Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.
ABSTRACT: OBJECTIVE:To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS:This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n?=?1196, and Japan cohort n?=?495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS:During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P?=?0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P?=?0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P?=?0.805), overall survival (HR not estimated, P?=?0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P?=?0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P?=?0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P?=?0.021), but was not associated with overall survival (HR not estimated, P?=?0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9?years, and all cases were salvaged. CONCLUSION:Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.
Project description:OBJECTIVE:To examine survival of women who develop metachronous uterine malignancy after definitive pelvic radiotherapy for cervical cancer. METHODS:This retrospective observational study examined the Surveillance, Epidemiology, End Results Program between 1973 and 2013. Women with cervical cancer who received definitive radiotherapy without hysterectomy were examined for the diagnosis of metachronous uterine malignancy (n?=?5277). Survival was compared between metachronous and non-metachronous uterine malignancies according to tumor factors. RESULTS:The 10- and 20-year cumulative incidences of metachronous uterine malignancy were 0.6% and 1.2%, respectively. When compared to non-metachronous uterine malignancy, metachronous tumor were more likely to be non-endometrioid and advanced-stage (both, P?<?0.001). As a whole cohort, metachronous uterine malignancy was significantly associated with decreased overall survival (OS) compared to non-metachronous tumors (hazard ratio [HR] 4.22, P?<?0.001). OS was significantly worse in metachronous compared to non-metachronous malignancies, although the magnitude of statistical significance was greater for endometrioid tumors (HRs for endometrioid versus non-endometrioid: 6.17 versus 1.92). For grade 1-2 endometrial cancer, metachronous cases had significantly decreased OS compared to non-metachronous cases, a larger difference than that seen in higher grade tumors (HRs for grade 1-2 versus 3: 7.79 versus 2.15). Similarly, in early-stage endometrial cancer, metachronous cases had significantly decreased OS, with a greater HR compared to advanced-stage disease (HRs for stage I-II versus III-IV: 5.29 versus 2.29). CONCLUSION:Radiotherapy-associated metachronous uterine malignancy after cervical cancer is rare but commonly presents with aggressive tumor characteristics. The impact on survival is considerably high when metachronous uterine malignancy is endometrioid, low-grade, and early-stage.
Project description:OBJECTIVE:To characterize contributing factors for ovarian conservation during surgical treatment for endometrial cancer and to examine the association of ovarian conservation on survival of young women with early-stage, low-grade tumors. METHODS:This was a population-based study using the Surveillance, Epidemiology, and End Results program to identify surgically treated stage I type I (grade 1-2 endometrioid histology) endometrial cancer cases diagnosed between 1983 and 2012 (N=86,005). Multivariable models were used to identify independent factors for ovarian conservation. Survival outcomes and cause of death were examined for women aged younger than 50 with stage I type I endometrial cancer who underwent ovarian conservation (1,242 among 12,860 women [9.7%]). RESULTS:On multivariable analysis, age younger than 50 years, grade 1 endometrioid histology, and tumor size 2.0 cm or less were noted to be independent factors for ovarian conservation (all, P<.001). For 9,110 women aged younger than 50 years with stage I grade 1 tumors, cause-specific survival was similar between ovarian conservation and oophorectomy cases (20-year rates 98.9% compared with 97.7%, P=.31), whereas overall survival was significantly higher in ovarian conservation cases than oophorectomy cases (88.8% compared with 82.0%, P=.011). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.73, 95% confidence interval [CI] 0.54-0.98, P=.036) and was independently associated with a lower cumulative risk of death resulting from cardiovascular disease compared with oophorectomy (20-year rates, 2.3% compared with 3.7%, adjusted hazard ratio 0.40, 95% CI 0.17-0.91, P=.029). Contrary, cause-specific survival (20-year rates 94.6% compared with 96.1%, P=.68) and overall survival (81.0% compared with 80.6%, P=.91) were similar between ovarian conservation and oophorectomy among 3,750 women aged younger than 50 years with stage I grade 2 tumors. CONCLUSION:Ovarian conservation is performed in less than 10% of young women with stage I type I endometrial cancer. Ovarian conservation is associated with decreased mortality in young women with stage I grade 1 tumors.
