Does serous tubal intraepithelial carcinoma (STIC) metastasize?:The clonal relationship between STIC and subsequent high-grade serous carcinoma in BRCA1/2 mutation carriers several years after risk-reducing salpingo-oophorectomy

Objective: The majority of high-grade serous carcinomas (HGSC) of the ovary, fallopian tube, and peritoneum arise from the precursor lesion called serous tubal intraepithelial carcinoma (STIC). It has been postulated that cells from STICs exfoliate into the peritoneal cavity and give rise to peritoneal HGSC several years later. While co-existent STICs and HGSCs have been reported to share similarities in their mutational profiles, clonal relationship between temporally distant STICs and HGSCs have been infrequently studied and the natural history of STICs remains poorly understood. Methods: We performed focused searches in two national databases from the Netherlands and identified a series of BRCA1/2 germline pathogenic variant (GPV) carriers (n = 7) who had STIC, and no detectable invasive carcinoma, at the time of their risk-reducing salpingo-oophorectomy (RRSO), and later developed peritoneal HGSC. The clonal relationship between these STICs and HGSCs was investigated by comparing their genetic mutational profile by performing next-generation targeted sequencing. Results: Identical pathogenic mutations and loss of heterozygosity of TP53 were identified in the STICs and HGSCs of five of the seven patients (71%), confirming the clonal relationship of the lesions. Median interval for developing HGSC after RRSO was 59 months (range: 24–118 months). Conclusion: Our results indicate that cells from STIC can shed into the peritoneal cavity and give rise to HGSC after long lag periods in BRCA1/2 GPV carriers, and argues in favor of the hypothesis that STIC lesions may metastasize.</p

The effect of hormone therapy on breast density following risk-reducing salpingo-oophorectomy in women with an increased risk for breast and ovarian cancer

OBJECTIVE: To compare the effect of tibolone to conjugated estrogens with medroxyprogesterone-acetate (CEE + MPA) on breast density, as a predictor for breast cancer risk, in women with a high risk of breast and ovarian cancer. METHODS: Women aged 30-50 (N = 114) who had undergone risk-reducing salpingo-oophorectomy (RRSO) were randomized to tibolone or CEE + MPA. RESULTS: Breast density decreased 46% after RRSO in untreated women, 39% after treatment with tibolone, and 17% after treatment with CEE + MPA; the decrease in breast density after CEE + MPA was significantly different compared with that of untreated women (P = 0.017). CONCLUSIONS: A decline in breast density is seen after premenopausal RRSO despite the use of both CEE + MPA or tibolone, although lower breast density is seen after tibolone use

Cytoreductive surgery followed by chemotherapy versus chemotherapy alone for recurrent platinum- sensitive epithelial ovarian cancer (SOCceR trial):a multicenter randomised controlled study

BACKGROUND: Improvement in treatment for patients with recurrent ovarian cancer is needed. Standard therapy in patients with platinum-sensitive recurrent ovarian cancer consists of platinum-based chemotherapy. Median overall survival is reported between 18 and 35 months. Currently, the role of surgery in recurrent ovarian cancer is not clear. In selective patients a survival benefit up to 62 months is reported for patients undergoing complete secondary cytoreductive surgery. Whether cytoreductive surgery in recurrent platinum-sensitive ovarian cancer is beneficial remains questionable due to the lack of level I-II evidence. METHODS/DESIGN: Multicentre randomized controlled trial, including all nine gynecologic oncologic centres in the Netherlands and their affiliated hospitals. Eligible patients are women, with first recurrence of FIGO stage Ic-IV platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, who meet the inclusion criteria. Participants are randomized between the standard treatment consisting of at least six cycles of intravenous platinum based chemotherapy and the experimental treatment which consists of secondary cytoreductive surgery followed by at least six cycles of intravenous platinum based chemotherapy. Primary outcome measure is progression free survival. In total 230 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Where the role of cytoreductive surgery is widely accepted in the initial treatment of ovarian cancer, its value in recurrent platinum-sensitive epithelial ovarian cancer has not been established so far. A better understanding of the benefits and patients selection criteria for secondary cytoreductive surgery has to be obtained. Therefore the 4(th) ovarian cancer consensus conference in 2010 stated that randomized controlled phase 3 trials evaluating the role of surgery in platinum-sensitive recurrent epithelial ovarian cancer are urgently needed. We present a recently started multicentre randomized controlled trial that will investigate the role of secondary cytoreductive surgery followed by chemotherapy will improve progression free survival in selected patients with first recurrence of platinum-sensitive epithelial ovarian cancer. TRIAL REGISTRATION: Netherlands Trial Register number: NTR3337

