Right-sided Tumors Research Articles

Prognostic role of systemic inflammatory markers in patients with metastatic MSI-h/dMMR colorectal cancer receiving immunotherapy.

3524 Background: Markers of systemic inflammation including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (LMR) are prognostic in patients with metastatic colorectal cancer receiving systemic chemotherapy. The presence of liver metastases has also been hypothesized to modulate response to immunotherapy. In this study, we assess the prognostic role of these markers in patients with microsatellite high (MSI-H)/deficient mismatch repair (dMMR) tumors receiving immunotherapy for metastatic or unresectable colorectal cancer (CRC). Methods: This was a single-institution retrospective analysis of patients with dMMR/MSI-H CRC who received anti-PD-(L)1 and/or anti-CTLA-4 therapy for metastatic or unresectable disease at between 2015 and 2021 (n = 59). NLR, PLR, and LMR were calculated based on the complete blood count obtained within 1 week prior to treatment. Patient and tumor characteristics were obtained from the clinical record. Patient characteristics were compared using Fisher’s exact test and Mann-Whitney U where appropriate. Progression free survival (PFS) and overall survival (OS) were the primary endpoints and log-rank test was used for comparison of survival distribution among groups. Results: 59 patients with metastatic dMMR/MSI-H CRC were identified. Median age was 60, 53% (n = 31) had right-sided tumors, 35% (n = 35) of patients with testing available had RAS-mutated tumors, and 37% (n = 22) received prior chemotherapy. Most common sites of metastatic disease were peritoneum (n = 23, 39%) and liver (n = 17, 29%). Patients were divided into NLR-High (NLR ≥ 3, n = 20) and NLR-Low (NLR < 3, n = 39), and both groups had similar baseline characteristics. The rate of progressive disease as best response was not different in NLR-Low versus NLR-High (15% vs 30%, p = 0.3). At a median follow-up of 32 months, neither median PFS nor median OS were reached. 74% (n = 29) remained progression free at 1 year in the NLR-Low group versus 60% (n = 12) in NLR-High group which was not statistically significant (p = 0.37); 90% (n = 35) remained alive at 2 years in the NLR-low versus 80% (n = 16) in the NLR-High group (p = 0.4). Similarly, using a cut-off of 150 and 3 for PLR and LMR respectively, there was no significant difference between PFS at 1 year in the PLR-Low (n = 32) vs PLR-High (n = 27) (66% vs 74%, p = 0.58) and LMR-Low (n = 35) vs LMR-High (n = 24) (60% vs 83%, p = 0.084) groups. The presence of liver metastasis or the presence of a RAS mutation did not influence PFS at 1 year (p = 0.35 and p = 1.00, respectively). Conclusions: Markers of systemic inflammation may have a limited prognostic role for patients with dMMR/MSI-H CRC receiving immunotherapy.

Molecular correlates of MAEA expression in colorectal cancer (CRC).

3128 Background: Macrophage Erythroblast Attacher (MAEA) plays an important role in actin cytoskeleton rearrangement in macrophages and erythroid cells. We previously reported that MAEA suppresses migration, invasion and enhances chemosensitivity in CRC cell lines. Here we aimed to characterize the molecular features associated with MAEA gene expression in CRC. Methods: 14416 CRC were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS). Top quartile transcripts per million (TPM) for MAEA expression were considered high (Q4) while bottom quartile low (Q1). Consensus molecular subtypes (CMS) were assessed using RNAseq. Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by QuantiSEQ. X2 and Fisher-Exact tests were used and significance was determined as P-value adjusted for multiple comparisons ( Q < 0.05). Results: MAEA expression was highest in rectal tumors (13.6 median TPM) followed by transverse and right-sided tumors (13.0 and 12.8, respectively) and lowest in left-sided tumors (12.5). Overall, MAEA TPM were associated with higher tumor mutational burden (≥ 10 Mut/Mb) (11.8% vs. 8.2%) and dMMR/MSI-H (8.7% vs. 5.1%) ( Q < 0.0001); however, the association with TMB was not observed in MSS tumors. In the MSS cohort, MAEA expression was the highest in CMS4 (14.9 median TPM) followed by CMS1 (12.5), CMS2 (11.9), and the lowest in CMS3 (10.3, all intergroup Q < 0.05). MAEA high was associated with lower mutation rates of APC and amplification of FLT1/ FLT3 while higher mutation rates of ASXL1, KMT2A/C/D, SMARCA4, FBXW7, PTEN, RNF43, BRCA2, HNF1A in the overall cohort ( Q < 0.05). In the MSS cohort, FBXW7 mutation significance with MAEA high expression held true ( Q < 0.05) while MAEA high expression trended to associate with higher mutation rates of KMT2D, SMARCA4, PTEN, BRCA2 mutations, and a lower frequency of FLT1/ FLT3 CNA ( P < 0.05 but Q > 0.05). High MAEA was associated with higher immune CI in the TME, including B cells, macrophages (M1 and M2), neutrophils, NK cells, Tregs, CD4+ T cells and myeloid dendritic cells both in the overall cohort and in MSS tumors (fold change: 1.11-1.33, all Q < 0.001). Conclusions: Our data show a strong association between MAEA gene expression and distinct molecular features (including CMS and immune biomarkers) and TME cell infiltration in CRC. These findings suggest that targeting MAEA may have relevant clinical applications in selected CRC subgroups and MAEA may be an important player in determining the composition of the TME.

