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Taselisib is a potent β‐sparing phosphatidylinositol 3‐kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA)‐mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib + fulvestrant, tumour protein p53 (TP53; encoding p53) and fibroblast growth factor receptor 1 (FGFR1) alterations were associated with shorter progression‐free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CAmut ctDNA harbouring a neurofibromin 1 (NF1) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co‐)alterations on outcomes with one of the largest clinico‐genomic datasets of ER+, HER2−, PIK3CAmut breast cancer patients treated with a PI3K inhibitor. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow‐up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of longitudinal circulating tumour DNA (ctDNA) measurements in patients with advanced PDAC undergoing palliative chemotherapy. Using KRAS peptide nucleic acid clamp‐PCR, we measured ctDNA levels in plasma samples obtained at baseline and every 4 weeks during chemotherapy from 81 patients with locally advanced and metastatic PDAC. Cox proportional hazard regression showed that ctDNA detection at baseline was an independent predictor of progression‐free and overall survival. Joint modelling demonstrated that the dynamic ctDNA level was a strong predictor of time to first disease progression. Longitudinal ctDNA measurements during chemotherapy successfully revealed disease progression in 20 (67%) of 30 patients with ctDNA detected at baseline, with a median lead time of 23 days (P = 0.01) over radiological imaging. Here, we confirmed the clinical relevance of ctDNA in advanced PDAC with regard to both the prediction of clinical outcome and disease monitoring during treatment. [ABSTRACT FROM AUTHOR]

The introduction of immune checkpoint inhibitors has transformed the treatment landscape of metastatic non‐small cell lung cancer. However, challenges remain to increase the fraction of patients achieving durable clinical responses to these drugs and to help monitor the treatment effect. In this phase II trial, we investigated the toxicity, systemic responses and circulating tumour DNA responses in patients (n = 21) with advanced non‐small‐cell lung cancer treated with atezolizumab and stereotactic body radiotherapy in the second or later line. We found the combined treatment to be safe with grade 3 toxicity reported in three patients. As the best overall response, four patients had a partial response, eight had stable disease and five had progressive disease. Median overall survival time was still not reached after a median follow‐up of 26.5 months and 10/15 patients with programmed death‐ligand 1 negative tumours were alive >18 months after the start of the study treatment. ctDNA was detectable at baseline in 11 patients. A rapid decline in ctDNA to <30% of baseline levels was seen in three patients, two of which were radiographic responders and one was considered clinically benefiting from therapy for almost 1 year. [ABSTRACT FROM AUTHOR]

• Liquid biopsy can guide treatment optimization (de-/intensification) in patients with resected non-metastatic melanoma. • ctDNA-based molecular residual disease (MRD) assessment has a sensitivity/specificity of 11–80%/55–100% to predict relapse. • More and more data about the correlation between detectable ctDNA and clinical outcomes are emerging. • Clinical trials assessing the clinical utility of ctDNA-based MRD assessment are ongoing. In patients with resected non-metastatic melanoma, the liquid biopsy for the assessment of molecular residual disease (MRD) by circulating tumour DNA (ctDNA) represents a promising tool to stratify the risk and to monitor tumour evolution. However, its validation requires the demonstration of analytical validity, clinical validity and utility. Indeed, the development of sensitive and specific assays can optimize prognostication and eventually help clinicians to modulate adjuvant treatments, in order to improve clinical outcomes. Data about ctDNA-guided prognosis stratification is emerging, but clinical trials assessing ctDNA-guided therapeutic decisions are still ongoing. This review aims to depict the role of ctDNA-based MRD assessment in patients with non-metastatic melanoma and to provide a roadmap to face challenges for its introduction into clinical practice. [ABSTRACT FROM AUTHOR]

Circulating tumour DNA (ctDNA) detection for postoperative risk stratification in cancer patients has great clinical potential. However, low ctDNA abundances complicates detection. Multitarget (MT) detection strategies have been developed to increase sensitivity. Yet, empirical evidence supporting performance gains of MT vs. single-target (ST) strategies in a postoperative setting is limited. We compared ctDNA detection in 379 paired plasma samples from 112 stage II–III colorectal cancer patients by ST digital PCR and MT sequencing of 16 patient-specific variants. The strategies exhibited good concordance (90%, Cohen’s Kappa 0.79), with highly correlated ctDNA quantifications (Pearson r = 0.985). A difference was observed in ctDNA detection preoperatively (ST 72/92, MT 88/92). However, no difference was observed immediately after surgery in recurrence (ST 11/22, MT 10/22) or nonrecurrence (both 2/34) patients. In serial samples, detection was similar within recurrence (ST 13/16, MT 14/16) and nonrecurrence (ST 3/49, MT 1/49) patients. Both approaches yielded similar lead times to standard-of-care radiology (ST 4.0 months, MT 4.1 months). Our findings do not support significant performance gains of the MT strategy over the ST strategy for postoperative ctDNA detection. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is a malignant tumor with strong invasiveness and high mortality. It has the characteristics of easy metastasis, fast growth, high degree of malignancy and strong invasiveness. The prognosis of patients is generally poor. The current clinical diagnosis of SCLC is mainly based on tissue biopsy, which is invasive, long cycle time and high cost. In recent years, liquid biopsy has been gradually applied because of its non-invasive, comprehensive and real-time characteristics that traditional tissue biopsy does not have. The main detection objects of liquid biopsy include circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and exosomes in peripheral blood. The application of liquid biopsy in the clinical treatment of SCLC will help clinicians to improve the detailed diagnosis of SCLC patients, as well as the timely control and response to the treatment response of patients. [ABSTRACT FROM AUTHOR]

