Risk for endometrial cancer following breast cancer: a prospective study in Sweden

The risk for endometrial cancer among women with breast cancer might increase following use of tamoxifen, recently classified as a carcinogen of the human endometrium. However, the strength of the association remains uncertain and it is unknown whether use of this drug - widely prescribed in Sweden since the mid-1980s - has had any measurable effect at the population level. We analyzed all cases of breast cancer (n = 131,614) detected in the nationwide Swedish Cancer Registry in 1958-93. Incident cases of endometrial cancer during follow-up were identified also through the Cancer Registry. Standardized incidence ratios (SIR) and their 95 percent confidence intervals(CI) were computed by use of nationwide rates of endometrial cancer, adjusted for age and calendar year. During follow-up of up to 35 years of the breast cancer cohort, 803 incident endometrial cancers were identified, yielding an overall SIR of 1.58 (CI = 1.47-1.70). In univariate analyses, there was no increase in SIR in recent years. However, the excess risk increased linearly with increasing age at breast cancer diagnosis (P trend < 0.0001) and decreased markedly with longer follow-up (P trend < 0.0001). A multivariate regression analysis, with adjustment for age and year of follow-up, revealed no increased risk for subsequent endometrial cancer among breast cancer cases diagnosed more recently (P trend = 0.19); compared with the period 1958-63,the risk estimate in the last time period (1989-93) was 0.72 (CI =0.51-1.01). We conclude that the risk for endometrial cancer following breast cancer has not increased over time in Sweden. This revised version was published online in July 2006 with corrections to the Cover Date.     

Prognostic characteristics in breast cancers after hormone replacement therapy

Summary We examined the influence of hormone replacement therapy (HRT) on breast tumour biology by comparing the prognostic characteristics of breast cancers and survival in 121 women prescribed replacement hormones before diagnosis with those in 1468 women without such treatment. The women receiving HRT had a lowered relative risk of being diagnosed with tumours of more than 20 mm in diameter, OR = 0.7 (CI 0.5–1.0) and axillary lymph node dissemination, OR = 0.7 (CI 0.4–1.1). These risk reductions were most pronounced and statistically significant in the women who had been prescribed a combined estradiol-progestin regimen. The patients in this compound group also had a diminished relative risk of having poorly differentiated tumours. Further, there was an indication that the women prescribed HRT, and especially those with conjugated estrogens/estradiols alone, had a decreased relative risk of developing aneuploid tumours. There was no clear pattern for women receiving the biologically weak oestriol, although risk estimates were generally higher for unfavourable tumours in comparison with those receiving the higher potency compounds. Adjustments for indications of earlier detection (i.e. lead time bias) did not influence the pattern or magnitude of the risk estimates. No association between any type of HRT and survival after breast cancer diagnosis was noted, but analyses were based only on 19 breast cancer deaths among exposed patients. We conclude that breast cancers occurring after treatment with HRT, especially the combined estrogen-progestin regimen, seem to have more favourable tumour features than tumours in non-treated women. Our findings may reflect a less aggressive biological behaviour of breast cancers in women receiving HRT, or in part be explained by the earlier detection of the tumours in these women.     

Risk of endometrial cancer following estrogen replacement with and without progestins.

BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.     

Hormone replacement therapy and breast cancer mortality in Swedish women: results after adjustment for ‘healthy drug-user’ effect

No change of breast cancer mortality has been reported previously after long-term hormone replacement therapy. A conceivable explanation for the apparent discrepancy between incidence and mortality may be selection bias due to lower prevalence of breast cancer in women who receive replacement hormones, compared with nonexposed women. We used a new approach to correct for bias due to this healthy drug-user effect, by adjusting the external, population-based, mortality rates for such cases prevalent during the recruitment period of our cohort. In this cohort of some 23,000 Swedish women, who were prescribed various hormone replacement regimens, breast cancer mortality was analyzed after follow-up to 12 years. External analyses revealed overall standardized mortality ratios for breast cancer rising from 0.71 to 0.81, but not significantly different from unity, after adjustment procedures. In multivariate regression models, excluding prevalent cases in the cohort, women prescribed estradiol, conjugated estrogens, or an estrogen-progestin combination were not at a higher risk relative to those given other and weak estrogens, relative risks being 0.81 and 0.68, respectively. On the basis of the present analytical approach, we conclude that breast cancer mortality does not appear to be changed overall or in subgroups, despite increased incidence.This project is funded in part by grants from the Swedish Cancer Society and from the National Cancer Institute, National Institute of Health, USA.     

