Background/Objectives: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small-Cell Lung Cancer (NSCLC) accounts for 80–90% of all lung cancers. Antibody-Drug Conjugates (ADCs) represent an expanding targeted therapy option for the treatment of NSCLC. The aim is to perform a systematic literature review to evaluate the efficacy and safety profiles of ADCs currently undergoing clinical trials for the treatment of NSCLC. Methods: The study adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Literature searches were conducted in PubMed, ClinicalTrial.gov and Web of Science databases, covering the period from 2014 to 2024. Only randomized and non-randomized phase II-IV clinical trials focusing on ADC-based therapies for adult patients affected by NSCLC were selected. The Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2.0) and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) were used to evaluate the overall risk of bias in the included randomized and non-randomized studies, respectively. While GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology was used to assess the certainty of the evidence. Efficacy endpoints were categorized based on primary outcomes while safety was assessed through the frequency and severity of Treatment-Emergent Adverse Events (TEAEs), and a qualitative summary of the findings was conducted. Results: A total of seven studies, including three randomized, three non-randomized, and one without specific allocation, were included, comprising 1287 patients, with 693 (54%) men, and an average age of 63 years old. Two studies were deemed to have a low risk of bias, while six had a moderate risk or some concerns. Five ADCs were evaluated: trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), telisotuzumab vedotin, patritumab deruxtecan, and datopotamab deruxtecan (Dato-DXd). T-DXd demonstrated superior efficacy in HER2-overexpressing and HER2-mutant NSCLC, with an ORR of 52.9% and 49.0%, respectively. However, HER2-mutant patients exhibited a longer median DOR (16.8 vs. 6.2 months) but a higher incidence of grade ≥ 3 TEAEs (38.6% vs. 22%). T-DM1 showed modest efficacy, with an ORR of 20% in HER2-overexpressing NSCLC and 6.7% in HER2-mutant patients. Dato-DXd demonstrated improved ORR (26.4% vs. 12.8%) and PFS (4.4 vs. 3.7 months) compared to docetaxel. Patritumab deruxtecan achieved an ORR of 39% in EGFR-mutant NSCLC, while telisotuzumab vedotin exhibited limited activity in c-MET-positive NSCLC (ORR 9%, median DOR 7.5 months). Frequency and severity of TEAEs varied across ADCs, with ILD being a major concern, highlighting the need for strict patient monitoring and early intervention to mitigate severe adverse events. Conclusions: ADCs represent a promising advancement in NSCLC treatment, offering targeted therapeutic options beyond conventional chemotherapy and immunotherapy. T-DXd has emerged as the most effective ADC for HER2-mutant NSCLC with manageable safety profile, whereas Dato-DXd provides a viable alternative for TROP2-expressing tumors. While ADCs offer significant clinical benefits, careful patient selection and proactive management of adverse events remain crucial. Ongoing and future trials will further refine the role of ADCs in personalized NSCLC treatment, potentially expanding their tumor-agnostic use to broader patient populations.

Background: Cholangiocarcinoma (CCA) is a cancer with a low survival rate. New drugs targeting molecular alterations, oncogenic mutations, and gene fusions are being tested as second-line treatments. Objectives: This systematic review aims to summarize the results obtained with three new targeted therapies—pemigatinib, futibatinib, and ivosidenib—for the treatment of CCA, evaluating their safety and tolerability profiles in patients, compared to current standard therapies. Data sources and methods: A systematic literature search was performed with a cutoff date of July 24, 2023, in MEDLINE, Embase, and the Cochrane Library. The authors also conducted an advanced search in the ClinicalTrials.gov database, evaluated conference abstracts, article bibliographies, and drug monographs. Studies involving the treatment of patients with pemigatinib, futibatinib, and ivosidenib were considered. The selected studies had to report adverse events (AEs) that occurred during treatment with these therapies. Results: The most common AEs observed with pemigatinib, futibatinib, and ivosidenib were alopecia, diarrhea, fatigue, and dysgeusia. In addition, hyperphosphatemia, hypophosphatemia, and ocular disorders were observed with fibroblast growth factor receptor (FGFR) inhibitors, while the isocitrate dehydrogenase 1 (IDH1) inhibitor was associated with dose-dependent prolongation of the corrected QT interval (QTc). These AEs were effectively managed through dose adjustments. Conclusion: FGFR2 and IDH1 inhibitors have good tolerability in the population examined. All AEs were optimally managed with dose modulation. Future studies should focus on identifying the most effective dosages to further enhance treatment safety.

