Left-sided Tumors Research Articles

Surgical therapy of a Fetal Lung Interstitial Tumor (FLIT) in an infant – A case report and review of surgical considerations

Congenital lung masses are rare and their clinical presentation is highly variable. If newborns present with respiratory distress immediately after birth, early surgical therapy can be necessary. Here, we present the case of a newborn with a very large left-sided lung tumor. The severe respiratory compromise warranted surgical resection at the age of 11 days. The surgery was conducted by an interdisciplinary team. Cardiopulmonary bypass was used to maintain hemodynamic stability. The postoperative histopathological workup identified the tumor as a Fetal Lung Interstitial Tumor (FLIT). The patient developed well and is doing fine 15 months after surgery.

A phase II study to evaluate the efficacy and safety of fruquintinib combined with tislelizumab and hepatic artery infusion chemotherapy (HAIC) for advanced colorectal cancer liver metastases: An updated analysis of survival.

3543 Background: We previously have showed that fruquintinib combined with tislelizumab and HAIC had an ORR benefit (25.71%) consisting of 1 CR and 8 PR in advanced colorectal cancer liver metastases (CRLM) patients (pts) who had failed to standard therapy in this single-arm, open-label, single center phase II study (NCT05435313). Here, we aim to update the survival results. Methods: We enrolled CRLM pts who had failed to standard therapy. Eligible pts received fruquintinib (3mg, qd, po, D2-21, Q3W), combined with tislelizumab (200mg, ivgtt, D2,Q3W) and HAIC (TOMOX: raltitrexed 2mg/m2, D1, oxaliplatin 85mg/m2, D1, Q3W; or TOMIRI: raltitrexed 2mg/m2, D1, irinotecan 120mg/m2, D1, Q3W) for 4-6 cycles, followed by maintenance therapy with fruquintinib and tislelizumab until disease progression, death or unacceptable toxicity. The primary endpoint was ORR. The secondary endpoints included DCR, PFS, 6mo-PFS rate, OS and safety. In addition, subgroup analysis of ORR and PFS according to primary tumor site, RAS/BRAF status and history of bevacizumab (bev) were performed. Results: Between July 17, 2022 and June 15, 2023, 39 pts (median age, 59 years [range: 35--73], 25 [64.1%] male, 7 [17.95%] right-sided tumor, 38 [97.44%] MSS, 20 [51.28%] RAS/BRAF mutation) were enrolled. Among them, 23 (58.97%) pts had previously received bev. As of December 31, 2023, there were 4 pts drop out and 35 pts with MSS were included in the efficacy analysis. At a median follow-up of 12.52 mo, the median PFS was 7.43 mo (95%CI, 5.36-9.82) and 6mo-PFS rate was 60%, the median OS was 15.51mo (95%CI, 10.84-NA) and 1 year-OS rate was 61%. In the subgroup analysis, the median PFS was significantly longer with right-sided tumor pts than left-sided tumor pts (13.31 vs 6.90 mo, HR, 0.121 [95%CI, 0.046-0.320], p= 0.0062). Compared with pts who received bev in prior therapy, the median PFS of pts without bev was significantly improved (5.16 vs 8.31 mo, HR, 0.358 [95%CI, 0.133-0.965], p=0.0361). Favorable PFS was observed in RAS/BRAF mutation pts compared with RAS/BRAF wide-type pts (8.18 vs 7.43 mo). The results of PFS subgroups were consistent with ORR subgroup results (right-sided vs left-sided: 42.86% vs 21.43%, with bev vs without bev: 10% vs 46.67%) which was previously reported. Compared with safety profile reported previously, no additional safety signals were observed. Conclusions: The updated data on the survival analysis revealed that fruquintinib combined with tislelizumab and HAIC had a survival benefit in CRLM pts with MSS who had failed to standard therapy, especially for right-sided tumor pts. Based on these results, another study is ongoing to explore the efficacy for MSS CRLM pts with two cohorts (cohort 1: right-sided tumor, cohort 2: left-sided tumor), and the results will be presented in the future. Clinical trial information: NCT05435313 .

Fruquintinib plus capecitabine versus capecitabine as first-line maintenance treatment of metastatic colorectal cancer (mCRC): Update results from the randomized, controlled, phase Ib/II study.