Risks of breast and endometrial cancer after estrogen and estrogen–progestin replacement

Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens.Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987–88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group.Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9–2.3) after 1–6 years of intake, and RR=1.7 (95% CI 1.1–2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5–8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6–3.3).Conclusions: We conclude that long-term recent use of estrogen–progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins.     

Second primary cancers in patients with cutaneous malignant melanoma: a population-based study in Sweden.

To quantify the risk of second primary cancers among patients with cutaneous malignant melanoma, we studied 20,354 patients in the Swedish Cancer Register during 1958-88. A second primary cancer was reported in 1605 patients, compared with an expected number of 1109.5 [standardised incidence ratio (SIR) = 1.45, 95% confidence interval (CI) = 1.38-1.52]. The highest risk was found among patients younger than 60 years. The greatest risk was seen during the first year after diagnosis (SIR = 1.91, CI = 1.69-2.14), but even after long-term follow-up--15 years or more--the risk was still significantly elevated (SIR = 1.56, CI = 1.35-1.79). The strongest association was found for a second primary malignant melanoma (men, SIR = 10.0, CI = 8.26-12.00; women, SIR = 8.66, CI = 7.22-10.30) and non-melanoma skin cancer (men, SIR = 3.58, CI = 2.85-4.44; women, SIR = 2.41, CI = 1.71-3.29). The risk of second cancers associated with tissues of neuroectodermal origin was increased, especially tumours of the nervous system (men, SIR = 1.73, CI = 1.10-2.60; women, SIR = 2.03, CI = 1.45-2.78). The SIR of second cancers involving the immune system was also increased. An excess risk of endometrial cancer was seen (SIR = 1.41, CI = 1.03-1.88), but no significant associations existed for cancers of the breast, ovary, testis or other endocrine glands. Among tumours of the digestive tract, only colon cancer in men had a significantly increased SIR (1.33, CI = 1.00-1.74).     

Primary Malignancy after Primary Female Breast Cancer in the South of the Netherlands, 1972–2001

Summary Objectives. To assess the risk of second primary cancers among women with previous breast cancer and calculate the excess burden of second cancer in the population. Methods. A population-based longitudinal study was conducted using the Eindhoven cancer registry data on 9919 breast cancer patients diagnosed in the period 1972–2000 and followed until 2001. Standardised incidence ratios (SIR) and absolute excess risks (AER) were calculated. Results. In total, 1298 (13%) women developed a second primary cancer. The risk of overall second cancer was higher among breast cancer patients compared to the general population (SIR: 2.8; 95% CI: 2.6–2.9), with an AER of 115 second cancers for every 10,000 breast cancer patients per year. High SIR and AER were observed for breast cancer (SIR: 4.1; 95% CI: 3.8–4.4; AER: 64/10,000 patients/year) and ovarian cancer (SIR: 2.0; 95% CI: 1.5–2.7; AER: 4.5/10,000 patients/year). Conclusions. Our recent data show that women with previous breast cancer have an elevated risk of developing a second cancer compared to the general population. Excess burden for the population is especially high for second cancers of the breast, ovary and colon. Screening may only be justified for breast, ovary and colon cancer in certain groups of patients.     

Risk of endometrial and breast cancer in patients with diabetes mellitus

Diabetes mellitus patients have metabolic and endocrine alterations that could contribute to an increased incidence of hormone-related cancers. We assessed the incidence of endometrial and breast cancer among 80,005 women and the incidence of breast cancer among 73,847 men (total of 153,852 patients) identified in the Swedish In-patient Register as having been hospitalized for diabetes mellitus in the period 1965-1983. These patients underwent follow-up through 1989 via the Swedish Cancer Register and other nation-wide Swedish registers. The outcome measures were standardized incidence ratios (SIR) based on age-, sex- and calendar period-specific incidence rates from the entire Swedish population. To minimise the effect of selection bias, we excluded from the calculation of incidence ratios the first year of observation and cases diagnosed incidentally at autopsy. Only first cancers were considered for the estimates. A total of 328 endometrial cancers (SIR = 1.8; 95% confidence interval [CI] = 1.6-2.0), 1,145 female breast cancers (SIR = 1.3; 95% CI = 1.2-1.4) and 13 male breast cancers (SIR = 2.0; 95% CI = 1.0-3.4) were observed. We conclude that compared with the general population, patients with diabetes mellitus have an increased incidence of endometrial and breast cancers. Int. J. Cancer 71:360-363, 1997. © 1997 Wiley-Liss Inc.     

