Plasma versus tissue tumor mutational burden as biomarkers of durvalumab plus tremelimumab response in patients with metastatic colorectal cancer in the CO.26 trial.

PURPOSE: Tissue derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset on which this was validated lacked colorectal cancers (CRCs), and there is limited evidence for immunotherapy benefit in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients comparing durvalumab and tremelimumab (D+T, n=119 patients) versus best supportive care (BSC, n=61 patients). ctDNA sequencing was available for 168 patients (n=118 D+T, n=50), of which 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on overall survival were determined using a minimal p-value approach. This report includes the final overall survival analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D+T compared to BSC in microsatellite stable (MSS) metastatic CRC (HR 0.71 [95% CI:0.28-1.80], p=0.47). No tissue TMB threshold could identify a high TMB group that benefited from ICI. In contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D+T (HR=0.34 [95%CI:0.13-0.85], p=0.022), as was clonal pTMB ≥10.6 mutations/Mb (HR=0.10 [95%CI:0.014-0.79], p=0.029) and subclonal pTMB ≥25.9/Mb (HR=0.20 [95% CI:0.061-0.69], p=0.010). Higher pTMB was associated with length of time on cytotoxic agents (p=0.021) and prior anti-EGFR exposure (p=2.44x10-06). CONCLUSION: pTMB derived from either clonal or subclonal mutations may identify a group more likely to benefit from immunotherapy, though validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.

Impact of grade on workup of rectal neuroendocrine tumors: a retrospective cohort study : Grade impact on workup of rectal NETs.

BACKGROUND: Rectal neuroendocrine tumors (RNETs) are often discovered on screening colonoscopy. Indications for staging and definitive resection are inconsistent in current guidelines. We evaluated the role of grade in guiding staging and procedural decision-making. METHODS: Patients with biopsy confirmed RNETs between 2004 and 2015 were reviewed. Baseline characteristics, staging investigations (biochemical and imaging), and endoscopic/surgical treatment were recorded. Associations between grade, preoperative staging, interventions, and survival were determined using Fisher-Freeman-Halton Exact, log-rank, and Kaplan-Meier analysis. RESULTS: Amongst 139 patients with RNETs, 9% were aged ≥ 75 years and 44% female. Tumor grade was: 73% grade 1 (G1), 18%, grade 2 (G2) and 9% grade 3 (G3). Staging investigations were performed in 52% of patients. All serum chromogranin A and 97% of 24-hour urine 5-hydroxyindoleacetic acid tests were normal. The large majority of staging computed tomography (CT) scans were negative (76%) with subgroup analysis showing no G1 patients with CT identified distant disease compared with 38% of G2 and 50% of G3 patients (p < 0.001). G1 patients were more likely to achieve R0/R1 resections compared to G2 (95% vs. 50%, p < 0.001) and G1 patients had significantly better 5-year overall survival (G1: 98%, G2: 67%, G3: 10%, p < 0.001). CONCLUSION: Tumor grade is important in preoperative workup and surgical decision-making. Biochemical staging may be omitted but staging CT should be considered for patients with grade ≥ 2 lesions. Anatomic resections should be considered for patients with grade 2 disease.

Symptom Burden and Time from Symptom Onset to Cancer Diagnosis in Patients with Early-Onset Colorectal Cancer: A Multicenter Retrospective Analysis.

Background: The incidence of colorectal cancer (CRC) is decreasing in individuals >50 years due to organised screening but has increased for younger individuals. We characterized symptoms and their timing before diagnosis in young individuals. Methods: We identified all patients diagnosed with CRC between 1990-2017 in British Columbia, Canada. Individuals <50 years (n = 2544, EoCRC) and a matched cohort >50 (n = 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis. Results: Across all stages of CRC, EoCRC presented with significantly more symptoms than LoCRC (Stage 1 mean ± SD: 1.3 ± 0.9 vs. 0.7 ± 0.9, p = 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7, p < 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC (p < 0.0001) and LoCRC (p < 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8-1.0, p = 0.008) and increasing symptom number were independently associated with worse survival in multivariate models. Conclusions: Patients with EoCRC present with a greater number of symptoms of longer duration than LoCRC; however, time from patient reported symptom onset was not associated with worse outcomes.

Transverse Colon Primary Tumor Location as a Biomarker in Metastatic Colorectal Cancer: A Pooled Analysis of CCTG/AGITG CO.17 and CO.20 Randomized Clinical Trials.

PURPOSE: Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. EXPERIMENTAL DESIGN: Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. RESULTS: A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28-1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone. CONCLUSIONS: Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.

