Correlation between peritoneal cancer index and survival in advanced epithelial ovarian cancer with complete resection.

OBJECTIVE: The aim of this study was to investigate the relation between the peritoneal cancer index, overall survival, and recurrence free survival, in patients with epithelial ovarian cancer. METHODS: Patients treated at the Gustave-Roussy Institute between December 2004 and November 2017 for advanced epithelial ovarian cancer in complete resection were included. The correlation between the peritoneal cancer index and survival was studied using statistical modeling. Multivariate analysis was performed with a logistic regression model. RESULTS: Of the 351 patients included, 94 (27%) had initial surgery and 257 (73%) had interval surgery. Median follow-up was 52.7 months (range 47.6-63.9). Median peritoneal cancer index was 10 (range 0-32). The linear model best represented the relationship between peritoneal cancer index and overall survival. Patients with neoadjuvant chemotherapy had a greater instantaneous risk of baseline death than those with initial surgery, as well as a more rapid increase in this risk as the peritoneal cancer index increased. Overall survival and recurrence free survival were better in the initial surgery group (103.4 months (79.1-not reached (NR)) vs 66.5 months (59.1-95.3) and 31.8 months (23.7-48.7) vs 25.9 months (23.2-29), respectively). Risk factors for death were body mass index, peritoneal cancer index, and need for neoadjuvant chemotherapy. CONCLUSION: The peritoneal cancer index is a prognostic indicator, but its linear relationship with survival precluded setting a unique peritoneal cancer index cut-off. Moreover, the prognostic impact of peritoneal cancer index was stronger in the setting of neoadjuvant chemotherapy.

[Current post-surgical treatment strategies in first-line ovarian cancer]. / Stratégies thérapeutiques post-chirurgicales actuelles dans les cancers de l'ovaire en première ligne de traitement.

Although the management of epithelial ovarian cancer has evolved significantly over the past few years, it remains a public health issue, as most patients are diagnosed at an advanced stage and relapse after first line treatment. Chemotherapy remains the standard adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) stage I and II tumors, with some exceptions. For FIGO stage III/IV tumors, carboplatin- and paclitaxel-based chemotherapy are the standard of care, in combination with targeted therapies, especially bevacizumab and/or poly-(ADP-ribose) polymerase inhibitors, that have become a key milestone of first-line treatment. Our decision making for the maintenance therapy is based on the FIGO stage, tumor histology, timing of surgery (i.e. primary or interval debulking surgery), residual tumor, response to chemotherapy, BRCA mutation and homologous recombination (HR) status.

Homologous recombination deficiency (HRD) testing on cell-free tumor DNA from peritoneal fluid.

BACKGROUND: Knowing the homologous recombination deficiency (HRD) status in advanced epithelial ovarian cancer (EOC) is vital for patient management. HRD is determined by BRCA1/BRCA2 pathogenic variants or genomic instability. However, tumor DNA analysis is inconclusive in 15-19% of cases. Peritoneal fluid, available in > 95% of advanced EOC cases, could serve as an alternative source of cell-free tumor DNA (cftDNA) for HRD testing. Limited data show the feasibility of cancer panel gene testing on ascites cfDNA but no study, to date, has investigated HRD testing. METHODS: We collected ascites/peritoneal washings from 53 EOC patients (19 from retrospective cohort and 34 from prospective cohort) and performed a Cancer Gene Panel (CGP) using NGS for TP53/HR genes and shallow Whole Genome Sequencing (sWGS) for genomic instability on cfDNA. RESULTS: cfDNA was detectable in 49 out of 53 patients (92.5%), including those with limited peritoneal fluid. Median cfDNA was 3700 ng/ml, with a turnaround time of 21 days. TP53 pathogenic variants were detected in 86% (42/49) of patients, all with HGSOC. BRCA1 and BRCA2 pathogenic variants were found in 14% (7/49) and 10% (5/49) of cases, respectively. Peritoneal cftDNA showed high sensitivity (97%), specificity (83%), and concordance (95%) with tumor-based TP53 variant detection. NGS CGP on cftDNA identified BRCA2 pathogenic variants in one case where tumor-based testing failed. sWGS on cftDNA provided informative results even when tumor-based genomic instability testing failed. CONCLUSION: Profiling cftDNA from peritoneal fluid is feasible, providing a significant amount of tumor DNA. This fast and reliable approach enables HRD testing, including BRCA1/2 mutations and genomic instability assessment. HRD testing on cfDNA from peritoneal fluid should be offered to all primary laparoscopy patients.

