz & Korde (2015), Strahm & Malkin (2006)
Multiple endocrine neoplasia type 1 (MEN1)MEN1Parathyroid adenoma, pancreatic endocrine tumors, pituitary adenomaPilarski & Nagy (2012), Strahm & Malkin (2006)
Multiple endocrine neoplasia type 2 (MEN2)RETMedullary thyroid carcinoma, pheochromo­cytoma, parathyroid hyperplasiaPilarski & Nagy (2012), Strahm & Malkin (2006)
Succinate dehydrogenase complex (SDHX)SDHBParaganglioma, pheochromocytomaPilarski & Nagy (2012)
SDHC
SDHD
von Hippel–Lindau syndrome (VHL)VHLRetinal and central nervous system ­hemangioblastoma, renal cell carcinoma, pheochromocytoma, pancreatic islet cell tumor, endolymphatic sac tumorPilarski & Nagy (2012)
Adenomatous polyposis of the colonAPCColon cancer, small intestine cancer, thyroid cancer, stomach cancer, hepatoblastomaStrahm & Malkin (2006)
Beckwith–Wiedemann syndromeCDKN1C/NSD1Nephroblastoma, hepatoblastoma, adrenal carcinoma, rhabdomyosarcomaStrahm & Malkin (2006)
DICER1 syndromeDICER1Pleuropulmonary blastoma, ovarian tumor, cystic nephroma, sarcoma, thyroid tumor, pituitary tumorFoulkes et al. (2014)

Childhood cancer survivors at highest risk for secondary malignant neoplasms include survivors of Hodgkin lymphoma, leukemia, sarcoma, and central nervous system malignancies (Fig. 1B) (Inskip & Curtis 2007, Friedman et al. 2010, Reulen et al. 2011). This seems to be related to administered treatment modalities. Radiotherapy is the most important risk factor for the development of secondary neoplasms (Inskip & Curtis 2007, Friedman et al. 2010, Reulen et al. 2011). Risk for radiation-induced secondary malignant neoplasms depends on cumulative radiation dose, radiotherapy fractionation, radiation field, radiosensitivity, radiotherapy technique, quality of radiation, and other confounding factors (Kumar 2012). Besides radiotherapy, chemotherapeutic agents (i.e. alkylators, anthracyclines, and topoisomerase II inhibitors), as well as hematopoietic stem cell transplantation, have been associated with an increased risk for secondary malignant neoplasms in childhood cancer survivors (Meadows et al. 2009, Socie et al. 2012, Choi et al. 2014).

Besides the factors mentioned above, environmental and lifestyle determinants may also be important in secondary tumor development (Travis et al. 2002, Carpenter & Bushkin-Bedient 2013, Kamiya et al. 2015). However, studies specifically addressing the risk-modifying effects of these determinants in childhood cancer survivors have to be performed yet.

Breast cancer

Epidemiology and host-related risk factors

Breast cancer risk in childhood cancer survivors has recently been addressed in several large cohort studies (Table 2) (Inskip & Curtis 2007, Olsen et al. 2009, Friedman et al. 2010, Reulen et al. 2011). After 30 years of follow-up since childhood cancer diagnosis, secondary breast cancer affects approximately 5% of childhood cancer survivors (Friedman et al. 2010). This represents a standardized incidence ratio of 2.2–9.8 in comparison with the general population (Inskip & Curtis 2007, Olsen et al. 2009, Friedman et al. 2010, Reulen et al. 2011). Latency periods for the development of secondary breast cancer following childhood cancer vary between 6.7 and 39 years (average 21.8 years) (Table 3) (Gold et al. 2003, Taylor et al. 2007, 2008, Constine et al. 2008, Diallo et al. 2009, Friedman et al. 2010, O’Brien et al. 2010, Lange et al. 2014, Dorffel et al. 2015, Henderson et al. 2015). This is illustrated by Reulen and coworkers, who observed an increased risk for secondary breast cancer in female childhood cancer survivors during the first three decades following primary cancer diagnosis, which gradually declined to general population norms at an attained survivor’s age of 50 years (Reulen et al. 2008).

Table 2

Risk of secondary breast cancer following childhood cancer in recent large cohort studies.

Study (year)Study populationTreatment eraPatientsAge at primary cancer Dx (year)Median FU (year)Breast cancer casesSIR (95% CI)EAR per 10,000/year (95% CI)Cumulative incidence at 30 year following primary cancer Dx (95% CI)Median latency time (range) (year)
Inskip & Curtis (2007)Population-based cohort from United States1973–2002♂ 11,922<186.3518.41.9NANA
♀ 14,043
Olsen et al. (2009)Population-based cohort from Denmark, Finland, Iceland, Norway and Sweden1943–2005♂ 26,168<20NA1482.4 (2.0–2.8)NANANA
♀ 21,529
Friedman et al. (2010)Cohort from 26 institutions in United States and Canada1970–1986♂ 7714<2122.92529.8 (8.4–11.5)NA5.0% (4.2–5.9%)21.3 (6.7–33.5)
♀ 6645
Reulen et al. (2011)Population-based cohort from Britain1940–1991♂/♀ 17,981<1524.3972.2 (1.8–2.7)1.4 (0.9–2.0)NANA

♂, male; ♀, female; CI, confidence interval; Dx, diagnosis; EAR, excess absolute risk; FU, follow-up; NA, not available; SIR, standardized incidence ratio.

Table 3

Latency time between childhood cancer and secondary breast cancer.

Latency period
Study (year)Study populationTreatment eraPatientsAge at primary cancer Dx (year)Median follow-up (year)Radiotherapy (%)Breast cancers (N)Median (year)Range (year)
Gold et al. (2003)Single-center cohort of survivors of several childhood cancers from Minnesota1954–1980♂/♀ 446<1819.510082010–32
Taylor et al. (2007)Population-based cohort of Hodgkin lymphoma survivors from Britain1940–1991♀ 383<1520.3a67.61621.6*9.5–34.1
Constine et al. (2008)Cohort Hodgkin lymphoma survivors from 5 institutions in the United States1960–1990♂ 532<1916.8a91.22917.29.4–36.1
♀ 398
Taylor et al. (2008)Population-based cohort of nephroblastoma survivors from Britain1940–1991♂ 732<1519.3a82.4926.7*12.4–34.5
♀ 709
Diallo et al. (2009)Cohort of survivors of several childhood cancers from 8 institutions in France and Britain1942–1986♂/♀ 4581<1715.4NA13219–37
Friedman et al. (2010)Cohort of survivors of several childhood cancers from 26 institutions in United States and Canada1970–1986♂ 7714<2122.968.025221.36.7–33.5
♀ 6645
O’Brien et al. (2010)Single-center cohort of Hodgkin lymphoma survivors from Stanford1970–1990♂ 75<1920.6100616.612.1–29.9
♀ 35
Lange et al. (2014)Cohort of nephroblastoma survivors from the National Wilms Tumor Studies 1–41969–1995♀ 2492<20NA50.72827.17.9–35.7
Dorffel et al. (2015)Cohort from German, Austrian and Swiss pediatric Hodgkin lymphoma studies1978–2002♂ 1424<1914.3NA3722.014.3–32.1
♀ 1124
Henderson et al. (2015)Cohort of survivors of several childhood cancers from 26 institutions in United States and Canada1970–1986♀ 3768<2125.504724.010.0–34.0

mean. ♂, male; ♀, female; Dx, diagnosis; N, number; NA, not available.