Characterization of NTRK alterations in metastatic colorectal cancer.

e15569 Background: Increased molecular profiling ability has resulted in the recognition of important actionable genes that can be used to direct targeted therapies in colorectal cancers (CRC). Neurotrophin receptor tyrosine kinase (NTRK) gene fusions are one of these molecular alterations that are potentially actionable with novel targeted therapeutics. However, other biologically pathogenic NTRK alterations, including point mutations, are not yet actionable in CRC. This study aimed to characterize NTRK alterations, including fusions in metastatic CRC patients. Methods: Molecular characteristics of 917 patients with CRC were collected from the Moffitt Cancer Center Clinical Genomics Action Committee database. Demographic, clinicopathological, and molecular data and treatment history were abstracted from electronic medical records. Mutations with potential oncogenic activity are considered “potentially pathogenic”, while alterations with proven oncogenic activity such as fusions are considered “pathogenic”. Results: There were 917 patients with CRC from November 2013 to December 2021, and 77 of them had NTRK alterations excluding synonymous mutations (8.3%, 77/917). Six patients had potentially pathogenic NTRK alterations, including one NTRK rearrangement (0.6%, 7/917); however, only 1 patient had an actionable pathogenic NTRK1 fusion (0.1%, 1/917), while the others (70) were a variant of unknown significance (VUS). The majority of NTRK alterations were missense mutations (92%; 71/77). The NTRK1 fusion partner was LMNA and occurred in the setting of an MSI-H tumor (3.7%; 1/27). Among patients with pathogenic and potentially pathogenic alterations (N = 7), there was only 1(14%) patient who had low tumor mutation burden (TMB) (< 10 mut/MB). Most patients were older than 50 years (70.1%, 54/77) and male (58.4%, 45/77). Thirty-six patients (46..7%) had right-sided tumor, while 41 patients (53.2%) left-sided. Across all NTRK alterations cohort, MSI-H was found in 10.3% (7/77), and POLE/POLD1 pathogenic mutations were seen in 6.4% (5/77) patients. Conclusions: NTRK gene fusion is a relatively rare event (< 1%) in CRC, including the MSI-H subtype. The majority of NTRK alterations in CRC are VUS, and they are not actionable, and they tend to be seen in the tumors with high TMB (TMB > 10). Hypermutator tumors cause frequent VUS alterations in the NTRK gene with unknown clinical relevance.

P-36 Real-world outcomes in BRAFV600E metastatic colorectal cancer – the Glasgow experience