Evolution of synchronous female bilateral breast cancers and response to treatment.

Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.

Management of patients with advanced epithelial ovarian cancer: a European survey.

BACKGROUND: The aim of this study was to assess current European practices in the management of patients with advanced epithelial ovarian cancer in 2021. METHODS: A 58-question electronic survey was distributed anonymously to the members of six European learned societies. Initial diagnostic workup and staging, pathological data, surgical data, treatments and follow-up strategies were assessed. RESULTS: A total of 171 participants from 17 European countries responded to emailed surveys. Most participants were experienced practitioners (superior than 15 years of experience) specializing in gynecology-obstetrics (29.8%), surgical oncology (25.1%), and oncogynecology (21.6%). According to most (64.8%) participants, less than 50% of patients were eligible for primary debulking surgery. Variations in the rate of primary debulking surgery depending on the country of origin of the practitioners were observed in this study. The LION study criteria were applied in 70.4% of cases during PDS and 27.1% after chemotherapy. In cases of BRCA1-2 mutations, olaparib was given by 75.0-84.8% of respondents, whereas niraparib was given in cases of BRCA wild-type diseases. CONCLUSIONS: This study sheds light on current practices and attitudes regarding the management of patients with advanced epithelial ovarian cancer in Europe in 2021.

Surgical management of patients with advanced ovarian cancer: Results of a French National Survey.

INTRODUCTION: Desire to homogenize advanced stage ovarian cancer management has led to a debate on the need to centralize cares. The aim was to assess current practices to compare them with centralization motivation and to overview possible perspectives of evolution. METHODS: An anonymous questionnaire of 57 questions has been submitted from August 2021 to October 2021 to members of French gynecological oncological surgical societies. Questions encompassed all aspects of ovarian cancer surgical management, including institutions, technics, indications, and outcomes. RESULTS: Of the 40 responses, 77.5% managed less than 20 cases by themselves, but 67.5% practiced in institution managing more than 30 cases annually. Since the LION trial results' publication, 95% of practitioners have evolved their lymphadenectomy indications. More than 10% of surgery needed digestive resection for 90% of practitioners. Digestive resections rate was significantly higher for practitioners managing more than 20 cases (p<0.01), but it was not for institutions managing more than 30 cases annually (p=0,07). Surgeons performing more than 20 ovarian cancers annually reported less severe complications (p=0.04) compared to low-volume surgeons independently of institution volume. For more than a quarter of the practitioners, less than half of the patients can benefit from the enhanced recovery after surgery program despite benefits of such care. CONCLUSION: Our survey provides an overview of French practices in ovarian cancer management. This survey seems to confirm that minimum volume thresholds could lead to better outcomes. It also underlines that individual performances are as valuable as center volume.

Cervical Cancer and Fertility-Sparing Treatment.

Radical hysterectomy with pelvic node dissection is the standard treatment for early-stage cervical cancer. However, the latter can be diagnosed at a young age when patients have not yet achieved their pregnancy plans. Dargent first described the vaginal radical trachelectomy for patients with tumors <2 cm. It has since been described a population of low risk of recurrence: patients with tumors <2 cm, without deep stromal infiltration, without lymphovascular invasion (LVSI), and with negative lymph nodes. These patients can benefit from a less radical surgery such as conization or simple trachelectomy with the evaluation of the pelvic node status. Tumors larger than 2 cm have a higher risk of recurrence and their treatment is a challenge. There are currently two options for these patients: abdominal radical trachelectomy or neoadjuvant chemotherapy (NACT), followed by fertility-sparing surgery. All patients who wish to preserve their fertility must be referred to expert centers.

Results of a 2021 French National Survey on Management of Patients with Advanced Stage Epithelial Ovarian Cancer.

