Introduction

The American Cancer Society estimated that 1,638,910 cases of new cancer would be diagnosed in the United States in 2012, a figure that excludes cancer in situ and nonmelanoma skin cancer. In the same time period, 577,190 persons were expected to die from cancer. Because of the rising incidence of and survival from cancer, an estimated 12.8 million survivors of cancer are now alive in the United States, with 5-year survival rates of 67% for adults and 82% for children now being diagnosed with cancer, according to the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER). With a growing cohort of cancer survivors now living, efforts have focused on decreasing the risk for adverse long-term health-related outcomes, the most significant of which are subsequent malignant neoplasms (SMNs). According to current data from SEER, SMNs represent 16% (1 in 6) of reported cancers.¹

The most recent monograph from the NCI on subsequent malignancies, published in 2006, does not reflect the current percentage because it reports on the period from 1973 to 2000,² expanding on the prior report issued more than 20 years earlier.³ However, this monograph represents the largest overview of subsequent malignancies that includes data on both adult and pediatric cancers. In this report, among 2 million patients with cancer who survived at least 2 months with close to 11 million person-years at risk, cancer survivors had a 14% higher risk of having a new malignancy than would have been expected in the general SEER population (observed/expected = 1.14). A total of 185,407 new primary cancers were observed compared with the expected number of 162,602 which translates to an excess absolute risk (EAR) of 21 per 10,000 person-years. However, the risk of SMN compared with the general population was highly dependent on the age of the patient at first cancer diagnosis, because risk for cancer rises with increased attained age in the general population. For example, for persons younger than 18 years at initial diagnosis, the relative risk (RR) was 6.13 and the EAR was 15 per 10,000 person-years. The RR and EAR for persons 70 to 79 years at initial diagnosis dropped to their lowest values, 1.02 and 4, respectively. The highest EARs of 32 to 39 were noted in young to middle-age adults ages 30 to 59 years at initial cancer diagnosis. Gender also influenced risk, with a slightly increased risk for females (RR = 1.17) compared with males (RR = 1.11), a pattern that remained even when gender-specific malignancies were excluded from the analyses. Blacks also had elevated RR and EAR (1.31 and 46, respectively) compared with whites (1.12 and 20, respectively). Overall, an SMN developed in 14% of SEER patients by 25 years of follow-up. Although RRs were highest in the first 5 years from diagnosis, cumulative incidence increased by years of follow-up: 5.0%, 8.4%, 10.8%, and 13.7% at 5, 10, 15, and 25 years, respectively. More than 80% of multiple primary cancers reported arose in separate or independent organ systems. New malignancies that occurred in the same site or organ as the first primary cancer accounted for 13.2%, with the most common sites being the female breast, colon, lung, and skin (melanoma). Another 3.8% of new malignancies originated in neighboring tissues or organs.² Table 62-1 shows the significant relative and excess absolute risks by primary cancer site. As is obvious, risk is highest for survivors of childhood cancer. However, for adult-onset cancers, although detailed lifestyle or environmental data were clearly not obtained for this analysis, the EAR for cancers occurring at tobacco- or alcohol-related sites, such as the oral cavity, pharynx, esophagus, larynx, and lung, was 114 cases per 10,000 person-years and overall accounted for 10,000 excess subsequent cancers.²

The etiology of SMNs is multifactorial. Host and environmental factors clearly play a role, but defining those contributions can be difficult. Superimposed on this general population risk for second and subsequent primary cancers are treatment-associated malignancies, where chemotherapy and radiotherapy for the primary cancer can increase risk for a subsequent cancer. This risk is then modified by host and environmental factors that affect risk of primary cancer, such as lifestyle (e.g., use of tobacco and alcohol, sun exposure, and diet), workplace and home exposures to carcinogens, viruses, age, gender, genetics, infection, immune function, hormone levels, and interactions of all of these factors. It is difficult to evaluate disease separate from known genetic associations with those diseases (e.g., breast, colon, and retinoblastoma) or separate from exposure to specific therapeutic modalities used to treat those malignancies (e.g., chemotherapy and radiation therapy). Table 62-2 summarizes common risk factors for SMNs in these general categories, but categories are not fully exclusive of one another.

Genetic Risks for Subsequent Malignancy

When considering the risk of SMNs associated with genetic predisposition, one must consider genetic disorders with high risk for both primary and subsequent malignancy, as well as less well-defined gene-environment interactions. The former category, which accounts for a small minority of SMNs, includes hereditary breast cancer (BRCA1/BRCA2), heritable retinoblastoma, neurofibromatosis, nevoid basal cell carcinoma (BCC), Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer (Lynch syndrome), multiple endocrine neoplasia, Bloom syndrome, xeroderma pigmentosum, and other syndromes.4,5 Table 62-3 summarizes these syndromes and common sites for primary and subsequent neoplasms; in addition, several are discussed here.

