AT-rich interactive domain 1A (
) is commonly mutated in colorectal cancer, frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch repair during DNA ...replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models, but its role in patients with colorectal cancer is being explored.
The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients.
Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had
mutation. Among 58 genes most commonly mutated in colorectal cancer,
mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold,
< 0.001). In MSS,
mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNγ expression (Δ
score +1.91,
< 0.001). Compared with
wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further confirmed by higher infiltration of T cells in IHC of tumors with
mutation (
= 0.01).
The immunogenicity of
-mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden and frameshift mutations. Tumors with
mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.
There has been rapid implementation of virtual oncology appointments in response to the COVID-19 pandemic, particularly in its first wave. Our objective was to assess patterns and perspectives ...towards virtual oncology appointments during the pandemic among patients with cancer undergoing active treatment. We conducted an international Internet-based cross-sectional survey. Participants were eligible if they (
) were ≥18 years of age; (
) had been diagnosed with cancer (
) were currently undergoing cancer treatment, and (
) spoke English or French. Between 23 April 2020 and 9 June 2020, 381 individuals accessed the survey, with 212 actively undergoing treatment for cancer, including 27% with colorectal, 21% with breast, 7% with prostate and 7% with lung cancer. A total of 52% of respondents were from Canada and 35% were from the United States. Many participants (129, 62%) indicated having had a virtual oncology appointment during the COVID-19 pandemic and most were satisfied with their experience (83%). We found older participants (≥50 years; adjusted OR 0.22, 95% CI 0.06 to 0.85 compared to <50 years) and those with shortest duration of treatment (≤3 months; adjusted OR 0.06; 95% CI 0 to 0.69 compared to >12 months) were less likely to be satisfied with virtual oncology appointments. Virtual health platforms used differed across countries with higher telephone use in Canada (87%) and other countries (86%) as compared to the United States (54%;
-value < 0.05), where there was higher use of video conferencing. Altogether, our findings demonstrate favorable patient perspectives towards virtual oncology appointments experienced during the first wave of the COVID-19 pandemic.
BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors ...potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.
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).
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.
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.
Three months of induction chemotherapy may successfully downstage a significant proportion of patients with early-stage rectal cancer, allowing well-tolerated organ-preserving surgery.
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.
This study showed that almost half of patients receiving octreotide LAR for metastatic neuroendocrine tumors had evidence of subcutaneous nodules. However, missed administration of octreotide LAR did not result in worse survival. Factors such as sex, younger age skin‐to‐muscle distance, and obesity may affect subcutaneous nodule development and should be considered when choosing a somatostatin analogue.
Goal
To determine patient-reported financial and family burden associated with treatment of cancer in the previous 28 days across Canada.
Methods
A self-administered questionnaire (P-SAFE v7.2.4) was ...completed by 901 patients with cancer from twenty cancer centres nationally (344 breast, 183 colorectal, 158 lung, 216 prostate) measuring direct and indirect costs related to cancer treatment and foregone care. Monthly self-reported out-of-pocket-costs (OOPCs) included drugs, homecare, homemaking, complementary/ alternative medicines, vitamins/supplements, family care, accommodations, devices, and “other” costs. Travel and parking costs were captured separately. Patients indicated if OOPC, travel, parking, and lost income were a financial burden.
Results
Mean 28-day OOPCs were CA$518 (US Purchase Price Parity PPP $416), plus CA$179 (US PPP $144) for travel and CA$84 (US PPP $67) for parking. Patients self-reporting high financial burden had total OOPCs (33%), of CA$961 (US PPP $772), while low-burden participants (66%) had OOPCs of CA$300 (US PPP $241). “Worst burden” respondents spent a mean of 50.7% of their monthly income on OOPCs (median 20.8%). Among the 29.4% who took time off work, patients averaged 18.0 days off. Among the 26.0% of patients whose caregivers took time off work, caregivers averaged 11.5 days off. Lastly, 41% of all patients had to reduce spending. Fifty-two per cent of those who reduced spending were families earning < CA$50,000/year.
Conclusions
In our Canadian sample, high levels of financial burden exist for 33% of patients, and the severity of burden is higher for those with lower household incomes.
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.
: 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.
: We identified all patients diagnosed with CRC between 1990-2017 in British Columbia, Canada. Individuals <50 years (
= 2544, EoCRC) and a matched cohort >50 (
= 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis.
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,
= 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7,
< 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC (
< 0.0001) and LoCRC (
< 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8-1.0,
= 0.008) and increasing symptom number were independently associated with worse survival in multivariate models.
: 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.
Patterns of recurrence help to inform surveillance of patients with resected gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Patients with GEP-NETs in British Columbia, Canada (2004–2015) ...were reviewed. Associations between tumor characteristics, recurrence and survival were analyzed.
Among 759 patients, 41%, 25%, and 17% had grade 1, 2, and 3 disease, respectively. 387 patients had R0/R1 resections, of which 30% recurred (median 25 months). 5-year incidence of recurrence was 22% (grade 1), 46% (grade 2), and 59% (grade 3) (p < 0.001). Grade predicted distant recurrence (Grade 2 HR 1.89, 95% CI 1.16–3.07; p = 0.011; Grade 3 HR 3.29, 95% CI 1.81–5.99; p < 0.001). Compared to small bowel NETs, pancreas NETs had less peritoneal recurrence (OR 0.15, 95% CI 0.03–0.68, p = 0.014). No patients had isolated pulmonary recurrences.
Higher grade tumors and pancreatic NETs require more frequent surveillance. Evidence is limited for pulmonary surveillance.
•Among patients with resected GEP-NETs, tumor grade and primary location predicts timing and site of disease recurrence.•Peritoneal recurrences were most commonly associated with small bowel primaries.•Among 116 patients with recurrence, not a single GEP-NET had a first site of recurrence as the lung.•Surveillance imaging frequency and type should be based on characteristics of resected tumors to optimize patient outcomes.
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