Diana Giannarelli

Lifestyle and environmental factors in women carrying BRCA pathogenic variants with and without cancer

Abstract Background In the development of breast cancer and ovarian cancer there may be an influence of lifestyle and environmental factors. This influence could be relevant also in patients with genetic predisposition such as in carriers of germline pathogenic variants in the BRCA genes. However, this issue has been addressed in only a few studies so far. Methods In this retrospective, multicenter case-control study, we enrolled participants with a pathogenic variant BRCA gene and divided into 2 groups: group 1, patients with breast cancer and/or ovarian cancer, and group 2, subjects without cancer. We compared these groups regarding demographic data as age, body mass index, smoking habits, estroprogestinic use, Mediterranean diet, and physical activity. Multivariable analyses were used to identify predisposing factors. All evaluations were 2-tailed and considered statistically significant if the P value was less than .05. Results We enrolled 281 participants, 135 (79.4%) with breast cancer, 32 (18.8%) with ovarian cancer, 3 (1.8%) with both, and 111 unaffected (39.5%) women. Independent risk factors associated with cancer were age (P < .0001); body mass index (P = .007); family history (P = .002); occupation (P = .003); smoking habits (P = .012), number of cigarettes smoked (P = .016), and pack-year index (P = .022); and estroprogestinic use (P = .032) and years of estroprogestinic use (P = .029). At multivariate analysis, age (odds ratio [OR] = 1.062; P < .0001), family history (OR = 0.129; P = .001), number of cigarettes smoked (P = .014), and estroprogestinic use (OR = 2.009; P = .025) were statistically significant risk factors associated with cancer development. Conclusions In the development of breast cancer and ovarian cancer, lifestyle and environmental factors seem to play a statistically significant role in the presence of genetic predisposition associated with BRCA1 and BRCA2 gene mutations.

Focal lymphovascular space invasion: Friend or foe? A large retrospective analysis on stage I endometrioid endometrial carcinomas

Literature is inconsistent with respect to clinical value of lymphovascular space invasion (LVSI) semiquantitative assessment. We aim to investigate the prognostic role of LVSI extent in stage I endometrioid endometrial carcinomas (ECs) classified by immunohistochemistry (IHC) analysis. Patients with stage I endometrioid EC undergone primary surgery were retrospectively included. Following World Health Organization definition for LVSI pathologic evaluation, subjects were divided into: LVSI-negative; LVSI-focal; LVSI-substantial. An IHC-based model was utilized to classify patients into: p53-aberrant (p53abn); mismatch repair deficient (MMRd); mismatch repair proficient with positive estrogen receptors (MMRp-ERpos); and mismatch repair proficient with negative estrogen receptors (MMRp-ERneg). 2091 subjects were included and divided into: 78.0 % (n:1631) LVSI-negative, 10.6 % (n:221) LVSI-focal, and 11.4 % (n:239) LVSI-substantial. Presence of LVSI (any extent) was associated with older age, larger tumor size and deeper myometrial infiltration. Patients with LVSI-substantial presented with higher incidence of grade 3 tumors, p53abn and MMRd status. Conversely, most LVSI-negative and LVSI-focal cases were MMRp-ERpos. At multivariable regression, LVSI-substantial was independently associated with reduced 5-year disease-free survival (DFS) and overall-survival (OS). LVSI-negative and LVSI-focal groups had similar DFS (p = 0.42) and OS (p = 0.09), whereas comparison with LVSI-substantial demonstrated significantly poorer outcomes for patients with substantial invasion. These findings were confirmed in sub-analyses of cases with grade 1-2 endometrioid and myometrial infiltration, and in the MMRp-ERpos cohort. In stage I endometrioid ECs, LVSI-focal was not associated with reduced oncologic outcomes compared to LVSI-negative. In contrast, LVSI-substantial was associated with aggressive clinicopathologic and molecular features and behaved as an independent prognostic factor for reduced survival. Our results were further confirmed in two low-risk EC settings: grade 1-2 with myometrial infiltration, and the MMRp-ERpos group.