Chondrosarcoma (CS) is a rare tumour type and the most common primary malignant bone cancer in adults. The prognosis, currently based on tumour grade, imaging and anatomical location, is not reliable, and more objective biomarkers are required. We aimed to determine whether the level of circulating tumour DNA (ctDNA) in the blood of CS patients could be used to predict outcome. In this multi‐institutional study, we recruited 145 patients with cartilaginous tumours, of which 41 were excluded. ctDNA levels were assessed in 83 of the remaining 104 patients, whose tumours harboured a hotspot mutation in IDH1/2 or GNAS. ctDNA was detected pre‐operatively in 31/83 (37%) and in 12/31 (39%) patients postoperatively. We found that detection of ctDNA was more accurate than pathology for identification of high‐grade tumours and was associated with a poor prognosis; ctDNA was never associated with CS grade 1/atypical cartilaginous tumours (ACT) in the long bones, in neoplasms sited in the small bones of the hands and feet or in tumours measuring less than 80 mm. Although the results are promising, they are based on a small number of patients, and therefore, introduction of this blood test into clinical practice as a complementary assay to current standard‐of‐care protocols would allow the assay to be assessed more stringently and developed for a more personalised approach for the treatment of patients with CS. [ABSTRACT FROM AUTHOR]

Circulating tumour DNA (ctDNA) is very useful for purposes of cancer genetics; however, it has some limitations. Recently, ctDNA in body fluids, such as urine, sputum, and pleural effusion, has been investigated. The aim of this study was to evaluate the quantity of ctDNA derived from urine (trans -renal ctDNA) and the accuracy of KRAS mutation detection in relation to disease stage in colorectal cancer. Urine, plasma, and tissue samples were collected from consecutively resected colorectal cancer patients. DNA was extracted from each sample and the quantity was determined. From each DNA sample, KRAS mutations were detected using droplet digital PCR. 200 patients participated and KRAS mutations were detected in 84 patients (42.0%) from tumour tissue. The concentration of trans -renal ctDNA (trtDNA) was significantly lower than that of plasma; however, there was no significant difference between the sensitivity using ctDNA and that using trtDNA (29.8% VS 33.3%, p = 0.62). Concordance between these two tests was only 17.5%. Combination analysis (ctDNA + trtDNA) improved the sensitivity to 53.6%, and sensitivity was significantly higher than that of corresponding single assays (p = 0.003). In early cancer stages, trtDNA had greater sensitivity for detecting KRAS mutations than ctDNA (37.7% vs. 21.3%, p = 0.047). Conversely, it was less useful for advanced cancer stages (21.7% vs. 52.2%, p = 0.07). Notably, KRAS mutations were detected using ctDNA or trtDNA in 12 of 116 (10.3%) patients who had no KRAS mutations in their tissue samples. Conclusions: trtDNA and ctDNA have equal potential and combination analysis significantly improved the sensitivity. [ABSTRACT FROM AUTHOR]

Determination of tumour‐specific transcription based on liquid biopsies possesses a large diagnostic and prognostic potential in non‐small cell lung cancer (NSCLC). Cell‐free DNA (cfDNA) packed in nucleosomes mirrors the histone modification profiles present in the cells of origin. H3 lysine 36 trimethylation (H3K36me3)‐modified nucleosomes are associated with active genes, and therefore, cell‐free chromatin immunoprecipitation (cfChIP) of H3K36me3‐associated cfDNA has the potential to delineate whether transcription of a particular gene is occurring in the cells from which its cfDNA originates. We hypothesized that cfChIP can delineate transcriptional status of genes harbouring somatic cancer mutations and analysed the recurrently observed EGFR‐L858R mutation as an example. In representative NSCLC cell lines, the relationship between wild‐type (WT) and mutated EGFR transcriptional activity and mRNA expression levels was analysed using H3K36me3 ChIP and EGFR mRNA reverse transcription quantitative PCR (RT‐qPCR), respectively. The ChIP analysis showed that both WT and mutated EGFR are transcribed and that mRNA is similarly expressed per EGFR copy. Based on this observation, we proceeded with EGFR cfChIP using blood plasma from NSCLC patients harbouring the EGFR‐L858R mutation. EGFR‐WT fragments can originate from both nontumour cells with no or low EGFR transcription and tumour cells with active EGFR transcription, whereas EGFR‐L858R fragments must specifically originate from tumour cells. H3K36me3 cfChIP followed by droplet digital PCR (ddPCR) revealed significantly higher enrichment of EGFR‐L858R compared to EGFR‐WT fragments. This is in alignment with EGFR‐L858R being actively transcribed in the NSCLC tumour cells. This study is proof‐of‐principle that cfChIP can be used to identify tumour‐specific transcriptional activity of mutated alleles, which can expand the utility of liquid biopsy‐based cfDNA analyses to enhance tumour diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

