Clinical research in endometrial cancer: consensus recommendations from the Gynecologic Cancer InterGroup.

The Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Consensus Conference on Clinical Research (ECCC) was held in Incheon, South Korea, Nov 2-3, 2023. The aims were to develop consensus statements for future trials in endometrial cancer to achieve harmonisation on design elements, select important questions, and identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and finalisation of 18 statements within four topic groups, addressing adjuvant treatment in high-risk disease; treatment for metastatic and recurrent disease; trial designs for rare endometrial cancer subgroups and special circumstances; and specific methodology and adaptation for trials in low-resource settings. In addition, eight areas of unmet need were identified. This was the first GCIG Consensus Conference to include patient advocates and an expert on inclusion, diversity, equity, and access to take part in all aspects of the process and output. Four early-career investigators were also selected for participation, ensuring that they represented different GCIG member groups and regions. Unanimous consensus was obtained for 16 of the 18 statements, with 97% concordance for the remaining two. Using the described methodology from previous Ovarian Cancer Consensus Conferences, this conference did not require even one minority statement. The high acceptance rate following active involvement in the preparation, discussion, and refinement of the statements by all representatives confirmed the consensus progress within a global academic setting, and the expectation that the ECCC will lead to greater harmonisation, actualisation, inclusion, and resolution of unmet needs in clinical research for individuals living with and beyond endometrial cancer worldwide.

TEDOVA: vaccine OSE2101 +/- pembrolizumab as maintenance in platinum-sensitive recurrent ovarian cancer.

Ovarian cancer is a leading cause of death from gynecological cancers worldwide. Platinum-based chemotherapy provides the cornerstone of the medical management. In first line and subsequent relapses, maintenance strategies are offered to prolong intervals between lines of chemotherapy. Current maintenance options involve bevacizumab and poly ADP-ribose polymerase inhibitors, but these lines of therapy can only be used once in the disease course. Patients in first or second platinum sensitive relapse after poly ADP-ribose polymerase inhibitors and bevacizumab represent an area of unmet medical need. This academic sponsored, international Phase II randomized trial is evaluating the combination of a therapeutic cancer vaccine (OSE2101) with anti-PD1 (pembrolizumab) as maintenance therapy, in patients with platinum-sensitive recurrence regardless of number of prior lines and no progression after platinum-based chemotherapy.Clinical Trial Registration: NCT04713514 (ClinicalTrials.gov).

Ongoing Phase II study randomizing vaccine OSE2101 +/- Pembrolizumab vs supportive care as maintenance in platinum-sensitive recurrent ovarian cancer.

Treatment strategies for breast cancer brain metastases.

Brain metastases from breast cancer (BCBM) constitute the second most common cause of brain metastasis (BM), and the incidence of these frequently lethal lesions is currently increasing, following better systemic treatment. Patients with ER-negative and HER2-positive metastatic breast cancer (BC) are the most likely to develop BM, but if this diagnosis remains associated with a worse prognosis, long survival is now common for patients with HER2-positive BC. BCBM represents a therapeutic challenge that needs a coordinated treatment strategy along international guidelines. Surgery has always to be considered when feasible. It is now well established that stereotaxic radiosurgery allows for equivalent control and less-cognitive toxicities than whole-brain radiation therapy, which should be delayed as much as possible. Medical treatment for BCBM is currently a rapidly evolving field. It has been shown that the blood-brain barrier (BBB) is often impaired in macroscopic BM, and several chemotherapy regimens, antibody-drug conjugates and tyrosine-kinase inhibitors have been shown to be active on BCBM and can be part of the global treatment strategy. This paper provides an overview of the therapeutic option for BCBM that is currently available and outlines potential new approaches for tackling these deadly secondary tumours.

A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours.

BACKGROUND: AsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation. METHODS: The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design. RESULTS: The MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies. CONCLUSION: The dose of 600 mg was identified as the optimal dose for further clinical development. CLINICAL TRIAL REGISTRATION: Clinical trial registration (NCT number): NCT03579628.

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings.

LESSONS LEARNED: The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance. BACKGROUND: This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. METHODS: Open-label phase Ia/b study comprising 3+3 dose-limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28-day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. RESULTS: Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment-emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment-related TEAEs. The most common grade ≥3 treatment-related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 µg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression-free survival was 3.3 months (95% confidence interval [CI]: 1.6-4.4). Median overall survival was 8.9 months (95% CI: 3.5-12.7). There were no associations between genetic alterations and efficacy. CONCLUSION: Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC.

