The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas.

Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS- and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.

Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer.

Current standard-of-care for metastatic colorectal cancer patients includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor for microsatellite stable tumors and pembrolizumab for microsatellite instable tumors. However, despite the available therapies, the prognosis remains poor. In recent years, new drugs combined with immune checkpoint inhibitors have been tested in microsatellite stable metastatic colorectal cancer patients, but the benefit was modest. Here, we review the metabolic interactions between the immune microenvironment and cancer cells. More specifically, we highlight potential correlatives of tumor immune and metabolic features with transcriptomic classifications such as the Consensus Molecular Subtype. Finally, we discuss the unmet need of immune-metabolic signatures and the value of a new signature (IMMETCOLS) for guiding new strategies in metastatic colorectal cancer. We conclude that the field is ready to propose customized strategies for modifying metabolism and improving immunotherapy and targeted therapy efficacy.

Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: A randomized controlled trial.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFß inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. METHODS: This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. RESULTS: One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. CONCLUSION: In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.

Time Interval Between the End of Neoadjuvant Therapy and Elective Resection of Locally Advanced Rectal Cancer in the CRONOS Study.

Importance: The treatment for extraperitoneal locally advanced rectal cancer (LARC) is neoadjuvant therapy (NAT) followed by total mesorectal excision (TME). Robust evidence on the optimal time interval between NAT completion and surgery is lacking. Objective: To assess the association of time interval between NAT completion and TME with short- and long-term outcomes. It was hypothesized that longer intervals increase the pathologic complete response (pCR) rate without increasing perioperative morbidity. Design, Setting, and Participants: This cohort study included patients with LARC from 6 referral centers who completed NAT and underwent TME between January 2005 and December 2020. The cohort was divided into 3 groups depending on the time interval between NAT completion and surgery: short (≤8 weeks), intermediate (>8 and ≤12 weeks), and long (>12 weeks). The median follow-up duration was 33 months. Data analyses were conducted from May 1, 2021, to May 31, 2022. The inverse probability of treatment weighting method was used to homogenize the analysis groups. Exposure: Long-course chemoradiotherapy or short-course radiotherapy with delayed surgery. Main outcome and Measures: The primary outcome was pCR. Other histopathologic results, perioperative events, and survival outcomes constituted the secondary outcomes. Results: Among the 1506 patients, 908 were male (60.3%), and the median (IQR) age was 68.8 (59.4-76.5) years. The short-, intermediate-, and long-interval groups included 511 patients (33.9%), 797 patients (52.9%), and 198 patients (13.1%), respectively. The overall pCR was 17.2% (259 of 1506 patients; 95% CI, 15.4%-19.2%). When compared with the intermediate-interval group, no association was observed between time intervals and pCR in short-interval (odds ratio [OR], 0.74; 95% CI, 0.55-1.01) and long-interval (OR, 1.07; 95% CI, 0.73-1.61) groups. The long-interval group was significantly associated with lower risk of bad response (tumor regression grade [TRG] 2-3; OR, 0.47; 95% CI, 0.24-0.91), systemic recurrence (hazard ratio, 0.59; 95% CI, 0.36-0.96), higher conversion risk (OR, 3.14; 95% CI, 1.62-6.07), minor postoperative complications (OR, 1.43; 95% CI, 1.04-1.97), and incomplete mesorectum (OR, 1.89; 95% CI, 1.02-3.50) when compared with the intermediate-interval group. Conclusions and Relevance: Time intervals longer than 12 weeks were associated with improved TRG and systemic recurrence but may increase surgical complexity and minor morbidity.

Total neoadjuvant therapy with or without aflibercept in rectal cancer: 3-year results of GEMCAD-1402.

BACKGROUND: The results of the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)-1402 phase II randomized trial suggested that adding aflibercept to modified fluorouracil, oxaliplatin, and leucovorin (mFOLFOX6) induction, followed by chemoradiation and surgery, could increase the pathological complete response (pCR) rate in patients with high-risk, locally advanced rectal cancer. Here we update results up to 3 years of follow-up and evaluate the predictive value of consensus molecular subtypes identified with immunohistochemistry (IHC). METHODS: Patients with magnetic resonance imaging-defined T3c-d and/or T4 and/or N2 rectal adenocarcinoma in the middle or distal third were randomly assigned to mFOLFOX6 induction, with aflibercept (mF+A; n = 115) or without aflibercept (mF; n = 65), followed by capecitabine plus radiotherapy and surgery. The risk local relapse, distant metastases, disease-free survival (DFS), and overall survival (OS) were estimated at 3 years. Selected samples were classified via IHC into immune-infiltrate, epithelial, or mesenchymal subtypes. RESULTS: mF+A and mF had 3-year DFS of 75.2% (95% confidence interval [CI] = 66.1% to 82.2%) and 81.5% (95% CI = 69.8% to 89.1%), respectively; 3-year OS of 89.3% (95% CI = 82.0% to 93.8%) and 90.7% (95% CI = 80.6% to 95.7%), respectively; 3-year cumulative local relapse incidences of 5.2% (95% CI = 1.9% to 11.0%) and 6.1% (95% CI = 1.7% to 15.0%), respectively; and 3-year cumulative distant metastases rates of 17.3% (95% CI = 10.9% to 25.5%) and 16.9% (95% CI = 8.7% to 28.2%), respectively. pCRs were achieved in 27.5% (n = 22 of 80) and 0% (n = 0 of 10) of patients with epithelial and mesenchymal subtypes, respectively. CONCLUSION: Adding aflibercept to mFOLFOX6 induction was not associated with improved DFS or OS. Our findings suggested that consensus molecular subtypes identified with IHC subtypes could be predictive of pCR with this treatment.