3567 Background: Capecitabine (Cap) is a standard first-line maintenance treatment option for colorectal cancer. Fuquinitinib (Fru) is a highly selective small molecule tyrosine kinase inhibitor that inhibits VEGFR1/2/3, which has been approved by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and has recommended by NCCN guidelines as a standard treatment. Preliminary research results found that adding Fru to Cap as maintenance treatment was safe and improved progression-free survival (PFS, primary endpoint) for mCRC patients (pts). Methods: Eligible pts had been confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m2, p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was PFS 1 (defined as time from randomization to disease progression or death). Secondary were PFS 2 (defined as time from first time receiving 1L treatment to disease progression or death), ORR and DCR. Results: At data cutoff (Jan 23, 2024), 46 pts were enrolled and 38 pts who had at least one tumor assessment post treatment were randomly assigned in Fru plus Cap arm (n=20) and Cap arm (n=18). Of these pts, the median age was 59.5 (39-78) and 58.5 (32-75) years, 11 (55.0%) and 10 (55.6%) had left-sided tumors, respectively. Most pts had previously received bevacizumab therapy (65.0% /66.7%) or cetuximab (30% /22.2%). The median cycles of first-line treatment were 8 (5-12) and 8 (4-13), 8 (40.0%) and 8 (44.4%) achieved PR in the pts who had received first-line therapy, respectively. The median PFS 1 was 9.2 mo in Fru plus Cap arm and 3.1 mo in Cap arm (HR=0.385 [95% CI: 0.163 - 0.906], p=0.024). And PFS 2 was also significantly prolonged in Fru plus Cap vs Cap (16.8 vs 8.5 mo, HR=0.314 [95% CI: 0.125 - 0.788], p=0.0098). Consistently, ORR (15.0% vs 5.6%) and DCR (80% vs 55.6%) were improved in Fru plus Cap arm. The safety was similar to the previous results without new safety signals appearing. Conclusions: PFS was significantly prolonged and ORR was improved in mCRC pts treated with Fru plus Cap as first-line maintenance treatment. This trial is ongoing and updated data will be presented in the future. Clinical trial information: NCT05451719 .

The impact of metformin on clinical outcomes of metastatic colorectal cancer with known molecular profile treated with cytotoxic chemotherapy or immune checkpoint inhibitor.

e15580 Background: Colorectal cancer (CRC) is the third most common cancer in the US, with a dismal 5-year OS of 13% in mCRC. Concomitant metformin with chemotherapy or immune checkpoint inhibitors (ICIs) revealed improved outcomes in various cancers. Metformin's anti-cancer effects stem its effects on cancer metabolism, cell cycle modulation, cancer stem cells, gut microbiota, immunomodulatory properties. The aim of this retrospective study was to study the impact of concomitant metformin use with the type of systemic therapy (chemotherapy or ICIs) in CRC. Methods: CRC tumors were analyzed by NGS of DNA (592-gene) and RNA (whole transcriptome) at Caris Life Sciences. MSS was assessed by NGS, with MSI-H and MSS patients subcategorized by concomitant metformin use with ICI or with chemotherapy, respectively. Real-world OS, derived from insurance claims data, was calculated from the time of CRC sample collection to the last contact. Hazard ratio (HR) was calculated using the Cox proportional hazards model, with p values calculated using the log-rank test. Results: The study cohort included 31,083 CRC cases (male: female = 1.2, age: 80% > = 50 years). Common molecular alterations included TP53 (73.6%), APC (77.6%), KRAS (47.4%), CTNNB1 (2.0%), and HER2 amplification (1.7%). 1,503 patients were MSI-H (4.83%), 21,330 as MSS (68.6%), and 8,250 indeterminate. MSI-H patients receiving concurrent ICI/metformin had similar OS (52.7 vs. 55.4 months, HR = 0.78, 95% CI: 0.41 – 1.51, p = 0.462). Conversely, OS was increased in MSS patients on concomitant chemotherapy and metformin (38.1 vs 31.1 months, HR = 0.77, 95% CI: 0.69 – 0.86, p < 0.00001). In comparing real-world OS between left-sided and right-sided colorectal cancer (CRC), regardless of metformin use, multivariate analysis incorporating molecular alterations revealed longer OS for left-sided MSS CRC compared to right-sided (HR = 0.80, 95% CI: 0.76 – 0.84, p < 0.00001). However, further improvement in OS was associated with concurrent metformin use in both right-sided and left-sided tumors. Conclusions: In this retrospective analysis of real-world clinical outcomes, patients receiving concomitant metformin and cytotoxic chemotherapy had improved clinical outcomes in MSS CRC compared to those not on concurrent metformin. However, the concurrent use of metformin with ICIs in MSI-H CRC did not show an impact on clinical outcomes given low sample size. These results add to the existing body of literature on the potential benefits of metformin in the context of MSS CRC and underscore the importance of a prospective controlled study of concurrent metformin use with systemic chemotherapy in metastatic CRC. Limitations of this study involves the potential inclusion of cases with prior metformin use, small sample size, retrospective analyses, and the lack of control for the patients with type II DM.