Several studies identified pubertal age at primary cancer diagnosis to be an important risk factor for secondary breast cancer (Metayer et al. 2000, Constine et al. 2008, Inskip et al. 2009). In a study by Metayer and coworkers, risk for ­secondary breast cancer was highest in women aged 10–16 years at Hodgkin lymphoma diagnosis (Metayer et al. 2000). In addition, 114 of the 120 secondary breast cancers observed in a study by Inskip and coworkers were diagnosed in women aged 10–20 years at childhood cancer diagnosis (Inskip et al. 2009). Therefore, an increased susceptibility of proliferating breast tissue for carcinogenic factors in adolescent girls has been suggested (Metayer et al. 2000, Inskip et al. 2009, Barcellos-Hoff 2013). However, several other studies could not confirm a risk-modifying effect of age at childhood cancer diagnosis (Travis et al. 2003, Guibout et al. 2005, Reulen et al. 2008). This inconsistency might be explained by shorter follow-up durations since childhood cancer in studies reporting an increased secondary breast cancer risk by pubertal age compared with studies not reporting such an effect (average 11.0–16.8 vs 16–25.1 years) (Metayer et al. 2000, Guibout et al. 2005, Constine et al. 2008, Reulen et al. 2008). Secondary breast cancer risk in childhood cancer survivors by follow-up since childhood cancer diagnosis, attained survivor’s age and age at childhood cancer diagnosis is represented in Tables 4 and 5 (Kenney et al. 2004, Guibout et al. 2005, Inskip & Curtis 2007, Reulen et al. 2008).

Table 4

Secondary breast cancer risk in childhood cancer survivors by follow-up since primary cancer diagnosis.

Study (year)Study populationTreatment eraPatientsFollow-up (year)Breast cancers (N)Follow-up since Dx (SIR (95% CI))Follow-up since Dx (EAR per 10,000 per year (95% CI))
Kenney et al. (2004)Cohort from 26 institutions in United States and Canada1970–1986♀ 6068Median 18.51115–9 years6.3 (2.0–20.3)NA
10–14 years11.8 (7.0–19.8)
15–19 years9.2 (5.8–14.5)
≥20 years6.0 (3.8–9.4)
Guibout et al. (2005)Cohort of solid tumor survivors from 8 institutions in France and Britain1946–1986♀ 1814Mean 1616NANANA
Inskip & Curtis (2007)Population-based cohort from United States1973–2002♂ 11,922Median 6.3510.16–<1 year0NA
♀ 14,0431–4 years0
5–9 years7.6
10–14 years15.1
15–19 years11.8
≥20 years5.0
Reulen et al. (2008)Population-based cohort from Britain1940–1991♀ 8093Mean 25.1815–9 years9.3 (1.3–66.3)0.2 (0.0–2.0)
10–19 years9.2 (6.1–14.0)1.9 (1.8–4.7)
20–29 years2.6 (1.8–3.8)4.2 (2.2–8.0)
30–39 years1.5 (1.0–2.3)4.9 (1.4–17.0)
≥40 years1.0 (0.5–1.8)0.0

♀, female; CI, confidence interval; Dx, diagnosis; EAR, excess absolute risk; N, number; NA, not available; SIR, standardized incidence ratio.

Table 5

Secondary breast cancer risk in childhood cancer survivors by attained survivors’ age and age at primary cancer diagnosis.

StudyAttained age (SIR (95% CI))Attained age (EAR per 10,000 per year (95% CI))Age at Dx (SIR (95% CI))Age at Dx (EAR per 10,000 per year (95% CI))
Kenney et al. (2004)NANANA0–20 years24.7 (19.3–31.0)NA
Guibout et al. (2005)3–9 years0NA0–16 years16.9 (9.9–26.6)NA
10–19 years185.0 (30.8–572.6)
20–29 years18.8 (4.7–48.9)
30–39 years23.2 (11.6–40.6)
≥40 years2.9 (0.2–12.8)
Inskip & Curtis (2007)NANANA0–17 years8.41.9
Reulen et al. (2008)0–19 years10.9 (1.5–77.0)0.1 (0.0–1.2)0–4 years2.5 (1.7–3.6)1.7 (0.8–3.6)
20–29 years5.7 (3.3–9.8)1.9 (1.0–3.7)5–9 years1.1 (0.6–2.1)0.0
30–39 years3.1 (2.3–4.3)8.5 (5.3–13.6)10–14 years2.5 (1.9–3.4)5.8 (3.5–9.7)
40–49 years1.5 (1.0–2.3)6.9 (2.0–23.7)
≥50 years0.9 (0.5–1.8)0.0

♀, female; CI, confidence interval; Dx, diagnosis; EAR, excess absolute risk; N, number; NA, not available; SIR, standardized incidence ratio.

Genetic susceptibility might contribute to secondary breast cancer development in childhood cancer survivors. This is illustrated by studies reporting an increased secondary breast cancer risk in survivors of childhood cancer with a positive family history for breast and/or ovarian cancer (Kenney et al. 2004, Hill et al. 2005). However, germline mutations in known high- to moderate-penetrance breast cancer susceptibility genes like BRCA1, BRCA2, TP53 and ATM are only found in a minority of childhood cancer survivors who develop a secondary breast malignancy (Broeks et al. 2000, Nichols et al. 2003). Therefore, less pathogenic low-penetrance genetic susceptibility might be more important. Recent studies identified allelic variants in PRDM1 and FGFR2 to predispose Hodgkin lymphoma survivors to radiation-induced breast cancer (Best et al. 2011, Ma et al. 2012).

Kenney and coworkers identified the presence of thyroid disease to be a risk factor for secondary breast cancer in childhood cancer survivors (RR 1.7 (95% CI: 1.1–2.6)) (Kenney et al. 2004). An association between thyroid disease and breast cancer has also been observed in the general population (Hardefeldt et al. 2012, Prinzi et al. 2014). Although no clear explanations for this finding have been found, stimulation of breast cancer cells by deregulated thyroid hormone receptors, estrogen-receptor activation by triiodothyronine, and a potential role of the sodium–iodide symporter expressed in breast cancer tissue have been proposed (Nogueira & Brentani 1996, Silva et al. 2002, Portulano et al. 2014).

Treatment-related risk factors for secondary breast cancer

Radiotherapy

Chest irradiation is the most important treatment-related risk factor for secondary breast cancer in childhood cancer survivors. In a recent review, Henderson and coworkers summarized the risk for secondary breast cancer after treatment with chest irradiation for pediatric cancer (Henderson et al. 2010). In the included higher quality cohort studies, standardized incidence ratios for secondary breast cancer varied between 13.3 and 55.5, excess absolute risks varied between 18.6 and 79.0 per 10,000 person-years, and cumulative incidences varied between 12 and 26% at 25–30 years follow-up since childhood cancer (Ng et al. 2002, Bhatia et al. 2003, Kenney et al. 2004, Taylor et al. 2007, Constine et al. 2008, De Bruin et al. 2009). These risk estimates are comparable to risks for breast cancer in women harboring a germline BRCA1 or BRCA2 gene mutation (Moskowitz et al. 2014).

Radiation fields associated with an increased secondary breast cancer risk in childhood cancer survivors include mantle field, whole lung, hemithorax, mediastinum, supradiaphragmatic abdomen, axilla, neck and clavicle, as well as total body (Table 6) (De Bruin et al. 2009, Swerdlow et al. 2012, Lange et al. 2014, Moskowitz et al. 2014). Smaller radiation fields seem to be associated with lower risks for radiation-induced breast cancer (De Bruin et al. 2009, Swerdlow et al. 2012, Schaapveld et al. 2015). However, despite an increased use of less extensive supradiaphragmatic radiation fields over the past decades, the incidence of radiation-induced breast cancer remained stable in Hodgkin lymphoma survivors (Schaapveld et al. 2015). This may be partly related to an earlier detection of secondary breast malignancies by improved screening practices (Ng et al. 2013). In a recent study on secondary breast cancer risk after craniospinal irradiation for pediatric central nervous system malignancies and leukemia, Moskowitz and coworkers observed an increased risk for secondary breast cancer in the subgroup of leukemia survivors solely (SIR 3.8 (95% CI: 1.2–11.7)) (Moskowitz et al. 2015). This observation might be related to genetic susceptibility, as illustrated by a population-based study in Italy that observed an increased standardized mortality ratio attributable to breast cancer in mothers of children diagnosed with leukemia (Zuccolo et al. 2007).