Hyperthermic Intraperitoneal Chemotherapy in Platinum-Sensitive Recurrent Ovarian Cancer: A Randomized Trial on Survival Evaluation (HORSE; MITO-18)

PURPOSE To investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to secondary cytoreductive surgery (SCS) without neoadjuvant chemotherapy has a benefit on progression-free survival (PFS), as opposed to SCS alone in patients with platinum-sensitive recurrent epithelial ovarian cancer (platinum-free interval, >6 months). METHODS This was a multicenter randomized phase III study. Random assignment was performed at the time of surgery in cases with residual tumor ≤0.25 cm. HIPEC with cisplatin (CDDP) 75 mg/m 2 for 60 minutes at 41.5°C was administered at the end of surgery in the experimental arm. Both groups received postoperative platinum-based chemotherapy. The primary end point was PFS. The safety profile and postrecurrence survival (PRS) were the secondary end points. RESULTS A total of 167 patients underwent random assignment, 82 patients to SCS plus HIPEC (experimental arm) and 85 to SCS alone (control arm). The median follow-up was 83 months (IQR, 64-102). The median PFS was 23 months (95% CI, 17 to 29) in the group that underwent surgery alone and 25 months (95% CI, 18 to 32) in the group that underwent cytoreductive surgery with HIPEC. The probability of PRS at 5 years was 61.6% (95% CI, 50.8 to 72.4) in the SCS group and 75.9% (95% CI, 66.5 to 85.3) in the SCS plus HIPEC group. The incidence of postoperative adverse events of any grade was similar between the two groups. CONCLUSION The addition of HIPEC to complete or nearly complete primary SCS did not confer a benefit in terms of PFS in patients with platinum-sensitive peritoneal recurrence.

Sentinel-node biopsy in apparent early stage ovarian cancer: final results of a prospective multicentre study (SELLY)

To evaluate the sensitivity and specificity of sentinel-lymph-node mapping compared with the gold standard of systematic lymphadenectomy in detecting lymph node metastasis in apparent early stage ovarian cancer. Multicenter, prospective, phase II trial, conducted in seven centers from March 2018 to July 2022. Patients with presumed stage I-II epithelial ovarian cancer planned for surgical staging were eligible. Patients received injection of indocyanine green in the infundibulo-pelvic and, when feasible, utero-ovarian ligaments and sentinel lymph node biopsy followed by pelvic and para-aortic lymphadenectomy was performed. Histopathological examination of all nodes was performed including ultra-staging protocol for the sentinel lymph node. 174 patients were enrolled and 169 (97.1 %) received study interventions. 99 (58.6 %) patients had successful mapping of at least one sentinel lymph node and 15 (15.1 %) of them had positive nodes. Of these, 11 of 15 (73.3 %) had a correct identification of the disease in the sentinel lymph node; 7 of 11 (63.6 %) required ultra-staging protocol to detect nodal metastasis. Four (26.7 %) patients with node-positive disease had a negative sentinel-lymph-node (sensitivity 73.3 % and specificity 100.0 %). In a multicenter setting, identifying sentinel-lymph nodes in apparent early stage epithelial ovarian cancer did not reach the expected sensitivity: 1 of 4 patients might have metastatic lymphatic disease unrecognized by sentinel-lymph-node biopsy. Nevertheless, 35.0 % of node positive patients was identified only thanks to ultra-staging protocol on sentinel-lymph-nodes.

Are all mismatch repair deficient endometrial cancers created equal? A large, retrospective, tertiary center experience

One third of endometrial carcinomas (ECs) presents with mismatch repair deficiency (MMRd). Of these, 70 % are caused by somatic hypermethylation of MLH1 promoter; the remaining cases are determined by Lynch syndrome or double somatic inactivation of MMR genes. Although associated with good-intermediate prognosis, heterogeneity in treatment response and survival has been reported among MMRd ECs. We aim to investigate differences in pathologic aggressiveness and event-free survival (EFS) among three MMRd EC subtypes, classified by immunohistochemistry (IHC) and MLH1 methylation analysis. Subjects undergone surgical staging for EC were retrospectively included. IHC analysis was performed in all patients to assess MMR and p53 status. Methylation analysis was performed in MMRd patients with IHC-negative MLH1. The MMRd population was classified into: 1)MLH1-hypermethylated (MLH1-HyMet); 2)MLH1-unmethylated (MLH1-UnMet); 3)IHC-negative MSH2 and/or MSH6 or PMS2 alone (non-MLH1). Of 1171 patients undergoing surgical staging and IHC assessment, 362 (30.9 %) were classified as MMRd and included in the analysis. Among these, 59.7 % (n = 216) were MLH1-HyMet, 11 % (n = 40) MLH1-UnMet, and 29.3 % (n = 106) non-MLH1. Compared to MLH1-UnMet and non-MLH1, MLH1-HyMet was associated with older age, higher BMI, larger tumor size, deeper myometrial invasion, substantial lymphovascular space invasion, lower frequency of early-stage and low-risk disease. EFS was similar when comparing the MMRd subtypes, even after adjusting for stage and tumor histology. However, a trend of MLH1-HyMet toward poorer prognosis can be observed, particularly in the advanced/metastatic setting. MLH1-hypermethylated MMRd ECs display more aggressive clinicopathologic features compared to the other MMRd subgroups. However, although a suggestive trend toward poorer EFS was observed in the hypermethylated subset, particularly in the advanced setting, no significant differences in prognosis were detected among the MMRd subtypes.