Prevention of brain metastases in human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE OF REVIEW: For patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, treatments that could prevent or delay occurrence of brain metastases would improve outcome. RECENT FINDINGS: Few studies were specifically designed to assess brain metastasis prevention. Most evidence derives from subgroup analyses of randomized trials. In the first-line metastatic setting, lapatinib, was not superior to trastuzumab to prevent CNS metastases as first site of relapse. Pertuzumab when added to trastuzumab and taxane significantly delay occurrence of brain metastases. In the second line setting, trastuzumab-emtansine has shown to improve overall survival of patients with brain metastases when compared with capecitabine-lapatinib, but there was no significant delay in brain metastases progression. Neratinib, has shown that it was able to delay brain metastases progression. Finally, tucatinib, has demonstrated benefit in progression-free survival and overall survival in combination with trastuzumab and capecitabine over trastuzumab and capecitabine for patients with or without brain metastases. SUMMARY: There has been an impressive improvement of the outcome of patients with HER2-positive metastatic breast cancer, with improved control of systemic disease and delayed occurrence of CNS progression. Specific studies are needed to assess TKI for brain metastases prevention, particularly in the adjuvant setting.

The off-label use of targeted therapies in sarcomas: the OUTC'S program.

BACKGROUND: Few targeted therapies (TTs) are registered for sarcoma treatment despite numerous phase II studies and yet there are potential treatment options for patients after standard treatment escape. The French Sarcoma Group - Bone Tumor Study Group (GSF-GETO) created a national registry to evaluate the outcome of patients treated with off-label TTs. METHODS: Every consecutive sarcoma-patient receiving an off-label TT outside a clinical trial was included. The objective was to describe this patient efficacy and safety data in routine practice. RESULTS: From October 2008 to October 2011, 249 patients in 24 centers received 278 treatment lines with TTs. Twenty-five histological subtypes were included: most frequent were leiomyosarcoma (n=48, receiving sorafenib in 63%, and sunitinib in 27%), GIST (n=39, receiving sorafenib in 79%), and angiosarcoma (n=18, receiving sorafenib in 78%). The overall response rate to TTs was 15% (95% CI [10,6-20,2]), the disease control rate at 2 months was 59%. The median progression-free survival was 4,1 months (IC 95% [3,2-4,8]). Three complete responses were observed. No toxic death occurred, grade 3 and 4 toxicities were reported in 74 (27%) and 14 patients (5%) respectively. CONCLUSION: Off-label TTs can be used for sarcoma patients in routine practice with an acceptable toxicity profile and efficacy similar to that reported in non-randomized clinical trials.

Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial.

PURPOSE: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells. PATIENTS AND METHODS: Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy. RESULTS: Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%). CONCLUSIONS: Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.

The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers.

Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14lowCD16high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L- but not GM-CSF-dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.

Variability of treatment of locally advanced cervical cancer: How French multidisciplinary teams follow European guidelines?

INTRODUCTION: Cervical cancer is a global public health concern. Despite ESGO recommendations and FIGO classification changes, management of locally advanced cervical cancer (LACC) remains debated in France. Our study aimed to review LACC treatment practices and assess adherence to ESGO recommendations among different practitioners. METHODS: From February 2021 to August 2022, we conducted a survey among gynecologic oncology surgeons, radiation oncologists, and medical oncologists practicing in France and managing LACC (FIGO stages IB3-IVA) according to the 2018 FIGO classification. We analyzed responses against the 2018 ESGO recommendations as a "gold standard." RESULTS: Among 115 respondents (56% radiation oncologists, 30% surgeons, 13% medical oncologists), 48.6% of gynecologic surgeons didn't perform para-aortic lymphadenectomy (PAL) with significant radiologic pelvic involvement. PAL, when indicated by PET-CT, was more common in university hospitals (66.7% of surgeons). Surgeons in university hospitals also followed ESGO recommendations more closely. Overall, compliance with all ESGO recommendations was low: 5.7% of surgeons, 21.5% of radiation oncologists, and 60% of medical oncologists. Prophylactic para-aortic irradiation, per ESGO, was more frequent in comprehensive cancer centers (52% of radiation oncologists). CONCLUSION: Adherence to ESGO recommendations for LACC treatment appears low in France, particularly in surgery, with limited PAL in cases of lymph node negativity on PET-CT. However, these recommendations are more often followed by surgeons in university hospitals and radiation oncologists in cancer centers. Adherence to these recommendations may impact patient survival and warrants evaluation of care quality, justifying the organization of LACC management in expert centers.

