NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts.

Human epididymal secretory protein E4 (HE4, also known as WAP four-disulphide core domain protein 2) is a new promising biomarker for ovarian cancer but its specificity against ovarian endometriotic cysts is only superficially known. We, thus, analysed serum HE4 concentrations together with a tumour marker CA125 in serum samples of women diagnosed with various types of endometriosis, endometrial cancer or ovarian cancer, and in samples from healthy controls. The mean serum concentration of HE4 was significantly higher in serum samples of patients with both endometrial (99.2 pM, P<0.001) and ovarian (1125.4 pM, P<0.001) cancer but not with ovarian endometriomas (46.0 pM) or other types of endometriosis (45.5 pM) as compared with healthy controls (40.5 pM). The serum CA125 concentrations were elevated in patients with ovarian cancer, advanced endometriosis with peritoneal or deep lesions, or ovarian endometriomas, but not in the patients with endometrial cancer. The microarray results revealed that the mRNA expression of the genes encoding HE4 and CA125 reflected the serum protein concentrations. Taken together, measuring both HE4 and CA125 serum concentrations increases the accuracy of ovarian cancer diagnosis and provides valuable information to discriminate ovarian tumours from ovarian endometriotic cysts.

Radiation therapy and biological compounds for consolidation therapy in advanced ovarian cancer.

Consolidation therapy is used in order to maximize the benefit of first-line therapy and to improve the progression-free and overall survival of patients. In women with advanced epithelial ovarian cancer, tested maintenance and consolidation strategies following first-line chemotherapy include high-dose chemotherapy, radiation therapy, intraperitoneal radionuclides including those linked to an antibody, and biological and immunologic agents. This review focuses on the current understanding of the benefit of radiation therapy and biological agents used as consolidation in women with advanced ovarian cancer. Whole abdominal radiation has given promising results only in the subgroup of patients with pathologic complete response. However, this treatment modality is associated with considerable intestinal toxicity. Single treatment with intraperitoneal radionuclides, either alone (32P) or in combination with an antibody (90Y-muHMFG1) has not improved survival. Biological agents used for consolidation include, eg, alpha- and gamma-interferon, tanomastat, a matrix metalloprotease inhibitor and oregovomab, a murine antibody that targets CA125. Randomized trials with these agents have not demonstrated any significant improvement in the overall survival of ovarian cancer patients. Currently, two ongoing studies (GOG 218, ICON7) are examining the potential of bevacizumab in the maintenance therapy of advanced epithelial ovarian cancer. Evaluation of new agents is indicated in order to achieve long-term disease-free survival in these patients. Toxicity and ease of administration must be reflected against the benefits of therapy.

Clinical Value of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Response Evaluation after Primary Treatment of Advanced Epithelial Ovarian Cancer.

AIMS: To prospectively evaluate the use of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the definition of the treatment response after primary treatment of advanced epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Forty-nine patients with advanced EOC had an 18F-FDG PET/CT scan before and after primary treatment. The treatment response was defined with the currently used radiological and serological Response Criteria in Solid Tumors (RECIST1.1/GCIC) criteria and the modified PET Response Criteria in Solid Tumors (PERCIST). The concordance of the two methods was analysed. If the patient had a complete response to primary treatment by conventional criteria, the end of treatment 18F-FDG PET/CT scan (etPET/CT) was not opened until retrospectively at the time of disease progression. The ability of etPET/CT to predict the time to disease recurrence was analysed. The recurrence patterns were observed with an 18F-FDG PET/CT at the first relapse. RESULTS: The agreement of the RECIST1.1/GCIC and modified PERCIST criteria in defining the primary treatment response in the whole patient cohort was good (weighted kappa coefficient = 0.78). Of the complete responders (n = 28), 34% had metabolically active lesions present in the etPET/CT, most typically in the lymph nodes. The same anatomical sites tended to activate at disease relapse, but were seldom the only site of relapse. In patients with widespread intra-abdominal carsinosis at diagnosis, the definition of metabolic response was challenging due to problems in distinguishing the physiological FDG accumulation in the bowel loops from the residual tumour in the same area. The presence of metabolically active lesions in the etPET/CT did not predict earlier disease relapse in the complete responders. CONCLUSIONS: In the present study, etPET/CT revealed metabolically active lesions in complete responders after EOC primary therapy, but they were insignificant for the patient's prognosis. The current study does not favour routine use of 18F-FDG PET/CT after EOC primary treatment for complete responders.