Morbidity and mortality in gynecological cancers among first- and second-generation immigrants in Sweden

We studied the effect of new environment on the risk in and mortality of gynecological cancers in first- and second-generation immigrants in Sweden. We used the nationwide Swedish Family-Cancer Database to calculate standardized incidence/mortality ratios (SIRs/SMRs) of cervical, endometrial and ovarian cancers among immigrants in comparison to the native Swedes. Risk of cervical cancer increased among first-generation immigrants with Danish (SIR = 1.64), Norwegian (1.33), former Yugoslavian (1.21) and East European (1.35) origins, whereas this risk decreased among Finns (0.88) and Asians (SIRs varies from 0.11 in Iranians to 0.54 in East Asians). Risk of endometrial (SIRs varies from 0.28 in Africans to 0.86 in Finns) and ovarian (SIRs varies from 0.23 in Chileans to 0.82 in Finns) cancers decreased in first-generation immigrants. The overall gynecological cancer risk for the second-generation immigrants, independent of the birth region, was almost similar to that obtained for the first generations. The birth region-specific SMRs of gynecological cancers in first- and second-generation immigrants co-varied with the SIRs. Risk of gynecological cancers among the first-generation immigrants is similar to that in their original countries, except for cervical cancer among Africans and endometrial cancer among North Americans and East Europeans. Our findings show that risk and mortality of gynecological cancers observed in the first-generation immigrants remain in the second generation. We conclude that the risk and protective factors of gynecological cancers are preserved upon immigration and through generations, suggesting a role for behavioral factors or familial aggregation in the etiology of these diseases.     

Cancer risk in patients with earlier diagnosis of cutaneous melanoma in situ.

We calculated the short-term and long-term risks of developing cancer among 3,766 patients with a diagnosis of cutaneous melanoma in situ in Sweden from 1958 to 1992. In total, 393 patients developed a primary cancer at any site compared with an expected number of 177 [standardized incidence ratio (SIR) = 2.2, 95% confidence interval (CI) = 2.0-2.4]. Patients below 60 years of age at diagnosis had the highest SIR (2.7, 95% CI = 2.3-3.2). The overall risks were similar between men and women. The highest risk was seen during the first year of follow-up, though the risk remained elevated also after 15 or more years of follow-up. For specific sites, the highest SIR was found for developing invasive cutaneous malignant melanoma (SIR = 22.2). The risk of subsequent primary non-melanoma skin cancer was elevated 8-fold in men and almost 7-fold in women. An elevated risk was also found for female breast cancer (SIR = 1.4). Especially among women, other sites with increased cancer risk (though not significant) were non-Hodgkin's lymphoma (SIR = 1.9), multiple myeloma (3.2) and cancers of the colon (1.6) and pancreas (1.6). In conclusion, patients with melanoma in situ run a generally increased risk of developing primary cancers, especially cutaneous malignant melanoma and non-melanoma skin cancer. The increased long-term risk of cancer after diagnosis of melanoma in situ may be due to continuing carcinogenic exposure or to intrinsic tumor susceptibility.     

Exogenous estrogens and development of breast and endometrial cancer

The risk of breast cancer and endometrial cancer in 1483 menopausal and postmenopausal women who had received estrogen therapy for other than contraceptive use was examined. The incidence and mortality rates of the study cohort (cohort A) were compared with the age-specific cancer incidence and mortality rates of the female populations of Ontario (cohort B) and of Saskatchewan (cohort C). A significant difference was found in each of the two comparisons between the observed and expected survival curves for breast cancer incidence and breast cancer mortality. However, the incidence rate of endometrial cancer in the study cohort (cohort A) did not differ significantly from the rates of the reference populations (cohorts B and C). The results suggest that the women in the study may have received some protective effect against breast cancer by taking estrogens, but the estrogens did not protect them against endometrial cancer and may indeed have predisposed them to this cancer.     

