Rate Of Cancer Development Research Articles

Abstract ED02-02: The Challenges of Lobular Carcinoma

Abstract Infiltrating lobular carcinoma (ILC) and lobular carcinoma in situ (LCIS) were first described in the1940s by two Memorial Hospital pathologists, Foote and Stewart. They were most intrigued by the infiltrative appearance of these lobular cancers which they described as demonstrating large numbers of isolated, loose or dyscohesive cells of rather uniform size but of varying shape. We now recognize that this dyscohesive growth pattern is the result of loss of a functional e-cadherin protein; a distinguishing feature between ILC and invasive ductal carcinoma (IDC). Several studies comparing clinical features and outcomes between ILC and IDC have generated consistent findings. Lobular cancers are more likely to be ER+, larger, lower grade, less likely to be detected on MMG and more likely to have positive margins at breast conserving surgery (BCS), or to require mastectomy. Yet importantly, if BCS is successful, local recurrence and rates of contralateral breast cancer are equal for ILC and IDC. Although lobular cancers represents only 5-15% of all breast cancer, numerically, if ILC was an independent cancer in women, it would rank as the 6th most common cancer in women. Notably the incidence of ILC rose sharply in the late 80s throughout the 90s, and it has become clear that there is a strong relationship between ILC and hormone replacement therapy. Perhaps the “strongest” risk factor for ILC, is LCIS. Classic LCIS is an incidental finding – there are no pathnogmonic features on breast imaging or gross examination of tissue. On microscopic examination it is often multicentric and bilateral. Although originally considered a precursor to ILC and treated with mastectomy, over the years it was realized that rates of ipsilateral cancer in women who were not treated for LCIS were lower than expected and were quite similar to rates of contralateral breast cancer – and this combined with the fact that only 50% of the cancers were of the lobular phenotype led to a movement to consider LCIS as a high risk lesion. Contemporary data continue to support this management approach as rates of cancer development in women with a diagnosis of LCIS are consistently reported at 1-2% per year and the risk is conferred bilaterally, with a slightly higher representation of ILC in the ipsilateral breast. In this presentation we will review areas of clinical controversy, including the use of MRI, the safety of breast conservation, the role of neoadjuvant chemotherapy and the utility of genomic assays in patients with ILC. Citation Format: T. King. The Challenges of Lobular Carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED02-02.

Strong Hereditary Predispositions to Colorectal Cancer

Cancer is one of the most common causes of death worldwide. A strong predisposition to cancer is generally only observed in colorectal cancer (5% of cases) and breast cancer (2% of cases). Colorectal cancer is the most common cancer with a strong genetic predisposition, but it includes dozens of various syndromes. This group includes familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, NTHL1-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Lynch syndrome, and Muir-Torre syndrome. The common symptom of all these diseases is a very high risk of colorectal cancer, but depending on the condition, their course is different in terms of age and range of cancer occurrence. The rate of cancer development is determined by its conditioning genes, too. Hereditary predispositions to cancer of the intestine are a group of symptoms of heterogeneous diseases, and their proper diagnosis is crucial for the appropriate management of patients and their successful treatment. Mutations of specific genes cause strong colorectal cancer predispositions. Identifying mutations of predisposing genes will support proper diagnosis and application of appropriate screening programs to avoid malignant neoplasm.

A Single-Center Follow-Up Study of Low-Grade Gastric Intraepithelial Neoplasia and the Screening of Key Genes of Precancerous Lesions.

ObjectiveThe study aimed to summarize the morphological characteristics of low-grade gastric intraepithelial neoplasia (LGIN) and explore its outcomes and risk factors. Additionally, it aimed to screen the core different expression genes (DEGs) of high-grade gastric intraepithelial neoplasia (HGIN) using bioinformatics methods to identify biomarkers for early gastric cancer outcomes.MethodsThe clinical and pathological data of 449 patients with LGIN in the endoscopy center of the Second Hospital of Hebei Medical University from June 2013 to September 2018 were collected for retrospective analysis. The GSE130823 and GSE55696 data sets were selected from the Gene Expression Omnibus database, and the GEO2R tool was used to screen DEGs in HGIN and chronic gastritis tissue types. A DEG functional enrichment analysis was conducted using the Database for Annotation, Visualization, and Integrated Discovery. The STRING database was utilized to create a protein–protein interaction network, and the CytoHubba plug-in was used to screen the key genes of HGIN.ResultsThe incidence of LGIN increased with age, and most of the patients were aged between 45–59 years (P = 0.048). Lesions were found mainly in the cardia, mostly in people aged 60 (P < 0.05). Progression occurred in 42 of 449 patients, with a 9.4% rate of cancer development. Foci larger than 10 mm, ulcerative lesions, and an Helicobacter pylori-positive result were factors affecting the outcome of LGIN (P < 0.05). Seven core genes of HGIN were screened, including MYC, SOX2, CDX2, TBX3, KRT7, CDKN2A, and MUC5AC.ConclusionThe patients with LGIN reflected the potential for developing cancer. A magnifying gastroscope can contribute to the detection of early gastric cancer. Additionally, the MYC, CDX2, and TBX3 genes may act as specific biomarkers of HGIN.

