Tumor KRAS Status Research Articles

Prospective, Observational Study of Aflibercept Use in Combination with FOLFIRI in Patients with Metastatic Colorectal Cancer: A Real-World Effectiveness Study.

This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9-9.9] and 27.0 months [95% CI, 23.9-30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed.

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.

SBRT with ipilimumab and nivolumab to metastatic MSS colorectal and pancreatic cancer: A pooled analysis of four prospective phase II trials.

752 Background: The role of immunotherapy (IO) in microsatellite stable (MSS) pancreatic and colorectal cancer is limited. Stereotactic body radiation therapy (SBRT) is increasingly used in the limited metastatic setting, however its use with IO remains an area of investigation for both target response and overall systemic response. Here we evaluate the local failure rate of irradiated target lesions with and without IO. Methods: We pooled four prospective phase II single-arm studies of patients with metastatic MSS colorectal or pancreatic cancer treated with SBRT alone or with IO. Those in the first study (NCT01239381) received ablative liver SBRT to a maximum biologically effective dose (BED) of 48-100 Gy. Patients in the remaining studies received low dose SBRT to liver, lung, or nodal metastases with 24 Gy in 3 fractions to a BED of 43.2 Gy in combination with Ipilimumab and Nivolumab during the first (NCT04361162, NCT04575922) or second (NCT03104439) cycles. Local failure rates at the time of first progression were estimated by the cumulative incidence with non-target progression only and death as competing risks and compared using Gray’s test. The best response at the target was measured with the RECIST 1.1 criteria using the largest reduction in target size during follow up. Fisher’s exact test was used to compare objective response (ORR) and disease control rates (DCR), while the Wilcoxon rank sum test was performed to compare target size and percentage of tumor reduction. Results: Across all four studies there were 154 evaluable patients including 50 who received ablative SBRT and 104 patients who received low dose SBRT with IO. There were 92 patients with colorectal and 62 with pancreatic cancer. Median target size was 3.7 cm in the ablative SBRT group and 2.8 cm in the IO group (P=0.04). The 6-month, 1-year, and 2-year local failure rates were 10%, 18%, and 20% respectively following ablative SBRT and 24%, 25%, and 26% following low dose SBRT with IO (P=0.32). The ORR was 50.0% with SBRT alone and 23.1% with the addition of IO (P=0.001). There was no significant difference in the DCR (80.0% vs. 68.3%, P=0.18). The percent decrease in size was significantly higher in those with ablative SBRT (median -53.0% vs. -10.6%, p=0.02). There was no difference in the percent tumor response with respect to primary tumor type (P=0.13), KRAS (P=0.11) or TP53 (P=0.27) status. Conclusions: Despite the use of low dose SBRT with immune checkpoint inhibitors, there was no significant difference in local failure rates compared to ablative SBRT. Ablative SBRT dosing yielded a significantly higher depth of response. As clinical and preclinical studies suggest liver metastases are less responsive to IO, understanding dose and fractionation schemas for optimal local control is critical. Further studies are needed to explore the radiation dose with regards to local control when delivered with IO.

Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts.

The associations of vitamin C intake with colorectal cancer (CRC) survival according to tumour KRAS or BRAF mutation status remain unclear. We used the inverse probability weighted multivariable Cox proportional hazards regression model to calculate the hazard ratio (HR) of mortality, and spline analysis to evaluate the dose-response relationship in the Nurses' Health Study and Health Professionals Follow-up Study. We also assessed SLC2A1 mRNA expression according to KRAS or BRAF mutation in the TCGA database. During an average of 12.0 years of follow-up, we documented 2,096 CRC cases, of which 703 cases had KRAS and BRAF mutation data. The association between total vitamin C intake and CRC-specific mortality suggestively differed according to KRAS or BRAF mutation status (Pinteraction = 0.04), with the multivariable HR (95% CI) per 400 mg/day increase in vitamin C intake for CRC-specific mortality of 1.07 (0.87-1.32, Ptrend = 0.52) in cases with both wild type and 0.74 (0.55-1.00, Ptrend < 0.05) in cases with either KRAS or BRAF mutant type. TCGA analysis showed a higher mRNA SLC2A1 expression in KRAS or BRAF-mutated tumours than in wild-type tumours (P = 0.02). Our findings support the laboratory evidence for a potential benefit of vitamin C for CRC patients with KRAS or BRAF mutated tumours.