Racial and age differences in multiple primary cancers after breast cancer: A population-based analysis

Summary The occurrence of multiple primary cancers was evaluated among 17,944 white and black female residents of Metropolitan Detroit diagnosed with breast cancer between 1973 and 1983. Invasive second primary cancers were diagnosed among 1106 of these women, almost twice the expected number. Subsequentin situ cancers were detected four times more often than expected. Fifty-six percent of the subsequent invasive cancers were of the breast (Standardized Incidence Ratio, SIR = 3.80). Black women experienced higher risk of subsequent breast cancers (SIR = 5.30) than white women (SIR = 3.62). Highest risk was seen among women first diagnosed before age 40 (SIR for black women = 26.15, SIR for white women = 10.87) and within five years of initial diagnosis. These findings suggest that young breast cancer patients, especially black women, are at high risk of developing a second primary breast cancer soon after their initial diagnosis and should be under continued medical surveillance. The occurrence of multiple primary breast cancers among young women suggests a genetic component to risk. Identification of this subpopulation would be useful in the study of molecular and genetic markers for cancer. Subsequent colon (SIR = 1.24) and cervical (SIR = 1.54) cancers also were diagnosed significantly more often than expected, as were ovarian cancers among white women (SIR = 1.45). These findings are consistent with common etiologic factors associated with these cancers.     

Lung cancer mortality risk among breast cancer patients treated with anti-estrogens

BACKGROUND:

The Women's Health Initiative randomized clinical trial reported that menopausal hormone therapy increases lung cancer mortality risk. If this is true, use of anti‐estrogens should be associated with decreased lung cancer mortality risk. The authors compared lung cancer incidence and mortality among breast cancer patients with and without anti‐estrogen therapy.

METHODS:

Our study included all 6655 women diagnosed with breast cancer between 1980 and 2003 and registered at the Geneva Cancer Registry. Among these women, 46% (3066) received anti‐estrogens. All women were followed for occurrence and death from lung cancer until December 2007. The authors compared incidence and mortality rates among patients with and without anti‐estrogens with those expected in the general population by Standardized Incidence Ratios (SIRs) and Standardized Mortality Ratios (SMRs).

RESULTS:

After a total of 57,257 person‐years, 40 women developed lung cancer. SIRs for lung cancer were not significantly decreased among breast cancer patients with and without anti‐estrogens (0.63, 95% confidence intervals [CI], 0.33‐1.10; and 1.12, 95% CI, 0.74‐1.62, respectively) while SMR was decreased among women with anti‐estrogens (0.13, 95% CI, 0.02‐0.47, P<.001) but not for women without anti‐estrogens (0.76, 95% CI, 0.43‐1.23).

CONCLUSIONS:

Compared with expected outcomes in the general population, breast cancer patients receiving anti‐estrogen treatment for breast cancer had lower lung cancer mortality. This study further supports the hypothesis that estrogen therapy modifies lung cancer prognosis. Cancer 2011. © 2011 American Cancer Society.     

High cardiovascular disease mortality after endometrial cancer diagnosis: Results from the Surveillance,Epidemiology, and End Results (SEER) Database

Obesity is a strong risk factor for developing endometrial cancer and cardiovascular disease (CVD); consequently, understanding CVD mortality among endometrial cancer survivors is important. We analyzed Surveillance, Epidemiology and End Results Program data for 157,496 endometrial cancer cases diagnosed between 1988 and 2012. We calculated standardized mortality ratios (SMRs) for CVD and all‐cause mortality comparing endometrial cancer cases and general population women. We categorized women into one of three prognostic groups (excellent, intermediate and poor) based on tumor characteristics. Cumulative incidence function curves were plotted to visualize absolute mortality risk in the presence of competing risks. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression for cause‐specific mortality. Deaths were as follows: endometrial cancer 40.6%, CVD 20.5%, other cancers 18.7% and other causes 20.3%. Women with endometrial cancer were more likely to die from CVD (age‐adjusted SMR = 8.8, 95% CI = 8.7–9.0) and all causes (age‐adjusted SMR = 15.9, 95% CI = 15.8–16.0) compared to general population women. In case‐only analyses, higher CVD mortality was associated with older age, Black ethnicity and lack of surgical treatment. Poor prognosis cancers (non‐endometrioid histology and late stage) were related to higher mortality from each cause, with the highest HRs observed for endometrial cancer‐specific mortality. Among women diagnosed with excellent prognosis tumors (endometrioid, well‐differentiated and early stage), absolute risk of CVD mortality surpassed endometrial cancer‐specific mortality 5 years after diagnosis. Women diagnosed with common forms of endometrial cancer have a high CVD burden. After diagnosis, cardiovascular health should be emphasized for these women to reduce mortality.     