Oncoprotective Effect of Short-Term Hypoxic Training in Model of Ehrlich Ascites Carcinoma in Mice

The search for non-drug therapies to enhance antitumor protection is one of the most urgent tasks of pathophysiology and medicine. We evaluated the impact of a course of interval hypobaric hypoxia (0.306 kg/cm2) on the development of Ehrlich ascites carcinoma (EAC) in mice. In the first series of experiments, the mice were subjected to hypoxic training over 10 days, and in the second series the hypoxic training was provided daily for 3 weeks, except for weekends. The tumor volume was analyzed using a caliper on day 16 (the terminal period). The weight of the mice was measured on day 0, and the final net weight was measured on day 22. The rate of cancer development in mice exposed to hypoxic training within the first 10 days decreased by 58%. Exposure to 3 weeks of hypoxic training showed no significant antitumor effect. Upon completion of the hypoxic training, the rate of tumor development increased, and at the end of the study, no significant differences in survival were found. Further research is needed to determine the optimal antitumor effect and duration of the course of interval hypobaric training.&#x0D; Keywords: Ehrlich ascites carcinoma (EAC), mice, hypobaric hypoxia, antitumor protection, leukocytes, leukogram

Tübeküloz Tanısı ile Takip Edilen Hastalarda Primer Akciğer Kanseri Gelişme Oranı ve Hastaların Klinik Özellikleri

Amaç: Akciğer kanseri ve tüberküloz (TB) dünya üzerinde önde gelen mortalite ve morbidite nedenleridir. İki hastalığın birlikteliğinde sigara içimi, altta yatan diğer komorbid hastalıklar gibi multifaktöriyel etkilenme söz konusu olup yeterli kanıt toplanamamıştır. İki önemli halk sağlığı problemi olan bu iki hastalığın birbiri ile ilişkisinin gösterilmesi hem tüberküloz tedavisine hem de kanser tarama programı ve karsinogenez mekanizmasına katkı sağlayacaktır. Yöntem: 01.01.2013-31.12.2016 tarihleri arasında TB servisinde yatarak izlenen 1004 aktif akciğer tüberkülozu tanılı hasta retrospektif incelenmiş ve TB tanısı ile izlenen hastalardan sito/histopatolojik olarak akciğer kanseri tanısı alan 39 hasta çalışmada incelenmiştir. Bulgular: Çalışmamızda tüm vakaların (n=1004) 39’unda (%3,88) TB akciğer kanseri birlikteliği saptanmıştır. Hastaların büyük bir kısmı squamöz hücreli (n=23, % %58,9) olup tanı anında evre III-IV (n=34, %87,1) hastalardan oluşmaktaydı. Akciğer kanseri tanısı alan hastaların çoğunluğunda sigara içme öyküsü mevcuttu (n=25, %64,1). Tüm evrelerde medyan sağkalım 8,94 (%95 Cl, 3,91-13,97) ay iken evre I ve II’de 8,94 ay, Evre III’de 7,89 ay, Evre IV’de ise 3,58 aydı (p=0,381). Hastalarımızdan 37’sinde (%94,8) ölüm görülürken 2 (%5,12) hastanın takibi devam etmektedir. Sonuç: Çalışmamızda TB ile akciğer kanseri birlikteliği araştırılmış ve çoğunlukla squamöz sitolojinin hakim olduğu görülmüştür. TB klinik ve radyolojik olarak akciğer kanserini maskeleyip, akciğer kanseri tanısında gecikmeye, hastaların ileri evrede tanı almasına ve tedavide gecikmelere neden olabilir. TB tanısıyla takip edilen hastalarda spesifik tedaviye rağmen tedavisinin etkisiz olması akla akciğer kanseri tanısını getirmeli ve hastalar bu yönde takip edilmelidir.

