mutations are grouped in activating
-independent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and
-dependent with impaired kinase activity (class 3-codons 594/596). ...Although clinical, pathologic, and molecular features of
-mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes.
Data from 117 patients with
(92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540
wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan-Meier and log-rank test.
Class 3
-mutated mCRC was more frequently left sided (
= 0.0028), pN0 (
= 0.0159), and without peritoneal metastases (
= 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with
wt, was 2.38 95% confidence interval (CI), 1.61-3.54 for class 1, 1.90 (95% CI, 0.85-4.26) for class 2, and 0.93 (95% CI, 0.51-1.69) for class 3 (
< 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in
-mutated class 2 (
= 0.033) compared with class 3 cases.
For the first time, different clinical and pathologic features and outcome data were reported according to the three
mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.
Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage ...response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29-0.85; P = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.
The HER2 splice variant characterized by the deletion of exon 16 and denominated as d16HER2, is associated with HER2-positive breast cancer (BC) aggressiveness, stemness, and trastuzumab ...susceptibility and is considered to be a "flag" of HER2 dependence. However, with the exception of quantitative real-time PCR analysis, easily reproducible assays are still lacking to clinically detect and quantify the d16HER2 expression. Further, no data on d16HER2 expression and its potential role are available in HER2-positive gastrointestinal malignancies. Here, we used a novel RNA in situ hybridization technique (BaseScope) to discriminate d16HER2 variant expression from the wild type isoform (WTHER2) and to assess their levels across different HER2-positive histological samples. Our results demonstrate the existence of outliers, with d16HER2 mRNA high scores restricted to HER2-positive gastric cancer (GC) and colorectal cancer (CRC) coupled with increased d16HER2 expression compared with BC. Consistent with previously reported data on BC, experiments performed in HER2-positive GC patient-derived xenografts suggest that increased d16HER2 expression is associated with a clinical benefit/response to single-agent trastuzumab. Therefore, d16HER2 may be considered as a "flag" of HER2 dependence in GC and can be clinically investigated as a marker of trastuzumab susceptibility in several other HER2-driven cancers, including CRC. As a clinical proof-of-concept, we indicate that high d16HER2 mRNA scores are exclusively found in patients with a long-term benefit from trastuzumab exceeding 12 months (clinical "outliers"), and that d16HER2 expression is also increased in circulating tumor-released exosomes obtained from baseline plasma samples of long-term responders.
Long non-coding RNAs (lncRNAs) are emerging as fundamental players in cancer biology. Indeed, they are deregulated in several neoplasias and have been associated with cancer progression, tumor ...recurrence, and resistance to treatment, thus representing potential biomarkers for cancer diagnosis, prognosis, and therapy. In this study, we aimed to identify lncRNAs associated with pituitary tumorigenesis
.
We have analyzed the lncRNA expression profile of a panel of gonadotroph pituitary adenomas in comparison with normal pituitaries. Then, we focused on RPSAP52, a novel lncRNA antisense for the
HMGA2
gene, whose overexpression plays a critical role in the development of pituitary adenomas. We report that RPSAP52 expression is highly upregulated in gonadotroph and prolactin-secreting pituitary adenomas, where it correlates with that of HMGA2, compared with normal pituitary tissues. Conversely, its expression showed a variable behavior in somatotroph adenomas. We also demonstrate that RPSAP52 enhances HMGA2 protein expression in a ceRNA-dependent way acting as sponge for miR-15a, miR-15b, and miR-16, which have been already described to be able to target HMGA2. Interestingly, RPSAP52 also positively modulates HMGA1, the other member of the High-Mobility Group A family. Moreover, functional studies indicate that RPSAP52 promotes cell growth by enhancing the G1-S transition of the cell cycle. The results reported here reveal a novel mechanism, based on the overexpression of the lncRNA RPSAP52, which contributes to pituitary tumorigenesis, and propose this lncRNA as a novel player in the development of these tumors.
Key Messages
RPSAP52 is overexpressed in pituitary adenomas.
RPSAP52 increases HMGA protein levels.
A ceRNA mechanism is proposed for the increased HMGA1/2 expression.