Projecting overall survival in health-economic models: uncertainty and maturity of data.

OBJECTIVE: As lifetime horizons are considered for economic evaluations, the Kaplan-Meier (KM) estimate is used to extrapolate survival in cases of immature overall survival (OS) data. This study estimated the error induced by the choice of distribution when extrapolating different levels of OS maturity. METHODS: Fifteen phase 3 trials reporting KM estimates of OS where at least 70% maturity (i.e. 70% of the population had died during follow-up) were included and compared to artificially created truncated data (30 and 50% maturity). Individual patient-data were reproduced using the Guyot algorithm based on digitized KM curves. Parametric survival distributions were fit for each arm in each study, for each maturity level, using the same time horizon (equal to the maximum follow-up). For each KM curve, the best distribution was chosen based on visual inspection, Akaike/Bayesian information criteria, and external validity. Outcomes were measured as life expectancy in months (LM) and life months gained (LMG). RESULTS: The Weibull (33%), log-logistic (32%) and log-normal (27%) were most often selected as the best fitting distribution. Compared to LM at full maturity, LM was overestimated in 23 and 40% of cases, at 30 and 50% maturity, respectively. Mean absolute error was 2.12months at 30% maturity, and decreased to 0.88months at 50% maturity. When comparing to mature data, the mean percentage of error in LMG was 126.4 and 62.4% at 30 and 50% maturity, respectively. CONCLUSION: The extent of OS maturity increases the risk of error when projecting long-term life expectancy for economic models. Even marginal gains in OS maturity result in more accurate estimations and should be considered when developing models.

Real-world dostarlimab use in advanced/recurrent endometrial cancer in France.

INTRODUCTION: In October 2020, the French Health Authority granted early access outside of the clinical trial setting for dostarlimab, a programmed death-1 inhibitor. Dostarlimab was approved by the European Medicines Agency (in April 2021) as monotherapy for patients with post-platinum mismatch repair deficient/microsatellite instability-high advanced/recurrent endometrial cancer, based on the results of the GARNET trial (NCT02715284). METHODS: This was a real-world descriptive analysis of patients granted cohort temporary authorization of use to receive dostarlimab between November 2020 and June 2021. Physicians could complete follow-up forms at each treatment cycle to provide clinical information, safety, and efficacy data. Safety and disease progression data were also captured through pharmacovigilance reports. RESULTS: Of 95 temporary authorization of use requests made by 80 oncologists in 59 French hospitals, 87 patients were eligible, and 80 received≥1 dose of dostarlimab. Based on treatment response assessments received (n=43), the mean (standard deviation) time from treatment initiation to response evaluation was 11 (6) weeks. The disease control rate (complete plus partial responses plus stable disease rates) was 56% (n=24/43), and the overall response rate was 35% (n=15/43); both consistent with those reported in the GARNET trial. No new safety signals were reported. DISCUSSION: The enrolment of 80 patients in an 8-month period highlights the need for access to novel treatment regimens in France for these patients post-platinum. Prospective randomized studies are ongoing to assess the efficacy and safety of dostarlimab and other checkpoint inhibitors as first-line treatment in patients with endometrial cancer.

Clinical outcome of patients with isolated central nervous system progression on first-line pertuzumab and trastuzumab treatment for HER2-positive metastatic breast cancer in a real-life cohort.

BACKGROUND: More than 10% of HER2-positive metastatic breast cancer (mBC) will develop Central Nervous System (CNS) metastases as first and isolated site of relapse on trastuzumab and pertuzumab first-line therapy. However, few clinical data are available to guide the best strategy in this setting. METHODS: Patients experiencing isolated CNS progression on trastuzumab and pertuzumab first-line therapy were retrospectively identified from the French Epidemiological Strategy and Medical Economics (ESME) real-life database between 2008 and 2016. RESULTS: Among 995 patients treated with first-line trastuzumab and pertuzumab for HER2-positive mBC, 132 patients (13%) experienced isolated CNS progression with a median time of 12 months after mBC diagnosis. Twelves patients did not receive any treatment and were excluded from the analysis. Among the 120 patients considered, 76 (63%) received CNS-directed local therapy, 73 (60%) continued trastuzumab and pertuzumab, whereas 47 (39%) started another systemic treatment. After a median follow-up of 21 months, there was no difference in progression-free survival for patient who continued trastuzumab-pertuzumab or switched to another systemic treatment. In multivariate analysis, trastuzumab-pertuzumab continuation was associated with longer OS (HR 0,28 IC 95%: 0,14-0,54 p < 0,001). mOS was not reached (95% 37.6-NE) and was 23.2 months (95% CI 15.5-53.6) in patients who continued trastuzumab and pertuzumab therapy and in patients who switched for another systemic therapy, respectively. CONCLUSION: In this real-life cohort, trastuzumab-pertuzumab continuation after local treatment for isolated CNS progression did not negatively impact PFS and OS. Prospective trials and assessment of new strategies are warranted in this specific situation.