Abstract IA04: Mutational spectra of environmental carcinogens as biomarkers for early detection of cancer

Abstract In a multicellular organism, somatic mutations represent a permanent record of the biochemical perturbations experienced by a cell in its local microenvironment. Akin to a perpetual recording device, with every replication, genomic DNA accumulates mutations in patterns that reflect: i) the sequence context-dependent formation of DNA damage, due to environmental or endogenous reactive species, including spontaneous processes; ii) the activity of DNA repair pathways, which, depending on the type of lesion, can erase, ignore, or exacerbate the mutagenic consequences of that DNA damage; and iii) the choice of replication machinery that synthesizes the nascent genomic copy. These three factors result in a richly contoured sequence context-dependent mutational spectra, each characteristic of each type of DNA damage. Such mutagenic legacy, if appropriately decoded, can reveal the local history of genome-altering events such as chemical or pathogen exposures, metabolic stress, and inflammation, which in turn can provide an indication of the underlying causes and mechanisms of genetic disease. Modern tools have positioned us to develop a deep mechanistic understanding of the cellular factors and pathways that modulate a mutational process and, in turn, provide opportunities for better diagnostic and prognostic biomarkers, better exposure risk assessment, and even actionable therapeutic targets. One such tool is duplex consensus sequencing (DS), which is a type of highly accurate sequencing that allows the recording of mutational spectra of carcinogens from heterogenous collections of cells. Using DS, we identified the characteristic high-resolution mutational spectrum of the liver carcinogen aflatoxin B1 in a mouse model, 6-9 months before aflatoxin-induced tumors are detectable. In human terms, this timeline corresponds to the detection of a carcinogen exposure, through their mutational spectrum, 1-2 decades before clinical disease. Our DS spectrum is highly similar to the mutational spectra of aflatoxin recorded in cell culture, mouse tumors, and the computationally extracted mutational signature of aflatoxin (signature 24) from human tumors, suggesting that its features reflect fundamental sequence-context dependent biochemical processes of lesion formation, repair avoidance, and misreplication. Importantly, while the exposure to carcinogen, as quantified through its mutational imprint, increases the odds of cancer development, it does not provide direct information on the rate of tumor formation. Gender-specific differences and the presence of tumor-promoting factors are strong modulators of the rate of cancer development under the same carcinogen exposure conditions. Nevertheless, mutational spectra as biomarkers of carcinogen exposure present a significant clinical promise. The identification of at-risk individuals, based on their exposure mutational spectra, could lead to accelerated screening programs and early detection of malignancies at a surgically resectable stage. Citation Format: Bogdan I. Fedeles, Supawadee Chawanthayatham, Amanda L. Armijo, Robert G. Croy, John M Essigmann. Mutational spectra of environmental carcinogens as biomarkers for early detection of cancer [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA04.

Inhibitory effects of viral infection on cancer development

Immune responses evoked on viral infections prevent the dissemination of infection that otherwise leads to the development of diseases in host organisms. In the present study, we investigated whether viral infection influences tumorigenesis in cancer-bearing animals using a Drosophila model of cancer. Cancer was induced in the posterior part of wing imaginal discs through the simultaneous inhibition of apoptosis and cell-cycle checkpoints. The larvae and embryos of cancer-induced flies were infected with Drosophila C virus, a natural pathogen to Drosophila, and larval wing discs and adult wings were morphologically examined for cancer characteristics relative to uninfected controls. We found that viral infections brought about an approximately 30% reduction in the rate of cancer development in both wing discs and wings. These inhibitory effects were not observed when growth-defective virus was used to infect animals. These results indicate that productive viral infections repress tumorigenesis in Drosophila.

Does Circadian Rhythm and Environment Factor Affect the Risk of Breast Cancer? A New Evidence from Kediri, East Java