Clinical impact of unsuccessful subcutaneous administration of octreotide LAR instead of intramuscular administration in patients with metastatic gastroenteropancreatic neuroendocrine tumors.

Octreotide LAR is a long-acting somatostatin analogue (SSA) used in the management of metastatic gastroenteropancreatic neuroendocrine tumors (GEP NETs). It requires intramuscular (IM) injection. Missed IM injections cause subcutaneous nodules (SCNs) on radiologic images. We reviewed the rates of SCNs in a real-world cohort of GEP NETs receiving octreotide LAR and explored treatment outcomes. Patients commencing octreotide LAR between August 5, 2010 and March 8, 2018 at a single cancer center in Canada were identified from pharmacy records. Patients were included if they had a computed tomography (CT) scan performed at the time of progression and a preceding CT with pelvis included to enable assessment for the presence of nodules. Fisher's exact test was used to examine predictors of SCNs, and Kaplan-Meier curves summarized differences in progression free (PFS) and overall survival (OS) that were compared with log-rank tests. Of 243 patients receiving octreotide LAR, 45 had all required CT images available for central review. SCNs were found in 20/45 (44%) of patients on the last scan showing stable disease before progression and were numerically but not statistically more likely in females (OR: 2.36, 95% CI: 0.66-8.29, p = .23). There was an increased risk of SCNs in patients with a skin-to-muscle distance >38 mm (the length of an octreotide LAR needle) on CT (OR: 5.09, 95% CI: 1.39-16.6, p = .018) and a trend toward increased risk in obese patients (OR: 5.71, 95% CI: 1.26-23.4, p = .061). PFS (HR: 1.01, 95% CI: 0.56-1.78, p = .98) and OS (HR: 0.86, 95% CI: 0.41-1.8, p = .70) was similar between those with/without SCNs. In conclusion, almost half of patients receiving octreotide LAR had SCNs; however, missed administration of SSA did not appear to result in worse survival in this small study. Factors such as sex, younger age skin-to-muscle distance, and obesity may affect SCN development and should be considered when choosing an SSA.

PRESSING Need of Precision Care in HER2-Positive Colorectal Cancer: The ELEPHANT in the Room.

Although dual HER2 inhibition has shown promising clinical activity in patients with RAS wild-type HER2-positive metastatic colorectal cancer, predictive biomarkers of response/resistance are less well characterized. Activating HER2/RTK/MAPK genomic alterations appears to blunt the clinical benefit of dual anti-HER2 therapy and may hold a potential albeit partial role in patient selection. See related article by Randon et al., p. 436.

Direct Medical Spending on Young and Average-Age Onset Colorectal Cancer before and after Diagnosis: a Population-Based Costing Study.

BACKGROUND: Despite a better understanding of the increasing incidence of young-onset colorectal cancer (yCRC; age at diagnosis <50 years), little is known about its economic burden. Therefore, we estimated direct medical spending on yCRC before and after diagnosis. METHODS: We used linked administrative health databases in British Columbia, Canada, to create a study population of yCRC and average-age onset colorectal cancer (aCRC; age at diagnosis ≥50 years) cases, along with cancer-free controls. Over the 1-year period preceding a colorectal cancer diagnosis, we estimated direct medical spending on hospital visits, healthcare practitioners, and prescription medications. After diagnosis, we calculated cost attributable to yCRC and aCRC, which additionally included the cost of cancer treatments (e.g., chemotherapy and radiotherapy) across phases of care. RESULTS: We included 1,058 yCRC (45.4% females; age at diagnosis 42.4 ± 6.2 years) and 12,619 aCRC (44.8% females; age at diagnosis of 68.1 ± 9.2 years) cases. Direct medical spending on the average yCRC and aCRC case during the year before diagnosis was $6,711 and $8,056, respectively. After diagnosis, the overall average annualized cost attributable to yCRC significantly differed in comparison with aCRC for the initial ($50,216 vs. $37,842; P < 0.001), continuing ($8,361 vs. $5,014; P < 0.001), and end-of-life cancer phase ($86,125 vs. $61,512; P < 0.001) but not end-of-life non-cancer phase ($77,273 vs. $23,316; P = 0.372). CONCLUSIONS: Reported cost estimates may be used as inputs for future economic evaluations pertaining to yCRC. IMPACT: We provided comprehensive cost estimates for healthcare spending on young-onset colorectal cancer.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Intervention: Durvalumab plus tremelimumab or best supportive care. Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

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.

Effect of Immunosuppressive or Immunomodulatory Agents on Severe COVID-19 Outcomes: A Population-Based Cohort Study.

