Kjell Bergfeldt

Risk of Leukemia after Platinum-Based Chemotherapy for Ovarian Cancer

BACKGROUND Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment. METHODS We conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups. RESULTS Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia. CONCLUSIONS Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.

Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival

Use of hormone replacement therapy (HRT) has been hypothesized to affect survival of epithelial ovarian cancer (EOC). We studied 5‐year survival in patients with invasive EOC and borderline ovarian tumors (BOT) according to HRT use before and after diagnosis in a prospective nation‐wide cohort study of 799 women diagnosed with EOC (n = 649) and BOT (n = 150) aged 50–74 years in 1993–1995 in Sweden. Cox regression was used to obtain multivariate age‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate models included indicator variables for age, tumor stage, grade and histological subtype. After 5 years of follow‐up, 45% of the patients with EOC and 93% of the patients with BOT were alive. For women with BOT there were no associations between HRT‐use pre‐ or postdiagnosis and survival. There was no overall difference in 5‐year EOC survival according to use HRT before diagnosis (multivariate HR = 0.83, 95% CI = 0.65–1.08), except for serous EOC (HR = 0.69, 95% CI = 0.48–0.98). Analyses of different HRT preparations, duration and recency of use did not reveal any variations in pattern of survival. We observed a better survival for EOC‐patients who used HRT after diagnosis (multivariate HR = 0.57, 95% CI = 0.42–0.78). We conclude that HRT‐use prior to diagnosis of EOC does not affect 5‐year survival, except for a possible survival advantage in serous EOC. Women using HRT after diagnosis had a better survival than women with no use, but we cannot rule out that this latter finding may reflect a subtle selection process.

Risk of ovarian cancer in breast-cancer patients with a family history of breast or ovarian cancer: a population-based cohort study.

BACKGROUND Patients with breast cancer who have mutations in the high penetrance genes BRCA1 and BRCA2, have an increased risk of ovarian cancer. Because these mutations are rare, easily obtained information such as age and family history of breast or ovarian cancer might be preferable for assessment of ovarian cancer risk in clinical practice. METHODS We linked data from the Swedish Cancer Register to the Swedish Generation Register and generated a cohort of 30552 breast-cancer patients born after 1931, with information on breast and ovarian cancer diagnosis from 146117 first-degree relatives. Standardised incidence ratios (SIRs) with 95% CIs were calculated with nationwide rates of ovarian cancer, adjusted for age and calendar year. FINDINGS During a mean follow-up of 6 years, 122 incident ovarian cancers were identified in the cohort, yielding an overall SIR of 2.0 (95% CI 1.6-2.4). The risk was higher in breast-cancer patients diagnosed before the age of 40 years, with a family history of breast cancer (5.6; 1.8-13.1) or ovarian cancer (17.0; 3.5-50.0). A consistently increased risk was noted in patients with a relative who was diagnosed before the age of 50 years, with either breast or ovarian cancer. Women with a family history of ovarian cancer have an almost 10% risk of developing ovarian cancer before the age of 70. INTERPRETATION In young women with breast cancer, the risk of ovarian cancer is greatly raised when a family history of breast or ovarian cancer is present. Close medical surveillance, and perhaps even prophylactic oophorectomy, might be justified in high-risk groups.

Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden

OBJECTIVE To study the association between hormonal infertility treatment and ovarian neoplasia. DESIGN Historical cohort study. SETTING Three university hospitals in Sweden. PATIENT(S) A total of 2,768 women assessed and treated for infertility and infertility-associated disorders between 1961 and 1975. INTERVENTION(S) Exposed women received clomiphene citrate and/or gonadotropins. MAIN OUTCOME MEASURE(S) Incidence of ovarian neoplasia. RESULT(S) No overall excess risk of invasive ovarian cancer emerged compared with the general population. In women with gonadotropin treatment for non-ovulatory disorders, the risk was elevated (standardized incidence ratio [SIR] = 5.89; 95% confidence interval [CI] 1.91-13.75); four of the five cases reported hCG treatment only, rendering the biological plausibility uncertain. Multivariate analysis within the cohort indicated that treatment with gonadotropins only was associated with an increased risk of invasive cancer (relative risk = 5.28; 95% CI 1.70-16.47). For borderline tumors, a more than threefold overall increase of tumors (SIR = 3.61; 95% CI 1.45-7.44) was noted; women exposed to clomiphene because of ovulatory disorders showed the highest risk (SIR = 7.47; 95% CI 1.54-21.83). CONCLUSION(S) Our findings of increased risk of ovarian cancer after gonadotropins and of borderline tumors after clomiphene treatment need to be interpreted with caution. However, concern is raised, and further research on the long-term safety particularly of modern hormonal infertility treatment in IVF programs is warranted.

Increased Risk of Second Primary Malignancies in Patients with Gynecological Cancer: A Swedish record-linkage study

The Stockholm-Gotland Cancer Register was used to study the risk of developing second primary malignancies (SPM) in women diagnosed with cancer of the uterine cervix, uterine corpus and ovaries during the period 1958-1992. Among 5,325 patients with uterine cervix cancer, 619 developed SPM. Standardized incidence ratio (SIR) was 1.29 (95% confidence interval (CI) 1.19-1.39). Significantly increased risks were observed for cancer of the colon, rectum, lung, vulva, kidney and bladder. A total of 4,815 women with uterine corpus cancer were followed and 660 SPM were found. The overall SIR was 1.21 (95% CI 1.12-1.30) with significantly increased risk for cancer of the colon, ovary, vulva and bladder. The incidence of leukemia was also significantly elevated (SIR = 3.03; 95% CI 1.70-5.00). Among 5,060 patients with ovarian cancer, 379 SPM were found (SIR 1.49; 95% CI 1.34-1.64). Increased risks of cancer of the colon, rectum, breast, uterine corpus, bladder and leukemia were observed. All three primary sites showed elevated risks of cancer of the colon and bladder. For patients with a primary cancer of the corpus and ovary an elevated risk of leukemia was also noted. The conclusion from these findings is that SPM to some extent can be explained by previously known factors, i.e. treatment and common risk factors. However, further studies concerning the role of common etiology, for instance hereditary and hormonal factors, are needed to increase the knowledge on the etiology of second primary malignancies.

