Navigating the liquid biopsy Minimal Residual Disease (MRD) in non-small cell lung cancer: Making the invisible visible

Liquid biopsy has gained increasing interest in the growing era of precision medicine as minimally invasive technique. Recent findings demonstrated that detecting minimal or molecular residual disease (MRD) in NSCLC is a challenging matter of debate that need multidisciplinary competencies, avoiding the overtreatment risk along with achieving a significant survival improvement. This review aims to provide practical consideration for solving data interpretation questions about MRD in NSCLC thanks to the close cooperation between biologists and oncology clinicians. We discussed with a translational approach the critical point of view from benchside, bedside and bunchside to facilitate the future applicability of liquid biopsy in this setting. Herein, we defined the clinical significance of MRD, focusing on relevant practical consideration about advantages and disadvantages, speculating on future clinical trial design and standardization of MRD technology

Low plasma PD-L1 levels, early tumor onset and absence of peritoneal carcinomatosis improve prognosis of women with advanced high-grade serous ovarian cancer

BackgroundThe most common subtype of ovarian cancer (OC) showing immunogenic potential is represented by the high-grade serous ovarian cancer (HGSOC), which is characterized by the presence of tumor-infiltrating immune cells able to modulate immune response. Because several studies showed a close correlation between OC patient's clinical outcome and expression of programmed cell death protein-1 or its ligand (PD-1/PD-L1), the aim of our study was to investigate if plasma levels of immunomodulatory proteins may predict prognosis of advanced HGSOC women.Patients and methodsThrough specific ELISA tests, we analyzed plasma concentrations of PD-L1, PD-1, butyrophilin sub-family 3A/CD277 receptor (BTN3A1), pan-BTN3As, butyrophilin sub-family 2 member A1 (BTN2A1), and B- and T-lymphocyte attenuator (BTLA) in one hundred patients affected by advanced HGSOC, before surgery and therapy. The Kaplan-Meier method was used to generate the survival curves, while univariate and multivariate analysis were performed using Cox proportional hazard regression models.ResultsFor each analyzed circulating biomarker, advanced HGSOC women were discriminated based on long (>= 30 months) versus short progression-free survival (PFS < 30 months). The concentration cut-offs, obtained by receiver operating characteristic (ROC) analysis, allowed to observe that poor clinical outcome and median PFS ranging between 6 and 16 months were associated with higher baseline levels of PD-L1 (> 0.42 ng/mL), PD-1 (> 2.48 ng/mL), BTN3A1 (> 4.75 ng/mL), pan-BTN3As (> 13.06 ng/mL), BTN2A1 (> 5.59 ng/mL) and BTLA (> 2.78 ng/mL). Furthermore, a lower median PFS was associated with peritoneal carcinomatosis, age at diagnosis > 60 years or Body Mass Index (BMI) > 25. A multivariate analysis also suggested that plasma concentrations of PD-L1 <= 0.42 ng/mL (HR: 2.23; 95% CI: 1.34 to 3.73; p = 0.002), age at diagnosis <= 60 years (HR: 1.70; 95% CI: 1.07 to 2.70; p = 0.024) and absence of peritoneal carcinomatosis (HR: 1.87; 95% CI: 1.23 to 2.85; p = 0.003) were significant prognostic marker for a longer PFS in advanced HGSOC patients.ConclusionsThe identification of high-risk HGSOC women could be improved through determination of the plasma PD-L1, PD-1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA levels

Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

The molecular pathways which promote lung cancer cell features have been broadly explored, leading to significant improvement in prognostic and diagnostic strategies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment approach for patients with metastatic non-small cell lung cancer (NSCLC). Latest investigations by using next-generation sequencing (NGS) have shown that other oncogenic driver mutations, believed mutually exclusive for decades, could coexist in EGFR-mutated NSCLC patients. However, the exact clinical and pathological role of concomitant genomic aberrations needs to be investigated. In this systematic review, we aimed to summarize the recent data on the oncogenic role of concurrent genomic alterations, by specifically evaluating the characteristics, the pathological significance, and their potential impact on the treatment approach

Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?

: Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need for non-BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non-BRCA, HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA, expands the possibility of a successful non-BRCA, HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit

Immuno-targeted combinations in oncogene-addicted non-small cell lung cancer

The identification of tumor “oncogenic drivers” and the subsequent development of targeted therapy represented a milestone in the treatment of lung cancer over the last years. Tumor genotyping has been incorporated into therapeutic decision making of advanced non-small cell lung cancer (NSCLC) since has become clear that individuals with actionable molecular alterations receiving a matched targeted agent certainly live longer and better. The recent understanding of biological mechanisms underlying cancer immune evasion has allowed the development of a new class of immunomodulatory agents which are able to reactivate host immune-response, offering the potential for long-term disease control and survival in a significant subgroup of lung cancer patients. The complementary therapeutic effects of these two different approaches suggested intriguing potential for therapeutic synergy with combination strategies. Indeed, immunotherapy could consolidate the dramatic but transient tumor responses achieved with targeted therapy into long-term survival benefit, due to the induction of specific anti-tumor memory. However, the great emphasis and expectations linked to immune-targeted combinations have been mostly disappointed by the initial controversial results of early-phase trials, raising relevant concerns about the use of these combinations for lung cancer treatment. This review briefly summarizes the basis of immunogenicity and immune escape in oncogene addicted NSCLC, providing an updated overview of clinical trials, with the final aim of defining the current unmet needs of immuno-targeted combinations in clinical practice

Hereditary Breast and Ovarian Cancer in Families from Southern Italy (Sicily)—Prevalence and Geographic Distribution of Pathogenic Variants in BRCA1/2 Genes

Recent advances in the detection of germline pathogenic variants (PVs) in BRCA1/2 genes have allowed a deeper understanding of the BRCA-related cancer risk. Several studies showed a significant heterogeneity in the prevalence of PVs across different populations. Because little is known about this in the Sicilian population, our study was aimed at investigating the prevalence and geographic distribution of inherited BRCA1/2 PVs in families from this specific geographical area of Southern Italy. We retrospectively collected and analyzed all clinical information of 1346 hereditary breast and/or ovarian cancer patients genetically tested for germline BRCA1/2 PVs at University Hospital Policlinico “P. Giaccone” of Palermo from January 1999 to October 2019. Thirty PVs were more frequently observed in the Sicilian population but only some of these showed a specific territorial prevalence, unlike other Italian and European regions. This difference could be attributed to the genetic heterogeneity of the Sicilian people and its historical background. Therefore hereditary breast and ovarian cancers could be predominantly due to BRCA1/2 PVs different from those usually detected in other geographical areas of Italy and Europe. Our investigation led us to hypothesize that a higher prevalence of some germline BRCA PVs in Sicily could be a population-specific genetic feature of BRCA-positive carriers

How to Deal with Second Line Dilemma in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy with chemotherapy (CT) as second line treatment for metastatic colorectal cancer (mCRC). The right sequence of the treatments in all RAS (KRAS/NRAS) wild type (wt) patients has not precisely defined. We evaluated the impact of aforementioned targeted therapies in second line setting, analyzing efficacy and safety data from phase III clinical trials. We performed both direct and indirect comparisons between anti-EGFR and anti-VEGF. Outcomes included disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and G3-G5 toxicities. Our results showed significantly improved OS (HR 0.83, 95% CI 0.72–0.94) and DCR (HR 1.27, 95% CI 1.04–1.54) favouring anti-VEGF combinations in overall population; no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70–1.09). Anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31–0.96), showing a trend also in all RAS wt patients (RR 0.63, 95% CI 0.48–0.83). No significant difference in PFS and DCR all RAS was registered. Our results provided for the first time a strong rationale to manage both targeted agents in second line setting