Circulating tumour DNA (ctDNA) has been increasingly incorporated into the treatment of cancer patients. ctDNA is generally accepted as a powerful diagnostic tool, whereas the utility of ctDNA to monitor disease activity needs to be fully validated. Central to this challenge is the question of whether changes in longitudinal ctDNA measurements reflect disease activity or merely biological variation. Thus, the aim of this study was to explore the intra‐individual biological variation of ctDNA in lung cancer patients. We identified tumour‐specific mutations using next‐generation sequencing. Day‐to‐day and hour‐to‐hour variations in plasma concentrations of the mutant allele and wild‐type cell‐free DNA (cfDNA) were determined using digital PCR. The levels of the mutant alleles varied by as much as 53% from day to day and 27% from hour to hour. cfDNA varied up to 19% from day to day and up to 56% from hour to hour, as determined using digital PCR. Variations were independent of the concentration. Both mutant allele concentrations and wild‐type cfDNA concentrations showed considerable intra‐individual variation in lung cancer patients with nonprogressive disease. This pronounced biological variation of the circulating DNA should be investigated further to determine whether ctDNA can be used for monitoring cancer activity. [ABSTRACT FROM AUTHOR]

Darwin had many close connections with medical men, and made a number of observations on inherited diseases, clearly describing the inheritance of sex-linked diseases, inherited diseases at corresponding ages, infectious disease and the causes of diseases. Darwin's Pangenesis provides an alternative explanation for cancer metastasis, and is now supported by the discovery of circulating tumour DNA. The "genometastasis hypothesis" proposed by Garcia-Olmo et al. is consistent with Pangenesis. Darwin's view of animal regeneration and his pangenetic explanation is also supported by the recent finding regarding the role of small RNAs and extracellular vesicles in regeneration. There is increasing evidence for genetic information exchange between the donor and recipient cells during transplantation, supporting Darwin's "graft hybridization" concept that gemmules released from the cells of the stock (or scion) could move into the scion (or stock) and incorporated into their cells. In addition, there is also increasing evidence for transposition of the viscera. It appears to me that there is a need to expand the concept of Darwinian medicine by incorporating Darwin's Pangenesis into it. [ABSTRACT FROM AUTHOR]

The main objectives of the studies are to analyze melanoma markers from the tumour and blood samples. Lactate dehydrogenase (LDH) was assayed from the serum sample to determine metastatic melanoma. The prevalence of circulating tumour cells was explored in tumour subjects and compared with non-tumour cases. Expression analysis of TGF-β and cathepsin-K was determined from the non-melanoma and melanoma cases using western blotting analysis. The amount of LDH was elevated in most metastatic patients (p < 0.0001). About 10% of patients were associated with the micrometastatic stage and 16.3% of patients were linked with multiple melanomas. The amount of ctDNA considerably declined at <0.01% level after one month of clinical development. The amount of ctDNA in the blood in an initial stage indicates resistance to specific targeted therapy. Expression of S100 level also decreased after two weeks of treatment. TGF-β showed maximum variation in mRNA expression between diseased and healthy cases, whereas, an increased amount of cathepsin-K biosynthesis was observed in tumour tissues (p < 0.001). MDH, ctDNA, TGF-β and S100 could be potential markers to predict early determination of tumour and non-tumour tissues. Monitoring of ctDNA and S100 is useful to analyze the health benefits of melanoma patients. [ABSTRACT FROM AUTHOR]

Background The detection of circulating DNA is considered a promising strategy in cancer patients. Digital PCR has emerged as a sensitive method able to quantify both circulating free and tumour DNA. Aim The aim of this study was to prospectively evaluate the clinical value of a chip-based digital PCR for the detection of circulating DNA. Methods Digital PCR was used in 34 metastatic colorectal cancer patients to detect and quantify circulating free and tumour DNA based on K-ras mutational status. Clinical outcomes were analyzed according to circulating DNA measurements. Results Digital PCR yielded a detection rate of 69% for circulating tumour DNA. The median concentrations of circulating free and tumour DNA were 20 and 6.8 ng/mL, respectively, with significant correlation between both biomarkers ( p < 0.001). Median overall survival was 4.8 months in patients with high circulating free DNA (>75% quartile) versus not reached in patients with a low level (<25% quartile) ( p = 0.029). Moreover, median overall survival was significantly decreased in patients with detectable circulating tumour DNA compared to those without (respectively 11.8 months versus not reached, p = 0.04). Conclusions Chip-based digital PCR is a simple and non-invasive method allowing the efficient detection of circulating DNA. Our results highlight that levels of these circulating markers may have a potential prognostic value. [ABSTRACT FROM AUTHOR]