Advanced low grade serous ovarian cancer: A retrospective analysis of surgical and chemotherapeutic management in two high volume oncological centers.

Simple summary: Low-grade serous ovarian cancer (LGSOC) represents an uncommon histotype of serous ovarian cancer (accounting for approximately 5% of all ovarian cancer) with a distinct behavior compared to its high-grade serous counterpart, characterized by a better prognosis and low response rate to chemotherapeutic agents. Similar to high-grade serous ovarian cancer, cytoreductive surgery is considered crucial for patient survival. This retrospective study aimed to analyze the outcomes of women affected by advanced stages (III-IV FIGO) of LGSOC from two high-volume oncological centers for ovarian neoplasm. In particular, we sought to evaluate the impact on survival outcomes of optimal cytoreductive surgery [i.e., residual disease (RD) <10 mm at the end of surgery]. The results of our work confirm the role of complete cytoreduction (i.e., no evidence of disease after surgery) in the survival of patients and even the positive prognostic role of a minimal RD (i.e., <10 mm), whenever complete cytoreduction cannot be achieved. Background: Low-grade serous ovarian cancer (LGSOC) is a rare entity with different behavior compared to high-grade serous (HGSOC). Because of its general low chemosensitivity, complete cytoreductive surgery with no residual disease is crucial in advanced stage LGSOC. We evaluated the impact of optimal cytoreduction on survival outcome both at first diagnosis and at recurrence. Methods: We retrospectively studied consecutive patients diagnosed with advanced LGSOCs who underwent cytoreductive surgery in two oncological centers from January 1994 to December 2018. Survival curves were estimated by the Kaplan-Meier method, and 95% confidence intervals (95% CI) were estimated using the Greenwood formula. Results: A total of 92 patients were included (median age was 47 years, IQR 35-64). The median overall survival (OS) was 142.3 months in patients with no residual disease (RD), 86.4 months for RD 1-10 mm and 35.2 months for RD >10 mm (p = 0.002). Progression-free survival (PFS) was inversely related to RD after primary cytoreductive surgery (RD = 0 vs RD = 1-10 mm vs RD >10 mm, p = 0.002). On multivariate analysis, RD 1-10 mm (HR = 2.30, 95% CI 1.30-4.06, p = 0.004), RD >10 mm (HR = 3.89, 95% CI 1.92-7.88, p = 0.0004), FIGO stage IV (p = 0.001), and neoadjuvant chemotherapy (NACT) (p = 0.010) were independent predictors of PFS. RD >10 mm (HR = 3.13, 95% CI 1.52-6.46, p = 0.004), FIGO stage IV (p <0.0001) and NACT (p = 0.030) were significantly associated with a lower OS. Conclusions: Optimal cytoreductive surgery improves survival outcomes in advanced stage LGSOC s . When complete debulking is impossible, a RD <10 mm confers better OS compared to an RD >10 mm in this setting of patients.

Neoadjuvant chemotherapy followed by radical surgery in locally advanced vulvar carcinoma: a single-institution experience.

BACKGROUND: Squamous cell carcinoma of the vulva is a rare malignancy that affects elderly women. About one-third of vulvar cancers are diagnosed in an advanced stage, requiring extensive surgery. Neoadjuvant chemotherapy (NACT) has been introduced to reduce local tumor burden. In this retrospective study, we analyze the efficacy and toxicity of NACT followed by radical surgery. METHODS: Patients with locally advanced vulvar cancer (LAVC) treated at our institution with neoadjuvant platinum and paclitaxel-based chemotherapy ± ifosfamide followed by surgery at our institution were retrospectively identified. RESULTS: Fourteen patients (93%) completed NACT with tolerable toxicities (G3-G4 toxicity: 30%). Thirteen patients (87%) underwent surgery. The overall clinical response rate on vulvar disease was 66% (20% complete response, 46% partial response), confirmed by histopathologic analysis, while on inguinal lymph nodes it was 69% (23% complete response, 46% partial response). At the pathologic examination, all patients had negative surgical margins. Three out of 9 patients (33%) with lesions infiltrating the urethral meatus and 4 patients out of 7 (57%) with anal involvement did not require urethral amputation or colostomy, respectively, after NACT. No severe postoperative complications were described. Overall survival at 5 years was 60%, and median overall survival was 76 months. CONCLUSION: NACT followed by surgery in locally advanced vulvar cancer is well tolerated and allows surgical modulation.

Genome-wide Copy-number Alterations in Circulating Tumor DNA as a Novel Biomarker for Patients with High-grade Serous Ovarian Cancer.

