Flora E. van Leeuwen

Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies

Paul Pharoah and colleagues evaluate the prognostic significance of immunohistochemical subtype classification in more than 10,000 breast cancer cases with early disease, and examine the influence of a patients survival time on the prediction of future survival.

Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease

PURPOSE To assess long-term cause-specific mortality of young Hodgkins disease (HD) patients. PATIENTS AND METHODS The study population consisted of 1,261 patients treated for HD before age 41 between 1965 and 1987. Follow-up was complete until October 2000. For 95% of deaths, the cause was known. Long-term cause-specific mortality was compared with general population rates to assess relative risk (RR) and absolute excess risk (AER) of death. RESULTS After a median follow-up of 17.8 years, 534 patients had died (55% of HD). The RR of death from all causes other than HD was 6.8 times that of the general population, and still amounted to 5.1 after more than 30 years. RRs of death resulting from solid tumors (STs) and cardiovascular disease (CVD) were increased overall (RR = 6.6 and 6.3, respectively), but especially in patients treated before age 21 (RR = 14.8 and 13.6, respectively). When these patients grew older, this elevated mortality decreased. The overall AER of death from causes other than HD increased throughout follow-up. Patients receiving salvage chemotherapy had a significantly increased RR of death from STs, compared to patients receiving initial therapy only. CONCLUSION The main cause of death among HD patients was lymphoma, but after 20 years, HD mortality was negligible. The RRs and AERs of death from second primary cancers (SCs) and CVDs continued to increase after 10 years. Even more than 30 years after diagnosis, HD patients experienced elevated risk of death from all causes other than HD. Increased risk of death from SCs and CVDs was found especially in patients treated before age 21, but these risks seemed to abate with age.

Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

BACKGROUND Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. METHODS We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53. FINDINGS Tamoxifen had been used by 108 (36.1%) of 299 cases and 245 (28.5%) controls (relative risk 1.5 [95% CI 1.1-2.0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p < 0.001), with relative risks of 2.0 (1.2-3.2) for 2-5 years and 6.9 (2.4-19.4) for at least 5 years compared with non-users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users (> or = 2 years) than in non-users (17.4% vs 5.4%, p=0.006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15.4% vs 2.9%, p < or = 0.02), p53-positive tumours (31.4% vs 18.2%, p=0.05), and negative oestrogen-receptor concentrations (60.8% vs 26.2%, p < or = 0.001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for > or = 5 years, 85% for 2-5 years vs 94% for non-users, p=0.02). INTERPRETATION Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.

Leukemia Following Hodgkin's Disease

To investigate the effect of different treatments for Hodgkins disease on the risk of leukemia, we used an international collaborative group of cancer registries and hospitals to perform a case-control study of 163 cases of leukemia following treatment for Hodgkins disease. For each case patient with leukemia, three matched controls were chosen who had been treated for Hodgkins disease but in whom leukemia did not develop. The use of chemotherapy alone to treat Hodgkins disease was associated with a relative risk of leukemia of 9.0 (95 percent confidence interval, 4.1 to 20) as compared with the use of radiotherapy alone. Patients treated with both had a relative risk of 7.7 (95 percent confidence interval, 3.9 to 15). After treatment with more than six cycles of combinations including procarbazine and mechlorethamine, the risk of leukemia was 14-fold higher than after radiotherapy alone. The use of radiotherapy in combination with chemotherapy did not increase the risk of leukemia above that produced by the use of chemotherapy alone, but there was a dose-related increase in the risk of leukemia in patients who received radiotherapy alone. The peak in the risk of leukemia came about five years after chemotherapy began, and a large excess persisted for at least eight years after it ended. After adjusting for drug regimen, we found that patients who had undergone splenectomy had at least double the risk of leukemia of patients who had not, and an advanced stage of Hodgkins disease carried a somewhat higher risk of leukemia than Stage I disease. We conclude that chemotherapy for Hodgkins disease greatly increases the risk of leukemia and that this increased risk appears to be dose-related and unaffected by concomitant radiotherapy. In addition, the risk is greater for patients with more advanced stages of Hodgkins disease and for those who undergo splenectomy.

Physical activity and breast cancer: a systematic review.

