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This study investigated the health economic evaluations of predictive biomarker testing in solid tumours treated with immune checkpoint inhibitors (ICIs). Searching PubMed, EMBASE, and Web of Science from June 2010 to February 2022, 58 relevant articles were reviewed out of the 730 screened. The focus was predominantly on non-small cell lung cancer (NSCLC) (65%) and other solid tumours (40%). Among the NSCLC studies, 21 out of 35 demonstrated cost-effectiveness, notably for pembrolizumab as first-line treatment when preceded by PD-L1 assessment, cost-effective at a threshold of $100,000/QALY compared to the standard of care. However, for bladder, cervical, and triple-negative breast cancers (TNBCs), no economic evaluations met the affordability threshold of $100,000/QALY. Overall, the review highlights a certain degree of uncertainty about the cost-effectiveness of ICI. In particular, we found PD-L1 expression associated with ICI treatment to be a cost-effective strategy, particularly in NSCLC, urothelial, and renal cell carcinoma. The findings suggest the potential value of predictive biomarker testing, specifically with pembrolizumab in NSCLC, while indicating challenges in achieving cost-effectiveness for certain other solid tumours.

Our study aims to prospectively report the functional outcomes of 31 sportsmen following anterior cruciate ligament (ACL) reconstruction, up to 12 months after surgery, with regards to subjective tests and drop jump performance, and to investigate the correlations between these variables, to be used for determining the return to sports after ACL reconstruction. Lysholm score, Tegner activity level, and the ACL-Return to Sport after Injury (ACL-RSI) scale were evaluated preoperatively, at 6 months, and at 12 months after surgery. Drop vertical jump was recorded using an infrared optical acquisition system. Lysholm and ACL-RSI scores significantly improved at the 12-month follow-up compared to the baseline and 6-month evaluations ( p < 0.001). Concerning Tegner activity level, no statistically significant differences were reported between pre- and post-operative status ( p = 0.179). Drop jump limb symmetry index significantly improved at 12 months, with the mean value improving from 76.6% (SD: 32,4) pre-operatively to 90.2% (SD: 14.7; p < 0.001) at follow-up. Scarce positive correlation was reported between the ability to perform drop jumps and activity level in athletes one year after ACL reconstruction. In addition, subjective knee score and psychological readiness were not related to jumping performance.

ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- ( n = 35) or second-line ( n = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; p = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment ( p = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found ( p = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.

Immune checkpoint inhibitors (ICIs) are largely used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Novel biomarkers that provide biological information that could be useful for clinical management are needed. In this respect, extracellular vesicles (EV)-associated microRNAs (miRNAs) that are the principal vehicle of intercellular communication may be important sources of biomarkers. We analyzed the levels of 799 EV-miRNAs in the pretreatment plasma of 88 advanced NSCLC patients who received anti-PD-1 therapy as single agent. After data normalization, we used a two-step approach to identify candidate biomarkers associated to both objective response (OR) by RECIST and longer overall survival (OS). Univariate and multivariate analyses including known clinicopathologic variables and new findings were performed. In our cohort, 24/88 (27.3%) patients showed OR by RECIST. Median OS in the whole cohort was 11.5 months. In total, 196 EV-miRNAs out 799 were selected as expressed above background. After multiplicity adjustment, abundance of EV-miR-625-5p was found to be correlated with PD-L1 expression and significantly associated to OR by RECIST ( p = 0.0366) and OS ( p = 0.0031). In multivariate analysis, PD-L1 staining and EV-miR-625-5p levels were constantly associated to OR and OS. Finally, we showed that EV-miR-625-5p levels could discriminate patients with longer survival, in particular in the class expressing PD-L1 ≥50%. EV-miRNAs represent a source of relevant biomarkers. EV-miR-625-5p is an independent biomarker of response and survival in ICI-treated NSCLC patients, in particular in patients with PD-L1 expression ≥50%.

Immune dysregulation, in combination with genetic and epigenetic alterations, induces an excessive proliferation of uncontrolled melanoma cells followed by dissemination of the tumor cells to distant sites, invading organs and creating metastasis. Although immunotherapy, checkpoint inhibitors and molecular targeted therapies have been developed as treatment options for advanced melanoma, there are specific mechanisms by which cancer cells can escape treatment. One of the main factors associated with reduced response to therapy is the ability of residual tumor cells to persist in a dormant state, without proliferation. This comprehensive review aimed at understanding the genetic basis of dormancy/awakening phenomenon in metastatic melanoma will help identify the possible therapeutical strategies that might eliminate melanoma circulating tumor cells (CTCs) or keep them in the dormant state forever, thereby repressing tumor relapse and metastatic spread.