Common polymorphisms in checkpoint kinase 2 are not associated with breast cancer risk.

A substantial proportion of the familial risk of breast cancer may be attributable to genetic variants each contributing a small effect. Polymorphisms in DNA repair genes are good candidates for such low penetrance breast cancer susceptibility alleles. Checkpoint kinase 2 (CHEK2) is a kinase in which the yeast counterpart regulates a cell cycle checkpoint and causes cells to arrest proliferation after DNA damage. A rare, protein truncating mutation in the CHEK2 gene has recently been shown to confer a modest risk of breast cancer. The aim of this study was to determine whether common polymorphic variants in CHEK2 are associated with an increase in breast cancer risk. We assessed two variants in CHEK2 using a case control study design (n = 1786 cases and 1828 controls). No differences in genotype frequencies were found between cases and control for either the IVS1 + 38insa or the a1013g polymorphisms (P = 0.3 and 0.2 respectively), and no genotype-specific risk was significantly different from unity. The haplotype frequency distribution in cases and controls were also similar (P = 0.3). We conclude that the CHEK2 polymorphisms IVS + 1a and a1013g do not confer an increased risk of breast cancer. It is also unlikely that other, as yet unidentified, common polymorphisms that affect risk are present in the gene in the British population.

BRCA1 and BRCA2 mutations among Finnish ovarian carcinoma families.

Germ-line mutations in BRCA1 and BRCA2 predispose to hereditary breast-ovarian cancer syndrome. In Finland, 21 different BRCA1/2 mutations have been identified and 14 of the mutations are founders that account for the great majority of all BRCA1/2 mutations. Our aim was to determine the prevalence of the 21 BRCA1/2 mutations in Finnish ovarian carcinoma families. Mutations were screened in 23 families with at least two cases of invasive epithelial ovarian carcinoma in the first-degree relatives. The families had been identified from a population-based series of 559 Finnish epithelial ovarian carcinoma patients. Fourteen of the families were site-specific ovarian carcinoma families, while breast cancer was present in nine families. Mutations were detected in five families: two had a mutation in BRCA1 and three in BRCA2. In one family, a novel, apparently disease-causing missense mutation in the BRCA2 gene had been identified previously. Thus, 26% of the Finnish ovarian carcinoma families were found to be BRCA1/2 mutation-positive. Strong ovarian cancer family history and early-onset breast cancer were strongly associated with BRCA1/2 mutation status; all families with three ovarian carcinoma cases or early-onset breast cancer (<50 years) were mutation-positive, whereas all families with later-onset breast cancer as well as the majority (9/11) of the site-specific ovarian carcinoma families with minor ovarian cancer history (i.e. two affected cases) remained mutation-negative.

Prognostic factors of ovarian granulosa cell tumor: a study of 35 patients and review of the literature.

