Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7.

With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.

Long-term follow-up of efficacy and safety of selinexor maintenance treatment in patients with TP53wt advanced or recurrent endometrial cancer: A subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study.

OBJECTIVE: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy. METHODS: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed. RESULTS: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2 months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9 months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7 months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified. CONCLUSION: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).

[Hyperreactio Luteinalis and an Incidentally Detected FIGO IIIB Borderline Tumor of the Ovary in Pregnancy - Diagnostic, Therapy and Review of Literature]. / Hyperreactio luteinalis mit Zufallsbefund eines serösen Borderline-Tumor des Ovars FIGO IIIB im 3. Trimenon ­ Diagnostik, Therapie, Literaturrecherche.

Adnexal masses affect 2-10% of all pregnancies. The highest incidence of 1-6% can be seen in the first trimester, with a high rate of spontaneous remission. Two percent of these masses are malignant neoplasms or borderline tumors. A rare benign mass of the adnexa in pregnancy is hyperreactio luteinalis characterised by bilateral, multicystic ovaries with a frequent occurrence in the 3rd trimester. Clinical signs include maternal hyperandrogenaemia with virilisation, hyperemesis, nonspecific abdominal pain or laboratory findings of hyperthyroidism and elevated ß-HCG. Hyperreactio luteinalis does not require therapy due to complete spontaneous remission postpartum, but is often treated surgically in graviditate. In our case we report a first-time gravida in the 31st week of pregnancy with a symptomatic 25-cm multicystic, partly solid mass. After antenatal corticosteroid therapy, an exploratory laparotomy with right adnexectomy was performed on suspicion of malignancy. Histology revealed a hyperreactio luteinalis with an incidental finding of a serous borderline tumor of the ovary (FIGO IIIB). At 33 weeks of gestation, a pathological CTG was observed, and an urgent secondary caesarean section by re-longitudinal laparotomy was performed. Postpartum completion surgery revealed no further neoplastic cells.

Is there evidence behind pre- or perioperative cognitive training in gynaecological patients on the prevention of perioperative cognitive dysfunction? A review.

PURPOSE: Perioperative cognitive dysfunction can be observed in all age groups of patients. Sometimes, this is more stressful to the patient than the actual surgical wound. Enhanced recovery after surgery pathways screen for patients at risk and lead to early post-surgical intervention. To prevent cognitive dysfunction, a prehabilitation approach might be useful. METHODS: This systematic literature review provides an overview on the current knowledge on prehabilitation for cognitive dysfunction for gynaecological patients by searching the National Library of Medicine (PubMed) in February 2020 to identify publications regarding presurgical cognitive training with three different search terms. RESULTS: 501 articles were identified and after screening for eligibility five were left for further analysis. Generally, cognitive function is split into several cognitive aspects like anxiety or memory, speed, attention, flexibility or problem-solving functions. Each of these aspects can/need to be trained to show an improvement after general anaesthesia. Training possibilities range from relaxation methods via music, one-on-one personal training sessions to electronically supported training units. CONCLUSION: Prehabilitation of the cognitive function can be split in different cognitive domains. Each of these domains seem to be influenced by training. The training itself can be based on applications or known relaxation methods or even old-fashioned board games. The evidence is, however, still low and there is a need for further studies.

Prevalence of circulating tumor cells in early breast cancer patients 2 and 5 years after adjuvant treatment.

PURPOSE: Several studies have provided evidence on the prognostic relevance of circulating tumor cells (CTCs) detected before and after chemotherapy regarding overall survival (OS) and progression-free survival (PFS) in early breast cancer (EBC). We provide data on the prevalence of CTCs 2 and 5 years after primary diagnosis in a cohort of patients with EBC. METHODS: The SUCCESS study is a multicenter, prospective, randomized trial comparing PFS in primary breast cancer patients undergoing one of two adjuvant chemotherapy regimens followed by 2 versus 5 years of treatment with zoledronate. CTCs from patients without signs of breast cancer recurrence were analyzed in peripheral blood using the FDA cleared CellSearch® System (Veridex, USA) 2 and 5 years after primary diagnosis. RESULTS: CTCs were detected at 2 and 5 years after primary diagnosis in 96 (16.7%) and 47 (8.2%) of the 574 patients, respectively. There were no associations between CTC status and patient and tumor characteristics or treatment regimens. In 442 (77.0%) patients, no CTCs were detected at either of the two time points, and in 11 patients (1.9%), CTCs were found at both 2 and 5 years after primary diagnosis. In 85 (14.8%) patients, CTCs were present 2 years after primary diagnosis but not after 5 years, while 36 (6.3%) patients had CTCs in their blood only at the 5-year follow-up. CONCLUSIONS: In patients with EBC, CTCs can be detected even 5 years after primary diagnosis without clinical signs of disease recurrence.