Table 6

Secondary breast cancer risk after various radiation fields.

Study (year)Study populationTreatment eraPatientsAge at primary cancer Dx (year)Breast cancers (N)Radiation fieldMedian radiation dose in Gy (range)SIR (95% CI)
De Bruin et al. (2009)Cohort of Hodgkin lymphoma survivors from 5 institutions in the Netherlands1965–1995♀ 1122<51 (27.7% <21 years)120MantleNA8.2 (6.6–10.1)
Mediastinal3.7 (1.2–8.7)
Other supradiaphragmatic1.6 (0.3–4.6)
Infradiaphragmatic0.0
Swerdlow et al. (2012)Population-based cohort of England and Wales1956–2003♀ 5002<36 (23.7% <20 years)373Mantle366.0 (5.3–6.7)
Two mantle component fieldsa31–333.4 (2.4–4.7)
One mantle component fielda31–332.5 (1.7–3.7)
Lange et al. (2014)Cohort of nephroblastoma survivors from the National Wilms Tumor Studies 1–41969–1995♀ 2492<2028ChestNA27.6 (16.1–44.2)
Abdominal6.0 (2.9–11.0)
Moskowitz et al. (2014)Cohort of survivors of several childhood cancers from 26 institutions in United States and Canada1970–1986♀ 1230<21203Mantle40 (5–54)24.2 (20.7–28.3)
Mediastinal30 (3–54)13.0 (8.4–20.2)
Whole lung14 (2–20)43.6 (27.1–70.1)
Total body12 (4–16)19.3 (7.3–51.5)
Abdominalb20 (4–40)10.8 (2.7–43.2)
Posterior chestc31 (6–54)0.0
Other one-sided anterior41 (10–61)9.9 (3.2–30.6)

mediastinum, axilla, neck or clavicle

abdominal field extending above diaphragm

posterior thoracic or paravertebral fields.

♂, male; ♀, female; CI, confidence interval; Dx, diagnosis; Gy, Gray; N, number; NA, not available; SIR, standardized incidence ratio.

The relationship between chest radiation dose and breast cancer risk has been investigated by several studies (Table 7) (Travis et al. 2003, van Leeuwen et al. 2003, Guibout et al. 2005, Hill et al. 2005, Inskip et al. 2009). A linear dose–response curve has been established (Fig. 2A) (Inskip et al. 2009, Berrington de Gonzalez et al. 2013). Risk for radiation-induced breast cancer was traditionally studied after moderate- to high-dosed chest irradiation (i.e. ≥20 Gy) (Henderson et al. 2010). However, recent studies also demonstrated an increased secondary breast cancer risk after lower dosed chest irradiation (Lange et al. 2014, Moskowitz et al. 2014). Lange and coworkers observed an increased breast cancer risk of 14.4% (95% CI: 7.6–30.1) at an attained survivors’ age of 40 years after 1–12 Gy chest irradiation for nephroblastoma (Lange et al. 2014). In a recent study by Moskowitz and coworkers, breast cancer risk was 30.6-fold increased (95% CI: 18.4–50.7) in comparison with the United States general population after 10–19 Gy chest irradiation for various childhood cancer subtypes (Moskowitz et al. 2014). Currently, there is no evidence of a significant effect of radiotherapy fractionation on secondary breast cancer risk following childhood cancer (Guibout et al. 2005).

Figure 2
Figure 2

Fitted radiation dose–response relationships for chest irradiation and breast cancer, as well as thyroid gland irradiation and thyroid cancer as observed as in the Childhood Cancer Survivors Study by Inskip et al. (2009) and Bhatti et al. (2010), respectively. (A) Fitted dose–response relationship between chest radiation and breast cancer risk by radiation dose to the chest and ovaries. Reproduced from Inskip PD et al.: Journal of Clinical Oncology Vol. 27(24), 2009: 3901–3907. Reprinted with permission. Copyright 2009 American Society of Clinical Oncology. All rights reserved. (B) Fitted dose–response relationship for thyroid gland irradiation and thyroid cancer risk (based on two constructed models (model 5 and 10) and adjusted for attained age, gender, and primary childhood cancer subtype). Reproduced from Bhatti P et al.: Radiation Research Vol. 174(6), 2010: 741–752. Reprinted with permission. Copyright 2010 Radiation Research Society. All rights reserved.

Citation: Endocrine-Related Cancer 23, 6; 10.1530/ERC-16-0113

Table 7

Estimated excess relative risk for secondary breast cancer per Gy chest irradiation in childhood cancer survivors.

Study (year)Study populationTreatment eraPatientsaAge at primary cancer Dx (year)ERR for subsequent breast cancer per Gy (95% CI)
Travis et al. (2003)Nested case–control study in a cohort of Hodgkin lymphoma survivors from 6 population-based cohorts1965–1994Cases 105<310.15 (0.04–0.73)
Controls 266
van Leeuwen et al. (2003)Nested case–control study in a cohort of Hodgkin lymphoma survivors from 4 institutions in the Netherlands1965–1988Cases 48<410.03 (0.002–0.06)
Controls 175
Guibout et al. (2005)Cohort of solid tumor survivors from 8 institutions in France and Britain1946–19861814<170.13 (<0.00–0.75)
Hill et al. (2005)Nested case–control study in 6 population-based cohorts of Hodgkin lymphoma survivors1965–1999Cases 105<311.04 (1.00–1.07)b
Controls 266
Inskip et al. (2009)Nested case–control study in a cohort of survivors of several childhood cancers from 26 institutions in United States and Canada1970–1986Cases 120<210.36 (0.14–0.93)
Controls 464

all patients were females.

relative risk per Gy. CI, confidence interval

Dx, diagnosis

ERR, excess relative risk.

Studies investigating radiation-related secondary cancer risk in childhood cancer survivors have predominantly assessed older radiotherapeutic modalities (Kumar 2012). Contemporary radiotherapeutic techniques like conformal radiotherapy, intensity-modulated radiation therapy and proton-beam therapy allow for more precise radiation delivery to the tumor target, thereby sparing healthy surrounding tissue. Therefore, these techniques may yield lower risks for secondary malignant neoplasm development compared with older radiotherapeutic modalities of earlier treatment eras (Armstrong et al. 2010, Kumar 2012). However, there are also concerns of a potentially increased secondary cancer risk following modern radiotherapeutic techniques due to a larger amount of leakage radiation (Kumar 2012). To our knowledge, observational studies on secondary breast cancer risk in childhood cancer survivors following modern radiotherapeutic techniques have to be performed yet.

Hematopoietic stem cell transplantation

Childhood cancer survivors who received hemato­poietic stem cell transplantation are at increased risk for secondary breast cancer (Friedman et al. 2008, Danner-Koptik et al. 2013). Friedman and coworkers, observed a standardized incidence ratio of 2.2 (95% CI: 1.7–2.9) for secondary breast cancer following allogeneic hematopoietic stem cell transplantation. In their study, secondary breast cancer risk was associated with total-body irradiation, follow-up duration, and age at stem cell transplantation (Friedman et al. 2008). In addition, Danner-Koptik and coworkers observed a standardized incidence ratio of 93 (95% CI 11–336) for secondary breast cancer following autologous hematopoietic stem cell transplantation. However, they could not demonstrate an association between secondary breast cancer risk and age, gender, childhood cancer subtype, follow-up duration, response to primary cancer treatment, and use of total-body irradiation or etoposide as part of pretransplant conditioning regimen (Danner-Koptik et al. 2013). Intriguingly, three cases of secondary breast cancer in male childhood cancer survivors following total-body irradiation and hematopoietic stem cell transplantation have been described (Latz et al. 2004, Lowe et al. 2008, O’Flynn et al. 2011).