PURPOSE: High-grade serous epithelial ovarian cancer (HGS-EOC) is defined by high levels of somatic copy-number alterations (SCNA) with marked spatial and temporal tumor heterogeneity. Biomarkers serving to monitor drug response and detect disease recurrence are lacking, a fact which reflects an unmet clinical need. EXPERIMENTAL DESIGN: A total of 185 plasma samples and 109 matched tumor biopsies were collected from 46 patients with HGS-EOC, and analyzed by shallow whole-genome sequencing (sWGS). The percentage of tumor fraction (TF) in the plasma was used to study the biological features of the disease at the time of diagnosis (T0) and correlated with patients' survival. Longitudinal analysis of TF was correlated with CA-125 levels and radiological images to monitor disease recurrence. RESULTS: Gain in the clonal regions, 3q26.2 and 8q24.3, was observed in the 87.8% and 78.05% of plasma samples, suggesting that plasma sWGS mirrors solid biopsies. At T0, multivariate analysis revealed that plasma TF levels were an independent prognostic marker of relapse (P < 0.022). After platinum (Pt)-based treatment, circulating tumor DNA (ctDNA) analysis showed a change in the heterogeneous pattern of genomic amplification, including an increased frequency of amplification, compared with before Pt-based treatment in the 19p31.11 and 19q13.42 regions. TF in serially collected ctDNA samples outperformed CA-125 in anticipating clinical and radiological progression by 240 days (range, 37-491). CONCLUSIONS: Our results support the notion that sWGS is an inexpensive and useful tool for the genomic analysis of ctDNA in patients with HGS-EOC to monitor disease evolution and to anticipate relapse better than serum CA-125, the routinely used clinical biomarker.See related commentary by Dhani, p. 2372.

Early-stage clear cell ovarian cancer compared to high-grade histological subtypes: An outcome exploratory analysis in two oncology centers.

OBJECTIVE: advanced stage clear cell ovarian cancer (CCOC) carries a higher risk of relapse and death compared to other histological subtypes. The prognosis of early-stage CCOC is controversial. METHODS: Early-stage high-grade OC patients from two Italian oncologic centers were included. Patients with early-stage CCOC were compared with those with high-grade endometrioid (HGE) and serous (HGS) OC in terms of relapse-free interval (RFI), cancer-specific survival (CSS) and post relapse cancer-specific survival (prCSS). The Cox proportional hazard model and the restricted mean survival time were used. RESULTS: Between 1981 and 2012, 134 patients with CC, 152 with HGE and 160 with HGS were treated at two referral centers. Median follow-up was 11.5 years. Ten years RFI rates were 80.6%, 72.1%, 60.6%, and CSS rates were 84.3%, 82.6%, 81.7% respectively. Adjuvant chemotherapy significantly improved RFI (aHR 0.61, 95%CI 0.40 to 0.91, P = 0.015). In the multivariable analysis HGS histotype was associated with a shorter RFI compared to CC, (Hazard Ratio [HR]: 1.81; 95%CI: 1.12-2.93; P = 0.016), whereas CSS was not statistically different. prCSS was longer in HGS compared to CCOC (HR, 0.36; 95% CI, 0.17-0.74; P = 0.006). According to the stage, IA/IB/IC1 HGSOC had a shorter RFI (HR, 2.13; 95% CI, 1.14-3.99; P = 0.018) compared to IA/IB/IC1 CCOC, but similar CSS. For prCSS, CC compared to HGS conferred a worse prognosis regardless of the initial stage. CONCLUSIONS: Early-stage CCOC is associated with a longer RFI, similar CSS and a shorter prCSS compared to HGSOC. No prognostic differences were observed between CC and HGE OC. The relapse risk was the lowest in IA/IB/IC1 CC compared to HGS, whereas CC displayed poor sensitivity to chemotherapy after relapse.

The impact of low-volume metastasis on disease-free survival of women with early-stage cervical cancer.

PURPOSE: We aimed to assess the impact of low-volume metastasis (micrometastasis and isolated tumor cells) on disease-free survival (DFS) of women with early-stage cervical cancer. METHODS: Women with clinically suspected stage 1A-IB2 (FIGO 2018 classification) disease who underwent retroperitoneal nodal staging between October 2010 and April 2018, were retrospectively analyzed. The group of women who had undergone lymphadenectomy and standard node pathologic analysis (H&E group), were compared to the group undergoing sentinel node mapping (SLN) and ultrastaging with or without lymphadenectomy (ultrastaging group). At a median follow-up of 45 months, the DFS curves were analyzed. RESULTS: Overall, 573 patients were revised (272 in the H&E group and 302 in the ultrastaging group). Eighty-five patients presented lymph node metastasis (32 in H&E, 53 in ultrastaging). Ultrastaging protocol increased the rate of low-volume metastasis by 5.6%. Twenty patients showed exclusive micrometastasis or ITC's. Seventy-three recurrences occurred (35 in H&E, 38 in ultrastaging). Only 1 out of 53 patients in the ultrastaging group (1.9%) presented with micrometastasis recurred. The 3-year disease-free survival was 89% for the H&E group, and 88% for the ultrastaging group, respectively (p = 0.175). CONCLUSION: Ultrastaging analysis allowed increasing the detection of low volume metastasis in women with early-stage cervical cancer. However, the type of nodal staging did not have an impact on patients' 3-year disease-free survival.