Project description:While there is an increasing trend of ovarian conservation at the time of surgical treatment for young women with stage I cervical cancer, the risk for subsequent ovarian cancer after ovarian conservation has not been well studied.We sought to examine the incidence of and risk factors for metachronous ovarian cancer among young women with stage I cervical cancer who had ovarian conservation at the time of hysterectomy.The Surveillance, Epidemiology, and End Results Program was used to identify women aged <50 years who underwent hysterectomy with ovarian conservation for stage I cervical cancer from 1983 through 2013 (n = 4365). Time-dependent analysis was performed for ovarian cancer risk after cervical cancer diagnosis.Mean age at cervical cancer diagnosis was 37 years, and the majority of patients had stage IA disease (68.2%) and squamous histology (72.9%). Median follow-up time was 10.8 years, and there were 13 women who developed metachronous ovarian cancer. The 10- and 20-year cumulative incidences of metachronous ovarian cancer were 0.2% (95% confidence interval, 0.1-0.4) and 0.5% (95% confidence interval, 0.2-0.8), respectively. Mean age at the time of diagnosis of metachronous ovarian cancer was 47.5 years, and stage III-IV disease was seen in 55.6%. Age (?45 vs <45 years, hazard ratio, 4.22; 95% confidence interval, 1.16-15.4; P = .018), ethnicity (non-white vs white, hazard ratio, 4.29; 95% confidence interval, 1.31-14.0; P = .009), cervical cancer histology (adenocarcinoma or adenosquamous vs squamous, hazard ratio, 3.50; 95% confidence interval, 1.17-10.5; P = .028), and adjuvant radiotherapy use (yes vs no, hazard ratio, 3.69; 95% confidence interval, 1.01-13.4; P = .034) were significantly associated with metachronous ovarian cancer risk. The presence of multiple risk factors was associated with a significantly increased risk of metachronous ovarian cancer compared to the no risk factor group: 1 risk factor (hazard ratio range, 2.96-8.43), 2 risk factors (hazard ratio range, 16.6-31.0), and 3-4 risk factors (hazard ratio range, 62.3-109), respectively.Metachronous ovarian cancer risk after ovarian conservation for women with stage I cervical cancer is <1%. Older age, non-white ethnicity, adenocarcinoma or adenosquamous histology, and adjuvant radiotherapy may be associated with an increased metachronous ovarian cancer risk.
Project description:BACKGROUND: This study examined the risk of third cancer of non-breast origin (TNBC) among women with bilateral breast cancer (BBC; either synchronous or metachronous), focussing on the relation with breast cancer treatment. METHODS: Risk was assessed, among 8752 Dutch women diagnosed with BBC between 1989 and 2008, using standardised incidence ratios (SIR) and Cox regression analyses to estimate the hazard ratio (HR) of TNBC for different treatment modalities. RESULTS: Significant increased SIRs were observed for all TNBCs combined, haematological malignancies, stomach, colorectal, non-melanoma skin, lung, head and neck, endometrial, and ovarian cancer. A 10-fold increased risk was found for ovarian cancer among women younger than 50 years (SIR=10.0, 95% confidence interval (CI)=5.3-17.4). Radiotherapy was associated with increased risks of all TNBCs combined (HR=1.3; 95%CI=1.1-1.6, respectively). Endocrine therapy was associated with increased risks of all TNBCs combined (HR=1.2; 95%CI=1.0-1.5), haematological malignancies (HR=2.0; 95%CI=1.1-3.9), and head and neck cancer (HR=3.3; 95%CI=1.1-10.4). After chemotherapy decreased risks were found for all TNBCs combined (HR=0.63; 95%CI=0.5-0.87). CONCLUSION: Increased risk of TNBC could be influenced by genetic factors (ovarian cancer) or an effect of treatment (radiotherapy and endocrine therapy). More insight in the TNBC risk should further optimise and individualise treatment and surveillance protocols in (young) women with BBC.
Project description:Endometrioid adenocarcinoma of the uterus and ovarian endometrioid carcinoma share many morphological and molecular features. Differentiation between simultaneous primary carcinomas and ovarian metastases of an endometrial cancer may be very challenging but is essential for prognostic and therapeutic considerations.In the present case study of a 33 year-old patient we used targeted amplicon next-generation re-sequencing for clarifying the origin of synchronous endometrioid cancer of the corpus uteri and the left ovary. The patient developed a metachronous lung metastasis of an endometrioid adenocarcinoma four years after hyster- and adnexectomy, vaginal brachytherapy and treatment with the synthetic steroid tibolone. Removal of the metastasis and megestrol treatment for seven years led to a complete remission. A total of 409 genes from the Ampliseq Comprehensive Cancer Panel (Ion Torrent, Thermo Fisher) were analysed by next generation sequencing and mutations in 10 genes, including ARID1A, CTNNB1, PIK3CA and PTEN were identified and confirmed by Sanger sequencing. Primary endometrial as well as ovarian cancer showed an identical mutational profile, suggesting the presence of an ovarian metastasis of the endometrial cancer, rather than a simultaneous endometrial and ovarian cancer. The metachronous lung metastasis showed a different mutational profile compared to the primary cancer. Immunohistochemical staining of the corresponding proteins suggested that the tumour development was driven by alterations in the protein function rather than by changes of the protein abundance in the cell.Our results have demonstrated next generation sequencing as a valuable tool in the differentiation of synchronous primary tumours and metastases, which has an important impact on the clinical decision making process. Similar to breast cancer, targeted therapies based on mutational tumour profiling will become increasingly important in endometrial and ovarian cancer. In summary, our results support the usage of next generation sequencing as a supplementary diagnostic tool, assisting in personalized precision medicine.
