SECOND CANCER OCCURRENCE AND RISK FACTORS

The Rising Incidence of Second Cancers: Patterns of

Occurrence and Identication of Risk Factors for Children
and Adults
Lindsay M. Morton, PhD, Kenan Onel, MD, PhD, Rochelle E. Curtis, MA, Eric A. Hungate, PhD, and
Gregory T. Armstrong, MD, MSCE
OVERVIEW
As the population of cancer survivors has increased and continues to age, the occurrence of second cancers has risen dramatically
from 9% of all cancer diagnoses in 19751979 to 19% in 20052009. The Childhood Cancer Survivor Study, a cohort of more than 14,000
childhood cancer survivors with detailed exposure data and long-term follow-up, has substantially contributed to our understanding of
the roles of radiotherapy and chemotherapy in second cancer occurrence. In particular, dose-related risks have been demonstrated for
second cancers of the breast, thyroid, central nervous system, gastrointestinal tract, and sarcomas following radiation. Cytotoxic
chemotherapywhich has long been known to be leukemogenicalso appears to contribute to risk for a range of other second cancer
types. Individuals who develop a second cancer are at particularly high risk for developing additional second cancers. A genome-wide
association study of survivors of Hodgkin lymphoma who received radiotherapy identied a locus on chromosome 6q21 as being
associated with second cancer risk, demonstrating that recent advances in genomics are likely to prove invaluable for elucidating the
contribution of genetic susceptibility to second cancer etiology. Among adults, risk of second cancers varies substantially by type of
rst and second cancer, patient age, and prevalence of second cancer risk factors, including primary cancer treatments, environmental
and lifestyle exposures, and genetic susceptibility. Further research is needed to quantify second cancer risks associated with specic
etiologic factors and to identify the patients at highest risk of developing a second cancer to target prevention and screening efforts.

rognosis following a cancer diagnosis has improved dramatically over the past several decades because of advances in early detection, treatment, and supportive care.
The fve-year relative survival rate in the United States increased from less than 50% in 19751979 to 67% in 2001
2005 for all cancers combined and now exceeds 80% for
childhood cancer.1 With these improvements in survival and
the aging of the population, approximately one in six cancers
diagnosed today occurs among the nearly 14 million cancer
survivors in the United States.2 These second cancers are a
leading cause of morbidity and mortality among cancer survivors; thus, understanding their causes is of substantial clinical and public health importance. However, the burden of
second cancers is borne unequally by survivors of different
types of cancer, and the etiology of second cancers is complex
and multifactorial. For survivors of childhood cancer, primary cancer treatments and genetic susceptibility likely play
key roles. For adults, other cancer risk factorssuch as environmental exposures and lifestyle factors that may accumulate over timeare likely to make a greater contribution to

second cancer occurrence.3 This article summarizes the patterns of second cancer occurrence and identifcation of second cancer risk factors in survivors of childhood and adult
cancers, as well as the increasing role of genomics in second
cancers research.

SECOND CANCERS IN SURVIVORS OF CHILDHOOD

CANCER
Although cancers occurring during childhood account for
only 1% of all cancer diagnoses, investigation of second cancer etiology in childhood cancer survivors is particularly important because their good prognosis allows for a long time
period in which to experience second cancer occurrence.1,4
In addition, because younger individuals have relatively
fewer exposures to other environmental and lifestyle cancer
risk factors, studies of childhood cancer survivors can provide clear insight on the role of primary cancer treatments in
second cancer etiology.

From the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD; Department of Pediatrics, The University of Chicago,
Chicago, IL; and Department of Epidemiology and Cancer Control, St. Jude Childrens Research Hospital, Memphis, TN.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Lindsay M. Morton, PhD, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, 9609
Medical Center Drive 7E-454 MSC 9778, Bethesda, MD 20892; email: mortonli@mail.nih.gov.
2014 by American Society of Clinical Oncology.

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The substantially increased second cancer risks faced by

survivors of childhood cancer are well documented.5-8 Second cancers are the most common cause of treatment-related
death in long-term survivors (standardized mortality ratio
15.2, 95% CI 13.9 16.6).9 These high risks combined with the
substantially increasing cumulative incidence of second cancers over time make it clear that the development of second
cancers is a central issue as survivors of childhood cancer age.
As a retrospective cohort study, with longitudinal
follow-up of 5-year survivors of childhood cancer treated at
26 institutions in the United States and Canada, the Childhood Cancer Survivor Study (CCSS) cohort provides a
unique surveillance resource for estimating the incidence of
and risks factors for second cancer development.10,11 Briefly,
eligibility for participation in CCSS included diagnosis of
cancer before age 21, initial treatment between January 1,
1970, and December 31, 1986, and survival for 5 years or
longer after diagnosis. Participants were recruited from survivors treated for initial diagnoses of leukemia, central nervous system malignancy, Hodgkin lymphoma (HL), nonHodgkin lymphoma (NHL), Wilms tumor, neuroblastoma,
soft tissue sarcoma, and bone tumors. Within CCSS, second
cancers are defned as new neoplasms (malignant and benign) ascertained through self- or proxy-report questionnaires and/or death certifcates. Cases were subsequently
confrmed by pathology report or, when not available, confrmed by death certifcate or other medical records reviewed
by study investigators. Only second cancers occurring 5 years
or more following the childhood cancer diagnosis were evaluated.

