Published papers

BACKGROUND: We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. METHODS: Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. RESULTS: Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). CONCLUSIONS: Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

Notwithstanding recent treatment advances in metastatic colorectal cancer (mCRC), chemotherapy with a combination of a fluoropyrimidine and a folate agent, often 5-fluorouracil (5-FU) and leucovorin, remains the backbone of treatment regimens for the majority of patients with mCRC. This is despite a recent focus on molecular-targeted treatments and patient stratification according to mutational status or expression levels of specific genes. Intracellular folate concentration was discovered to be pivotal in the cytotoxic efficacy of 5-FU, paving the way to the current standard combination therapy approach. Subsequent discovery that systemic chemotherapy agents, such as irinotecan and oxaliplatin, can further increase the efficacy of 5-FU-based treatments led to the development of several combination chemotherapy regimens, including FOLFOX, FOLFIRI and FOLFOXIRI. Subsequent efforts to optimise 5-FU-based treatments have focused on 5-FU analogues, initially capecitabine and the combination drug tegafur/gimeracil/oteracil (S-1) and then TAS-102, which has recently been evaluated in phase 3 clinical trials for refractory colorectal cancer. Further approaches taken to improve the efficacy of 5-FU chemotherapy regimens have focused on optimising the route and dosing schedules and regulating folate metabolism. Pharmacokinetic variability caused by the requirement for metabolic conversion of leucovorin has been central to recent research, and the development of agents such as arfolitixorin which bypass the need for metabolic conversion remains promising for future therapeutic candidates. In this review, we summarise the evidence leading to the current treatment regimens employing 5-FU and leucovorin, focusing on recent approaches taken to optimise and refine treatments to improve clinical outcomes in patients with mCRC.

UNLABELLED: Although the gut microbiome is associated with cancer development and progression, little is known about the effects of the gut microbiome landscape and the efficacy of immune checkpoint inhibitors (ICI) across cancer types. We investigated the association between the microbiome, clinical features, and ICI efficacy across cancer types in a large nationwide screening project for solid tumors. Among 2,180 patients with advanced solid tumors enrolled in the SCRUM-Japan MONSTAR-SCREEN between October 2019 and September 2021, in the chemotherapy-naïve cohort (n = 817), a high prevalence of oral bacteria was observed in patients using proton pump inhibitors (PPI) and those with upper gastrointestinal cancers, particularly postoperative patients with gastric or pancreatic cancer. Among patients treated with ICIs (n = 333), a high abundance of sequence variants in the gut microbiome was not significantly associated with ICI efficacy across cancer types (HR = 0.94; 95% confidence interval, 0.73-1.21). However, high oral bacteria in feces significantly correlated with a shorter progression-free survival compared with low oral bacteria (median, 4.34 vs. 6.97 months; HR = 1.38; 95% confidence interval, 1.07-1.78). Notably, in patients using PPIs, a higher proportion of oral bacteria influenced progression-free survival outcomes of ICI treatment (median, 3.15 vs. 2.04 months; P = 0.08), unlike in PPI nonusers (median, 7.13 vs. 5.55 months; P = 0.74). This study of the gut microbiome has unveiled significant insights into its landscape and potential impact on ICI efficacy. It highlights that the abundance of oral bacteria in feces may play a critical role in diminishing ICI efficacy among patients using PPIs. SIGNIFICANCE: As part of the MONSTAR-SCREEN, a prospective nationwide project for patients with solid tumors, we found that although gut microbiome diversity does not consistently predict ICI efficacy across cancer types, a high level of oral bacteria in the gut is linked to reduced ICI effectiveness, especially in patients using PPIs. These findings highlight the potential clinical impact of microbiome variations on cancer treatment outcomes.

PURPOSE: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

PURPOSE:In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain.MATERIALS AND METHODS:Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors.RESULTS:MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses.CONCLUSION:Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

We have developed a circularly polarized dielectric rutile (TiO$_2$) cavity with a high quality-factor that can generate circularly polarized microwaves from two orthogonal linearly polarized microwaves with a phase difference of $\pm π/2$ using a hybrid coupler. Using this cavity, we have established a new methodology to measure the microwave Hall conductivity of a small single crystal of metal in the skin-depth region. Based on the cavity perturbation technique, we have shown that all components of the surface impedance tensor can be extracted under the application of a magnetic field by comparing the right- and left-handed circularly polarized modes. To verify the validity of the developed method, we performed test measurements on tiny Bi single crystals at low temperatures. As a result, we have successfully obtained the surface impedance tensor components and confirmed that the characteristic field dependence of the ac Hall angle in the microwave region is consistent with the expectation from the dc transport measurements. These results demonstrate a significant improvement in sensitivity compared to previous methods. Thus, our developed technique allows more accurate microwave Hall measurements, opening the way for new approaches to explore novel topological quantum phenomena, such as time-reversal symmetry breaking in superconductors.

