Age Distribution of Cancer: The Incidence Turnover at Old Age

In recent years data on cancer incidence in the USA, the Netherlands, and in Hong Kong indicate a flattening and perhaps a turnover at advanced age, but no model has been successful in fitting this data and thus providing clues to the underlying biology. In this work we assume these data are reliable and free from bias. We find that a Beta distribution fits SEER age-specific cancer incidence data for all adult cancers extremely well, and its interpretation as a model leads to the possibility that there is a beneficial cancer extinction process that becomes important at elevated age. Particularly evident from the data is the apparent remarkable uniformity of adult cancers peaking in incidence at about the same age, including cancers in other countries. Possible biological mechanisms include increasing apoptosis and cell senescence with age. Further, the model suggests that cancer is not inevitable at advanced age, but reaches a maximum cumulative probability of affliction with any cancer of about 70% for men and 53% for women in the US, and much smaller values for individual cancers.     

Parallel Routes of Human Carcinoma Development: Implications of the Age-Specific Incidence Data

Background

The multi-stage hypothesis suggests that cancers develop through a single defined series of genetic alterations. This hypothesis was first suggested over 50 years ago based upon age-specific incidence data. However, recent molecular studies of tumors indicate that multiple routes exist to the formation of cancer, not a single route. This parallel route hypothesis has not been tested with age-specific incidence data.

Methodology/Principal Findings

To test the parallel route hypothesis, I formulated it in terms of a mathematical equation and then tested whether this equation was consistent with age-specific incidence data compiled by the Surveillance Epidemiology and End Results (SEER) cancer registries since 1973. I used the chi-squared goodness of fit test to measure consistency. The age-specific incidence data from most human carcinomas, including those of the colon, lung, prostate, and breast were consistent with the parallel route hypothesis. However, this hypothesis is only consistent if an immune sub-population exists, one that will never develop carcinoma. Furthermore, breast carcinoma has two distinct forms of the disease, and one of these occurs at significantly different rates in different racial groups.

Conclusions/Significance

I conclude that the parallel route hypothesis is consistent with the age-specific incidence data only if carcinoma occurs in a distinct sub population, while the multi-stage hypothesis is inconsistent with this data.     

Age-specific acceleration of cancer

One of the great challenges of cancer research is to explain the epidemiological patterns of cancer incidence based on the molecular processes that lead to uncontrolled cellular proliferation. The epidemiological data demonstrate that the age-specific incidence of many cancers increases in an approximately linear way with age when plotted on a log-log scale, with different slopes for different cancers. However, those epidemiological data also show that cancers of various tissues depart from log-log linearity in particular ways. Here, I illustrate those departures from log-log linearity by introducing plots of the age-specific acceleration of cancer. I then develop a very general model of cancer progression, which I use to explain the observed differences between tissues in age-specific acceleration. In one application of the model, I show that the spectacular rise and fall in age-specific acceleration observed in prostate cancer may be explained by multiple rounds of clonal expansion. In a second application, I demonstrate that the steady decline in age-specific acceleration of breast cancer may occur because precancerous mutations accumulate in many cellular lineages.     

Age-specific incidence data indicate four mutations are required for human testicular cancers

Normal human cells require a series of genetic alterations to undergo malignant transformation. Direct sequencing of human tumors has identified hundreds of mutations in tumors, but many of these are thought to be unnecessary and a result of, rather than a cause of, the tumor. The exact number of mutations to transform a normal human cell into a tumor cell is unknown. Here I show that male gonadal germ cell tumors, the most common form of testicular cancers, occur after four mutations. I infer this by constructing a mathematical model based upon the multi-hit hypothesis and comparing it to the age-specific incidence data. This result is consistent with the multi-hit hypothesis, and implies that these cancers are genetically or epigenetically predetermined at birth or an early age.     