Ovarian granulosa cell tumors (GCT) are rare tumors with a tendency of late relapse and good prognosis. FIGO stage, tumor size, degree of cellular atypia, and mitotic index have been reported to predict recurrence. The objective of this study is to evaluate treatment practice and prognostic factors of GCT. For this purpose, a detailed review of patient files and histopathologic evaluation of tumor samples, including estimation of growth pattern, presence of Call-Exner bodies, nuclear atypia, mitotic index, and immunohistochemical staining for inhibin and Ki-67 were analyzed. Thirty-five patients had histologically confirmed GCT. Four patients had a simultaneous endometrial adenocarcinoma. Median follow-up time was 135 months (range 19-334 months). Recurrent disease was detected in seven patients. Time from diagnosis to the first recurrence varied from 24 to 141 months. There was no difference in tumor size, nuclear atypia, mitotic index, presence of Call-Exner bodies, or Ki-67 staining between nonrecurred and recurred patients. The only factor associated with risk of recurrence was rupture of the tumor (P < 0.0001), and the only factor associated with overall survival was FIGO stage (P = 0.032). The disease-free and overall survivals were not statistically different between patients treated (N = 18) or not treated (N = 17) with adjuvant therapy. One patient has experienced seven recurrences, has been treated with surgery, radiation therapy, chemotherapy, and hormonal therapy, and is still alive 26 years from diagnosis. FIGO stage and tumor rupture were the only factors associated with the outcome of GCT. Treatment of relapse, even in case of multiple recurrences, is usually worthwhile.

Hormonal treatments and epithelial ovarian cancer risk.

Exogenous sex hormones are widely used by women either for pregnancy prevention, as part of infertility treatment, or for treatment of menopausal symptoms. The role of these hormones in the development of ovarian cancer has been vastly explored. The protective effect of combined oral contraceptive pill is confirmed in multiple studies, but it is not clear whether this protection also covers women with a genetic predisposition to ovarian cancer. There is no conclusive evidence of infertility treatments increasing ovarian cancer risk, but infertility as such is a risk factor. Currently available data suggest that long-term users of hormone replacement therapy may have a slightly increased risk for ovarian cancer compared to women who have never used estrogen. The risk might particularly involve the endometrioid type of ovarian cancer. Most data on ovarian cancer and estrogen comes from epidemiological studies, since the normally high concentrations of estrogens in ovarian tissue and follicular fluid make direct biologic studies on the effects of exogenous estrogens on the ovarian cell difficult. This review discusses the risk of ovarian cancer associated with the use of sex steroid hormones, with special emphasis on the possible risk associated with estrogens.

Segregation analysis of epithelial ovarian cancer in Finland.

Epithelial ovarian cancer is known to aggregate in families. The dominantly inherited ovarian cancer predisposing genes, BRCA1, BRCA2 and genes involved in the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, have recently been identified. However, in the majority of families with more than one case of ovarian cancer, dominant inheritance cannot be recognized. We investigated familial clustering of epithelial ovarian cancer in a population-based sample of 663 Finnish ovarian cancer patients. A segregation analysis with the POINTER software was conducted on the 937 nuclear families from these 663 pedigrees. The major gene model was favoured, and the sporadic and multifactorial models were strongly rejected. In the studied population, the best fitting model was a recessive mode of inheritance, and 8% of ovarian cancer patients were estimated to be homozygous for the deleterious genotype. This evidence for recessively inherited ovarian cancer predisposition should be interpreted cautiously, as the analysis is subject to certain errors, which are discussed in the article. Results of this analysis, however, strongly emphasize the role of genetic factors in all familial aggregation of epithelial ovarian cancer.

The rate of drug biotransformation reactions and cellular viability in the livers of patients with biliary diseases.

The cytochrome P-450 level, the rate of o-amino-phenylglucuronide synthesis and the oxygen consumption of liver slices from female patients with various gall bladder disease were determined. The cytochrome P-450 level showed a decreasing trend in patients with chronic cholecystitis, choledocholithiasis or obstructive icterus when compared with those with uncomplicated gall bladder stones. The rate of o-aminophenylglucuronide synthesis was markedly increased in patients with obstructive icterus when compared with other groups. The oxygen consumption was also enhanced in this group. The enhanced rate of glucuronidation is suggested to be caused by endogenous induction of increased bilirubin level or by accumulation of bile acids in the liver cells. The present study proposes that the drug hydroxylation and glucuronidation activities are under separate control mechanisms.

Immunohistochemically detected p53 and HER-2/neu expression and nuclear DNA content in familial epithelial ovarian carcinomas.