OBJECTIVE: We estimated the association between immunosuppressive and immunomodulatory agent (IIA) exposure and severe COVID-19 outcomes in a population-based cohort study. METHODS: Participants were 18 years or older, tested positive for SARS-CoV-2 between February 6, 2020, and August 15, 2021, and were from administrative health data for the entire province of British Columbia, Canada. IIA use within 3 months prior to positive SARS-CoV-2 test included conventional disease-modifying antirheumatic drugs (antimalarials, methotrexate, leflunomide, sulfasalazine, individually), immunosuppressants (azathioprine, mycophenolate mofetil/mycophenolate sodium [MMF], cyclophosphamide, cyclosporine, individually and collectively), tumor necrosis factor inhibitor (TNFi) biologics (adalimumab, certolizumab, etanercept, golimumab, infliximab, collectively), non-TNFi biologics or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) (rituximab separately from abatacept, anakinra, secukinumab, tocilizumab, tofacitinib and ustekinumab collectively), and glucocorticoids. Severe COVID-19 outcomes were hospitalizations for COVID-19, ICU admissions, and deaths within 60 days of a positive test. Exposure score-overlap weighting was used to balance baseline characteristics of participants with IIA use compared with nonuse of that IIA. Logistic regression measured the association between IIA use and severe COVID-19 outcomes. RESULTS: From 147,301 participants, we identified 515 antimalarial, 573 methotrexate, 72 leflunomide, 180 sulfasalazine, 468 immunosuppressant, 378 TNFi biologic, 49 rituximab, 144 other non-TNFi biologic or tsDMARD, and 1348 glucocorticoid prescriptions. Risk of hospitalizations for COVID-19 was significantly greater for MMF (odds ratio [95% CI]): 2.82 [1.81-4.40], all immunosuppressants: 2.08 [1.51-2.87], and glucocorticoids: 1.63 [1.36-1.96], relative to nonuse. Similar outcomes were seen for ICU admission and MMF: 2.52 [1.34-4.74], immunosuppressants: 2.88 [1.73-4.78], and glucocorticoids: 1.86 [1.37-2.54]. Only glucocorticoids use was associated with a significant increase in 60-day mortality: 1.58 [1.21-2.06]. No other IIAs displayed statistically significant associations with severe COVID-19 outcomes. CONCLUSION: Current use of MMF and glucocorticoids were associated with an increased risk of severe COVID-19 outcomes compared with nonuse. These results emphasize the variety of circumstances of patients taking IIAs.

Association of Reducing the Recommended Colorectal Cancer Screening Age With Cancer Incidence, Mortality, and Costs in Canada Using OncoSim.

Importance: Recent US guideline updates have advocated for colorectal cancer (CRC) screening to begin at age 45 years in average-risk adults, whereas Canadian screening programs continue to begin screening at age 50 years. Similarities in early-onset CRC rates in Canada and the US warrant discussion of earlier screening in Canada, but there is a lack of Canadian-specific modeling data to inform this. Objective: To estimate the association of a lowered initiation age for CRC screening by biennial fecal immunochemical test (FIT) with CRC incidence, mortality, and health care system costs in Canada. Design, Setting, and Participants/Exposures: This economic evaluation computational study used microsimulation modeling via the OncoSim platform. Main Outcomes and Measures: Modeled rates of CRC incidence, mortality, and health care costs in Canadian dollars. Results: This analysis included 4 birth cohorts (1973-1977, 1978-1982, 1983-1987, and 1988-1992) representative of the Canadian population accounting for previously documented effects of increasing CRC incidence in younger birth cohorts. Screening initiation at age 45 years resulted in a net 12 188 fewer CRC cases, 5261 fewer CRC deaths, and an added 92 112 quality-adjusted life-years (QALYs) to the cohort population over a 40-year period relative to screening from age 50 years. Screening initiation at age 40 years yielded 18 135 fewer CRC cases, 7988 fewer CRC deaths, and 150 373 QALYs. The cost per QALY decreased with younger birth cohorts to a cost of $762 per QALY when Canadians born in 1988 to 1992 began screening at age 45 years or $2622 per QALY with screening initiation at age 40 years. Although costs associated with screening and resulting therapeutic interventions increased with earlier screening, the overall health care system cost of managing CRC decreased. Conclusions and Relevance: This economic evaluation study using microsimulation modeling found that earlier screening may reduce CRC disease burden and add life-years to the Canadian population at a modest cost. Guideline changes suggesting earlier CRC screening in Canada may be justified, but evaluation of the resulting effects on colonoscopy capacity is necessary.

Optimizing the number of variants tracked to follow disease burden with circulating tumor DNA assays in metastatic colorectal cancer.