Project description:Identification of novel therapeutics in pelvic high-grade serous carcinoma (HGSC) has been hampered by a paucity of actionable point mutations in target genes. The aim of the present study was to investigate the extent of amplification of the therapeutically targetable NSD3-CHD8-BRD4 pathway in pelvic HGSC, and to determine whether amplification is associated with worse prognosis. The Cancer Genome Atlas (TCGA) ovarian and endometrial cancer cohorts were retrospectively analyzed via online data-mining tools to test the association of NSD3, CHD8 and BRD4 genomic alterations with survival of pelvic HGSC patients. It was demonstrated that amplification of the NSD3-CHD8-BRD4 pathway in the ovarian HGSC cohort (observed in 18% of the cases, 88/489) was significantly associated with worse overall and progression-free survival compared with non-amplified cases. In addition, amplification of NSD3, CHD8 and BRD4 also occurred in 9% (21/232) of overall endometrial cancer TCGA cases, which was associated with worse overall survival. In the endometrial cancer TCGA cohort, NSD3, CHD8 and BRD4 amplification occurred specifically in the serous carcinoma (25%, 13/53) and 'serous-like' copy number high endometrial carcinoma (33%, 20/60) subgroups, compared with the polymerase e (0%, 0/17), microsatellite instability high (0%, 0/65) or low copy number (1%, 1/90) subgroups. These findings support the hypothesis that amplification of the NSD3-BRD4-CDH8 axis is frequent in pelvic HGSC of both ovarian and endometrial origin, and that this pathway is potentially targetable in a subset of HGSC patients.
Project description:Purpose: The aim of our study was to investigate the rate of secondary carcinomas in patients with endometrial carcinoma (EC). In particular, we wanted to describe the subset of patients with endometrial and simultaneous ovarian carcinoma (OC), including outcomes. The study also compared patients with EC and ovarian metastasis with patients with EC and simultaneous OC. Patients and Methods: Data from 251 patients with primary endometrial carcinoma who underwent surgery in the years 2005-2009 at the Department of Obstetrics and Gynaecology, University of Tübingen, were analysed retrospectively. Results: A total of 28 patients (11.1?%) had a secondary carcinoma: 18 patients (7.1?%) had OC; 9 (3.5?%) patients had a history of breast cancer, and one patient (0.4?%) respectively had simultaneous carcinoma of the vulva or bladder. 14 patients (5.5?%) had advanced stage EC with ovarian metastasis or, in one case, metastasis to the ovarian tube. Patients with ovarian metastasis had a mean age of 71.2?±?9.2 years at primary diagnosis, making them significantly older compared to patients with EC and simultaneous OC (55.3?±?11.8 years, p?<?0.001). Moreover, patients with ovarian metastasis significantly more often had EC with a higher tumour grade (grade 1: 0, grade 2: 21.4?%, grade 3: 78.6?%) compared to patients with simultaneous EC and OC (grade 1: 11.1?%, grade 2: 77.8?%, grade 3: 11.1?%; p?<?0.001). Conclusion: Almost one in 10 patients with EC had a secondary carcinoma. The most common secondary carcinoma was OC followed by breast cancer. This should be taken into account in the diagnosis and therapy of patients with EC. Patients with simultaneous EC and OC were significantly younger than patients with EC and ovarian metastasis. In addition, their tumour had better prognostic features: thus, the tumour grade of the EC was significantly lower. Overall, the prognosis for patients with synchronous EC and OC is better than that for patients with EC and ovarian metastasis.
