Assessment of Salvage Surgery in Persistent Cervical Cancer after Definitive Radiochemotherapy: A Systematic Review.

Background and Objectives: The standard treatment approach in locally advanced cervical cancer (LACC) is exclusive concurrent chemoradiation therapy (RTCT). The risk of local residual disease after six months from RTCT is about 20-30%. It is directly related to relapse risk and poor survival, such as in patients with recurrent cervical cancer. This systematic review aims to describe studies investigating salvage surgery's role in persistent/recurrent disease in LACC patients who underwent definitive RTCT. Materials and Methods: Studies were eligible for inclusion when patients had LACC with radiologically suspected or histologically confirmed residual disease after definitive RTCT, diagnosed with post-treatment radiological workup or biopsy. Information on complications after salvage surgery and survival outcomes had to be reported. The methodological quality of the articles was independently assessed by two researchers with the Newcastle-Ottawa scale. Following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we systematically searched the PubMed, Scopus, Cochrane, Medline, and Medscape databases in May 2022. We applied no language or geographical restrictions but considered only English studies. We included studies containing data about postoperative complications and survival outcomes. Results: Eleven studies fulfilled the inclusion criteria and all were retrospective observational studies. A total of 601 patients were analyzed concerning the salvage surgery in LACC patients for persistent/recurrent disease after RTCT treatment. Overall, 369 (61.4%) and 232 (38.6%) patients underwent a salvage hysterectomy (extrafascial or radical) and pelvic exenteration (anterior, posterior, or total), respectively. Four hundred and thirty-nine (73%) patients had histologically confirmed the residual disease in the salvage surgical specimen, and 109 patients had positive margins (overall range 0-43% of the patients). The risk of severe (grade ≥ 3) postoperative complications after salvage surgery is 29.8% (range 5-57.5%). After a median follow-up of 38 months, the overall RR was about 32% with an overall death rate of 40% after hysterectomy or pelvic exenteration with or without lymphadenectomy. Conclusions: There is heterogeneity between the studies both in their design and results, therefore the effect of salvage surgery on survival and recurrence cannot be adequately estimated. Future homogeneous studies with an appropriately selected population are needed to analyze the safety and efficacy of salvage hysterectomy or pelvic exenteration in patients with residual tumors after definitive RTCT.

Hereditary Women's Cancer: Management and Risk-Reducing Surgery.

Hereditary women's syndromes due to inherited mutations result in an elevated risk of developing gynecological cancers over the lifetime of affected carriers. The BRCA 1 and 2 mutations, Lynch syndrome (LS), and mutations in rare hereditary syndromes increase this risk and require more effective management of these patients based on surveillance and prophylactic surgery. Patients need counseling regarding risk-reducing surgery (RRS) and the time required to perform it, considering the adverse effects of premenopausal surgery and the hormonal effect on quality of life, bone density, sexual activity, and cardiological and vascular diseases. Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard for BRCA-mutated patients. An open question is that of endometrial cancer (EC) risk in patients with BRCA1/2 mutation to justify prophylactic hysterectomy during RRSO surgical procedures. RRS provides a 90-95% risk reduction for ovarian and breast cancer in women who are mutation carriers, but the role of prophylactic hysterectomy is underinvestigated in this setting of patients. In this review, we evaluate the management of the most common hereditary syndromes and the benefits of risk-reducing surgery, particularly exploring the role of prophylactic hysterectomy.

L1CAM Expression in Microcystic, Elongated, and Fragmented (MELF) Glands Predicts Lymph Node Involvement in Endometrial Carcinoma.

In endometrial carcinoma, both L1CAM overexpression and microcystic, elongated and fragmented (MELF) patterns of invasion have been related to epithelial-to-mesenchymal transition and metastatic spread. We aimed to assess the association between L1CAM expression, the MELF pattern, and lymph node status in endometrial carcinoma. Consecutive cases of endometrial carcinoma with MELF pattern were immunohistochemically assessed for L1CAM. Inclusion criteria were endometrioid-type, low-grade, stage T1, and known lymph node status. Uni- and multivariate logistic regression were used to assess the association of L1CAM expression with lymph node status. Fifty-eight cases were included. Most cases showed deep myometrial invasion (n = 42, 72.4%) and substantial lymphovascular space invasion (n = 34, 58.6%). All cases were p53-wild-type; 17 (29.3%) were mismatch repair-deficient. Twenty cases (34.5%) had positive nodes. No cases showed L1CAM positivity in ≥10% of the whole tumor. MELF glands expressed L1CAM at least focally in 38 cases (65.5%). L1CAM positivity in ≥10% of the MELF component was found in 24 cases (41.4%) and was the only significant predictor of lymph node involvement in both univariate (p < 0.001) and multivariate analysis (p < 0.001). In conclusion, L1CAM might be involved in the development of the MELF pattern. In uterine-confined, low-grade endometrioid carcinomas, L1CAM overexpression in MELF glands may predict lymph node involvement.

