Peritoneal Tumor DNA as a Prognostic Biomarker in Gastric Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Gastric cancers commonly spread to the peritoneum. Its presence significantly alters patient prognosis and treatment-intent; however, current methods of peritoneal staging are inaccurate. Peritoneal tumor DNA (ptDNA) is tumor-derived DNA detectable in peritoneal lavage fluid. ptDNA positivity may indicate peritoneal micrometastasis and may be more sensitive than cytology in staging the peritoneum. In this meta-analysis, we evaluated the prognostic potential of ptDNA in gastric cancer. METHODS: PubMed, Embase, Scopus, and Web of Science databases were searched using PRISMA guidelines. Studies published between January 1, 1990, and April 30, 2023, containing quantitative data relating to ptDNA in gastric cancer were meta-analyzed. RESULTS: Six studies were analyzed. Of the total 757 patients with gastric adenocarcinoma, 318 (42.0%) were stage I, 311 (41.0%) were stage II/III, 116 (15.3%) were stage IV, and 22 (2.9%) were undetermined. Overall, ptDNA detected cytology-positive cases with a sensitivity and specificity of 85.2% (95% CI, 66.5 to 100.0) and 91.5% (95% CI, 86.5 to 96.6), respectively. Additionally, ptDNA was detected in 54 (8.5%) of 634 cytology-negative patients. The presence of ptDNA negatively correlated with pathological stage I (relative risk [RR], 0.29 [95% CI, 0.13 to 0.66]) and positively correlated with pathological stage IV (RR, 8.61 [95% CI, 1.86 to 39.89]) disease. Importantly, ptDNA positivity predicted an increased risk of peritoneal-specific metastasis (RR, 13.81 [95% CI, 8.11 to 23.53]) and reduced 3-year progression-free (RR, 5.37 [95% CI, 1.39 to 20.74]) and overall (hazard ratio, 4.13 [95% CI, 1.51 to 11.32]) survival. CONCLUSION: ptDNA carries valuable prognostic information and can detect peritoneal micrometastases in patients with gastric cancer. Its clinical utility in peritoneal staging for gastric cancer deserves further investigation.

Adjuvant Chemotherapy for Older Patients With Stage III Colorectal Cancer: A Real-World Analysis of Treatment Recommendations, Treatment Administered and Impact on Cancer Recurrence.

BACKGROUND: A substantial proportion of patients with stage III colorectal cancer (CRC) are older than 70 years. Optimal adjuvant chemotherapy (AC) for older patients (OP) continues to be debated, with subgroup analyses of randomized trials not demonstrating a survival benefit from the addition of oxaliplatin to a fluoropyrimidine backbone. PATIENTS AND METHODS: We analyzed the multisite Australian ACCORD registry, which prospectively collects patient, tumor and treatment data along with long term clinical follow-up. We compared OP (≥70) with stage III CRC to younger patients ([YP] <70), including the proportion recommended AC and any reasons for not prescribing AC. AC administration, regimen choice, completion rates, and survival outcomes were also examined. RESULTS: One thousand five hundred twelve patients enrolled in the ACCORD registry from 2005 to 2018 were included. Median follow-up was 57.0 months. Compared to the 827 YP, the 685 OP were less likely to be offered AC (71.5% vs. 96.5%, P < .0001) and when offered, were more likely to decline treatment (15.1% vs. 2.8%, P < .0001). Ultimately, 60.0% of OP and 93.7% of YP received AC (P < .0001). OP were less likely to receive oxaliplatin (27.5% vs. 84.7%, P < .0001) and to complete AC (75.9% vs. 85.7%, P < .0001). The probability of remaining recurrence-free was significantly higher in OP who received AC compared to those not treated (HR 0.73, P = .04) but not significantly improved with the addition of oxaliplatin (HR 0.75, P = .18). CONCLUSION: OP were less likely than YP to receive AC. Receipt of AC reduced recurrences in OP, supporting its use, although no significant benefit was observed from the addition of oxaliplatin.

