Subsequent Cancer Occurrence Research Articles

Abstract 29: Autoimmune diseases and the risk of cancer

Abstract Background: Many autoimmune diseases (AD) are known to be associated with comorbidities, and certain ADs have been suggested to influence cancer risk. Immunosuppression and dysregulation of the immune system promote the development of certain cancers, particularly hematological malignancies. There is also evidence on an increased risk of several types of solid tumors among individuals with an AD. The aim of this population-based cohort study was to evaluate the risk of any cancer, except non-melanoma skin cancer, in 31 different ADs. We explored associations between both common (such as rheumatoid arthritis) and rare (such as Behcet’s disease) ADs and cancer. Material and methods: The data consists of a population-based random sample of 2.5 million individuals who lived in Finland on January 1, 2000. It includes information on hospital diagnoses between 1970 and 2017 for each individual, with a total of 92 million hospital care records. There were 70 694 individuals with prevalent AD and 68 002 individuals with prevalent cancer. Those with prevalent cancer were removed from the analyses. Participants were followed up for subsequent occurrence of cancer, based on data from the nationwide cancer registry. We estimated relative risks (RRs) with 95% confidence intervals (CIs) using piecewise constant hazard regression models, adjusting for age, sex, and calendar period. Time since AD diagnosis was treated as a time-varying covariate. Results: During the follow-up, 222 211 primary cancers were diagnosed, 18 409 with and 203 802 without a pre-existing AD. Overall, the risk of cancer was 2.02 (95% CI 1.93-2.12) for <1 year since any AD diagnosis and 1.05 (1.03-1.07) for ≥10 years since diagnosis. The largest increase in cancer risk was observed for individuals with autoimmune hemolytic anemia, and there was evidence of a persisting risk even after 10 years since diagnosis (RR 8.53 (6.76-10.77) for <1 year since diagnosis and 1.62 (1.18-2.24) for ≥10 years since diagnosis). Long-term impact on cancer risk was also observed for autoimmune vasculitis, Crohn's disease, discoid lupus erythematosus, pemphigus, psoriasis, systemic lupus erythematosus and ulcerative colitis. For individuals with these ADs, cancer risk was still elevated after 10 or more years after AD diagnosis. Discussion: Cancer incidence was greatly dependent on AD duration. Cancer risk was increased soon (<1 year) after AD diagnosis in 24 different ADs and elevated risks were still observed after ≥10 years in 8 ADs. Cancer and comorbid diseases may have partly shared etiologies. Many lifestyle factors such as smoking, alcohol consumption, and obesity are established causes of many common diseases. Also, AD treatments may in some cases be tumorigenic. In conclusion, many ADs were associated with a significantly increased risk of cancer long after diagnosis, and this should be considered in patient counseling and monitoring. The findings also encourage search for shared risk factors underlying both diseases. Citation Format: Sanna Heikkinen, Tomas Tanskanen, Lauri Sipilä, Janne Pitkäniemi. Autoimmune diseases and the risk of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 29.

Incidence and outcomes of malignant ovarian germ cell tumors in Korea, 1999–2017

ObjectiveMalignant ovarian germ cell tumor (MOGCT) is a rare ovarian malignancy accounting for less than 5% of all ovarian cancers. We aimed to evaluate the incidence, survival, and subsequent malignancies after the diagnosis of MOGCT. MethodsData from the Korea Central Cancer Registry were used to identify MOGCTs between 1999 and 2017. The age-standardized rates (ASRs), 5-year relative survival rates (RSR) and standardized incidence ratio (SIR) for subsequent cancer after diagnosis of MOGCT were estimated. ResultsOf 2125 cases of newly diagnosed MOGCTs, 596 (28.0%) were diagnosed with dysgerminoma and 1529 (72.0%) with non-dysgerminoma. The ASR per 100,000 women-years was 0.539; ASR slightly increased over the study period (annual percent change [APC] = 1.01%; p = 0.02). There was an increase and decrease in the incidence of MOGCTs in the age groups 0–19 years (APC = 1.96%; p < 0.01) and ≥ 50 years (APC = −6.51%; p < 0.01), respectively. Patients with dysgerminoma showed significantly higher RSR than patients with non-dysgerminoma (98.0% vs. 94.9%, p < 0.01). Patients aged ≥50 years showed worst 5-year RSR (68.7%) than patients aged 0–19 years (97.8%) and 20–34 years (96.4%) (p < 0.01). The overall SIR for a subsequent cancer occurrence was 2.07, with the most frequent site of subsequent primary cancer being the thyroid (SIR = 2.78). ConclusionsOur data demonstrated an excellent prognosis of MOGCTs among Korean women. There was a slight increase in MOGCT prevalence, which was more pronounced among those aged <19 years. After MOGCT diagnosis, the risk of developing a subsequent malignancy was doubled compared with the general population.