Laparoscopic tumor load as an independent prognostic marker in advanced ovarian cancer: a 3-year cohort study

To evaluate the association between pre-operative tumor load, progression-free survival, and overall survival in patients with advanced epithelial ovarian cancer. Patients diagnosed with The International Federation of Gynecology and Obstetrics (FIGO) stage III to IV primary ovarian, tubal, or peritoneal carcinoma, who underwent intraoperative abdominal disease spread assessment using the laparoscopic predictive index value (PIV) at the Gynecologic Oncology Unit of the Policlinico-Agostino Gemelli University Hospital-IRCCS, Rome, from January 2018 to December 2020, were included. Patients were divided into 2 groups based on median laparoscopic PIV at diagnosis in our population: group A (low tumor load) with PIV from 0 to 6, group B (high tumor load), with PIV from 8 to 12, and/or with extensive miliary carcinomatosis and mesentery retraction. During the study period, 817 patients with newly diagnosed advanced epithelial ovarian cancer were included, with a median age of 60 years (range;18-87), a median CA125 level of 584 (range; 5-6262), and ascites presence in 436 cases (54.0%). With a median follow-up of 51.0 months (95% CI 49.5 to 52.5), 571 (69.9%) recurrences and 388 (47.5%) deaths were observed. The median progression-free and overall survival were 22.0 months (95% CI 19.8 to 24.2) and 53.0 months (95% CI 48.7 to 57.3), respectively. A statistically significant correlation between PIV and risk of recurrence or death was observed (p < .001). The median progression-free survival was 27 months for PIV < 8 versus 16 months for PIV ≥ 8 (p < .001). The 5-year survival rate was 54.8 % (95% CI 49.1 to 60.5) for PIV < 8 and 30.4% (95% CI 23.7 to 37.1) for PIV ≥ 8 (p < .001). This correlation was maintained in the subgroup analysis by stage. Specifically, for FIGO stage III, the 5-year survival rate was 57.2 % for the group with PIV < 8 and 26.3 % for the group with PIV ≥ 8; for FIGO stage IV, it was 47.9 % for the group with PIV < 8, and 32.8 % for the group with PIV ≥ 8. In multivariate analysis, PIV was confirmed as an independent prognostic factor for both progression-free and overall survival, along with BRCA status and residual tumor after surgery, as well as ascites for progression-free survival and age for overall survival. This study underscores tumor burden at diagnosis, quantified by PIV, as a key independent prognostic factor in advanced ovarian cancer, irrespective of FIGO stage or BRCA status, even in the era of maintenance therapies.

ENDOESTRO score: Where is the dark side? Evaluation of estrogen receptor expression cutoff in endometrial cancer molecular classification, an ambispective study

Estrogen receptor (ER) expression has prognostic value in endometrial cancer (EC), also in the context of molecular classification. However, a standardized cutoff to define ER positivity is lacking. To identify the ER expression cutoff that best correlates with survival outcomes overall and within each molecular subgroup. We conducted an ambispective study comprising a retrospective phase (Feb 2017-Feb 2022) and a prospective phase (Mar 2022-Jan 2024), including patients with EC who underwent surgery at our institution. In the retrospective cohort, molecular subgroups were defined by immunohistochemistry (IHC): 1) MMRp Among 2084 patients, ER < 10 % was the strongest cutoff for prognosis based on disease-free survival (DFS). Patients with ER < 10 % and < 1 % shared similar unfavorable clinicopathological and molecular features, while ER ≥ 10 % was associated with more favorable profiles. ER < 10 % was an independent adverse prognostic factor in uni- and multivariate analyses for DFS and overall survival, particularly in MMRp ER < 10 % expression is a robust prognostic indicator, associated with worse outcomes and may serve as a clinically meaningful cutoff in endometrial cancer risk stratification. Further prospective validation is warranted.