Background: Many epidemiologic studies have found an association between physical activity and breast cancer risk, although this has not been a consistent finding. Methods: Studies were identified through a systematic review of literature available on PubMed through February 2006. We included all cohort and case–control studies that assessed total or leisure time activities in relation to occurrence or mortality of breast cancer. The fully adjusted risk estimates and 95% confidence intervals for the highest versus lowest level of activity were documented for each study as well as evidence for a dose–response relationship. Methodologic quality was also assessed. Due to statistical and methodologic heterogeneity among studies, we did not carry out statistical pooling. To draw conclusions, we performed a best-evidence synthesis taking study quality into account. Results: Nineteen cohort studies and 29 case–control studies were evaluated. There was strong evidence for an inverse association between physical activity and postmenopausal breast cancer with risk reductions ranging from 20% to 80%. For premenopausal breast cancer, however, the evidence was much weaker. For pre- and postmenopausal breast cancer combined, physical activity was associated with a modest (15–20%) decreased risk. Evidence for a dose–response relationship was observed in approximately half of the higher-quality studies that reported a decreased risk. A trend analysis indicated a 6% (95% confidence interval = 3% to 8%) decrease in breast cancer risk for each additional hour of physical activity per week assuming that the level of activity would be sustained. Conclusions: There is evidence for an inverse association between physical activity and breast cancer risk. The evidence is stronger for postmenopausal breast cancer than for premenopausal breast cancer.

Long-Term Risk of Second Malignancy in Survivors of Hodgkin’s Disease Treated During Adolescence or Young Adulthood

PURPOSE To quantify the long-term risk of second primary cancers (SCs) in patients diagnosed with Hodgkins disease (HD) during adolescence or young adulthood. PATIENTS AND METHODS The risk of SCs was assessed in 1,253 patients diagnosed with HD before the age of 40 years and treated in two Dutch cancer centers between 1966 and 1986. The median follow-up duration was 14.1 years. RESULTS In all, 137 patients developed SCs, compared with 19.4 cases expected on the basis of incidence rates in the general population (relative risk [RR] = 7.0; 95% confidence interval, 5.9 to 8.3). The 25-year actuarial risk of SC overall was 27.7%. The RR of solid tumors increased greatly with younger age at the first treatment of HD, not only for breast cancer but also for all other solid tumors, with RRs of 4.9, 6.9, and 12.7 for patients first treated at ages 31 to 39 years, 21 to 30 years, and </= 20 years, respectively. Among patients first treated at the age of 20 years or younger, the RR of developing a solid tumor before the age of 40 years was significantly greater than the RR of solid tumor development at ages 40 to 49 years (RR = 27.9 v RR = 4.2; P =.0001). Patients who received salvage chemotherapy had significantly greater risk of solid cancers other than breast cancer than did patients whose treatment was restricted to initial radiotherapy or initial combined-modality treatment (RR = 9.4 and 4.7, respectively; P =. 004). CONCLUSION After more than 20 years of follow-up, the risk of solid tumors is still much greater in survivors of HD than in the population at large. Reassuringly, the greatly increased risk of solid tumors in patients who were young (</= 20 years of age) at the first treatment seems to decrease as these patients grow older. Our data suggest that chemotherapy may increase the risk of solid tumors from radiotherapy.

Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer

PURPOSE To compare radiotherapy and chemotherapy effects on long-term risks of second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) in testicular cancer (TC) survivors. PATIENTS AND METHODS In our nationwide cohort comprising 2,707 5-year TC survivors, incidences of SMNs and CVDs were compared with general-population rates by calculating standardized incidence ratios (SIRs) and absolute excess risks (AERs). Treatment effects on risks of SMN and CVD were quantified in multivariable Cox regression and competing risks analyses. RESULTS After a median follow-up time of 17.6 years, 270 TC survivors developed SMNs. The SIR of SMN overall was 1.7 (95% CI, 1.5 to 1.9), with an AER of 32.3 excess occurrences per 10,000 person-years. SMN risk was 2.6-fold (95% CI, 1.7- to 4.0-fold) increased after subdiaphragmatic radiotherapy and 2.1-fold (95% CI, 1.4- to 3.1-fold) increased after chemotherapy, compared with surgery only. Subdiaphragmatic radiotherapy increased the risk of a major late complication (SMN or CVD) 1.8-fold (95% CI, 1.3- to 2.4-fold), chemotherapy increased the risk of a major late complication 1.9-fold (95% CI, 1.4- to 2.5-fold), and smoking increased the risk of a major late complication 1.7-fold (95% CI, 1.4- to 2.1-fold), compared with surgery only. The median survival time was 1.4 years after SMN and 4.7 years after CVD. CONCLUSION Radiotherapy and chemotherapy increased the risk of developing SMN or CVD to a similar extent as smoking. Subdiaphragmatic radiotherapy strongly increases the risk of SMNs but not of CVD, whereas chemotherapy increases the risks of both SMNs and CVDs. Prolonged follow-up after chemotherapy is needed to reliably compare the late complications of radiotherapy and chemotherapy after 20 years.