Long-term cancer risk after hysterectomy on benign indications: Population-based cohort study.

Hysterectomy on benign indications is associated with an increased risk for adverse health effects. However, little is known about the association between hysterectomy and subsequent cancer occurrence later in life. The purpose of this study was to assess the effect of hysterectomy on the incidence of cancer. In this population-based cohort study, we used data on 111,595 hysterectomized and 537,9843 nonhysterectomized women from nationwide Swedish Health Care registers including the Inpatient Register, the Cancer Register and the Cause of Death Register between 1973 and 2009. Hysterectomy with or without concomitant bilateral salpingo-ophorectomy (BSO) performed on benign indications was considered as exposure and incidence of primary cancers was used as outcome measure. Rare primary cancers (<100 cases for the two groups combined) were excluded from analysis. A marginal risk reduction for any cancer was observed for women with previous hysterectomy and for those with hysterectomy and concurrent BSO (HR 0.93, 95% CI 0.91-0.95 and HR 0.92, 95% CI 0.87-0.96, respectively). Compared to nonhysterectomized women, significant risks were observed for thyroid cancer (HR 1.76, 95% CI 1.45-2.14). For both hysterectomy and hysterectomy with BSO, an association with brain cancer was observed (HR 1.48, 95% CI 1.32-1.65 and HR 1.45, 95% CI 1.15-1.83, respectively). Hysterectomy, with or without BSO, was not associated with breast, lung or gastrointestinal cancer. We conclude that hysterectomy on benign indications is associated with an increased risk for thyroid and brain cancer later in life. Further research efforts are needed to identify patient groups at risk of malignancy following hysterectomy.

Postoperative brachytherapy and electron beam irradiation for keloids: A single institution retrospective analysis.

The aim of the present study was to perform a retrospective analysis of the control rate and toxicity of postoperative brachytherapy and electron beam irradiation for keloids. A retrospective review was performed of 116 keloid patients who underwent postoperative brachytherapy and electron beam irradiation between January 1, 2002 and June 30, 2012. Several different radiotherapy techniques and fractionation schedules were performed in the analysis, including high-dose rate (HDR) irradiation with 192Ir at 8 Gy/1 fraction (F)+9 Gy/3F or 20 Gy/4F; HDR brachytherapy with 60Co at 20 Gy/4F or 18 Gy/6F; or external beam electron therapy at 26 Gy/13F or 30 Gy/15F. The endpoints of the study were analysis of the control rate and toxicity. The median observation period was 46.5 months (range, 10.0-120.0 months) for all patients. In total, 18 of the 116 patients relapsed, and 16.7 months (range, 10.0-30.0 months) was the median time to recurrence for these patients. The control rates for the patients who received hypofractionation (>2 Gy per fraction) and conventional fraction (2 Gy per fraction) were 88.5 and 76.3%, respectively (P=0.043). The control rates for the patients whose calculated biological effective doses (BED) were >30 Gy and <30 Gy were 89.7 and 79.3%, respectively (P=0.104). There were no grade 2 or higher adverse effects based on the Common Terminology Criteria for Adverse Events v3.0 in the late phase. No evidence was identified for a link between radiotherapy and the subsequent occurrence of cancer. The results of the present study indicate that hypofractionated radiotherapy played an important role as an adjuvant therapy following surgical excision of keloids. A BED of >30 Gy appears to be sufficient. No definitive evidence was found for an association between radiotherapy and the occurrence of cancer during the follow-up, however, more cases and longer follow-up periods are required.