Approximately 8 - 10% of metastatic colorectal cancers (mCRC) have a BRAF V600E mutation. BRAF V600E mutant mCRC represents a distinct clinical subset with a poor prognosis. Previous treatment guidelines have been derived from subgroup analyses of non-designated BRAF V600E trials. Real world studies have shown that outcomes and treatment practices can vary widely. Here, we report on our regional practices and outcomes. We undertook a retrospective analysis of all mCRC patients with confirmed BRAF V600E mCRC diagnosed in NHS Greater Glasgow and Clyde Health Board (Scotland, UK) between 01/01/2015 - 31/12/2020. Clinical and pathological features were obtained from electronic records. Univariate analysis of prognostic factors was performed using Kaplan Meier analysis and log-rank test. Multivariate analysis was performed using Cox regression. A total of 139 patients were identified for study with 1 excluded for missing follow up information. Median age at metastatic diagnosis was 69 years, with a female preponderance (59% female, 41% male). 31% of tumours also had deficient mismatch repair (dMMR) or high levels of microsatellite instability (MSI-H). Primary tumour site was mostly right-sided (n=102, 74%), with less left-sided (n=20, 15%) and rectal (n=15, 11%) tumours. 1 patient had 2 synchronous primaries (1 right colon and 1 rectal). 64% presented with de novo metastatic disease. For those with initial loco-regional disease, the median time to metastatic progression was 10 months. The most common metastatic sites were liver (54%), peritoneal (33%), lymph node (31%), and lung (28%). 36% of patients did not receive any systemic treatment, 36% received 1 line, and 28% received 2 or more lines of treatment. Most (69%) received a cytotoxic chemotherapy doublet as first-line treatment, and 6% received triplet cytotoxic chemotherapy. 7% received immunotherapy. Among the treated patients, only 19% received some form of targeted therapy over their full treatment course, usually a combination containing an anti-EGFR inhibitor. The median overall survival was poor at 7.2 months. Features significantly associated with shorter survival were performance status (PS) of 2 or worse (p < 0.01), the presence of lymph node metastasis (p = 0.010) and peritoneal metastasis (p < 0.01), a higher modified Glasgow Prognostic Score (GPS) of 2 (p = 0.035) and a high neutrophil-lymphocyte ratio >5 (p = 0.032). Primary tumour site was also significantly associated with survival (p < 0.01), with worse survival for right-sided tumours (6.6 months), compared to 14.0 months for left-sided/rectal tumours. Using multivariate analysis, independent prognostic markers were PS, presence of lymph node metastasis, presence of peritoneal metastasis and right-sided primary tumour location. This is a representative cohort of BRAF V600E metastatic colorectal cancer patients, which confirms previously known clinical features. Of the common metastatic sites, peritoneal or lymph node metastases confer a poorer prognosis. There was not widespread adoption of more intensive triplet chemotherapy over the study time period. Overall survival is poor, and changed treatment strategies facilitated by recent clinical trial advances with targeted therapies may improve outcomes in this poor prognostic group.

Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience

BackgroundEncorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage.Patients and methodsThis real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019.ResultsOut of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome.ConclusionsOur real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Real-world treatment outcomes from nationwide Onco-colon Turkey registry in RAS wi̇ld-type patients treated with biologics second-line mCRC.

e15562 Background: Varieties of systemic treatments in second-line treatment for metastatic colorectal cancer (mCRC) patients have showed an improvement on survival. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. Therefore, we aimed to investigate second-line treatment selection in patients with RAS-wild type mCRC. Methods: Medical records from 28 centers were collected for patients diagnosed with RAS wild-type and were included into the study. Histopathological, molecular and clinical characteristics of the patients were recorded. The treatment duration, response rate, progression-free survival and safety results were determined. Patients were compared according to the second-line biological treatments as anti-EGFR group (Group A and B; panitumumab and cetuximab) and anti-VEGF group (group C; bevacizumab or aflibercept). Results: A total of 1064 patients with documented RAS wild-type status were evaluated. Fifty-six percent of all first line patients were treated with regimen including biologics received second line treatment. Median age was 60 years. 34,7 percent of the patients were female. Nineteen percent of the patients had a right-sided colon tumor. 16,3 %, 22,5% and 61,2 % of all second-line patients were treated with regimen including panitumumab, cetuximab and anti-VEGF, respectively. Patients received median 5 (1-21) cycles of treatment. Also, responded patients received median 4 (1-23) cycles of treatment as maintenance treatment with biologics plus fluoropyrimidine. Overall response rate was 28,5 % for all patients. Disease control rate also was 70,6 %. The median OS was 15,7, 14,3, and 14,7 months in A, B and C group respectively (p = 0.764). The median PFS of the patients in second-line setting that received panitumumab, cetuximab and bevacizumab/ aflibercept were 7,8, 6,6 and 7,4 months respectively (p = 0.848). There was not found as independent prognostic factors in multivariate analysis. Conclusions: According to the results of our real-life data study, there is no significant difference in efficacy between the combinations of biological agent and chemotherapy used in the second-line treatments. Therefore, the results of the first-line treatment become important and the use of the most effective agent at this setting also increases survival.

The clinical relevance of tumor RAS/TP53 dual mutation in early and metastatic colorectal cancer (CRC).