Complete Laparoscopic Interval Debulking Surgery for Advanced Ovarian Cancer Achieves Similar Survival Outcomes to Open Approach: A Propensity-Matched Study.

To assess the laparoscopic interval debulking surgery (IDS) outcomes compared to laparotomy, by analyzing the overall survival (OS) and the progression free survival (PFS), as well as the intra- and post-operative morbidity.In this retrospective propensity-score-matched cohort study, all patients with stage III or IV FIGO (International Federation of Gynecology and Obstetrics) serous ovarian cancer, undergoing complete IDS after neoadjuvant chemotherapy, from January 1st of 2009 to June 1st 2019, were included.Thirty-seven patients were included in the laparoscopy group and 40 in the laparotomy group. There was no significant difference in terms of median OS between laparoscopy and laparotomy (23.1 months [95% CI 15.7-29.7] versus 26.3 months [95% CI 21.7-31.7], respectively, p = 0.17) and median PFS (14.8 months [95% CI 10.6-21.5] versus 12 months [95% CI 11-15.1], p = 0.057). After applying the propensity score, 25 patients were included in each group. Laparoscopy was associated with significantly less early postoperative complications (6 versus 17, p = 0.01) and shorter hospital stay (7.6 days versus 12.1, p < 0.001) and a significantly better OS (HR 0.45 [95% CI 0.19-0.95], p = 0.04), but with no significant difference in terms of PFS (HR 0.71 [95% CI 0.27-1.88], p = 0.49).In carefully-selected patients with advanced ovarian cancer, complete laparoscopic interval debulking surgery achieves similar survival outcomes to open laparotomy. Therefore, laparoscopy appears as a safe alternative to laparotomy for IDS after NACT in selected patients with advanced ovarian cancer and a low burden of disease.

Basics of immunotherapy for epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal of all gynecological cancers. Despite excellent responses to standard treatment in approximately 70% of patients, most of them will relapse within 5 years of initial treatment and many of them will develop chemotherapy-resistant disease. It is then important to find other means of treatment for these patients such as immunotherapy or targeted therapy. To understand immunotherapy, it is important to explain the dynamic interplay between cancer and the immune system. Compared to traditional tumor therapies, immunotherapy acts primarily on the immune system or the tumor microenvironment but not directly on the tumor cells, and it may also promote synergistic anti-tumor actions as part of a combined treatment. The aim of this narrative review is to provide a basic understanding of immunotherapy the interest of this treatment in EOC, and to present the main ongoing studies that could change patient management in the future.

Precision medicine for patients with gastro-oesophageal cancer: A subset analysis of the ProfiLER program.

BACKGROUND: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents. METHODS: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program. RESULTS: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1-3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without. CONCLUSION: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.

Alterations in Homologous Recombination-Related Genes and Distinct Platinum Response in Metastatic Triple-Negative Breast Cancers: A Subgroup Analysis of the ProfiLER-01 Trial.

BACKGROUND: a specific subset of metastatic triple-negative breast cancers (mTNBC) is characterized by homologous recombination deficiency (HRD), leading to enhanced sensitivity to platinum-based chemotherapy. Apart from mutations in BRCA1/2 genes, the evaluation of other HRD-related alterations has been limited to date. As such, we analyzed data from mTNBC patients enrolled in the ProfiLER-01 study to determine the prevalence of alterations in homologous recombination-related (HRR) genes and their association with platinum sensitivity. METHODS: next-generation sequencing and promoter methylation of BRCA1 and RAD51C were performed on tumors from patients with mTNBC, using a panel of 19 HRR genes. Tumors were separated into three groups based on their molecular status: mutations in BRCA1/2, mutations in other HRR genes (BRCA1/2 excluded) or BRCA1/RAD51C promoter methylation and the absence of molecular alterations in HRR genes (groups A, B and C, respectively). Sensitivity to platinum-based chemotherapy was evaluated through the radiological response. RESULTS: mutations in BRCA1/2 were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in BRCA1 or RAD51C were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients (n = 29; 55.8%). Among 27 patients who received platinum-based chemotherapy, the disease control rate was 80%, 55% and 18% (groups A, B and C, respectively; p = 0.049). Regarding group B, patients with disease control exhibited mutations in FANCL, FANCA and the RAD51D genes or RAD51C methylation; Conclusion: mutations in HRR genes and epimutations in RAD51C were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in BRCA1/2, a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.