AN OMNIBUS TEST FOR DETECTION OF SUBGROUP TREATMENT EFFECTS VIA DATA PARTITIONING.

Late-stage clinical trials have been conducted primarily to establish the efficacy of a new treatment in an intended population. A corollary of population heterogeneity in clinical trials is that a treatment might be effective for one or more subgroups, rather than for the whole population of interest. As an example, the phase III clinical trial of panitumumab in metastatic colorectal cancer patients failed to demonstrate its efficacy in the overall population, but a subgroup associated with tumor KRAS status was found to be promising (Peeters et al. (Am. J. Clin. Oncol. 28 (2010) 4706-4713)). As we search for such subgroups via data partitioning based on a large number of biomarkers, we need to guard against inflated type I error rates due to multiple testing. Commonly-used multiplicity adjustments tend to lose power for the detection of subgroup treatment effects. We develop an effective omnibus test to detect the existence of, at least, one subgroup treatment effect, allowing a large number of possible subgroups to be considered and possibly censored outcomes. Applied to the panitumumab trial data, the proposed test would confirm a significant subgroup treatment effect. Empirical studies also show that the proposed test is applicable to a variety of outcome variables and maintains robust statistical power.

KRAS mutation status between left- and right-sided colorectal cancer: are there any differences in computed tomography?

To investigate the differences in clinicopathological and imaging features according to KRAS mutation status in left- and right-sided colorectal cancer. A total of 157 patients with pathologically proven colorectal cancer and preoperative contrast-enhanced multidetector CT examinations were enrolled. According to the tumor location and KRAS status, they were divided into two groups: the left-sided colorectal cancer (LCC) group (wild type, mutant type) and the right-sided colorectal cancer (RCC) group (wild type, mutant type). Clinicopathological and imaging features were recorded in each group. The imaging observation indicators included short axis diameter (SAD), longitudinal tumor length (LTL), tumor shape, pericolic fat stranding, bowel stenosis, intratumoral low-density range, enhancement pattern, and bowel obstruction. Univariate and multivariate logistic regression analyses were performed to compare the difference in KRAS mutation status between groups. In the LCC group, SAD, tumor shape, degree of pericolic fat stranding, and bowel obstruction were significant indicators for predicting KRAS status (P < 0.05). In the RCC group, CA19-9, SAD, and intratumoral low-density range were significant indicators for predicting KRAS status (P < 0.05.). The area under the curve (AUC) of the combination image indicators in the LCC group was 0.802 [cutoff point 0.372, 95% confidence interval (CI) 0.718-0.888, sensitivity 85.4%, specificity 72.0%]. The AUC in the RCC group was 0.828 (cutoff point 0.647, 95% CI 0.726-0.931, sensitivity 79.5%, specificity 75.0%). The CT imaging features associated with KRAS mutation status in the LCC and RCC groups were different. The combination of tumor location and imaging features can help to further improve the predictive value of KRAS status.

