Rucaparib for PARP inhibitor-pretreated ovarian cancer: A GEICO retrospective subgroup analysis from the Spanish Rucaparib Access Program.

The poly(ADP-ribose) polymerase inhibitor (PARPi) rucaparib is approved as maintenance therapy for patients with platinum-sensitive recurrent high-grade ovarian cancer (HGOC). The efficacy and safety of rucaparib after PARPi therapy are largely unknown; therefore, we analyzed outcomes in the subgroup of PARPi-pretreated patients from Spanish hospitals participating in the Rucaparib Access Program. This post hoc subgroup analysis explored baseline characteristics, treatment exposure, safety, effectiveness, and subsequent therapy among women receiving rucaparib 600 mg twice daily after at least one prior PARPi for HGOC. Of 14 women eligible for the analysis, 11 (79%) had tumors harboring BRCA1/2 mutations. Patients had received a median of 5 (range 3-8) treatment lines before rucaparib. Twelve patients (86%) had previously received olaparib and two (14%) niraparib; 12 patients received rucaparib as treatment for platinum-resistant HGOC, one as treatment for platinum-sensitive HGOC, and one as maintenance therapy. Progression-free survival was 0.2-9.1 months. One of seven patients assessable for response by RECIST achieved stable disease. Adverse events occurred in 11 patients (79%; grade 3 in 29%), leading to treatment interruption in eight patients (57%), dose reduction in six (43%), but treatment discontinuation in only one (7%). No new safety signals were observed. This is one of the first reported series of real-world data on rucaparib after prior PARPi for HGOC. In this heavily pretreated population, rucaparib demonstrated meaningful activity in some patients and tolerability consistent with previous prospective trials. Future investigation should focus on identifying patients who may benefit from rucaparib after prior PARPi exposure.

Rucaparib in recurrent ovarian cancer: real-world experience from the rucaparib early access programme in Spain - A GEICO study.

BACKGROUND: Rucaparib is a poly(ADP-ribose) polymerase inhibitor approved in Europe as maintenance therapy for recurrent platinum-sensitive (Pt-S) ovarian cancer (OC). The Rucaparib Access Programme (RAP) was designed to provide early access to rucaparib for the above-mentioned indication, as well as for patients with BRCA-mutated Pt-S or platinum-resistant (Pt-R) OC and no therapeutic alternatives. METHODS: In this observational, retrospective study we analysed the efficacy and safety of rucaparib within the RAP in Spain. Hospitals associated with the Spanish Ovarian Cancer Research Group (GEICO) recruited patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with rucaparib 600 mg twice daily as maintenance or treatment (Pt-S/Pt-R) in the RAP. Baseline characteristics, efficacy, and safety data were collected. RESULTS: Between July 2020 and February 2021, 51 patients treated in 22 hospitals in the RAP were included in the study. Eighteen patients with a median of 3 (range, 1-6) prior treatment lines received rucaparib as maintenance; median progression-free survival (PFS) for this group was 9.1 months (95% confidence interval [CI], 4.2-11.6 months). Among 33 patients (median 5 [range, 1-9] prior treatment lines) who received rucaparib as treatment, 7 and 26 patients had Pt-S and Pt-R disease, respectively. Median PFS was 10.6 months (95% CI, 2.5 months-not reached) in the Pt-S group and 2.2 months (95% CI, 1.1-3.2 months) in the Pt-R group. Grade ≥ 3 treatment-emergent adverse events were reported in 39% of all patients, the most common being anaemia (12% and 15% in the maintenance and treatment groups, respectively). At data cut-off, 5 patients remained on treatment. CONCLUSION: Efficacy results in these heavily pre-treated patients were similar to those from previous trials. The safety profile of rucaparib in real life was predictable and manageable.

MicroRNA-4732-3p Is Dysregulated in Breast Cancer Patients with Cardiotoxicity, and Its Therapeutic Delivery Protects the Heart from Doxorubicin-Induced Oxidative Stress in Rats.

Anthracycline-induced cardiotoxicity is the most severe collateral effect of chemotherapy originated by an excess of oxidative stress in cardiomyocytes that leads to cardiac dysfunction. We assessed clinical data from patients with breast cancer receiving anthracyclines and searched for discriminating microRNAs between patients that developed cardiotoxicity (cases) and those that did not (controls), using RNA sequencing and regression analysis. Serum levels of 25 microRNAs were differentially expressed in cases versus controls within the first year after anthracycline treatment, as assessed by three different regression models (elastic net, Robinson and Smyth exact negative binomial test and random forest). MiR-4732-3p was the only microRNA identified in all regression models and was downregulated in patients that experienced cardiotoxicity. MiR-4732-3p was also present in neonatal rat cardiomyocytes and cardiac fibroblasts and was modulated by anthracycline treatment. A miR-4732-3p mimic was cardioprotective in cardiac and fibroblast cultures, following doxorubicin challenge, in terms of cell viability and ROS levels. Notably, administration of the miR-4732-3p mimic in doxorubicin-treated rats preserved cardiac function, normalized weight loss, induced angiogenesis, and decreased apoptosis, interstitial fibrosis and cardiac myofibroblasts. At the molecular level, miR-4732-3p regulated genes of TGFß and Hippo signaling pathways. Overall, the results indicate that miR-4732-3p is a novel biomarker of cardiotoxicity that has therapeutic potential against anthracycline-induced heart damage.

High risk of thrombosis in patients with advanced lung cancer harboring rearrangements in ROS1.

INTRODUCTION: Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. METHODS: The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. RESULTS: A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period. CONCLUSIONS: The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs.

