DNA double-strand breaks are the most critical DNA damage to cells, and their repair is tightly regulated to maintain cellular integrity. Some cancers exhibit homologous recombination deficiency ...(HRD), a faithful double-strand break repair system, making them more sensitive to poly (ADP ribose) polymerase inhibitors (PARPi). PARPi have shown substantial efficacy in BRCA-mutated ovarian cancer for several years, and their indication has gradually been extended to other tumour locations such as breast, prostate and pancreas. More recently, PARPi were demonstrated to be effective in cancers with an HRD phenotype beyond BRCA mutations. Today, a major challenge is developing tests capable of detecting the HRD phenotype of cancers (HRD tests) and predicting sensitivity to PARPi to select patients likely to benefit from this therapy. This review provides a synthesis of the existing HRD tests, divided into three main approaches to detect HRD: the investigation of the HRD causes, the study of its consequences and the evaluation of the HR activity itself.
•Homologous recombination deficiency (HRD) is targetable by PARP inhibitors.•HRD tests are helpful to select patients who may benefit from PARP inhibitors.•Genomic scars assays increased the number of patients eligible for PARP inhibitors.•Functional tests allow a real-time assessment of homologous recombination activity.•Acquired resistances to PARPi have been described and need to be carefully studied.
In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with ...carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib.
Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (< median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status (
mutation, HR deficiency HRD, or HR proficiency HRP).
The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and
mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or
wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a
mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect.
In addition to HRD/
status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.
The Consolidated Standards of Reporting Trials (CONSORT) guidance was extended in 2004 to provide a set of 10 specific and comprehensive guidelines regarding adverse event (AE) reporting in ...randomized clinical trials (RCTs). Limited data exist regarding adherence to these guidelines in publications of oncology RCTs.
All phase III RCTs published between 2007 and 2011 were reviewed using a 16-point AE reporting quality score (AERQS) based on the 2004 CONSORT extension. Multivariable linear regression was used to identify features associated with improved reporting quality.
A total of 325 RCTs were reviewed. The mean AERQS was 10.1 on a 16-point scale. The most common items that were poorly reported were the methodology of AE collection (adequately reported in only 10% of studies), the description of AE characteristics leading to withdrawals (15%), and whether AEs are attributed to trial interventions (38%). Even when reported, the methods of AE collection and analysis were highly heterogeneous. The multivariable regression model revealed that industry funding, intercontinental trials, and trials in the metastatic setting were predictors of higher AERQS. The quality of AE reporting did not improve significantly over time and was not better among articles published in journals with a high impact factor.
Our findings show that some methodologic aspects of AE collection and analysis were poorly reported. Given the importance of AEs in evaluating new treatments, authors should be encouraged to adhere to the 2004 CONSORT guidelines regarding AE reporting.
To improve the quality of reporting of randomized clinical trials (RCTs), international registries for RCTs and guidelines for primary end point (PEP) analysis were established. The objectives of ...this systematic review were to evaluate concordance of PEP between publication and the corresponding registry and to assess intrapublication consistency in PEP reporting.
All adult oncology RCTs in solid tumors published in 10 journals between 2005 and 2009 were reviewed. Registration information was extracted from international trial registries.
A total 366 RCTs were identified. Trial registration was found for 215 trials, and the rate increased from 43% in 2005 to 82% in 2009 (P < .001). There were 134 RCTs with clearly defined PEPs in registry, with the rate increasing from 15% to 67% (P < .001). PEP differed between registration and final publication in 14% trials with clearly defined PEPs. Reporting issues in methodology were found in 15% of RCTs, mainly because of inadequate reporting of PEP or sample size calculation. Problems with the interpretation of trial results were found in 22% publications, mostly resulting from negative superiority studies being interpreted as showing equivalence.
The rates of trial registration and of trials with clearly defined PEPs have improved over time; however, 14% of these trials reported a different PEP in the final publication. Intrapublication inconsistencies in PEP reporting are frequent. Our findings highlight the need for investigators, peer reviewers, and readers to exercise increased awareness and scrutiny of reporting outcomes of oncology RCTs.
YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects.
This FIH study was designed ...to determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) to assess the tolerance, pharmacokinetics (PK) and pharmacodynamics profiles of YS110 and preliminary efficacy. YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours.