Chemotherapy

Most studies in cohorts of solely childhood cancer survivors and childhood- and adult-onset cancer survivors combined did not observe a relationship between chemotherapy and secondary breast cancer risk (Guibout et al. 2005, Reulen et al. 2008, Alm El-Din et al. 2009, Little et al. 2014), or observed a protective effect of certain chemotherapeutic agents on the development of radiation-related breast cancer (van Leeuwen et al. 2003, Travis et al. 2003, 2005, De Bruin et al. 2009, Swerdlow et al. 2012, Schaapveld et al. 2015). However, two studies reported an increased risk for secondary breast cancer attributable to chemotherapy (Hancock et al. 1993, Henderson et al. 2015). In a combined cohort of childhood- and adult-onset Hodgkin lymphoma survivors, Hancock and coworkers observed a higher risk for secondary breast cancer following treatment with mechlorethamine, vincristine, procarbazine and prednisone in combination with radiotherapy compared with treatment with radiotherapy alone during the first 15 years following Hodgkin lymphoma (SIR 6.3 (95% CI: 3.1–11.6) for combination chemoradiation therapy vs SIR 0.8 (95% CI: 0.1–2.5) for radiotherapy alone). After 15 years of follow-up since Hodgkin lymphoma, secondary breast cancer risk became equivalently increased in both treatment groups (SIR 14.8 (95% CI: 3.7–40.4) for combination chemoradiation therapy vs SIR 13.0 (95% CI: 6.6–23.1) for radiotherapy alone) (Hancock et al. 1993). In addition, in a recent Childhood Cancer Survivor Study report by Henderson and coworkers on the risk for secondary breast cancer in childhood cancer survivors not treated with chest irradiation, exposure to anthracyclines and alkylating agents was associated with an increased secondary breast cancer risk (relative SIR 3.8 (95% CI: 1.7–8.3) for anthracyclines dosed ≥250mg/m2, and relative SIR 3.0 (95% CI: 1.2–7.7) for alkylating agents dosed ≥18,000mg/m2 compared with no treatment with anthracyclines or alkylating agents) (Henderson et al. 2015). As suggested by Van Leeuwen and coworkers, the observed increased risk for secondary breast cancer attributable to anthracyclines and alkylating agents in childhood cancer survivors not treated with chest irradiation might be partly related to genetic susceptibility (van Leeuwen & Ronckers 2016).

Primary cancer diagnosis and secondary breast cancer risk

In a series of three articles, Maule and coworkers reported standardized incidence ratios and excess absolute risks for secondary malignant neoplasms in childhood cancer survivors derived from 13 population-based cancer registries (Maule et al. 2007, 2008, 2011). They observed an increased risk for secondary breast cancer after several childhood cancer subtypes (Table 8). The highest risk for secondary breast cancer was observed in survivors of Hodgkin lymphoma (Maule et al. 2007), which likely reflect treatment with mantle field irradiation. However, Guibout and coworkers also observed an increased risk for secondary breast cancer in Hodgkin lymphoma survivors after adjustment for chest irradiation and treatment with chemotherapy (RR 7.01 (95% CI: 1.4–30.9) compared with survivors of other childhood cancer subtypes) (Guibout et al. 2005). This supports the idea that factors other than treatment exposures, like genetic determinants, may also contribute to secondary breast cancer development in Hodgkin lymphoma survivors. Although Maule and coworkers did not observe a significantly increased risk for secondary breast cancer in survivors of soft-tissue sarcoma, retinoblastoma, nephroblastoma, neuroblastoma, germ cell tumors and non-Hodgkin lymphoma, other studies did (Kenney et al. 2004, Guibout et al. 2005, Inskip & Curtis 2007, Marees et al. 2008, Reulen et al. 2011, Lange et al. 2014, Little et al. 2014). The increased risk for secondary breast cancer in survivors of sarcoma might also be partly related to genetic factors. Data from the Childhood Cancer Survivor Study demonstrated an increased standardized incidence ratio for secondary breast cancer in sarcoma survivors not treated with chest irradiation (5.3 (95% CI: 3.6–7.8)) (Henderson et al. 2015). In addition, a positive family history for sarcoma was associated with an increased secondary breast cancer risk (RR 5.3 (95% CI: 1.3–21.5)) (Kenney et al. 2004). The increased risk for secondary breast cancer after retinoblastoma is observed in both heritable and nonheritable retinoblastoma survivors (Little et al. 2014), and seems to become apparent after ≥40 years of follow-up since primary cancer diagnosis in heritable retinoblastoma survivors (Marees et al. 2008).

Table 8

Risk for secondary breast cancer by childhood cancer subtype.

Primary childhood cancer diagnosisSIR (95% CI)EAR per 100,000 person-years
Leukemia2.42 (0.06–13.5)0.8
Hodgkin lymphoma20.9 (7.66–45.4)40.6
Non-Hodgkin lymphoma0.00 (0.00–0.33)−1.7
Glioma1.4 (0.2–5.2)1.3
Other central nervous system tumors1.3 (0.0–7.4)2.5
Retinoblastoma1.5 (<0.1–8.5)1.6
Renal tumors3.0 (0.1–16.7)2.7
Bone sarcomas6.8 (1.9–17.5)26.9
Soft-tissue sarcomas1.3 (<0.1–7.4)1.1
Epithelial tumors1.8 (0.5–4.6)8.7

CI, confidence interval; EAR, excess absolute risk; SIR, standardized incidence ratio.

Hormonal influences on secondary breast cancer risk

In the general population, prolonged exposure to estrogens has been associated with an increased breast cancer risk (Clemons & Goss 2001). Therefore, several studies investigated the risk-modifying effects of age at menarche, menopausal age, and age at first childbirth on secondary breast cancer in childhood- and young-adult-onset cancer survivors (Travis et al. 2003, van Leeuwen et al. 2003, Kenney et al. 2004, Hill et al. 2005, De Bruin et al. 2009, Cooke et al. 2013). In contrast to observations in the general population, Cooke and coworkers demonstrated an increased risk for secondary breast cancer in Hodgkin lymphoma survivors experiencing a late menarche (OR 3.74 (95% CI: 1.08–12.98) for age at menarche 17 vs 13 years) (Cooke et al. 2013). In addition, they observed a relationship between timing of chest irradiation in relation to menarche and secondary breast cancer risk. Secondary breast cancer risk was significantly increased in survivors treated with chest irradiation within 5 years of menarche; the smaller the interval between chest irradiation and menarche, the higher the risk for secondary breast cancer (P<0.001 for trend) (Cooke et al. 2013). Other studies could not demonstrate an association between age at menarche and secondary breast cancer risk (van Leeuwen et al. 2003, Kenney et al. 2004, Hill et al. 2005). In addition, no studies observed a risk-modifying effect of age at first childbirth on secondary breast cancer development in childhood- and young-adult-onset cancer survivors (van Leeuwen et al. 2003, Kenney et al. 2004, Hill et al. 2005). However, Hill and coworkers demonstrated a relationship between timing of childbirth in relation to Hodgkin lymphoma diagnosis and secondary breast cancer risk. Women not treated with alkylating agents or ovarian irradiation ≥5Gy who had childbirth within 5 years following Hodgkin lymphoma diagnosis demonstrated an increased secondary breast cancer risk compared with women who had childbirth at least 5 years after Hodgkin lymphoma diagnosis (OR 2.6 (95% CI: 1.0–6.7)) (Hill et al. 2005). An increased risk for breast cancer shortly after childbirth has also been observed in the general population, and is thought to be related to gestational hormone exposure, immunosuppressive effects of pregnancy and postpartum breast involution (Lyons et al. 2009).