KEY POINTS
The population of cancer survivors has increased
substantially in recent decades as a result of
improvements in survival from advances in early detection,
treatment, and supportive care.
Approximately 19% of cancers diagnosed today occur
among individuals with a history of previous malignancy.
Thus, understanding the causes of second cancers has both
public health and clinical importance.
The most commonly diagnosed second cancers among
childhood cancer survivors include nonmelanoma skin
cancer and cancers of the breast, central nervous system,
and thyroid. Primary cancer treatmentsincluding
radiotherapy and, to a lesser extent, chemotherapyare
associated with risk for second cancers after primary
childhood cancer.
Second cancer risks after adult cancer have a more
complex multifactorial etiology with an important role for
environmental and lifestyle risk factors in addition to
primary cancer treatments.
Advances in genomics hold promise for identication of
individuals who may be genetically susceptible to the
development of second cancers.

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Occurrence of Second Cancers in Survivors of

Childhood Cancer
In the most recent analysis of the 14,359 survivors in the
CCSS cohort, 1,402 survivors developed 2,703 second cancers, including 802 invasive cancers, 1,574 nonmelanoma
skin cancers (NMSC), and 159 nonmalignant meningiomas.7
Following NMSC, breast cancer (252 diagnoses), tumors of
the central nervous system (245 diagnoses), and thyroid carcinoma (128 diagnoses) were most commonly observed. At
30 years from primary cancer diagnosis, the cumulative incidence of all second cancers was 20.5% (95% CI 19.1%21.8%;
Fig. 1), with a cumulative incidence of 7.9% (7.2% 8.5%) for
invasive cancers, 9.1% (8.1%10.1%) for NMSC, and 3.1%
(2.5%3.8%) for meningioma. Survivors of HL had the highest cumulative incidence of second cancers (18.4%, 6.1%
11.1%) followed by survivors of Ewing sarcoma (10.1%,
6.7%13.5%) and soft tissue sarcomas (8.8%, 6.5%11.1%).
Survivors of HL also had the highest cumulative incidence of
both invasive cancers (18.4%, 16.1%20.8%) and NMSC
(20.8%, 17.6%24.1%). The highest cumulative incidence of
meningioma occurred among survivors of medulloblastoma
(16.4%, 7.5%25.3%).
Utilizing age-, sex-, race- and calendar year-specifc rates
from the Surveillance, Epidemiology, and End Results
(SEER) population-based cancer registries, survivors of
childhood cancer overall had six-fold (95% CI 5.5 6.4) increased risk of developing cancer compared with the general
population (i.e., standardized incidence ratio [SIR], observed/expected). Highest risks were observed for subsequent bone cancer (SIR 19.0, 95% CI 14.225.5), thyroid
cancer (10.9, 9.112.9), head and neck cancer (10.8, 7.8
15.0), central nervous system malignancies (10.4, 8.313.1),
and breast cancer (9.8, 8.4 11.5). The median interval between frst and second cancer diagnosis was 17.8 years (range
5.0 35.2), with the shortest interval for subsequent leukemia
(8.9 years, range 5.0 31.1) and longest for subsequent small
intestine and colorectal cancers (23.1 year, range 7.0 29.4).
Because of the long latency associated with the development
of second cancers, it may be that the list of cancers for which
pediatric cancer survivors are at increased risk will expand as
survivors continue to age, such that these data are actually an
underrepresentation of the lifetime burden of second cancers
in this population.

Risk Factors for Specic Second Cancers in Survivors

of Childhood Cancer
Utilizing the detailed treatment data collected for all survivors in the CCSS cohort, numerous studies have quantifed
the risk of second cancers in relation to primary childhood
cancer treatments. Although multiple studies have identifed
increased risk for breast cancer among young females who
receive chest-directed radiotherapy, a case control study
within the CCSS cohort further defned that risk increases
linearly with radiotherapy dose.5,12 Importantly, this risk was
reduced for women who also received 5 Gy or higher ovarian
radiation, presumably because of suppression of hormonal
stimulation to breast tissue. Comprehensive evaluation of

SECOND CANCER OCCURRENCE AND RISK FACTORS

FIG 1. Cumulative incidence of second cancers in the Childhood Cancer Survivor Study, overall and for selected second cancer types
(nonmelanoma skin cancer [NMSC], subsequent neoplasm [SN], subsequent malignant neoplasm [SMN]). This gure is reprinted from
Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer
Survivor Study.
J Natl Cancer Inst. 2010;102;1083-1095, by permission of the Journal of the National Cancer Institute.