Project description:Background:Postmenopausal bone fracture's have been proposed as a marker of lifetime estrogen exposure and have been associated with decreased risk of breast and endometrial cancer. It is plausible that prediagnostic fractures may be related to survival of estrogen-sensitive cancers. Methods:We evaluated a cohort of breast (n = 6411), endometrial (n = 1127), and ovarian (n = 658) cancer cases diagnosed between 1992 and 2010 while participating in the Women's Health Initiative. Postmenopausal fracture history was assessed from baseline reports of fractures after age 55 years and incident fractures that occurred at least one year prior to cancer diagnosis during study follow-up. Using Cox regression, we compared women with and without a history of fractures with respect to overall and cancer-specific survival. Estimates were adjusted for participant factors, including hormone therapy use; hormone receptor status was not included in our analysis. Results:Among women with breast cancer, a history of prediagnostic fractures at any site was associated with poorer overall survival (hazard ratio [HR] = 1.22, 95% confidence interval [CI] = 1.05 to 1.43). A history of hip, forearm, or spine fractures, or hip fracture alone, was associated with increased risk of mortality (HR = 1.26, 95% CI = 1.01 to 1.58, and HR = 2.05, 95% CI = 1.27 to 3.32, respectively). Fracture history was associated neither with cancer-specific survival among breast cancer survivors, nor with overall or disease-specific mortality among endometrial and ovarian cancer survivors. Conclusions:Postmenopausal breast cancer patients with a history of fractures, especially of the hip, are more likely to die of any cause than breast cancer survivors without a fracture history. Identifying and intervening in fracture risk factors should be standard of care for all women diagnosed with breast cancer.
Project description:This study investigated the clinical significance of keratin 5 and 6 expression in serous ovarian cancer progression and chemotherapy resistance. KRT5 and KRT6 (KRT6A, KRT6B & KRT6C) gene expression was assessed in publically available serous ovarian cancer data sets, ovarian cancer cell lines and primary serous ovarian cancer cells. Monoclonal antibodies which detect both K5/6 or only K5 were used to assess protein expression in ovarian cancer cell lines and a cohort of high grade serous ovarian carcinomas at surgery (n = 117) and after neoadjuvant chemotherapy (n = 21). Survival analyses showed that high KRT5 mRNA in stage III/IV serous ovarian cancers was significantly associated with reduced progression-free (HR 1.38, P < 0.0001) and overall survival (HR 1.28, P = 0.013) whilst high KRT6 mRNA was only associated with reduced progression-free survival (HR 1.2, P = 0.031). Both high K5/6 (? 10%, HR 1.78 95% CI; 1.03-2.65, P = 0.017) and high K5 (? 10%, HR 1.90, 95% CI; 1.12-3.19, P = 0.017) were associated with an increased risk of disease recurrence. KRT5 but not KRT6C mRNA expression was increased in chemotherapy resistant primary serous ovarian cancer cells compared to chemotherapy sensitive cells. The proportion of serous ovarian carcinomas with high K5/6 or high K5 immunostaining was significantly increased following neoadjuvant chemotherapy. K5 can be used to predict serous ovarian cancer prognosis and identify cancer cells that are resistant to chemotherapy. Developing strategies to target K5 may therefore improve serous ovarian cancer survival.
Project description:This study aimed to investigate the association between diet and the risk of breast, endometrial and ovarian cancer in the UK Women's Cohort Study. A total of 35 372 women aged 35-69 years were enrolled between 1995 and 1998 and completed a validated 217-item FFQ. The individual foods were collapsed into sixty-four main food groups and compared using Cox proportional models, adjusting for potential confounders. Hazard ratio (HR) estimates are presented per portion increase in food items. After approximately 18 years of follow-up, there were 1822, 294 and 285 cases of breast, endometrial and ovarian cancer, respectively. A high consumption of processed meat and total meat was associated with an increased risk of breast and endometrial cancer. High intake of tomatoes (HR 0·87, 99 % CI 0·75, 1·00) and dried fruits (HR 0·60, 99 % CI 0·37, 0·97) was associated with a reduced risk of breast and endometrial cancer, respectively. Mushroom intake was associated with a higher risk of ovarian cancer (HR 1·57, 99 % CI 1·09, 2·26). Subgroup analysis by pre- or postmenopausal cancer further demonstrated an association between processed meat intake and both postmenopausal breast cancer and endometrial cancer. Intake of dried fruits was associated with a reduced risk of postmenopausal endometrial cancer (HR 0·55, 99 % CI 0·31, 0·98). Our findings suggest that while some foods may trigger the risk of these cancers, some foods may also be protective; supporting the call for further randomised controlled trials of dietary interventions to reduce the risk of cancer among pre- and postmenopausal women.