Survival impact of KRAS mutation in metastatic colorectal cancer (mCCR) under first-line treatment.

3547 Background: Activating mutations in the MAPK pathway are predictive biomarkers in mCCR and 50% of patients (pts) present KRAS mutations. There is a large spectrum of molecular aberrations with a lack of data regarding tumor side correlations and their impact on treatment response and overall survival. Methods: Retrospective cohort of mCRC pts and KRAS activating mutations treated between 2019-2022 in a tertiary cancer center in Brazil. KRAS gene was analyzed by next-generation sequencing in tumor tissue samples. Electronic medical records were reviewed with case report forms registered in RedCap software. The primary endpoint was Overall survival (OS), estimated using Kaplan-Meir and compared with the log-rank test. Cox proportional models were applied to estimate hazard ratios (HR). Results: We included 490 patients with a mean age of 59 years (y), mostly male, 51.4%. Primary left-side location was present in 65.5% and liver metastasis in 66.7%. The spectrum of KRAS mutations found were G12D (31.2%), G12V (20.2%), G13D (15.1%), G12C (9.4%), G12A (4.9%), G12S (3.5%), and G12R (2%). First line regimen was 5-FU and Oxaliplatin (mFLOX) in 84.9% (n=388), with a median PFS of 9.2 months (95%CI 7.8 - 11.6) and OS of 21 months (95%CI;19-23) in this group. Treatment related outcomes in first-line therapy at first evaluation were 40% partial response, 20.4% stable disease, 30,9% disease progression and 1.3% complete response. G12S mutation was associated with better PFS 18.62 vs. 8.75m compared with other codon mutations (HR:0.52;95%CI 0.28-0.98) and OS NR vs. 21.58m HR (HR:0.48;95%CI;0.24-0.97). G12R was associated with worse PFS 5.31 vs. 9.90 m (HR:2.2;95%CI;1.09-4.47) and OS 17.89 vs. 21.88m (HR:1.61;0.79-3.24). Sideness was not associated with prolonged response or overall survival right-sided tumors 20.72 vs. vs. left-sided tumors 22.14m (HR:1.04;95%CI;0.82-1.31). Conclusions: Specific mutated codons in the KRAS gene impact PFS and OS independently of primary tumor sidedness. G12S mutation demonstrated an improved OS and PFS. [Table: see text]

The molecular landscape of PIWIL1 expression in colorectal adenocarcinoma (CRC).

3546 Background: PIWIL1 is a cancer testis antigen overexpressed in solid tumors, particularly CRC, and is associated with advanced stage and poor prognosis. It is potentially a new therapeutic target as PIWIL1 is not expressed in adult somatic tissue. A novel T cell receptor/PIWIL1 bispecific antibody is in development, restricted to individuals with human leukocyte antigen (HLA) A-02. We sought to characterize the molecular landscape of PIWIL1 in CRC. Methods: 26,581 CRC tumors were tested by next-generation sequencing (NGS) on DNA (592-gene or whole exome [WES]) and RNA (whole transcriptome [WTS]) at Caris Life Sciences (Phoenix, AZ). dMMR/MSI-H was tested by immunohistochemistry (IHC) and NGS, HLA genotypes by WES and PD-L1 by IHC (SP142, 2+, 5%). Tumor mutational burden (TMB) high was defined as ≥ 10 mt/Mb. RNA expression was used to estimate the tumor microenvironment using QuantiSEQ and RNA signatures (interferon gamma [IFNγ]; T-cell inflamed [TIS]) predictive of immune checkpoint blockade (IO) response. The top (H) and bottom (L) quartiles of PIWIL1 expression were compared using Chi-square/Fisher-Exact, and significance was determined as p adjusted for multiple comparisons (Q<0.05). Real-world overall survival (rwOS) was obtained from insurance claims and calculated from tissue collection to last contact. Results: Patients with PIWIL1-H were older (median age 65 v 61, Q<0.01) and more likely to be female (50.8% v 41.3%, Q<0.01), compared to PIWIL1-L. PIWIL1 median expression was higher in right- v left-sided primary tumors (2.0 v 1.3 transcripts per million [TPM], Q<0.05). No significant difference in PIWIL1 expression was observed among HLA genotypes. dMMR/MSI-H, TMB-H and PD-L1+ were higher in PIWIL1-H v PIWIL1-L (13.9% v 6.5%, 17.6% v 10.4%, 6.4% v 3.4%, all Q<0.05). IO-related gene expression ( LAG3, IDO1, CTLA4 and others) were positively associated with PIWIL1 expression (fold change [FC]: 1.4-2.7, Q<0.05). High IFNγ and TIS were associated with PIWIL1-H (Q<0.001). PIWIL1 expression showed a positive association with infiltration of neutrophils, monocytes, CD4+T, dendritic and NK cells (FC: 1.3-2.9, Q<0.05) while Tregs and M1 macrophages had a negative association (0.8-0.9, Q<0.05). In pMMR/MSS CRC, KRAS, BRAF and TP53 mutations and loss of heterozygosity were higher in PIWIL1-H v PIWIL1-L (81% v 69%, 53% v 41%, 16% v 3%, 14% v 10%, all Q<0.05) but not for PIK3CAmutations (14% v 17%). For rwOS, PIWIL1-H had longer median OS than PIWIL1-L, 31.2 v 28.8 months (HR 0.95; 95% CI 0.90-0.99, p=0.043). There was no significant rwOS difference observed in IO-treated tumors. Conclusions: PIWIL1-H CRC is associated with higher rates of dMMR/MSI-H, TMB-H and PD-L1+ as well as IO-related gene expression and signatures that are predictive of response to IO. These data suggest the PIWIL1-H subpopulation could potentially derive substantial benefit from PIWIL1-targeted immunotherapy which should be evaluated in clinical trials.