BACKGROUND: The aim of this study was to assess current French practices in the management of patients with advanced epithelial ovarian cancer. METHOD: a 58-question electronic survey was distributed anonymously to the members of the SFOG (French Society of Gynaecological Oncology), GINECO-ARCAGY (National Investigators Group for Ovarian and Breast Cancer Studies in France) and FRANCOGYN (French research group in oncological and gynaecological surgery). Initial diagnostic workup and staging, pathological data, surgical data, treatments and follow-up strategies were assessed. RESULTS: a total of 107 participants responded to emailed surveys. Most of the respondents were obstetrician-gynaecologists (37.4%), surgical oncologists (34.6%) and medical oncologists (17.8%). According to most (76.8%) participants, less than 50% of patients were eligible for primary debulking surgery (PDS). The LION study criteria were applied in 69.5% of cases during PDS and 39% after chemotherapy. The timing of BRCA testing was very heterogeneous and ranged from 1 to 6 months. The use of bevacizumab as an adjuvant schedule was lower in cases of no residual disease (for 54.5% of respondents) compared to cases of residual disease (for 63.6% of respondents). In cases of BRCA1-2 mutations, olaparib was given by 75.8-84.8% of respondents, whereas niraparib was given in cases of BRCA wild-type diseases. CONCLUSION: this survey provides an extensive and a unique review of current French practices in the management of patients with advanced epithelial ovarian cancer in 2021.

[Surgical de-escalation in gynecologic oncology]. / Désescalade chirurgicale en oncologie gynécologique.

The evolution of knowledge in gynecologic oncology is leading to surgical de-escalation in several areas, particularly in lymph node staging. Sentinel lymph node biopsy that was initially used in low and intermediate risk endometrial cancer, has now been extended to high-intermediate and high-risk endometrial cancer. Sentinel lymph node biopsy plays also an important role in the nodal staging of early-stage cervical cancer. The radicality of hysterectomies in patients with early cervical cancer is under debate. Similarly, surgical staging with para-aortic lymphadenectomy in locally advanced cervical cancer should be performed only for few cases. Systematic pelvic and para-aortic lymphadenectomy in patients with advanced ovarian cancers is not recommended anymore.

Comparison of survival outcomes between laparoscopic and abdominal radical hysterectomy for early-stage cervical cancer: A French multicentric study.

OBJECTIVES: A recent randomized controlled trial has reconsidered the use of laparoscopy for treating patients with early-stage cervical cancer with radical hysterectomy (RH). We aimed to evaluate if surgical approach had an impact on surgical and oncological outcomes in these patients in a French setting. METHODS: Data of 1706 patients with cervical cancer treated between 1996 and 2017 were extracted from maintained databases of 9 French University hospitals. Patients, with FIGO stage IA2 to IIB tumors, treated by radical hysterectomy were selected for further analysis. A propensity score matching was used with a ratio of 2:1 in favor of laparoscopic approach was used. The Kaplan Meier method was used to estimate the survival distribution. RESULTS: 34 patients treated with laparotomy were matched with 61 patients treated by minimally invasive surgery (MIS). There was no difference regarding overall survival (91 % vs 81 %, p > 0.05) or disease-free survival (82 % vs 78 %, p > 0.05). There was no difference regarding surgical outcomes with no excess of postoperative complication in patients with MIS. Hospital stay was significantly longer in patients operated on laparotomy. CONCLUSION: In our study, there was no evidence of a difference in survival between minimally invasive surgery and laparotomy in patients treated with radical hysterectomy for early-stage cervical cancer.

Oncological management of pregnancy-associated cancers: analysis from the French CALG (Cancer Associé à La Grossesse) network.