Development, Implementation and Assessment of Molecular Diagnostics by Next Generation Sequencing in Personalized Treatment of Cancer: Experience of a Public Reference Healthcare Hospital.

The establishment of precision medicine in cancer patients requires the study of several biomarkers. Single-gene testing approaches are limited by sample availability and turnaround time. Next generation sequencing (NGS) provides an alternative for detecting genetic alterations in several genes with low sample requirements. Here we show the implementation to routine diagnostics of a NGS assay under International Organization for Standardization (UNE-EN ISO 15189:2013) accreditation. For this purpose, 106 non-small cell lung cancer (NSCLC) and 102 metastatic colorectal cancer (mCRC) specimens were selected for NGS analysis with Oncomine Solid Tumor (ThermoFisher). In NSCLC the most prevalently mutated gene was TP53 (49%), followed by KRAS (31%) and EGFR (13%); in mCRC, TP53 (50%), KRAS (48%) and PIK3CA (16%) were the most frequently mutated genes. Moreover, NGS identified actionable genetic alterations in 58% of NSCLC patients, and 49% of mCRC patients did not harbor primary resistance mechanisms to anti-EGFR treatment. Validation with conventional approaches showed an overall agreement >90%. Turnaround time and cost analysis revealed that NGS implementation is feasible in the public healthcare context. Therefore, NGS is a multiplexed molecular diagnostic tool able to overcome the limitations of current molecular diagnosis in advanced cancer, allowing an improved and economically sustainable molecular profiling.

Biologically active and antimicrobial peptides from plants.

Bioactive peptides are part of an innate response elicited by most living forms. In plants, they are produced ubiquitously in roots, seeds, flowers, stems, and leaves, highlighting their physiological importance. While most of the bioactive peptides produced in plants possess microbicide properties, there is evidence that they are also involved in cellular signaling. Structurally, there is an overall similarity when comparing them with those derived from animal or insect sources. The biological action of bioactive peptides initiates with the binding to the target membrane followed in most cases by membrane permeabilization and rupture. Here we present an overview of what is currently known about bioactive peptides from plants, focusing on their antimicrobial activity and their role in the plant signaling network and offering perspectives on their potential application.

Advantages of one step nucleic acid amplification (OSNA) whole node assay in sentinel lymph node (SLN) analysis in breast cancer.

BACKGROUND: The purpose of this study is to present our first results of sentinel node analysis (SLN) by one step nucleic acid amplification (OSNA) in routine clinical practice in our centre and compare them with the results of classic histopathological analysis in a historical cohort from our same institution. METHODS: 407 patients (total study population) with early breast cancer and no clinical nodal involvement underwent SLN biopsy in our institution. The SLN was analysed by OSNA in 164 biopsies. OSNA results were compared with the conventional histopathology study of 244 patients who had undergone SLN biopsy previously. The characteristics of the patients in both groups were evaluated and a comparison was made of the rate of metastases detected by both methods and of the surgical procedures needed in each group. We also investigated the state of non-sentinel lymph nodes if micrometastases where found in SLN. RESULTS: SLN biopsy result was considered as positive in 45 patients (28%) in the OSNA group and in 58 in the historical group (24%). There was no difference in the rate of macrometastases (16,5% for OSNA, 20% for HE) but we found differences in the rate of micrometastases (11% for OSNA and 3,6% for HE p = 0.0007). Axillary lymphadenectomy (ALND) was performed in 43/45 cases in the OSNA group and in 51/58 of the historical group. In all patients diagnosed by OSNA, ALND was performed during the initial surgical procedure. In the historical cohort ALND was performed during the initial surgical procedure in 41 patients and in a second surgical procedure in 10 patients. Patients from both groups with micrometastases in the SLN had no metastases in other nodes when the ALND was performed. CONCLUSIONS: OSNA analysis allows the detection of SLN metastases as precisely as conventional pathology with an increased detection of micrometastases. The OSNA method can reduce the need of a deferred lymphadenectomy.

Gallbladder carcinoma: the role of p53 protein overexpression and Ki-67 antigen expression as prognostic markers.

BACKGROUND: The overexpression of p53 protein and the expression of Ki-67 antigen may affect the survival of patients with gallbladder carcinoma. This association has been tested in a series of 41 patients with relatively early carcinoma of the gallbladder. METHODS: Forty-one surgical specimens from patients with a postoperative histological diagnosis of gallbladder carcinoma were studied. All patients were operated by simple cholecystectomy only because the tumours were not advanced and/or their general condition was poor. Patients submitted to radical operations were excluded. p53 expression was calculated from nuclear staining according to the intensity and extent of positive cells, as graded on a scale from 1 to 3; a combined score of >3 was considered as overexpression. Ki-67 expression was calculated by the MIB-I index: the percentage of positively stained tumour cell nuclei out of the total tumour cells counted (n = 1000); >20% of stained cells was considered positive. RESULTS: Twenty-nine gallbladder carcinomas (71%) overexpressed p53 protein in the cell nuclei. No significant differences were found in relation to cell differentiation on the level of tumour infiltration through the gallbladder wall. Five-year survival of patients with gallbladder carcinoma overexpressing p53 was 17.2%, while survival of patients without p53 overexpression was 30% (not significant). Twenty-four cases (58.5%) were considered positive for the MIB-I index. There were no differences between the grade of cell differentiation and wall infiltration. Five-year survival of the patients with a MIB-I positive index was 9.2% as opposed to 27.7% for those with a negative index (not significant). CONCLUSIONS: p53 protein nuclear overexpression and Ki-67 protein expression in gallbladder carcinoma were not related to histological differentiation, level of gallbladder wall invasion or patient survival.