Surgery of the primary tumor in patients with de novo metastatic breast cancer: a nationwide population-based retrospective cohort study in Belgium.

PURPOSE: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer. METHODS: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis. RESULTS: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings. CONCLUSION: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not.

Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer.

OBJECTIVES: External beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects. Radical vulvectomy post-radiation for persistent disease is often compromised with poor wound healing. We describe clinical outcomes for patients who received neoadjuvant chemotherapy plus bevacizumab followed by radical vulvectomy for locally advanced vulvar cancer. METHODS: We performed retrospective analyses of all patients at our institution who underwent radical vulvectomy from January 2015 to November 2023. Of 113 patients, 13 patients underwent neoadjuvant chemotherapy. Demographics and clinicopathologic data were extracted, and descriptive statistical analyses were performed. Cases with neoadjuvant chemotherapy plus bevacizumab were further evaluated for response, adverse effects, and survival. RESULTS: Neoadjuvant chemotherapy was administered to 13 patients with stage II-IV disease that involved the urethra, vagina, or anus. Lesion sizes ranged from 4 to 20 cm (median 7 cm). Patients received 2-6 cycles of carboplatin or cisplatin, paclitaxel, and bevacizumab. Nine (69.2%) patients had partial pathologic responses, and four patients had complete responses. All patients had negative surgical margins. Ten (76.9%) patients had radiographic evidence of inguinal lymph node metastasis prior to neoadjuvant chemotherapy, and four had residual nodal disease. Only one patient developed a superficial groin seroma. Three patients developed recurrence, two locally and one distant, and there was one death. The median follow-up was 23 months (range 6-84 months). CONCLUSIONS: Neoadjuvant chemotherapy using combination platinum/paclitaxel/bevacizumab was efficacious for locally advanced vulvar cancer, resulting in complete resections, negative margins, and excellent wound healing. A multi-institutional phase II trial is warranted to validate these findings.

Preclinical models to understand the biology and to discover new targets in brain metastases.

PURPOSE OF REVIEW: Incidence of brain metastases increases overtime therefore it is important to rapidly progress in the discovery of new strategies of treatment for these patients. In consequence, more and more preclinical models of brain metastases (BM) are established to study new treatments for melanoma, lung, and breast cancer BM. Here, we reviewed the most recent findings of new drugs assessed in BM mouse preclinical models. RECENT FINDINGS: BM are a common metastatic site of several types of solid cancers and can be difficult to treat due to the unique environment of the brain and the blood-brain barrier. Currently, several preclinical models of BM have been demonstrated that new molecular targeted therapies, small metabolic inhibitors, immunotherapies or a combination of these drugs with radiotherapy lead to a reduction of BM growth and an improvement of mouse survival. SUMMARY: The use of preclinical models of BM is crucial to discover new treatment strategies for patients with BM. In the last years, some new drugs have been highlighted in preclinical models and are now tested in clinical trials including patients with brain metastases.

Lurbinectedin in patients with pretreated endometrial cancer: results from a phase 2 basket clinical trial and exploratory translational study.

Second-line treatment of endometrial cancer is an unmet medical need. Lurbinectedin showed promising antitumor activity in a phase I study in combination with doxorubicin in advanced endometrial cancer. This phase 2 Basket trial evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 73 patients with pretreated endometrial cancer. The primary endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and an exploratory translational study. Confirmed complete (CR) and partial response (PR) was reported in two and six patients, respectively (ORR = 11.3%; 95%CI, 5.0-21.0%). Median DoR was 9.2 months (95%CI, 3.4-18.0 months), median PFS was 2.6 months (95%CI, 1.4-4.0 months) and median OS was 9.3 months (95%CI, 6.1-12.8 months). Molecular subtypes showed differences in PFS rate at 6 months (p53abn 23.7% vs. "No Specific Molecular Profile" [NSMP] 42.9%) and median OS (p53abn 6.6 months vs. NSMP 16.1 months). The most common treatment-related adverse events (mostly grade 1/2) were fatigue (54.8% of patients), nausea (50.7%), vomiting (26.0%) decreased appetite (17.8%). and constipation, (19.2%). The most common grade 3/4 toxicity was neutropenia (43.8%; grade 4, 19.2%; febrile neutropenia, 4.1%). In conclusion, considering the exploratory aim of this trial and the hints of antitumor activity observed together with a predictable and manageable safety profile, further biomarker-based development of lurbinectedin is recommended in this indication in combination with other agents. Clinicaltrials.gov identifier: NCT02454972.

Malignant peritoneal cytologic contamination with robotic hysterectomy for endometrial cancer.

BACKGROUND: Malignant peritoneal cytology in endometrial cancer (EC) is not considered an independent adverse prognostic factor for uterine-confined disease and is not a determinant factor in the International Federation of Gynecology and Obstetrics (FIGO) staging system. NCCN Guidelines still recommend obtaining cytologies. The aim of this study was to determine the prevalence of peritoneal cytologic contamination following robotic hysterectomy for EC. METHODS: Peritoneal cytology from the pelvis and diaphragm were obtained at the initiation of surgery, and from the pelvis only at the completion of robotic hysterectomy with sentinel lymph node mapping (SLNM). Cytology specimens were evaluated for the presence of malignant cells. Pre- and post-hysterectomy cytology results were compared, and pelvic contamination was defined as conversion from negative to positive cytology following surgery. RESULTS: 244 patients underwent robotic hysterectomy with SLNM for EC. Pelvic contamination was identified in 32 (13.1%) cases. In multivariate analysis, pelvic contamination was associated with >50% myometrial invasion, tumor size >2 cm, lymphovascular space invasion (LVSI), and lymph node metastasis. There was no association with FIGO stage or histology subtypes. CONCLUSIONS: Malignant peritoneal contamination occurred during robotic surgery for EC. Large lesions (>2 cm), deep invasion (>50%), LVSI, and lymph node metastasis were each independently associated with peritoneal contamination. Whether or not peritoneal contamination increases risk for disease recurrence should be studied in larger series, including an evaluation of patterns of recurrence and the potential impact of adjuvant therapies. Until the clinical impact of peritoneal contamination during hysterectomy for EC is better understood, methods to reduce peritoneal contamination are warranted.