Background: First-line decision making is the key to the successful care of mCRC patients and RAS/BRAF status is crucial to select the best targeted agent. In hub centers, a relevant proportion of patients referred from small volume centers may not have standard tissue-based (STB) molecular results available at the time of the first visit (T0). Liquid biopsy (LB) may help circumvent these hurdles., Methods: A monoinstitutional prospective head-to-head comparison of LB versus (vs.) STB testing was performed in a real-world setting. Selection criteria included: mCRC diagnosis with unknown RAS/BRAF status at T0, tumoral tissue archived in external centers, no previous treatment with anti-EGFR. At T0, patients underwent plasma sampling for LB testing and procedure for tissue recovery. RAS/BRAF genotyping was carried out by droplet digital PCR on circulating-tumoral (ct) DNA. The primary endpoint was the comparison of time to LB (T1) vs. STB (T2) results using the Mann-Whitney U test. Secondary endpoints were the concordance between LB and STB defined as overall percent agreement and the accuracy of LB in terms of specificity, sensitivity, positive and negative predictive value. We also performed an exploratory analysis on urinary (u) ctDNA., Results: A total of 33 mCRC patients were included. Mean T1 and T2 was 7 and 22 days (d), respectively ( p < 0.00001). T2 included a mean time for archival tissue recovery of 17 d. The overall percent agreement between LB and STB analysis was 83%. Compared to STB testing, LB specificity and sensitivity were 90% and 80%, respectively, with a positive predictive value of 94% and negative one of 69%. In detail, at STB and LB testing, RAS mutation was found in 45% and 42% of patients, respectively; BRAF mutation in 15%. LB results included one false positive and four false negative. False negative cases showed a significantly lower tumor burden at basal CT scan. Concordance between STB and uctDNA testing was 89%., Conclusions: Faster turnaround time, high concordance and accuracy are three key points supporting the adoption of LB in routinary mCRC care, in particular when decision on first-line therapy is urgent and tissue recovery from external centers may require a long time. Results should be interpreted with caution in LB wild-type cases with low tumor burden.

Pancreatic ductal adenocarcinoma (PDAC) is a non-immunogenic tumor poorly responsive to immune checkpoint inhibitors. This study investigates the effect of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX), and gemcitabine plus nab-paclitaxel (GEMnPAC) regimens on PD-L1 mRNA expression in plasma-derived microvesicles (MVs) in 50 PDAC patients. Plasma was collected before starting chemotherapy and after 3 months of treatment. mRNA was extracted from MVs, and PD-L1 expression was measured by digital droplet PCR. Twenty-eight patients were PD-L1 positive in MVs at baseline, of which 18 were in the GEMnPAC cohort and 10 in the FOLFIRINOX one. The amount of PD-L1 expression in MVs increased from baseline to 3 months of treatment in patients receiving GEMnPAC (median value 0.002 vs. 0.005; p = 0.01) compared to those treated with FOLFIRINOX (median 0.003 vs. 0.004; p = 0.97). The increase in PD-L1 mRNA expression in MVs was not related to tumor response (PR + SD: p = 0.08; PD: p = 0.28). Our findings demonstrate that GEMnPAC can increase PD-L1 mRNA expression in patient-derived circulating MVs, providing a rationale for testing the efficacy of this regimen in sequential or simultaneous combinations with immunotherapy in PDAC patients.

Background: Malignant pleural mesothelioma (MPM) is a fatal tumor with a poor prognosis. The recent developments of liquid biopsies could provide novel diagnostic and prognostic tools in oncology. However, there is limited information about the feasibility of this technique for MPMs. Here, we investigate whether cancer-specific DNA sequences can be detected in pleural fluids and plasma of MPM patients as free circulating tumor DNA (ctDNA)., Methods: We performed whole-exome sequencing on 14 tumor biopsies from 14 patients, and we analyzed 20 patient-specific somatic mutations with digital droplet PCR (ddPCR) in pleural fluids and plasma, using them as cancer-specific tumor biomarkers., Results: Most of the selected mutations could be detected in pleural fluids (94%) and, noteworthy, in plasma (83%) with the use of ddPCR. Pleural fluids showed similar levels of somatically mutated ctDNA (median = 12.75%, average = 16.3%, standard deviation = 12.3) as those detected in solid biopsies (median = 21.95%; average = 22.21%; standard deviation = 9.57), and their paired difference was weakly statistically significant ( p = 0.048). On the other hand, the paired difference between solid biopsies and ctDNA from plasma (median = 0.29%, average = 0.89%, standard deviation = 1.40) was highly statistically significant ( p = 2.5 × 10 -7 ), corresponding to the important drop of circulating somatically mutated DNA in the bloodstream. However, despite the tiny amount of ctDNA in plasma, varying from 5.57% down to 0.14%, the mutations were detectable at rates similar to those possible for other tumors., Conclusions: We found robust evidence that mutated DNA is spilled from MPMs, mostly into pleural fluids, proving the concept that liquid biopsies are feasible for MPM patients.

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor ( EGFR )-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR -dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [ MET ] gene amplification, Kirsten Rat Sarcoma [ KRAS ], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [ PI3KCA ], and RAF murine sarcoma viral oncogene homolog B1 [ BRAF ] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR -mutant NSCLC.

Background: In the era of precision medicine, more attention is paid to the search for predictive markers of treatment efficacy and tolerability. Statins are one of the classes of drugs that could benefit from this approach because of their wide use and their incidence of adverse events., Methods: Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such as statins, pharmacogenetics, epigenetics, toxicity and drug-drug interaction, among others. The search was performed until 1 October 2016 for articles published in English language., Results: Several technical and methodological approaches have been adopted, including candidate gene and next generation sequencing (NGS) analyses, the latter being more robust and reliable. Among genes identified as possible predictive factors associated with statins toxicity, cytochrome P450 isoforms, transmembrane transporters and mitochondrial enzymes are the best characterized. Finally, the solute carrier organic anion transporter family member 1B1 ( SLCO1B1 ) transporter seems to be the best target for future studies. Moreover, drug-drug interactions need to be considered for the best approach to personalized treatment., Conclusions: Pharmacogenetics of statins includes several possible genes and their polymorphisms, but muscular toxicities seem better related to SLCO1B1 variant alleles. Their analysis in the general population of patients taking statins could improve treatment adherence and efficacy; however, the cost-efficacy ratio should be carefully evaluated., Competing Interests: The authors declare no conflict of interest.