Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's ...subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval CI 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.
Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a ...milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.
Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients.
A review of clinical trials, retrospective ...studies and case reports was performed regarding molecular biomarkers with therapeutic implications.
wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of
status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for
mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (
) mutant patients. Data are still lacking on
, and TGF-β, which require further research.
Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.
Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently, the RAS WT ...status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population.
CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status.
A total of 26 patients were included in our analysis. In the global population, RR was 25.0%, median overall survival (mOS) was 5.0 months, and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months, HR: 0.26,
= 0.048); anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months, HR: 0.27,
= 0.013 and not reached vs. 3.0 months, HR: 0.20,
= 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months, HR: 0.27,
= 0.013 and 13.0 vs. 5.0 months, HR: 0.20,
= 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month, HR: 0.05,
= 0.041) and with improved mOS (7.0 vs. 1.0 month, HR: 0.045,
= 0.034). In a multiple logistic regression model, only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS.
Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS, the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.
Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) ...and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.
e15575 Background: Even if anti-angiogenic agents are crucial for metastatic colorectal cancer (mCRC) patients (pts) treatment, to date, no validated prognostic biomarkers are available. We conducted ...at our Centre a retrospective research to identify a prognostic tool to be applied in clinical practice in this population. Methods: We retrospectively collected laboratory, radiological and clinical data of mCRC pts treated with anti-angiogenic agents at the Medical Oncology Unit of Cagliari University Hospital (2018- 02/2024) in order to identify a potential prognostic tool. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; cut-off: ROC curves; differences among variables: Chi-square test). Results: Globally, 33 mCRC pts were evaluated in our study (19 male, 14 female; 13 RAS wild-type, 22 left-sided primary). 10 were treated with anti-angiogenic drugs in the 1st-line, 13 in the 2nd-line (bevacizumab and aflibercept) and 10 in 1st-2nd line. Median OS was 39.5 months (m) (95%CI:28.2-41.3), median Progression Free Survival (PFS) was 14.9 m (95%CI:9.5-18.5). Pts with lower platelet to lymphocyte ratio (P; ≤253; p < 0.0001, HR = 0,00000048; 95%CI 24.7-39.5 versus vs 95% CI 8.2-10.5), alkaline phosphatase (A; < 136 U/l; p = 0.0001, HR = 0.0001; 95%CI 12-39.5 vs 95% CI 8.2-10.5) and lactate dehydrogenasis (L; < 365 U/l; p < 0.0001, HR = 0.0000004; 95%CI 24.7-39.5 vs 95% CI 8.2-10.5) and higher monocyte count (M; > 0.3x10 3 /μL; p = 0.0093, HR 0.01; 95%CI 26.5-39.5 vs 95%CI 8.2-24.7), showed a statistically improved OS. We created the “PALM score” and separated pts in two prognostic groups: good prognostic group (0 unfavorable variables: PALM = 0) and poor prognostic group (≥1 unfavorable variable, PALM = 1). OS was significantly improved in the good prognostic group (PALM = 0): 31.5 m (95%CI:24.7-39.5) vs 10.5 m (PALM = 1) (p = 0.0031, HR = 0.00006). Chi-square test revealed also a statistically significant correlation of upfront resection of primary tumor with the PALM score (73.9% of patients belonging to the PALM = 0 group had undergone surgery for primary tumor and all patients with resected primary belonged to the PALM = 0 group (p = 0.0352). Conclusions: Our research showed a promising prognostic role of easy-to-use PALM score tool in mCRC patients treated with anti-angiogenic drugs in a limited population at our center. Further prospective studies with larger sample size are needed to confirm our findings.