BACKGROUND: Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8). METHODS: CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed. RESULTS: From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3-4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified. CONCLUSIONS: The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted. TRIAL REGISTRATION NUMBER: NCT03414983.

The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic profiling. Tumors with higher immune signatures showed a trend towards increased OS benefit with Enco+Bini+Cetux. RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+Cetux±Bini, and more frequent in patients with a high baseline cell-cycle gene signature; baseline TP53 mutation was associated with acquired MET amplification. Acquired mutations were subclonal and polyclonal, with evidence of increased tumor mutation rate with Enco+Cetux±Bini and mutational signatures (SBS17a/b). These findings support treatment with Enco+Cetux±Bini for patients with BRAF-V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration: NCT02928224.

Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer (CRC) relapse. Circulating tumor DNA (ctDNA) analysis may enable postsurgical risk stratification and adjuvant chemotherapy (ACT) treatment decision-making. We report results from GALAXY, which is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analyzed presurgical and postsurgical ctDNA in patients with stage II–IV resectable CRC (n = 1,039). In this cohort, with a median follow-up of 16.74 months (range 0.49–24.83 months), postsurgical ctDNA positivity (at 4 weeks after surgery) was associated with higher recurrence risk (hazard ratio (HR) 10.0, P < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III CRC (HR 10.82, P < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III CRC who derived benefit from ACT (HR 6.59, P < 0.0001). The results of our study, a large and comprehensive prospective analysis of ctDNA in resectable CRC, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from ACT.

OBJECTIVE: To evaluate the prognostic utility of postoperative circulating tumor DNA (ctDNA) for recurrence and treatment response in patients with rectal cancer undergoing upfront surgery. SUMMARY BACKGROUND DATA: ctDNA-based molecular residual disease (MRD) testing shows promise in colorectal cancer, but its role in patients with rectal cancer not receiving neoadjuvant therapy is unclear. This study evaluates whether postoperative ctDNA predicts disease-free survival (DFS) and guides adjuvant chemotherapy (ACT) decisions. METHODS: We analyzed ctDNA from patients with stage II-III rectal cancer (N=250) enrolled in the GALAXY study, multi-center registry in Japan. A clinically validated, personalized, tumor-informed 16-plex PCR-NGS assay (SignateraTM) was used to detect and quantify ctDNA. The primary outcome was DFS, defined as time from landmark to recurrence, death, or latest radiological assessment. RESULTS: In the MRD window (2-10 wks post-surgery, before ACT), 14.2% (35/246) of patients were ctDNA-positive and had significantly shorter DFS (HR: 9.96, 95% CI: 5.76-17.2, P<0.0001). Among patients who were ctDNA-positive in the MRD window, a significant benefit from ACT was observed (HR: 0.28, 95% CI: 0.09-0.89, P=0.031), whereas no benefit was seen in ctDNA-negative patients (HR: 0.59, 95% CI: 0.26-1.35, P=0.211). When analyzing ctDNA dynamics from MRD window to 6-months post-surgery, recurrence risk was higher in patients who converted from ctDNA-negative to positive (HR: 8.22, 95% CI: 1.86-36.32, P=0.0055) and who remained ctDNA-positive (HR: 45.48, 95% CI: 14.31-144.57, P<0.0001) compared to serially ctDNA-negative patients. CONCLUSIONS: Postoperative ctDNA status is a robust biomarker predicting recurrence risk and ACT benefit in patients with rectal cancer undergoing upfront surgery.

The body of evidence supporting the utility of the detection of molecular residual disease (MRD) in resected colorectal cancer (CRC) using circulating tumor DNA (ctDNA) analysis is rapidly growing. Furthermore, this evidence provides the rationale for escalation and de-escalation adjuvant chemotherapy (ACT) strategies using ctDNA MRD analysis. This has led to various randomized clinical trials, and CIRCULATE-Japan is one of the largest of these trial platforms. In this review, we provide an overview of the potential utility of ctDNA-based MRD detection for escalation and de-escalation ACT approaches. Furthermore, we highlight the feasibility using ctDNA clearance as a surrogate endpoint for ACT trials in patients with resected CRC, based on findings of the CIRCULATE-Japan project.