Comparison of SBRT for Oligometastatic Colorectal Cancer by Site: Lung vs. Liver

<h3>Purpose/Objective(s)</h3> We seek to report patient outcomes following Stereotactic Body Radiotherapy (SBRT) to the lung and liver for oligometastatic colorectal cancer (oCRC), and identify differences by tumor site and KRAS status. <h3>Materials/Methods</h3> An IRB-approved prospective registry of 2138 lung SBRT patients and 294 liver SBRT patients was surveyed for patients with oCRC (defined as ≤ 5 lesions) involving the lung or liver treated with SBRT from 2005 to 2020. Patient, tumor, and treatment factors were analyzed. Actuarial rates for local control (LC), first local, regional or distant failure (TTFF), and overall survival (OS) were evaluated. Univariate analysis of outcome by KRAS status was conducted. <h3>Results</h3> 86 patients met study criteria, with 61 having lung, 24 patients having liver, and 1 patient having lung and liver SBRT. Median follow up was 24.8 months. Median age was 65.9 years (range 36.4 – 89.7), 63.9 for lung and 72.5 for liver (<i>P</i> = 0.022). 56.3% of patients were male, 48.4% for lung and 76% for liver (<i>P</i> = 0.018). Median KPS was 90 (range 70 – 100). 21.0% of lung patients had prior metastasis-directed therapy (MDT) (wedge resection, lobectomy). 60.0% of liver patients had prior MDT (surgery, bland embolization, RFA, Y-90). Mean liver lesion size (2.92 cm) was larger than mean lung lesion size (1.69 cm) (<i>P</i> < 0.0001). SBRT dose was 30 – 60 Gy in 1 – 8 Fx, with median dose of 50 Gy in 5 Fx for both lung and liver. 36% of patients were treated to 2+ synchronous lesions. 14% of patients had further SBRT to metachronous lesions. KRAS status was known for 71.3% of patients, 67.8% for lung, 80% for liver. Of those, KRAS mutation was present in 48.4% of patients, 47.6% for lung and 50% for liver. LC at 1 and 2 years was 87.9% (95% CI: 80.4 – 95.3) and 78.0% (95% CI: 68.1 – 88.0), respectively. OS at 1 and 2 years was 88.3% (95% CI: 81.5 – 95.1) and 74.1% (95% CI: 64.6 – 83.7), respectively. Median OS for all patients was 51.5 months, 59.0 months for lung and 19.5 months for liver (<i>P</i> < 0.0001). There was a statistically significant difference on log rank test between the lung and liver cohorts in both local control (<i>P</i> = 0.008) and overall survival (<i>P</i> < 0.0001), see table. Median TTFF was 12.4 months for all patients, 14.3 months for lung and 5.1 months for liver patients (<i>P</i> = .690). There were no differences in LC or OS by KRAS status across all patients (<i>P</i> = .124 and <i>P</i> = .923 respectively), or for lung SBRT (<i>P</i> = .811 and <i>P</i> = .455 respectively), or liver SBRT (<i>P</i> = .167 and <i>P</i> = .247, respectively). <h3>Conclusion</h3> Local control and overall survival with SBRT for oCRC were inferior in the liver compared to lung, likely due to larger lesion size, more extensive prior therapy, and more advanced age in the liver cohort. There were no differences in outcomes by KRAS status.

Nutrient-Dependency of CendR Endocytosis Pathway is Uniquely Regulated by Mutant Kras and Targetable

Kras is the hallmark mutation of Pancreatic Ductal Adenocarcinoma (PDAC) and reprograms tumor metabolism towards glycolysis. Evolutionarily, PDAC instigates diabetes to increase glucose concentrations and fuel tumor growth. The C-end Rule (CendR)-pathway mediates nutrient endocytotic transcytosis and trans-tissue molecular transport. A discrepancy exists in that the CendR pathway is primed to high activity when glucose is low. Ongoing PDAC clinical trials utilize tumor-penetrating peptides (iRGD) to activate the CendR-pathway and dispense cargo. Here, we determine how glucose metabolism changes based on tumor Kras-status might affect the CendR pathway and hijack it to deliver therapy. Under diabetic-like conditions, iRGD increases its penetration and spread throughout patient-derived and mouse PDAC. Importantly, all CendR peptides delivered higher concentrations of co-administered therapeutic cargo in a glucose-dependent manner. Neuropilin-1 (NRP-1), the receptor for peptide-mediated activation of the CendR pathway, is expressed in greater abundance under high glucose concentrations in parallel with glycolytic machinery. Hypoglycemic Kras-mutant tumors, hyperglycemic Kras-wildtype tumors, and inhibition of the mitogen-activated protein kinase (MAPK) pathway all suppressed NRP-1, CendR-peptide transport, and cargo uptake. Overall, mutant Kras enhances CendR peptide-directed cargo delivery in glycolytic metabolic environments via NRP-1 expression. Manipulating patient blood glucose levels may enhance CendR-based targeting of therapeutics into Kras-mutant tumors.

MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors.