A novel approach to estimate the German-wide incidence of testicular cancer

Background: Currently, only 7 out of 16 Federal States of Germany provide testicular cancer incidence rates with an estimated completeness of at least 90% which complicates the regional comparison of incidence rates. The aim of this study was to provide a novel approach to estimate the testicular cancer incidence in Germany by using nationwide hospitalization data. Methods: We used the nationwide hospitalization data (DRG statistics) of the years 2005–2006 including 16,6 million hospitalizations among men. We identified incident testicular cancer cases by the combination of a diagnosis of testicular cancer and an orchiectomy during the same hospitalization and estimated the age-specific and age-standardized (World Standard Population) incidence of testicular cancer across Federal States. We also analyzed available cancer registry data from 2005 to 2006. Results: A total of 8544 hospitalizations indicated incident testicular cancer cases in 2005–2006. The nationwide crude incidence rate of testicular cancer was 10,6 per 100.000 person-years. The ratio of the number of registered cases (cancer registry) to the estimated number of cases based on the hospitalization statistics ranged between 79% and 100%. There was only little variation of the age-standardized DRG-based incidence estimates across Federal States (range: 8,2–10,6 per 100.000 person-years). Discussion: We provided testicular cancer incidence estimates for each of the 16 Federal States of Germany based on hospitalization data for the first time. The low within-population incidence variability in Germany and high between-population incidence variability in Europe may indicate that ecologic factors play a causal role in the European variation of testicular cancer.     

Age-related differences in colon and rectal cancer survival by stage,histology, and tumour site: An analysis of United States SEER-18 data

Age-related differences in colon and rectal cancer survival have been observed, even after accounting for differences in background mortality. To determine how stage, tumour site, and histology contribute to these differences, we extracted age-specific one-year relative survival ratio (RS) stratified by these factors. We used colon and rectal cancer cases diagnosed between 2012 and 2016 from 18 United States Surveillance Epidemiology and End Results cancer registries. For colon cancer, 1-year RS ranged from 87.8 % [95 % Confidence Interval: 87.5–88.2] in the 50–64-year-olds to 62.3 % [61.3–63.3] in 85–99-year-olds and for rectal cancer ranged from 92.3 % [91.8–92.7] to 65.0 % [62.3–67.5]. With respect to stage, absolute differences in RS between 50-64-year-olds and 75–84-year-olds increased with increasing stage (from 6 [5–7] %-points in localised disease to 27 [25–29] %-points in distant disease) and were the highest for cancers of unknown stage (> 28 %-points). Age-related differences in survival were smallest for persons with tumours in the right-sided colon (8 [7–9] %-points) and largest for tumours of the colon without tumour site further specified (25 [21–29] %-points). With respect to histology, differences ranged from 7.4 % to 10.6 %-points for cancers with one of the three primary histologies (adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma) and were several-fold higher (42 %-points) for those with unknown/other histology (< 6 % of cases). Because age-related differences in survival were observed for all histologies and tumour sites, RS differences are unlikely to be driven by differences in the distribution of these factors by age. Differences in stage distribution by age are likely to contribute toward age-related differences in survival. Within stage groups, age differences in survival could be explained by frailty and/or therapy. Future studies incorporating data on treatment and geriatric conditions including frailty and comorbidity would support further understanding of the age gap in colon and rectal cancer survival.     

Differences in cancer incidence by age at diagnosis between Aboriginal and non-Aboriginal people for cancer types included in Australian national screening programs

BackgroundThis study examined age distributions and age-specific incidence of screened cancers by Aboriginal status in New South Wales (NSW) to consider the appropriateness of screening target age ranges.MethodsThe NSW Cancer Registry identified invasive (female) breast, cervical and bowel cancers in people diagnosed in 2001–2014.ResultsAboriginal people were younger at diagnosis with higher proportions of breast and bowel cancers diagnosed before the screening target age range (<50 years) compared with non-Aboriginal people (30.6% vs. 22.8%, and 17.3% vs. 7.3%, respectively). Age-specific incidence rate ratios (IRRs) were lower/similar for breast and bowel cancers in younger and higher in older Aboriginal than non-Aboriginal people. All age-specific cervical cancer IRRs were higher for Aboriginal compared with non-Aboriginal people.ConclusionAlthough higher proportions of breast and colorectal cancers were diagnosed before screening commencement age in Aboriginal people, this does not necessarily indicate a need for earlier screening commencement. Other aspects needing consideration include benefits, harms and cost-effectiveness.     

Risk of testicular cancer after vasectomy: cohort study of over 73,000 men.