Therapeutic intervention based on circulating tumor cell phenotype in metastatic breast cancer: concept of the DETECT study program.

PURPOSE: The aim of the ongoing DETECT study program is to evaluate therapeutic intervention based on phenotypes of circulating tumor cells (CTC) in patients with metastatic breast cancer (MBC). Currently (as of July 2015) more than half of the projected about 2000 patients with MBC have already been screened for CTC. METHODS: Women with HER2-negative primary tumor and presence of CTC are recruited into different DETECT trials according to the HER2-phenotype of CTC. Patients with HER2-positive CTC are randomized to treatment with physicians' choice therapy (standard chemo- or endocrine therapy) with or without additional HER2-targeted therapy with lapatinib in the DETECT III trial. In DETECT IVa, postmenopausal patients with hormone-receptor positive primary cancer and HER2-negative CTC receive everolimus and standard endocrine therapy. For women with HER2-negative CTC and triple negative MBC or hormone-receptor positive tumor and indication for chemotherapy, a treatment with eribulin is offered (DETECT IVb). The clinical efficacy is investigated by CTC-Clearance and progression-free survival (PFS). The DETECT V/CHEVENDO trial extends the DETECT study program for women with HER2-positive and hormone-receptor positive MBC. The primary objective of this trial is to compare safety and quality of life (QoL) as assessed by the occurrence of adverse events in patients treated with dual (trastuzumab plus pertuzumab) HER2-targeted therapy plus either endocrine or chemotherapy. The translational research projects of the DETECT study program focus on further molecular characterization of CTC and evaluation of markers for their suitability to predict treatment response and to facilitate the development of more personalized treatment options.

Is open surgery the solution to avoid morcellation of uterine sarcomas? A systematic literature review on the effect of tumor morcellation and surgical techniques.

PURPOSE: Today's surgical standard of care for uterine leiomyomas is laparoscopic and/or vaginal surgery with larger specimens requiring morcellation to avoid open surgery. This is often associated with intra-abdominal dissemination of cellular material which in case of a uterine sarcoma might result in iatrogenic seeding of malignant tumor cells. The aim of this systematic literature review is to evaluate the surgical techniques and the impact of accidental tumor morcellation on the outcome of patients postoperatively diagnosed with malignant uterine sarcomas. METHODS: The National Library of Medicine database (pubmed) and Web of science were searched individually using three different search terms ('morcel* sarcoma', 'survival, sarcoma, treatment, Uter*', and 'disease free survival, sarcoma, treatment, uter*'). After excluding duplicates and screening for relevance, 16 articles were left for full-text review, resulting in seven case series with more than 5 patients. RESULTS: The case numbers range from 14 to 123 patients with the majority of cases being leiomyosarcomas. CONCLUSION: There is no reliable diagnostic tool to differentiate a fibroid from a uterine sarcoma preoperatively. Tumor morcellation occurs in various open and closed surgical techniques and is not limited to laparoscopic surgery only. There is an urgent need for a presurgical diagnostic parameter.

Treatment cost evaluation of extrauterine gravidity: a literature review of medical and surgical treatment costs.

BACKGROUND: The diagnosis of extrauterine pregnancy is possible very early giving the patient and doctors treatment options. As the risks and success rate of medical and surgical treatment are similar, the decision is increasingly influenced by cost-effectiveness. OBJECTIVE: The following article systematically reviews the known literature regarding cost, decision criteria and possible follow-up. METHODS: Literature review of extrauterine gravity in combination with cost in the online National Library of Medicine since 1.1.1997 following the PRISMA recommendations. RESULTS: Six articles were identified in which the cost of the laparoscopic versus medical treatment is reviewed. In five articles, the medical treatment was shown to be more cost effective and in the sixth article the costs were found to be equal. The cost saving varies between 18 and 88% depending on the consideration of direct and indirect costs. If indirect expenses are considered, the total sum increases with treatment failures. Failure rates are given as up to 27% depending on the type of failure (surgical or medical). These rates seem to be linked indirectly with the ß-HCG levels. Predictive parameters for the successful medical treatment are missing. CONCLUSIONS: The treatment of small extrauterine gravidities in haemodynamically stable patients (defined by HCG levels <1,500 IU/l) is medically successful and cost-effective. With HCG levels between 1,500 IU/l and 3,000 IU/l, the treatment costs are similar. HCG levels >5,000 IU/l favour the surgical treatment as being more cost-effective. A similar cut-off for the sonographic imaging is missing.