Risk of new or recurrent cancer after a high perioperative inspiratory oxygen fraction during abdominal surgery

Administration of supplemental oxygen in the perioperative period is controversial, as it may increase long-term mortality. Our aim was to assess the association between 80% oxygen and occurrence of subsequent cancer in patients undergoing abdominal surgery in a post hoc analysis of the PROXI trial. The 1386 patients in the PROXI trial underwent elective or emergency laparotomy between 2006 and 2008 with randomization to either 80% or 30% oxygen during and for 2 h after surgery. We retrieved follow-up status regarding vital status, new cancer diagnoses, and new histological cancer specimens. Data were analysed using the Cox proportional hazards model. Follow-up was complete in 1377 patients (99%) after a median of 3.9 yr. The primary outcome of new cancer diagnosis or new malignant histological specimen occurred in 140 of 678 patients (21%) in the 80% oxygen group vs 150 of 699 patients (21%) assigned to 30% oxygen; hazards ratio 1.06 [95% confidence interval (CI) 0.84, 1.34], P=0.62. Cancer-free survival was significantly shorter in the 80% oxygen group; hazards ratio 1.19 (95% CI 1.01, 1.42), P=0.04, as was the time between surgery and new cancer, median 335 vs. 434 days in the 30% oxygen group. In patients with localized disease, non-significant differences in cancer and cancer-free survival were found with hazard ratios of 1.31 and 1.29, respectively. Although new cancers occurred at similar rate, the cancer-free survival was significantly shorter in the 80% oxygen group, but this did not appear to explain the excess mortality in the 80% oxygen group. ClinicalTrials.gov (NCT01723280).

Invasive colorectal cancer within 5 years of negative colonoscopy in a Japanese population

Colonoscopy provides imperfect protection against colorectal cancer (CRC). In an attempt to improve cancer detection we evaluated the clinical features of invasive CRC detected within 5 years of a negative colonoscopy. The details of colonoscopies performed in a rural hospital in Japan were prospectively recorded at the time of the examination. The patients were followed over 5 years for the subsequent occurrence of cancer. In a 5-year period, 10148 patients underwent colonoscopy and 202 without previous colonoscopy were diagnosed with invasive CRC. Of 3212 patients with a colonoscopy negative for cancer, nine developed invasive cancer within 5 years. The ratios for invasive CRC detected without/with previous colonoscopy were 60:1 in the rectum, 54:1 in the sigmoid colon, 15:1 in the descending colon, 28:0 in the transverse colon, 31:5 in the ascending colon and 14:1 in the caecum (P=0.041). The ratio between left- and right-sided colonic cancer was also significantly different (129:3 and 45:6, P=0.0078). Six (67%) of the invasive CRCs were in the ascending colon or caecum. Five of six patients with invasive CRC in the ascending colon and caecum had right-sided small adenomas at prior colonoscopy. The majority of early/missed CRCs were right-sided and associated with prior right-sided colonic adenomas. Repeated colonoscopy of patients with right-sided adenomas at a shorter surveillance interval deserves consideration.

464 CONSISTENCY OF TUMOR POSITION ON REPEAT PROSTATE BIOPSY IN MEN ON ACTIVE SURVEILLANCE FOR PROSTATE CANCER-IMPLICATIONS FOR HEMIABLATION

INTRODUCTION AND OBJECTIVES: Hemiablation is a minimally invasive treatment option for men with prostate cancer on active surveillance (AS). The main concern with this approach is the possibility of missing an undiagnosed cancer or the growth of a new cancer in another part of the gland. Our aim was to investigate initial positive and repeat TRUS-BX findings in men on AS to determine how often and to what extent an altered disease profile occurred on second biopsy. We also sought to determine histologic predictors of subsequent cancer occurrence in non-cancerous areas. METHODS: A prospective database is maintained at our institution of all patients undergoing prostate biopsy. Three radiologists perform all biopsies ( 2000 systematic biopsies/year) at our institution using a systematic 11 core initial and 15 core repeat biopsy approach. From this database we retrospectively identified 423 AS patients who had at least 2 biopsies. AS inclusion criteria were; 3 cores positive, less than 50% of any core positive, Gleason score 7. We compared the site of occurrence of cancer between the first biopsy and second biopsy. Histologic predictors of contralateral cancer occurrence and worsening disease grade were also assessed. RESULTS: Our AS cohort included 423 men who had 2 biopsies. The mean age was 65 and the median time between biopsies was 14 months with a decrease in mean PSA from 7.3 to 7.0 (p 0.01). On second biopsy, 17% of man had an increase in Gleason score, 49% had no change and 35% had no cancer detected. The mean number of positive cores decreased on second biopsy from 1.9 to 1.4 (p 0.01). Cancer position on second biopsy remained the same in 36%, occurred on the contralateral side in 29%, and was undetectable in 35%. The only predictor of cancer occurrence on the contralateral side on second biopsy was having contralateral ASAP or HGPIN on the first biopsy (OR 1.82, p 0.02). Having 1 core positive on first biopsy was a predictor of higher grade disease on the second biopsy (OR 2.54; p 0.01). CONCLUSIONS: Follow-up prostate biopsy in men on AS can uncover cancers in the contralateral part of the gland in approximately one third of cases with the only pathologic predictors being ASAP or HGPIN in the contralateral area. Prostate hemiablation should not rely on one set of prostate biopsies.