Therapeutic relevance of molecular screening program in patients with metastatic sarcoma: Analysis from the ProfiLER 01 trial.

BACKGROUND: Advanced sarcoma is a group of heterogeneous disease with poor prognosis and poor efficacy of medical treatment. They represent a promising group of tumors to assess molecular-based therapy (MBT) strategy. PATIENTS AND METHODS: Genomic profiles of patients with advanced sarcoma included in the ProfiLER program were established by NGS using a 69 genes panel and CGH array. A weekly molecular board reviewed genomic reports to select relevant genomic alterations and propose recommendations for MBT. RESULTS: A genomic profile was available for 158 of 164 patients. At least 1 relevant genomic alteration was reported for 106 patients (67%), with frequent multiple alterations (68%). In total, 289 relevant genomic alterations were identified in 143 different genes; 139 homozygous deletions, 86 gene amplifications and 64 somatic mutations. The most frequently impacted genes were TP53, Rb1, CDKN2A, CDK4, MDM2, and PTEN. MBT was recommended for 47 patients and initiated for 13 patients. One objective response was observed for an angiosarcoma treated with pazopanib for FLT4 amplification; 4 patients had a stable disease, including a long-lasting 33 months stabilization. CONCLUSION: Genomic profiling for advanced sarcoma is feasible, even for bone sarcoma. A small proportion of patients are eventually treated with MBT, similar to other tumor types. We could not demonstrate this strategy to be beneficial to patients. Our data suggest that molecular profiling should not be used in routine practice but warrants further exploration in clinical trials, focusing on sarcoma with complex genomic, and adding transcriptomic analysis to the copy number and mutational analyses.

Uncovering the Translational Regulatory Activity of the Tumor Suppressor BRCA1.

BRCA1 inactivation is a hallmark of familial breast cancer, often associated with aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. We previously showed that BRCA1 was implicated in translation regulation. Here, we asked whether translational control could be a novel function of BRCA1 that contributes to its tumor suppressive activity. A combination of RNA-binding protein immunoprecipitation, microarray analysis, and polysome profiling, was used to identify the mRNAs that were specifically deregulated under BRCA1 deficiency. Western blot analysis allowed us to confirm at the protein level the deregulated translation of a subset of mRNAs. A unique and dedicated cohort of patients with documented germ-line BRCA1 pathogenic variant statues was set up, and tissue microarrays with the biopsies of these patients were constructed and analyzed by immunohistochemistry for their content in each candidate protein. Here, we show that BRCA1 translationally regulates a subset of mRNAs with which it associates. These mRNAs code for proteins involved in major programs in cancer. Accordingly, the level of these key proteins is correlated with BRCA1 status in breast cancer cell lines and in patient breast tumors. ADAT2, one of these key proteins, is proposed as a predictive biomarker of efficacy of treatments recently recommended to patients with BRCA1 deficiency. This study proposes that translational control may represent a novel molecular mechanism with potential clinical impact through which BRCA1 is a tumor suppressor.

Detailed overview on rare malignant ovarian tumors.

The group of rare malignant ovarian tumors includes the group of germ cell tumors, sex cords stromal ovarian tumors, small cell carcinoma, malignant Brenner tumors, rare epithelial tumors such as mucinous carcinoma, clear cell carcinoma, or low-grade serous carcinoma, as well as ovarian carcinosarcoma. Together they comprise about 10% of all ovarian tumors. Due to their low prevalence and their heterogeneity, data and treatment recommendations are limited. Even though all ovarian tumors are staged according to the FIGO staging of epithelial ovarian tumors, treatment differs especially in germ cell tumors and sex cords stromal ovarian tumors. Non-epithelial ovarian tumors can arise from a variety of ovarian precursor cells such as germ cells, granulosa cells, theca cells, or stromal fibroblasts. As can be expected already due to their divergent precursor lesions, these malignancies are substantially different but united by their rarity. This overview article gives a comprehensive summary on the pathology and clinical presentation, as well as therapy recommendations of a selection of those rare ovarian tumors, based on the latest national guidelines and related important publications.