Detection of TP53 Clonal Variants in Papanicolaou Test Samples Collected up to 6 Years Prior to High-Grade Serous Epithelial Ovarian Cancer Diagnosis.

Importance: The low 5-year survival rate of women with high-grade serous epithelial ovarian cancer (HGS-EOC) is related to its late diagnosis; thus, improvement in diagnosis constitutes a crucial step to increase the curability of this disease. Objective: To determine whether the presence of the clonal pathogenic TP53 variant detected in matched primary tumor biopsies can be identified in DNA purified from Papanicolaou test samples collected from women with HGS-EOC years before the diagnosis. Design, Setting, and Participants: This cohort study was conducted among a single-center cohort of women with histologically confirmed diagnosis of HGS-EOC recruited at San Gerardo Hospital, Monza, Italy, from October 15, 2015, to January 4, 2019. Serial dilutions of DNA derived from tumor samples and DNA extracted from healthy women's Papanicolaou test samples were analyzed to define the sensitivity and specificity of droplet digital polymerase chain reaction assays designed to detect the TP53 variants identified in tumors. All available brush-based Papanicolaou test slides performed up to 6 years before diagnosis were investigated at the Mario Negri Institute, Milano, Italy. Data were analyzed from October 2018 to December 2019. Main Outcomes and Measures: The presence of tumor pathogenic TP53 variants was assessed by the droplet digital polymerase chain reaction approach in DNA purified from Papanicolaou test samples obtained from the same patients before diagnosis during cervical cancer screenings. Results: Among 17 included patients (median [interquartile range] age at diagnosis, 60 [53-69] years), Papanicolaou tests withdrawn before diagnosis presented tumor-matched TP53 variants in 11 patients (64%). In 2 patients for whom longitudinal Papanicolaou tests were available, including 1 patient with Papanicolaou tests from 25 and 49 months before diagnosis and 1 patient with Papanicolaou tests from 27 and 68 months before diagnosis, the TP53 clonal variant was detected at all time points. Conclusions and Relevance: These findings suggest that noninvasive early molecular diagnosis of HGS-EOC is potentially achievable through detection of TP53 clonal variants in the DNA purified from Papanicolaou tests performed during cervical cancer screening.

Impact of Bevacizumab-containing Primary Treatment on Outcome of Recurrent Ovarian Cancer: An Italian Study.

BACKGROUND/AIM: The aim of the study was to assess the outcome of advanced ovarian cancer patients who i) underwent primary surgery followed by carboplatin/paclitaxel-based chemotherapy with or without bevacizumab, ii) were in complete response after chemotherapy, iii) and subsequently recurred. PATIENTS AND METHODS: The hospital records of 138 complete responders after chemotherapy with (n=58) or without (n=80) bevacizumab were reviewed. RESULTS: Both survival after recurrence and overall survival were related to age (≤61 vs. >61 years, p=0.002 and p=0.0001), performance status (0 vs. ≥1, p=0.002 and p=0.001), histotype (serous vs. non serous, p=0.005 and p=0.01), time to recurrence (≥12 vs. <12 months, p<0.0001 and p<0.0001) and treatment at recurrence (surgery plus chemotherapy vs. chemotherapy, p=0.01 and p=0.004), but not to first-line treatment. CONCLUSION: This investigation failed to detect a more aggressive behavior of recurrent ovarian cancer after bevacizumab-containing primary treatment.

Expression profiles of PRKG1, SDF2L1 and PPP1R12A are predictive and prognostic factors for therapy response and survival in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGS-EOCs) is generally sensitive to front-line platinum (Pt)-based chemotherapy although most patients at an advanced stage relapse with progressive resistant disease. Clinical or molecular data to identify primary resistant cases at diagnosis are not yet available. HGS-EOC biopsies from 105 Pt-sensitive (Pt-s) and 89 Pt-resistant (Pt-r) patients were retrospectively selected from two independent tumor tissue collections. Pathway analysis was done integrating miRNA and mRNA expression profiles. Signatures were further validated in silico on a cohort of 838 HGS-EOC cases from a published dataset. In all, 131 mRNAs and 5 miRNAs belonging to different functionally related molecular pathways distinguish Pt-s from Pt-r cases. Then, 17 out of 23 selected elements were validated by orthogonal approaches (SI signature). As resistance to Pt is associated with a short progression-free survival (PFS) and overall survival (OS), the prognostic role of the SI signature was assessed, and 14 genes associated with PFS and OS, in multivariate analyses (SII signature). The prognostic value of the SII signature was validated in a third extensive cohort. The expression profiles of SDF2L1, PPP1R12A and PRKG1 genes (SIII signature) served as independent prognostic biomarkers of Pt-response and survival. The study identified a prognostic molecular signature based on the combined expression profile of three genes which had never been associated with the clinical outcome of HGS-EOC. This may lead to early identification, at the time of diagnosis, of patients who would not greatly benefit from standard chemotherapy and are thus eligible for novel investigational approaches.