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Background: The standard treatment of locally advanced rectal cancer (LARC) consists of giving preoperative chemoradiation therapy (CT/RT) followed by surgery. Recently, total neoadjuvant therapy ...(TNT) has shown greater efficacy in terms of increasing the rate of complete pathological response (pCR) and reducing local and systemic relapse. However, based on the proposed therapy scheme, the risk of overtreatment and side effects is not negligible. The objective of this study was to evaluate the efficacy and safety of neoadjuvant doublet with oxaliplatin-based CT and concomitant RT. Methods: Patients with clinically staged II-III rectal cancer were treated with preoperative CT/RT using up to 3 cycles of oxaliplatin and fluoropyrimidine plus pelvic radiation daily, for a total dose of 46.2 Gy in 18 fractions. The first cycle of mXELOX (oxaliplatin 85 mg/m2 D1 Q14 plus capecitabine 825 mg/m2 BID) was administrated before RT (as induction CT); the other 2 cycles of mXELOX were administrated concurrent with RT, with capecitabine continued until the end of RT. Radical resection was performed within median 11 weeks of the last dose of RT. Adjuvant CT with FOLFOX or XELOX was administered according to pathological report. Results: Between 2007 and 2022, a total of 186 patients were enrolled, mean age was 61 years. 19 (10.2%) patients were clinically stage II and 167 (89.8%) were clinically stage III. Any grade most common toxicities during neoadjuvant CT/RT included diarrhea (53.2%), proctitis (51.2%) and neutropenia (14.5%). The most common grade 3/4 toxicity was diarrhea (9.1%). A total of 146 (78.5%) patients achieved a downstaging after CT/RT and 174 (93.5%) patients underwent surgery with R0 resection. Clinical meaningful surgical morbidities included infections (10.7%), anastomotic fistula (10.2%) and anastomotic leakage (7.5%). The pathological complete response (pCR) rate was 25.3%. Adjuvant CT was administered in 122 (65.6%) patients. Local recurrences and distant metastases were confirmed in 6 (3.2%) and 54 (29%) cases respectively. Median observation time, calculated with reverse Kaplan-Meier estimator, was 84 months and median overall survival (OS) was not reached. The estimated probability of OS (Kaplan-Meier method) at 3-5 years were 92.8% and 85.5% respectively. The median disease-free survival (DFS) was not reached and the estimated probability of DFS at 3-5 years were 74.7% and 69% respectively. Conclusions: Considering the low rate of toxicities and the comparable efficacy in terms of downstaging, pCR, probability of DFS and OS to other TNT regimens proposed in recent studies, our schedule of neoadjuvant CT/RT may represent a potential alternative to standard CT/RT in selected patients with LARC.
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Background: Anti-angiogenic drugs represent a cornerstone of metastatic colorectal cancer (mCRC) patients (pts) treatment. Currently, no prognostic/predictive biomarkers were validated to ...identify who is more likely to benefit from these agents. We performed at our Centre a retrospective research to assess potential prognostic/predictive factors in this population. Methods: We retrospectively collected laboratory, radiological and clinical data of mCRC pts receiving anti-angiogenic agents at the Medical Oncology Unit of Cagliari University Hospital (2018- 09/2023) in order to assess their correlation with overall survival (OS) and progression free survival (PFS) from the treatment start. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; cut-off: ROC curves). Results: Globally, 32 mCRC pts were included in our research (19 male, 13 female; 12 RAS wild-type, 21 left-sided primary). 10 received anti-angiogenic drugs in the 1st-line, 12 in the 2nd-line (bevacizumab and aflibercept) and 10 in 1st-2nd line. Median OS was 34.8 months (m) (95%CI:24.7-41.6). We observed a statistically significant improve in OS (34.8 months m versus vs 8.2 m) in pts with higher monocyte count (>0.3x10
3
/μL; 95%CI 26.5-39.5 vs 95%CI 8.2-24.7, p=0.0103, HR 0.01), lower alcalin phosphatase (ALP; <136 U/l; p=0.0001, HR=0.0001; 95%CI 12-39.5 vs 95% CI 8.2-10.4), lactate dehydrogenasis (LDH; <365 U/l; p<0,0001, HR=0.0000006; 95%CI 24.7-39.5 vs 95% CI 8.2-10.4) and platelet to lymphocyte ratio (PLR; ≤253; p<0.0001, HR= 0.00000062; 95%CI 24.7-39.5 vs 95% CI 8.2-10.4). Median PFS was 14.9 m (95% CI 9.5-18.5). The same factors were significantly related to PFS, which was 18.3 m vs 2.7 m for higher monocyte count (95%CI 11.4-22.1 vs 95%CI 2.7-14, p=0.0386, HR=0.05), lower LDH (95%CI 11.4-22.1 vs 95%CI 2.7-8.9, p=0.0024, HR=0.004), lower PLR (95%CI 11.4-22.1 vs 95%CI 2.7-8.9, p=0.0024, HR=0.004) and 18.3 m vs 8.9 m for lower ALP (95%CI 11.4-23.3, p=0.0369, HR=0.04). Furthermore pts not developing bleeding during treatment showed a significant benefit in OS (39.5 m 95%CI 26.5-41.6 vs 8.2 m 95%CI 8.2-12, p< 0.0001, HR 0.000001761) and improved PFS (17.9 m 95%CI 9.9-18.4 vs 2.4 m 95%CI 2.4-2.7; p<0.0001). Conclusions: Our findings showed a promising prognostic role of baseline monocytes, ALP, LDH and PLR and absence of bleeding occurrence in mCRC patients receiving anti-angiogenic drugs, even if in a limited population. Further larger prospective studies are encouraged for confirmation.