Predictors of nodal positivity in clinically under-staged patients with colon cancer: A National Cancer Database study and proposal of a predictive scoring system

BackgroundColon cancer pathological and clinical staging may be disoncordant. This study assessed patients with colon cancer in whom the nodal status was clinically understaged. MethodsPatients with stage I-III clinical node-negative colon cancer from the National Cancer Database were included. Regression analyses were conducted to elucidate risk factors for clinical nodal understaging and a scoring system was developed to identify high-risk patients. ResultsThe study included 94,945 patients with 78.4 ​% of patients correctly staged and 21.6 ​% clinically understaged. The predictors of nodal positivity in clinically understaged patients were age <65 (OR 1.43), left-sided tumors (OR 1.41), elevated CEA (OR 2.03), moderately (OR 1.81) or poorly/undifferentiated tumors (OR 3.76), T1 tumors (OR 1.29), signet-ring cell histology (OR 2.26), and microsatellite-stable tumors (OR 1.4). ConclusionPatients with colon cancer and the above factors are more likely to have their nodal status clinically understaged. A scoring system has been developed to identify high-risk patients.

Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D.

The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.

Abstract PO3-02-13: Breast Cancer in Very Young Adult Women At or Under the Age of 35 Years: Characteristics and Outcomes

Abstract Background: Breast cancer (BC) is the most common malignancy among women in Saudi Arabia. Noticeably, it shows a higher incidence in younger age groups than what is reported from Western countries. Age 35 years and less is an applied cut-off age for clinically defining BC in very young women (BCVY). This study describes characteristics, survival and risk of death associated factors in this rare subset of patients. Methods: A retrospective cohort study included females &amp;gt; 18 and &amp;lt; 35 years with histologically confirmed primary non-metastatic breast cancer from an academic hospital in Jeddah, Saudi Arabia between the years 2009-2019. Demographic data, tumor clinicopathological features, and outcomes were obtained. Survival and potential associated factors were examined. A p-value of less than 0.05 was regarded as statistically significant. Results: 204 female patients with a confirmed breast cancer diagnosis were included. The mean age at diagnosis was 31.43 ± 2.94 years. Fifty-three percent of the patients had a left-sided tumor with the majority being IDC (92%) and one-third with positive axillary lymph nodes (N+) and multifocal disease in 17%. One-quarter of the tumors showed LVI, 45% revealed associated DCIS and 26% showed tumor necrosis on histopathology examination. The presence of tumor-infiltrating lymphocytes (TILs) was reported in 23% of TNBC cases. Tubular differentiation score 3 was reported in 79.4%, nuclear pleomorphism score 3 in 79% and mitosis activity score 3 in 19% while the most reported overall grade was II in 48.5% followed by grade III in 34%. HER2-positive in 33.8 %, HR-positive in 34.3 %, TNBC in 24% and unknown in 8% of the patients. Thirty percent had a distant recurrence and 15% were deceased. The mean survival time was 4.61 years with a maximum of 6.54 years and a minimum of 3.67 years. Table 1 shows the multivariate logistic regression analysis of factors influencing the risk of death in very young patients with breast cancer. Conclusions: The current study describes the clinicopathological characteristic, survival and related factors of breast cancer in very young patients &amp;lt; 35 years, which is considered an uncommon presentation. Large, high-grade tumors and a high frequency of HER2 and TNBC were observed in BCVY patients. Involvement of the regional lymph nodes and the development of distant recurrence were associated significantly with an increased risk of death. The presence or absence of TILs, LVI and tumor necrosis on histopathological examination did not influence the risk of recurrence or death in this cohort. Table 1. The multivariate logistic regression analysis of factors influencing the risk of death in very young patients with breast cancer. Citation Format: Atlal Abusanad, Rana Ajabnoor, Aydah Al-Awadhi, Omalkhair Abualkhair. Breast Cancer in Very Young Adult Women At or Under the Age of 35 Years: Characteristics and Outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-13.