3540 Background: The relevance of individual RAS (KRAS and NRAS) and TP53 mutations in CRC is well described, but the impact of the combination of both mutations together is less understood. RAS/TP53-mutant (mut) patients (pts) were selected in FOCUS 4-C for treatment with Adavosertib (Wee1 inhibitor) due to hypothesised sensitivity due to replication stress and loss of cell cycle checkpoint control. Initial analyses in CRC suggest that RAS/TP53-mut pts may be prognostically distinct from either mutation alone. Here we examine the impact of RAS/TP53-mut status in both early stage and metastatic CRC (mCRC). Methods: RAS and TP53 mutational status were assessed by whole gene targeted NGS or PCR in hotspot regions. Pts with RAS/TP53 status in the following studies were included after exclusion of BRAF-V600E mutants and MSI-H cases: for early-stage, QUASAR2 trial (N = 408) and an Australian community cohort (N = 654); for mCRC, FOCUS (N = 373) and FOCUS4 (N = 721). Biomarker prevalence, clinical characteristics and outcome data in the RAS/TP53-mut group were compared to pts not showing dual RAS/TP53-mut. Results: The prevalence of RAS/TP53-mut was greater in mCRC compared to early CRC (43.9% vs 25.4% respectively, p &lt; 0.001). In early-stage (II &amp; III) cohorts combined, RAS/TP53-mut pts were more likely to be female, have a right-sided primary tumour, and involved lymph nodes. In early CRC RAS/TP53-mut pts had worse outcome: DFS HR = 1.49[1.19-1.88], p = 0.001, and OS HR = 1.48[1.16-1.89], p = 0.001. In FOCUS, RAS/TP53-mut mCRC pts had inferior PFS with 1st line chemotherapy than not dual RAS/TP53-mut: 6.9 vs 8.6 months (HR = 1.44[1.17-1.79], p = 0.001), and also shorter post-progression survival (HR = 1.49, p = 0.001), and overall survival (14.9 vs 18.9 mths [HR = 1.60, p &lt; 0.0005]). Consistently, during 16 weeks of induction chemotherapy for mCRC pts in FOCUS4, 27.4% of RAS/TP53-mut pts had progressive disease, compared with 18.4% in not dual RAS/TP53-mut; PFS from study registration was reduced in RAS/TP53-mut (5.3 vs 6.1 mths;HR = 1.53[1.22-1.94],p &lt; 0.001), but no statistically significant difference in OS (13.6 vs 17.6 mths;HR = 1.27,p = 0.23). Outcomes by each of the four biomarker groups (RAS/TP53 dual mut; RASwt/TP53mut; RASmut/TP53 wt; RAS/TP53 dual wt) will be presented but in all cases the dual mut subgroup had the worst outcomes compared to the other three groups, marginally better than BRAF-V600E CRC. Conclusions: RAS/TP53 dual mutation status provides useful and readily available prognostic information in both early and mCRC, independent of MSI and BRAF status. It is associated with increased risk of recurrence in early CRC, and a higher risk of chemotherapy resistance and inferior outcomes in mCRC. Evaluation of treatment strategies in this sizeable patient group and further understanding of the underlying mechanism of poor outcomes are urgently required.

BRAF-mutant metastatic colorectal cancer: Prognostic and predictive value of primary tumor location—A pooled analysis of the AIO studies FIRE-1, CIOX, XELAVIRI, FIRE-3, and VOLFI.