Thirty-three patients (22 mesothelioma) received a median of 3 (range 1-30) YS110 infusions across six dose levels (0.1-6 mg kg
). MTD was not reached and two dose-limiting toxicities (infusion hypersensitivity reactions) led to the institution of a systemic premedication. Low-grade asthenia (30.3%), hypersensitivity (27.3%), nausea (15.2%), flushing (15.2%), chills (12.1%) and pyrexia (12.1%) were reported as ADRs. Pharmacokinetic parameters (AUC and C
) increased in proportion with the dose. sCD26/DPPIV assays indicated CD26 modulation. Prolonged stable diseases were observed in 13 out of 26 evaluable patients.
YS110 is well tolerated up to 6 mg kg
Q1W, which has been defined as the RP2D, with encouraging prolonged disease stabilisations observed in a number of patients with advanced/refractory mesothelioma.
Background Gestational trophoblastic diseases include premalignant (partial and complete hydatidiform moles) and malignant entities referred to as gestational trophoblastic neoplasia. Use of the ...International Federation of Gynecology and Obstetrics prognostic score is encouraged in cases of gestational trophoblastic neoplasia to predict the potential for the development of resistance to single-agent chemotherapy. An International Federation of Gynecology and Obstetrics score of ≥7 defines a high-risk patient and requires combination chemotherapy. Appropriate and rapid diagnosis, treatment by specialized centers, and reduction of early deaths at the time of chemotherapy initiation have led to significant improvements in survival for patients with high-risk gestational trophoblastic neoplasia. There is a crucial need for the early identification of high-risk patients with gestational trophoblastic neoplasia who have an increased death risk to organize their treatment in highly specialized centers. Objectives The purpose of this study was to describe cases of gestational trophoblastic neoplasia that have resulted in death, particularly in a subgroup with an International Federation of Gynecology and Obstetrics prognostic score of ≥13, for whom low-dose etoposide and cisplatin induction chemotherapy recently was shown to reduce early death rate. Study Design We identified 974 patients from the French Center for Trophoblastic Diseases who had a diagnosis of gestational trophoblastic neoplasia from November 1999 to March 2014. Among 140 patients who were at high risk of resistance to single-agent chemotherapy (International Federation of Gynecology and Obstetrics score, ≥7), 29 patients (21%) had a score of ≥13. Mortality rate was estimated with the use of the Kaplan-Meier method. Results The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, was 2% for patients with gestational trophoblastic neoplasia (95% confidence interval, 1.25–3.13%). High-risk patients had a 5-year mortality rate of 12% (95% confidence interval, 7.49–18.9%). Patients with an International Federation of Gynecology and Obstetrics score of ≥13 had a higher 5-year mortality rate (38.4%; 95% confidence interval, 23.4–58.6%) and accounted for 52% of the deaths in the entire cohort. Early deaths, defined as those that occur within 4 weeks after treatment initiation, occurred in 8 patients of the entire cohort. Six of them had an International Federation of Gynecology and Obstetrics score of ≥13 at presentation, of whom 5 patients had brain and/or liver metastases. Conclusion Gestational trophoblastic diseases with an International Federation of Gynecology and Obstetrics score of ≥13 have an increased risk of early death. We suggest that an International Federation of Gynecology and Obstetrics score of ≥13 becomes a consensual criterion for prediction of patients with gestational trophoblastic neoplasia with increased risk of death, particularly early death. These patients justify treatment in highly specialized gestational trophoblastic disease centers and may benefit from the use of induction low-dose etoposide and cisplatin.
Ovarian cancer is the gynecological cancer with the worst prognosis and the highest mortality rate because 75% of patients are diagnosed with advanced stage III-IV disease. About 50% of patients are ...now treated with neoadjuvant chemotherapy followed by interval debulking surgery (IDS). In that context, there is a need for accurate predictors of tumor primary chemosensitivity, as it may impact the feasibility of subsequent IDS. Across seven studies with more than 12,000 patients, including six large randomized clinical trials and a national cancer registry, along with a mega-analysis database with 5842 patients, the modeled CA-125 ELIMination rate constant K (KELIM), the calculation of which is based on the longitudinal kinetics during the first three cycles of platinum-based chemotherapy, was shown to be a reproducible indicator of tumor intrinsic chemosensitivity. Indeed, KELIM is strongly associated with the likelihood of complete IDS, subsequent platinum-free interval, progression-free survival, and overall survival, along with the efficacy of maintenance treatment with bevacizumab or veliparib. As a consequence, KELIM might be used to guide more subtly the medical and surgical treatments in a first-line setting. Moreover, it could be used to identify the patients with poorly chemosensitive disease, who will be the best candidates for innovative treatments meant to reverse the chemoresistance, such as cell cycle inhibitors or immunotherapy.