Several studies investigated the risk-modifying effects of age at menopause, premature ovarian insufficiency, alkylating agents and ovarian irradiation on radiation-induced breast cancer in survivors of childhood- and young-adult-onset cancer (Table 9) (Travis et al. 2003, van Leeuwen et al. 2003, Kenney et al. 2004, Hill et al. 2005, Taylor et al. 2007, De Bruin et al. 2009, Cooke et al. 2013, Schaapveld et al. 2015). Studies in combined cohorts of childhood- and adult-onset Hodgkin lymphoma survivors consistently reported a protective effect of premature ovarian insufficiency on radiation-induced breast cancer risk (Travis et al. 2003, van Leeuwen et al. 2003, Hill et al. 2005, De Bruin et al. 2009, Cooke et al. 2013). Risk for radiation-induced breast cancer seems to be lower in women experiencing less premenopausal years following Hodgkin lymphoma treatment (De Bruin et al. 2009, Cooke et al. 2013). Alkylating agent chemotherapy and ovarian irradiation are known to potentially induce premature ovarian insufficiency. Therefore, several studies investigated the risk-modifying effects of these therapies on radiation-induced breast cancer development. A protective effect of alkylating agent chemotherapy on radiation-induced breast cancer has been observed in combined cohorts of childhood- and adult-onset Hodgkin lymphoma survivors (Travis et al. 2003, 2005, van Leeuwen et al. 2003, De Bruin et al. 2009, Swerdlow et al. 2012, Schaapveld et al. 2015). In the studies by Travis and coworkers, and Van Leeuwen and coworkers, increasing cycles of alkylating agent chemotherapy and a high dose of procarbazine were significantly associated with a decreased risk for radiation-induced breast cancer (Travis et al. 2003, van Leeuwen et al. 2003). Note that no studies in cohorts of childhood cancer survivors solely could demonstrate a beneficial effect of alkylating agents on radiation-induced breast cancer risk. In addition, several studies in cohorts of childhood cancer survivors solely and childhood- and adult-onset cancer survivors combined observed a protective effect of ovarian irradiation on radiation-induced breast cancer (Fig. 2A) (Kenney et al. 2004, Constine et al. 2008, Inskip et al. 2009, Swerdlow et al. 2012, Moskowitz et al. 2014).

Table 9

Risk-modifying effects of gonadotoxic treatment, premature ovarian insufficiency and age at menopause on secondary breast cancer risk in childhood cancer survivors.

Study (year)Study populationTreatment eraPatientsAge at primary cancer Dx (year)RR (95% CI) associated with alkylating agents (yes vs no)RR (95% CI) associated with ovarian irradiation (yes vs no)RR (95% CI) associated with premature ovarian insufficiency (yes vs no)a
Studies in combined cohorts of childhood- and adult-onset Hodgkin lymphoma survivors
Travis et al. (2003)Nested case–control study in a cohort of Hodgkin lymphoma survivors from 6 population-based cohorts1965–1994Cases 105<310.7 (0.3–1.7) 1–4 cycles0.4 (0.1–1.1)b0.2 (0.05–0.6) <30 years
Controls 2660.6 (0.3–1.1) 5–8 cycles0.3 (0.1–0.8) 30–39 years
0.2 (0.1–0.7) ≥9 cycles
van Leeuwen et al. (2003)Nested case–control study in a cohort of Hodgkin lymphoma survivors from 4 institutions in the Netherlands1965–1988Cases 48<410.31 (0.09–1.05) <6 cycles0.13 (0.02–1.08)b0.09 (0.01–0.81) 19–30 years
Controls 1750.33 (0.13–0.86) ≥6 cycles0.25 (0.07–0.92) 31–40 years
0.84 (0.23–3.05) ≥41 years
Hill et al. (2005)Nested case–control study in 6 population-based cohorts of Hodgkin lymphoma survivors1965–1999Cases 105<31NANA0.3 (0.2–0.7)c
Controls 266
De Bruin et al. (2009)dCohort of Hodgkin lymphoma survivors from 5 institutions in the Netherlands1965–1995♀ 1122<51 (27.7% <21 years)0.6 (0.3–0.9)e,f0.4 (0.1–1.4)e0.4 (0.2–0.8)e
0.4 (0.1–1.3)e,g
Cooke et al. (2013)Nested case–control study in a cohort of Hodgkin lymphoma survivors from Wales and Britain treated with chest irradiation1956–2003Cases 260<36NANA0.65 (0.44–0.94)c
Controls 2237
Schaapveld et al. (2015)Cohort of Hodgkin lymphoma survivors from 7 institutions in the Netherlands1965–2000♂ 220715–500.84 (0.52–1.36)e,hNANA
♀ 16980.71 (0.47–1.07)e,i
0.33 (0.16–0.68)e,g
Studies in cohorts childhood cancer survivors solely
Kenney et al. (2004)Cohort from 26 institutions in United States and Canada1970–1986♀ 6068<210.8 (0.4–1.6) AA-score 1–20.6 (0.4–0.9)NA
0.8 (0.4–1.4) AA-score 3–4
1.11 (0.6–2.0) AA-score≥5
Taylor et al. (2007)Population-based cohort of Hodgkin lymphoma survivors from Britain1940–1991♀ 383<150.49 (0.18–1.33)NANA

premature ovarian insufficiency is defined as menopause <40 years of age.

≥5 Gy ovarian irradiation.

odds ratio.

analyses of risk-modifying effects restricted to women <41 years of age at Hodgkin lymphoma diagnosis.

hazard ratio.

≤8.4 g/m2 procarbazine.

>8.4 g/m2 procarbazine.

≤4.2 g/m2 procarbazine.

4.2–8.4 g/m2 procarbazine.

♂, male; ♀, female; AA-score, alkylating agent score (i.e. a categorical variable accounting for exposure to various alkylating agents and a range of doses developed by Tucker et al. (1987)); CI, confidence interval; Dx, diagnosis; Gy, Gray; NA, not available; RR, relative risk.

Although the aforementioned studies suggest protective effects of premature ovarian insufficiency and gonadotoxic therapies on radiation-induced breast cancer development, it is important to keep in mind that most of these studies were performed in combined cohorts of childhood- and adult-onset Hodgkin lymphoma survivors (Travis et al. 2003, 2005, van Leeuwen et al. 2003, Hill et al. 2005, De Bruin et al. 2009, Swerdlow et al. 2012, Cooke et al. 2013, Schaapveld et al. 2015). The beneficial effect of gonadotoxic treatment on radiation-induced breast cancer risk seems less pronounced in childhood- compared with adult-onset cancer survivors. This is underscored by a recent study in survivors of Hodgkin lymphoma by Swerdlow and coworkers which observed a beneficial effect of gonadotoxic therapy on radiation-induced breast cancer risk only in women aged ≥20 years at primary cancer treatment (Swerdlow et al. 2012). The less pronounced protective effect of gonadotoxic therapy in childhood- compared with adult-onset cancer survivors may be explained by a greater reserve of follicles in young women, which might be less likely to deplete following ovarian toxic treatment (Sklar 2005). Note that in a recent study in childhood cancer survivors not treated with chest irradiation, Henderson and coworkers could not demonstrate a protective effect of ovarian irradiation or alkylating agent chemotherapy on secondary breast cancer risk (Henderson et al. 2015). This indicates that gonadotoxic treatment only protects for radiation-induced breast cancer development.