over 6,000 women in the CCSS cohort also identifed that

survivors of bone and soft tissue sarcoma who did not receive
radiotherapy and survivors who had a family history of breast
cancer were at increased risk.13 Among the 1,230 female survivors exposed to chest radiotherapy, the most recent assessment of cumulative incidence of breast cancer was 30% (95%
CI 25 to 34) by age 50, with a 35% incidence among survivors
of HL (95% CI 29 to 40)a rate comparable to that of BRCA
mutation carriers in the general population.14
Similarly, in another case control study, the development
of both central nervous system glioma (odds ratio [OR] 6.8,
95% CI 1.529.7) and meningioma (9.9, 2.2 45.6) was identifed to be associated with radiotherapy in a linear doseresponse relationship.15 Risk for glioma was highest for
children treated with radiotherapy before age 5. In contrast,
the risk for thyroid cancer increased with radiotherapy dose
only up to 20 29 Gy, with a decline in the radiation-related
risks above 30 Gy (linear-exponential dose response), consistent with a cell-killing effect at high doses.16 However, for patients with thyroid doses of 20 Gy or less, treatment with
alkylating agents was associated with a 2.4-fold increased risk
for thyroid cancer.17 Using CCSS data, a risk calculator for
thyroid cancer has been developed.18
The majority of NMSCs that occur in survivors of childhood cancer are basal cell carcinomas, and although 95% can
be cured with surgery alone, the cosmetic outcome can be
disfguring. In a CCSS case-control study, survivors who received 35 Gy or more to the skin were at a signifcantly increased risk of developing NMSC (OR 39.8, 95% CI 8.6 185,
p 0.05) compared to those with no exposure, with results
consistent with a linear dose-response relationship.19

In addition to identifying dose-response relationships between primary childhood cancer treatments and risk of the
most common second cancers, the size and extended longitudinal follow-up of the aging CCSS cohort have allowed
identifcation of increased risk for additional second cancers,
including melanoma (SIR 2.4, 95% CI 1.8 3.2), renal carcinoma (8.0, 5.211.7), gastrointestinal carcinoma (4.6, 2.8
6.3), and salivary gland cancer (39.4, 25.4 57.8).20-23 Finally,
contrary to previous understanding, the incidence of subsequent leukemia does not appear to plateau more than 15
years from primary treatment, with an SIR of 3.5 (1.9 6.0).24

Risk for Multiple Second Cancers in Survivors of

Childhood Cancer
With the aging of the CCSS cohort, it appears that the rising
cumulative incidence of a second cancer occurring after
childhood cancer does not fully describe the risk for this population because survivors who experience a second cancer
may be at risk for the development of multiple subsequent
cancers. A recent analysis identifed that among survivors
who experienced their frst subsequent neoplasm (SN1), 386
(27.8%) developed a second subsequent neoplasm (SN2).25
Of those with SN2, 153 (39.6%) developed more than two
SNs. Among survivors with SN1, the cumulative incidence of
SN2 was 33.4% (95% CI 30.3%36.5%) at 10 years and 46.9%
(41.6%52.2%) at 20 years. Similar patterns were observed
when analyses were restricted to invasive second cancers
(SMNs): 735 (5.1%) of survivors developed SMN1, of whom
68 (9.3%) developed SMN2. When SN1 was an SMN, the cumulative incidence of developing SMN2 following SMN1
was 12.4% (9.1%15.6%) at 15 years. Considering the young
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age (median: 32 years) of the CCSS cohort, these survivors

have yet to reach ages when sharp increases in the incidence
of cancer in the general population occur. Therefore, it appears that the multiple tissue injuries accrued because of cancer therapy, along with the effect of genetic susceptibility on
some survivors of multiple cancers set the stage in the second
decade of survival (median follow-up: 18 years) for a signifcant increase in the number of survivors experiencing multiple second cancers. Among individuals exposed to
radiation who developed NMSC as SN1 in this analysis, one
in fve developed an invasive neoplasm within 15 yearsan
incidence almost twice that of those also exposed to radiation
but who had an invasive neoplasm (SMN) as SN1.25 Therefore, NMSC may represent a clinical marker for early identifcation of a population at high risk for a future malignant
neoplasm, possibly because of genetic susceptibility to radiation injury and/or defcient DNA repair.

SURVEILLANCE OF SECOND CANCERS IN

SURVIVORS OF CHILDHOOD CANCER
Of all second cancers, screening for subsequent breast cancer, with its high cumulative incidence in females exposed to
chest-directed therapy, may offer the best opportunity for
beneft. The International Late Effects of Childhood Cancer
Guideline Harmonization Group currently recommends annual surveillance with both mammography and breast MRI
for females who have received 20 Gy or higher chest radiation
(strong recommendation) and 10 19 Gy (moderate recommendation) starting at age 25 or 8 years after completion of
radiotherapy, whichever occurs last.26 A recent prospective
assessment of combined serial screening with both mammography and breast MRI identifed that the sensitivity of
screening was signifcantly improved with combined modality (sensitivity 94%) as opposed to individual modality
screening (mammography alone, 68%; breast MRI alone,
67%).27
Women with early-stage breast cancer after radiotherapy
exposure have a high likelihood of a favorable outcome, suggesting that early detection may be benefcial. However,
treatment options may be more limited for these survivors
depending on their previous exposure to radiotherapy and
anthracycline chemotherapy. In addition, more information
on the potential harms of screening is needed, including the
risk for false-positive results, the accompanying fnancial and
emotional costs of additional screening or biopsy, and the
potential risk attributable to mammography by increasing
the lifetime exposure to radiation. Nonetheless, considerable
effort should now be given to dissemination and implementation of breast cancer screening. Additional recommendations by the Childrens Oncology Group for periodic
screening for thyroid carcinoma, skin cancers, gastrointestinal carcinoma, and subsequent leukemia exist, and a growing
body of literature identifying the value of risk-based screening is providing supportive evidence for these consensusbased recommendations.28,29
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SECOND CANCERS IN SURVIVORS OF ADULT