Cytoreductive surgery for advanced epithelial ovarian cancer in the poly(ADP-ribose) polymerase inhibitors era—Is it time for a new paradigm shift? A systematic review and meta-analysis

In patients with newly diagnosed advanced high-grade serous and endometrioid epithelial ovarian cancer (EOC) first-line maintenance therapy with poly(ADP-ribose) polymerase inhibitors (PARPi) tremendously improved progression-free survival (PFS). Yet, data on the effect of PARPi in proportion to postoperative residual disease status were lacking. A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items of Systematic reviews and Meta-Analysis (PRISMA) guidelines. We searched Medline/Pubmed, Embase and Cochrane databases as well as meeting abstracts until 18th March 2023. Hazard ratios (HRs) alongside their 95% confidence intervals (CIs) for PFS were extracted from the studies. A subgroup analysis was conducted to examine the effect of PARPi according to postoperative residual disease. A total of six phase III randomised controlled trials were included and comprised SOLO 1, PAOLA 1, PRIMA, PRIME, ATHENA-MONO and VELIA. Patients who received PARPi following complete gross resection showed greatest PFS benefit. Compared with placebo, maintenance with PARPi significantly improved PFS in patients with macroscopic residual disease (pooled HR 0.55; 95% CI 0.44-0.68). This magnitude was comparable to that found in patients with complete gross resection (pooled HR 0.53; 95% CI 0.41-0.67). Patients with macroscopic residual disease benefit from PARPi at the same extent as cases with complete gross resection. However, patients with complete gross resection who were treated with PARPi show the most favourable PFS rates. Hence, the pursuit of achieving complete cytoreduction remains valid in the PARPi era.

Hormone replacement therapy in gynecological cancer survivors and BRCA mutation carriers: a MITO group survey

Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. A total of 61 participants completed the questionnaire (47 out of 180 MITO centers; compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO. Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.

Lymph node staging in grade 1–2 endometrioid ovarian carcinoma apparently confined to the ovary: Is it worth?

The aim of this study was to assess the disease-free survival (DFS) and overall survival (OS) of patients with grade 1-2 endometrioid ovarian carcinoma apparently confined to the ovary, according to surgical staging. Multicenter, retrospective, observational cohort study. Patients with endometrioid ovarian carcinoma, surgical procedure performed between May 1985 and December 2019, stage pT1 N0/N1/Nx, grade 1-2 were included. Patients were stratified according to lymphadenectomy (defined as removal of any lymph node versus no lymph node assessment), and subgroup analyses according to tumor grade were performed. Kaplan-Meier curves and cox regression analyses were used to perform survival analyses. 298 patients were included. 199 (66.8 %) patients underwent lymph node assessment. Of these, 166 (83.4 %) had unilateral/bilateral pelvic and para-aortic/caval lymphadenectomy. Eleven (5.5 %) patients of those who underwent lymph node assessment showed pathologic metastatic lymph nodes (FIGO stage IIIA1). Twenty-seven patients (9.1 %) had synchronous endometrioid endometrial cancer. After a median follow up of 45 months (95 %CI:37.5-52.5), 5-year DFS and OS of the entire cohort were 89.8 % and 96.2 %, respectively. Age ≤ 51 years (HR=0.24, 95 %CI:0.06-0.91; p = 0.036) and performance of lymphadenectomy (HR=0.25, 95 %CI: 0.07-0.82; p = 0.022) represented independent protective factors toward risk of death. Patients undergoing lymphadenectomy had better 5-year DFS and OS compared to those not receiving lymphadenectomy, 92.0 % versus 85.6 % (p = 0.016) and 97.7 % versus 92.8 % (p = 0.013), respectively. This result was confirmed after exclusion of node-positive patients. When stratifying according to tumor grade (node-positive excluded), patients with grade 2 who underwent lymphadenectomy had better 5-year DFS and OS than those without lymphadenectomy (93.0 % versus 83.1 %, p = 0.040 % and 96.5 % versus 90.6 %, p = 0.037, respectively). Staging lymphadenectomy in grade 2 endometrioid ovarian carcinoma patients was associated with improved DFS and OS. Grade 1 and grade 2 might be considered as two different entities, which could benefit from different approach in terms of surgical staging. Prospective studies, including molecular profiles are needed to confirm the survival drivers in this rare setting.