Mutations in BRCA1 and BRCA2 are associated with high risk for secondary breast cancer.6,7 In a study of 810 women with a stage I or II primary breast cancer in the setting of BRCA1 or BRCA2, a contralateral breast cancer developed in 149 subjects (18.4%), with a 15-year actuarial risk of 36.1% and 28.5%, respectively, for women with a BRCA1 or BRCA2 mutation. Younger age (<50 years) at primary breast cancer diagnosis and having two or more first-degree relatives with breast cancer also increased risk. A reduction of risk was noted with oophorectomy (RR = 0.47).⁶ Among 396 women with stage I or stage II primary breast cancer in the setting of a BRCA1 or BRCA2 mutation, the 5-year actuarial risk of ipsilateral breast cancer was 5.8%, and the 10-year risk was 12.9%. Receipt of chemotherapy and radiotherapy both reduced risk (RR = 0.45 and 0.28, respectively). Oophorectomy was associated with a significant risk reduction (RR = 0.33). On average, after a diagnosis of breast cancer, the annual risk of ipsilateral breast cancer risk in BRCA mutation carriers is 1.2% per year.⁷ Of course, in addition to these risks, patients with BRCA1 and BRCA2 also have an increased risk for primary ovarian cancer,⁸ and patients with BRCA2 have an increased risk for prostate cancer, pancreatic cancer, gallbladder and bile duct cancer, stomach cancer, and malignant melanoma.⁹ Of note, mutations in BRCA1, BRCA2, or TP53 are not thought to be responsible for the increased incidence of SMN among Hodgkin lymphoma survivors. In a study of 44 patients who experienced one or more SMNs, mutations in the TP53 gene were examined in all 44 patients and BRCA1 and BRCA2 were examined in 19 female patients in whom one or more secondary breast cancer developed. One of 44 patients tested for TP53 harbored a novel homozygous germline abnormality, and one of 19 patients tested for BRCA2 carried a previously described heterozygous inactivating mutation; no germline BRCA1 mutations were identified.¹⁰

Mutations in mismatch repair genes in persons with hereditary nonpolyposis colorectal cancer can lead to the more site-specific colorectal cancer syndrome associated with other gastrointestinal cancers (Lynch syndrome type I) or the family cancer syndrome, in which early-onset endometrial and stomach cancers are seen in addition to colorectal cancer (Lynch syndrome type II).11,12

Neurofibromatosis type 1 (NF1), which results from a mutation in the NF1 gene at chromosome 11q12, is not associated with malignancy in the majority of patients with this syndrome. However, patients (and particularly children) with NF1 have an increased risk for leukemias, central nervous system (CNS) tumors, and peripheral nerve sheath tumors.13,14 In a report from the Late Effects Study Group, NF1 was second only to retinoblastoma among children with a predisposition to SMN.¹⁵

Retinoblastoma, which is associated with germline mutation of the RB1 gene at chromosome 13q14, is the most common hereditary syndrome associated with SMN after childhood cancer.18–18 Survivors of retinoblastoma have a significantly increased risk of sarcomas both inside and outside the radiotherapy field, along with leukemia, melanoma, and epithelial tumors such as breast and lung cancers. In a cohort of 1604 patients treated from 1914 to 1984, the cumulative incidence of SMN was 51% and 5% at 50 years for heritable and nonheritable retinoblastoma survivors, respectively.¹⁹ A follow-up 9 years later found 50-year cumulative incidences to be 36% and 5.7%, with standardized incidence ratios (SIRs) of observed/expected SMNs of 19 and 1.2, respectively, for persons with heritable disease versus nonheritable disease. Radiotherapy increased SMN risk in heritable patients 3.1-fold.²⁰ The cumulative probability of death from SMN was 25.5% for bilateral disease survivors, and the increased risk extended beyond 40 years after retinoblastoma diagnosis.²¹

Li-Fraumeni syndrome, which is associated with germline mutation in the TP53 gene at chromosome 17q13, is characterized by increased risk for breast cancer, sarcoma, leukemia, brain tumors, adrenocortical carcinoma, and gonadal germ cell tumors.22,23 Several small studies have reported an excess of multiple primary tumors in patients with Li-Fraumeni syndrome, but this phenomenon has not been systematically studied.^10,24,25

Nevoid BCC syndrome associated with mutation of the PTCH1 gene on chromosome 9 is associated with BCC and medulloblastoma, and many BCCs can develop during a patient’s lifetime. Although multiple BCCs are reported in survivors of childhood cancer, it is likely that only persons who experience these along the track of radiotherapy within a very short latency of 6 months have this genetic predisposition. In other persons, including those treated with total body irradiation (TBI) for stem cell transplant or radiotherapy after childhood cancer, early-onset nonmelanoma skin cancers are noted, although environmental and lifestyle factors have not been systematically collected and represent an area of future research.26,27

Bloom syndrome, xeroderma pigmentosum, and ataxia telangiectasia are all rare disorders of DNA repair that can lead to multiple primary cancers, including leukemia and lymphoma, skin cancer, soft tissue sarcomas, and epithelial tumors. However, these syndromes have well-recognized phenotypes and thus are not an occult cause of SMN.28–32