Currently, there is no evidence of a harmful effect of estrogen–progestin replacement therapy on secondary breast cancer risk in premature ovarian-insufficient childhood cancer survivors (Travis et al. 2003, van Leeuwen et al. 2003, De Bruin et al. 2009). However, the number of women using estrogen–progestin replacement therapy in the available studies addressing this issue is too small to reliably evaluate this topic. Only recently, estrogen–progestin replacement therapy is prescribed commonly in premature ovarian-insufficient childhood cancer survivors (van Leeuwen et al. 2003). Since potential benefits of premature ovarian insufficiency on radiation-induced breast cancer risk have not been demonstrated in cohorts of solely childhood cancer survivors, and harms of estrogen–progestin replacement therapy on radiation-induced breast cancer risk in premature ovarian-insufficient childhood cancer survivors have not been described thus far, castration of female childhood cancer survivors at high risk for radiation-induced breast cancer should not be performed. This is underscored by the clearly demonstrated beneficial effects of estrogen–progestin replacement therapy on bone and cardiovascular health, as well as quality of life in women from the general population experiencing premature ovarian insufficiency (National Collaborating Centre for Women’s and Children’s Health 2015). The effect of oral contraceptives on secondary breast cancer risk in childhood cancer survivors has only been studied in combined cohorts of childhood- and adult-onset Hodgkin lymphoma survivors. No risk-modifying effects have been demonstrated (van Leeuwen et al. 2003, Hill et al. 2005, De Bruin et al. 2009).

Thyroid cancer

Epidemiology and host-related risk factors

Several recent large cohort studies in childhood cancer survivors observed significantly increased standardized incidence ratios for secondary thyroid carcinoma between 5.4 and 18.0 in comparison with the general population (Inskip & Curtis 2007, Olsen et al. 2009, Taylor et al. 2009, Friedman et al. 2010). This represents a 30-year cumulative incidence of 1.4% (95% CI: 1.1–1.6) since childhood cancer diagnosis (Friedman et al. 2010). The increased risk for secondary thyroid cancer in childhood cancer survivors involves predominantly differentiated thyroid carcinoma (i.e. papillary or follicular thyroid carcinoma) (Black et al. 1998, Taylor et al. 2009). Latency periods for the development of secondary thyroid carcinoma in childhood cancer survivors vary between 0.6 and 38 years (average 12.3 years) (Table 10) (Black et al. 1998, Bhatia et al. 2002, Acharya et al. 2003, Cohen et al. 2007, Constine et al. 2008, Diallo et al. 2009, Taylor et al. 2009, Veiga et al. 2012a, Danner-Koptik et al. 2013, Dorffel et al. 2015, Finke et al. 2015, Brignardello et al. 2016). A recent study by Veiga and coworkers included pooled data from the Childhood Cancer Survivor Study cohort (Bhatti et al. 2010), the Late Effects Study Group cohort (Tucker et al. 1991), the Nordic countries cohort (Svahn-Tapper et al. 2006) and a combined French and British cohort (de Vathaire et al. 1999). The study found that female gender (RR 2.0 (95% CI: 1.5–2.8)), younger age at primary cancer (P<0.01 for trend), longer follow-up since primary cancer (P=0.01 for trend), older attained survivor’s age (P<0.01 for trend), and treatment with radiotherapy (RR 5.5 (95% CI: 3.1–9.7)) were significantly associated with secondary thyroid carcinoma risk in childhood cancer survivors (Veiga et al. 2012b). A risk-modifying effect of gender and age at childhood cancer diagnosis has also been observed in other studies (Cohen et al. 2007, Constine et al. 2008), but not all (Somerville et al. 2002, Taylor et al. 2009). A recent study by De Vathaire et al. investigated the influence of smoking and overweight on secondary thyroid cancer risk in childhood cancer survivors, but could not demonstrate a significant effect (RR 0.75 (95% CI: 0.32–1.6) for smoking; RR 1.4 (95% CI: 0.7–2.80 for overweight)) (de Vathaire et al. 2015). Best and coworkers identified allelic variants in PRDM1 to predispose Hodgkin lymphoma survivors to radiation-induced thyroid cancer (Best et al. 2011). In addition, several studies identified allelic variants in TP53, ATM and FOXE1 to be associated with radiation-induced papillary thyroid carcinoma in survivors of the Chernobyl nuclear accident (Akulevich et al. 2009, Takahashi et al. 2010, Damiola et al. 2014).

Table 10

Latency time between childhood cancer and secondary thyroid cancer.

Latency period
Study (year)Study populationTreatment eraPatientsAge at primary ­cancer Dx (year)Median follow-up (year)Radiotherapy (%)Thyroid cancers (N)Median (year)Range (year)
Black et al. (1998)Population-based study in Germany, Austria and Switzerland1980–1997NA<16NANA1884–19
Bhatia et al. (2002)Cohort of leukemia survivors from 122 institutions in United States and Canada1983–1995♂ 5034<21153849.75.5–11.8
♀ 3797
Acharya et al. (2003)Single-center cohort of survivors of several childhood cancers from the United States1970–1998♂ 10<21NA1003313.06.2–30.1
♀ 23
Cohen et al. (2007)Cohort of hematopoietic stem cell transplantation survivors from 166 institutions participating in the European Group for Blood and Marrow Transplantation (EBMT) registry1985–2003♂ 40,148<52 (27.5% <21 years)12.775.0328.50.6–18.5
♀ 30,538
Constine et al. (2008)Cohort of Hodgkin lymphoma survivors from 5 institutions in the United States1960–1990♂ 532<1916.8a91.21414.48.5–23.0
♀ 398
Diallo et al. (2009)Cohort of survivors of several childhood cancers from 8 institutions in France and Britain1942–1986♂/♀ 4581<1715.4NA17188–38
Taylor et al. (2009)Population-based cohort from Britain1940–1991♂/♀ 17,980<1517.4NA5019.56–38
Veiga et al. (2012)Cohort from 26 institutions in United States and Canada1970–1986♂ 6621<2116a68.011914.3a5–34
♀ 5926
Danner-Koptik et al. (2013)Cohort of survivors of autologous hematopoietic stem cell transplantation survivors from >450 institutions participating in the Center for International Blood and Marrow Transplantation (CIBMT)1987–2003♂ 895<21822b56.81.9–12.5
♀ 592
Dorffel et al. (2015)Cohort from German, Austrian and Swiss pediatric Hodgkin lymphoma studies1978–2002♂ 1424<1914.3NA4713.24.0–29.2
♀ 1124
Finke et al. (2015)Population-based cohort from German Childhood Cancer Registry1980–2002♂/♀ 33,809<15NANA179.34.0–17.6
Brignardello et al. (2016)Single-center cohort of survivors of several childhood cancers from Italy1985–2007♂ 113<1815.191001413.088.22–23.65
♀ 84

mean.

radiotherapy as part of conditioning regimen for hematopoietic stem cell transplantation.

♂, male; ♀, female; Dx, diagnosis; N, number; NA, not available.

Treatment-related risk factors for secondary thyroid carcinoma

Radiotherapy involving the thyroid gland is the most important risk factor for secondary thyroid carcinoma in childhood cancer survivors, and seems to exert its effect via a sigmoidal dose–response relationship (Veiga et al. 2012b, de Vathaire et al. 2015). In the aforementioned pooled study by Veiga and coworkers, the dose–response relationship for thyroid carcinoma in survivors of pediatric cancer increased linearly until a radiation dose of approximately 10Gy, leveled off at a radiation dose of approximately 10–30Gy, and declined again at a radiation dose >30Gy. However, the risk for thyroid cancer still remained increased at a radiation dose >50Gy (Veiga et al. 2012b). The downturn in the dose–response relationship for radiation-induced thyroid carcinoma is thought to be related to a cell-killing effect (Sigurdson et al. 2005). In Fig. 2B, the dose–response curve for secondary thyroid carcinoma following thyroid gland irradiation as reported by Bhatti and coworkers is shown (Bhatti et al. 2010). This study by Bhatti and coworkers is also included in the pooled analysis by Veiga and coworkers (Veiga et al. 2012b). Besides increasing the risk for differentiated thyroid carcinoma, radiotherapy involving the thyroid gland is also known to promote the occurrence of benign thyroid nodules in childhood cancer survivors (Table 11). Clinically, it may be difficult to distinguish malignant from benign thyroid nodules (Healy et al. 1996, Crom et al. 1997, Somerville et al. 2002, Acharya et al. 2003, Haddy et al. 2012, Vivanco et al. 2012, Kelly et al. 2013, Caglar et al. 2014, Li et al. 2014, Agrawal et al. 2016, Brignardello et al. 2016). Studies investigating radiation-related thyroid carcinoma risk after childhood cancer treatment have predominantly assessed older radiotherapeutic modalities. To our knowledge, observational studies on secondary thyroid carcinoma risk in childhood cancer survivors treated with modern radiotherapeutic techniques like conformal radiotherapy, intensity-modulated radiation therapy and proton-beam therapy have to be performed yet.