Background : Disruption of sleep patterns, and thereby the internal body clock, of shift workers directly influences their physiology and the rate of cancer development. Studies have shown that working night shifts three or more times per month elevates the risk of breast cancer in humans. Disrupted expression of circadian genes can alter breast biology and may promote cancer. This study aimed to examine the effects of circadian rhythm and environment factor on the risk of breast cancer in Kediri, East Java. Subjects and Method : This was a case-control study conducted in Kediri, East Java, from April to May 2018. A sample of 200 women was selected by fixed disease sampling. The dependent variable was breast cancer. The independent variables were work schedule, sleep duration, room light, room temperature, chemical exposure, and air pollution. The data were collected by questionnaire and analyzed by a multiple logistic regression. Results : Circadian rhythm and environment factor affected the risk of breast cancer. The risk of breast cancer increased with irregular shift work schedule (OR= 5.82; 95% CI= 2.26 to 14.95; p<0.001), sleep duration <5 hours (OR= 6.32; 95% CI= 2.59 to 15.39; p<0.001), room light (OR= 7.03; 95% CI= 2.39 to 20.65; p<0.001), warm room temperature (OR= 13.48; 95% CI= 5.26 to 34.53; p<0.001), air pollution (OR= 8.21; 95% CI= 3.19 to 21.11; p<0.001), and chemical exposure (OR= 2.90; 95% CI= 1.22 to 6.84; p= 0.015). Conclusion : The risk of breast cancer increased with irregular shift work schedule, sleep duration <5 hours, room light, warm room temperature, air pollution, and chemical exposure. Keywords : breast cancer, circadian rhythm, environment factor Correspondence: Anindiya Ningtyas. Masters Program in Public Health, Universitas Sebelas Maret, Jl. Ir. Sutami No. 36 A, Surakarta 57126, Central Java. Email: Anindyaningtyas.an@gmail.com. Mobile: +6282232189898. Journal of Epidemiology and Public Health (2019), 4(1): 20-29 https://doi.org/10.26911/jepublichealth.2019.04.01.03

Renal-cell carcinoma risk estimates based on participants in the prostate, lung, colorectal, and ovarian cancer screening trial and national lung screening trial

PurposeCurrent knowledge regarding risk of renal-cell carcinoma (RCC) is based on meta-analyses of case–control studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and National Lung Screening Trial (NLST) provide robust prospective databases with clinical information and rates of cancer development. PLCO and NLST were used to identify risk factors for RCC. MethodsData were extracted from PLCO and NLST to stratify risk of RCC by sex, race, age at inclusion, obesity, and smoking status. Incidence rates between groups were compared using the chi-square test. We excluded urothelial carcinomas. ResultsOverall, 701/154,118 and 190/53,242 RCCs were detected in PLCO and NLST, respectively. Incidence rates were higher in men (PLCO: 0.56 vs. 0.28/1000 person y, NLST: 0.73 vs. 0.35/1000 person y; both with P<0.0001). In the PLCO, male sex, age>60 years, obesity, and intensity of smoking were associated with higher risk of developing RCC. In the NLST, sex and morbid obesity increased the risk for RCC but age, ethnicity, and smoking intensity were not predictors. There was no effect of screening for other cancers on detection of RCC.High-grade (grades ≥3) RCCs were diagnosed in 145 (20.7%) and 60 (31.6%) in the PLCO and NLST. In PLCO, age (60–64y), male sex, obesity, and current smokers with>50 pack years were at increased risk for high-grade RCC. In NLST, only male sex was an independent predictor of high-grade RCC. ConclusionsAge over 60 years, male sex, smoking intensity, and obesity affect the risk of RCC. Identification of a high-risk population may allow a pilot study of rational screening for RCC.

Assisted reproduction and cancer risk: how useful are national databases?