A Practical Approach to Interpreting Circulating Tumor DNA in the Management of Gastrointestinal Cancers.

BACKGROUND: There is accumulating evidence supporting the clinical use of circulating tumor DNA (ctDNA) in solid tumors, especially in different types of gastrointestinal cancer. As such, appraisal of the current and potential clinical utility of ctDNA is needed to guide clinicians in decision-making to facilitate its general applicability. CONTENT: In this review, we firstly discuss considerations surrounding specimen collection, processing, storage, and analysis, which affect reporting and interpretation of results. Secondly, we evaluate a selection of studies on colorectal, esophago-gastric, and pancreatic cancer to determine the level of evidence for the use of ctDNA in disease screening, detection of molecular residual disease (MRD) and disease recurrence during surveillance, assessment of therapy response, and guiding targeted therapy. Lastly, we highlight current limitations in the clinical utility of ctDNA and future directions. SUMMARY: Current evidence of ctDNA in gastrointestinal cancer is promising but varies depending on its specific clinical role and cancer type. Larger prospective trials are needed to validate different aspects of ctDNA clinical utility, and standardization of collection protocols, analytical assays, and reporting guidelines should be considered to facilitate its wider applicability.

Machine learning to detect the SINEs of cancer.

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature-the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.

Pharmacogenetics testing (DPYD and UGT1A1) for fluoropyrimidine and irinotecan in routine clinical care: Perspectives of medical oncologists and oncology pharmacists.

BACKGROUND: Despite robust evidence and international guidelines, to support routine pharmacogenetic (PGx) testing, integration in practice has been limited. This study explored clinicians' views and experiences of pre-treatment DPYD and UGT1A1 gene testing and barriers to and enablers of routine clinical implementation. METHODS: A study-specific 17-question survey was emailed (01 February-12 April 2022) to clinicians from the Medical Oncology Group of Australia (MOGA), the Clinical Oncology Society of Australia (COSA) and International Society of Oncology Pharmacy Practitioners (ISOPP). Data were analysed and reported using descriptive statistics. RESULTS: Responses were collected from 156 clinicians (78% medical oncologists, 22% pharmacists). Median response rate of 8% (ranged from 6% to 24%) across all organisations. Only 21% routinely test for DPYD and 1% for UGT1A1. For patients undergoing curative/palliative intent treatments, clinicians reported intent to implement genotype-guided dosing by reducing FP dose for DPYD intermediate metabolisers (79%/94%), avoiding FP for DPYD poor metabolisers (68%/90%), and reducing irinotecan dose for UGT1A1 poor metabolisers (84%, palliative setting only). Barriers to implementation included: lack of financial reimbursements (82%) and perceived lengthy test turnaround time (76%). Most Clinicians identified a dedicated program coordinator, i.e., PGx pharmacist (74%) and availability of resources for education/training (74%) as enablers to implementation. CONCLUSION: PGx testing is not routinely practised despite robust evidence for its impact on clinical decision making in curative and palliative settings. Research data, education and implementation studies may overcome clinicians' hesitancy to follow guidelines, especially for curative intent treatments, and may overcome other identified barriers to routine clinical implementation.

Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer.

Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. We describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment, AGITG FORECAST-1 (n = 30 patients). "Resistant" predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. Our findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC.

Circulating Tumour DNA Guided Adjuvant Chemotherapy Decision Making in Stage II Colon Cancer-A Clinical Vignette Study.