OBJECTIVE--To confirm or refute reports that vasectomy may increase the risk of cancers of the testis and prostate. DESIGN--Computerised record linkage study of cohort of men with vasectomy and comparison of cancer rates with those in the whole Danish population; manual check of all records of patients with testicular and prostate cancer diagnosed within the first year of follow up. SETTING--Denmark 1977-89. SUBJECTS--Cohort of 73,917 men identified in hospital discharge and pathology registers as having had a vasectomy for any reason during 1977-89. MAIN OUTCOME MEASURES--Observed incidences of testicular, prostate, and other cancers up to the end of 1989. RESULTS--The overall pattern of cancer incidence in the study cohort was similar to that expected nationally. No increased incidence in testicular cancer was observed (70 cases; standardised morbidity ratio 1.01 (95% confidence interval 0.79 to 1.28)). The incidence during the first year of follow up was also close to that expected (nine cases; standardised morbidity ratio 0.80 (0.36 to 1.51)). The incidence of prostate cancer was not increased (165 cases; standardised morbidity ratio 0.98 (0.84 to 1.14)). CONCLUSIONS--The incidence of testicular cancer in men with vasectomy is no higher than in other men. Vasectomy does not cause testicular cancer and does not accelerate the growth or diagnosis of pre-existing testicular neoplasms. Data concerning a causal relation between vasectomy and prostate cancer were inconclusive.     

Cancer Incidence among Adolescents and Young Adults in Urban Shanghai, 1973-2005

Background

Lack of cancer incidence information for adolescents and young adults led us to describe incidence trends within the young population of 15 to 49 year-olds in urban Shanghai between 1973 and 2005.

Methods

During 1973 to 2005, data on 43,009 (45.8%) male and 50,828 (54.2%) female cancer cases aged 15–49 years from the Shanghai Cancer Registry were analyzed. Five-year age-specific rates, world age-standardized rates, percent change (PC), and annual percent change (APC) were calculated using annual data on population size and its estimated age structure.

Results

During the 33-year study period, overall cancer incidence of adolescents and young adults among males marginally decreased by 0.5% per year (P<0.05). However, overall cancer incidence for females slightly increased by 0.8% per year (P<0.05). The leading cancer for males in rank were liver, stomach, lung, colorectal, and nasopharyngeal cancers and for females were breast, stomach, colorectal, thyroid, and ovarian cancers. Among specific sites, incidence rates significantly decreased for cancers of the esophagus, stomach, and liver in both sexes. In contrast, incidence rates significantly increased for kidney cancers, non-Hodgkin lymphoma, and brain and nervous system tumors in both sexes and increased for breast and ovarian cancers among females.

Conclusions

Overall cancer incidence rates of adolescents and young adults decreased in males whereas they increased in females. Our findings suggest the importance of further epidemiology and etiologic studies to further elucidate factors contributing to the cancer incidence trends of adolescents and young adults in China.     

Incidence patterns and trends of malignant gonadal and extragonadal germ cell tumors in Germany, 1998–2008

BackgroundMalignant gonadal (GGCT) and extragonal germ cell tumors [GCT (EGCT)] are thought to originate from primordial germ cells. In contrast to well reported population-based data of GGCTs in males, analyses of GGCTs in females and EGCTs in both sexes remain limited.MethodsIn a pooling project of nine population-based cancer registries in Germany for the years 1998–2008, 16,883 malignant GCTs and their topographical sites were identified using ICD-O morphology and topography for persons aged 15 years and older. We estimated age-specific and age-standardized incidence rates.ResultsAmong males, the incidence of testicular GCTs increased over time. In contrast, there was no increase in the incidence of EGCTs. Among females, rates of ovarian GCTs were stable, while rates of EGCTs declined over time. The most frequent extragonadal sites were mediastinum among males and placenta among females.ConclusionsOur results underline different incidence trends and distinct age-specific incidence patterns of malignant GGCTs and EGCTs, as reported recently by several population-based registries. The differences suggest that GGCT and EGCT may have different etiologies.     

CD200: a putative therapeutic target in cancer

CD200 was recently described as a new prognosis factor in multiple myeloma and acute myeloid leukemia. CD200 is a membrane glycoprotein that imparts an immunoregulatory signal through CD200R, leading to the suppression of T-cell-mediated immune responses. We investigated the expression of CD200 in cancer using publicly available gene expression data. CD200 gene expression in normal or malignant human tissues or cell lines was obtained from the Oncomine Cancer Microarray database, Amazonia database and the ITTACA database. We found significant overexpression of CD200 in renal carcinoma, head and neck carcinoma, testicular cancer, malignant mesothelioma, colon carcinoma, MGUS/smoldering myeloma, and in chronic lymphocytic leukemia compared to their normal cells or their tissue counterparts. Moreover, we show that CD200 expression is associated with tumor progression in various cancers. Taken together, these data suggest that CD200 is a potential therapeutic target and prognostic factor for a large array of malignancies.     

