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.     

TrkC: a new predictive marker in breast cancer?

Available data involve neurotrophins and their receptors in carcinomas. Quantitative evaluation of these molecules in these tumors might be useful as prognostic marker and eventual treatments. Our study on 40 mammary tumors tries to correlate expression of these molecules and prognosis. Immunohistochemistry for NGF, BDNF, NT3, TrkA, TrkB, TrkC, and p75 was used. Patient's age, histopathology, Bloom-Richardson grading, estrogen and progesterone receptors, Ki-67 index, HER-2, p53 were evaluated. Statistics found inverse relationship between grading and TrkC expression. We found significantly higher TrkC expression in Grade I than in Grade III tumors. Rise in TrkC expression could indicate good prognosis.     

BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients – A study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD)

BackgroundMutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients.MethodsThe cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR).Results14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group ⩽58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations.ConclusionsOur data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.     

Podoplanin—a novel marker in oral carcinogenesis

Podoplanin, a transmembrane sialoglycoprotein, is a specific marker for lymphatic endothelial cells which in recent years has gained prominent notoriety for its role in tumor progression and metastasis. It is an extensively studied biomarker for predictive assessment of malignant transformation as well as biologic behavior in both human precancer and cancer, respectively. This review summarizes the association of podoplanin overexpression in oral potentially malignant disorders and oral cancer with special emphasis on its putative role in carcinogenesis as well as its prospective use in targeted therapy.     

Bullatacin — in vivo and in vitro experience in an ovarian cancer model

The cytotoxicity and antitumor effects of the acetogenin Bullatacin were evaluated in vitro in multiple ovarian cancer cell lines and in vivo in a murine ovarian teratocarcinoma (MOT) model in C3HeB/FeJ mice. The in vitro cytotoxicity of Bullatacin against four human ovarian epithelial tumor cell lines (OC-194, OC-222, OVCAR-3, and A-2780) was assessed in 48- and 72-h tetrazolium-dye (MTT) cytotoxicity assays. The percentage of cytotoxicity was determined on the basis of the mean optical density of the respective untreated cells and the dose effective against 50% of the cells (ED₅₀) was calculated for each cell line. In vivo experiments were performed on adult female C3HeB/FeJ mice, which were injected i.p. with 10⁵ MOT cells and varying amounts of Bullatacin given either in a single dose or in 5 subsequent doses over 72 h. All mice were observed for survival relative to that of the control groups, which were injected either with 10⁵ MOT cells with or without serial injections of vehicle or with vehicle only. All four epithelial ovarian cancer cell lines displayed sensitivity to Bullatacin. The relative cytotoxic effects were very heterogeneous, with the ED₅₀ value ranging between 10^–7 g/ml for OC-194 and 4 g/ml for the cisplatin-resistant cell line OVCAR-3 in a 72-h MTT cytotoxicity assay. All mice that had been injected i.p. with 10⁵ MOT cells and 1.4 mg/kg or more of Bullatacin died within the first 24 h after injection, whereas all mice that had received 600 g/kg of Bullatacin or less survived equally as long as the controls that had been injected with MOT only (21.1±0.9 days). Mice that had received Bullatacin at a dose ranging from 600 g/kg to 1.4 mg/kg either died during the 1st day postinjection or survived, but not longer than the MOT control group. Serial i.p. injections of Bullatacin again either led to death of the mice within 24–48 h of the last dose of Bullatacin or did not have any effect on the survival of the mice as compared with the respective control groups, which had been injected with the tumor and serial injections of vehicle (22.5±2.2 days). In summary, Bullatacin showed no effect on MOT-caused animal death in C3HeB/FeJ mice at nonlethal dose ranges, whether it was given as a single i.p. dose or serially over 72 h. In vitro, however, it proved to be a very potent cytotoxic agent in a variety of ovarian cancer cell lines. As compared with other chemotherapeutic agents, which we accept as having clinically important antitumor efficacy against ovarian cancer, such as cisplatin or carboplatin, Bullatacin demonstrated a very favorable ED_{50 in vitro}/LD_{50 in vivo} (the dose lethal to 50% of the mice) ratio.This work was supported by the Bertha Warshaver Rubin Research Fund and was presented at the 21st annual meeting of the Western Association of Gynecologic Oncologists, May 19–23, 1993, Santa Monica, California     

Epithelial–mesenchymal transition in ovarian cancer

Ovarian cancer is a highly metastatic disease and the leading cause of death from gynecologic malignancy. Hence, and understanding of the molecular changes associated with ovarian cancer metastasis could lead to the identification of targets for novel therapeutic interventions.     

Controversies in surgery in ovarian cancer — what is its real role?

