Ofer Purim

Tumor microRNA-29a expression and the risk of recurrence in stage II colon cancer

There is emerging evidence for the prognostic role of various microRNA (miRNA) molecules in colon cancer. The aim of this study was therefore to compare the miRNA profiles in the primary tumor of patients with recurrent and non-recurrent colon cancer. The study population included 110 patients, 51 (46%) with stage I and 59 (54%) with stage II disease, who underwent curative colectomies between 1995 and 2005 without adjuvant therapy and for whom reliable miRNA expression data were available. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor samples. Initial profiling, using microarrays, was done in order to identify potential biomarkers of recurrence. The miRNA expression was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 months of surgery (bad prognosis group, n=23, 21%) and those who did not (good prognosis group, n=87, 79%) in the entire group and within each stage. The results showed that in stage I, none of the 903 miRNAs tested showed differential expression between patients with good prognosis compared with those with poor prognosis. In contrast, in stage II, one miRNA, miR-29a, showed a clear differential expression between the groups (p=0.028). High expression of miR-29a was associated with a longer disease-free survival (DFS), on both univariate and multivariate analyses. Using miR-29a, the positive predictive value for non-recurrence was 94% (2 recurrences among 31 patients). The differential expression of miR-29a was verified by qRT-PCR, showing a similar impact of this miR on DFS. In conclusion, this study demonstrated a significant impact of miR-29a on the risk of recurrence in patients with stage II but not in patients with stage I colon cancer. Based on these results, a validation study is planned.

Cancer of the colon and rectum: Potential effects of sex-age interactions on incidence and outcome

Background Sex differences in epidemiological, clinical and pathological characteristics of colorectal cancer have been under intensive investigation for the last three decades. Given that most of the sex-related differences reported were also age-related, this study sought to determine the potential effect of a sex-age interaction on colorectal cancer development and progression. Material/Methods Statistical data on sex- and age-specific colon or rectal cancer incidence, disease stage and survival for white persons were derived from the United States Surveillance, Epidemiology and End Results (SEER) Program. Age-specific incidence rates in 2002–2006 were analyzed by 5-year age groups (45–49, 50–54, 55–59, 60–64, 65–69, 70–74, 75–79, 80–84 years) in men and women. Sex differences were measured by calculating rate differences (RD) and rate ratios (RR). Equivalent analyses for a similar time period were performed for stage distribution and 5-year relative survival. Results Age-specific incidence rates were higher for men, for all life-time periods. However, the magnitude of the male predominance was age-dependent. The RR and RD did not remain constant over time: they increased gradually with age, peaked at 70–74 years, and declined thereafter. The distribution of stage at diagnosis was similar between men and women, but women seemed to have better survival, until the age of 64 years for colon cancer and 74 years for rectal cancer. Conclusions There seem to be significant age-related sex differences in the incidence of colorectal cancer, and maybe also in its prognosis.

Impact of the 12-Gene Colon Cancer Assay on Clinical Decision Making for Adjuvant Therapy in Stage II Colon Cancer Patients

OBJECTIVES To evaluate the impact of the 12-gene Colon Cancer Recurrence Score Assay-a clinically validated prognosticator in stage II colon cancer after surgical resection-on adjuvant treatment decisions in T3 mismatch repair proficient (MMR-P) stage II colon cancer in clinical practice. METHODS This retrospective analysis included all patients with T3 MMR-P stage II colon cancer (Clalit Health Services members) with Recurrence Score results (time frame January 2011 to May 2012). Treatment recommendations pretesting were compared with the treatments received. Changes were categorized as decreased (to observation alone/removing oxaliplatin from the therapy) or increased (from observation alone/adding oxaliplatin to the therapy) intensity. RESULTS The analysis included 269 patients; 58%, 32%, and 10% of the values were in the low (<30), intermediate (30-40), and high (≥41) score groups, respectively. In 102 patients (38%), treatment changed post-testing (decreased/increased intensity 76/26 patients). The overall impact was decreased chemotherapy use (45.0% to 27.9%; P < 0.001). Treatment changes occurred in all score groups, but more frequently in the high (change rate 63.0%; 95% confidence interval [CI] 42.3%-80.6%) than in the intermediate (30.6%; 95% CI 21.0%-41.5%) and low (37.6%; 95% CI 30.0%-45.7%) score groups. The direction of the change was consistent with the assay result, with increased intensity more common in higher score values and decreased intensity more common in lower score values. CONCLUSIONS Testing significantly affected adjuvant treatment in T3 MMR-P stage II colon cancer in clinical practice. The study is limited by its design, which compared treatment recommendations pretesting to actual treatments received post-testing, lack of a control group, and nonassessment of confounding factors that may have affected treatment decisions.