Evaluation of decision regret and reproductive concerns following fertility-sparing treatment in adolescents and young adults with atypical endometrial hyperplasia or endometrioid endometrial cancer-a single-center cross-sectional study.

To examine decision regret and reproductive concerns following fertility-sparing treatment in adolescents and young adults (defined as aged 15-39 years) with endometrial atypical hyperplasia or endometrioid endometrial cancer. All adolescents and young adults diagnosed with endometrial atypical hyperplasia or endometrioid endometrial cancer between January 1, 2021, and December 31, 2023, who underwent fertility-sparing treatment at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS hospital in Rome, Italy, were contacted. Patients were asked to fill out the 5-item Decision Regret Scale score and the 18-item Reproductive Concerns After Cancer score, assessing the following areas of concern: fertility potential, partner disclosure of fertility status, child's health, personal health, acceptance of possible infertility, and becoming pregnant. Thirty-two patients gave informed consent and were included. Complete treatment response was achieved in 93.9% of cases, whereas among those with endometrioid endometrial cancer the complete response rate was 100.0%. After a median follow-up of 29 months (range; 11-44 months), 1 patient (3.1%) experienced persistent disease and 6 patients (18.8%) had a relapse. Five patients (15.6%) underwent hysterectomy. Among the 20 patients who tried to conceive following diagnosis, a total of 12 pregnancies were achieved in 11 patients (pregnancy rate 60.0%). The live birth rate per pregnancy was 66.7%; 2 pregnancies were still ongoing. Mean Decision Regret Scale score was 16.6 (SD 24.0, range; 0-100). Mean Reproductive Concerns After Cancer score for all items was 2.78 (SD 1.17, range; 1-5), with greatest concern for acceptance of possible infertility (mean 3.23, SD 1.08), fertility potential (mean 3.12, SD 1.24) and child's health (mean 3.02, SD 1.31). Regardless favorable oncological and obstetrical outcomes and mild decision regret, reproductive concerns are common following fertility-sparing treatment in adolescents and young adults with endometrial atypical hyperplasia or endometrioid endometrial cancer.

Patent Blue SLN in Early Ovarian Cancer Prospective Study (FIGO I-II) Evaluating Patent Blue SLN Mapping. Injection Into IP/UO Ligaments in Situ. Goals: Assess Feasibility and Accuracy vs Standard Lymphadenectomy to Minimize Surgical Morbidity

the standard of care in case of early ovarian cancer (stage I or II) is a complete surgery. This surgery includes : hysterectomy (remove of the uterus), bilateral salpingo-oophorectomy (remove of the adnexa), omentectomy (remove of the epiploon), bilateral pelvic lymphadenectomy (remove of pelvic lymph nodes) and para-aortic lymphadenectomy (remove of para-aortic lymph nodes). This procedure is diagnostic, curative and prognostic surgery. In fact, it allows us provider care giver to stratify the stage of the cancer, hence we give the appropriate adjuvant therapy. However, this surgery, especially the extended lymphadenectomy, is associated with some risks: lymphocele, vessel injury, blood loss, morbidity, long recovery period ... In order to reduce these risks, we propose a sentinel lymph node biopsy. This intervention allows us to detect first lymph node relay whether pelvic or para-aortic. In our study, we chose the patent blue dye as a tracer. This tracer is widely used in oncologic surgery (for example in breast cancer) and approved but not in ovarian cancer yet. During surgery for early stage ovarian cancer, we will inject the patent blue dye on both side of the ovarian tumor. Then, we will check for first colorful lymph node, in both pelvic and para-aortic regions. We will send these dissected lymph node to pathology for analysis. Finally, we will continue the procedure as the standard of care. Our objective is to compare the results between the sentinel lymph node and the complete lymphadenectomy and to study the technique of sentinel lymph node biopsy using the blue patent dye as tracer.

Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence

The purpose of this study is to determine the role of surgery followed by hyperthermic intra-peritoneal chemotherapy (HIPEC) versus surgery alone in patients with platinum-sensitive first recurrence of ovarian cancer. Moreover it is a prospective randomized multicenter trial, aimed to investigate the prognostic role of surgery plus HIPEC versus surgery alone in terms of progression free interval, overall survival, morbidity and mortality, second recurrence pattern, quality of life with EORTC QLQ-C30 and QLQ OV28 questionnaires.