CANCER
Survivors of cancers diagnosed during adulthood account for
99% of the population of cancer survivors in the United
States, with 45% of survivors age 70 and older and just 4% age
20 to 39.1 Breast and prostate cancers are the most common
frst primary diagnoses among cancer survivors (22% and
20%, respectively), followed by colorectal (9%), gynecologic
(8%), and hematologic (8%) cancers.30
Population-based cancer registries provide unique insight
on the patterns of second cancer occurrence because of their
systematic collection of all cancer diagnoses occurring within
large populations and long-term follow-up. Using data from
nine SEER registries during 19752010, including 2,741,239
individuals or 9% of the US population, we quantifed the risk
of second cancers for selected populations of adult cancer
survivors, including survivors of testicular cancer, HL, breast
cancer, colon cancer, and bladder cancer.1 Specifcally, we
calculated the cumulative incidence of second cancers in
analyses with death as a competing risk.31 We also used age-,
sex-, race- and calendar year-specifc rates from SEER to calculate the (1) SIR (observed/expected), a measure of the risk
of developing a second cancer relative to the general population, and (2) excess absolute risk (EAR; [(observed-expected)/person years at risk] x 10,000), a measure of the overall
burden of second cancers.32 SIRs and EARs with p 0.05
were considered statistically signifcant. We then reviewed
the current understanding of risk factors for selected second
cancers among adults.

Occurrence of Second Cancers in Survivors of Adult

Cancer
The occurrence of second cancers has risen dramatically as
the population of cancer survivors has increased and as the
population has aged, rising from 9% of all cancer diagnoses in
19751979 to 19% of all cancer diagnoses in 20052009 (Fig.
2). In terms of the absolute numbers of cancer diagnoses, the
number of frst primary malignancies has increased by 70%,
from 317,000 diagnoses in 19751979 (nine SEER registries)
to 548,000 diagnoses in 20052009. Over the same time period, the number of subsequent primary malignancies has
increased by more than 300%, from 30,000 to 125,000 diagnoses.
The burden of second cancers is borne unequally by survivors of different types of cancer because of variation in the
typical age at diagnosis, prognosis, and prevalence of second
cancer risk factors, including primary cancer treatments, environmental and lifestyle exposures, and genetic susceptibility. Testicular cancer and HL are among the most commonly
diagnosed malignancies in younger adults (median age at diagnosis, 35.6 and 41.4, respectively). At 30 years from primary cancer diagnosis, the cumulative incidence of second
cancers was 17.0% (95% CI 16.0%18.0%) for survivors of
testicular cancer and 21.0% (20.0%22.0%) for survivors of
HL, although HL survivors a had substantially higher cumulative incidence of death from other causes (47.1% versus
21.7% at 30 years; Fig. 3A). Among individuals diagnosed

SECOND CANCER OCCURRENCE AND RISK FACTORS

FIG 2. Occurrence of rst and subsequent primary malignancies among adults during 1975-2009* in nine SEER
registries.
Abbreviation: SEER ,Surveillance, Epidemiology, and End Results.
* Data from 2010 were excluded so that each category for year of diagnosis included 5 years.

with some of the most common adult cancers, cumulative

incidence of second cancers at 30 years from primary cancer
diagnosis was 21.2% (21.0%21.4%) for survivors of breast
cancer (median age at diagnosis, 59.8), 17.8% (17.6%18.1%)
for survivors of colon cancer (median age at diagnosis, 67.2),
and 27.1% (26.7%27.4%) for survivors of bladder cancer
(median age at diagnosis, 67.2), with substantially higher cumulative incidence of death from other causes for survivors
of colon cancer than survivors of bladder cancer (76.1% versus 65.3% at 30 years), despite a similar median age at diagnosis (Fig. 3B).
Second cancer SIRs typically were highest for individuals
diagnosed at younger ages and declined thereafter, particu-

larly after breast cancer, where the SIR declined from 5.4 at
age 20 to 29 to 1.0 at age 70 to 79 (Fig. 4A). Bladder cancer was
the exception to this pattern, with second cancer SIRs increasing slightly from 1.0 at age 20 to 29 to 1.3 at age 70 to 79.
For survivors of breast and colon cancer, the second cancer
EARs were highest for individuals diagnosed at younger ages
and declined thereafter (Fig. 4B). In contrast, the second cancer EARs increased with increasing age for survivors of HL
and bladder cancer and followed a U-shape pattern for survivors of testicular cancer.
Although understanding these patterns of overall second
cancer occurrence helps to provide a general picture of the
burden of second cancers for certain populations of cancer

FIG 3. Cumulative incidence of any second cancer and death because of other (non-second cancer) causes among adult survivors* of
rst primary Hodgkin lymphoma or testicular cancer (A), and colon, breast, or bladder cancers (B), 1975-2010, nine SEER registries.
Abbreviation: SEER, Surveillance, Epidemiology, and End Results.
* Individuals diagnosed with their rst primary cancer at age 20 to 84 and who survived 2 months or longer following diagnosis were eligible for inclusion.