Circulating tumour DNA (ctDNA) is a promising biomarker that may better identify stage II colon cancer (CC) patients who will benefit from adjuvant chemotherapy (AC) compared to standard clinicopathological parameters. The DYNAMIC study demonstrated that ctDNA-informed treatment decreased AC utilisation without compromising recurrence free survival, but medical oncologists' willingness to utilise ctDNA results to inform AC decision is unknown. Medical oncologists from Australia, Canada and New Zealand were presented with clinical vignettes for stage II CC comprised of two variables with three levels each (age: ≤50, 52-69, ≥70 years; and clinicopathological risk of recurrence: low, intermediate, high) and were queried about ctDNA testing and treatment recommendations based on results. Sixty-four colorectal oncologists completed at least one vignette (all vignettes, n = 59). The majority of oncologist were Australian (70%; Canada: n = 13; New Zealand: n = 6) and had over 10 years of clinical experience (n = 41; 64%). The proportion of oncologists requesting ctDNA testing exceeded 80% for all vignettes, except for age ≥ 70 and low-risk disease (63%). Following a positive ctDNA result, the proportion of oncologists recommending AC (p < 0.01) and recommending oxaliplatin-based doublet (p < 0.01) increased in all vignettes. Following a negative result, the proportion recommending AC decreased in all intermediate and high-risk vignettes (p < 0.01).

A tailored approach to horizon scanning for cancer medicines.

BACKGROUND: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement. METHOD: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type. RESULTS: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation. CONCLUSION: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective. POLICY SUMMARY: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities.

Patient and healthcare professional acceptability of pharmacogenetic screening for DPYD and UGT1A1: A cross sectional survey.

This study explored the acceptability of a novel pharmacist-led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs) taking part in a multicenter clinical trial of PGx testing (PACIFIC-PGx ANZCTR:12621000251820). Medical oncologists, oncology pharmacists, and patients with cancer from across four sites (metropolitan/regional), took part in an observational, cross-sectional survey. Participants were recruited from the multicenter trial. Two study-specific surveys were developed to inform implementation strategies for scaled and sustainable translation into routine clinical care: one consisting of 21 questions targeting HCPs and one consisting of 17 questions targeting patients. Responses were collected from 24 HCPs and 288 patients. The 5-to-7-day PGx results turnaround time was acceptable to HCP (100%) and patients (69%). Most HCPs (92%) indicated that it was appropriate for the PGx clinical pharmacist to provide results to patients. Patients reported equal preference for receiving PGx results from a doctor/pharmacist. Patients and HCPs highly rated the pharmacist-led PGx service. HCPs were overall accepting of the program, with the majority (96%) willing to offer PGx testing to their patients beyond the trial. HCPs identified that lack of financial reimbursements (62%) and lack of infrastructure (38%) were the main reasons likely to prevent/slow the implementation of PGx screening program into routine clinical care. Survey data have shown overall acceptability from patients and HCPs participating in the PGx Program. Barriers to implementation of PGx testing in routine care have been identified, providing opportunity to develop targeted implementation strategies for scaled translation into routine practice.

Re: Molecular testing to deliver personalised chemotherapy recommendations.

BACKGROUND: There is an increasing focus over time on the discovery and validation of biomarkers in cancer medicine, which can inform the identification of patients that are most likely to benefit from treatment, which therapy is most likely to be effective, and treatments that may not be safe. BODY: Creating the necessary evidence base for biomarker-informed management is a different challenge to developing a new therapy, and many biomarkers have been adopted into routine clinical practice without phase III randomised studies where the primary endpoint was to evaluate the direct impact of a biomarker-informed approach. This has generated a robust discussion in the research and clinical community regarding the most appropriate trial methodologies for biomarker validation, and the level of evidence required to support the incorporation of individual biomarker-driven approaches as a standard of care. This ongoing debate is key to optimising clinical trial design and ultimately delivering the best possible care to patients in an environment increasingly focused on personalised and patient-focused management. CONCLUSION: Ongoing deliberation as to the optimal design of biomarker-driven clinical trials is critical to informing future clinical trial design and will ultimately greatly benefit patients and the clinicians that care for them.

Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial.

Importance: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers. Objective: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts. Interventions: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control). Main Outcomes and Measures: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation. Results: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001). Conclusions and Relevance: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population. Trial Registration: ANZCTR Identifier: ACTRN12618000811202.