Impact of metabolic factors on subsequent cancer risk: results from a large-scale population-based cohort study in Japan

The impact of metabolic factors, which are major risk factors for cardiovascular disease, on total cancer risk has not been clarified. We prospectively examined whether metabolic factors and their aggregates predict the subsequent occurrence of total and major sites of cancer in the Japan Public Health Center-based Prospective Study. A total of 27 724 participants (9548 men and 18 176 women) aged 40-69 years participating in a questionnaire and health checkup survey in 1993-1995 were followed for total cancer incidence through 2004. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for metabolic factors and for two criteria of their aggregates (three or more than three factors and two or more than two additional factors in addition to being overweight) with a Cox proportional hazards model to control for potential confounding factors. In both sexes, the presence of metabolic factors in the aggregate did not predict subsequent occurrence of cancer as a whole. By site, a significant increase in risk was observed for male liver cancer [HR = 1.73, CI = 1.03-2.91 (three or more than three factors); HR = 1.99, CI = 1.11-3.58 (two or more than two additional factors in addition to being overweight)], and female pancreatic cancer [HR = 1.99, CI = 1.00-3.96 (two or more than two additional factors in addition to being overweight)]. For other sites, positive associations were observed only for specific metabolic factors, that is, high triglycerides and male colon cancer (HR = 1.71, CI = 1.11-2.62), and obesity and female breast cancer (HR = 1.75, CI = 1.21-2.55). Metabolic factors in the aggregate may have little impact on total cancer risk in the Japanese population, although the association between specific components and specific cancers suggests an etiologic link between them.

Multiple primary tumours: incidence estimation in the presence of competing risks

BackgroundEstimating the risk of developing subsequent primary tumours in a population is difficult since the occurrence probability is conditioned to the survival probability.MethodsWe proposed to apply Markov models studying the transition intensities from first to second tumour with the Aalen-Johansen (AJ) estimators, as usually done in competing risk models. In a simulation study we applied the proposed method in different settings with constant or varying underlying intensities and applying age standardisation. In addition, we illustrated the method with data on breast cancer from the Piedmont Cancer Registry.ResultsThe simulation study showed that the person-years approach led to a sensibly wider bias than the AJ estimators. The largest bias was observed assuming constantly increasing incidence rates. However, this situation is rather uncommon dealing with subsequent tumours incidence. In 9233 cases with breast cancer occurred in women resident in Turin, Italy, between 1985 and 1998 we observed a significant increased risk of 1.91 for subsequent cancer of corpus uteri, estimated with the age-standardised Aalen-Johansen incidence ratio (AJ-IRstand), and a significant increased risk of 1.29 for cancer possibly related to the radiotherapy of breast cancer. The peak of occurrence of those cancers was observed after 8 years of follow-up.ConclusionThe increased risk of a cancer of the corpus uteri, also observed in other studies, is usually interpreted as the common shared risk factors such as low parity, early menarche and late onset of menopause. We also grouped together those cancers possibly associated to a previous local radiotherapy: the cumulative risk at 14 years is still not significant, however the AJ estimators showed a significant risk peak between the eighth and the ninth year. Finally, the proposed approach has been shown to be reliable and informative under several aspects. It allowed for a correct estimation of the risk, and for investigating the time trend of the subsequent cancer occurrence.