Cancer in Guam and Hawaii: A comparison of two U.S. Island populations

BackgroundCancer disparities within and across populations provide insight into the influence of lifestyle, environment, and genetic factors on cancer risk.MethodsGuam cancer incidence and mortality were compared to that of Hawaii using data from their respective population-based, central cancer registries.ResultsIn 2009–2013, overall cancer incidence was substantially lower in Guam than in Hawaii for both sexes while overall cancer mortality was higher for Guam males. Cervical cancer incidence and prostate cancer mortality were higher in Guam. Both incidence and mortality were higher among Guam men for cancers of the lung & bronchus, liver & intrahepatic bile duct, and nasopharynx; Chamorro men were disproportionately affected by these cancers. Filipinos and Whites in Guam had lower overall cancer incidence compared to Filipinos and Whites in Hawaii. Although breast cancer incidence was significantly lower in Guam compared to Hawaii, women in Guam presented at younger ages and with rarer disease histologies such as inflammatory carcinoma were more prevalent. Guam patients were also diagnosed at younger ages for cancers of bladder, pancreas, colon & rectum, liver & intrahepatic bile duct, lung & bronchus, stomach, non-Hodgkin lymphoma, and leukemia.ConclusionSmoking, infectious agents, and betel nut chewing appear to be important contributors to the burden of cancer in Guam. Earlier onset of cancer in Guam suggests earlier age of exposure to key risk factors and/or a more aggressive pathogenesis. Contrasting cancer patterns within Guam and between Guam and Hawaii underscore the potential influence of genes, lifestyle, and environmental factors on cancer development and progression.     

Marked increase in breast cancer incidence in young women: A 10-year study from Northern Iran, 2004–2013

IntroductionBreast cancer is the most frequent cancer among women worldwide. Breast cancer incidence in young women is a health issue of concern, especially in middle-income countries such as Iran. The aim of this study is to report the breast cancer incidence variations in Golestan province, Iran, over a 10-year period (2004–2013).MethodsWe analyzed data from the Golestan Population-based Cancer Registry (GPCR), which is a high-quality cancer registry collecting data on primary cancers based on standard protocols throughout the Golestan province. Age-standardized incidence rates (ASRs) and age-specific incidence rates per 100,000 person-years were calculated. Time trends in ASRs and age-specific rates were evaluated using Joinpoint regressions. The average annual percentage change (AAPC) with correspondence 95% confidence intervals (95%CIs) were calculated.ResultsA total of 2106 new breast cancer cases were diagnosed during the study period. Most cases occurred in women living in urban areas: 1449 cases (68%) versus 657 cases (31%) in rural areas. Statistically significant increasing trends were observed over the 10-year study period amongst women of all ages (AAPC = 4.4; 95%CI: 1.2–7.8) as well as amongst women in the age groups 20–29 years (AAPC = 10.0; 95%CI: 1.7–19.0) and 30–39 years (AAPC = 5.1; 95%CI: 1.4–9.0).ConclusionThe incidence of breast cancer increased between 2004 and 2013 in Golestan province amongst all age groups, and in particular amongst women aged 20–39 years. Breast cancer should be considered a high priority for health policy making in our community.     