3576 Background: Primary tumor location (PTL: left vs. right) is an established prognostic marker in metastatic colorectal cancer (mCRC) and has predictive impact for anti-EGFR antibody (mAb) efficacy in patients with RAS ( KRAS and NRAS) wild-type (WT) mCRC. This analysis of five pooled studies evaluates PTL as a prognostic and - concerning anti-EGFR mAb efficacy - predictive marker in BRAF V600E-mutant/ RAS WT and mCRC. Methods: The analysis is based on individual patient data of five pooled 1st-line studies with varying treatment strategies: the pooled population comprises of BRAF V600E-mutant/ RAS WT ( BRAFmt) mCRC with known PTL. For analysis, treatment was stratified into two groups: treated with or without anti-EGFR mAb. Dichotomous variables (overall response rate, ORR; characteristics) were compared by Chi-Square or Fisher’s exact test and time-to event endpoints (progressive-free survival, PFS; overall survival, OS) by Kaplan-Meier method, log rank test and Cox regression. Results: Of 102 patients (pts) with BRAFmt mCRC, 55 pts (54%) presented with right-sided primary tumors (RPT), 47 (46%) presented with left-sided primary tumors (LPT). Pts with RPT were more likely to be female ( p= 0.04). ORR was inferior in RPT compared to LPT (35% vs. 55%; p= 0.04). No difference was seen in PFS (HR 0.8 (95% CI 0.6-1.3; p= 0.32) or OS (HR 0.8; 95% CI 0.8-1.3; p= 0.46). In male pts PTL trended to be associated with longer OS (HR 0.6; 95% CI 0.3-1.0; p= 0.06). 25 pts with RPT (45%) and 21 with LPT (45%) received anti-EGFR mAb. In pts with LPT anti-EGFR mAb based treatment was associated with higher ORR (81% vs. 35%; p&lt; 0.01). No effect was seen in RPT (ORR 35% vs. 36%; p= 0.82). Anti-EGFR mAb treatment resulted in inferior PFS in RPT (HR 2.0; 95% CI 1.1-3.5; p= 0.02) and showed a trend towards improved PFS in LPT (HR 0.6; 95% CI 0.3-1.1; p= 0.11). Pts with RPT had a worse OS when treated with anti-EGFR mAb (HR 1.8; 95% CI 1.0-3.1; p= 0.05), whereas pts with LPT appeared to have a favorable outcome when treated with an anti-EGFR mAb containing regimen (HR 0.4; 95% CI 0.2-0.7; p&lt; 0.01). Conclusions: This exploratory analysis of five studies suggests that PTL has limited prognostic impact in BRAFmt mCRC but might carry predictive information regarding anti-EGFR mAb efficacy in a 1st-line treatment setting. Further prospective studies are needed to validate these results and to grasp the differences in the heterogeneous group of BRAFmt pts. Clinical trial information: FIRE-1 was before mandatory registration, NCT00254137, NCT00433927, NCT01249638, NCT01328171.

Clinical impact of DNA methylation status on first-line antiepidermal growth factor receptor treatment in patients with metastatic colorectal cancer.

3528 Background: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer. However, there is a lack of consensus of CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. Previously, we reported that genome-wide DNAmethylation statuscould predict the effect of epidermal growth factor receptor (EGFR) inhibitors more accurately than previously reported methylation classifications (Ouchi et al. Cancer Sci 2015). Moreover, we had developed a DNA methylation assay based on MethyLight to reflect genome-wide DNA methylation status and reported its usefulness in predicting prognosis in patients with metastatic colorectal cancer (mCRC) treated with EGFR inhibitors as a third-line chemotherapy (Ouchi et al. Cancer Sci 2022). This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with mCRC treated with first-line EGFR inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment, and analyzed the associations between genome-wide DNA methylation status using a novel comprehensive methylation marker panel and clinical outcomes and evaluated the predictive power and value of the methylation status. Results: Total 169 patients were included in the final analyses. The frequency of highly methylated CRC (HMCC) was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAFV600E mutation (P &lt; 0.001). Patients with HMCC showed worse clinical outcomes than those with low methylated CRC in terms of response rate (P = 0.017), progression-free survival (PFS; P = 0.004), and overall survival (P = 0.019). In the multivariate analysis, peritoneal metastasis (Hazard ratio (HR): 2.24, P = 0.017), methylation status (HR: 3.04, P = 0.037), and BRAFV600E mutations (HR: 5.83, P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status may be an independent predictor of first-line EGFR inhibitors in patients with mCRC.

Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3

SummaryBackgroundThe evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients’ age and sidedness of primary tumour.MethodsThe study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.ResultsOverall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).ConclusionsIn FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.Clinical trialFIRE-3 (NCT00433927).