First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours.

BACKGROUND: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy. METHODS: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04. RESULTS: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses. CONCLUSIONS: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition. CLINICAL TRIAL REGISTRATION: NCT03267316.

Molecular oncology: what is needed to speed access to innovative therapies in clinical research?

PURPOSE OF REVIEW: A better understanding of the biology of cancer cells has led in the past 20 years to more and more molecular and immunological driven treatment strategies impacting both clinical trials and day-to-day practice. The aim of this review is to describe new approaches to conduct clinical trials in this area to speed up drug development and increase access to innovation for cancer patients. RECENT FINDINGS: The design of an early phase trial has an impact on its clinical benefit. Trials deriving from a specific biomarker or histologic characteristic (also known as enrichment design) are more likely to demonstrate benefit than trials based on a more conventional design. However, the increase of low incidence cancer molecular subtypes poses a major hurdle in the clinical management and drug development research for cancer patients. SUMMARY: With the identification of news targets and the subsequent introduction of precision medicine, new strategies and tools are needed to provide access to biomarker identification and target-oriented clinical trials to all cancer patients. We propose to set up a new patient-centered model to conduct clinical trials allowing simply to 'bring the trial to the patient'.

Soluble ST2 is increased in systemic lupus erythematous and is a potential marker of lupus nephritis.

OBJECTIVES: To investigate the role of the interleukin IL-33/ST2 axis in systemic lupus erythematosus (SLE). METHODS: Serum concentrations of IL-33 and sST2 were measured by sandwich ELISA in SLE patients (n=111) compared to sex- and age-matched healthy controls (n=36). The serum concentrations of IL-33 and sST2 were correlated with various clinical and biological parameters. The expressions of IL-33 and ST2L were investigated in kidney sections by immunohistochemistry in lupus nephritis patients (n=23) and controls (n=10). RESULTS: Serum levels of IL-33 were significantly higher in SLE patients (11.64±3.141 pg/mL) than in controls (1.043±0.8526 pg/mL) (p<0.0001). Similarly, the serum concentrations of sST2 were significantly higher in SLE patients (34.013±2.043 pg/mL) than in controls (25.278±2.258 pg/mL) (p=0.046). sST2, but not IL-33, correlated significantly with disease activity index (SLEDAI). In addition, serum levels of sST2 were significantly higher in patients with lupus nephritis (45.438±5.661 pg/mL) that in SLE patients without renal involvement (30.691±1.941 pg/mL) (p=0.016). The immunoreactivity of IL-33 in renal biopsies of patients with lupus nephritis was not increased compared to controls, while the glomerular expression of ST2L was significantly higher in nephritis patients compared to controls. CONCLUSIONS: Although IL-33 and sST2 levels are both increased in SLE, sST2 represents a surrogate marker of disease activity and complications of nephritis.

A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours.

BACKGROUND: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. METHODS: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles. RESULTS: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. CONCLUSIONS: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. CLINICAL TRIAL REGISTRATION: NCT02316197.

Analyses of the Rationale and Implementation of Research Biopsies in Oncology Clinical Trials at a Tertiary Cancer Center.

BACKGROUND: Biomarkers in clinical trials have led to massive incorporation of research biopsies, with potentially risks and no direct benefit for patients. In 2018, the American Society of Clinical Oncology (ASCO) released an ethical framework to provide guidance on incorporating research biopsies in cancer clinical trials. MATERIALS AND METHODS: We collected biopsy requirements of cancer clinical trials conducted at Institut Jules Bordet (IJB) between 2015 and 2019 to examine adherence with the ASCO Ethical Framework. We used logistic regression models to test the association between the request for biopsy, the request for tissue, and the adherence to the ASCO framework as well as some trial characteristics. RESULTS: Between January 2015 and December 2019, 178 oncological studies were conducted at IJB. Of these, 138 (78%) were sponsored by industry, 132 (74%) were phase II and III studies, and 141 (79%) concerned metastatic disease. Tissue was required for inclusion for 119 (67%) studies, among which 59 required at least one new biopsy. Adherence to ASCO's Ethical Framework was 67% for studies requiring tissue and went down to 39% for studies requiring at least one new biopsy. In multivariate analysis, requests for tissue or new biopsies increased in early-phase studies (p < .001, p < .001, respectively) and in studies investigating innovative treatments (immunotherapy or targeted therapies; p < .01, p = .02). Compliance to the ASCO framework significantly decreased with time (p < .001) and in early-phase studies (p < .001). CONCLUSION: Numerous studies required tissue or new biopsies for exploratory objectives of unknown clinical utility. Requests for tissue increased over the years, whereas compliance to ASCO's Ethical Framework decreased. IMPLICATIONS FOR PRACTICE: In 2019, the American Society of Clinical Oncology (ASCO) developed an ethical framework to provide guidance on incorporating research biopsies in clinical trials. This study underlines the growing request for tissue in clinical trials with potentially no impact on drug development and no benefit to actual or future patients. Adherence to ASCO's Ethical Framework decreases through time. These results highlight the importance of improving the ethics of research biopsies. ASCO's Ethical Framework offers an opportunity to improve quality of care in clinical research by maximizing scientific utility and allowing for clinically meaningful correlative science and safe access to innovative treatments for a maximum number of patients.