Increased Risk of Second Cancer Among Patients With Ovarian Borderline Tumors

Objectives. Several studies have demonstrated a higher risk of colorectal and breast cancers subsequent to invasive ovarian cancer. Such risk has not been investigated for ovarian borderline tumors. We aim to evaluate the risk of subsequent cancer occurrence among patients with borderline ovarian tumors in a population-based setting. Methods. We identified 171 patients with a diagnosis of borderline ovarian tumors recorded at the Geneva Cancer Registry, Switzerland. We calculated age and period standardized incidence ratios (SIR) of second tumor occurrence by dividing the number of observed cases by the number of expected cases in the cohort, using cancer incidence rates of the general female population. Results. The risk of developing second cancer was 1.85-fold (95% Confidence Interval [CI]: 1.10–2.92, n=16) higher among women with borderline ovarian tumors compared to that expected in the general population. The excess of risk primarily concerned colorectal cancer (SIR: 3.97, CI: 1.38–12.95, n=5) and breast cancer (SIR: 2.09, CI: 0.84–4.31, n=7), but the latter result was not statistically significant ( p=0.09). The increased risk of developing second cancer was mainly observed among patients diagnosed with ovarian borderline tumors occurring before the age of 50. These results were not explained by surveillance bias or by metastasis from one site to another. Conclusion. Women with ovarian borderline tumors have an increased risk of developing secondary cancer, particularly colorectal cancer. These results point to potential common risk factors for these tumors and ask for close surveillance of patients with borderline ovarian tumors.

The occurrence of invasive cancers following a diagnosis of breast carcinoma in situ

Approximately 1 in every 600 women attending breast-screening programmes in the United Kingdom is diagnosed with breast carcinoma in situ (BCIS). However, there is little information on the occurrence of subsequent cancers (other than second breast cancers) in these women. We investigated the occurrence of invasive cancers in 12 836 women diagnosed with BCIS in southeast England between 1971 and 2003, using data from the Thames Cancer Registry. A greater than expected number of subsequent cancers was found for two sites: breast (standardised incidence ratio (SIR) 1.96; 95% confidence interval (CI) 1.79–2.14) and corpus uteri (SIR 1.42; 95% CI 1.11–1.78). For subsequent ipsilateral breast cancer in those treated with breast conservation, the excess was independent of the time since diagnosis of BCIS, whereas for subsequent contralateral breast cancer, there was a steady decline in excess over time. For subsequent uterine cancer, the excess became statistically significant only at >5 years after BCIS diagnosis, consistent with a treatment effect. This was further supported by Cox regression anaysis: the risk of subsequent uterine cancer was significantly increased in women receiving hormonal therapy compared with those not receiving it, with a hazard ratio of 2.97 (95% CI 1.84–4.80).

Increased risk of second cancer among patients with ovarian borderline tumors

Objectives Several studies have demonstrated a higher risk of colorectal and breast cancers subsequent to invasive ovarian cancer. Such risk has not been investigated for ovarian borderline tumors. We aim to evaluate the risk of subsequent cancer occurrence among patients with borderline ovarian tumors in a population-based setting. Methods We identified 171 patients with a diagnosis of borderline ovarian tumors recorded at the Geneva Cancer Registry, Switzerland. We calculated age and period standardized incidence ratios (SIR) of second tumor occurrence by dividing the number of observed cases by the number of expected cases in the cohort, using cancer incidence rates of the general female population. Results The risk of developing second cancer was 1.85-fold (95% Confidence Interval [CI]: 1.10–2.92, n = 16) higher among women with borderline ovarian tumors compared to that expected in the general population. The excess of risk primarily concerned colorectal cancer (SIR: 3.97, CI: 1.38–12.95, n = 5) and breast cancer (SIR: 2.09, CI: 0.84–4.31, n = 7), but the latter result was not statistically significant ( p = 0.09). The increased risk of developing second cancer was mainly observed among patients diagnosed with ovarian borderline tumors occurring before the age of 50. These results were not explained by surveillance bias or by metastasis from one site to another. Conclusion Women with ovarian borderline tumors have an increased risk of developing secondary cancer, particularly colorectal cancer. These results point to potential common risk factors for these tumors and ask for close surveillance of patients with borderline ovarian tumors.

Cancer Risk in Children with Birth Defects and in Their Families: A Population Based Cohort Study of 5.2 Million Children from Norway and Sweden