Adrenal carcinoma: a case report

BackgroundAdrenocortical carcinoma is a rare malignancy (0.5–2 cases/million/year) with a poor prognosis. Hypercortisolism, virilization, and compressive features are among the common presentations of adrenocortical carcinoma. Hematuria is one of the rare initial presentations of adrenocortical carcinoma reported in the literature. We report a case of adrenal carcinoma presenting with microscopic hematuria.Case presentationA 67-year-old Sri Lankan patient with diabetes, hypertension, and ischemic heart disease presented with an acute coronary event. During the routine evaluation, microscopic hematuria was detected without proteinuria or active sediments. She denied any painful micturition, previous similar episodes, or abdominal pain. Further evaluation revealed a hypokalemia with biochemical evidence of hypercortisolism and high testosterone levels with suppressed adrenocorticotropic hormone levels. On imaging, there was evidence of a right suprarenal mass 7 cm × 3 cm × 6 cm in size that was hypoechoic and lobulated and suggestive of a lipid-poor tumor. She underwent adrenalectomy. By the time of surgery 3 weeks later, significant weight gain with features of Cushing syndrome, including hirsutism, skin atrophy, easy bruising without virilization, and proximal myopathy, were noted. Histology identified a right-sided adrenal tumor with capsular and vascular invasion. Hypercortisolism and hematuria disappeared after surgery. The patient was referred for further oncological management.ConclusionThis case illustrates a rare presentation of adrenal carcinoma. Awareness of this presentation may facilitate early evaluation and management.

Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer.

The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patientswith metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. Genome-wide DNA methylation status is an independent factor associated with PFS in patientswith mCRC treated with first-line EGFR inhibitors.

Associations of Complete Blood Count Parameters with Disease-Free Survival in Right- and Left-Sided Colorectal Cancer Patients.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Some complete blood count (CBC) parameters are found to be associated with CRC prognosis. In this study, ninety-seven pretreated CRC patients were included, and the patients were divided into two groups: left-sided and right-sided, depending on the anatomical location of the tumor. Based on clinicopathologic features including tumor budding, disease stages, and tumor anatomical location, levels of CBC parameters were compared, and disease-free survivals (DFS) were determined. There were differences between patients with different tumor budding scores for only three parameters, including red cell distribution width (RDW), numbers of platelets, and mean platelet volume (MPV). Furthermore, numbers of WBCs, monocytes, and MPV in CRC patients with early disease stages were higher than those with advanced stages. However, levels of eosinophil in CRC patients with advanced stages were higher than those with early stages. Depending on the tumor anatomical location, we observed that numbers of red blood cells (RBCs), hemoglobin (Hgb), and hematocrit (Hct) in CRC patients with left-sided tumors were higher than those with right-sided tumors. We found that low levels of MPV were associated with shorter DFS. However, high levels of eosinophils were associated with shorter DFS in all CRC patients. When patients were divided based on the tumor anatomical location, higher levels of MPV, MCHC, and Hgb were associated with better DFS in the left-sided but not right-sided CRC patients. However, left-sided, but not right-sided, CRC patients with high levels of eosinophil and RDW had shorter DFS. Furthermore, right-sided, but not left-sided, CRC patients with high levels of platelets tended to have a shorter DFS. Our data show that MPV and eosinophils could serve as potential prognostic biomarkers in pre-treatment CRC patients, regardless of the tumor anatomical location. Additionally, lower levels of MPV, MCHC, and Hgb, and high levels of eosinophils and RDW could be negative predictive biomarkers in left-sided CRC patients.

Exposure of the heart in lung cancer radiation therapy: A systematic review of heart doses published during 2013 to 2020

Background and purposeLung cancer radiotherapy increases the risk of cardiotoxicity and heart radiation dose is an independent predictor of poor survival. This study describes heart doses and strategies aiming to reduce exposure. Materials and methodsA systematic review of lung cancer dosimetry studies reporting heart doses published 2013–2020 was undertaken. Doses were compared according to laterality, region irradiated, treatment modality (stereotactic ablative body radiotherapy (SABR) and non-SABR), planning technique, and respiratory motion management. ResultsFor 392 non-SABR regimens in 105 studies, the average MHD was 10.3 Gy (0.0–48.4) and was not significantly different between left and right-sided tumours. It was similar between IMRT and 3DCRT (10.9 Gy versus 10.6 Gy) and lower with particle beam therapy (proton 7.0 Gy; carbon-ion 1.9 Gy). Active respiratory motion management reduced exposure (7.4 Gy versus 9.3 Gy). For 168 SABR regimens in 35 studies, MHD was 4.0 Gy (0.0–32.4). Exposure was higher in central and lower lobe lesions (6.3 and 5.8 Gy respectively). MHD was lowest for carbon ions (0.5 Gy) compared to other techniques. Active respiratory motion management reduced exposure (2.4 Gy versus 5.0 Gy). Delineation guidelines and Dose Volume Constraints for the heart varied substantially. ConclusionsThere is scope to reduce heart radiation dose in lung cancer radiotherapy. Consensus on planning objectives, contouring and DVCs for the heart may lead to reduced heart doses in the future. For IMRT, more stringent optimisation objectives may reduce heart dose. Active respiratory motion management or particle therapy may be considered in situations where cardiac dose is high.