The utility of heated intraperitoneal chemotherapy (HIPEC) in the management of epithelial ovarian cancer (EOC) has been assessed in several randomised clinical trials and meta-analyses, and it is ...still a subject of controversy. Therefore, we performed an umbrella review of existing meta-analyses to summarise the outcomes of HIPEC and cytoreductive surgery (CRS) association in ovarian cancer.
We examined the MEDLINE, Cochrane Library, Scopus, Prospero, Web of Science and Science Direct from inception to May 30, 2020, for meta-analyses of randomised controlled trials and observational studies. Analyses of overall survival, disease free survival and progression survival were performed separately for primary and recurrent ovarian cancers.
We identified 6 meta-analyses investigating the association of HIPEC with CRS in the management of ovarian cancer. Three year overall survival was significantly improved by the association of CRS and HIPEC for primary (HR: 0.66, 95%CI:0.56-0.78) and recurrent ovarian cancers (HR:0.50, 95%CI:0.38-0.64). This benefit was also demonstrated on disease-free survival for primary (HR: 0.54, 95%CI:0.48-0.61) and recurrent ovarian cancer (HR: 0.60, 95%CI:0.46-0.78). The pooled hazard ratios confirmed the advantage of HIPEC and CRS association with respect to CRS alone on progression free survival for primary and recurrent ovarian cancer respectively with HR: 0.50, 95%CI: 0.43-0.58 and HR: 0.59, 95%CI: 0.41-0.85.
While waiting for the results of the current prospective studies, the present umbrella study suggests that HIPEC performed at the end of CRS may be a complementary effective asset for ovarian cancer patient management.
In metastatic prostate cancer (PCa) patients, androgen-deprivation therapy (ADT) combined with chemotherapy or next-generation androgen receptor targeted agents is a new standard treatment. The ...objective of the present study is to assess longitudinal PSA kinetics during treatment using mathematical modeling, to identify the modeled PSA kinetic parameters able to exhibit early prognostic/predictive values.
Phase III clinical trial dataset (NCT00764166) comparing ADT +/- docetaxel in 250 locally treated patients for PCa with rising PSA levels, who were at high risk of metastatic disease was assessed. A kinetic-pharmacodynamic (K-PD) model was used to fit PSA kinetics during the first 100 treatment days, to estimate the modeled PSA production rate K (KPROD) and elimination constant rate K (KELIM). The prognostic value of these parameters, considered as categorized (favorable vs. unfavorable) covariates regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), was assessed using univariate/multivariate analyses.
Data from 177/250 patients was assessed. KELIM exhibited a significant prognostic value regarding PSA-PFS and KPROD regarding OS (univariate analysis). In the PSA-PFS final multivariate model, KELIM and the primary therapy type were significant. The OS multivariate model integrated both KPROD and baseline PSA doubling-time.
In this first study assessing the modeled PSA kinetics prognostic value in PCa patients treated with systemic treatments, KELIM and KPROD exhibited respective prognostic values regarding PSA-PFS and OS.
Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The ...standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. Most patients experience a relapse in the years following the initial treatment. During the last decade, anti-angiogenic agents used in the maintenance setting improved progression free survival (PFS) over chemotherapy alone. More recently, PARP inhibitors demonstrated substantial efficacy, mainly in patients with germinal or somatic
mutations or other homologous recombination deficiencies (HRD), all involved in double strand DNA Damage Repair (DDR). Other therapeutic paradigms are currently being explored, including combinations of immune-checkpoints inhibitors, chemotherapy, bevacizumab and PARP inhibitors. In addition to these clinical advances, molecular characterization of the tumors and their correlations with drugs efficacy are needed to better understand which patient will benefit the most from the various treatments available to date.
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