Background: Pregnancy-associated cancers constitute a major medical challenge. The objective of this study was to describe their epidemiological, oncological and obstetrical outcomes from the French CALG (Cancer Associé à La Grossesse) network.Material and methods: Retrospective analysis of patients diagnosed with a cancer associated with pregnancy between January 2015 and December 2018 after advice from the CALG network.Results: Of 218 patients, 197 (90%) were diagnosed with a cancer during pregnancy and 21 the year following delivery. Requests to the CALG network increased from 36 cases in 2015 to 77 cases in 2018. The disease was diagnosed at local and regional stages in 77% of cases. Breast cancer was the most frequent (56%), followed by ovarian (12%) and uterine cervical cancers (10%). Of the 218 patients, 157 (72%) underwent a treatment during pregnancy. Surgery and chemotherapy during pregnancy were performed in 83 patients (83/218, 38%) and 101 patients (46%) at a median term of 17 (IQR 11-24) and 25 (IQR 18-30) WG, respectively. Eighteen (8.5%) of the women had a pregnancy termination, two (1%) an abortion, one (0.5%) a miscarriage, one (0.5%) had a stillbirth and one (0.5%) patient died during pregnancy. The remaining 174 patients (88%) were allowed to continue the pregnancy. Eight recurrences and four deaths were observed with a median follow-up time of 2.6 years (IQR 2.2-3.8).Conclusions: Our data further describe the incidence and management of pregnancy-associated cancers in western Europe allowing comparisons with other regions.

Author Correction: Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane.

In the original version of this Article, financial support and contributions in manuscript preparation were not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following:'M.P. and P.O. would like to thank Prof. Roderick Y.H. Lim for advice during manuscript preparation and for providing the laboratory and microscopy infrastructure.… [We also thank] the NanoteraProject, awarded to the PATLiSciII Consortium (M.P and P.O)…'.

Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane.

At the stage of carcinoma in situ, the basement membrane (BM) segregates tumor cells from the stroma. This barrier must be breached to allow dissemination of the tumor cells to adjacent tissues. Cancer cells can perforate the BM using proteolysis; however, whether stromal cells play a role in this process remains unknown. Here we show that an abundant stromal cell population, cancer-associated fibroblasts (CAFs), promote cancer cell invasion through the BM. CAFs facilitate the breaching of the BM in a matrix metalloproteinase-independent manner. Instead, CAFs pull, stretch, and soften the BM leading to the formation of gaps through which cancer cells can migrate. By exerting contractile forces, CAFs alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion. Blocking the ability of stromal cells to exert mechanical forces on the BM could therefore represent a new therapeutic strategy against aggressive tumors.Stromal cells play various roles in tumor establishment and metastasis. Here the authors, using an ex-vivo model, show that cancer-associated fibroblasts facilitate colon cancer cells invasion in a matrix metalloproteinase-independent manner, likely by pulling and stretching the basement membrane to form gaps.

Wild-type amyloid beta 1-40 peptide induces vascular smooth muscle cell death independently from matrix metalloprotease activity.

Cerebral amyloid angiopathy (CAA) is an important cause of intracerebral hemorrhages in the elderly, characterized by amyloid-ß (Aß) peptide accumulating in central nervous system blood vessels. Within the vessel walls, Aß-peptide deposits [composed mainly of wild-type (WT) Aß(1-40) peptide in sporadic forms] induce impaired adhesion of vascular smooth muscle cells (VSMCs) to the extracellular matrix (ECM) associated with their degeneration. This process often results in a loss of blood vessel wall integrity and ultimately translates into cerebral ischemia and microhemorrhages, both clinical features of CAA. In this study, we decipher the molecular mechanism of matrix metalloprotease (MMP)-2 activation in WT-Aß(1-40) -treated VSMC and provide evidence that MMP activity, although playing a critical role in cell detachment disrupting ECM components, is not involved in the WT-Aß(1-40) -induced degeneration of VSMCs. Indeed, whereas this peptide clearly induced VSMC apoptosis, neither preventing MMP-2 activity nor hampering the expression of membrane type1-MMP, or preventing tissue inhibitors of MMPs-2 (TIMP-2) recruitment (two proteins evidenced here as involved in MMP-2 activation), reduced the number of dead cells. Even the use of broad-range MMP inhibitors (GM6001 and Batimastat) did not affect WT-Aß(1-40) -induced cell apoptosis. Our results, in contrast to those obtained using the Aß(1-40) Dutch variant suggesting a link between MMP-2 activity, VSMC mortality and degradation of specific matrix components, indicate that the ontogenesis of the Dutch familial and sporadic forms of CAAs is different. ECM degradation and VSMC degeneration would be tightly connected in the Dutch familial form while being two independent processes in sporadic forms of CAA.