Clinical impact of primary tumor sidedness and sex on unresectable post-recurrence survival in resected pathological stage II-III colorectal cancers: a nationwide multicenter retrospective study

BackgroundSeveral studies have demonstrated that right-sided tumors have poorer prognosis than left-sided tumors in patients with unresectable colorectal cancer (CRC). The predictive ability of the tumor sidedness in CRC treated with chemotherapy in each sex is unclear.MethodsSubjects were 964 unresectable recurrent patients treated with chemotherapy with stage II-III CRC after curative resection between 2004 and 2012. Post-recurrence cancer-specific survival (CSS) for each sex was examined.ResultsPatients were 603 males (222 right-side tumors (cecum to transverse colon) and 381 left-sided tumors (descending colon to rectum)), and 361 females (167 right-side tumors and 194 left-sided tumors). Right-sided tumors developed peritoneal recurrences in males and females. Left-sided tumors were associated with locoregional recurrences in males and with lung recurrences in females. Right-sided tumors were associated with shorter post-recurrence CSS in both sexes. In males, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.53, P < 0.0001) together with the presence of regional lymph node metastasis histopathological type of other than differentiated adenocarcinoma, the recurrence of liver only, the recurrence of peritoneal dissemination only, and relapse-free interval less than one-year. In females, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.50, P = 0.0019) together with advanced depth of invasion, the presence of regional lymph node metastasis, and recurrence of liver only.ConclusionsPrimary tumor sidedness in both sexes in unresectable recurrent CRC patients treated with chemotherapy may have prognostic implications for post-recurrence CSS.

Genomic Landscape of Primary Tumor Site and Clinical Outcome for Patients with Metastatic Colorectal Cancer Receiving Standard-of-Care Chemotherapy.

Primary tumor site and genomic status are utilized for regimen selection in metastatic colorectal cancer; however, the impact on clinical practice is not well known. We aimed to clarify the impact of primary tumor site and genomic status on clinical practice in metastatic colorectal cancer. The relationship between primary tumor site, genomic alterations, and clinical outcomes was evaluated in patients with untreated metastatic colorectal cancer using real-world data of a prospective observational study, SCRUM-Japan GI-SCREEN with clinical and genomic data set in 1011 patients enrolled from February 2015 to March 2017. Five hundred and sixty-one patients were eligible for this study. Patients with right-sided tumors had a significantly worse survival, left-sided tumors with wild-type RAS had favorable outcomes when treated with anti-epidermal growth factor receptor monoclonal antibodies, and cecum tumors had poor prognosis when treated with bevacizumab. The rate of gene alterations varied considerably depending on the primary site. In addition, gene alterations of KRAS, BRAF, SMAD4, or TP53 had individually different contributions to survival from site to site. KRAS, BRAF, PTEN, or SMAD4 mutations were associated with efficacy of bevacizumab or anti-epidermal growth factor receptor monoclonal antibodies. Primary tumor site is a clinically useful biomarker to predict survival in patients with metastatic colorectal cancer treated with first-line chemotherapy. Moreover, the prognostic or predictive value of several gene alterations by primary tumor site should be considered in clinical practice.

Detection of BRAFV600E Biomarker In Patients With Colorectal Cancer Using Immunohistochemical Techniques / Clinico-Pathological Study

Background : Colorectal cancer (CRC) is the 4th common gastrointestinal cancer. (BRAFV600E) is a member of RAF family of serine/threonine protein kinases that function to regulate the (MAPK) / (ERK) pathway. BRAFV600E mutated CRC are associated with right-sided primary tumors, older women and high-grade tumors. Aims of the study: Study the immunohistochemical expression of BRAFV600E biomarker in a sample of Iraqi patients with colorectal cancer and the correlation of BRAFV600E expression with other clinicopathological variables such as patient's age and tumor grade. Materials and Methods : in this prospective study a total of 90 colorectal cases of a sample of Iraqi patients were collected from teaching labs of AL-Yarmouk Teaching Hospital including 60 cases of colorectal carcinoma and 30 cases of colorectal adenoma. Result: BRAFV600E biomarker was positive in 16.6% of colorectal carcinoma group and negative in colorectal adenoma group. Conclusions: BRAF expression was higher in older patients ages &amp; higher tumor stages and there is no expression of BRAFV600E in adenoma cases.