Correlation between HLA-A2 gene frequency, latitude, ovarian and prostate cancer mortality rates

Molecular-target therapies are novel approaches to the treatment of prostate and ovarian cancer, but to ensure the best response, a very careful selection of patients, based on immunological characteristics, must be performed. We screened for HLA type, 24 patients with advanced ovarian cancer and 26 patients with hormone-refractory prostate cancer, in order to be recruited to vaccine protocols. HLA typing was performed with PCR in ovarian cancer patients and with serological assay in prostate cancer patients. The results were then extended to a population level, comparing the HLA genotype frequencies in Europe with ovarian and prostate cancer mortality rates. An overrepresentation of HLA-A2 phenotype was observed in both patient groups compared to the normal Swedish population (p=0.01). As it is already known, the higher phenotype frequency of this allele found in Scandinavian countries decreases significantly as one moves further south in Europe. Ovarian and prostate cancer mortality rates decrease as well as the demographic changes in HLA-A2. These observations have to be confirmed by more extended investigations in order to elucidate if HLA-A2 higher frequency is already present at the diagnosis (risk factor) or is selected during the course of the disease (prognostic factor). Moreover, this fact would suggest different strategies for specific immunotherapy in addition to first line conventional treatments.

Correlation of HLA-A02* genotype and HLA class I antigen down-regulation with the prognosis of epithelial ovarian cancer

BackgroundIn recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue.Materials and methodsOne hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and β2-microglobulin (β2-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan–Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression.ResultsImmunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and β2-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation.ConclusionsHLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down-regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III–IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products.

Overestimated risk of second primary malignancies in ovarian cancer patients

Registry-based cohort studies have established an increased risk of developing second primary malignancies (SPM) in patients with a primary ovarian cancer. In order to examine the accuracy of cancer registration with emphasis on registration of SPM, 344 women with ovarian cancer and 379 subsequent SPM, registered between 1958 and 1992 in the Stockholm-Gotland Cancer Registry (SGCR), a division of the Swedish Cancer Registry (SCR), were investigated. Complete records including pathology reports were examined and an additional histopathological evaluation was conducted for a sample of the group. The results revealed that 28 diagnoses of SPM were incorrectly registered (14 cases were misdiagnosed SPM of the gastrointestinal tract, mainly colon and rectum) and 34 women (with 38 SPM) were incorrectly registered with ovarian cancer. Recalculations of the risk of a subsequent cancer were performed on the basis of these findings and the results suggest an overestimation of the risk of developing SPM. Inferences of these findings to other primary sites of multiple malignancies should be made with caution and further studies are needed.

Breast cancer risk in women with a primary ovarian cancer—a case–control study

Register-based studies show that women with ovarian cancer are at increased risk of developing breast cancer. Primary suggested explanations are heredity factors and a common hormonal aetiology. However, clinical surveillance that is provided for cancer patients during, and after, treatment of their primary malignancies together with possible mistakes in the registering procedures could affect the risk estimates. In order to examine these factors in women registered with ovarian cancer who develop subsequent breast cancer, a case-control study was performed. Using a regional Swedish cancer registry including 5060 women registered with ovarian cancer, 89 cases of breast cancer were found. After corrections for discrepancies in the registered and recorded information, 75 cases remained, of which 72 cases were included in the study. Information concerning possible risk factors were extracted from hospital records and compared with 177 matched controls. Suggested risk factors such as parity (relative risk (RR)=1.41), late age at menopause (52-61 years; RR=1.61) and heredity for breast and/or ovarian cancer (RR=1.50) were all connected with a non-significant increased risk of subsequent breast cancer. In all, 43% of the breast cancer cases were revealed without preceding symptoms at clinical follow-up, indicating that increased clinical surveillance is a factor of importance when explaining the increased risk. The fact that only 75 (missing records included) out of the 89 registered breast cancer cases could be linked to the preceding ovarian cancer indicates that the actual risk of developing breast cancer is smaller than previously described. The clinical implications from these findings could be that, beside general screening programmes and health controls offered to women in cancer-prone families, additional mammography examinations based on the assumption of an increased risk of breast cancer are not warranted in ovarian cancer patients.

Survival rates in HLA-A2 positive patients, with stage III-IV serous adenocarcinomas of the ovary, correlates with increased expression of COX-2 and iNOS, loss of MHC Class I and II and defects of the antigen processing mechanisms at the tumour level

16544 Background: We have shown that the high prevalence of HLA-A2 in Scandinavia is associated to poor prognosis in advanced (stage III-IV) serous adenocarcinoma of the ovary. Our objective was to analyse whether there exists a relationship between the expression of HLA molecules and components of the antigen processing pathway as well as the presence of high COX-2 activity and the patients´ survival. Methods: To test our hypothesis, 40 Swedish women with epithelial ovarian cancer were selected from an unbiased database of ovarian cancer patients at our department. Their HLA haplotypes were defined by the PCR/sequence-specific oligonucleotide hybridization method (PCR/SSOP) Tissue slides from paraffin embedded tumour material were stained with antibodies recognising COX-2, iNOS, MHC-class I/II heavy chain (HC) and molecules of the antigen processing machinery (APM). The probability of survival was defined by Kaplan-Meier analysis. Results: HLA-A2 positive patients, in stage III-IV were distinguished with...