SEOM-GEMCAD-TTD clinical guidelines for the systemic treatment of metastatic colorectal cancer (2022).

Colorectal cancer (CRC) is the second leading cause of cancer deaths in Spain. Metastatic disease is present in 15-30% of patients at diagnosis and up to 20-50% of those with initially localized disease eventually develop metastases. Recent scientific knowledge acknowledges that this is a clinically and biologically heterogeneous disease. As treatment options increase, prognosis for individuals with metastatic disease has steadily improved over recent decades. Disease management should be discussed among experienced, multidisciplinary teams to select the most appropriate systemic treatment (chemotherapy and targeted agents) and to integrate surgical or ablative procedures, when indicated. Clinical presentation, tumor sidedness, molecular profile, disease extension, comorbidities, and patient preferences are key factors when designing a customized treatment plan. These guidelines seek to provide succinct recommendations for managing metastatic CRC.

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. METHODS: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. RESULTS: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. CONCLUSIONS: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. PLAIN LANGUAGE SUMMARY: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy.

A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study.

BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.

Mutational Status of SMAD4 and FBXW7 Affects Clinical Outcome in TP53-Mutated Metastatic Colorectal Cancer.

Next-generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first-line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time-dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%), and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (p = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (p = 0.02; HR, 3.31) as well as double-mutated TP53 and SMAD4 (p = 0.03; HR, 2.91). Analysis of the MSK-IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time-dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53-defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53-altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first-line regimens.

Cytology Smears: An Enhanced Alternative Method for Colorectal Cancer pN Stage-A Multicentre Study.

Stage II colorectal cancer (CRC) recurrence remains a clinical problem. Some of these patients are true stage III CRC with a pN0 pathology stage. This large prospective multicentre cohort study aimed at evaluating the diagnostic ability of lymph node (LN) cytology smears to perform the pN stage and compare it with the conventional haematoxylin and eosin (H&E) pathology pN stage. Additionally, we used the One-Step Nucleic Acid Amplification (OSNA), a high-sensitive molecular method of LN staging. A total of 3936 fresh LNs from 217 CRC surgical specimens were examined by three methods, H&E, LN cytology smears, and OSNA. H&E detected 29% of patients with positive LNs, cytology smears 35%, and OSNA 33.2% (p < 0.0001). H&E and cytology concordantly classified 92.2% of tumours, and 88.5% between OSNA and H&E. Cytology had 96.8% sensitivity and 90.3% specificity to discriminate positive/negative patients compared to H&E (p = 0.004), and 87.3% sensitivity and 89% specificity when compared to OSNA (p = 0.56). Patients with positive LNs detected by any of the three methods had significantly worse disease-free and overall survival. We conclude that pN stage accuracy for detecting positive LNs is superior with LN cytological smears than with conventional H&E, which would enable a better pN stage and management of early-stage CRC patients.

A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.

Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/ß-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.

Randomized phase II trial of FOLFIRI-panitumumab compared with FOLFIRI alone in patients with RAS wild-type circulating tumor DNA metastatic colorectal cancer beyond progression to first-line FOLFOX-panitumumab: the BEYOND study (GEMCAD 17-01).

PURPOSE: Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). METHODS: In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). RESULTS: Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. CONCLUSIONS: The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.

Prognostic value of cutaneous reinnervation with GAP-43 in oxaliplatin-induced neuropathy.