Second Cancers Among Long-Term Survivors of Hodgkin’s Disease Diagnosed in Childhood and Adolescence

PURPOSE To quantify the risk of second cancers among long-term survivors of Hodgkins disease (HD) diagnosed before 21 years of age and to explore sex-, age-, and site-related differences. PATIENTS AND METHODS We analyzed data from 5,925 pediatric HD patients, including 2,646 10-year and 755 20-year survivors, who were reported to 16 population-based cancer registries in North America and Europe between 1935 and 1994. RESULTS A total of 157 solid tumors (observed/expected ratio [O/E] = 7.0; 95% confidence interval [CI], 5.9 to 8.2.) and 26 acute leukemias (O/E = 27.4; 95% CI, 17.9 to 40. 2) were reported. Risk of solid tumors remained significantly increased among 20-year survivors (O/E = 6.6, observed [O] = 40, cumulative risk = 6.5%) and persisted for 25 years (O/E = 4.6, O = 15, cumulative risk = 11.7%). Temporal trends for cancers of thyroid, female breast, bone/connective tissue, stomach, and esophagus were consistent with the late effects of radiotherapy. Greater than 50-fold increased risks were observed for tumors of the thyroid and respiratory tract (one lung and one pleura) among children treated before age 10. At older ages (10 to 16 years), the largest number of second cancers occurred in the digestive tract (O/E = 19.3) and breast (O/E = 22.9). Risk of solid tumors increased with decreasing age at HD on a relative but not absolute scale. CONCLUSION Children and adolescents treated for HD experience significantly increased risks of second cancers at various sites for 2 to 3 decades. Although our results reflect the late effects of past therapeutic modalities, they underscore the importance of lifelong follow-up of pediatric HD patients given early, more aggressive treatments.

Long-Term Risk of Cardiovascular Disease in 5-Year Survivors of Testicular Cancer

PURPOSE To evaluate the long-term risk of cardiovascular disease (CVD) in survivors of testicular cancer (TC). PATIENTS AND METHODS We compared CVD incidence in 2,512 5-year survivors of TC, who were treated between 1965 and 1995, with general population rates. Treatment effects on CVD risk were quantified in multivariate Cox regression analysis. RESULTS After a median follow-up of 18.4 years, 694 cardiovascular events occurred, including 141 acute myocardial infarctions (MIs). The standardized incidence ratio (SIR) for coronary heart disease was 1.17 (95% CI, 1.04 to 1.31), with 14 excess cases per 10,000 person-years. The SIR for MI was significantly increased in nonseminoma survivors with attained ages of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors with attained ages of 55 years or older (SIR = 0.53). In Cox analysis, mediastinal irradiation was associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased MI risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk, and bleomycin, etoposide, and cisplatin (BEP) CT was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1). Recent smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk. CONCLUSION Nonseminomatous TC survivors experience a moderately increased MI risk at young ages. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is especially important in TC survivors. Whether BEP treatment increases CVD risk should be evaluated after more prolonged follow-up.

Hypospadias in sons of women exposed to diethylstilbestrol in utero : a cohort study

BACKGROUND Transgenerational effects of diethylstilbestrol (DES) have been reported in animals, but effects in human beings are unknown. Alerted by two case reports, we aimed to establish the risk of hypospadias in the sons of women who were exposed to DES in utero. METHODS We did a cohort study of all sons of a Dutch cohort of 16284 women with a diagnosis of fertility problems. We used a mailed questionnaire assessing late effects of fertility treatment to identify boys with hypospadias. We compared the prevalence rate of hypospadias between boys with and without maternal DES exposure in utero. FINDINGS 16284 mothers (response rate 67%) reported 8934 sons. The mothers of 205 boys reported DES exposure in utero. Four of these children were reported to have hypospadias. In the remaining 8729 children, only eight cases of hypospadias were reported (prevalence ratio 21.3 [95% CI 6.5-70.1]). All cases of hypospadias were medically confirmed. Maternal age or fertility treatment did not affect the risk of hypospadias. Children conceived after assisted reproductive techniques such as in-vitro fertilisation were not at increased risk of hypospadias compared with children conceived naturally (1.8, 0.6-5.7). INTERPRETATION Our findings suggest an increased risk of hypospadias in the sons of women exposed to DES in utero. Although the absolute risk of this anomaly is small, this transgenerational effect of DES warrants additional studies.