Pregnancy after advanced ovarian cancer with spontaneous uterine rupture in second trimester: A case report and review of the literature.

Fertility-preserving surgery (FPS) in advanced ovarian cancer (AOC) is extremely rare and consequently, information about the pregnancies of these patients is anecdotal. Therefore, management of the pregnancy after AOC is challenging, especially if an unexpected situation arises. A 31-year-old nulliparous woman was admitted to our tertiary hospital in the 18th week of twin pregnancy with sudden severe abdominal pain. Her medical history included a low-grade AOC stage IIIc diagnosed 2 years before pregnancy and treated by debulking FPS and systemic therapy with carboplatin/paclitaxel and bevacizumab. Clinical examination described normal vital signs and peritoneal irritation without any vaginal discharge. Sonography revealed free fluid in the pouch of Douglas and intact twin pregnancy. Laboratory work showed elevated leukocytes with neutrophilia. To evaluate appendicitis magnetic resonance imaging of the abdomen was indicated. This revealed a uterine rupture with the now extra-cavitary position of the twins. Simultaneously, the patient's symptoms deteriorated, and emergency surgery was necessary where hemoperitoneum with avital fetuses were present. Despite excessive blood loss the uterus could be repaired and preserved. Previous resection of the uterine serosa during her debulking FPS, administration of bevacizumab affecting smooth muscles, and overstretching the uterus in the twin pregnancy were considered as possible risk factors for the presenting uterine rupture. Pregnancy after AOC is possible but should be monitored closely, especially due to the hidden long-term consequences of its therapy. In the differential diagnosis of sudden abdominal pain during pregnancy uterine rupture should be considered even in patients with an unscared uterus.

Curative Polyendocrine Therapy in a 21-year-Old Patient with Endometrial Carcinoma: Case Report and Review of the Literature.

INTRODUCTION: As the numbers of young patients diagnosed with early-stage endometrial carcinoma continue to rise, the question regarding fertility-preserving therapeutic options will increasingly gain significance in the future. CASE PRESENTATION: Here, we present the case of a 21-year-old patient diagnosed with symptomatic atypical endometrial hyperplasia. After 4 months of treatment with medroxyprogesterone acetate, a follow-up dilatation and curettage revealed early-stage, well-differentiated endometrioid endometrial carcinoma. Despite national guidelines recommending hysterectomy, the nulliparous patient expressed a desire to preserve her fertility. Subsequently, she underwent polyendocrine therapy with letrozole, everolimus, metformin, and Zoladex. Forty-three months after diagnosis, the patient successfully gave birth to a healthy child, and there have been no indications of recurrence thus far. DISCUSSION: This case suggests that triple endocrine therapy may be an option for selected patients with early endometrial cancer and a desire for fertility-sparing therapy.

Which Patients Do We Need to Test for BRCA1/2 Mutation? Feasibility of Adjuvant Olaparib Treatment in Early Breast Cancer-Real-World Data from Two Large German Breast Centers.