Abstract only
3143
Background: The anti-VEGFR-2 monoclonal antibody ram, alone or with paclitaxel, is a cornerstone of second-line treatment of mGC. Even if about half patients do not benefit from ...ram, no predictive biomarkers have been identified so far. In TCGA, VEGF-A amplification was found in 7% of cases, almost exclusively in chromosomal instability subtype. We hypothesize that VEGF-A amplification in tumor cells could lead to autocrine/paracrine stimulation of tumor growth beside angiogenesis, potentially identifying a patients’ subgroup with exceptional responses to ram. Methods: VERA was a multicentric, prospective study based on a translational hypothesis. mGC patients were included according to the following criteria: 1) complete (CR) or partial response (PR) to single-agent ram; 2) >6 months PFS to single-agent ram; 3) >10 months PFS to paclitaxel+ram. According to a Fleming single-stage design, hypothesizing a prevalence of VEGF-A amplification of 1% and 15% among all-comers and exceptional responders, 20 exceptional responders were required to reject the null hypothesis of low prevalence of VEGF-A amplification, with alpha- and beta- errors of 0.05 and 0.10, respectively. VEGF-A amplification (defined as >10% tumor cells with ≥10 VEGF-A copies, variably sized signal clusters or a ratio of VEGF-A gene to centromere of ≥2) was centrally assessed through fluorescent in situ hybridization on pre-treatment FFPE tumor tissue. Results: At 7 Italian Centers, we included 20 patients satisfying the 1st (n=1), 2nd (n=2), or 3rd (n=17) criterion. Clinical-pathological features were: M/F, 11/9; median age 63 years; gastric/GEJ, 17/3; intestinal/diffuse, 14/6, HER2+/HER2-, 4/16. Median PFS and overall survival to ram-based treatment were 15.6 and 25.7 months, with best response: CR/PR/SD, 0/10/10. VERA met its primary endpoint, revealing 3/20 (15%) tumors with VEGF-A amplification (1 case presenting big clusters, 1 small clusters and 1 with >10% tumor cells with ≥10 VEGF-A copies). Conclusions: Validation analyses of first- and second-line randomized trials could confirm VEGF-A amplification as a biomarker of long-term response to ram-based treatment in mGC patients, advancing treatment personalization.
Abstract only
3509
Background: Overall response rate (ORR) to temozolomide (TMZ) is ∼10% in refractory mCRC pts with MGMT methylation detected by qualitative assays, e.g. methylation-specific PCR ...(MSP). ORR to irinotecan/FOLFIRI in second-line trials was 4-16%. The efficacy of TMZ may be improved by its combinatorial use in earlier lines and molecular selection beyond MSP. Lack of MGMT expression by immunohistochemistry (IHC) and high MGMT % methylation by MethylBEAMing (MB) are prognostic for higher ORR/PFS in TMZ-treated pts. Methods: This multicenter, randomized phase 2 trial investigated PFS superiority of second-line CAPTEM (Arm A: capecitabine 750 mg/sqm bid days1-14/TMZ 75 mg/sqm bid days10-14q28 days) over FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts: ECOG PS 0-1, measurable disease, failure of 1
st
-line oxaliplatin-based tx (or relapse within 6 mos from oxaliplatin-based adjuvant tx). Randomization was stratified by time from the start of oxaliplatin-based therapy to PD ( < /≥9 months); prior bevacizumab (yes/no). A one-sided log-rank test with a sample size of 82 pts (41 per arm) achieved 90% power at a 5% significance level to detect mPFS increase from 2 to 4 mos. Secondary endpoints: safety, QoL, OS, ORR. Exploratory endpoints: predictive value of MGMT IHC/MB. Results: From Nov 2014 to Feb 2019, 82 pts (arm A/B: 41/41) were enrolled in 18 Italian sites. Baseline characteristics (arm A/B): males 44/56%, median age 70/67, ECOG PS 0 54/51%, right-sidedness 37/39%, 1 metastatic site 44/34%, prior bevacizumab 68/66%, 1
st
-line PFS 9,4/10,2 months. At a median follow up of 26.6 mos, 70 PFS/46 OS events were collected. The mPFS was 3.6 vs 4.1 mos in arm A vs B (HR = 1.26;95%CI 0.78-2.02;p = 0.34) and mOS was 9.1 vs 14.2 mos (HR =1.08;95%CI 0.60-1.94;p = 0.79). ORR and DCR (arm A/B): 12/10% and 51/51%. Grade 3-4 adverse events: 15/44% (diarrhea 0/12%, stomatitis 0/7%, anemia 2/10%, neutropenia 2/22%, thrombocytopenia 7/0%). Neither MGMT IHC nor MB status were prognostic. MGMT IHC positive subgroup, arm A (n = 12) vs arm B (n = 22): mPFS, 2.0 vs 4.1 mos (HR = 2.06;95%CI 0.96-4.45;p = 0.06), mOS, 6.4 vs 10.6 mos (p = 0.78), ORR (0% vs 14%) and DCR (25% vs 55%;OR = 0.28;95%CI 0.06-1.31;p = 0.11). In MGMT IHC negative subgroup, no PFS/OS/ORR/DCR differences were noted between the two arms. P interaction IHCxArm: 0.171 for PFS, 0.917 for OS, 0.06 for DCR. Similar accuracy was achieved by MB. Conclusions: The use of TMZ should be explored by phase 3 trials enrolling MGMT IHC-negative +/- high MGMT % methylated mCRC. Clinical trial information: NCT02414009.
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