Solid cancer incidence in atomic bomb survivors: 1958-1998

This is the second general report on radiation effects on the incidence of solid cancers (cancers other than malignancies of the blood or blood-forming organs) among members of the Life Span Study (LSS) cohort of Hiroshima and Nagasaki atomic bomb survivors. The analyses were based on 17,448 first primary cancers (including non-melanoma skin cancer) diagnosed from 1958 through 1998 among 105,427 cohort members with individual dose estimates who were alive and not known to have had cancer prior to 1958. Radiation-associated relative risks and excess rates were considered for all solid cancers as a group, for 19 specific cancer sites or groups of sites, and for five histology groups. Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, how these risks vary with gender, age at exposure, and attained age, and the evidence for inter-site variation in the levels and patterns of the excess risk. For all solid cancers as a group, it was estimated that about 850 (about 11%) of the cases among cohort members with colon doses in excess of 0.005 Gy were associated with atomic bomb radiation exposure. The data were consistent with a linear dose response over the 0- to 2-Gy range, while there was some flattening of the dose response at higher doses. Furthermore, there is a statistically significant dose response when analyses were limited to cohort members with doses of 0.15 Gy or less. The excess risks for all solid cancers as a group and many individual sites exhibit significant variation with gender, attained age, and age at exposure. It was estimated that, at age 70 after exposure at age 30, solid cancer rates increase by about 35% per Gy (90% CI 28%; 43%) for men and 58% per Gy (43%; 69%) for women. For all solid cancers as a group, the excess relative risk (ERR per Gy) decreases by about 17% per decade increase in age at exposure (90% CI 7%; 25%) after allowing for attained-age effects, while the ERR decreased in proportion to attained age to the power 1.65 (90% CI 2.1; 1.2) after allowing for age at exposure. Despite the decline in the ERR with attained age, excess absolute rates appeared to increase throughout the study period, providing further evidence that radiation-associated increases in cancer rates persist throughout life regardless of age at exposure. For all solid cancers as a group, women had somewhat higher excess absolute rates than men (F:M ratio 1.4; 90% CI 1.1; 1.8), but this difference disappears when the analysis was restricted to non-gender-specific cancers. Significant radiation-associated increases in risk were seen for most sites, including oral cavity, esophagus, stomach, colon, liver, lung, non-melanoma skin, breast, ovary, bladder, nervous system and thyroid. Although there was no indication of a statistically significant dose response for cancers of the pancreas, prostate and kidney, the excess relative risks for these sites were also consistent with that for all solid cancers as a group. Dose-response estimates for cancers of the rectum, gallbladder and uterus were not statistically significant, and there were suggestions that the risks for these sites may be lower than those for all solid cancers combined. However, there was emerging evidence from the present data that exposure as a child may increase risks of cancer of the body of the uterus. Elevated risks were seen for all of the five broadly classified histological groups considered, including squamous cell carcinoma, adenocarcinoma, other epithelial cancers, sarcomas and other non-epithelial cancers. Although the data were limited, there was a significant radiation-associated increase in the risk of cancer occurring in adolescence and young adulthood. In view of the persisting increase in solid cancer risks, the LSS should continue to provide important new information on radiation exposure and solid cancer risks for at least another 15 to 20 years.     

Risks and probabilities of breast cancer: short-term versus lifetime probabilities.

OBJECTIVE: To calculate age-specific short-term and lifetime probabilities of breast cancer among a cohort of Canadian women. DESIGN: Double decrement life table. SETTING: Alberta. SUBJECTS: Women with first invasive breast cancers registered with the Alberta Cancer Registry between 1985 and 1987. MAIN OUTCOME MEASURES: Lifetime probability of breast cancer from birth and for women at various ages; short-term (up to 10 years) probability of breast cancer for women at various ages. RESULTS: The lifetime probability of breast cancer is 10.17% at birth and peaks at 10.34% at age 25 years, after which it decreases owing to a decline in the number of years over which breast cancer risk will be experienced. However, the probability of manifesting breast cancer in the next year increases steadily from the age of 30 onward, reaching 0.36% at 85 years. The probability of manifesting the disease within the next 10 years peaks at 2.97% at age 70 and decreases thereafter, again owing to declining probabilities of surviving the interval. CONCLUSIONS: Given that the incidence of breast cancer among Albertan women during the study period was similar to the national average, we conclude that currently more than 1 in 10 women in Canada can expect to have breast cancer at some point during their life. However, risk varies considerably over a woman''s lifetime, with most risk concentrated after age 49. On the basis of the shorter-term age-specific risks that we present, the clinician can put breast cancer risk into perspective for younger women and heighten awareness among women aged 50 years or more.     