BACKGROUND: Some epithelial ovarian carcinomas tend to occur more frequently in certain families. This clustering may be due to a genetic predisposition, but the role of inherited susceptibility in all families with multiple cases of ovarian carcinoma is currently unresolved. Studies characterizing familial ovarian carcinomas are few. METHODS: From a population-based study of 559 patients with epithelial ovarian carcinoma, 27 families with 2 or more ovarian carcinoma cases occurring in first-degree relatives were identified. Histopathology, ploidy, and immunohistochemically detected p53 and HER-2/neu expression in these tumors were examined. RESULTS: The mean age of the patients with familial ovarian carcinoma was 56.7 years. Approximately 67% of the tumors were either serous or undifferentiated adenocarcinomas. The percentage of aneuploid tumors was 46%, that of p53 positive tumors was 51%, and that of HER-2/neu positive tumors was 69%. When the families were divided into families with cases of breast carcinoma in addition to ovarian carcinoma cases and/or ovarian carcinoma in 2 consecutive generations (12 families) and families with ovarian carcinoma occurring in sisters only without cases of breast carcinoma (15 families), no differences were noted in the frequency of any of the studied variables. CONCLUSIONS: Familial ovarian carcinomas do not appear to differ from sporadic ovarian carcinomas with regard to patient age at presentation, histopathology, ploidy, and immunohistochemically detected p53 expression. Immunohistochemically detected HER-2/neu expression was found to occur more frequently in familial ovarian carcinomas than has been reported in sporadic ovarian carcinomas.

Borderline ovarian tumors in Finland: epidemiology and familial occurrence.

A total of 1,197 borderline ovarian tumors were reported to the Finish Cancer Registry in 1973-1992. The mean age of the patients was 52 years, while the mean age of the 7,060 patients with an invasive epithelial ovarian carcinoma reported in the same time period was 62 years. The incidence of borderline ovarian tumors did not increase with age after patients became 35 years old and older. The overall age-adjusted incidence of borderline ovarian tumors was 1.8 per 100,000 women-years. Familial cancer occurrence during 1967-1992 was studied among relatives of 144 index patients diagnosed in 1980-1982. No borderline ovarian tumors were detected in the relatives, and only one of the 446 female first-degree relatives had an epithelial ovarian cancer. The expected number (borderline and invasive combined) was 1.9. The mothers of the index patients had an increased risk for pancreatic cancer (standardized incidence ratio 4.9, 95% confidence interval 1.0-14.3) and for cancer of the uterine cervix (standardized incidence ratio 7.8, 95% confidence interval 1.6-22.8). No significant increase in cancer risk was observed for fathers, brothers, or sisters of the patients with borderline ovarian tumors.

Cancer incidence in the first-degree relatives of ovarian cancer patients.

Cancer incidence was studied among 3072 first-degree relatives of 559 unselected ovarian cancer patients. Among cohort members there were 306 cancer cases. The overall cancer incidence was not increased: the standardised incidence ratio (SIR) in males was 0.9 (95% confidence interval 0.8-1.1) and in females 1.0 (0.8-1.1). The female relatives had a significantly increased risk for ovarian cancer (SIR 2.8, 1.8-4.2). The excess was attributable to sisters only (SIR 3.7, 2.3-5.7). The relative risk for ovarian cancer among sisters decreased both by increasing age of the sister and by increasing age at diagnosis of the index patient: the SIRs were 7.3 (1.5-21.4), 4.5 (1.6-9.8) and 3.1 (1.7-5.4) for sisters of index patients diagnosed in age < 45, 45-54 and 55-75 years respectively. The age dependency of the risk supports the role of genetic factors in familial ovarian cancer. Although the risk of ovarian cancer among sisters from families with breast cancer (SIR 9.2, 3.7-19.0) was significantly higher than among sisters from families with no breast cancer patients (SIR 2.9, 1.6-4.8, rate ratio 3.1, P < 0.05), the excess was not solely attributable to coaggregation of breast and ovarian cancer. Among the 27 families with two or more ovarian cancers, only sisters were affected in 24 families, which might implicate recessive inheritance or shared environmental factors influencing ovarian cancer risk in sisters.