Cancer risk in women prenatally exposed to diethylstilbestrol

Prenatal diethylstilbestrol (DES) exposure is associated with excess risks of clear cell adenocarcinoma (CCA), and breast cancer in older women. Whether overall cancer risk is also elevated is unclear. Total and site-specific cancer risks were evaluated in the DES Combined Cohort Follow-up Study using age- and calendar-year specific standardized incidence rate ratios (SIR), and age-adjusted incidence rate ratios (RR) comparing DES exposed and unexposed women. A total of 143 and 49 cancer cases occurred in 97,831 and 34,810 person-years among the exposed and unexposed, respectively. There was no overall excess risk among exposed women when compared with external rates (SIR 1.01; 95% confidence interval [CI] 0.86-1.2). The overall RR comparing exposed with unexposed women was 1.32 (95% CI 0.94-1.8). Breast cancer risk was elevated only among women over 40 years (RR 1.83; 95% CI 1.1-3.2). The CCA SIR among exposed women was nearly 40, and the estimated attack rate through age 39 was 1.6/1,000 women. CCA incidence decreased by over 80% after age 25 when compared with 20-24 years. Excluding CCA and breast cancer, the overall RR was 1.21 (95% CI 0.74-2.0). DES was not associated with excess risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA incidence remains elevated through the reproductive years. There was no consistent evidence of risk excesses for cancers other than CCA, and breast cancer in older women. Given that the population is still young, continued follow-up is necessary to assess the overall carcinogenic impact of prenatal DES exposure.     

Reduced risk of breast and endometrial cancer among women with hip fractures (Sweden)

To test the hypothesis that osteoporosis, which results partly from long-term estrogen deficiency, is associated with a lowered risk of breast and endometrial cancer, a population-based cohort study was performed in Sweden. Some 18,000 women were followed through record-linkages after a first hip fracture, on average for almost six years, to ascertain the incidence of breast and endometrial cancer. Expected numbers were derived from the general population. Overall, 253 cases of breast cancer were observedcf 300 expected (standardized incidence ratio [SIR]=0.84; 95 percent confidence interval [CI]=0.74–0.95). Forty-eight cases of endometrial cancer were foundcf 55 expected (SIR=0.87, CI=0.54–1.16). There was no clearcut pattern of breast cancer risk by age at diagnosis of hip fracture, follow-up time, or calendar period. Our results are consistent with thea priori hypothesis that long-term estrogen deficiency is associated with a reduced risk of developing breast cancer as well as endometrial cancer.     