In the ART group 2.0% of women developed a cancer over an average period of 7.3 years. In the non-ART group 2.9% of women developed a cancer over an average period of 16 years. Controlling for some basic confounders resulted in a hazard rate of 1.16 (95% confidence intervals (CI) 1.04–1.29) for the ART group versus the non-ART group. This suggests a 16% increase in cancer development rate over time in the women in the ART group. The large difference in follow-up time between the two groups is a little problematic; the hazard rate assumes the hazard or event rate in one group is a constant proportion of the hazard in the other group and there is no way to know whether this assumption holds. Stratified analysis per cancer group suggested that women in the ART group have a higher hazard rate for developing breast cancer— strangely enough not reported in the present study—and central nervous system (CNS) cancer (Reigstad et al. ,2 015a,b). This was even more pronounced in women that had undergone IVF. However, these excess risks were statistically non-significant after correction for multiple analyses. For all other cancers results seemed reassuring as no evidence for further differences in hazard rate were observed. Breast cancer is the most highly prevailing cancer in women in general but also in women during the fertile age period. Breast cancer accounts for .40% of all cancers in women below 40 years of age (Anders et al., 2009). In the Reigstad study database breast cancer accounted for almost 40% of all cancers. CNS cancer is rarer in these relatively young women. In the general population CNS cancers account for 4% of all cancers (Cancer Research UK—original data sources are available from http://www.cancerresearchuk.org). In the Reigstad study, CNS cancer occurred at a somewhat higher rate and accounted for 9% of cancers in the ART group and for 7% in the non-ART group. As the investigators suggest in their discussion, CNS cancer in women in the ART group might have been caused by fertility specific factors. Certain tumors of the pituitary gland are for instance known to be associated with infertility (Fourman and Fazeli, 2015). I am actually quite reassured in reading these data for two reasons. First, although the population data were very large and likely to be complete it was not collected for this analysis. As a result many wellestablished risk factors for cancer rates could not be accounted for as they are simply not known. Well-known risk factors for many cancers are BMI, cigarette smoking, use of alcohol, physical activity, socioeconomic status and ethnicity. A high BMI is also a risk factor for infertility. If obesity was more prevalent in the ART group, this risk factor for cancer could potentially explain (part) of the excess risk. However, imagine that some important adjustments for risk factors had been made and that an excess risk was still there. Would that prove that parous women after ART have a higher risk to develop cancer than women that did not undergo ART? Not necessarily as there is at least a second possible explanation for the observed higher incidence of cancer in women in the ART group—an earlier detection. Before undergoing ART, women undergo a fertility work-up. The family history, hormonal measurements and ultrasound scans can alert physicians at a much earlier stage. Though the investigators ruled out a large early detection effect by doing subanalyses excluding the first year of treatment, this earlier detection bias cannot completely be ruled out. Familiarity with the hospital and association with a successful ART might render women in the ART group more inclined to seek medical help when the first signs of their developing cancer appeared. Thus cancers may have been detected that would never have caused symptoms, or would have caused symptoms only many years later. Furthermore, women in the ART group that have been noticed in previous studies to have a relatively high social-economic status might also visit a specialist at an earlier stage. If true, the resulting earlier detection of the cancer would make a higher incidence rate of cancer in the ART group a logical finding. A longer follow-up time

Abstract 1833: Longitudinal associations between telomere length, chronic stress, and immune stance in cervical cancer survivors

Abstract Introduction: There is a growing recognition of a potential role of chronic psychological stress in increasing the rate of cancer development and growth; however, potential mechanisms remain poorly understood and under active investigation. Recently, accelerated telomere shortening has been observed in cross sectional studies of non-cancer populations experiencing chronic stress suggesting a potential link between chronic stress and genomic integrity thus, raising the possibility that modulation of stress might affect telomere dynamics. We examined archived peripheral blood mononuclear cell (PBMC) samples collected in a longitudinal randomized study evaluating a psychosocial telephone counseling (PTC) intervention to improve cervical cancer patient coping and hence stress, as measured by improvement in quality of life (QOL), and stress-associated biomarkers (Clin Cancer Res 14(7): 2111-18). In this pilot study, we examined the longitudinal associations between telomere length, QOL, and immunologic stance in this cohort obtaining data in support of the above hypothesis. Methods: Archived PBMC specimens were analyzed from a completed randomized trial that demonstrated PTC associated improvement in QOL and an association between improved QOL and a shift to a more prominent Th1 immunologic stance. Briefly, QOL data (FACT-Cx and BSI) and biospecimens were collected at baseline and four months after enrollment (N = 31). Telomere length of archived PBMCs, T cells (including CD4 and CD8 subsets), B cells (CD19) and monocytes (CD14) were examined using the Flow-FISH assay. Results: Longitudinal changes in the Physical Well-Being subscale of the FACT-Cx were significantly associated with increased telomere length within the total PBMC population (r=0.799, p=0.031); the FACT-CX score showed a borderline association, likely due to the fact no other FACT subscales were associated with longitudinal changes in telomere length. Improved BSI scores showed a similar, although non-significant trend. The observed shift toward a Th1 immune stance in subjects with improved QOL were correlated with increased telomere length in CD4 (r=0.810; p=0.027) and CD8 (r=0.705; p=0.075) cellular subsets; however, no significant associations were observed between a more pronounced Th1 stance and CD14 or CD19 subsets. The finding of a longitudinal increase in telomere length in circulating PBMCs is not without precedent as this has been observed in several murine models Discussion: This is the first study of longitudinal changes in telomere length associated with immune profile and QOL as an index of chronic stress and has provocative implications for the association between the psychoneuroimmune axis, telomere dynamics, genomic stability, and cancer survivorship outcomes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1833. doi:10.1158/1538-7445.AM2011-1833