3004 Background: HER2 ( ERBB2) amplification and/or overexpression is observed in 2–3% of solid tumors, and is often associated with more aggressive disease. Thus far, HER2-targeted therapies are FDA-approved only for breast, gastric, and gastroesophageal cancers. MyPathway (NCT02091141) is a non-randomized, phase 2a multi-basket study assessing the activity of FDA-approved targeted therapies in non-indicated advanced solid tumors with relevant molecular alterations. We report results from the MyPathway HER2 basket, comprising a large, tissue-agnostic cohort of patients (pts) with HER2-altered tumors treated with P + H. Methods: Pts in this analysis were aged ≥18 years and had HER2-amplified and/or overexpressed tumors. Pts received P (840-mg IV loading dose, then 420-mg every 3 weeks [q3w]) + H (8-mg/kg IV loading dose, then 6-mg/kg q3w). The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Other endpoints included disease control rate (DCR, defined by objective response or stable disease &gt;4 mos) and duration of response (DOR). Subgroup analyses were completed by tumor type and KRAS status. Results: Pts were fully enrolled from April 14, 2014 to June 15, 2020. By January 22, 2021, 260 pts were efficacy-evaluable. Confirmed ORR (cORR) was 23.1% (60/260, including 5 complete responses; 95% confidence interval [CI] 18.1–28.7), DCR was 44.2% (115/260, 95% CI 38.1–50.5), and median DOR was 7.9 mos (95% CI 6.2–9.3). In 199 pts with wild-type KRAS tumors, cORR was 25.6% (51/199, 95% CI 19.7–32.3), DCR was 48.7% (97/199, 95% CI 41.6–55.9), and median DOR was 8.3 mos (95% CI 6.2–10.8). In comparison, in 26 pts with KRAS-mutated tumors, cORR was 3.8% (1/26, responder had colorectal cancer; 95% CI 0.1–19.6), DCR was 3.8% (1/26, 95% CI 0.1–19.6), and DOR was 2.7 mos. KRAS status was unknown in 35/260 pts (cORR 22.9% [8/35, 95% CI 10.4–40.1]; median DOR 6.7 mos [95% CI 2.5–12.7]). Clinical outcomes by tumor type are shown in the Table. Conclusions: P+H was active in a wide variety of KRAS wild-type HER2-amplified/overexpressed tumor types, but had limited activity in KRAS-mutated tumors. Clinical trial information: NCT02091141. [Table: see text]

Pretreatment Apparent Diffusion Coefficient Cannot Predict Histopathological Features and Response to Neoadjuvant Radiochemotherapy in Rectal Cancer: A Meta-Analysis

Aim: Our purpose was to perform a systemic literature review and meta-analysis regarding use of apparent diffusion coefficient (ADC) for prediction of histopathological features in rectal cancer (RC) and to prove if ADC can predict treatment response to neoadjuvant radiochemotherapy (NARC) in RC. Methods: MEDLINE library, EMBASE, Cochrane, and SCOPUS database were screened for associations between ADC and histopathology and/or treatment response in RC up to June 2020. Authors, year of publication, study design, number of patients, mean value, and standard deviation of ADC were acquired. The methodological quality of the collected studies was checked according to the Quality Assessment of Diagnostic Studies instrument. The meta-analysis was undertaken by using the RevMan 5.3 software. DerSimonian and Laird random-effects models with inverse-variance weights were used to account the heterogeneity between the studies. Mean ADC values including 95% confidence intervals were calculated. Results: Overall, 37 items (2,015 patients) were included. ADC values of tumors with different T and N stages and grades overlapped strongly. ADC cannot distinguish RC with a high- and low-carcinoembryonic antigen level. Regarding KRAS status, ADC cannot discriminate mutated and wild-type RC. ADC did not correlate significantly with expression of vascular endothelial growth factor and hypoxia-inducible factor 1a. ADC correlates with Ki 67, with the calculated correlation coefficient: −0.52. The ADC values in responders and nonresponders overlapped significantly. Conclusion: ADC correlates moderately with expression of Ki 67 in RC. ADC cannot discriminate tumor stages, grades, and KRAS status in RC. ADC cannot predict therapy response to NARC in RC.

Trifluridine/tipiracil: A practical guide to its use in the management of refractory metastatic colorectal cancer in Australia.

Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.

LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target.

We performed a prospective immunohistochemical analysis of lymphocyte activation gene 3 (LAG3) for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic cancer (33.3%, 2/6), gastric cancer (24.7%, 21/85), colorectal cancer (23.6%, 48/203), melanoma (12.5%, 1/8), genitourinary cancer (9.5%, 4/46), biliary tract cancer (6.3%, 1/16), and sarcoma (5.4%, 2/37), but not miscellaneous (0.0%, 0/14) or hepatocellular (0.0%, 0/15) cancer. Among 149 metastatic colorectal cancer patients, there was no statistically significant difference in sex, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. nonexpressed). Among 53 metastatic gastric cancer patients, LAG3 was only significantly associated with Epstein Barr virus status (P=0.042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy.