Upfront laparotomy versus conversion from minimally invasive surgery to open surgery in colon cancer: Is there a difference in outcomes?

BackgroundIt is unclear whether conversion from minimally invasive surgery to laparotomy in patients with colon cancer contributes to worse outcomes compared with those operated by laparotomy. In this study, we aimed to assess the implications of transitioning from minimally invasive surgery to laparotomy in patients with colon cancer compared with patients undergoing upfront laparotomy. MethodsA retrospective analysis of the National Cancer Database, including patients with stages I to III colon cancer (2010–2019). Patients who underwent either upfront laparotomy (Open Surgery Group) or minimally invasive surgery converted to open surgery (Converted Surgery Group) were included. Groups were balanced using propensity-score matching. Primary outcome was overall survival, and secondary outcomes included 30- and 90-day mortality and 30-day readmission rates. ResultsThe study included 65,083 operated patients with stage I to III colon cancer; 57,091 patients (87.7%) were included in the Open Surgery group and 7,992 (12.3%) in the Converted Surgery group. 93.5% were converted from laparoscopy, and 6.5% were converted from robotic surgery. After propensity-score matching, 7,058 patients were included in each group. Median overall survival was significantly higher in the Converted Surgery group (107.3 months) than in the Open Surgery group (101.5 months; P = .006). A survival benefit was seen in patients >65 years of age (79.5 vs 71.9 months; P = .001), left-sided disease (129.4 vs 114.5 months; P < .001), and with a high Charlson comorbidity index score (=3; 58.9 vs 42.3 months; P = .03). Positive margin rates were similar between the groups (6.3% vs 5.6%; P = .07). Converted patients had a higher 30-day readmission rate (6.7% vs 5.6%, P = .006) and shorter duration of stay (median, 5 vs 6 days, P < .001) than patients in the Open Surgery group. In addition, 30-day mortality was comparable between the groups (2.9% vs 3.5%; P = .07). ConclusionConversion to open surgery from minimally invasive surgery was associated with better overall survival compared with upfront open surgery. A survival benefit was mainly seen in patients >65 years of age, with significant comorbidities, and with left-sided tumors. We believe these data suggest that, in the absence of an absolute contraindication to minimally invasive surgery, it should be the preferred approach in patients with colon cancer.

CD10 Expression Correlates with Earlier Tumour Stages and Left-Sided Tumour Location in Colorectal Cancer but Has No Prognostic Impact in a European Cohort.

The role of CD10 expression in colorectal cancer has been controversially discussed in the literature. Some data suggest a predictive capacity for lymph node and liver metastases, thus influencing overall survival (OS) and disease-free survival (DFS). This study aims to analyse the relationship between CD10 expression and overall survival (OS) in a European cohort. To determine the association of CD10 expression with tumour phenotype, molecular features, and prognosis, a tissue microarray of 1469 colorectal carcinomas was analysed using immunohistochemistry and was compared with matched clinicopathologic data. CD10 expression correlated with earlier tumour stages (p = 0.017) and left-sided colon cancer (p < 0.001). However, no correlation was found between CD10 expression and lymph node involvement (p = 0.711), tumour grading (p = 0.397), or overall survival (p = 0.562). Even in the subgroup analysis of tumour or nodal stage, CD10 did not affect overall survival, although it was significantly associated with p53 and nuclear β-catenin expression (p = 0.013 and p < 0.001, respectively). CD10 expression correlates with earlier tumour stages, colon cancer location, and indicators of aggressive CRC subtypes. However, we can exclude CD10 as a relevant independent prognosticator for CRC.

Clinical and molecular heterogeneity associated with tumor sidedness in colorectal liver metastasis: a multicenter propensity cohort study.