Cancer and birth defects may share factors that influence risk. A malformation may involve physiologic changes or changes in lifestyle that might affect cancer risks. In Norway and Sweden, the population-based medical birth and cancer registries were linked to identify subsequent cancer occurrence in children with birth defects and among their parents and siblings. Altogether, 5.2 million children and their families were included. The standardized incidence ratio (SIR) served as a measure of relative risk. There was an increased overall cancer risk in individuals with birth defects in the two countries [SIR, 1.7; 95% confidence interval (95% CI), 1.6-1.9], and the increased risk remained into early adulthood. Individuals with malformations in the nervous system were at increased risk of developing cancer in the brain/nervous system (Norway: SIR, 58; 95% CI, 41-80; Sweden: SIR, 8.3; 95% CI, 4.0-15), individuals with Down syndrome were at an increased risk of leukemia (Norway: SIR, 36; 95% CI, 26-48; Sweden: SIR, 36; 95% CI, 28-46), and there was an increased overall cancer risk for individuals with multiple birth defects (Norway: SIR, 5.5; 95% CI, 3.3-8.7; Sweden: SIR, 3.6; 95% CI, 2.2-5.4). There was no increased overall cancer risk among mothers (SIR, 1.0; 95% CI, 1.0-1.0), fathers (SIR, 1.0; 95% CI, 0.9-1.0), and siblings (SIR, 1.0; 95% CI, 0.9-1.1) of children with birth defects. We observed an increased overall cancer risk in individuals with birth defects. The highest risks were seen for individuals with malformations in the nervous system, Down syndrome, and multiple defects. No increased overall cancer risk was seen among their parents or siblings.

Epithelial atypia in biopsies performed for microcalcifications. practical considerations about 2,833 serially sectioned surgical biopsies with a long follow-up.

This study analyzes the occurrence of epithelial atypia in 2,833 serially sectioned surgical breast biopsies (SB) performed for microcalcifications (median number of blocks per SB:26) and the occurrence of subsequent cancer after an initial diagnosis of epithelial atypia (median follow-up 160 months). Epithelial atypia (flat epithelial atypia, atypical ductal hyperplasia, and lobular neoplasia) were found in 971 SB, with and without a concomitant cancer in 301 (31%) and 670 (69%) SB, respectively. Thus, isolated epithelial atypia were found in 670 out of the 2,833 SB (23%). Concomitant cancers corresponded to ductal carcinomas in situ and micro-invasive (77%), invasive ductal carcinomas not otherwise specified (15%), invasive lobular carcinomas (4%), and tubular carcinomas (4%). Fifteen out of the 443 patients with isolated epithelial atypia developed a subsequent ipsilateral (n = 14) and contralateral (n = 1) invasive cancer. The high slide rating might explain the high percentages of epithelial atypia and concomitant cancers and the low percentage of subsequent cancer after a diagnosis of epithelial atypia as a single lesion. Epithelial atypia could be more a risk marker of concomitant than subsequent cancer.

TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study

In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis.

Breast cancer (BC) risk among 3-year survivors of a first pediatric cancer (FC)

8531 Background: Long-term survival of patients treated for a pediatric cancer is dramatically improved. Nevertheless, in this context, the risk for occurrence of subsequent cancer, and particularly of breast cancer knowing that child's breast is very radiosensitive, is a significant data for the monitoring of the survivors. Methods: Data on chemotherapy and radiotherapy were collected for each of the 1,817 3-year female, survivors from a FC diagnosed before age 17, treated in eight French and English centers. Individual estimation of radiation dose to each breast was performed for the 1,261 patients treated by external radiotherapy, delivered in 24 fractions (mean); mean dose to breasts was 5.06 Gy (range 0.0–78.6). Results: Within a 16-year mean follow-up, sixteen BC occurred leading to a cumulative probability of 2.9% [95%CI: 0.98–4.9] 30 years after the FC and of 5.5% [95%CI: 2.1 to 8.9 %] at age 40. The annual excess incidence rose as age increased whereas the Standardized Incidence Ratio (SIR) decreased. On average, each Gy received to the breast increases the risk by 0.78 [95%CI: 0.0–5.4]. A non significant higher risk with less than 20 fractions versus 20 or more was observed. After adjustment on radiation dose and FC type, only a weak association between chemotherapy and BC risk was evidenced (RR=2.4, 95%IC: 0.8–7.1). Adjusting on age at FC, radiation dose and chemotherapy, a higher risk of a subsequent BC was associated with Hodgkin's disease (RR=4.7, 95%CI: 1.0–19.6) and non significantly with neuroblastoma (RR =3.20, 95%CI: 0.6–12.1). Conclusions: In this study, the higher risk of occurrence of BC following childhood Hodgkin's disease seems to be due not only to a higher radiation dose to the breasts but also to a specific susceptibility. No significant financial relationships to disclose.