Evaluating the Impact of Combination of Nivolumab and Ipilimumab to Liver/Lung SBRT on Local Control for Colorectal and Pancreatic Cancer: A Pooled Analysis of Two Prospective Trials

Immunotherapy (IO) has emerged as an effective treatment option for many metastatic cancers, however, its role in pancreatic or colorectal cancer is limited to those with microsatellite instability. It has been suggested that radiation (RT) and combination IO may work synergistically to increase the immune system’s exposure to tumor antigens, potentiating an abscopal effect. However, the impact of combination IO to stereotactic body radiation therapy (SBRT) on local control of irradiated lesions has not been elucidated. In this study, we combined two prospective phase II single arm studies to compare the impact of SBRT alone (NCT01239381) or with PD-L1/CTLA4 blockade (NCT03104439) on the growth of colorectal and pancreatic liver and lung metastases. Eligible patients had metastatic colorectal or pancreatic adenocarcinoma. Those treated on NCT01239381 received liver SBRT alone (30-50 Gy in 5 fractions), while those on NCT03104439 received combination IO 6 weeks prior to and concurrently with 24 Gy in 3 fractions to liver or lung metastases. Tumor genotyping was performed to assess for KRAS and TP53 mutations. Target lesions were measured on CT scans prior to and following RT. Peak response was measured via modified RECIST criteria as the largest tumor reduction at any time. Wilcoxon Rank Sum tests were performed to evaluate % tumor reduction with regards to combination IO, primary tumor site, metastasis site, and KRAS and TP53 mutation status. There were 50 eligible patients from NCT01239381 and 41 from NCT03104439, of whom 42 and 39 were evaluable, respectively. Of these 81 patients, 52 and 29 had colorectal and pancreatic cancer, respectively. Of those with molecular analysis, 50% (33/66) had a KRAS mutation and 55% (34/61) had a TP53 mutation. Median follow up was 78 days in the IO arm (driven by distant progression) and 160 days in the non-IO arm (P<0.0001). Mean BED in the IO arm was 43.2 Gy vs. 79.6 Gy in the SBRT alone arm (P<0.0001). Mean target size was 3.8 cm in the IO arm, and 5.0 cm in the SBRT alone arm (P=0.12). There was no difference with respect to overall response rate (38.5% vs. 52.4%, P=0.27) and disease control rate (92.3% vs. 92.9%, P>0.99). There was no significant difference in the % tumor reduction between the IO and non-IO arms (-21% vs. -41%, P=0.08). Among the entire cohort, there was no significant difference in response of irradiated lesion with respect to primary tumor type (P= 0.54), KRAS status (P=.67), TP53 status (P=0.10), or metastatic site (P=0.58). Despite receiving approximately half the BED dose compared to liver SBRT alone, patients treated with IO and RT had similar response rates, suggesting a potential synergistic effect in the irradiated lesions. Future studies should look to validate these findings and explore optimal RT dose/fractionation schemas in combination with IO. These results support ongoing randomized studies of IO with RT in locally advanced rectal (NRG GI002) and pancreatic (NCT03563248) cancers.

Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies

BackgroundMicrosatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. Patients and methodsPatients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. ResultsAmong 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19–85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69–0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58–1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73–2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67–4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. ConclusionsIn stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. Trial identification numbersNCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.

Circulating T cell subsets are associated with clinical outcome of anti-VEGF-based 1st-line treatment of metastatic colorectal cancer patients: a prospective study with focus on primary tumor sidedness

BackgroundIn a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen.MethodsThe study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8+ T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).Results1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8+ cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4+ subset. 2) A low proportion of circulating Tregs among CD4+ cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high.ConclusionsThe baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.

Abstract 1107: LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target

Abstract We performed prospective immunohistochemical analysis of LAG3 for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic (33.3%, 2 of 6), gastric (24.7%, 21 of 85), colorectal (23.6%, 48 of 203), melanoma (12.5%, 1 of 8), genitourinary (9.5%, 4 of 46), biliary tract (6.3%, 1 of 16), and sarcoma (5.4%, 2 of 37), but not miscellaneous (0.0%, 0 of 14) or hepatocellular (0.0%, 0 of 15) cancer. Among 149 metastatic CRC patients, there was no statistically significant difference in gender, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. non-expressed). Among 53 metastatic GC patients, LAG3 was only significantly associated with EBV status (P = .042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy. Citation Format: Su Jin Lee, Sun-ju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoung-Mee Kim, Seung Tae Kim. LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1107.