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FIG 4. Standardized incidence ratio (A) and excess absolute risk (B), by age, of any second cancer among adult survivors* of rst
primary Hodgkin lymphoma or testicular, colon, breast, or bladder cancers, 1975-2010, nine SEER registries.
Abbreviation: SEER, Surveillance, Epidemiology, and End Results.
Note that estimates are unadjusted and thus do not account for potential differences in other factors across age groups, such as latency.
* Individuals diagnosed with their rst primary cancer at age 20 to 84 and who survived 2 months or longer following diagnosis were eligible for inclusion.

survivors, consideration of specifc types of second cancers

paints a far more complex picture (Table 1). Among survivors of HL in the current SEER analysis, SIRs were signifcantly elevated for the vast majority of second cancer types,
particularly cancers of the digestive tract (SIRs 1.6 2.6), lung
(2.9), bone (3.6), soft tissue (5.0), breast (2.0), and thyroid
(2.6), as well as NHL (6.0) and acute nonlymphocytic leukemia (ANLL; SIR 12.4). In contrast, survivors of testicular cancer had signifcantly elevated SIRs for many fewer second
cancer types, with increased risks observed for cancers of the
pancreas (2.3), soft tissue (2.5), bladder (1.5), kidney (1.5),
and thyroid (2.4), as well as ANLL (3.8). Among the selected
common adult cancers, the few with signifcantly increased
SIRs of 1.5 or more included ANLL (1.8) and cancers of the
breast (1.6) or soft tissue (1.5) among survivors of breast cancer; cancers of the small intestine (3.7) and colon (1.6) among
survivors of colon cancer; and lung cancer (1.7) after bladder
cancer. Nevertheless, because of the steep increase in cancer
incidence with age, modestly increased second cancer SIRs
among older cancer survivors may correspond to substantially increased EARs (e.g., an excess of 25.7 cases of lung cancer per 10,000 person years after bladder cancer).

Risk Factors for Second Cancers in Survivors of

Adult Cancer
Ionizing radiation exposure is a known risk factor for numerous malignancies, particularly cancers of the thyroid, female
breast, brain, NMSC, gastrointestinal tract, lung, bladder,
and bone, as well as sarcomas and myeloid leukemias.33-38
Patients undergoing radiotherapy are exposed to a wide
range of radiation doses to tissues outside the treatment area
because of scatter. Numerous studies have demonstrated that
patients receiving radiotherapy are at risk for radiationrelated second cancers, and the risk persists for decades following exposure. Because the risk for most radiationsensitive malignancies increases with increasing radiation
dose, the tissues in or near the radiotherapy treatment felds
typically have the highest risks because they receive the highe62

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est scatter doses. For example, radiotherapy has been shown

to play a key role in the excess risk of cancers of the digestive
tract, lung, bone, soft tissue, breast, and thyroid among survivors of HL.12,16,39-42 Further research is needed to evaluate
radiation-related second cancer risks associated with newer
radiotherapy techniques (e.g., intensity-modulated radiation
therapy), proton therapy, and efforts to reduce treatment
doses and volumes.43
Chemotherapy-related leukemia has long been recognized
as a rare but highly fatal complication of use of cytotoxic
agents for primary cancer treatment.44 The excesses of ANLL
after HL, testicular cancer, and breast cancer (Table 1) can
be attributed to receipt of cytotoxic chemotherapy, with
previous studies also demonstrating increased risk of
chemotherapy-related leukemia in survivors of NHL and
myeloma as well as cancers of the ovary, lung, soft tissue, and
bone.43,44 However, the magnitude of risk of chemotherapyrelated leukemia has varied substantially over the past several
decades, consistent with changes in treatment protocols, introduction of new agents, increasing use of (neo)adjuvant
therapy, and use of maintenance therapy or repeated courses
of treatment.45 Chemotherapy increasingly is recognized as
affecting risk of nonhematologic malignancies as well, including cancers of the lung, stomach, bladder, breast, thyroid, and bone.7,12,39,40,42,46-50 Additional research will be
needed to better understand the role of specifc chemotherapeutic agents in second cancer risks, both individually and in
combination, particularly as new classes of anticancer agents
are developed.
Despite the well-established second cancer risks associated
with radiotherapy, a recent study estimated that less than
10% of second cancers occurring among adults can be attributed to radiotherapy, suggesting that other cancer risk factors
such as environmental exposures, lifestyle factors, and genetic susceptibility are important contributors.51 However,
much less is known about the potential role of these factors in
second cancer etiology because registries do not collect data
on cancer risk factors, and other epidemiologic and clinic-

SECOND CANCER OCCURRENCE AND RISK FACTORS

Table 1. Standardized Incidence Ratio (SIR) and Excess Absolute Risk (EAR) for Selected Second Cancers Among
Adult Survivors* of First Primary Hodgkin Lymphoma or Cancers of the Testis, Colon, Breast, or Bladder, 1975
2010, Nine SEER Registries
Hodgkin Lymphoma
(20,198 Patients)

Testicular Cancer
(20,950 Patients)

Breast Cancer
(442,721 Patients)

Colon Cancer
(213,761 Patients)

Bladder Cancer
(Patients 119,674)

Second cancer
type

SIR

(95% CI)

EAR n

SIR

(95% CI)

EAR n

SIR

(95% CI)

EAR n

SIR

(95% CI)

EAR n

SIR

(95% CI)

EAR

Total

2380

2.0

(1.9, 2.1)

54.0

1675

1.4

(1.3, 1.4)

15.4

62,374

1.2

(1.2, 1.2)

23.9

31,578

1.1

(1.1, 1.1)

15.4

26,963

1.3

(1.3, 1.3)

58.8

Total, excl.
same site

2375

2.0

(1.9, 2.1)

54.0

1403

1.2

(1.1, 1.2)

6.6

38,919

1.0

(1.0, 1.0)

3.7

25,214

1.0

(1.0, 1.0)