Outcomes of colorectal cancer resection in patients with inflammatory bowel disease: a national population-based analysis in England and Wales.

The aim was to compare early postoperative outcomes and 2-year cancer-specific mortality following colorectal cancer (CRC) resection in patients with and without inflammatory bowel disease (IBD) in England and Wales. Records for patients in the National Bowel Cancer Audit who had major CRC resection between April 2014 and December 2017 were linked to routinely collected hospital level administrative datasets and chemotherapy and radiotherapy datasets. Multivariable regression models were used to compare outcomes with adjustment for patient and tumour characteristics. In all, 63 365 patients were included. 1285 (2.0%) had an IBD diagnosis: 839 (65.3%) ulcerative colitis, 435 (33.9%) Crohn's disease and 11 (0.9%) were indeterminate. IBD patients were younger, had more advanced cancer staging and a higher proportion of right-sided tumours. They also had a higher proportion of emergency resection, total/subtotal colectomy, open surgery and stoma formation at resection, with longer hospital admissions and higher rates of unplanned readmission and reoperation. Fewer rectal cancer patients with IBD received neoadjuvant radiotherapy (24.8% vs. 36.0%, P= 0.005) whilst similar proportions of Stage III colon cancer patients received adjuvant chemotherapy. Ninety-day postoperative mortality was similar, but unadjusted 2-year cancer-specific mortality was significantly higher in patients with IBD (subdistribution hazard ratio 1.35, 95% CI 1.18-1.55). Risk adjustment for patient and tumour factors reduced this association (adjusted subdistribution hazard ratio 1.22, 95% CI 1.05-1.43). Patients with IBD and CRC are a distinct patient group who develop CRC at a younger age and undergo more radical surgery. They have worse cancer survival, with the difference in prognosis appearing after the early postoperative period.

Predictive preoperative clinical score for patients with liver-only oligometastatic colorectal cancer

BackgroundResection of liver metastases from colorectal cancer (CRC) in the oligometastatic stage improves survival and is a potentially curative treatment. Thus, predictive scores that reliably identify those patients who especially benefit from surgery are essential.Patients and methodsIn this multicenter analysis, 512 patients had undergone surgery for liver metastases from CRC. We investigated distinct cancer-specific risk factors that are routinely available in clinical practice and developed a predictive preoperative score using a training cohort (TC), which was thereafter tested in a validation cohort (VC).ResultsInflammatory response to the tumor, a right-sided primary tumor, multiple liver metastases, and node-positive primary tumor were significant adverse variables for overall survival (OS). Patients were stratified in five groups according to the cumulative score given by the presence of these risk factors. Median OS for patients without risk factors was 133.8 months [95% confidence interval (CI) 81.2-not reached (nr)] in the TC and was not reached in the VC. OS decreased significantly for each subsequent group with increasing number of risk factors. Median OS was significantly shorter (P < 0.0001) for patients presenting all four risk factors: 14.3 months (95% CI 10.5 months-nr) in the TC and 16.6 months (95% CI 14.6 months-nr) in the VC.ConclusionsIncluding easily obtainable variables, this preoperative score identifies oligometastatic CRC patients with prolonged survival rates that may be cured, and harbors potential to be implemented in daily clinical practice.

Intraparenchymal breast leiomyoma and atypical leiomyoma

BackgroundBreast leiomyoma is a rare benign mesenchymal tumor, accounting for less than 1% of all breast neoplasms. Cases of breast atypical leiomyoma is even more rarely reported and its diagnostic criteria together with its clinical courses is not cleared defined.Case presentationWe described two patients with breast leiomyomas. One has unilateral benign breast leiomyoma, the other one has bilateral breast leiomyomas. For the bilateral case, the left-side tumor was diagnosed as benign leiomyoma while the right-side tumor was diagnosed as atypical leiomyoma. The morphological features that lead to the diagnosis of atypical leiomyoma are its invasive growth pattern, mild nuclear atypia, and mitotic figures up to 3mitoses/10HPF.ConclusionsAtypical breast leiomyoma appears to behave like benign leiomyoma without recurrence in our study with nine-year follow-up. Due to the limited experience, cases presented as atypical intraparenchymal breast leiomyoma should be closely followed.