Apatinib combined with Raltitrexed in patients with metastatic colorectal cancer after failure of standard therapy (AHEAD-311): A single-arm phrase II pilot trial.

e15008 Background: To assess the safety and efficacy of apatinib, an oral vascular endothelial growth factor receptor-2 inhibitor, combined with thymidylate synthase inhibitor raltitrexed in patients with metastatic colorectal cancer (mCRC) as a third- or later-line therapy. Methods: Patients with mCRC after at least 2 lines of chemotherapy were enrolled whenever they previously treated with bevacizumab or not. Apatinib was given orally at 250mg or 500mg daily. Raltitrexed was administered intravenously at 3 mg/m2 on day 1 every 3 weeks. The primary endpoints were progression-free survival (PFS). The second endpoints were objective response rate (ORR), overall survival (OS) and safety. Results: From August 2017 to November 2018, thirty-one patients were enrolled in Chinese PLA General Hospital. After a median follow-up of 6.4 months, the median treatment cycle was 4. four patient achieved partial response(PR), and 11 patients achieved stable disease (SD) and 16 achieved progression disease (PD) in accordance with RECIST version 1.0, illustrating a DCR of 48.4% and an ORR of 12.9% .The Median PFS was 2.4 months and the median OS was 6.4 months. The most common adverse events were hypertension (n=12, 38.7%), nausea and vomiting (n=11, 33.8%), myelosuppression (n=9, 29.0%). The most common grade 3 to 4 adverse events were hypertension (n=2, 6.4%) and hand-foot syndrome (n=2, 6.4%). Grade 3 to 4 hematologic toxicities were rare. One patient died from cardiac arrest after three days treatment. There was no significantly association between PFS or OS, and clinical features including tumor location, KRAS status, and prior surgery or not, and number of metastatic organs. There was no trend showing patients who experienced had hypertension or myelosuppression had longer PFS and OS. Compared to the patients never received bevacizumab, the patients who had previously bevacizumab had the similar PFS and OS (3.9 versus 2.3months, P=0.787; 6.1 versus 6.4months, P=0.287). Grade1-2 nausea and vomiting and age &lt;57 were independent predictors for longer PFS and OS. Conclusions: Apatinib combined with raltitrexed had efficacy but had limited survival benefit in mCRC refractory to standard chemotherapy. This regime showed us a higher risk of adverse event incidence and warrant further exploring of benefit population. Clinical trial information: NCT03344614 .

Metastatic Profile of Colorectal Cancer: Interplay Between Primary Tumor Location and KRAS Status

BackgroundMutant KRAS tumors are purported to metastasize differently than wild-type KRAS tumors. The biological heterogeneity of tumors from different parts of the colon are also reported to affect metastasis. This study aims to characterize the metastatic profile by evaluating these factors in unison. MethodsRetrospective analysis of 899 patients with metastatic colorectal cancers treated from January 2010 to December 2014 was conducted. KRAS mutation status and primary tumors location were correlated with single-site metastasis (liver, lung, and peritoneum) and dual-site metastases (liver-peritoneum, liver-lung, and lung-peritoneum). Patients without KRAS analyses were excluded. ResultsRight-sided tumors had highest frequency of peritoneal metastasis as compared to left-sided or rectal tumors (34.7% versus 15.8% versus 8.8%, P = 0.00) regardless of KRAS status (32.6% versus 38.5%, P = 0.62). Left-sided tumors with wild-type KRAS had greater proportion of liver metastasis (78.6% versus 53.5%, P = 0.00), whereas those with mutant KRAS had greater proportion of lung metastasis (23.3% versus 8.7%, P = 0.02). Rectal tumors with wild-type KRAS tend to spread to the liver (81.4% versus 48.0%, P = 0.00) and not to the peritoneum (2.3% versus 20.0%, P = 0.01). In dual-site metastases, left-sided tumors with wild-type KRAS had more liver-peritoneal metastases (75.0% versus 29.4%, P = 0.00), whereas mutant KRAS had greater lung-liver metastases (64.7% versus 20.8%, P = 0.01). Rectal tumors had the predilection for lung-liver metastases as compared to right-sided and left-sided tumors (92.3% versus 40.0% versus 39.0%, P = 0.00) regardless of KRAS status (100% versus 75%, P = 0.12). ConclusionsOur results may streamline surveillance programs based on primary tumor location and KRAS mutational status.