Table 11

Detection and presence of benign and malignant thyroid nodules in childhood cancer survivors.

Study (year)Study populationTreatment eraPatientsAge at primary cancer Dx (year)Median follow-up (year)RTx (%)Method of nodule detectionBenign nodules (%)Malignant nodules (%)
Acharya et al. (2003)Single-center cohort of survivors of several childhood cancers from the United States1970–1998♂ 10<21NA100Retrospective search in hospital-based databases for thyroid nodules in childhood cancer survivors and histological confirmation by pathologist20 (60.6)13 (39.4)
♀ 23
Agrawal et al. (2016)Single-center cohort of survivors of several childhood cancers from the United StatesNA♂ 58<21NA50.4Ultrasonography and histological examination in suspected nodules31 (93.9)2 (6.1)
♀ 61
Brignardello et al. (2016)Single-center cohort of survivors of several childhood cancers from Italy1985–2007♂ 113<1815.19100Ultrasonography and histological examination in suspected nodules60 (81.1)14 (18.9)
♀ 84
Caglar et al. (2014)Single-center cohort of survivors of several childhood cancers from TurkeyNA♂ 84<187.8a56.7Ultrasonography and histological examination in suspected nodules24 (88.9)3 (11.1)
♀ 36
Crom et al. (1997)Single-center cohort of survivors of several childhood cancers from the United StatesNA♂ 53<2210.6100Ultrasonography and histological examination in suspected nodules21 (95.5)1 (4.5)
♀ 43
Haddy et al. (2012)Cohort of survivors of several childhood cancers from 5 institutions in France1940–1985♂ 1831<162570.3Self-reported questionnaire or retrospective search in medical records for histologically confirmed thyroid adenomas71 (2.2)NA
♀ 1423
Healy et al. (1996)Single-center cohort of Hodgkin lymphoma survivors from BritainNA46NA10.3100Ultrasonography and histological examination in suspected nodules28 (93.3)2 (6.7)
Kelly et al. (2013)Single-center cohort of survivors of several childhood cancers from the United States1987–2007♂ 17<188100Ultrasonography and histological examination in suspected nodules43 (91.5)4 (8.5)
♀ 30
Li et al. (2014)Single-center cohort of survivors of several childhood cancers from CanadaNA♂ 44<1917.90100Retrospective search in medical records for childhood cancer survivors who received ultrasonography and histological examination for suspected nodules41 (89.1)5 (10.9)
♀ 34
Somerville et al. (2002)Single-center cohort of survivors of several childhood cancers from AustraliaNA♂ 72NA14.0a100Ultrasonography and histological examination in suspected nodules81 (81.8)18 (18.2)
♀ 70
Vivanco et al. (2012)Single-center cohort of survivors of several childhood cancers treated with total-body irradiation preceding hematopoietic stem cell transplantation from France1989–2009♂ 43<185.1100Ultrasonography and histological examination in suspected nodules15 (71.4)6 (28.6)
♀ 33

mean. ♂, male; ♀, female; %, percentage; Dx, diagnosis; NA, not available; RTx, radiotherapy.

A few studies demonstrated an increased risk for secondary thyroid carcinoma in childhood cancer survivors attributable to chemotherapy (Veiga et al. 2012a, b, de Vathaire et al. 2015). Veiga and coworkers observed a 2.4-fold increased risk (95% CI: 1.3–4.5) for secondary thyroid cancer in childhood cancer survivors treated with a combination of alkylating agents and ≤20 Gy thyroid gland irradiation; the contribution of chemotherapy to secondary thyroid cancer risk declined with increasing thyroid gland irradiation dose (P=0.03 for trend) (Veiga et al. 2012a). In another study, Veiga and coworkers observed a 4.5-fold increased risk (95% CI: 1.4–17.8) for secondary thyroid carcinoma in childhood cancer survivors treated with anthracyclines without thyroid gland irradiation (Veiga et al. 2012b). A recent study by De Vathaire and coworkers demonstrated an increased secondary thyroid carcinoma risk in childhood cancer survivors treated with nitrosourea chemotherapy (RR 6.6 (95% CI: 2.5–15.7)) (de Vathaire et al. 2015). Interestingly, in this study by De Vathaire and coworkers, childhood cancer treatment with splenectomy was also associated with an increased risk for secondary thyroid cancer (RR 2.3 (95% CI: 1.3–4.0)), while pituitary irradiation >10 Gy decreased secondary thyroid carcinoma risk (RR 0.2 (95% CI: 0.1–0.6)) (de Vathaire et al. 2015). In our institution, we could not demonstrate an increased risk for secondary thyroid cancer in survivors of childhood Hodgkin lymphoma treated with chemotherapy solely (van Beek et al. 2009, van Dorp et al. 2012).

Autologous and allogeneic hematopoietic stem cell transplantations are also associated with an increased secondary thyroid cancer risk (Socie et al. 2000, Cohen et al. 2007, Vivanco et al. 2012, Danner-Koptik et al. 2013). In a cohort of childhood- and adult-onset autologous and allogeneic hematopoietic stem cell transplantation survivors, Cohen and coworkers identified young age at transplantation (RR 24.61 (95% CI: 4.45–136.25) for age 0–10 vs >20 years), pretransplant conditioning with total-body irradiation (RR 3.44 (95% CI: 1.41–8.37)), and chronic graft-versus-host disease (RR 2.94 (95% CI: 1.21–7.15)) to increase the risk for secondary thyroid cancer (Cohen et al. 2007).

Primary cancer diagnosis and secondary thyroid carcinoma risk

Several childhood cancer subtypes have been associated with an increased secondary thyroid cancer risk (Table 12). Particularly, high risks for secondary thyroid carcinoma have been observed in survivors of neuroblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, brain tumors, and leukemia (Maule et al. 2007, 2008, 2011). In addition, De Vathaire and coworkers observed an increased risk for secondary thyroid carcinoma in survivors of gonadal tumors (SIR 16.0 (95% CI: 4.0–41.4)) and soft-tissue sarcoma (SIR 8.2 (95% CI 2.0–21.2)) (de Vathaire et al. 2015). Administered treatment modalities, like 131I-MIBG and radiotherapy involving the thyroid gland, may conceivably explain the increased risks for secondary thyroid cancer. 131I-MIBG (131-iodine metaiodobenzylguanidine) may be used to treat neuroblastoma, and involves administering a radioiodine-labeled guanidine derivate (Kayano & Kinuya 2015). Approximately 2–5% of the administered 131I-MIBG enters the circulation as free radioiodine, and may affect thyroid functioning and induce thyroid nodules as well as secondary thyroid carcinoma (Clement et al. 2015).

Table 12

Risk for secondary thyroid cancer by childhood ­cancer subtype.

