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The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse 1 . We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45–8.92); P  < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43–0.79); P  = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41–0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) ( P  = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal–squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care. The authors report on prospective exploratory analyses of circulating tumour DNA in an urothelial carcinoma immunotherapy clinical trial.

Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R 2  = 0.87, p  < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies. The detection of aberrations in circulating tumour DNA represents a non-invasive method to survey the oncogenes and tumour suppressors that are modified within a patient’s cancer. Here, the authors analysed more than 10,000 patients using a targeted sequencing panel and report on the frequencies of the mutations that they found.

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2 + ) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2 + gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 ( ERBB2 ) plasma gene amplification. Other key driver gene amplifications, specifically MET , EGFR and FGFR2 , in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies. Exploratory analyses of the DESTINY-Gastric01 trial show that baseline HER2-associated biomarkers in circulating tumor DNA or tissue samples were associated with therapeutic response in patients with HER2-positive tumors, and these analyses identify potential drivers of resistance.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician’s choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician’s choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or ‘all’ patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician’s choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2–ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53 -altered patients. In summary, ARPIs outperform taxanes and physician’s choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 . In a biomarker-driven, outcome-adaptive platform trial for patients with metastatic castration-resistant prostate cancer, androgen receptor pathway inhibitors showed longer survival with respect to taxanes and physician’s choice treatment.

CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p  = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment. Circulating tumor DNA (ctDNA) may provide a prediction of treatment response, but could be impacted by tumor heterogeneity. Here, the authors investigate ctDNA in CDK4/6 inhibitor treatment in advanced breast cancer, finding ctDNA levels predict progression-free survival and anticipate clonal selection.

In patients with advanced breast cancer, switching to camizestrant with a CDK4/6 inhibitor after ESR1 -mutation detection (and before disease progression) led to significantly longer progression-free survival.

Circulating tumor DNA (ctDNA) assays are increasingly used for clinical decision-making, but it is unknown how well different assays agree. We aimed to assess the agreement in ctDNA mutation calling between BEAMing (beads, emulsion, amplification, and magnetics) and droplet digital PCR (ddPCR), 2 of the most commonly used digital PCR techniques for detecting mutations in ctDNA. Baseline plasma samples from patients with advanced breast cancer enrolled in the phase 3 PALOMA-3 trial were assessed for and mutations in ctDNA with both BEAMing and ddPCR. Concordance between the 2 approaches was assessed, with exploratory analyses to estimate the importance of sampling effects. Of the 521 patients enrolled, 363 had paired baseline ctDNA analysis. mutation detection was 24.2% (88/363) for BEAMing and 25.3% (92/363) for ddPCR, with good agreement between the 2 techniques (κ = 0.9l; 95% CI, 0.85-0.95). mutation detection rates were 26.2% (95/363) for BEAMing and 22.9% (83/363) for ddPCR, with good agreement (κ = 0.87; 95% CI, 0.81-0.93). Discordancy was observed for 3.9% patients with mutations and 5.0% with mutations. Assessment of individual mutations suggested higher rates of discordancy for less common mutations ( = 0.019). The majority of discordant calls occurred at allele frequency <1%, predominantly resulting from stochastic sampling effects. This large, clinically relevant comparison showed good agreement between BEAMing and ddPCR, suggesting sufficient reproducibility for clinical use. Much of the observed discordancy may be related to sampling effects, potentially explaining many of the differences in the currently available ctDNA literature.

The impact of ctDNA changes after chemotherapy on the clinical outcomes of patients with metastatic colorectal cancer (mCRC) remains unclear. The present study evaluated the clinical implications of the early change in ctDNA levels as a predictor of objective response and clinical outcome in mCRC patients who received chemotherapy. We investigated the effects of after/before ratio of ctDNA levels 2 and 8 weeks after initiation of second-line chemotherapy, on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). ctDNA was detected using amplicon-based deep sequencing with a molecular barcode encompassing >240 hotspot mutations in 14 colon cancer-related genes. In multivariate analysis, as compared to baseline, patients with lower ctDNA level (≤50%) 8 weeks after initiation of chemotherapy showed significantly longer PFS and OS than the patients with higher (>50%) ctDNA level. In patients achieving a partial response or stable disease, the after/before ratio of ctDNA level 8 weeks after initiation of chemotherapy was significantly lower than those in patients with progressive disease. The present study suggests that an early change in the ctDNA level might serve as a biomarker to predict the chemotherapeutic efficacy and clinical outcomes in patients with mCRC.

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P  < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P  < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients. An observational study on a large cohort of patients with gastrointestinal cancer demonstrates the utility of ctDNA analysis for accelerating the enrollment of patients in clinical trials with no accompanying deterioration in treatment efficacy.