Rupture of an ovarian malignant tumour should be avoided at the time of surgery for an early ovarian cancer. Laparoscopic removal of ovarian cysts should be restricted to patients with preoperative evidence that the cyst is benign. Degree of differentiation is the most important independent prognostic factor in stage I disease and should be used in decisions on therapy in clinical practice and the future FIGO (International Federation of Gynecology and Obstetrics) classification of stage 1. In early ovarian cancer, staging adequacy and tumour grade were the only two statistically significant prognostic factors for survival in the multivariate analysis of the EORTC (European Organisation for Research and Treatment of Cancer) ACTION (Adjuvant ChemoTherapy In Ovarian Neoplasms) trial. According to the present data there is no scientific basis to rely only on adjuvant chemotherapy or on optimal staging procedure in medium and high risk stage I ovarian cancer.Primary debulking surgery by a gynaecological oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumour load. Interval debulking is defined as an operation performed after a short course of induction chemotherapy, usually 2 or 3 cycles. Based on the randomised EORTC GCG (Gynaecological Cancer Group) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG (Gynecologic Oncology Group) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynaecological oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of the EORTC-GCG/NCI (National Cancer Institute) Canada randomised trial to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in some or all stage IIIc and IV patients.The most suitable candidates for secondary debulking surgery are those who had an initial complete response to chemotherapy, a long treatment-free interval (e.g. more than 12 months), and resectable disease (without diffuse carcinomatosis).     

Anti-α-enolase is a prognostic marker in postoperative lung cancer patients

Our previous studies suggest that antibodies against ENO1 (anti-ENO1 Ab) have a protective role in patients with non-small cell lung carcinoma. In this study, we evaluated the prognostic value of anti-ENO1 Ab levels in non-small cell lung carcinoma patients undergoing surgery. Circulating levels of anti-ENO1 Ab were assessed in 85 non-small cell lung carcinoma patients before and after surgery, and were correlated with clinical outcome. After surgery, patients with a higher increase of anti-ENO1 Ab had a lower hazard ratio and a better progression-free survival. Using animal models, we demonstrated that tumor cells reduce the circulating levels of anti-ENO1 Ab through physical absorption and neutralization of anti-ENO1 Ab with surface-expressed and secreted ENO1, respectively. Mice transplanted with ENO1-overexpressing tumors generated ENO1-specific regulatory T cells to suppress the production of anti-ENO1 Ab. Our results suggest that the increase of anti-ENO1 Ab may reflect anti-tumor immune responses and serve as a prognostic marker in postoperative lung cancer patients.     

Are CYP17 genotypes a biomarker for ovarian cancer in patients with cancer history in their family?

BRCA1 and BRCA2 genes are responsible for 5-10% of breast and ovarian cancer cases. However, the vast majority of ovarian and breast cancer cases do not display the hereditary form of the disease. Estrogen-metabolizing genes may also contribute to the predisposition of breast or ovarian cancer. Polymorphic variants of the estrogen-metabolizing gene, CYP17, have been associated with the risk of hormone-related cancers. In this study we investigated the CYP17 polymorphisms in ovarian cancer patients harboring mutations in the BRCA1 and BRCA2 genes, patients displaying familial characteristics but not carrying mutations and patients with sporadic ovarian cancer. Association between the allele frequencies, the CYP17 genotype and tumor characteristics or clinical parameters was evaluated. Our data suggest evidence for an association between ovarian cancer risk and the CYP17 genotype in the subgroup of patients with familial disease in whom no mutations in the BRCA genes are found. Although there were no statistically significant differences in the genotype distribution between the control group and the subgroup of patients with BRCA mutations, the frequency of the CYP17 A2 allele was significantly higher in the subgroup of patients without BRCA mutations. We found a four- to eightfold higher risk in ovarian cancer patients with family history but without BRCA mutations. Our data indicate that the CYP17 A2 allele polymorphism may confer an increased risk and can provide a biomarker for ovarian cancer patients in whom no mutations in the BRCA genes are observed.     

Preferential involvement of chromosome 11 as add(11)(p15) in ovarian cancer: is it a common cytogenetic abnormality in cancer?

Ovarian cancer represents the leading cause of death among patients with gynecological cancer. The genetic changes underlying the development and progression of ovarian cancer are not well defined. Identification of chromosomal aberrations is a useful strategy toward understanding tumorigenesis and specific chromosomal associations. Studying 15 ovarian cancer cases by conventional cytogenetic techniques, we previously reported that 11p15 was the most consistent chromosomal breakpoint involved. The aim of the present study was to investigate the presence of structural changes of chromosome 11 in ovarian cancer. Ten cases of ovarian cancer were cytogenetically studied by direct culture of tumour cells and G-banding technique. Eight cases presented structural aberrations of chromosome 11 with 11p15 involved as add(11)(p15) in all 8 cases and 11q23 involved as add(11)(q23) in 3 cases. Findings of the present study further support the possible role of chromosomal abnormalities add(11)(p15) and add(11)(q23) in ovarian cancer. These aberrations may result either in loss of genetic material from 11p and 11q, respectively, or in specific genes alterations. It is necessary, these chromosomal regions to be further investigated at molecular and clinical level. Improving the molecular understanding of ovarian cancer development and progression could facilitate the detection of specific tumor subtypes and contribute also to novel strategies for the management of ovarian cancer patients.     