Impact of tobacco smoking on subsequent cancer risk among middle-aged Japanese men and women: data from a large-scale population-based cohort study in Japan—the JPHC study

Background. The present study aimed to obtain a relevant epidemiological index of the impact of tobacco smoking on the subsequent risk of cancer in Japan. Methods. We conducted a cohort analysis on the possible association between tobacco smoking habits and total cancer risk among a middle-aged Japanese population, using a large-scale population-based cohort of 92,792 subjects (44,521 men and 48,271 women) with 10-year follow-up. Results. During 1990–2001, 4,922 cases of cancer (2,969 men and 1,953 women) were newly diagnosed. From the baseline questionnaire, 52.2% of men were current smokers and they presented a significantly increased hazard ratio (HR) of subsequent cancer occurrence compared with never-smokers [HR 1.64, 95% confidence interval (95% CI) 1.48–1.82]. Only 5.6% of women were current smokers and their HR also represented a significant increase (HR 1.46, 95% CI 1.21–1.75). The corresponding population attributable fraction (PAF) (%) of total cancer incidence in men was 22.4% (95% CI 15.7%–28.5%) and 7.0% (95% CI 3.7%–10.3%) in relation to current and past exposures to tobacco smoke. In women, the PAF was only 2.2% and 0.6% due to the low prevalence of current and former smokers. Conclusions. Our results suggest that 29% of male cancer and 3% of female cancer would be preventable in Japanese middle-aged population by avoidance of tobacco smoking.

Estimating the influence of rescreening interval on the benefits associated with cancer screening: approaches and limitations.

ABSTRACT Randomized controlled trials that seek to measure the ability of a screening test to lower cancer mortality generally do not provide data that bear on the relative efficacy of different screening intervals. Guidance regarding the choice of a screening interval that achieves a high level of case-finding, without being excessively costly, can be obtained from one or more of several study designs that examine the subsequent occurrence of cancer in persons who have had a negative screening test. However, each of these can potentially provide a misleading result, and so their limitations must be considered before using the data they generate to develop a rational rescreening policy.

Is history of squamous-cell skin cancer a marker of poor prognosis in patients with cancer?

Nonmelanoma skin cancer is associated with increased occurrence of subsequent cancer and death from cancer, but it is not known whether a history of skin cancer is associated with poor prognosis after a second diagnosis of cancer. To determine whether history of squamous-cell skin cancer is a marker of poor prognosis in patients with cancer. Population-based cohort study. Sweden, 1958 to 1996. All patients in the Swedish Cancer Registry with or without a first diagnosis of squamous-cell skin cancer and a subsequent or first diagnosis of non-Hodgkin lymphoma (including chronic lymphocytic leukemia) or cancer of the colon, breast, prostate, or lung. Relative risk (RR) for death determined by using Cox proportional hazards regression analysis. Patients with a history of squamous-cell skin cancer had a significantly greater risk for death than those with no such history after receiving a diagnosis of non-Hodgkin lymphoma (RR, 1.33), colon cancer (RR, 1.24), breast cancer (RR, 1.19), or prostate cancer (RR, 1.17). Patients with lung cancer and a history of squamous-cell skin cancer who survived for 1 year after diagnosis of lung cancer also had an increased risk for death (RR, 1.29). Patients with a registered history of squamous-cell skin cancer have a poor prognosis after diagnosis of subsequent cancer and warrant careful medical attention.

Evolution of Isolated High-Grade Prostate Intraepithelial Neoplasia in a Mediterranean Patient Population

The discovery of high-grade prostatic intraepithelial neoplasia (HGPIN) in prostatic needle biopsies is of clinical importance. Previous studies have shown prostate cancer to develop in 27–100% (average 55%) of the cases after HGPIN was diagnosed. Our preliminary findings in a Mediterranean population (Barcelona, Spain) revealed a prevalence of HGPIN of 4.4%, and an incidence of prostate cancer of 28.7% in cases in whom isolated HGPIN was identified at the first biopsy. The majority (64%) of these cases were diagnosed at the first biopsy after HGPIN diagnosis, and 52% within the first year. HGPIN persisted in 46.6% of the cases. The total mean serum prostate-specific antigen (PSA) was 9.9 ± 6.6 ng/ml in the prostate cancer cases, compared with 8.8 ± 7.5 in the cases without cancer. The low incidence of isolated HGPIN and subsequent cancer occurrence may be due to local factors or insufficient follow-up.