Role of 18 F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in malignant ovarian germ cell tumors: a single-center experience with long term follow-up.

INTRODUCTION: 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a diagnostic tool widely used in oncology, but to date there are no established recommendations for its use in malignant ovarian germ cell tumors. The aim of this study was to evaluate the role of 18F-FDG PET/CT in the clinical management of patients with malignant ovarian germ cell tumors. METHODS: This was a retrospective review of 18F-FDG PET/CT scans performed in patients diagnosed with malignant ovarian germ cell tumors treated at the gynecology department of San Gerardo Hospital (Monza, Italy) from June 2006 to December 2016. Data collected included clinical history, radiological, biochemical and pathological evaluation, treatment, follow-up, outcome, and clinical indication for the PET/CT scan. PET/CT findings were categorized as negative/normal (no abnormal FDG uptake or physiological uptake), positive/abnormal (FDG uptake considered to indicate active germ cell malignancy), or equivocal (FDG uptake of uncertain significance, not clearly correlated to neoplastic disease). RESULTS: A total of 69 PET/CT scans in 37 patients were evaluated. The mean age at diagnosis was 25 years (range 20-48). The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage I (22/37) disease and had a diagnosis of dysgerminomas (18/37). Imaging indications were initial staging before treatment (4/69, 6%), staging after inadequate staging surgery (24/69, 35%), restaging after adjuvant chemotherapy (17/69, 25%), relapse suspect (9/69, 13%), and follow-up (15/69, 21%). Pathology confirmation of PET/CT results was available in 28/69 (40.5%) studies. All negative PET/CT (15/28) cases were confirmed with laparoscopy as true negative; among 13/28 positive PET cases, histopathology confirmed 7 (54%) as true positive and 6 (46%) as false positive (5 inflammatory and 1 mature teratoma implants). Patient-based analysis showed 100% sensitivity, 71% specificity, 54% positive predictive value, 100% negative predictive value, and 79% accuracy. Clinical follow-up was available in 41 (59.4%) of 69 PET/CT images: 28/41 studies were negative and 13/41 positive. A mean follow-up of 28 months (median 15, range 5-102) confirmed negative PET/CT studies. A total of 13 positive PET/CT patients underwent chemotherapy with subsequent evidence of disease response. DISCUSSION: PET/CT in malignant ovarian germ cell tumors was mainly performed for staging after inadequate staging surgery or for restaging after adjuvant chemotherapy. PET/CT was associated with high sensitivity and negative predictive value.

Incorporating 3D laparoscopy for the management of locally advanced cervical cancer: a comparison with open surgery.

PURPOSE: To test the effects of the implementation of 3D laparoscopic technology for the execution of nerve-sparing radical hysterectomy. METHODS: Thirty patients undergoing nerve-sparing radical hysterectomy via 3D laparoscopic (3D-LNSRH, n = 10) or open surgery (NSRH, n = 20) were studied prospectively. RESULTS: No significant differences were observed in baseline patient characteristics. Operative times were similar between groups. We compared the first 10 patients undergoing 3D-LNSRH with the last 20 patients undergoing NSRH. Baseline characteristics were similar between groups (p>0.2). Patients undergoing 3D-LNSRH had longer operative time (264.4 ± 21.5 vs 217.2 ± 41.0 minutes; p = 0.005), lower blood loss (53.4 ± 26.1 vs 177.7 ± 96.0 mL; p<0.001), and shorter length of hospital stay (4.3 ± 1.2 vs 5.4 ± 0.7 days; p = 0.03) in comparison to patients undergoing open abdominal procedures. No intraoperative complication occurred. One (10%) patient had conversion to open surgery due to technical difficulties and the inability to insert the uterine manipulator. A trend towards higher complication (grade 2 or worse) rate was observed for patients undergoing NSRH in comparison to 3D-LNSRH (p = 0.06). Considering only severe complications (grade 3 or worse), no difference was observed (0/10 vs 2/20; p = 0.54). CONCLUSIONS: 3D-laparoscopic nerve-sparing radical hysterectomy is a safe and effective procedure. The implementation of 3D laparoscopic technology allows the execution of challenging operations via minimally invasive surgery, thus reducing open abdominal procedure rates. Further large prospective studies are warranted.