Background and aims The aim of this systematic review was to assess the risk of cardiac toxicity in patients undergoing approved PD-1 (nivolumab, pembrolizumab, cemiplimab, dostarlimab), PD-L1 (atezolizumab, avelumab, durvalumab), and CTLA-4 (ipilimumab) inhibitors. Results Among a total of 2272 articles, 11 phase II and III clinical trials included: 5463 patients and 175 cardiac adverse events. The most common cardiac disorder was atrial fibrillation (12%), while cardiac arrest and cardiac failure (6%) led to death in three cases. Overall, ICI treatment increased the risk of cardiotoxicity compared with control groups (RR=1.62, 95%-CI= 1.18-2.24, p-value=0.0033; OR=1.71, 95%-CI= 1.20-2.42, p-value=0.0027). Conclusions This study proved that the recognition of frequency and severity of all grade cardiotoxicity associated with ICIs is still underestimated. Thus, a systematic cardiological screening becomes necessary, in order to intercept the potential cardiological complications beforehand and optimize the outcomes of the respective treatment with PD-1, PD-L1 and CTLA-4 inhibitors.

e20036 Background: Lung cancerstill represents one of the most common and lethal diseases worldwide. There remains an unmet clinical need for the discovery of biomarkers to refine the management of patients with advanced non-small cell lung cancer (NSCLC). The combined evaluation of circulating cell-free DNA (cfDNA) and deep learning-based radiomic methods remains to be validated in the clinical setting. Methods: The RATIONALE study is a retro-prospective observational clinical trial consecutively enrolling treatment-naïve patients with advanced NSCLC who received standard first-line systemic treatments at Paolo Giaccone University Hospital, Palermo (Italy). Baseline and follow-up blood samples were collected according to computed tomography (CT) examinations performed using the same equipment (Siemens SOMATOM 128 slices), the same acquisition protocol, and the same contrast medium (Iomeron 400) every twelve weeks. All primary lung tumor internal regions of interest (ROIs) were segmented. Radiomic feature extraction was performed on the ROIs using Pyradiomics, an extension of the 3DSlicer. Circulating cfDNA was extracted from 1 ml of plasma using a QIAamp Circulating Nucleic Acid Kit (Qiagen) and quantified in terms of ng/μL using a QubitTM dsDNA HS Assay Kit (ThermoFisher Scientific). The diagnostic performance was evaluated using receiver operating characteristic (ROC) curves. Results: Between June 2021 and November 2023, fifty-five patients were included. Here we present the first results from the cohort of twenty patients undergoing first-line pembrolizumab-based treatments. Among the thirteen features extracted, the feature 'original_glcm_Id' evaluating the local image homogeneity emerged as statistically significant for differentiating adenocarcinoma and squamous cell carcinoma (sensitivity of 83.7%, specificity of 81.0%, accuracy of 82.8%; p < 0.001). When correlating cfDNA dynamics and radiologic response, out of the eight features examined, the feature 'first order_mean' measuring the average intensity of gray levels proved to be statistically significant (sensitivity of 86.0%, specificity of 87.7%, accuracy of 86.9%; p < 0.006). Finally, the feature 'size zone non-uniformity' measuring the variability of volumes in different gray level zones within the image showed a good performance in predicting overall survival (sensitivity of 65.8%, specificity of 100.0%, accuracy of 77.8%; p < 0.001). Conclusions: The preliminary results of this ongoing study suggest the combined evaluation of liquid biopsy and radiomic features for obtaining minimally invasive and cost-effective biomarkers in the first-line clinical setting of NSCLC undergoing first-line pembrolizumab.

Background The 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 methods Through 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. Results For 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. Conclusions The 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.

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.