A phase I clinical trial of dTCApFs, a derivative of a novel human hormone peptide, for the treatment of advanced/metastatic solid tumors

The aim of the present phase I first-in-human study was to investigate the safety/efficacy of dTCApFs (a novel hormone peptide that enters cells through the T1/ST2 receptor), in advanced/metastatic solid tumors. The primary objective of this open-label dose-escalation study was to determine the safety profile of dTCApFs. The study enrolled patients (aged ≥18 years) with pathologically confirmed locally advanced/metastatic solid malignancies, who experienced treatment failure or were unable to tolerate previous standard therapy. The study included 17 patients (64% male; median age, 65 years; 47% colorectal cancer, 29% pancreatic cancer). The patients received 1–3 cycles of escalating dTCApFs doses (6–96 mg/m2). The mean number ± standard deviation of treatment cycles/patient was 3.2±1.4; no dose-limiting toxicities were observed up to a dose of 96 mg/m2, and the maximum tolerated dose was not reached. Half-life, maximal plasma concentration, and dTCApFs exposure were found to be linearly correlated with dose. Five patients were treated for ≥3 months (12, 24, 48 mg/m2) and experienced stable disease throughout the treatment period, and 1 experienced pathological complete response. Analysis of serum biomarkers revealed decreased levels of angiogenic factors at dTCApFs concentrations of 12–48 mg/m2, increased levels of anticancer cytokines, and induction of the endoplasmic reticulum (ER) stress biomarker GRP78/BiP. Efficacy and biomarker data suggest that patients whose tumors were T1/ST2-positive exhibited a better response to dTCApFs. In conclusion, dTCApFs was found to be safe/well-tolerated, and potentially efficacious, with linear pharmacokinetics. Consistent with preclinical studies, the mechanism through which dTCApFs exerts anticancer effects appears to involve induction of ER stress, suppression of angiogenesis, and activation of the innate immune response. However, further studies are warranted.

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011–2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1–9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.

Abstract 3017: MicroRNAs as prognostic indicators in gastric cancer

Background: Our ability to determine the prognosis of an individual patient with gastric cancer and thereby to select patients for adjuvant therapy is still limited. Preliminary data suggest that microRNAs may have a prognostic role in this disease. We hence decided to compare the microRNA profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer and to evaluate the prognostic impact of these molecules. Patients and Methods: Eligible patients, who underwent curative gastrectomies between 1995 and 2005 and did not receive any pre- or postoperative adjuvant therapy, were identified from the database of the participating institutions. Total RNA was extracted from tumor formalin-fixed paraffin embedded (FFPE) samples using proprietary protocols that preserve the small RNA fraction. Initial profiling using microRNA microarrays identified potential microRNA biomarkers that can be used to predict recurrence of gastric cancer after resection. The expression of differential microRNAs, was verified by qRT-PCR. Results: Forty-five eligible patients had adequate tumor content and microRNA expression data and were included in the analysis. Of these, 14 (31%) experienced recurrence of disease within three years from surgery (“bad prognosis” group) and 31 (69%) did not (“good prognosis” group). Advanced pathological stage and extensive surgical procedure correlated with bad prognosis. Signal levels of three microRNAs were found to be significantly differentially expressed in tumors from patients with good prognosis vs. patients with bad prognosis. High expression of each of these microRNAs was associated with significantly poorer prognosis for both recurrence and survival. Proprietary microRNA qRT-PCR showed a high correlation to microarrays and similar separation into prognosis groups based on microRNA expression. Conclusion: We identified a set of microRNAs whose high expression was predictive of tumor recurrence and poor prognosis in patients with gastric cancer. This finding provides a basis for a novel tool for risk stratification in this disease and allows further insight into its pathogenesis. Based on these results, a validation study, on a larger and independent cohort of patients, is planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3017.