PROGNOSTICATION OF BREAST CANCER BY MULTIVARIATE METHODS.

Three multivariate prognostic models based on Cox's regression were tested in terms of how they predicted prognosis in a material of 134 patients with breast cancer. The multivariate models all incorporated tumor size, mitotic activity index (MAI), and axillary lymph node status in their formulas, and were originally produced through studies on different patient materials. The predictive behavior of MAI was also tested separately in the same material. The multivariate models gave roughly parallel predicted percentages of survival at two years (CV=5.2%), but showed clearly greater variation later (12.3% and 24.4% at 5 and 9 years, respectively). The results were more uniform between the multivariate models, than between the prediction by MAI and the multivariate models. The variation between repeated estimates was smaller within multivariate models than within the estimation of one of their components (MAI). We found the use of the multivariate models easy. However, traditional hospital practice does not necessarily favor the use of multivariate models, although they seem to group patients more reliably than single prognostic features.

Subrenal capsule assay in human breast cancer. Response to cytostatic drug combinations and correlation with receptor status.

The subrenal capsule assay (SRCA) was used to study the sensitivity of breast cancer to cytostatic drug combinations. The results were compared with steroid receptor status. Forty-five of 46 SRCAs (98%) were macroscopically evaluable. However, a histological study implied that the transplants should also be evaluated histologically, because in only 14/21 (67%) of the control SRCAs examined were histologically viable tumor cells seen. An inflammatory cell reaction was noticed in half of the cases. In the groups treated with cytostatics only 3/21 (14%) had vital tumor cells, whereas inflammation was evident in 4/21 (19%) of the cases. The rate of resistance to A + CTX was 30%. By testing several drug combinations against each tumor the rate of chemoresistance was reduced to 10%. The differences between A + CTX and the best combination were statistically significant (P less than 0.05). Of the tumors 79% were ER-positive and 67% PR-positive. Receptor-negative tumors tended to be more sensitive to cytostatics than receptor-positive tumors (100 vs 85%). The difference was not, however, statistically significant. It can be concluded that the SRCA under standardized conditions is a good method for studying the response of individual breast cancers to chemotherapy.

A missense mutation in the BRCA2 gene in three siblings with ovarian cancer.

Inherited susceptibility to ovarian cancer has been associated with germline defects at several loci. The major known ovarian cancer susceptibility gene is BRCA1 on chromosome 17q, which confers a risk of approximately 60% by the age of 70 years. Truncating mutations in BRCA2 on chromosome 13q also predispose to ovarian cancer, although they confer a lower risk than mutations in BRCA1. We have studied the molecular basis of ovarian cancer predisposition in a Finnish family with three affected sisters. Analysis of polymorphic markers provided evidence against linkage to BRCA1, but the sibship was consistent with linkage to BRCA2. Conformation-sensitive gel electrophoresis was used to screen the entire coding sequence of BRCA2. A G to A transition at nucleotide 8702 was observed, which is predicted to convert glycine 2901 to aspartate in the encoded protein. This sequence variant was not detected in 220 cancer-free Finnish control individuals, or in several hundred cancer families of many nationalities previously screened for BRCA2 mutations. Taken together with the fact that this amino acid residue and the surrounding region of BRCA2 is identical in mouse and chicken, the data suggest that this alteration is a disease-causing BRCA2 missense mutation. Previously published data indicate that the risks of breast and ovarian cancer conferred by BRCA2-truncating mutations varies with the position of the mutation in the gene. The missense mutation reported here suggests that the BRCA2 domain including and surrounding glycine 2901 may be more important in preventing neoplastic transformation in ovarian epithelium than in breast epithelium.