No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study

BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3-10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7-2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5-3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy:A Systematic Review and Individual Patient Data Meta-Analysis

PURPOSEAfter risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.METHODSUnpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study.RESULTSFrom 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P <.001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO.CONCLUSIONBRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events

Effect of surgical volume on short-term outcomes of cytoreductive surgery for advanced-stage ovarian cancer:A population-based study from the Dutch Gynecological Oncology Audit

Objective: Despite lacking clinical data, the Dutch government is considering increasing the minimum annual surgical volume per center from twenty to fifty cytoreductive surgeries (CRS) for advanced-stage ovarian cancer (OC). This study aims to evaluate whether this increase is warranted. Methods: This population-based study included all CRS for FIGO-stage IIB-IVB OC registered in eighteen Dutch hospitals between 2019 and 2022. Short-term outcomes included result of CRS, length of stay, severe complications, 30-day mortality, time to adjuvant chemotherapy, and textbook outcome. Patients were stratified by annual volume: low-volume (nine hospitals, &lt;25), medium-volume (four hospitals, 29–37), and high-volume (five hospitals, 54–84). Descriptive statistics and multilevel logistic regressions were used to assess the (case-mix adjusted) associations of surgical volume and outcomes. Results: A total of 1646 interval CRS (iCRS) and 789 primary CRS (pCRS) were included. No associations were found between surgical volume and different outcomes in the iCRS cohort. In the pCRS cohort, high-volume was associated with increased complete CRS rates (aOR 1.9, 95%-CI 1.2–3.1, p = 0.010). Furthermore, high-volume was associated with increased severe complication rates (aOR 2.3, 1.1–4.6, 95%-CI 1.3–4.2, p = 0.022) and prolonged length of stay (aOR 2.3, 95%-CI 1.3–4.2, p = 0.005). 30-day mortality, time to adjuvant chemotherapy, and textbook outcome were not associated with surgical volume in the pCRS cohort. Subgroup analyses (FIGO-stage IIIC-IVB) showed similar results. Various case-mix factors significantly impacted outcomes, warranting case-mix adjustment. Conclusions: Our analyses do not support further centralization of iCRS for advanced-stage OC. High-volume was associated with higher complete pCRS, suggesting either a more accurate selection in these hospitals or a more aggressive approach. The higher completeness rates were at the expense of higher severe complications and prolonged admissions.</p

Can ABCF2 protein expression predict the prognosis of uterine cancer?

Uterine cervical and endometrial cancers are common malignant solid neoplasms for which there are no useful prognostic markers. In this study, we evaluate the relationship between ATP-binding cassette superfamily F2 (ABCF2) expression and clinical factors including clinical stage, histologic type, grade and prognosis in uterine cervical and endometrial cancer. Two hundred and sixty seven cervical and 103 endometrial cancers were studied. ATP-binding cassette superfamily F2 cytoplasmic expression was detected by immunohistochemical staining and scored as positive or negative. Among cervical cancer cases, 149 (55.8%) expressed ABCF2. The overall survival was longer in ABCF2-negative than ABCF2-positive cases (P=0.0069). Statistically significant prognostic factors for survival were ABCF2 positivity (risk ratio (rr)=1.437), old age (rr=1.550) and advanced stage (rr=2.577). ATP-binding cassette superfamily F2 positivity was an independent prognostic factor by multivariate proportional hazard test (P=0.0002). Among endometrial cancer cases, 72 (69.9%) were cytoplasmic ABCF2 positive. However, there was no significant relationship between ABCF2 expression and age, clinical stage, histologic type, histologic grade, oestrogen receptor status or prognosis. ATP-binding cassette superfamily F2 expression may be a useful prognostic marker in cervical but not endometrial cancer. The role of ABCF2 protein may differ depending on the type of cancer