-0.2

23,361

1.2

(1.2, 1.2)

38.7

Oral cavity,
pharynx

86

2.6

(2.1, 3.2)

2.4

40

0.8

(0.6, 1.1)

-0.4

924

1.1

(1.0, 1.1)

0.2

597

1.0

(0.9, 1.0)

-0.2

469

0.9

(0.9, 1.0)

-0.3

Esophagus

25

2.0

(1.3, 2.9)

0.6

14

0.8

(0.4, 1.3)

-0.1

395

1.3

(1.1, 1.4)

0.2

346

1.1

(1.0, 1.2)

0.2

272

1.0

(0.9, 1.2)

0.1

Stomach

43

2.3

(1.7, 3.1)

1.1

25

1.2

(0.8, 1.7)

0.1

884

1.1

(1.0, 1.2)

0.2

792

1.2

(1.2, 1.3)

1.0

480

1.1

(1.0, 1.2)

0.4

Small Intestine

1.7

(0.7, 3.3)

0.1

10

1.7

(0.8, 3.1)

0.2

233

1.1

(1.0, 1.3)

0.1

398

3.7

(3.3, 4.0)

2.0

93

1.2

(1.0, 1.5)

0.2

Colon

133

1.6

(1.3, 1.9)

2.3

75

1.0

(0.8, 1.2)

-0.1

5403

1.0

(1.0, 1.0)

0.1

4901

1.6

(1.6, 1.7)

12.8

1943

1.0

(1.0, 1.0)

-0.1

Rectum

31

0.9

(0.6, 1.2)

-0.3

50

1.2

(0.9, 1.5)

0.3

1482

0.9

(0.9, 1.0)

-0.2

1378

1.4

(1.3, 1.5)

2.7

702

1.0

(0.9, 1.1)

0.0

Liver

25

2.0

(1.3, 2.9)

0.6

18

0.9

(0.5, 1.4)

-0.1

251

0.8

(0.7, 0.8)

-0.2

222

0.8

(0.7, 0.9)

-0.4

217

1.1

(0.9, 1.2)

0.2

Pancreas

42

1.6

(1.1, 2.1)

0.7

63

2.3

(1.8, 3.0)

1.3

1575

1.0

(0.9, 1.0)

-0.1

915

1.0

(1.0, 1.1)

0.2

599

1.1

(1.0, 1.1)

0.3

Lung

438

2.9

(2.6, 3.1)

13.0

169

1.1

(1.0, 1.3)

0.6

7556

1.0

(1.0, 1.0)

0.1

4410

1.0

(1.0, 1.0)

-0.7

5900

1.7

(1.7, 1.8)

25.7

Bone

3.6

(1.4, 7.3)

0.2

0.8

(0.1, 2.8)

0.0

65

1.3

(1.0, 1.7)

0.0

20

0.9

(0.5, 1.3)

0.0

17

1.0

(0.6, 1.7)

0.0

Soft tissue

36

5.0

(3.5, 6.9)

1.3

23

2.5

(1.6, 3.7)

0.5

357

1.5

(1.4, 1.7)

0.3

134

1.0

(0.9, 1.2)

0.0

98

1.0

(0.8, 1.3)

0.0

Cutaneous
melanoma

80

1.3

(1.1, 1.7)

0.9

97

1.2

(1.0, 1.4)

0.5

1525

1.1

(1.1, 1.2)

0.4

744

1.0

(0.9, 1.0)

-0.3

573

0.8

(0.8, 0.9)

-1.1

Female breast

327

2.0

(1.8, 2.3)

7.6

**

23,455

1.6

(1.6, 1.6)

20.2

3128

1.0

(1.0, 1.1)

0.6

934

1.0

(0.9, 1.0)

-0.3

Cervix

22

1.8

(1.2, 2.8)

0.5

**

405

0.7

(0.7, 0.8)

-0.4

111

1.0

(0.8, 1.2)

0.0

27

0.9

(0.6, 1.2)

-0.1

Uterine corpus

43

1.5

(1.1, 2.0)

0.6

**

4411

1.4

(1.4, 1.4)

3.0

787

1.3

(1.2, 1.3)

1.1

177

0.9

(0.8, 1.0)

-0.3

Ovary

11

0.7

(0.3, 1.2)

-0.3

**

2189

1.3

(1.2, 1.3)

1.1

344

0.9

(0.8, 1.0)

-0.2

112

1.0

(0.8, 1.2)

0.0

Prostate

187

0.9

(0.8, 1.0)

-1.0

309

0.9

(0.8, 1.0)

-0.9

**

5478

1.0

(1.0, 1.0)

-0.2

6527

1.2

(1.2, 1.2)

10.6

Bladder

65

1.2

(0.9, 1.5)

0.5

106

1.5

(1.2, 1.8)

1.2

1570

1.1

(1.0, 1.1)

1666

1.0

(0.9, 1.0)

-0.5

2186

1.4

(1.4, 1.5)

6.8

Kidney

55

1.7

(1.3, 2.2)

1.1

68

1.5

(1.2, 1.9)

0.8

1061

1.1

(1.0, 1.1)

0.1

754

1.2

(1.1, 1.3)

0.9

683

1.4

(1.3, 1.5)

2.0

Brain, nervous
system

18

1.0

(0.6, 1.7)

0.0

26

1.1

(0.7, 1.6)

