Solid tumor second primary neoplasms: who is at risk, what can we do?

Abstract

Eighteen percent of incident malignancies in the United States are a second (or subsequent) cancer. Second primary neoplasms (SPNs), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, genetic factors, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs.

Figure 1

Cumulative incidence (middle line) of breast cancer as a function of age of the cohort of female survivors of Hodgkin’s disease, with 95% CIs (upper and lower curves) From Bhatia S, Yasui Y, Robison LL, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s Disease. J Clin Oncol 21:4386–4394, with permission.

Figure 2

Panel A demonstrates a linear dose response relationship between radiation dose to the breast and risk of breast cancer. In contrast to the linear relationship between radiation dose and breast, colorectal, and stomach cancer, Panel B demonstrates the linear-exponential relationship between radiation dose and thyroid cancer. The peak risk occurs with thyroid radiation doses of 15 to 20 Gy, with diminishing excess risk with doses of more than 30 Gy. From Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 2005;365:2014-23 and Inskip PD, Robison LL, Stovall M, et al. Radiation dose and breast cancer risk in the Childhood Cancer Survivor Study. J Clin Oncol 2009;27:3901-7, with permission.

Figure 3

Cumulative incidence and 95% CIs of new cancers by time since diagnosis of hereditary retinoblastoma by radiotherapy. From Kleinerman RA, Smith SA, Holowaty E, et al. Radiation Dose and Subsequent Risk for Stomach Cancer in Long-term Survivors of Cervical Cancer. Int J Radiat Oncol Biol Phys. 2013;86:922-9, with permission.

Figure 4. Sources and Consequences of DNA Damage

DNA damage can be induced by exogenous physical agents, by endogenous chemical genotoxic agents that are the products of metabolism, such as reactive oxygen species (ROS), or by spontaneous chemical reactions, such as hydrolysis. Examples of DNA damage are ultraviolet (UV)-induced photoproducts (left), interstrand and intrastrand crosslinks, bulky chemical adducts (purple sphere), abasic sites, and oxidative damage such as 8-oxoguanine (8-oxoG). The consequences of DNA damage are essentially twofold. After misrepair or replication of the damaged template, surviving cells may be subject to permanent changes in the genetic code in the form of mutations or chromosomal aberrations, both of which increase the risk of cancer. Alternatively, damage may interfere with the vital process of transcription or induce replication arrest, which may trigger cell death or cellular senescence, contributing to aging. Damage-induced cell death protects the body from cancer. G denotes guanine, and T thymidine. From Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med 2009;361:1475-85, with permission.

Figure 5

Dendogram showing unsupervised hierarchical clustering of the gene expression data with BRB array tools using 4,040 significant oligos (centered correlation and complete linkage) IHC; ER status, PR, HER2 in red = positive, green = negative. Grade I = yellow, II = orange, III = red. Tumor subtype: normal = gray, lum A = light blue, lum B = dark blue, HER2 = orange, basal = red. CIN profile: no correlation = yellow, correlation = red. Radiation dose in white (0 Gy), light (1–4 Gy), middle (~20 Gy). dark (~40 Gy) blue. From Broeks A, Braaf LM, Wessels LF, et al: Radiation-associated breast tumors display a distinct gene expression profile. Int J Radiat Oncol Biol Phys 76:540-7, 2010, with permission.