BACKGROUND: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase III OlympiA trial, olaparib significantly improves overall survival in patients with HER2 negative (HER2-) early breast cancer who (1) carry a BRCA1 or BRCA2 germline mutation (gBRCA1/2-positive), (2) have received (neo)adjuvant chemotherapy and (3) are at high clinical risk. The objective of the current analysis was to determine the number of patients with early HER2- breast cancer who are at high clinical risk, according to the inclusion criteria of OlympiA, and to estimate how many of these patients would meet the criteria for hereditary cancer testing in a real-world analysis. METHODS: All patients included in this retrospective analysis were treated for early breast cancer (eBC) at the Department of Gynecology and Obstetrics, Ulm University Hospital, Germany, and the Department of Women's Health at Tuebingen University Hospital, Germany, between January 2018 and December 2020. Patients were identified as high risk, in line with the clinicopathological determiners used in the OlympiA trial. The criteria of the German Consortium for Hereditary Breast and Ovarian Cancer were used to identify patients who qualify for hereditary cancer testing. RESULTS: Of 2384 eligible patients, 1738 patients (72.9%) showed a hormone receptor positive (HR+)/HER2- tumor biology, 345 patients (14.5%) displayed HER2+ breast cancer and 301 patients (12.6%) suffered from HR-/HER2- breast cancer (TNBC). Of 2039 HER2- breast cancer patients, 271 patients (13.3%) were at high clinical risk. This cohort encompassed 130 of the 1738 patients with HR+/HER2- breast cancer (7.5%) and 141 of 301 patients with TNBC (46.8%). A total of 121 of 271 patients (44.6%) with high clinical risk met the criteria for hereditary cancer testing (34 of 130 (26.2%) HR+/HER2- patients and 87 of 141 (61.7%) patients with TNBC). CONCLUSION: Approximately one in ten patients with HR+/HER2-, and half of the patients with TNBC, meet the high-risk criteria according to OlympiA. Half of these patients do not meet the criteria for hereditary cancer testing and should therefore be tested for the presence of gBRCA1/2 mutations, irrespective of their own or family cancer history. The overall number of patients with early breast cancer benefiting from olaparib needs to be investigated in future studies.

Association Between Obesity and Circulating Tumor Cells in Early Breast Cancer Patients.

BACKGROUND: Obesity and the presence of circulating tumor cells (CTCs) before and/or after chemotherapy are associated with poor outcome in breast cancer (BC) patients. The activation of oncogenic pathways in fatty tissue leads to cell proliferation, suggesting a possible link between obesity and CTCs. MATERIALS AND METHODS: In the phase III SUCCESS A trial, 3754 patients with early BC were randomized to 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine. Data of 1088 patients with CTC assessments (CellSearch-System; Menarini Silicon Biosystems, Italy) and body mass index (BMI) measurements both before and after chemotherapy were available. Patients were classified according to the WHO's international definitions as underweight, normal weight, overweight, or obese, and according to their weight-change during chemotherapy into a weight-loss group (> 5% decrease), stable-weight group (≤ 5% weight-change) or weight-gain group (>5% increase). Associations between CTC positivity and, BMI or weight-change group were analyzed using frequency-table methods. RESULTS: At study entry, 47.4% patients were underweight or normal weight, 33.6% were overweight and 18.9% were obese. Before and after chemotherapy, CTCs were detected in 20.1% and 22.6% of patients, respectively. There was no association between CTC positivity and BMI before (P = 0.104) or after (P = 0.051) chemotherapy. Furthermore, there was no association between weight-change group and CTC status before/after chemotherapy (P = 0.332). CONCLUSIONS: According to our analysis, the risk factors obesity and prevalence of CTCs are not associated and may represent independent prognostic factors.

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer.

PURPOSE: Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS: ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS: Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION: The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.

Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses.

Circulating tumor cells (CTCs) traverse vessels to travel from the primary tumor to distant organs where they adhere, transmigrate, and seed metastases. To cope with these challenges, CTCs have reached maximal flexibility to change their differentiation status, morphology, migratory capacity, and their responses to genotoxic stress caused by metabolic changes, hormones, the inflammatory environment, or cytostatic treatment. A significant percentage of breast cancer cells are defective in homologous recombination repair and other mechanisms that protect the integrity of the replication fork. To prevent cell death caused by broken forks, alternative, mutagenic repair, and bypass pathways are engaged but these increase genomic instability. CTCs, arising from such breast tumors, are endowed with an even larger toolbox of escape mechanisms that can be switched on and off at different stages during their journey according to the stress stimulus. Accumulating evidence suggests that DNA damage responses, DNA repair, and replication are integral parts of a regulatory network orchestrating the plasticity of stemness features and transitions between epithelial and mesenchymal states in CTCs. This review summarizes the published information on these regulatory circuits of relevance for the design of biomarkers reflecting CTC functions in real-time to monitor therapeutic responses and detect evolving chemoresistance mechanisms.

Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis-Results from the Adjuvant SUCCESS A Trial.

The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch®-System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1-827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1-124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy (p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment.

MUC1 (CA27.29) before and after Chemotherapy and Prognosis in High-Risk Early Breast Cancer Patients.