Cancer in adolescents and young adults: National incidence and characteristics in Japan

ObjectiveAdolescents and young adults (AYA) with cancer are confronted with unique challenges in areas of paramount concern within their age group, such as fertility, education, career, and delayed and long-term effects of treatment. However, the extent and depth of the problem has never been examined in the Japanese population. The aim of this study was to describe the status of cancer patients in the AYA population, using data from the hospital-based cancer registry (HBCR).Study designPatients included in the HBCR from January 2011 to December 2014 were included in this study to evaluate the incidence and cancer distribution trends among AYA. The total number and the proportion of AYA (15–39 years of age) stratified by sex, age, and cancer type were obtained. The incidence of age-specific cancer among AYA was also calculated.ResultsWe identified 30,394 male (35.1%) and 56,100 female (64.9%) cancer patients in the population, which collectively constituted about 3% of all invasive cancer cases. The incidence of cancer in AYA was estimated as 86.2 per 100,000 per year, and increased with age. The most affected population was women between 35 and 39 years of age (35%). Breast cancer was the most common type of cancer, followed by cervical, uterine, and thyroid cancers.ConclusionA substantial number of AYA are diagnosed with cancer every year. The distribution of cancer types in AYA was dependent on age and sex. These diversities in cancer types can inform researchers and policy makers to fine-tune their studies and policies.     

Second Cancers in Patients with Neuroendocrine Tumors

Background

Second cancers have been reported to occur in 10-20% of patients with neuroendocrine tumors (NETs). However, most published studies used data from a single institution or focused only on specific sites of NETs. In addition, most of these studies included second cancers diagnosed concurrently with NETs, making it difficult to assess the temporality and determine the exact incidence of second cancers. In this nationwide population-based study, we used data recorded by the Taiwan Cancer Registry (TCR) to analyze the incidence and distribution of second cancers after the diagnosis of NETs.

Methods

NET cases diagnosed from January 1, 1996 to December 31, 2006 were identified from the TCR. The data on the occurrence of second cancers were ascertained up to December 31, 2008. Standardized incidence ratios (SIRs) of second cancers were calculated based on the cancer incidence rates of the general population. Cox-proportional hazards regression analysis was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of second cancers associated with sex, age, and primary NET sites.

Results

A total of 1,350 newly diagnosed NET cases were identified according to the selection criteria. Among the 1,350 NET patients, 49 (3.63%) developed a second cancer >3 months after the diagnosis of NET. The risk of second cancer following NETs was increased compared to the general population (SIR = 1.48, 95% CI: 1.09-1.96), especially among those diagnosed at age 70 or older (HR = 5.08, 95% CI = 1.69-15.22). There appeared to be no preference of second cancer type according to the primary sites of NETs.

Conclusions

Our study showed that the risk of second cancer following NETs is increased, especially among those diagnosed at age 70 or older. Close monitoring for the occurrence of second cancers after the diagnosis of NETs is warranted.     

Is there a real risk of radiation-induced breast cancer for postmenopausal women?

The risk of radiation-induced breast cancer decreases with increasing age at exposure. Thus, for calculating the individual risk for a patient undergoing mammography, age-related risk coefficients need to be used. In this report, the results of epidemiological studies on risks of radiation-induced breast cancer are reviewed indicating that the available data do not show the risk to be enhanced for women exposed at the age of 55 years or older. This lack of evidence is reflected by the fact that the risk coefficients recommended by national and international advisory bodies differ by a factor of 10 or more for age at exposure of 50–60 years or older. A hypothesis is proposed indicating that the risk of radiation-induced breast cancer might decrease considerably at the time of menopause. The hypothesis is based on the following line of arguments: (1) evidence has accumulated from molecular genetic studies indicating that the development of colorectal cancer requires a cascade of subsequent mutations consisting of at least seven genetic events. (2) For colorectal cancer, the annual rates of incidence and mortality increase with age to the power of 5–6. Thus, the number of mutation steps (minus 1) is approximately reflected by the power of age dependence. (3) For western populations, the incidence and mortality of breast cancer up to the age of about 50 years increase with age to the power of about 6, indicating that a similar number of genetic events might be involved in development of breast cancer as has been identified for colorectal cancer. (4) For women aged 50 years or older, breast cancer occurs at an annual rate that is about proportional to age or age squared. This may mean that after menopause, the processes in the multistep mutation cascade leading to breast cancer are slowed down by a factor of about 4 or more. (5) The constant relative risk model of radiation carcinogenesis implies for solid cancers that radiation acts by inducing additional mutations in the earlier steps of the multistep cascade. It is suggested that the break-point in the age-specific annual rate of breast cancer incidence at menopause is associated with a corresponding drop in radiation sensitivity with respect to induction of breast cancer. Received: 8 January 2001 / Accepted: 20 March 2001