BACKGROUND AND PURPOSE: Oxaliplatin-induced neuropathy (OIN) implies axonal damage of both small and large sensory nerve fibers. We aimed at comparing the neurophysiological changes occurred after treatment and the capability to recovery based on histological marker of re-innervation GAP-43. METHODS: 48 patients with cancer were assessed before and after chemotherapy (at 3 months and 12 months if available). We recorded ulnar and sural sensory nerve action potentials (SNAP), determined quantitative sensory thresholds for warm and cold (WDT, CDT), pain thresholds and collected a distal biopsy of skin to assess the intra-epidermal nerve fiber density (IENFD) with PGP9.5 and GAP-43 markers (in a subgroup of 19 patients). RESULTS: Increased WDT and CDT as well as diminished IENFD at distal leg were already found in 30% of oncologic patients before treatment. After oxaliplatin, there was a significant increase in thermal thresholds in 52% of patients, and a decrease of SNAP amplitude in the sural nerve in 67% patients. IENFD was reduced in 47% and remained unchanged in 37% after oxiplatin. The density of GAP-43 + fibers and GAP-43/PGP 9.5 ratio was similar before and after treatment showing that cutaneous re-innervation is preserved despite no clinical recovery was observed after one year. CONCLUSION: Non-selective axonal loss affects sensory fibers in OIN. However, the presence of intra-epidermal regenerative sprouts detected by GAP-43 may reduce the impact of neurotoxicity in the small fibers with long-term sequelae mostly on myelinated nerve endings. Pre-oxaliplatin GAP-43 failed to identify patients with higher risk of damage or worse recovery after treatment.

Impact of microscopic incomplete resection for colorectal liver metastases on surgical margin recurrence: R1-Contact vs R1 < 1 mm margin width.

BACKGROUND: Several studies highlighted an inferior outcome of R1 resection for colorectal cancer liver metastases (CRLM); it is still unclear whether directly involved margins (R1-contact) are associated with a poorer outcome compared to R1 < 1 mm. The aim of this study is to analyze the impact on surgical margin recurrence (SMR) of R1-contact vs R1 < 1 mm patients. METHODS: Patients who underwent surgery for CRLM between 2009-2018 with both R1 resections on final histology were included and compared in terms of recurrence and survival. Factors associated with SMR were assessed by univariate and multivariate analysis. RESULTS: Out of 477, 77 (17.2%) patients showed R1 resection (53 R1-Contact and 24 R1 < 1 mm). Overall recurrence rate was 79.2% (R1 < 1 mm = 70.8% vs R1-contact group = 83%, P = .222). Median disease-free survival (DFS) and disease-specific survival (DSS) were significantly higher in R1 < 1 mm vs R1-contact group (93 vs 55 months; P = .025 and 69 vs 46 months; P = .038, respectively). The SMR rate was higher in R1-contact compared to R1 < 1 mm group (30.2% vs 8.3%; P = .036). At univariate analysis, age, number of metastases, open surgical approach, RAS status, and R1-contact were associated with SMR. At multivariate analysis, R1-contact margin was the only factor independently associated with higher SMR (OR = 5.6; P = .046). CONCLUSIONS: R1-contact margin is independently associated with SMR after liver resection for CRLM. Patients with R1-contact margin will also experience poorer DFS and DSS.

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor.

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients' samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)-the main effector of muscular atrophy in cachexia-resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.

Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients.

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

Description of the genetic variants identified in a cohort of patients diagnosed with localized anal squamous cell carcinoma and treated with panitumumab.

Squamous cell carcinoma is the most frequent histologic type of anal carcinoma. The standard of care since the 1970s has been a combination of 5-fluorouracil, mitomycin C, and radiotherapy. This treatment is very effective in T1/T2 tumors (achieving complete regression in 80-90% of tumors). However, in T3/T4 tumors, the 3-year relapse free survival rate is only 50%. The VITAL trial aimed to assess the efficacy and safety of panitumumab in combination with this standard treatment. In this study, 27 paraffin-embedded samples from the VITAL trial and 18 samples from patients from daily clinical practice were analyzed by whole-exome sequencing and the influence of the presence of genetic variants in the response to panitumumab was studied. Having a moderate- or high-impact genetic variant in PIK3CA seemed to be related to the response to panitumumab. Furthermore, copy number variants in FGFR3, GRB2 and JAK1 were also related to the response to panitumumab. These genetic alterations have also been studied in the cohort of patients from daily clinical practice (not treated with panitumumab) and they did not have a predictive value. Therefore, in this study, a collection of genetic alterations related to the response with panitumumab was described. These results could be useful for patient stratification in new anti-EGFR clinical trials.

Are Quality of Randomized Clinical Trials and ESMO-Magnitude of Clinical Benefit Scale Two Sides of the Same Coin, to Grade Recommendations for Drug Approval?

The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic colorectal cancer (mCRC). We propose several definitions that would help to evaluate the quality of RCT, the magnitude of clinical benefit and the appropriate approval of new drugs in oncology.