Primary childhood cancer diagnosisSIR (95% CI)EAR per 100,000 person-years
Leukemia18.8 (8.60–35.7)11.3
Hodgkin lymphoma52.5 (24.0–99.6)62.7
Non-Hodgkin lymphoma40.4 (14.8–88.0)31.0
Glioma6.8 (1.9–18.0)7.2
Embryonal central nervous system tumors30 (8.2–77)25
Other central nervous system tumors7.7 (0.2–43)8.8
Sympathetic nervous system tumors143.7 (29.6–419.8)60.8
Retinoblastoma5.3 (0.1–29.6)3.8
Renal tumors13.9 (2.9–40.5)11.1
Bone sarcomas10.8 (1.3–38.9)14.3
Soft-tissue sarcomas4.1 (0.1–22.6)3.6
Epithelial tumors3.3 (0.1–18.4)3.4

CI, confidence interval; EAR, excess absolute risk; SIR, standardized incidence ratio.

Limitations of currently available literature, and recommendations for future research

The currently available literature on secondary endocrine-related cancer risk in childhood cancer survivors has some limitations. Follow-up durations since childhood cancer are generally too short to assess the risk for secondary malignant neoplasms in aging childhood cancer survivors. Average follow-up durations since childhood cancer vary between 6.3 and 27.3 years in studies assessing secondary breast cancer risk (Hancock et al. 1993, Metayer et al. 2000, Ng et al. 2002, Bhatia et al. 2003, Gold et al. 2003, Guibout et al. 2005, Inskip & Curtis 2007, Constine et al. 2008, Friedman et al. 2008, Marees et al. 2008, Alm El-Din et al. 2009, De Bruin et al. 2009, Maule et al. 2011, Reulen et al. 2011, Cooke et al. 2013, Danner-Koptik et al. 2013, Little et al. 2014, Dorffel et al. 2015, Moskowitz et al. 2015, Schaapveld et al. 2015), and 5.1–27 years in studies investigating secondary thyroid carcinoma risk (Crom et al. 1997, Bhatia et al. 2002, Cohen et al. 2007, Inskip & Curtis 2007, Constine et al. 2008, Taylor et al. 2009, van Beek et al. 2009, Friedman et al. 2010, Maule et al. 2011, Vivanco et al. 2012, Danner-Koptik et al. 2013, Caglar et al. 2014, Li et al. 2014, Clement et al. 2015, de Vathaire et al. 2015, Dorffel et al. 2015, Brignardello et al. 2016). Specific subtypes of secondary malignant neoplasms and potential risk-modifying factors yet unknown may become apparent at an advanced survivor’s age. Therefore, it is important to prospectively evaluate the growing cohort of aging childhood cancer survivors.

Furthermore, a large amount of the evidence on secondary breast cancer risk in childhood cancer survivors (Kenney et al. 2004, Marees et al. 2008, Inskip et al. 2009, Friedman et al. 2010, O’Brien et al. 2010, Moskowitz et al. 2014, 2015, Dorffel et al. 2015, Henderson et al. 2015) and, to a lesser extent, on secondary thyroid cancer risk in childhood cancer survivors (Sigurdson et al. 2005, Bhatti et al. 2010, Friedman et al. 2010, Veiga et al. 2012a, de Vathaire et al. 2015, Dorffel et al. 2015) has been derived from retrospective cohort studies using self-reported data to ascertain secondary malignant neoplasms, which may predispose to selection bias. Another source for selection bias may be the nature of the cohort. This is illustrated by Ness et al., who observed an overestimation of the prevalence of long-term adverse health conditions by 9.3% (95% CI: 7.0–11.6) in childhood cancer survivors ascertained in a hospital- compared with a population-based setting (Ness et al. 2009). Future studies on secondary endocrine-related malignancies after childhood cancer could be prospective, based on national registries, and use objective methods to collect data on secondary malignant neoplasms.

Although several studies reported a protective effect of gonadotoxic therapies and premature ovarian insufficiency on radiation-induced breast cancer (Travis et al. 2003, 2005, van Leeuwen et al. 2003, Kenney et al. 2004, Hill et al. 2005, Constine et al. 2008, De Bruin et al. 2009, Inskip et al. 2009, Cooke et al. 2013, Moskowitz et al. 2014, Schaapveld et al. 2015), it is important to consider that most of these studies were performed in combined cohorts of childhood- and adult-onset Hodgkin lymphoma survivors (Travis et al. 2003, 2005, van Leeuwen et al. 2003, Hill et al. 2005, De Bruin et al. 2009, Cooke et al. 2013, Schaapveld et al. 2015). Since the beneficial effects of gonadotoxic treatments on radiation-induced breast cancer risk seem less pronounced in childhood- compared with adult-onset cancer survivors (Swerdlow et al. 2012), and no studies assessed the risk-modifying effect of a diagnosis of premature ovarian insufficiency on radiation-induced breast cancer in childhood cancer survivors solely, more studies should be performed. Future studies may also address the potential harms and benefits of estrogen–progestin replacement therapy on radiation-induced breast cancer risk in women experiencing childhood cancer treatment-related premature ovarian insufficiency.

Studies on secondary malignant neoplasms after childhood cancer concern predominantly survivors treated with old-fashioned treatment regimens. Although childhood cancer therapy has changed considerably over the past five decades (Kumar 2012, Hudson et al. 2014), results described in this review are still highly valuable for those individuals treated in earlier treatment eras. Since the effects of modern radiotherapeutic techniques like conformal radiotherapy, intensity-modulated radiation therapy and proton-beam therapy on secondary endocrine-related cancer risk remain unknown, future studies should address the potential risks and benefits associated with these contemporary radiotherapeutic modalities. Risks for radiation-induced malignant neoplasms may be greater in small compared with large children due to a more significant contribution of scatter radiation (Hall 2006). Currently, no studies on secondary endocrine-related malignancies after childhood cancer accounted for this issue. Future studies may investigate radiation-induced cancer risks by dosimetry according to body size at cancer treatment.

Finally, there is a lack of studies specifically investigating the influence of environmental and lifestyle factors on secondary endocrine-related cancer risk in childhood cancer survivors. Future studies should address these potentially risk-modifying factors.

Conclusion

Secondary malignant neoplasm development in childhood cancer survivors depends on host factors, primary cancer diagnosis, and types and timing of primary cancer treatment. In addition, environmental factors and lifestyle factors may play a contributing role. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, there seems to be no harmful effect of estrogen–progestin replacement therapy on radiation-induced breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Childhood cancer survivors at risk for secondary endocrine-related malignancies should be regularly screened in a risk-based fashion, preferably by endocrinologists in close collaboration with physicians experienced in long-term complications of childhood cancer treatment.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    Distribution of secondary malignant neoplasms and primary cancer diagnoses among childhood cancer survivors who developed a secondary neoplasm as observed in the Childhood Cancer Survivor Study by Friedman et al. (2010). (A) Secondary malignant neoplasms (nonmelanoma skin cancers excluded). (B) Primary cancer diagnoses. CNS, central nervous system; SMN, secondary malignant neoplasm.

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    Fitted radiation dose–response relationships for chest irradiation and breast cancer, as well as thyroid gland irradiation and thyroid cancer as observed as in the Childhood Cancer Survivors Study by Inskip et al. (2009) and Bhatti et al. (2010), respectively. (A) Fitted dose–response relationship between chest radiation and breast cancer risk by radiation dose to the chest and ovaries. Reproduced from Inskip PD et al.: Journal of Clinical Oncology Vol. 27(24), 2009: 3901–3907. Reprinted with permission. Copyright 2009 American Society of Clinical Oncology. All rights reserved. (B) Fitted dose–response relationship for thyroid gland irradiation and thyroid cancer risk (based on two constructed models (model 5 and 10) and adjusted for attained age, gender, and primary childhood cancer subtype). Reproduced from Bhatti P et al.: Radiation Research Vol. 174(6), 2010: 741–752. Reprinted with permission. Copyright 2010 Radiation Research Society. All rights reserved.

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