e24020
Background: Aging inevitably leads to an accumulation of senescent cells, and immune system cells aren't an exception. They can contribute to a pro-inflammatory state and be involved in the ...immune escape of cancer cells through a boosted PD-L1 expression. Immunocheckpoint inhibitors (ICIs) represent the standard of care in several cancer histotypes, and immune-related adverse events (irAEs) seem to be associated with better outcomes. ICIs represent a valid therapeutic agent in elderly patients too. However, there is a lack of data on irAEs and outcomes correlation in this subgroup of patients. This retrospective-prospective study aims to evaluate the relationship between thyroid dysfunction and progression-free survival (PFS) and overall survival (OS) in elderly patients undergoing ICIs. Methods: From January 2019 to January 2023, we retrospectively collected data from 65 elderly patients under treatment with ICIs at the Medical Oncology Unit of the University Hospital and University of Cagliari, Italy. All patients were affected by stage IV disease. The primary endpoint was PFS and the secondary endpoint was overall survival OS. Statistical analyses were performed using the MedCalc Statistical Software Version 20.216. Results: The median age was 76 (± 5,5); 15.38% were female, whereas 84.62% were male. The histologies were: melanoma (26.9%), lung cancer (48.0%), kidney cancer (15.3%), and colorectal cancer (9.8%). Compared to those without thyroid dysfunction during immunotherapy treatment, individuals with thyroid irAE had, at univariate analysis, longer median PFS (68 versus 26 months, p = 0.02, CI 95% 18.0-68.0, HR 0.29 0.10-0.83) and longer median OS (59 versus 39 months, p = 0.04, CI 95% 25.0-90.0 HR 0.50 0.25-0.99). Conclusions: In an era where biomarkers for immunotherapeutic agents are lacking, thyroid dysfunction irAE could be a predictive factor of better PFS and OS in elderly patients affected by cancer of various histology.
752
Background: Glucose and other metabolites (lactates and glutamine) in the tumor microenvironment (TME) may alter the activity of the immune system cells. Cancer cells consume glucose and its ...decrease in the TME affects the function of tumour-infiltrating lymphocytes (TILs). Moreover, tumor-infiltrated immunosuppressive cells and vascular endothelial cells also deplete nutrients, in the TME, enhancing an immunosuppressive environment. On the basis of the results coming from our previous works regarding lymphocytes to monocytes ratio (LMr) and diabetes, suggesting a role for each of them as predictors of better outcomes, in this study we evaluate both of them in order to establish a possible role of them as outcomes predictive factors. Methods: Data from 228 patients (pts) were collected retrospectively from 2016 to 2021: 175 from the Medical Oncology Unit of University Hospital of Cagliari; 53 from the Medical Oncology Unit, AOU Ospedali Riuniti di Ancona. All pts had stage IV disease and received gemcitabine plus nab-paclitaxel 1st line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between treated DM2 and lymphocytes to monocytes ratio (LMr) ≥ 4 with outcomes. Survival distribution was assessed by Kaplan-Meier curves. Multivariate analysis was performed taking into consideration the following prognostic factors: sex, ECOG-PS, LMr, NLr, LDH, Ca19.9, and metastatic sites. Results: Median age was 68 (±9), 123/228 (54%) were male, 94/232 (40,6%) were affected by DM2 (insulin or metfomin-treated) and 138 (59,4%) pts were not affected by DM2. 52/228 (23%) pts had a LMr ≥ 4, 176/228 (77%) pts had a LMr < 4. In multivariate analysis, DM2 and LM ratio ≥ 4 were found to be independent factors associated with higher overall survival. Therefore, we divided the pts into 3 groups: co-presence DM2 and LM ≥ 4 (DM+LM+); absence of DM2 and LM ≥ 4 (DM-LM-); presence of DM2 or LM ≥ 4 (DM+LM- or DM-LM+). DM+LM+ demonstrated statistically significantly higher median OS than DM+LM-/DM-LM+ and DM-LM- (not reached versus 21 versus 9 months, respectively, p < 0.0001). Furthermore, DM+LM+ showed a statistically significant better median PFS than DM+LM-/DM-LM+ and DM-LM- (11 versus 9 versus 6 months, respectively, p = 0,0036). Conclusions: Results showed a correlation between pts with DM2/LMr ≥ 4 and better outcomes. This may suggest the presence of a link between glucose metabolism and lymphocytes activation. Antidiabetic medications could promote the inhibition of Warburg effect in tumor cells, and, consequently, provide a better glucose intake to extracellular microenvironment, and immune cells, including T lymphocytes. This process leads to a higher activity of T-cells and a better treatment response. Further studies are warranted.
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