The prognostic impact of peritoneal tumour DNA in gastrointestinal and gynaecological malignancies: a systematic review.

Peritoneal metastases from various abdominal cancer types are common and carry poor prognosis. The presence of peritoneal disease upstages cancer diagnosis and alters disease trajectory and treatment pathway in many cancer types. Therefore, accurate and timely detection of peritoneal disease is crucial. The current practice of diagnostic laparoscopy and peritoneal lavage cytology (PLC) in detecting peritoneal disease has variable sensitivity. The significant proportion of peritoneal recurrence seen during follow-up in patients where initial PLC was negative indicates the ongoing need for a better diagnostic tool for detecting clinically occult peritoneal disease, especially peritoneal micro-metastases. Advancement in liquid biopsy has allowed the development and use of peritoneal tumour DNA (ptDNA) as a cancer-specific biomarker within the peritoneum, and the presence of ptDNA may be a surrogate marker for early peritoneal metastases. A growing body of literature on ptDNA in different cancer types portends promising results. Here, we conduct a systematic review to evaluate the prognostic impact of ptDNA in various cancer types and discuss its potential future clinical applications, with a focus on gastrointestinal and gynaecological malignancies.

The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer.

Cell-free DNA (cfDNA) concentrations from patients with cancer are often elevated compared with those of healthy controls, but the sources of this extra cfDNA have never been determined. To address this issue, we assessed cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary and 64 patients without cancer. Eighty-three of these individuals had cfDNA concentrations much greater than those generally observed in healthy subjects. The major contributor of cfDNA in all samples was leukocytes, accounting for ∼76% of cfDNA, with neutrophils predominating. This was true regardless of whether the samples were derived from patients with cancer or the total plasma cfDNA concentration. High levels of cfDNA observed in patients with cancer did not come from either neoplastic cells or surrounding normal epithelial cells from the tumor's tissue of origin. These data suggest that cancers may have a systemic effect on cell turnover or DNA clearance. SIGNIFICANCE: The origin of excess cfDNA in patients with cancer is unknown. Using cfDNA methylation patterns, we determined that neither the tumor nor the surrounding normal tissue contributes this excess cfDNA-rather it comes from leukocytes. This finding suggests that cancers have a systemic impact on cell turnover or DNA clearance. See related commentary by Thierry and Pisareva, p. 2122. This article is featured in Selected Articles from This Issue, p. 2109.

Clinical application of circulating tumour DNA in colorectal cancer.

Liquid biopsies that detect circulating tumour DNA (ctDNA) have the potential to revolutionise the personalised management of colorectal cancer. For patients with early-stage disease, emerging clinical applications include the assessment of molecular residual disease after surgery, the monitoring of adjuvant chemotherapy efficacy, and early detection of recurrence during surveillance. In the advanced disease setting, data highlight the potential of ctDNA levels as a prognostic marker and as an early indicator of treatment response. ctDNA assessment can complement standard tissue-based testing for molecular characterisation, with the added ability to monitor emerging mutations under the selective pressure of targeted therapy. Here we provide an overview of the evidence supporting the use of ctDNA in colorectal cancer, the studies underway to address some of the outstanding questions, and the barriers to widespread clinical uptake.

Circulating tumour DNA in the evolving treatment landscape of locally advanced rectal cancer: where does it fit in?