Diabetes treatment with insulin glargine and risk of malignancy: methodological pitfalls and ethical issues

Diabetes treatment with insulin glargine and risk of malignancy: methodological pitfalls and ethical issues

Carcinomas of the Pancreas, Gallbladder, Extrahepatic Bile Ducts, and Ampulla of Vater Share a Field for Carcinogenesis: A Population-Based Study

Carcinomas co-occur in the pancreas, extrahepatic bile ducts, and ampulla of Vater. We investigated whether cancers originating in these sites represent a field effect similar to that observed in the lung and upper aerodigestive tract. To determine whether a field effect for carcinogenesis exists in the ampulla of Vater, extrahepatic bile ducts, gallbladder, and pancreas. Data were obtained from National Cancer Institute's Surveillance Epidemiology and End Results Program from 1973 through 2005. Cases were compared by age frequency density plots, age-specific incidence rates, and logarithmic plots of the age-specific incidence rates and age of diagnosis. Incidence rates were 11.71, 1.43, 0.88, and 0.49 per 100,000 persons at risk for pancreatic, gallbladder, extrahepatic bile ducts, and ampullary carcinomas, respectively. Age frequency density plots were congruent for cancers originating in all 4 sites. Logarithmic plots of the age-specific incidence rates with age of diagnosis produced parallel linear rate patterns for the 4 sites indicative of similar populations for tumor development. However, density and logarithmic plots of pancreatic endocrine carcinomas, a tumor of different cellular differentiation and carcinogenic pathway, served as a comparison. The endocrine carcinomas showed a different age distribution and nonparallel rate patterns with ductal carcinomas. Carcinomas of the pancreas, gallbladder, extrahepatic bile ducts, and ampulla have a common embryonic cellular ancestry, differentiation pathways, mucosal histologic patterns, and population-related tumor development indicating a field effect in carcinogenesis. Parallel linear rate patterns indicate (1) the rate of cancer development is similar in all 4 sites even though the absolute incidence rates vary and (2) regardless of location, the ductal epithelium is equally susceptible to malignant transformation. If carcinogenic pathways to cancer are similar, then the different incidence rates seen clinically may depend on the relative surface area of the ductal system in these sites. Pancreatic cancers are most common because the surface area of the pancreas' ductal system is greater than that of the gallbladder, extrahepatic bile ducts, and ampulla.

Cumulative Incidence of Secondary Neoplasms as a First Event After Childhood Acute Lymphoblastic Leukemia

Little is known about the incidence of secondary neoplasms after 15 to 20 years in children and adolescents who were treated for acute lymphoblastic leukemia. To investigate the cumulative incidence of secondary neoplasms in pediatric patients treated for acute lymphoblastic leukemia over 30 years and to characterize late-occurring tumors. Retrospective study of 2169 patients with acute lymphoblastic leukemia treated between 1962 and 1998 at St Jude Children's Research Hospital, Memphis, Tenn, who achieved complete remission and had a median follow-up time of 18.7 years (range, 2.4-41.3 years). Cumulative incidences of secondary neoplasms in first remission and standard incidence ratios of observed rates compared with rates of cancer development in the general US population. Secondary neoplasms developed as the first event in 123 patients and comprised 46 myeloid malignancies, 3 lymphomas, 14 basal cell carcinomas, 16 other carcinomas, 6 sarcomas, 16 meningiomas, and 22 other brain tumors. The cumulative incidence of secondary neoplasm was 4.17% (SE, 0.46%) at 15 years and increased substantially after 20 years, reaching 10.85% (SE, 1.27%) at 30 years. When meningiomas and basal cell carcinomas were excluded, the overall cumulative incidence was 3.99% (SE, 0.44%) at 15 years and 6.27% (SE, 0.83%) at 30 years, representing a 13.5-fold increase in overall risk compared with the general population. The cumulative incidence of each tumor type at 30 years was 2.19% (SE, 0.32%) for myeloid malignancy, 0.17% (SE, 0.10%) for lymphoma, 3.00% (SE, 0.59%) for brain tumor, 4.91% (SE, 1.04%) for carcinoma, and 0.57% (SE, 0.37%) for sarcoma. The cumulative incidence of secondary neoplasms increases steadily over 30 years after treatment of acute lymphoblastic leukemia. Although the majority of the late-occurring secondary neoplasms are low-grade tumors, the increase in incidence of more aggressive malignant neoplasms is significantly higher than expected in the general population. These results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development.