Cancer risk among Danish women with cosmetic breast implants

The available epidemiologic evidence does not support a carcinogenic effect of silicone breast implants on breast or other cancers. Data on cancer risk other than breast cancer are limited and few studies have assessed cancer risk beyond 10-15 years after breast implantation. We extended follow-up of our earlier cohort study of Danish women with cosmetic breast implants by 7 years, yielding 30 years of follow-up for women with longest implant duration. The study population consisted of women who underwent cosmetic breast implant surgery at private clinics of plastic surgery (n = 1,653) or public hospitals (n = 1,110), and a control group of women who attended private clinics for other plastic surgery (n = 1,736), between 1973-95. Cancer incidence through 2002 was ascertained using the Danish Cancer Registry. Risk evaluation was based on computation of standardized incidence ratios (SIR) and Cox proportional hazards models, adjusting for age, calendar period and reproductive history. We observed 163 cancers among women with breast implants compared to 136.7 expected based on general population rates (SIR = 1.2; 95% confidence interval [CI] = 1.0-1.4), during a mean follow-up period of 14.4 years (range = 0-30 years). Women with breast implants experienced a reduced risk of breast cancer (SIR = 0.7; 95% CI = 0.5-1.0), and an increased risk of non-melanoma skin cancer (SIR = 2.1; 95% CI = 1.5-2.7). Stratification by age at implantation, calendar year at implantation and time since implantation showed no clear trends, however, the statistical precision was limited in these analyses. When excluding non-melanoma skin cancer, the SIR for cancer overall was 1.0 (95% CI = 0.8-1.2). With respect to other site-specific cancers, no significantly increased or decreased SIR were observed. Similar results were found when directly comparing women who had implants at private clinics with women who attended private clinics for other plastic surgery, with rate ratios for cancer overall, breast cancer and non-melanoma skin cancer of 1.1 (95% CI = 0.8-1.6), 0.7 (95% CI = 0.4-1.3) and 1.5 (95% CI = 0.8-2.7), respectively. In conclusion, our study lends further support to the accumulating evidence that silicone breast implants are not carcinogenic. Reasons for the consistently reported deficit of breast cancer among women with breast implants remain unclear, whereas increased exposure to sunlight may explain the excess occurrence of non-melanoma skin cancer. We found no indication of delayed diagnosis of breast cancer due to the presence of breast implants.     

Cancer risk after radiotherapy for breast cancer

Among women with breast cancer, we compared the relative and absolute rates of subsequent cancers in 1541 women treated with radiotherapy (RT) to 4570 women not so treated (NRT), using all registered in the Swiss Vaud Cancer Registry in the period between 1978 and 1998, and followed up to December 2002. Standardised incidence ratios (SIRs) and the corresponding 95% confidence intervals (CIs) were based on age- and calendar year-specific incidence rates in the Vaud general population. There were 11 lung cancers in RT (SIR = 1.40; 95% CI: 0.70-2.51) and 17 in NRT women (SIR = 0.76; 95% CI: 0.44-1.22), 72 contralateral breast cancers in RT (SIR = 1.85; 95% CI: 1.45-2.33) and 150 in NRT women (SIR = 1.38; 95% CI: 1.16-1.61), and 90 other neoplasms in RT (SIR = 1.37; 95% CI: 1.10-1.68) and 224 in NRT women (SIR = 1.05; 95% CI: 0.91-1.19). Overall, there were 173 second neoplasms in RT women (SIR = 1.54, 95% CI: 1.32-1.78) and 391 among NRT women (SIR = 1.13, 95% CI: 1.02-1.25). The estimates were significantly heterogeneous. After 15 years, 20% of RT cases vs 16% of NRT cases had developed a second neoplasm. The appreciable excess risk of subsequent neoplasms after RT for breast cancer must be weighed against the approximately 5% reduction of breast cancer mortality at 15 years after RT.     

Risk of second non-hematological malignancies among 376,825 breast cancer survivors

Breast cancer survivors are at increased risk of treatment-related second cancers. This study is the first to examine risk 30 or more years after diagnosis and to present absolute risks of second cancer which accounts for competing mortality. We identified 23,158 second non-hematological malignancies excluding breast in a population-based cohort of 376,825 one-year survivors of breast cancer diagnosed from 1943 to 2002 and reported to four Scandinavian cancer registries. We calculated standardized incidence ratios (SIR) and utilized a competing-risk model to calculate absolute risk of developing second cancers. The overall SIR for second cancers was 1.15 (95% confidence interval [CI] = 1.14–1.17). The SIR for potentially radiotherapy-associated cancers 30 or more years after breast cancer diagnosis was 2.19 (95% CI = 1.87–2.55). However, the largest SIRs were observed for women aged <40 years followed for 1–9 years. At 20 years after breast cancer diagnosis, the absolute risk of developing a second cancer ranged from 0.6 to 10.3%, depending on stage and age; the difference in the absolute risk compared to the background population was greatest for women aged <40 years with localized disease, 2.3%. At 30 years post breast cancer diagnosis, this difference reached 3.2%. These risks were small compared to the corresponding risk of dying from breast cancer. Although the absolute risks were small, we found persistent risks of second non-hematological malignancies excluding breast 30 or more years after breast cancer diagnosis, particularly for women diagnosed at young ages with localized disease.