The management of locally advanced rectal cancer (LARC) requires multimodality treatment, typically with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. However, the treatment landscape is rapidly evolving with total neoadjuvant therapy and non-operative management for selected patients emerging as other novel treatment approaches. With so many treatment options, there is a need for biomarkers to direct a more personalised treatment strategy for patients with LARC. In this review, we summarise the available data regarding the use of circulating tumour DNA (ctDNA) in patients with LARC, as both a marker of treatment response to neoadjuvant therapy and as a marker of minimal residual disease (MRD) after patients have completed definitive local treatment. To date, the ability of ctDNA status to predict for pathologic complete response at any timepoint during multimodality treatment has been variably reported. The most consistent finding across available studies is the ability of ctDNA to detect MRD after CRT and surgery, the presence of which confers a significantly poor prognosis, with increased risk of cancer recurrence and worse overall survival. It is yet to be determined if providing additional therapies to patients with MRD improves outcomes. The available studies assessing the potential utility of ctDNA in LARC are limited by significant heterogeneity in the choice of ctDNA assay, timepoint at which ctDNA was collected, treatment that patients received and length of follow-up, leading to uncertainties about how to implement it into daily clinical practice. As the treatment landscape evolves, larger randomised trials assessing the role of ctDNA in LARC are needed.

Health economic evidence for adjuvant chemotherapy in stage II and III colon cancer: a systematic review.

OBJECTIVE: The aims of this study was to appraise the health economic evidence for adjuvant chemotherapy (AC) strategies in stage II and III colon cancer (CC) and identify gaps in the available evidence that might inform further research. METHOD: A systematic review of published economic evaluations was undertaken. Four databases were searched and full-text publications in English were screened for inclusion. A narrative synthesis was performed to summarise the evidence. RESULTS: Thirty-eight studies were identified and stratified by cancer stage and AC strategy. The majority (89%) were full economic evaluations considering both health outcomes, usually measured as quality-adjusted life years (QALYs), and costs. AC was found to be cost-effective compared to no AC for both stage II and III CC. Oral and oxaliplatin-based AC was cost-effective for stage III. Three months of CAPOX was cost-effective compared to 6-month in high-risk stage II and stage III CC. Preliminary evidence suggests that biomarker approaches to AC selection in stage II can reduce costs and improve health outcomes. Notably, assessment of QALYs were predominantly reliant on a small number of non-contemporary health-utility studies. Only 32% of studies considered societal costs such as travel and time off work. CONCLUSIONS: Published economic evaluations consistently supported the use of AC in stage II and III colon cancer. Biomarker-driven approaches to patient selection have great potential to be cost-effective, but more robust clinical and economic evidence is warranted. Patient surveys embedded into clinical trials may address critical knowledge gaps regarding accurate assessment of QALYs and societal costs in the modern era.

Cancer Treatment Patterns and Factors Affecting Receipt of Treatment in Older Adults: Results from the ASPREE Cancer Treatment Substudy (ACTS).

INTRODUCTION: Cancer treatment planning in older adults is complex and requires careful balancing of survival, quality of life benefits, and risk of treatment-related morbidity and toxicity. As a result, treatment selection in this cohort tends to differ from that for younger patients. However, there are very few studies describing cancer treatment patterns in older cohorts. METHODS: We used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and the ASPREE Cancer Treatment Substudy (ACTS) to describe cancer treatment patterns in older adults. We used a multivariate logistic regression model to identify factors affecting receipt of treatment. RESULTS: Of 1893 eligible Australian and United States (US) participants with incident cancer, 1569 (81%) received some form of cancer treatment. Non-metastatic breast cancers most frequently received treatment (98%), while haematological malignancy received the lowest rates of treatment (60%). Factors associated with not receiving treatment were older age (OR 0.94, 95% CI 0.91-0.96), residence in the US (OR 0.34, 95% CI 0.22-0.54), smoking (OR 0.57, 95% CI 0.40-0.81), and diabetes (OR 0.56, 95% CI 0.39-0.80). After adjustment for treatment patterns in sex-specific cancers, sex did not impact receipt of treatment. CONCLUSIONS: This study is one of the first describing cancer treatment patterns and factors affecting receipt of treatment across common cancer types in older adults. We found that most older adults with cancer received some form of cancer treatment, typically surgery or systemic therapy, although this varied by factors such as cancer type, age, sex, and country of residence.

A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study.

PURPOSE: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. PATIENTS AND METHODS: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. RESULTS: Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification. CONCLUSIONS: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.