Colorectal liver metastasis (CRLM) exhibits highly heterogeneity, with clinically and molecularly defined subgroups that differ in their prognosis. The aim of this study is to explore whether left-sided tumors is clinically and gnomically distinct from right-sided tumors in CRLM. This retrospective study included 1,307 patients who underwent primary tumor and metastases resection at three academic centers in China from January 1, 2012, to December 31, 2020. Propensity score matching with 1:1 ratio matching was performed. The prognostic impact of tumor sidedness was determined after stratifying by the KRAS mutational status. Moreover, whole-exome sequencing (WES) of 200 liver tumor tissues were performed to describe the heterogeneity across the analysis of somatic and germline profiles. The median follow-up was 68 months. Matching yielded 481 pairs of patients. Compared to right-sided CRLM, left-sided patients experienced with better 5-year overall survival (OS) in surgery responsiveness, with a 14.6 lower risk of death [hazard ratio (HR), 1.36, 95% confidence interval (CI), 1.10-1.69, P=0.004]. Interaction between tumor sidedness and KRAS status was statistically significant: left-sidedness was associated with better prognosis among KRAS wild-type patients (HR 1.71; 95% CI: 1.20-2.45; P=0.003), but not among KRAS mutated-type patients. Integrated molecular analyses showed that right-sided tumors more frequently harbored TP53, APC, KRAS, and BRAF alterations, and identified a critical role of KRAS mutation in correlation with their survival differences. Higher pathogenic germline variants were identified in the right-sided tumors compared with left-sided tumors (29.3% vs. 15.5%, P=0.03). We demonstrated that the prognostic impacts of tumor sidedness in CRLM is restricted patients with KRAS wild-type tumors. Tumor sidedness displays considerable clinical and molecular heterogeneity that may associate with their therapy benefits and prognosis.

Abstract 925: Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection

Abstract Introduction: Anti-EGFR monoclonal antibody plus doublet chemotherapy is the mainstay of first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Some of these patients might undergo secondary resection. However, there is no standardized suggestion on whether colorectal cancer liver metastasis patients should keep target therapy after secondary resection. NCCN guidelines suggest chemotherapy only in patients receiving primary liver resection. Whether we could spare the use of target therapy after secondary resection is the main aim of our study. Methods: Using Taiwan's National Health Insurance Research Database, we established a cohort of KRAS wild-type mCRC patients treated with first-line anti-EGFR therapy plus doublet chemotherapy between 2013 and 2018. Secondary surgery was defined as either resection of liver metastases or radiofrequency ablation. Results: 5694 stage IV mCRC patients received anti-EGFR MAb plus doublet chemotherapy as a first-line treatment between 2013 and 2018. 174 patients were enrolled in the final analysis, with 153 continuing anti-EGFR MAb after secondary resection and 21 patients without anti-EGFR MAb. Compared with those who without anti-EGFR therapy after secondary resection, patients who continued anti-EGFR MAb exhibited significantly longer overall survival (OS; median, 43.8 vs. 31.9 months, p = 0.031) but not in time to treatment failure (TTF; median, 22.2 vs. 26.6 months, p = 0.841). The OS benefits of continuing anti-EGFR MAb remained regardless of left-sided or right-sided primary tumors (40.9 vs. 43.0 months, p = 0.980). The patient cohort from 2016 to 2018 showed more prolonged survival than from 2012 to 2015 (not reached vs. 40.450, p = 0.0305). TTF has no statistical difference when considering patient cohort or primary tumor location. In multivariate analyses, continuing first-line anti-EGFR MAb therapy after secondary resection remained an independent predictor of longer OS. Conclusion: For mCRC patients who received secondary resection after first-line anti-EGFR and doublet chemotherapy, continuing anti-EGFR MAb after resection was associated with significantly longer OS regardless of primary tumor sidedness. Citation Format: Yao-Yu Hsieh, Chin-Wen Tsai, T-CARE Group, Yi-Hsieh Liang. Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 925.

Motor seizures confer overall survival benefit in who grade 2 glioma.

The prevalence of epilepsy in World Health Organization (WHO) grade 2 glioma is high, with seizures being the presenting symptom in 60%-90%. We explore the epidemiology of seizures in this patient population in a regional neurosurgical center. Electronic health records of patients with histologically-proven WHO grade 2 glioma (n = 228) were reviewed between 1997 and 2021, with data collected including patient demographics, epilepsy prevalence, and seizure semiology. The influence of seizure type on overall survival was calculated using a Cox proportional hazards model. Overall, 197 of 228 patients (86.4%) were diagnosed with epilepsy-either at presentation or during the course of their disease. Male patients were more likely than female patients to be diagnosed with epilepsy (91.1% vs 77.1%, p = .003) and, in those with epilepsy, more likely to experience at least one focal to bilateral tonic-clonic seizure (69.4% vs 54.1%, p = .05). Patients with left-sided tumors were twice as likely to have experienced a focal to bilateral tonic-clonic seizure (p = .02, odds ratio [OR] = .47). Predominantly experiencing seizures with motor activity appeared to confer better overall survival, with a 65% decrease in the risk of death 10 years post diagnosis (hazard ratio [HR] = .35, p = .02). This is despite accounting for previously described prognostic markers including tumor histology/genetics, time from diagnosis to surgery, and the extent of tumor resection. Motor seizure activity is a frequent feature in WHO grade 2 glioma and appears to confer a survival benefit regardless of histology or surgical factors. Seizures due to dominant hemisphere tumors may be more likely to propagate and cause bilateral tonic-clonic activity.

Clinical and biological significance of microRNA-127 and microRNA-138 expression in women with breast cancer: response to treatment and survival impact

Background and ObjectiveGenetic and epigenetic changes characterize the multi-step process of breast carcinogenesis. It is believed that abnormal microRNA (miRNA) expression has a role in the onset and progression of breast cancer. This study aimed to examine the link between miRNA-127 and miRNA-138 and metastasis, tumor invasion, and apoptosis in Egyptian women with breast cancer, as well as their correlation with its molecular types.MethodologyA total of 150 participants were included in this study, including 75 women with breast cancer and 75 supposedly healthy women who were age and gender-matched. Every patient underwent a thorough physical examination, a general clinical examination, a mammogram, and lab tests, such as the determination of the levels of miRNA-127 and miRNA-138 expression by real-time PCR and the measurement of blood carcinoembryonic antigen (CEA) and carcinoma antigen 15–3 (CA15-3) and CA15-3 and CEA levels.ResultsThere was a significant low expression of miRNA-127 in favor of high TNM stage (Classification of Malignant Tumors), left-sided tumor, metastasis, high-grade disease, increased axillary nodal involvement, absence of estrogen and progesterone receptors, and low antigen Kiel 67 (Ki67) expression. Also, a significant expression of miRNA 127 in triple-negative breast cancer was found, followed by human epidermal growth factor receptor 2 (HER2/neu) overexpression, then luminal B, and the highest expression was with the Luminal A molecular subtype. A significant negative correlation existed between miRNA 127 and miRNA 138 with CEA and CA15.3 levels.ConclusionThe miRNA-127 and miRNA-138 suppression may promote metastasis. Consequently, the restoration of miRNA-127 and miRNA-138 in breast cancer may have therapeutic potential; so, the miRNA-127 and miRNA-138 may play a role in breast cancer development.

Surgical and survival outcomes of early-onset colorectal cancer patients: a single-centre descriptive Australian study.

Early-onset colorectal cancer (EOCRC) incidence is increasing in Australia. However, no Australian studies have reported on EOCRC patients' surgical management and survival patterns. A retrospective study of 111 EOCRC patients treated at the Royal Prince Alfred Hospital (RPAH), Sydney, Australia between January 2013 and December 2021 was performed. RPAH is a quaternary referral centre for pelvic exenteration (PE) and cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Most patients had left-sided tumours (76.58%) and stage IV disease at the time of presentation (37.85%). 27.93% of patients underwent either CRS/HIPEC and PE and 72.07% of patients underwent other colorectal resections of which the most common was low anterior resection (19.82%). A stoma was fashioned in 50.54% of patients. Complications occurred in 54.95% of patients of which most were Clavien-Dindo grade II (47.54%). Absolute 1-, 3- and 5-year time intervals were 93.69%, 87.39% and 85.48%. Disease-free and overall survival were poorer in stage IV patients who had PE, followed by CRS/HIPEC then other colorectal resections (P < 0.001 and P = 0.003). Stoma formation, PE and CRS/HIPEC and minor postoperative complications were common in our EOCRC cohort. Despite this, the 5-year absolute survival rate was acceptable. Thus, an aggressive surgical approach in EOCRC patients at a quaternary referral centre may be feasible at the cost of greater postoperative morbidity. This information is imperative in the surgical consent and preoperative counselling of EOCRC patients and highlights the need for further research to assess the postoperative functional outcomes and quality of life of EOCRC patients.

Frequency of Programmed Death Receptor Ligand 1 Expression and Clinicopathological Factors Associated With Metastatic Triple-Negative Breast Cancer at a Tertiary Cancer Care Centre in South India.