Clinical Potential of Circulating Cell-Free DNA (cfDNA) for Longitudinally Monitoring Clinical Outcomes in the First-Line Setting of Non-Small-Cell Lung Cancer (NSCLC): A Real-World Prospective Study

Background: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. Methods: From February 2020 to May 2022, treatment-naive patients with advanced NSCLC were consecutively enrolled at the Medical Oncology Unit of the Paolo Giaccone University Hospital, Palermo (Italy). We quantified cfDNA in terms of ng/mu L using a Qubit (TM) dsDNA HS Assay Kit. The agreement between the cfDNA and radiologic response was evaluated from baseline (T0) to the radiologic evaluation (T1). Results: A total of 315 liquid biopsy samples were collected from 63 patients at baseline, with a total of 235 paired plasma samples from 47 patients at disease re-evaluation. A fair concordance was observed between early and durable radiographic and cfDNA response (Cohen's kappa coefficient = 0.001); 11 and 18 patients receiving TKI (Pearson's chi-squared test = 4.278; Cohen's kappa coefficient = 0.039) and IO treatments (Pearson's chi-squared test = 7.481; Cohen's kappa coefficient = 0.006) showed a significant and durable association between cfDNA dynamics and the first radiologic evaluation, whereas among the 18 patients undergoing CT, no significant correlation was observed (Pearson's chi-squared test = 0.720; Cohen's kappa coefficient = 0.396). The ECOG-PS 2 patients presented with the mean baseline cfDNA levels 2.6-fold higher than those with ECOG-PS 0-1 (1.71 vs. 0.65 ng/mu L; p = 0.105). Conclusions: Our real-world study demonstrates that quantitative changes in cfDNA values correlated with responses to therapy and relapse of disease in treatment-naive patients with advanced NSCLC undergoing TKI- and IO-based treatments

The diagnostic accuracy of PIK3CA mutations by circulating tumor DNA in breast cancer: an individual patient data meta-analysis

Background: The circulating tumor DNA (ctDNA) diagnostic accuracy for detecting phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations in breast cancer (BC) is under discussion. We aimed to compare plasma and tissue PIK3CA alterations, encompassing factors that could affect the results. Methods: Two reviewers selected studies from different databases until December 2020. We considered BC patients with matched tumor tissue and plasma ctDNA. We performed meta-regression and subgroup analyses to explore sources of heterogeneity concerning tumor burden, diagnostic technique, sample size, sampling time, biological subtype, and hotspot mutation. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the related area under the curve (AUC) were elaborated for the overall population and each subgroup. Results: The pooled analysis was carried out on 25 cohorts for a total of 1966 patients. The overall ctDNA sensitivity and specificity were 0.73 (95% CI: 0.70-0.77) and 0.87 (95% CI: 0.85-0.89). The AUC was 0.93. Pooled concordance, negative predictive value and positive predictive value values were 0.87 (95% CI: 0.82-0.92), 0.86 (95% CI: 0.81-0.90), and 0.89 (95% CI: 0.81-0.95) with pooled PLR, NLR, and DOR of 7.94 (95% CI: 4.90-12.86), 0.33 (95% CI: 0.25-0.45), and 33.41 (95% CI: 17.23-64.79), respectively. The pooled results consistently favored next-generation sequencing (NGS)- over polymerase chain reaction-based methodologies. The best ctDNA performance in terms of sensitivity, specificity, and AUC (0.85, 0.99, and 0.94, respectively) was observed in the low-time sampling subgroup (<= 18 days between tissue and plasma collection). Meta-regression and subgroup analyses highlighted sampling time as a possible major cause of heterogeneity. Conclusions: These findings reliably estimate the high ctDNA accuracy for the detection of PIK3CA mutations. A ctDNA-first approach for the assessment of PIK3CA mutational status by NGS may accurately replace tissue tumor sampling, representing the preferable strategy at diagnosis of metastatic BC in patients who present with visceral involvement and at least two metastatic lesions, primarily given low clinical compliance or inaccessible metastatic sites