0.1

456

0.9

(0.8, 0.9)

-0.2

231

0.9

(0.8, 1.0)

-0.2

183

0.9

(0.8, 1.1)

-0.2

Thyroid

70

2.6

(2.0, 3.3)

2.0

46

2.4

(1.8, 3.2)

1.0

948

1.3

(1.2, 1.4)

0.5

227

1.3

(1.1, 1.5)

0.4

105

1.0

(0.8, 1.2)

0.0

NHL

303

6.0

(5.4, 6.7)

11.6

76

1.2

(0.9, 1.5)

0.4

1972

0.9

(0.9, 1.0)

-0.5

1078

1.0

(0.9, 1.0)

-0.4

783

1.0

(0.9, 1.0)

-0.3

CLL

0.5

(0.2, 1.1)

-0.3

16

1.2

(0.7, 1.9)

0.1

438

0.8

(0.7, 0.9)

-0.3

292

0.8

(0.7, 0.9)

-0.5

228

0.8

(0.7, 0.9)

-0.5

ANLL

121

12.4

(10.3, 14.9)

5.1

40

3.8

(2.7, 5.1)

1.1

778

1.8

(1.7, 1.9)

0.8

266

1.0

(0.9, 1.1)

0.0

246

1.3

(1.1, 1.4)

0.5

0.2

Abbreviations: ANLL, acute non-lymphocytic leukemia; CLL, chronic lymphocytic leukemia; EAR, excess absolute risk; NHL, non-Hodgkin lymphoma; SIR, standardized incidence ratio; SEER,
Surveillance, Epidemiology, and End Results.
* Individuals diagnosed with their rst primary cancer at age 20 to 84 and who survived 2 months or longer following diagnosis were eligible for inclusion.
** Indicates sex-specic outcomes not ascertained in the opposite sex.
EAR calculated as excess number of cases per 10,000 person years.
Total excludes nonmelanoma skin cancer.
Total excluding same site also excludes rectum and anus for colon cancer survivors and renal pelvis, ureter, and other urinary tract cancers for survivors of bladder cancer survivor.31
ANLL includes acute myeloid leukemia, acute monocytic leukemia, acute panmyelosis, and acute leukemianot otherwise specied.31

based studies with data on such factors often lack suffcient

sample size and/or systematic, long-term follow-up to ascertain second cancer diagnoses.52 Some of the increased risks
described above emphasize the importance of future research
that can investigate the role of shared risk factors in second
cancer etiology, such as the clustering of ovarian, breast, and
uterine corpus cancers after breast cancer, which may be attributed to shared hormonal and genetic factors; digestive
tract cancers after colon cancer, which may arise from shared
lifestyle factors such as diet, obesity, and physical inactivity;
and lung cancer after bladder cancer, which may be related to
cigarette smoking.

GENOMIC APPROACHES IN SECOND CANCER

ETIOLOGY
Rapid evolution in genomics in the past decade has led to
advances in our understanding of the contribution of genetic
susceptibility to second cancer etiology and holds promise
for larger-scale studies in the near future. Initial studies suggest that investigating genetic susceptibility to second cancers may serve as a model for identifcation of gene-gene and
gene-environment interactions because individuals have
known exposures to high doses of genotoxic agents during
primary cancer treatment. These exposures allow for a
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MORTON ET AL

generation of hypotheses regarding specifc drug metabolism

pathways and suggest that genetic factors may have substantially larger effect sizes in second cancers than those observed
in sporadic cancers, making it possible to identify genetic effects
in smaller sample sets. Finally, because the exposure is known,
follow-up functional studies can be readily designed.
One of the frst genetic association studies for second cancers was an assessment of the relationship between therapyrelated acute myeloid leukemia (t-AML) and the inactivating
C609T polymorphism in the NQO1 gene, which encodes a
detoxifcation enzyme involved in the oxidative stress response pathway.53 Increasing dosage of this variant was signifcantly associated with increased risk for t-AML (p
0.036), Subsequently, other susceptibility variants, such as
GSTP1, have been found in DNA detoxifcation genes.54 In
addition, since genotoxic agents induce DNA damage, other
studies have investigated the association between repair
genes and second cancers. For example, development of
t-AML stemming from treatment with alkylating agents has
been associated with polymorphisms in the mismatch repair
genes MLH1 and MSH2.55,56 Furthermore, that the normal
variant of XRCC1 is actually the t-AML risk allele suggests a
role for base excision repair in t-AML susceptibility.57 Finally, the XPD codon 751Gln variant appears to promote myeloid cell survival after chemotherapy, resulting in earlier
relapse, suggesting that the DNA of chemotherapy-targeted
cancer cells is repaired too quickly for tumor cell death to
ensue.58
The increased power to detect genetic associations in second cancer studies has made it possible to detect interactive
and main effects. For example, Ellis et al investigated the association between t-AML and two common functional polymorphic variants in the p53 pathway.59 With 171 t-AML
cases, they found that whereas neither the TP53 codon 72 single nucleotide polymorphism (SNP) nor the MDM2 SNP309
was by itself associated with t-AML, the two variants interacted to modulate risk. Similarly, the XRCC3 Thr241Met and
RAD51 G135C variants interact to increase t-AML risk. Of
note, this interactive effect is enhanced in the presence of a
common GSTM1 deletion polymorphism that attenuates the
activity of this enzyme, demonstrating a link between DNA
damage response and detoxifcation processes in t-AML susceptibility.60,61 Several previous studies also have identifed
joint effects of genetic susceptibility and primary cancer
treatments on second cancer risk. For example, the
WECARE study (Womens Environment, Cancer, and Radiation Epidemiology) has investigated common variants in
ATM and deleterious germ-line BRCA1 or BRCA2 mutations
in association with radiation-related contralateral breast cancer, using a nested case-control study design with over 700
women with asynchronous contralateral breast cancer and
nearly 1,400 women with unilateral breast cancer.62,63
Despite the attraction of hypothesis-driven candidate studies, such studies are often diffcult to replicate and typically
have been confned to investigations of candidate genes
based on animal or in vitro data suggesting their role in
carcinogenesis. Over the past decade, researchers have
e64