Purpose Triple-negative breast cancer (TNBC) has a poor outcome compared to other subtypes. Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm in metastatic diseases as well as in neoadjuvant setting. The response to these agents is affected by programmed death ligand 1 (PDL1) receptor expression which are reported objectively as a score. PDL1 is a prognostic marker also. Here, we present clinicopathological characteristics of metastatic TNBCs, report the proportion of PDL1 expression and its association with clinicopathological factors as well as survival. Methods This is a prospective study carried out at a tertiary cancer care centre in South India. Case records of all breast cancer patients treated in two years between August 2021 and July 2023 were reviewed, patients with metastatic TNBC were selected. Patient's characteristics, histological features, molecular profile, and treatment were analyzed. PDL1 testing was carried out on pretreatment tumor tissue sections with immunohistochemistry (IHC) (Dako 22C3). PDL1 staining was interpreted as negative or positive based on combined positive score (CPS), with an expression less than 10 considered negative. Results A total of 118 patients were analyzed. With a median age of 46 years (36-65 years), 52.5% (62/118) were premenopausal. Family history of Ca Breast was seen in 22% (26/118) patients. A majority of patients had left-sided tumor 55.9% (66/118). Visceral metastasis was more common 96.6% (82/118) than skeletal. Radical intent of treatment was adopted in 10% as patients had oligometastatic disease at presentation. As front-line treatment, anthracycline-based chemotherapy was administered to the majority 54.2% (64/118). The PDL1 expression with CPS more or equal to 10 was seen in 32.2% (38/118) patients. Survival was associated with menopausal status (p value=0.000) and family history (p value=0.028) but notwith PDL1 nor sidedness in our study. Estimated survival at 12 months in PDL1 negative case is 10 ± 0.29 months, while in PDL1 positive case it is slightly more at 10± 0.75 months, but difference was not found to be statistically significant (p value=0.15). Conclusion TNBCs are highly aggressive subtype with limited treatment options and poorer outcomes. Our study shows PDL1 expression in 31.66% of the cases similar to other literature from India. Survival is associated with menopausal status and family history. No association was found between survival and PDL1 as well sidedness in our study.

Tumor location matters, next generation sequencing mutation profiling of left-sided, rectal, and right-sided colorectal tumors in 552 patients

Despite the introduction of new molecular classifications, advanced colorectal cancer (CRC) is treated with chemotherapy supplemented with anti-EGFR and anti-VEGF targeted therapy. In this study, 552 CRC cases with different primary tumor locations (250 left side, 190 rectum, and 112 right side) were retrospectively analyzed by next generation sequencing for mutations in 50 genes. The most frequently mutated genes were TP53 in left-sided tumors compared to right-sided tumors and BRAF in right-sided tumors compared to left-sided tumors. Mutations in KRAS, NRAS, and BRAF were not detected in 45% of patients with left-sided tumors and in 28.6% of patients with right-sided tumors. Liver metastases were more common in patients with left-sided tumors. Tumors on the right side were larger at diagnosis and had a higher grade (G3) than tumors on the left. Rectal tumors exhibit distinctive biological characteristics when compared to left-sided tumors, including a higher absence rate of KRAS, NRAS, and BRAF mutations (47.4% in rectal versus 42.8% in left-sided tumors). These rectal tumors are also unique in their primary metastasis site, which is predominantly the lungs, and they have varying mutation rates, particularly in genes such as BRAF, FBXW7, and TP53, that distinguish them from tumors found in other locations. Primary tumor location has implications for the potential treatment of CRC with anti-EGFR therapy.

Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database

BackgroundKRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit.MethodsIndividual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis.Results5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84–0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68–0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68–0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86–1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004).ConclusionThe benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Sidedness is not a prognostic factor in an unselected cohort of patients with colon cancer but prognosis for caecal carcinoma is worse – A multivariate analysis of a large single institution database

PurposeSidedness has emerged as a prognostic factor for metastatic colorectal cancer treated with modern systemic therapies. This study investigates whether it is also relevant for an unselected patient cohort including all stages.MethodsAll consecutive patients admitted with colon cancer between 1995 and 2018 were retrieved from an institution-held database. Patients were divided into two cohorts. The first cohort included patients without distant metastases who were able to undergo curative resection. The second cohort presented with distant metastases (stage IV). Potentially prognostic factors were subjected to multivariate Cox Regression analysis.ResultsOverall, 1,606 patients met the inclusion and exclusion criteria. An R0-resection was achieved in 1,222 patients without distant metastases. Five-year cause-specific survival rate was 89.3% for this group. There was no difference between right- and left-sided cancers (88.2% vs. 90.1%, p = 0.220). However, prognosis of caecal carcinoma was significantly worse than that of all other sites combined (83.5% vs. 90.2%, p = 0.007). In multivariate analysis, pT-category, pN-category, grading, vascular invasion, emergency operation, adjuvant chemotherapy, and caecal carcinoma remained as independent prognostic factors. In the 384 patients with stage IV-disease, 3-year overall survival for right- vs. left-sided cancers differed only in univariate analysis (17.7% vs. 28.6%, p = 0.013).ConclusionIn non-metastatic colon cancer, location in the caecum is an independent prognostic factor. In unselected patients with stage IV colon cancer, sidedness was not found to be a prognostic factor. Differentiation into right- and left-sided tumors may be simplistic, and further studies on the biological behavior of different colonic sites are warranted.