Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis.

BACKGROUND: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. PATIENTS AND METHODS: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. RESULTS: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. CONCLUSIONS: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. PATIENTS AND METHODS: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

Breech progression angle: new feasible and reliable transperineal ultrasound parameter for assessment of fetal breech descent in birth canal.

OBJECTIVE: To assess the feasibility and reliability of transperineal ultrasound in the assessment of fetal breech descent in the birth canal, by measuring the breech progression angle (BPA). METHODS: Women with a singleton pregnancy with the fetus in breech presentation between 34 and 41 weeks' gestation were recruited. Transperineal ultrasound images were acquired in the midsagittal view for each woman, twice by one operator and once by another. Each operator measured the BPA after anonymization of the transperineal ultrasound images. BPA was defined as the angle between a line running along the long axis of the pubic symphysis and another line extending from the most inferior portion of the pubic symphysis tangentially to the lowest recognizable fetal part in the maternal pelvis. Each operator was blinded to all other measurements performed for each woman. Intra- and interobserver reproducibility of BPA measurement was evaluated using the intraclass correlation coefficient (ICC). To investigate the presence of any bias, intra- and interobserver agreement was also analyzed using Bland-Altman analysis. Student's t-test and Levene's W0 test were used to investigate whether a number of different clinical factors had an effect on systematic differences and homogeneity, respectively, between BPA measurements. RESULTS: Overall, 44 women were included in the analysis. BPA was measured successfully by both operators on all images. Both intra- and interobserver agreement analyses showed excellent reproducibility in BPA measurement, with ICCs of 0.88 (95% CI, 0.80-0.93) and 0.83 (95% CI, 0.71-0.90), respectively. The mean difference between measurements was 0.4° (95% CI, -1.4 to 2.2°) for intraobserver repeatability and -0.4° (95% CI, -2.6 to 1.8°) for interobserver repeatability. The upper limits of agreement were 12.0° (95% CI, 8.9-15.1°) and 13.6° (95% CI, 9.9-17.3°) for intra- and interobserver repeatability, respectively. The lower limits of agreement were -11.2° (95% CI, -14.3 to -8.1°) and -14.4° (95% CI, -18.2 to -10.7°) for intra- and interobserver repeatability, respectively. No systematic difference between BPA measurements was found on either intra- or interobserver agreement analysis. None of the clinical factors examined (maternal body mass index, maternal age, gestational age at the ultrasound scan and parity) showed a statistically significant effect on intra- or interobserver reliability. CONCLUSIONS: BPA represents a new feasible and highly reproducible measurement for the evaluation of fetal breech descent in the birth canal. Future studies assessing its usefulness in the prediction of successful external cephalic version and breech vaginal delivery are needed. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Is it safe to perform rectal anastomosis in gynaecological debulking surgery without a diverting stoma?

AIM: Colorectal resection is frequently performed during cytoreductive surgery for gynaecological malignancy. The aim of this study was to assess the safety of colorectal anastomosis, and especially low rectal anastomosis, in the absence of a protective stoma in patients with gynaecological cancer and peritoneal metastasis. METHOD: Patient data were retrospectively collected from a database for gynaecological cancer procedures carried out between January 2013 and July 2015. All patients who underwent a colorectal resection during cytoreduction were included in the study. The primary outcome was anastomotic leakage in the presence or absence of a diverting stoma. Secondary outcome parameters were complications and reoperations. RESULTS: In the period of study, 43 major colorectal procedures were performed on 37 women. The most common colorectal procedure was low rectal resection (n = 22; 59%) followed by anterior rectal resection (n = 7; 19%) and sigmoid resection (n = 4; 11%). Five (14%) patients underwent Hartmann's procedure. In three (8%) patients, a diverting loop ileostomy was created. CONCLUSION: Low rectal resection during debulking procedures for gynaecological cancers with peritoneal carcinomatosis can safely be performed by an experienced surgeon without a diverting stoma.

Sphingosine-kinase-1 expression is associated with improved overall survival in high-grade serous ovarian cancer.

PURPOSE: Sphingosine-kinase-1 (SPHK1) is a key enzyme of sphingolipid metabolism which is involved in ovarian cancer pathogenesis, progression and mechanisms of drug resistance. It is overexpressed in a variety of cancer subtypes. We investigated SPHK1 expression as a prognostic factor in epithelial ovarian cancer patients. METHODS: Expression analysis of SPHK1 was performed on formalin-fixed paraffin-embedded tissue from 1005 ovarian cancer patients with different histological subtypes using immunohistochemistry. Staining intensity of positive tumor cells was assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. RESULTS: In our ovarian cancer collective, high levels of SPHK1 expression correlated significantly with complete surgical tumor resection (p = 0.002) and lower FIGO stage (p = 0.04). Progression-free and overall survival were further significantly longer in patients with high-grade serous ovarian cancer and overexpression of SPHK1 (p = 0.002 and p = 0.006, respectively). CONCLUSION: Our data identify high levels of SPHK1 expression as a potential favorable prognostic marker in ovarian cancer patients.

Completion of radical hysterectomy does not improve survival of patients with cervical cancer and intraoperatively detected lymph node involvement: ABRAX international retrospective cohort study.

BACKGROUND: The management of cervical cancer patients with intraoperative detection of lymph node involvement remains controversial. Since all these patients are referred for (chemo)radiation after the surgery, the key decision is whether radical hysterectomy should be completed as originally planned, taking into account an additional morbidity associated with extensive surgical dissection prior to adjuvant treatment. The ABRAX study investigated whether completing a radical uterine procedure is associated with an improved oncological outcome of such patients. PATIENTS AND METHODS: We performed retrospective analyses of 515 cervical cancer patients (51 institutions, 19 countries) who were referred for primary curative surgery between 2005 and 2015 (stage IA-IIB, common tumour types) in whom lymph node involvement was detected intraoperatively. Patients were stratified according to whether the planned uterine surgery was completed (COMPL group, N = 361) or abandoned (ABAND group, N = 154) to compare progression-free survival. Definitive chemoradiation was given to 92.9% patients in the ABAND group and adjuvant (chemo)radiation or chemotherapy to 91.4% of patients in the COMPL group. RESULTS: The risks of recurrence (hazard ratio [HR] 1.154, 95% confidence intervals [CI] 0.799-1.666, P = 0.45), pelvic recurrence (HR 0.836, 95% CI 0.458-1.523, P = 0.56), or death (HR 1.064, 95% CI 0.690-1.641, P = 0.78) were not significantly different between the two groups. No subgroup showed a survival benefit from completing radical hysterectomy. Disease-free survival reached 74% (381/515), with a median follow-up of 58 months. Prognostic factors were balanced between the two groups. FIGO stage and number of pelvic lymph nodes involved were significant prognostic factors in the whole study cohort. CONCLUSION: We showed that the completion of radical hysterectomy does not improve survival in patients with intraoperatively detected lymph node involvement, regardless of tumour size or histological type. If lymph node involvement is confirmed intraoperatively, abandoning uterine radical procedure should be considered, and the patient should be referred for definitive chemoradiation. CLINICAL TRIALS IDENTIFIER: NCT04037124.