MODUL cohort 2: an adaptable, randomized, signal-seeking trial of fluoropyrimidine plus bevacizumab with or without atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

BACKGROUND: MODUL is an adaptable, signal-seeking trial designed to test novel agents in predefined patient subgroups in first-line metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with measurable, unresectable, previously untreated mCRC received induction with ≤8 cycles of FOLFOX + bevacizumab followed by randomization to maintenance treatment comprising control [fluoropyrimidine (FP)/bevacizumab: 5-fluorouracil 1600-2400 mg/m2 46-h intravenous (i.v.) infusion day 1 q2 weeks plus leucovorin 400 mg/m2 2-h infusion i.v. day 1 q2 weeks or capecitabine 1000 mg/m2 b.i.d. orally days 1-14 every 21 days; bevacizumab 5 mg/kg 15-30-min i.v. infusion q2 weeks] or experimental treatment in one of four biomarker-driven cohorts. In patients with BRAF wild-type (BRAFwt) tumors (cohort 2), experimental treatment was FP/bevacizumab + atezolizumab (800 mg 60-min i.v. infusion q2 weeks). Primary efficacy endpoint was progression-free survival (PFS; intent-to-treat population). Enrollment is complete; efficacy and safety findings from cohort 2 are presented. RESULTS: Four hundred and forty-five patients with BRAFwt mCRC were randomized (2 : 1) to maintenance in cohort 2. At a median follow-up of 10.5 months, PFS outcome hypothesis was not met [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.72-1.17; P = 0.48]; overall survival (OS) was immature. At a median follow-up of 20.3 months (2-year survival follow-up), PFS benefit was also not met (HR 0.95; 95% CI 0.77-1.18; P = 0.666); OS HR with nearly two-thirds of patients with events was 0.83 (95% CI 0.65-1.05; P = 0.117). No new safety signals were identified. The most common grade ≥3 treatment-emergent adverse events (TEAEs) for experimental versus control arms were hypertension (6.1% versus 4.2%), diarrhea (3.1% versus 2.1%), and palmar-plantar erythrodysesthesia syndrome (1.0% versus 2.5%). Four patients experienced TEAEs with fatal outcome, two were study treatment-related: hepatic failure (experimental arm) and large intestine perforation (control arm; bevacizumab-related). CONCLUSIONS: Adding atezolizumab to FP/bevacizumab as first-line maintenance treatment after FOLFOX + bevacizumab induction for BRAFwt mCRC did not improve efficacy outcomes.

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer.

There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at 'type A' (ESR1, GATA5, HIC1, HPP1, SFRP1) and 'type C' markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. 'Type A' genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. 'Type C' methylation is more specific for neoplasia. The last five 'type C' markers comprise a CIMP panel. The mean 'type A' and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most 'type A' genes showed direct correlations between methylation and age (ESR1, rho=0.66, P<0.0001), with higher methylation distally (ESR1, P<0.0001). On multivariate analysis, 'type A' methylation was inversely associated with colorectal adenomas (odds ratio=0.23, P<0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio=5.1, P=0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.

Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk.

Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, breast cancers in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for ER-positive breast cancer in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis (CYP19) and metabolism (CYP1A1) as a risk factor for ER-positive breast cancers was evaluated. A case-control study was conducted with 257 breast cancer patients and 191 healthy female controls. Two polymorphisms, CYP19 (TTTA repeats) in intron 4 and CYP1A1 6235C/T in the 3' non-coding region, and their association with the breast cancer risk after adjustment for the other epidemiological risk factors were examined. CYP19 (TTTA)7(-3bp) allele carriers showed a significantly (P<0.05) increased risk of ER-positive breast cancers (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10-2.69), but not ER-negative breast cancers. CYP1A1 6235C allele carriers showed a non-significant (P=0.06) trend towards a decreased risk of ER-positive breast cancers (OR=0.65, 95% CI 0.42-1.02), but not ER-negative breast cancers. The combination of these two polymorphisms was found to be more useful in the assessment of the ER-positive breast cancer risk (OR=3.00, 95% CI=1.56-5.74) than the CYP19 (TTTA)7(-3bp) polymorphism alone. The combination of CYP19 (TTTA)7(-3bp) and CYP1A1 6235C/T polymorphisms is associated with an ER-positive, but not ER-negative, breast cancer risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen.