Alberts, Steven R.

PURPOSE A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

AbstractWe conducted the first large genome‐wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first‐line oxaliplatin‐based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population‐based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression‐free survival. The analysis was performed for studies individually, and the results were combined using fixed‐effect meta‐analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene‐based analysis as well as in silico bioinformatics analysis for CRC‐relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin‐based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10−8). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10−7). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene‐based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10−6). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first‐line treatment and improve clinical outcomes.

Purpose Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer. Patients and Methods Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity. Results The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively ( P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting. Conclusion The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal cancer.

PURPOSE Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.

Background Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. Patients and Methods A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0–100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0–50) vs not clinically deficient (nCD-QOL, score 51–100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. Results Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) ( P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS ( P = .017). Conclusions Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.

Abstract Background We sought to determine the safety and efficacy of trifluridine/tipiracil in combination with irinotecan in a phase II trial setting for refractory, advanced unresectable biliary tract carcinoma (BTC). Methods A total of 28 patients (27 were evaluable) with advanced BTCs who progressed on at least one prior systemic therapy were enrolled and were treated with trifluridine/tipiracil 25 mg/m2 (days 1-5 of 14-day cycle) and irinotecan 180 mg/m2 (day 1 of the 14-day cycle). The primary endpoint for the study was 16-week progression-free survival (PFS16) rate. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were pre-specified secondary endpoints. Results Of 27 patients, PFS16 rate was 37% (10/27; 95% CI: 19%-58%), thereby meeting the criteria for success for the primary endpoint. The median PFS and OS of the entire cohort were 3.9 months (95% CI: 2.5-7.4) and 9.1 months (95% CI: 8.0-14.3), respectively. In the patients evaluable for tumor response (n = 20), the ORR and DCR were 10% and 50%, respectively. Twenty patients (74.1%) had at least one grade 3 or worse adverse event (AE), and 4 patients (14.8%) had grade 4 AEs. A total of 37% (n = 10/27) and 51.9% (n = 14/27) experienced dose reductions in trifluridine/tipiracil and irinotecan, respectively. Delay in therapy was noted in 56% of the patients while 1 patient discontinued the therapy, primarily due to hematologic AEs. Conclusion The combination of trifluridine/tipiracil plus irinotecan is a potential treatment option for patients with advanced, refractory BTCs with good functional status and no targetable mutations. A larger randomized trial is needed to confirm these results. (ClinicalTrials.gov Identifier: NCT04072445)

Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tyrosine kinase inhibitors (TKIs) are approved as a first-line treatment for unresectable HCC. Lenvatinib and cabozantinib are two of the most used TKIs, but the therapeutic duration is limited due to the development of drug resistance. Therefore, understanding the mechanisms of resistance and combining TKIs with other drugs antagonizing resistance should lead to antitumor synergy, eliminating drug resistance. It turns out that the simultaneous use of TKIs together with an inhibitor of stearoyl-CoA desaturase 1 (SCD1) prevents the development of drug resistance, leading to a durable response. SCD1 is the enzyme responsible for de novo fatty acid (FAs) synthesis, converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). MUFAs are an alternative energy source to glucose, integral to cellular membranes, and prevent endoplasmic reticulum (ER) stress and other signaling pathways. In our laboratory, we developed a novel, highly specific SCD1 inhibitor - SSI-4. We have tested the biological activity of SSI-4 against different HCC cell lines and patient-derived xenografts (PDX) mouse models. Of the twelve tested HCC cell lines, four were highly sensitive to SSI-4 (IC50 1-50 nM). Other cell lines showed moderate or no sensitivity to SSI-4. We tested the concomitant use of SSI-4 with lenvatinib and cabozantinib, tyrosine kinase inhibitors (TKIs) FDA-approved for HCC, in HCC cell lines in vitro and using HCC PDX in vivo mouse models. Our studies showed that the combination of the SCD1 inhibitor with both lenvatinib and cabozantinib showed a highly synergistic effect and no development of drug resistance i.e. durable response versus single TKI therapy. Ongoing mechanistic studies are examining whether known molecular targets of tested TKI’s such as VEGFR1, 2, and 3, PDGFRα, FGFR, KIT, and RET dominate in HCC drug resistance to lenvatinib and cabozantinib, and how the use of SSI-4 overcomes the phenomenon of resistance. Citation Format: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew L. Pawlush, Ahmet Bilgili, Peyton G. Hickman, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, Han W. Tun, John A. Copland. Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5489.

3542 Background: Solid tumors can be characterized by distinct immune phenotypes based on the level of T cell infiltration in the tumor microenvironment (TME) which may provide prognostic information and also inform strategies to restore the anti-tumor immune response. Immune phenotypes were determined using an artificial intelligence (AI) algorithm in digitized whole-slide images (WSI) of tumors with deficient (d) mismatch repair (MMR) vs proficient (p) MMR. Methods: Stage III colon carcinomas (N = 401; 393 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy were analyzed including all available tumors with dMMR (n = 196) and a randomly selected cohort of pMMR tumors (n = 195). Using an AI algorithm (Lunit SCOPE) previously trained on solid tumors, digitized tumors were categorized into three immune phenotypes based on epithelial and stromal TIL data-driven cutpoints in dMMR and pMMR (inflamed: TIL high in epithelium (> upper 25%); excluded: TIL high in stroma (>lower 25%), low in epithelium; and desert: TIL low in epithelium and stroma). Phenotypes were then examined in relationship to disease-free survival (DFS) using Kaplan-Meier methodology. Results: Of the 3 immune phenotypes in dMMR tumors, 25% were inflamed, 50% were immune-excluded, and 25% were immune-desert. Based on univariate results, multivariable modeling was performed incorporating immune phenotype in addition to age, histological grade, N stage, T stage, performance status, treatment arm, BRAF and KRAS status and identified immune phenotypes and N stage to be significantly associated with DFS. Among dMMR tumors, immune desert phenotype was associated with the poorest DFS (Desert: HR adj 1.95, 95%CI (1.01, 3.80); Excluded: HR adj 0.89, 95%CI (0.47, 1.69); Inflamed: ref; p:0.01). When compared to immune desert tumors, immune-excluded tumors had significantly better DFS (HR adj 0.49, 95%CI (0.27, 0.88), p:0.01). At a median follow-up of 60 months, 3-year DFS of patients with dMMR was 71.2% with Immune inflamed, 78.5% with Excluded, and 54.5% with Desert phenotypes. In contrast to dMMR, univariate analyses of data-driven cutpoints in pMMR tumors was not prognostic. Using a different data-driven cutpoint (15%), the revised immune phenotypes remained non-significant for DFS within pMMR tumors. Conclusions: Distinct AI-derived immune phenotypes in the TME were identified that were significantly prognostic in patients with dMMR, but not pMMR colon cancers. A data-driven immune-desert phenotype was identified in dMMR tumors that was associated with significantly poorer survival. Further investigation of the potential predictive utility of these phenotypes for immunotherapy are planned. Support: https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 .

3527 Background: Advances in deep learning may improve the ability to evaluate and quantify pathological features in solid tumors to improve prediction of patient disease-free survival (DFS). We used an artificial intelligence (AI) algorithm to quantify morphological features in the tumor microenvironment of stage III colon cancers. Methods: We analyzed digitized stage III colon carcinomas (N = 402; 382 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy that included all available tumors with dMMR and a randomly selected cohort of pMMR tumors (median follow-up 60 months) [NCCTG N0147; Alliance for Clinical Trials in Oncology]. Fifteen morphological features were extracted using the QuantCRC algorithm that segments images into carcinoma (low-grade, high-grade, signet ring cell), stroma (immature, mature, and inflammatory), mucin, tumor/stroma ratio, tumor budding/poorly differentiated clusters (TB/PDC), necrosis, smooth muscle, fat, and tumor-infiltrating lymphocytes (TILs) and tumor area (mucin, epithelium and TB/PDC). Analysis of AI-derived features with clinical variables, molecular alterations ( BRAF/KRAS), and DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Among the 15 AI-derived morphological features, the following differed significantly between dMMR (n = 191) and pMMR (n = 189) whereby dMMR tumors had lower mature stroma, but higher inflammatory stroma and tumor, higher tumor grade and increased mucin, TB/PDCs, signet ring cells, and TILs (all p< 0.05). Among dMMR tumors, multivariable analysis revealed that tumor area [mucin, epithelium and TB/PDC] (HR adj 0.45, 95%CI (0.24, 0.84), p:0.01, [Q2/3 vs Q1]) and N stage were the only significant and independent prognostic variables. Among pMMR tumors, multivariable analysis identified that tumor budding/poorly differentiated clusters (TB/PDCs) (HR adj 0.20, 95%CI (0.06, 0.61), p:0.01, [Q1 vs Q4]) was the strongest prognostic variable and the only morphological feature that was significantly associated with DFS along with age, N stage and T stage. Conclusions: Using AI, we can extract and quantify distinct morphological features in tumor sections that differ between dMMR and pMMR and multivariately, can significantly and robustly enhance prognostication within each MMR group. Among pMMR tumors, tumor budding/poorly differentiated clusters was the strongest predictor of DFS. Support: NIH U10CA180821, U10CA180882, U24CA196171, R01 CA210509 (to FAS). Study NCCTG N0147 received funds from Sanofi https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 Key words Artificial Intelligence; Tumor Microenvironment; Colonic Neoplasms; Disease-free survival.

e16259 Background: Patients with KRAS mutant (mt) pancreatic ductal adenocarcinoma (PADC) have worse survival outcomes compared to KRAS wild-type (wt) PDAC patients. However, the prognostic implication of the KRAS mutation subtype (e.g. G12D, G12R, G12V and Q61) remains unclear. Furthermore, the clinical and molecular characteristics associated with these mutation subtypes remain not well defined. Methods: A retrospective review was conducted on patients with KRAS PDAC who underwent Next Generation Sequencing at Mayo Clinic between December 1, 2018 and December 1, 2021. Their somatic mutations, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcomes were collected via chart review. Results on KRAS wt were reported previously; KRAS mt are reported here. Results: A total of 158 KRAS mt patients (at diagnosis: average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months, unadjusted hazard ratio (HR) 0.68, p=0.05), particularly in patients with localized disease at diagnosis (median 35.4 vs 28.3 months, p=0.08). Among patients with metastatic disease at diagnosis, G12V had the lowest OS (median 9.8 vs 12.4 months, unadjusted HR 1.8, p=0.02). 137 (87%) patients had at least one pathogenic somatic variant, with statistically significant differences in SMAD4, TP53, MYC, RB1, KMT2D, RBM10, RNF43, KDM6A, KMT2C, RBM10, LRP1B, PIK3CA, and SMARC among the KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant, with statistically significant differences in CCND1, CCNE1, HRAS, MET, EGFR, and ERB3 among KRAS mt subtypes. Between these subtypes, there were no statistically significant differences in TMB value, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, or gender. Conclusions: KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes. To further examine this, transcriptomic analysis is underway. [Table: see text]