2014 ASCO EDUCATIONAL BOOK | asco.org/edbook

largely turned to agnostic genome-wide association studies

(GWAS) for the identifcation of variants associated with
cancer risk. However, because of the vast number of variants
interrogated the multiple testing burden in GWAS ensures
that only variants with large effects can be detected in studies
of rare diseases, such as second cancers. Two GWAS of second cancers have been published to dateneither of which
has observed associations for the variants identifed in previous candidate gene studies. In the frst GWAS of second cancers, Knight et al investigated genetic susceptibility to t-AML
by performing a GWAS in 80 cases and 150 controls, with
further genotyping of the 10 most signifcant SNPs (p
0.001) in an independent cohort of 70 cases and 95 controls.64
Although no SNP surpassed the genome-wide signifcance
threshold (p 1 108), three of 10 SNPs became more
signifcant when conditioning on the subset of patients with
t-AML with acquired mutations in chromosomes 5 and/or 7
in their leukemic blasts. This subset is associated with antecedent exposure to alkylating agents rather than chemotherapies that induce other forms of DNA damage, suggesting
that the power to detect associations may be increased when
accounting for etiological exposures.
In the second GWAS of second cancers, Best et al investigated 96 survivors of HL with at least one second cancer and
82 with HL only, with the study population restricted to survivors who received radiotherapy.65 That study identifed a
locus on chromosome 6q21 signifcantly associated with second cancer risk (rs4946728: p 1.09 108, rs1040411:
p 6.43 108). This association was replicated (p 0.002
and 0.03, respectively) in a second set of patients treated in
adolescence with radiotherapy for HL but not in patients
with HL treated as adults, thereby echoing genetically the epidemiologic observation that radiation-related cancer risks
may be higher for individuals exposed at younger ages. Because the etiologic exposure was known, the authors were
able to undertake functional studies in vitro to characterize
the risk locus, which was found to regulate induction of a
transcriptional repressor, PRDM1, by ionizing radiation,
thereby implicating PRDM1 as a radiation-responsive tumor
suppressor. When the authors investigated the prevalence of
this risk locus, they found that almost 30% of survivors of HL
with the risk haplotype developed a second cancer within 30
years versus only 3% with the protective haplotype. This high
penetrance approaches that of inherited cancer predisposing
variants, such as BRCA2 mutations. Moreover, that 50% of
Caucasians are homozygous for the risk variant suggests that
common variants may have very large effects but only in the
context of specifc exposures, whereas the variant appears
neutral in the absence of such exposures. These results underscore the importance of incorporating data on cancer risk
factors into genetic studies of association to better understand the etiology of complex diseases such as cancer.

CONCLUSION
The occurrence of second cancers has increased substantially
in recent decades as a result of improvements in survival fol-

SECOND CANCER OCCURRENCE AND RISK FACTORS

lowing cancer diagnosis and aging of the population. With

19% of cancers diagnosed today occurring among individuals with a history of previous malignancy, second cancer
research is of tremendous public health and clinical signifcance. Although second cancers are an important cause of
morbidity and mortality among cancer survivors, individuals
with different types of frst malignancies experience signifcantly different risks of second cancers. Substantial evidence
demonstrates that primary cancer treatments, including both
radiotherapy and chemotherapy, contribute to the burden of
second cancers, particularly among survivors of childhood
cancer. Other cancer risk factors, such as lifestyle and environmental factors and genetic susceptibility, also likely play a
role, but further research with detailed exposure data for
large populations of cancer survivors is needed to quantify
the contribution of these factors to second cancer etiology.
Additional research also is needed to identify the individuals
at greatest risk based on primary cancer type, treatment exposures, other cancer risk factors, and genetic susceptibili-

tywho might beneft the most from intervention programs

aimed at cancer prevention or screening programs aimed at
early detection.

ACKNOWLEDGEMENTS
Dr. Morton and Ms. Curtis were supported by the Intramural
Research Program of the National Cancer Institute, National
Institutes of Health. Dr. Armstrong was supported by the National Cancer Institute (grant number U24-CA55727, to LL
Robison, Principal Investigator); support to St. Jude Childrens Research Hospital also provided by the Cancer Center
Support (CORE) grant (CA 21765) and the American
Lebanese-Syrian Associated Charities (ALSAC). Dr. Onel
and Dr. Hungate were supported by grants from the National
Institutes of Health (HD0433871, CA129045, and CA40046),
American Cancer Society Illinois Division, St. Baldricks
Foundation, Hyundai Hope on Wheels, and Cancer Research
Foundation.

Disclosures of Potential Conicts of Interest

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

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