Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (OESIRI)-PRODIGE 62: A multicentre, randomised, non-comparative phase II study

Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy. Several molecules have been evaluated in phase I/II trials or retrospective studies (docetaxel, paclitaxel and irinotecan) but…

KRAS mutation signature in colorectal tumors significantly overlaps with the cetuximab response signature.

PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer

International audience; Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-c…

TH-302 + Gemcitabine (G + T) vs Gemcitabine (G) in Patients with Previously Untreated advanced Pancreatic Cancer (PAC)

ABSTRACT Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G…

Mitochondrial D310 mutations in colorectal adenomas: an early but not causative genetic event during colorectal carcinogenesis.

Somatic mutations of the D310 sequence of the mitochondrial DNA are reported in human cancers, including colorectal cancers (CRC). The presence of these mutations at early or late steps of colorectal carcinogenesis is unknown. Their prevalence increased significantly with the number of cytosines in the D310 sequence of the matched normal tissue (D310 polymorphism), suggesting that this polymorphism could be a risk factor for CRC. The aim of this study was (i) to investigate the prevalence of D310 mutations in 64 colorectal adenomas and 36 liver metastases from 15 CRC patients, (ii) to assess the relation between D310 polymorphism and the risk of colorectal adenoma in a case-control study in…

Decision for adjuvant treatment in stage II colon cancer based on circulating tumor DNA:The CIRCULATE-PRODIGE 70 trial

International audience; Background: Adjuvant treatment for stage II colon cancer remains debated. Finding a tool to select patients at risk for disease recurrence may help the clinical decision. Circulating tumor DNA (ctDNA) has been reported recently as a potential predictive marker for disease recurrence. We thus aim to test its ability to better select stage II colon cancer patients for adjuvant therapy.Methods: This national, phase III trial (NCT00002019-000935-15) conducted in more than 100 centers in France, plans to screen around 2640 patients in order to randomize (2:1; minimization method) 198 ctDNA positive patients. Patients aged 18 to 75 years with ECOG performance status ≤1 wit…

Intratumor CMS Heterogeneity Impacts Patient Prognosis in Localized Colon Cancer

Abstract Purpose: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications. Experimental Design: We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three …

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer

Contains fulltext : 165965.pdf (Publisher’s version ) (Closed access) Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and speciali…

Prognostic value of methylator phenotype in stage III colon cancer treated with oxaliplatin-based adjuvant chemotherapy

Abstract Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen. Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMP+ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3. Association between CIMP status and overall survival (OS), disease-free survi…

Validation of the prognostic impact of lymphocyte infiltration (LI) in patients (pts) with stage III colon cancer (CC) treated with adjuvant FOLFOX plus /- cetuximab: A PETACC8 translational study

International audience; The prognostic value of LI of CC has been demonstrated by several groups. However no validated test is available for clinical practice. We previously described an automated and reproducible method for testing LI (Allard MA et al2012) and aimed to validate it for clinical use. Methods: According to NIH criteria, we designed a prospective analysis of this biomarker in pts included in the PETACC8 phase III study. Primary objective was to compare % of pts without recurrence at 2 years in pts with high versus low LI (#NCT02364024). Secondary objectives were comparison of disease free (DFS) and overall (OS) survivals, and prognostic value of LI on these endpoints. Automate…

Colon cancer molecular subtype intratumoral heterogeneity and its prognostic impact: An extensive molecular analysis of the PETACC-8

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promot…

Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers

The RAS-MAPK, PI (3)K signaling pathways form a network that play a central role in tumorigenesis. The BRAF, KRAS and PI3KCA genes code 3 partners of this network and have been found to be activated by mutation in colorectal cancer; these mutations lead to unrestricted cell growth. We evaluated the clinicopathological features and the prognosis of patients with activated-network colon cancers in a population-based study. A total of 586 colon adenocarcinomas were evaluated using sequencing for mutations of KRAS and PI3KCA, and allelic discrimination for mutation of BRAF. Clinicopathological characteristics were correlated to the risk of bearing a mutation of the network using logistic regres…

Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1.

How dying tumor cells get noticed Besides killing tumor cells directly, some chemotherapies, such as anthracyclines, also activate the immune system to kill tumors. Vacchelli et al. discovered that in mice, anthracycline-induced antitumor immunity requires immune cells to express the protein formyl peptide receptor 1 (FPR1). Dendritic cells (DCs) near tumors expressed especially high amounts of FPR1. DCs normally capture fragments of dying tumor cells and use them to activate nearby T cells to kill tumors, but DCs lacking FPR1 failed to do this effectively. Individuals with breast or colon cancer expressing a variant of FPR1 and treated with anthracyclines showed poor metastasis-free and ov…

Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial

Abstract Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies. This comparative phase II trial (NCT 03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a s…

Genome-wide association studies identify four ER negative-specific breast cancer risk loci

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environm…

Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX.

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations…

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, whi…

Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases.

Abstract The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-…