Background: The number of somatic mutations detectable in circulating tumor DNA (ctDNA) is highly heterogeneous in metastatic colorectal cancer (mCRC). The optimal number of mutations required to assess disease kinetics is relevant and remains poorly understood. Objectives: To determine whether increasing panel breadth (the number of tracked variants in a ctDNA assay) would alter the sensitivity in detecting ctDNA in patients with mCRC. Design: We used archival tissue sequencing to perform an in silico assessment of the optimal number of tracked mutations to detect and monitor disease kinetics in mCRC using sequencing data from the Canadian Cancer Trials Group CO.26 trial. Methods: For each patient, 1, 2, 4, 8, 12, or 16 of the most clonal (highest variant allele frequency) somatic variants were selected from archival tissue-based whole-exome sequencing and assessed for the proportion of variants detected in matched ctDNA at baseline, week 8, and progression timepoints. Results: Data from 110 patients were analyzed. Genes most frequently encountered among the top four highest VAF variants in archival tissue were TP53 (51.9% of patients), APC (43.3%), KRAS (42.3%), and SMAD4 (9.6%). While the frequency of detecting at least one tracked variant increased when expanding beyond variant pool sizes of 1 and 2 in baseline (p = 0.0030) and progression (p = 0.0030) ctDNA samples, we observed no significant benefit to increases in variant pool size past four variants in any of the ctDNA timepoints (p < 0.05). Conclusion: While increasing panel breadth beyond two tracked variants improved variant re-detection in ctDNA samples from patients with treatment refractory mCRC, increases beyond four tracked variants yielded no significant improvement in variant re-detection.

Feasibility and value of genomic profiling in cancer of unknown primary: real-world evidence from prospective profiling study.

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. The most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging because of paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies.

Race-based reporting and participation of Black individuals in registered pain clinical trials, United States, 2000 to 2019.

ABSTRACT: There are numerous, well-established racial disparities in the management of pain. The degree to which these are evident at the stage of conducting clinical trials is unknown. To address this knowledge gap, we examined race-based reporting, participation of Black individuals, and the factors associated with reporting and participation in pain clinical trials in the United States. Data were extracted from Clinicaltrials.gov and published articles. One thousand two hundred trials met our inclusion criteria; 482 (40.2%) reported participant race. More recent, publicly funded, and larger trials were more likely to report race. Of 82,468 participants included in pain clinical trials that reported race, 15,101 were Black individuals (18.3%). Participation of Black individuals was significantly associated with pain type (ß = +27% in cardiovascular disease pain compared with acute pain, P < 0.05), study population (ß = +33% and +7% in pain in minoritized populations and women, respectively, compared with general population, P < 0.05), pain intervention (ß = +7.5% for trials of opioid interventions compared with nonopioid interventions, P < 0.05), and a diverse team of investigators (ß = +8.0% for studies incorporating a visible non-White investigator compared with those that did not, P < 0.05). Our results indicate that representation of Black participants in pain clinical trials generally aligns with national demographics in the United States. Increased representation corresponds with health conditions more prevalent among Black individuals (eg, cardiovascular disease) and with a diverse study team composition. Despite these encouraging results, less than half of pain trials reported race, which introduces potential publication bias and limits external validity.

Treatment Patterns and Outcomes of Preoperative Neoadjuvant Radiotherapy in Patients with Early-onset Rectal Cancer.

Preoperative radiotherapy for early-stage rectal cancer has risks and benefits that may impact treatment choice in young patients. We reviewed radiotherapy use and outcomes for rectal cancer by age. Patients with early-stage rectal cancer in the Canadian province of British Columbia from 2002 to 2016 were identified (n = 6,232). Baseline characteristics, treatment response, overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and locoregional recurrence rate (LRR) were compared between patients <50 (early-onset; n = 532) and ≥50 years old (average-onset; n = 5,700). Early-onset patients were more likely to receive preoperative chemoradiotherapy than short-course radiotherapy [OR, 2.20; 95% confidence interval (CI), 1.67-2.89; P < 0.0001], but also had higher nodal (P = 0.00096) and overall clinical staging (P = 0.033). Cancer downstaging and pathologic complete response rates were similar in those receiving neoadjuvant chemoradiotherapy by age. Early-onset and average-onset patients had similar DSS (P = 0.91) and DFS (P = 0.27) in multivariate analysis unless non-colorectal deaths, which were higher in older patients, were censored in the DFS model (HR, 1.30; 95% CI, 1.01-1.68; P = 0.042). LRR also did not differ between age groups (P = 0.88). Outcomes did not differ based on radiotherapy type. Young patients with rectal cancer are more likely to present with higher staging and receive long-course chemoradiotherapy. DSS did not differ by age group; however, young patients had worse DFS when we censored competing risks of death in older patients. Significance: This population-based study suggests younger patients are more likely to receive chemoradiotherapy, potentially due to higher stage at diagnosis, and response is comparable by age.

Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration.

There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1, was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy.

Association between surveillance imaging and survival outcomes in small bowel neuroendocrine tumors.

BACKGROUND: Surveillance guidelines following the resection of small bowel neuroendocrine tumors (SB-NETs) are inconsistent. We evaluated the impact of surveillance imaging on SB-NET recurrence and overall survival (OS). METHODS: Patients with completely resected SB-NETs referred to a provincial cancer center (2004-2015) were reviewed. Associations between imaging frequency, recurrence, post-recurrence treatment, and OS were determined using univariate and Cox-regression analyses. RESULTS: Among 195 completely resected SB-NET patients, 31% were ≥70 years, 43% were female, and 80% had grade 1 disease. Imaging frequency was predictive of recurrence (hazard ratio 2.52, 95% confidence interval 1.84-3.46, p < 0.001). 72% underwent interventions for recurrent disease. Patients who were treated for the recurrent disease had comparable OS to those who did not recur (median 152 vs. 164 months; p = 0.25). Imaging frequency was not associated with OS in those with treated recurrent disease (p = 0.65). Patients who recurred underwent more computerized tomography (CT) scans than those who did not recur (CT: 1.47 ± 0.89 vs. 1.02 ± 0.81 scans/year, p < 0.001). Detection of disease recurrence was 5%-7% per year during the first 6 years of surveillance and peaked at 17% in Year 9. CONCLUSION: Less frequent imaging over a longer duration should be emphasized to capture clinically relevant recurrences that can be treated to improve OS.

Circulating Tumor DNA Identifies Diverse Landscape of Acquired Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Metastatic Colorectal Cancer.

PURPOSE: Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance. METHODS: Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. RESULTS: ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR (P = .0007), KRAS (P = .0017), LRP1B (P = .0046), ZNF217 (P = .0086), MAP2K1 (P = .018), PIK3CG (P = .018), BRAF (P = .048), and NRAS (P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR (P < .0001), SMO (P < .0001), BRAF (P < .0001), MET (P = .0002), FLT3 (P = .0002), NOTCH4 (P = .0006), ERBB2 (P = .004), and FGFR1 (P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without (P = .010). Although tumor mutation burden (TMB) did not differ pretreatment (P = .63), anti-EGFR exposure increased TMB (P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB (P = .014). CONCLUSION: Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

Neoadjuvant Chemotherapy, Excision, and Observation for Early Rectal Cancer: The Phase II NEO Trial (CCTG CO.28) Primary End Point Results.

PURPOSE: Organ-sparing therapy for early-stage I/IIA rectal cancer is intended to avoid functional disturbances or a permanent ostomy associated with total mesorectal excision (TME). The objective of this phase II trial was to determine the outcomes and organ-sparing rate of patients with early-stage rectal cancer treated with neoadjuvant chemotherapy followed by transanal excision surgery (TES). METHODS: This phase II trial included patients with clinical T1-T3abN0 low- or mid-rectal adenocarcinoma eligible for endoscopic resection who were treated with 3 months of chemotherapy (modified folinic acid-fluorouracil-oxaliplatin 6 or capecitabine-oxaliplatin). Those with evidence of response proceeded to transanal endoscopic surgery 2-6 weeks later. The primary end point was protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1N0/X and who avoided radical surgery. RESULTS: Of 58 patients enrolled, all commenced chemotherapy and 56 proceeded to surgery. A total of 33/58 patients had tumor downstaging to ypT0/1N0/X on the surgery specimen, resulting in an intention-to-treat protocol-specified organ preservation rate of 57% (90% CI, 45 to 68). Of 23 remaining patients recommended for TME surgery on the basis of protocol requirements, 13 declined and elected to proceed directly to observation resulting in 79% (90% CI, 69 to 88) achieving organ preservation. The remaining 10/23 patients proceeded to recommended TME of whom seven had no histopathologic residual disease. The 1-year and 2-year locoregional relapse-free survival was, respectively, 98% (95% CI, 86 to 100) and 90% (95% CI, 58 to 98), and there were no distant recurrences or deaths. Minimal change in quality of life and rectal function scores was observed. CONCLUSION: Three months of induction chemotherapy may successfully downstage a significant proportion of patients with early-stage rectal cancer, allowing well-tolerated organ-preserving surgery.