Comparison of Different Near-Infrared Technologies to Detect Sentinel Lymph Node in Uterine Cancer: A Prospective Comparative Cohort Study.

OBJECTIVES: Sentinel lymph node biopsy is considered a crucial step in endometrial cancer staging. Cervical injection has become the most favored technique and indocyanine green has been demonstrated to be more accurate than other tracers. Different near-infrared camera systems are currently being used to detect indocyanine green in sentinel lymph nodes and have been compared in different patients. The present study aimed to determine the number and site of sentinel lymph nodes detected in the same patients with two different near-infrared technologies. METHODS: This is a prospective, single-center, observational, non-sponsored study. Patients with presumed uterine-confined endometrial cancer were prospectively enrolled. After cervical injection, two different near-infrared cameras were used to detect sentinel lymph nodes at the same time: Olympus, Tokyo, Japan-considered the standard (SNIR); and Medtronic, Minneapolis, MN, USA with VISION SENSE® which is a new laser near-infrared (LNIR) fluorescence laparoscope. The two cameras were alternatively switched on to detect sentinel lymph nodes in the same patients. RESULTS: Seventy-four consecutive patients were included in the study. Most of the patients were diagnosed with endometrioid histology (62, 83.8%), FIGO stage IA (48, 64.9%), grade 2 (43, 58.1%), and underwent surgery with laparoscopic approach (70, 94.0%). The bilateral detection rate was 56/74 (75.7%) with SNIR and 63/74 (85.1%) with LNIR (p = 0.214). The total number of sentinel lymph nodes identified in the left hemipelvis was 65 and 70 with SNIR and LNIR, respectively; while in the right hemipelvis, there were 74 and 76, respectively. The median number of sentinel lymph nodes identified with SNIR and LNIR was 2 (range, 0-4) and 2 (range, 0-4), respectively (p = 0.370). No difference in site of sentinel lymph node detection was evident between the two technologies (p = 0.994). Twelve patients (16.2%) had sentinel lymph node metastasis: in all cases metastatic sentinel lymph nodes were detected both with Olympus and LNIR. CONCLUSIONS: No difference in bilateral detection rate and number or site of sentinel lymph node detection was evident comparing two different technologies of near-infrared camera for ICG detection in endometrial cancer patients. No difference in sentinel lymph node metastases identification was detected between the two technologies.

Further refining 2020 ESGO/ESTRO/ESP molecular risk classes in patients with early-stage endometrial cancer: A propensity score-matched analysis.

BACKGROUND: The integration of molecular features with clinicopathological findings in endometrial cancer classification seems to be able to significantly refine risk assessment. Nevertheless, clinical management remains challenging, and different therapeutic options are available for each class. Further prognostic characterization of the subgroups within each risk class could be helpful in the decision-making process. METHODS: This study evaluated the role of the 2020 European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy and Oncology (ESTRO)/European Society of Pathology (ESP) risk assessment system and the three prognostic profiles adopted in the PORTEC-4a trial in predicting disease-free and overall survival in a retrospective study cohort of patients with early-stage endometrial cancer. Patients were selected according to a 1:2 propensity score matching analysis. Moreover, the sequencing of 29 genes was undertaken for tumor samples. RESULTS: The study included 137 patients. No differences in disease-free or overall survival at 5 years were observed among the 2020 ESGO/ESTRO/ESP risk classes without molecular features (p = .766 and p = .176, respectively). Once molecular features were integrated, the probability of overall survival was significantly different (p = .011). When the three prognostic profiles were applied, the probability of recurrence had a p value of .097, and significant differences were observed in overall survival (p = .004). Among patients experiencing recurrence, 17.6% showed mutations in BRCA1/2, RAD50, BRIP1, and XRCC2, whereas 22.5% had PD-L1-positive expression and an MUTYH mutation. CONCLUSIONS: Further stratification within each risk class according to the most relevant prognostic features could better define the prognosis of patients with early-stage endometrial cancer. Nearly half of the patients who experienced recurrence showed a targetable molecular alteration for which dedicated trials should be encouraged.

DHES0815A, a novel antibody-drug conjugate targeting HER2/neu, is highly active against uterine serous carcinomas in vitro and in vivo.

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. METHODS: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. RESULTS: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p < 0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p < 0.01). CONCLUSIONS: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.

Update on the secondary cytoreduction in platinum-sensitive recurrent ovarian cancer: a narrative review.