Δ133p53 is an independent prognostic marker in p53 mutant advanced serous ovarian cancer

Background:

We aimed to evaluate the clinical relevance of p53 and p73 isoforms that modulate the function of p53.

Methods:

This prospective multicentre study included 154 patients with stage III and IV serous ovarian cancer. A functional yeast-based assay and subsequent sequencing were performed to analyse the p53 mutational status. Expression of p53 and p73 isoforms was determined using RT–qPCR.

Results:

Δ133p53 expression constituted an independent prognostic marker for recurrence-free (hazard ratio=0.571, P=0.016, 95% CI: 0.362–0.899) and overall survival (hazard ratio=0.365, P=0.004, 95% CI: 0.182–0.731) in patients with p53 mutant ovarian cancer (n=121). High Δ40p53 expression was associated with favourable tumour grading (P=0.037) and improved recurrence-free survival (33.4 vs 19.6 months, P=0.029), but not overall survival (43.1 vs 33.6 months, P=0.139), in patients with p53 wild-type cancer (n=33). Neither the p53 mutational status nor p73 isoform expression possessed prognostic significance in the examined ovarian cancer cases.

Conclusion:

Δ133p53 expression was associated with prognosis in the vast majority of ovarian cancer cases, that is, patients with p53 mutant advanced serous carcinomas. Thus, our findings underline the importance of considering the complex p53 regulatory network.     

Immunotherapy – new perspective in lung cancer

Lung carcinoma is associated with a high mortality worldwide, being the leading cause of cancer death. It is mainly classified into squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, and small cell lung cancer. However, such malignancy has been increasingly subdivided into histological and molecular subtypes to guide treatment. Therapies can be used in adjuvant and palliative settings. Regarding immunotherapy, it has been widely tested in both first or subsequent palliative lines. In this sense, drugs such as pembrolizumab, nivolumab, atezolizumab, ipilimumab, avelumab, and durvalumab have been assessed in large studies. Some of these trials have also studied these medicines in adjuvant and in maintenance therapy. In recent years, advances in immunotherapy have raised the hope that the unfavorable prognosis observed in several affected individuals can be changed. Immunotherapy has increased the overall survival in squamous NSCLC, non-squamous NSCLC, and small cell lung cancer. However, it has added to the oncology practice some side effects that are unusual in standard chemotherapy and require special clinical support. In order to show how immunotherapy is being applied in the treatment of lung carcinoma, we reviewed the main studies in adjuvant and palliative scenarios. What is the better scheme? What is the better combination? What is the better dose? When should we use immunotherapy? Does programmed cell death ligand 1 expression significantly interfere in immunotherapy efficiency? Some of these questions have already been answered, while others require more investigations.     

Is adjuvant radiotherapy in early stages (FIGO I-II) of epithelial ovarian cancer a treatment of the past?

External abdomino-pelvic irradiation after primary surgery in early stages of epithelial ovarian carcinoma has been used as adjuvant therapy. The aims of this study were to evaluate efficacy and tolerability of abdomino-pelvic radiotherapy in ovarian carcinomas and to find predictive factors for recurrent disease. From January 1979 to December 1993, 215 patients with FIGO stage IA-IIC epithelial ovarian carcinoma were treated with postoperative radiotherapy. Whole-abdominal irradiation or lower abdomino-pelvic irradiation were used. The dose of specification was 20 Gy to the upper part of the abdominal cavity and 40 Gy to the lower part of the abdomen and the pelvic region. Primary cure was achieved in 210 patients (98%). During the period of follow-up, 79 tumor recurrences (38%) were recorded. Abdomino-pelvic metastases were most frequent (22%). The overall 5-year and 10-year survival rate for the complete series was 60 and 41%, respectively. In a multivariate analysis, FIGO-stage, histopathological type and tumor grade were independent prognostic factors with recurrent-free survival as the end-point. Among the histopathological subtypes, the highest survival rate (80%) was found for the subgroup of 24 patients with clear cell carcinomas. Early radiation reactions of any type were noted in 85% of the cases. The incidence of severe late bowel toxicity was 12% and, in 11 patients (5%), surgery was necessary due to late radiation complications of the intestine. In conclusion, adjuvant abdomino-pelvic radiotherapy is a treatment option in early stages of ovarian carcinoma together with chemotherapy. However, further studies are needed to find the subgroup of patients who specifically might benefit from radiotherapy in this setting.