Soluble MUC1 has been discussed as a biomarker for predicting prognosis, treatment efficacy, and monitoring disease activity in breast cancer (BC) patients. Most studies in adjuvant settings have used preoperative assessment. This study, part of the SUCCESS-A trial (NCT02181101), assessed the prognostic value of soluble MUC1 before and after standard adjuvant chemotherapy. Patients with high-risk BC were treated within the SUCCESS-A trial with either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide followed by three cycles of docetaxel or three cycles of FEC followed by three cycles of docetaxel and gemcitabine. Cox regression analyses were performed to investigate the prognostic value of CA27.29 before and after chemotherapy relative to disease-free survival (DFS), along with established BC prognostic factors such as age, body mass index, tumor size, nodal status, estrogen receptor, progesterone receptor, HER2 status, and grading. Pre-chemotherapy and post-chemotherapy CA27.29 assessments were available for 2687 patients of 3754 randomized patients. Pre-chemotherapy CA27.29 assessment was associated with DFS in addition to established prognostic factors. It had no prognostic value in node-negative patients, but there was a clear association in node-positive patients. Post-chemotherapy CA27.29 assessment did not add any prognostic value, either on its own or in addition to pre-chemotherapy CA27.29 assessment.

Risk for Pelvic Metastasis and Role of Pelvic Lymphadenectomy in Node-Positive Vulvar Cancer-Results from the AGO-VOP.2 QS Vulva Study.

The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients.

Evidence suggests that the DNA end-binding protein p53-binding protein 1 (53BP1) is down-regulated in subsets of breast cancer. Circulating tumor cells (CTCs) provide accessible "biopsy material" to track cell traits and functions and their alterations during treatment. Here, we prospectively monitored the 53BP1 status in CTCs from 67 metastatic breast cancer (MBC) patients with HER2- CTCs and known hormone receptor (HR) status of the primary tumor and/or metastases before, during, and at the end of chemotherapeutic treatment with Eribulin. Nuclear 53BP1 staining and genomic integrity were evaluated by immunocytochemical and whole-genome-amplification-based polymerase chain reaction (PCR) analysis, respectively. Comparative analysis of CTCs from patients with triple-negative and HR+ tumors revealed elevated 53BP1 levels in CTCs from patients with HR+ metastases, particularly following chemotherapeutic treatment. Differences in nuclear 53BP1 signals did not correlate with genomic integrity in CTCs at baseline or with nuclear γH2AX signals in MBC cell lines, indicating that 53BP1 detected features beyond DNA damage. Kaplan-Meier analysis revealed an increasing association between nuclear 53BP1-positivity and progression-free survival (PFS) during chemotherapy until the final visit. Our data suggest that 53BP1 detection in CTCs could be a useful marker to capture dynamic changes of chemotherapeutic responsiveness in triple-negative and HR+ MBC.

Detection of ESR1 Mutations in Single Circulating Tumor Cells on Estrogen Deprivation Therapy but Not in Primary Tumors from Metastatic Luminal Breast Cancer Patients.

Mutations in the ligand-binding domain (LBD) of the ESR1 gene result in resistance to estrogen deprivation therapy (EDT) in breast cancer. Their detection might enable optimization of therapy strategies. However, the predictive utility of the primary tumor (PT) is limited, and obtaining serial biopsies of metastatic lesions is challenging. To underline their application as a liquid biopsy, single circulating tumor cells (CTCs) were analyzed with a next-generation sequencing approach for the ESR1 coding region. CTCs from 46 metastatic luminal breast cancer patients were enriched using CellSearch system and isolated by micromanipulation. Their genomic DNA was amplified and the ESR1 gene was sequenced. Furthermore, tissue samples from corresponding PTs and/or metastatic lesions were investigated. ESR1 mutations were detected in 12 patients-exclusively in patients treated with EDT (P = 0.048). In seven cases mutations were located in the hotspot regions in the LBD. Six novel mutations were identified. ESR1 mutations were absent in PT tissue samples and were detected only in metastases obtained after CTC characterization. Single-cell CTC analysis for ESR1 mutations could be of clinical value to identify patients who progress under EDT and therefore benefit from an early switch to an alternative endocrine therapy or other treatment regimens. Furthermore, our data indicate that mutations outside the LBD's hotspot regions might also contribute to resistance to EDT.