The new multidisciplinary approach, called "Molecular Tumor board", arises from a collaboration of specialists and subspecialists, from a variety of fields, who meet to review and discuss cancer cases (general or site-specific), in order to provide the best treatment planning and reach a possibly better outcome for each cancer patient. Tumor Boards represent the involvement of all relevant disciplines in the treatment evaluation and planning process, allowing physicians to improve their approach to specific cancers by reviewing their cases and reconsidering changes in diagnosis and management, sharing them with all board members, and helping to ensure judicious use of health care resources. In this chapter, we aimed to summarize all the recent evidence on the molecular tumor board.

Historically, surgical biopsy has been considered the gold standard for cancer diagnosis. Nonetheless, surgical biopsies are not always feasible, and the procedures are often expensive, sometimes leading to clinical complications for the patient. Moreover, a patient's tumor genomic profile dynamically evolves, especially under oncological treatments, delineating the hurdle of tumor heterogeneity. In this fascinating scenario, liquid biopsy has emerged as a novel and intriguing diagnostic tool, providing a significant step forward in the field due to lower cost, accessibility, and repeatability. In this chapter, we aimed to summarize all the applications of liquid biopsy in the early setting of oncological disease

Liquid biopsy is a minimally or noninvasive technique for finding that circulates tumor components in biofluids. Generally, blood is used but any biological fluid can be used such as urine, pleural effusion, and saliva. Cells, including cancer cells, release DNA fragments called circulating tumor DNA, which represents a fraction of the circulating free DNA (cell-free DNA) and which represents the main biomarker user, through necrosis and apoptosis mechanisms; it is also possible to use exosomes, that is, subcellular structures encapsulated in the membrane containing proteins and nucleic acids released by tumor cells, microRNA, platelets. In this chapter, we aimed to summarize liquid biopsy applications in a real-world setting.

Non-small cell lung cancer (NSCLC) accounts approximately for 85% of all lung cancer cases and still represents the leading cause of cancer-related death worldwide. The vast majority of NSCLC patients present with advanced disease, with their clinical course being dramatically influenced by cancer-specific features at the molecular level. Although immune checkpoint inhibitors (ICIs) and targeted therapies have revolutionized the therapeutic approach in this setting, a valid universal biomarker is still missing. A potential predictive biomarker of ICI efficacy that has been suggested is a high tumor mutational burden (TMB), the quantity of acquired mutations in a tumour's genome, but evidence in this regard is controversial and not mature enough to drive decisions in NSCLC. TMB might be evaluated from tissue (tTMB) and from plasma (bTMB) yet, generally they are not concordant. Our aim was to provide a comparative analysis between plasma and tissue TMB in patients with advanced NSCLC treated with ICIs.

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-naïve 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/μL using a QubitTM 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/µL; 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-naïve patients with advanced NSCLC undergoing TKI- and IO-based treatments.

The most common subtype of ovarian cancer (OC) is the high-grade serous ovarian carcinoma (HGSOC), accounting for 70%–80% of all OC deaths. Although HGSOC is a potentially immunogenic tumor, clinical studies assessing the effectiveness of inhibitors of programmed death protein and its ligand (PD-1/PD-L1) in OC patients so far showed only response rates <15%. However, recent studies revealed an interesting prognostic role of plasma PD-1/PD-L1 and other circulating immunoregulatory molecules, such as the B- and T-lymphocyte attenuator (BTLA), butyrophilin sub-family 3A/CD277 receptors (BTN3A), and butyrophilin sub-family 2 member A1 (BTN2A1), in several solid tumors. Since evidence showed the prognostic relevance of pretreatment serum CA125 levels in OC, the aim of our study was to investigate if soluble forms of inhibitory immune checkpoints can enhance prognostic power of CA125 in advanced HGSOC women. Using specific ELISA tests, we examined the circulating PD-1, PD-L1, pan-BTN3As, BTN3A1, BTN2A1, and BTLA levels in 100 advanced HGSOC patients before treatment, correlating them with baseline serum CA125, age at diagnosis, body mass index (BMI), and peritoneal carcinomatosis. A multivariate analysis revealed that plasma BTN3A1 ≤4.75 ng/ml (HR, 1.94; 95% CI, 1.23–3.07; p=0.004), age at diagnosis ≤60 years (HR, 1.65; 95% CI, 1.05–2.59; p=0.03) and absence of peritoneal carcinomatosis (HR, 2.65; 95% CI, 1.66–4.22; p<0.0001) were independent prognostic factors for a longer progression-free survival (PFS) (≥30 months) in advanced HGSOC women. However, further two-factor multivariate analyses highlighted that baseline serum CA125 levels >401 U/ml and each soluble protein above respective concentration cutoff were covariates associated with shorter PFS (<30 months) and unfavorable clinical outcome, suggesting that contemporary measurement of both biomarkers than CA125 only could strengthen prognostic power of serum CA125 in predicting PFS of advanced HGSOC women. Plasma PD-L1, PD-1, BTN3A1, pan-sBTN3As, BTN2A1, or BTLA levels could be helpful biomarkers to increase prognostic value of CA125.