Surgical margins and risk of local recurrence after wedge resection of colorectal pulmonary metastases

ObjectiveDuring resection of pulmonary metastases, the need to spare lung parenchyma is often weighed against the increased risk of local recurrence if an inadequate surgical margin is obtained. We sought to identify risk factors for local recurrence after wedge resection of pulmonary metastases of a colorectal origin. MethodsA retrospective study of patients who underwent a wedge resection for colorectal pulmonary metastases from 2006 to 2016 was performed. Cox regression with robust variance was used to estimate the risk of local recurrence per nodule treated. ResultsWe identified 335 patients who underwent 679 wedge resections. The 2-year local recurrence risk for each nodule was 11.8% (95% confidence interval, 8.9%-14.6%), and the 5-year risk was 20.6% (95% confidence interval, 16.2%-24.8%). Longer margin length decreased the risk of local recurrence (hazard ratio, 0.434 per additional cm of length; P = .015), whereas larger tumor size increased this risk (hazard ratio, 1.520 per additional cm of size; P = .012). However, other factors tested, including tumor grade, KRAS mutation status, and response to induction chemotherapy, did not affect recurrence risk. A pathologic margin length of at least half the tumor size was estimated to result in a local recurrence rate <11%. ConclusionsAmong surgically resected colorectal pulmonary metastases, technical factors related to margin length and tumor size were associated with the risk of local recurrence, whereas tumor grade and KRAS status were not. However, the increased risk of local recurrence with larger tumors was diminished with a sufficient margin length.

162P - Real world use of palliative systemic therapy (tx) in elderly patients (pts) with metastatic colorectal cancer (mCRC) within a UK specialist cancer centre

Background: Given our ageing population, in mCRC, we are increasingly faced with the challenge of treating elderly pts. Real world evidence relating to the efficacy and tolerability of systemic tx in this specific group is lacking. Methods: Retrospective analysis of pts with mCRC age>70, treated with systemic tx at Royal Marsden Hospital (RMH) between Jan 2009 – Dec 2014 was conducted. Results: Out of 134 pts presenting with mCRC, 63% were male, median age 77 (range 70-94). 18% had performance status (PS) 0, 55% PS 1, 22% PS 2, 5% PS ≥ 3. 40% of pts had no comorbidities listed in the Charlson comorbidities index (CCI), whereas 23% had ≥2. 10% of pts did not take any concomitant medication (con mx), whereas 34% took ≥5. 72% of pts lived with family, 25% alone, 1% in a nursing home and 2% unknown. 71% had left-sided tumours. 73% had liver, 34% lung and 13% peritoneal metastases. From 82 pts with known KRAS status, 41% were mutant. When including pts with a recurrence that had palliative systemic tx (n = 163), the most commonly prescribed tx were: 18% CAPOX, 12% FOLFIRI, 11% capecitabine or 5FU alone and 9% FOLFIRI+Bevacizumab. Across all lines of tx 44% required ≥1 week tx delay. In 46% of cases a dose reduction or drug discontinuation in combination tx was required. Median overall survival (mOS) for pts presenting with mCRC was 16.7 months (95% C.I=13.7-20.7). Pts that had sequential systemic tx had a significant OS benefit, p < 0.005 (table). Poor PS and more con mx predicted for a statistically lower mOS (p < 0.005). Primary tumour location, KRAS status, social circumstances and number of comorbidities listed in CCI had no significant impact on mOS.Table: 162PMetastatic tx line1234N163823916Median PFS, months7.34.85.42.7Best response (%)CR 2 PR 33 SD 24 PD 27 NA 14CR 1 PR 27 SD 24 PD 34 NA 14CR 0 PR 23 SD 23 PD 39 NA 15CR 0 PR 13 SD 25 PD 31 NA 31mOS from diagnosis if last line of tx: months10.818.135.840.3 Open table in a new tab Conclusions: A significant number of older pts have no or few comorbidities and a good PS. These pts benefit from sequential systemic tx, including standard combination tx. Close supervision during tx is imperative, given the high rate of tx modifications. More real life data is needed to bridge the gap of the under-representation of elderly pts in clinical trials. Legal entity responsible for the study: Royal Marsden Hospital Funding: None Disclosure: All authors have declared no conflicts of interest.