The ovarian cancer recurrence occurs in 75% of patients with advanced FIGO stage, and its treatment is a challenge for the oncologist in gynecology. The standard treatment of recurrent ovarian cancer (ROC) usually includes intravenous chemotherapy according to platinum sensitivity. Furthermore, maintenance treatment with target therapies [e.g., anti-angiogenic drug or PARP inhibitors (PARPi)], should be provided if not precedently administrated. In this scenario, secondary cytoreductive surgery (SCS) remains a practical but controversial option for platinum-sensitive ROC (PSROC). So far, several retrospective series and a Cochrane meta-analysis had concluded that SCS could determine better survival outcomes in ROC with favorable prognostic characteristics, such as the presence of a single anatomical site of recurrence, or when patients are accurately selected for surgery based on complete resection's predictive models. Recently, three randomized clinical trials (RCTs) investigated the role of SCS in PSROC patients selected with different criteria. All the three RCTs showed a significant statistical advantage in progression-free survival (PFS) in the SCS group, with an even more significant difference in patients with complete cytoreduction (about 7-month PFS increased). Data on overall survival (OS) are different in the two completed trials. The GOG213 study has documented a longer OS of PSROC patients who received chemotherapy alone compared to surgery plus chemotherapy. Contrarily, the DESKTOP III trial showed 7.7 months of increased OS in the surgery group vs. chemotherapy alone, with a more difference in the complete tumor cytoreduction (CTC) group (12 months). These RCTs thereby suggest that undergoing complete cytoreduction may not be the only key and that the disease biology may also matter. Few recent retrospective series investigated the role of SCS according to BRCA mutation status and the effect of SCS in patients receiving emerging PARPi. A consequence of the developments in SCS and knowledge of different molecular pathways influencing the recurrent disease is that the future research objective should be to individualize and personalize the surgical approach.

Update on new imaging technologies in sentinel node detection.

In most cancers, lymph node status is the most critical factor impacting the evolution of the disease and the overall survival. Identifying potential nodal metastasis allows the oncologist to adjust the stage and, consequently, the patient's treatment. For this reason, a precise evaluation of the regional nodes is mandatory. In gynecological cancers, pelvic, paraaortic, and inguinal nodes are the region most frequently interested by metastasis. In the past years, comprehensive lymphadenectomy was the standard of care for endometrial, cervical, ovarian, and vulvar cancers. However, after introducing the sentinel lymph node (SNL) biopsy in breast cancers, this technique has gained much more interest in gynecology oncology. Several studies have shown that SLN allows an evaluation of the node status without the complications related to the lymphadenectomy that impacts the patient's quality of life. In this review, we discuss the role of SNL biopsy in gynecological cancers and the technique's evolution over the years. Moreover, we debate the OSNA method for SLN analysis that is recently introduced for uterine cancer.

Derangements in HUWE1/c-MYC pathway confer sensitivity to the BET bromodomain inhibitor GS-626510 in uterine cervical carcinoma.

OBJECTIVE: Whole-exome-sequencing (WES) studies reported c-MYC gene-amplification and HUWE1 gene deletion/mutations in a significant number of cervical-cancer-patients (CC) suggesting HUWE1/c-MYC pathway as potential therapeutic target. We investigated HUWE1/c-MYC expression in fresh-frozen-CC and the activity of the novel BET inhibitor GS-626510 (Gilead-Science-Inc) against primary WES CC-cultures and CC-xenografts. METHODS: HUWE1 and c-MYC expression were evaluated by qRT-PCR in 23 CC including 12 fresh-frozen-tumor-tissues and 11 primary-cell-lines. c-Myc expression was also evaluated by Western-Blot (WB) and fluorescence-in-situ-hybridization (FISH) in all 11 fully sequenced primary-CC-cell-lines. Primary tumors were evaluated for sensitivity to GS-626510 in-vitro using proliferation and viability-assays. siRNA experiments were used to evaluate the effect of HUWE1 silencing on primary-CC-cell-line growth and sensitivity to GS-626510. Finally, the in-vivo activity of GS-626510 was studied in CC-CVX8-mouse-xenografts. RESULTS: Fresh-frozen-CC and primary-CC-cell-lines overexpressed c-MYC when compared to normal tissues (p = .01). FISH demonstrated amplification of c-MYC in 9/11 (82%) of the primary-CC-cell-lines. Cell-lines with derangements in HUWE1/c-MYC pathway were highly sensitive to GS-626510, with a dose-response decrease in cell proliferation and viability. siRNA silencing of HUWE1 significantly increased c-MYC expression and CC cell-proliferation and enhanced the in-vitro sensitivity to GS-626510. Twice-daily oral doses of GS-626510 were well tolerated in-vivo and highly effective in decreasing tumor-growth (p = .004) and increasing survival (p = .004) of CC-CVX8 xenografts. CONCLUSIONS: Downregulation/inactivation of HUWE1 may increase c-MYC expression and proliferation in primary-CC-cell-lines. GS-626510 may represent a novel, potentially highly effective therapeutic agent against CC overexpressing c-MYC and/or harboring HUWE1 mutations. Clinical studies with BET inhibitor in CC-patients harboring radiation/chemotherapy-resistant disease are warranted.

Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer.

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2- tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.

Selection of HER2/NEU negative tumor cells as a mechanism of resistance to trastuzumab in uterine serous carcinoma.

BACKGROUND: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer overexpressing HER2/neu in about 30% of cases. Trastuzumab, a humanized monoclonal antibody targeting Her2/Neu, in combination with carboplatin/paclitaxel, is considered the preferred regimen for the treatment of advanced or recurrent HER2/Neu+ USC per NCCN guidelines. CASE: We describe two USC patients with overexpression of HER2/neu at 2+/3+ level by immunohistochemistry and c-erbB2 gene amplification by fluorescence in situ hybridization (FISH) assay that, after an initial clinical response to trastuzumab, developed resistance/progression. Post-treatment biopsy (collected at the time of clinical progression on trastuzumab) demonstrated loss of HER2/neu overexpression in the recurrent/progressing tumor cells in both patients. CONCLUSION: Selection of HER2/NEU negative tumor cells may represent a major mechanism of resistance to trastuzumab in USC patients.

Clinical outcome of recurrent endometrial cancer: analysis of post-relapse survival by pattern of recurrence and secondary treatment.

INTRODUCTION: Recurrence of endometrial cancer is an important clinical challenge, with median survival rarely exceeding 12 months. The aim of this study was to analyze patterns of endometrial cancer recurrence and associations of these patterns with clinical outcome. METHODS: The study included patients with endometrial cancer who underwent primary surgical treatment with or without adjuvant treatment between July 2004 and June 2017 at the Gynaecologic Oncology Unit of one of three tertiary hospitals of the Catholic University Network in Italy with complete follow-up data available. Information on the date and pattern of recurrence was retrieved for each relapse. Post-relapse survival was recorded as the time from the date of recurrence to the date of death or last follow-up. Survival probabilities were compared using log rank tests, and associations of clinico-pathological characteristics with post-relapse survival were tested using Cox's regression models. RESULTS: A total of 1503 patients were included in the analysis. We identified 210 recurrences (14.0%) and 105 deaths (7.0%) at a median follow-up of 34 months (range 1-162). One hundred and fifty-eight recurrences (78.1%) occurred during the first two years of follow-up. Most recurrences were multifocal (n=121, 57.6%) and involved extrapelvic sites (n=38, 65.7%). Parameters associated with post-relapse survival in the univariate analysis included histotype, grade, time to recurrence, pattern of recurrence, number of relapsing lesions, and secondary radical surgery. Only the pattern of recurrence and secondary radical surgery were independent predictors of post-relapse survival in the multivariate analysis (p=0.025 and p=0.0001, respectively). CONCLUSION: Lymph node recurrence and the feasibility of secondary radical surgery were independent predictors of post-relapse survival in patients with recurrent endometrial cancer.

Robotic versus laparoscopic radical hysterectomy in early cervical cancer: A case matched control study.

BACKGROUND: This study aims at evaluating the feasibility, surgical outcome and oncological results observed after robotic radical hysterectomy (RH) compared to laparoscopy for patients with early stage cervical cancer (ECC) patients. METHODS: Between January 2010 and October 2016, 210 patients underwent RH for treatment of ECC: 70 underwent robotic approach (Cases), and 140 underwent laparoscopic approach (Controls). RESULTS: There was no statistically significant difference between the two approaches with regard to clinical patient characteristics and in terms of extent of RH and rate of pelvic and aortic lymphadenectomy. Operative time was significantly longer in the robotic versus laparoscopic group (median = 243 min, range 90-612 versus median = 210 min, range 80-660; p value = 0.008). Conversion to laparotomy was necessary in 4 patients (1.9%) in the whole series. No difference was found in terms of intraoperative and postoperative complications between the two groups. Overall, during the observation period, 34 (16.2%) patients experienced any grade postoperative complications, and 21 (10.0%) had >G2 complications. The 3-yr DFS was 88.0% versus 84.0% in robotic and laparoscopic group, respectively (p value = 0.866). Central and/or lateral pelvic disease represented the most common site of relapse. The 3-yr OS was 90.8% in patients underwent robotic RH versus 94.0% in patients underwent laparoscopic RH (p value = 0.924). CONCLUSIONS: The present study shows the equivalence of robotic and laparoscopic approaches to radical surgery of ECC patients, in terms of perioperative and postoperative outcomes with equivalent survival figures, and thus the choice of approach can be tailored to the choice of patient and surgeon.