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.

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.

High-grade serous ovarian cancer (HGSOC) is the most frequent subtype of epithelial ovarian cancer (OC) with the greater immunogenic potential due to the abundance of tumor-infiltrating immune cells which modulate the anticancer immune response. Cancer cells may evade immune surveillance, by activating immunomodulatory proteins such as programmed death protein (PD-1) and its ligand PD-L1, butyrophilin sub-family 3A/CD277 receptors (BTN3A), butyrophilin sub-family 2 member A1 (BTN2A1), and the B and T lymphocyte attenuator (BTLA). Our study aimed to assess whether circulating levels of different immunoregulatory proteins could be helpful for predicting survival of advanced HGSOC patients. The plasma PD-L1, PD-1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA concentrations were analyzed in 100 advanced HGSOC women prior surgery and starting therapy, using specific ELISA tests not yet commercially available. This investigation allowed, for each tested circulating biomarker, to discriminate advanced HGSOC patients based on long (≥30 months) versus short Progression-free Survival (PFS <30 months). Through specific cut-offs obtained by ROC analysis, we showed that high baseline concentrations 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) were associated with unfavorable prognosis and median PFS from 6 to 16 months shorter. Additionally, age at diagnosis >60 years, BMI>25 or peritoneal carcinomatosis were correlated with a lower PFS (<30 months). Finally, a multivariate analysis highlighted that plasma levels 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 factors for a longer PFS in advanced HGSOC women. Assessing circulating PD-L1, PD-1, BTN3A1, pan-sBTN3As, BTN2A1 and BTLA levels could facilitate the identification of high-risk patients with unfavorable disease outcomes, suggesting their potential use as prognostic biomarkers.

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.

Breast cancer susceptibility genes 1 and 2 (BRCA 1/2) pathogenic germline variants (gPV) are involved in an increased cumulative risk for cancers (above all breast and ovarian cancers). Overweight/obesity is a well-known systemic condition conferring higher cancer risk too.

Several liquid biopsy methods for circulating tumoral DNA (ctDNA) analysis enabling detection and assessment of post-treatment molecular residual disease (MRD) have been recently developed. Hence, clinical trials have explored strategies to detect MRD and its correlation with clinical outcomes in different solid tumors.

BackgroundBreast cancer susceptibility gene 1 and 2 (BRCA 1/2) pathogenic germline variants (gPV) are involved in an increased cumulative risk for cancers (above all breast and ovarian cancers). Overweight/obesity is a well-known systemic condition conferring higher cancer risk too.MethodsWe performed a systematic review collecting data on Medline, Scopus, and Cochrane-Library database until August 2020. We included four case-control studies (Fu et al, Bissonauth et al, Khachatryan et al, Nkondjoc et al) assessing the risk for cancer according to different BMI strata in BRCA-positive healthy individuals.ResultsFour studies for a total of 1148 patients evaluated breast and ovarian cancer risk in a healthy BRCA1/2 population. No other tumor histotypes risk has been observed within the selected population. Pooled results demonstrated that different BMI conditions (lower or upper 25 kg/m2) were not associated with increased cancer risk (OR 1.15, 95% CI 0.92–1.44 and OR 1.48, 95% CI 0.84–2.62 respectively). Additionally, no differences were reported according to menopausal status.ConclusionDespite the need for other prospective investigations in larger cohorts, our results suggest no BMI contribution in cancer risk in this special population, determining a new important point of view and a new potential field of investigation.