Purpose: To determine the expression of circRTN4 in gastric cancer (GC) and its role in tumor progression. Methods: GEO dataset GSE93541 was analyzed using GEO2R. Starbase website was used to predict the combination of miRNA and circRTN4. The relationship between circRTN4 and prognosis was analyzed using Kaplan-Meier Plotter database, while expression levels of circRTN4, miR-424-5p, and LATS2 were assessed by quantitative real time-polymerase chain reaction (qRT-PCR). CCK8, EDU, Transwell, and Western blot were used to assess GC  proliferation, migration, invasion, and stemness. Lastly, co-transfection of miR-424-5p or si-LAST2 was reversely used to demonstrate the regulatory effect  of circRTN4 on the progression of gastric cancer cells. Significantly downregulated circRTN4 in GC was screened, and the combined miR-424-5p  and downstream gene LATS2 were predicted by Starbase. Results: The average relative expression of circRTN4 mRNA in GC tissues was significantly lower than in adjacent tissues. MiR-424-5p was highly  expressed in tumor tissues, while LATS2 decreased (p < 0.05). Low expression of circRTN4 was associated with a low survival rate in patients. pLCDH- circRTN4 significantly inhibited the proliferation of gastric cancer cells (p < 0.05). Overexpression of circRTN4 inhibited the migration and invasion of  tumor cells, while pLCDH-circRTN4 reduced the ability of GC stem cells and expressions of MMP2 and OCT4. Conclusion: Expression of circRTN4 decreases in GC, and contributes to the development and progression of this disease by increasing the levels of  LATS2 and binding with miR-424-5p. This suggests that circRTN4 may serve as a promising prognostic marker as well as a potential therapeutic target for  gastric cancer

Background: We previously showed in HER2+ models of breast cancer (BC) that potent inhibition of the HER receptor layer can lead to re-expression of estrogen receptor (ER) or activation of the ER pathway. Consequently, the anti-apoptotic ER gene product Bcl2 is upregulated, resulting in enhanced tumor cell survival and treatment resistance. In this study, we investigated whether Bcl2 and ER expression levels are simultaneously increased by neoadjuvant treatment with the dual HER1/2 tyrosine kinase inhibitor lapatinib in HER2+ BC patients. Methods: In a neoadjuvant phase II clinical trial 49 HER2+ BC patients were treated with lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before surgery. Tumor specimens were prospectively collected at different time-points during lapatinib treatment (baseline, and weeks 2 and 4). Bcl2, ER, progesterone receptor (PR), total (t) and phosphorylated (p)-HER2, and Ki67 were assessed by immunohistochemistry. Spearman correlation was used to evaluate the association among the biomarkers at baseline, and the correlation of their changes over time. Fisher's Exact test and non-parametric Wilcoxon rank sum test were used respectively to determine if the frequency and the magnitude of Bcl2 expression changes were associated with baseline ER status. Results: 35/49 HER2+ tumor specimens (71%) were available for baseline evaluation of Bcl2 and ER. Of those, 12 (34%) were ER-positive (Allred score ≥ 3) and 23 (66%) ER-negative. Baseline Bcl2 expression correlated positively with ER (r = .75; p &lt; .0001) and PR (r = .53; p = .0015), and inversely with t-HER2 (r = −.43; p = .0097). ER baseline expression correlated positively with PR (r = .57; p = .0004), and inversely with t and p-HER2 (r = −.55; p = .0005, and r = −.37; p = .0282, respectively) and Ki67 (r = −.39; p = .0271). Bcl2 changes at week 2 (w2) positively correlated with changes in both ER and PR levels (r = .70; p = .0002 and r = .57; p = .0076, respectively). Additionally, the increase in Bcl2 expression, observed in 9 of the 23 (39%) tumors with tissue available at w2, was significantly more frequent (p = .0147) and of greater magnitude (p = .0001) in ER-pos vs. ER-neg tumors — 8/9 ER-pos tumors at w2 (including 3 converted from ER-neg by lapatinib) had increased Bcl2, while only 1 of the 14 (7%) ER-neg tumors (at baseline and w2) had increased Bcl2. The expression of ER itself at w2 also increased in 3 out of the 6 (50%) tumors which were originally ER-pos and had tissue available at w2, and in all of them Bcl2 increased in parallel. Of note, the single baseline ER-pos tumor that showed a reduction in ER at w2 had a parallel decrease in Bcl2. Similar observations or trends were found at week 4. Conclusion: Our study suggests that Bcl2 is upregulated as a result of enhanced/restored ER activity upon anti-HER2 therapy with lapatinib in HER2+ tumors. This further supports the use of endocrine along with anti-HER-2 therapy to block this escape pathway which could otherwise cause treatment resistance. In addition, the ER re-expression with lapatinib treatment observed in this study emphasizes the need to re-biopsy HER2+/ER− patients receiving anti-HER2 therapy and to add endocrine therapy if the tumor becomes ER-positive. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-8.

Background: The primary objective for metastatic breast cancer is to prolong the patients survival. So the appropriate choice of the first-line therapy strategy is very important. For the HR-positive metastatic breast cancer, we haven't strong data to head-to-head compare the chemotherapy with endocrine therapy as the first-line treatment. Methods: Two hundreds patients with HR-positive metastatic breast cancer were enrolled at 47 cancer centers in China from 2009 to 2012. Investigators decided to give chemotherapy or endocrine therapy according to their clinical judgements. Chemotherapy and endocrine therapy regimens followed the NCCN guildline. All the patiens haven't take any treatment after relapse or metastasis. All the patients were estrogen- receptor positive and/or progesterone-receptor positive,HER2 negative. Chemotherapy or endocrine therapy was continued in the progressive disease(PD) or unacceptable toxicity. Primary endpoint was progression-free survival(PFS), second endpoints were time to failure(TTF), response rate. Results: According to the investigator judgements, one hundred patient took chemotherapy(CT arm), another one hundreds patients took endocrine therapy(ET arm). Pt characteristics were balanced between the two arms: median age 49y/50y, median disease-free survival(DFS) 40m/30m, visceral/non-visceral metastatic 52%/40%. There was more patients with ≥2 metastatic sites in CT arm than ET arm (50% vs 32%). Following up to Dec 2012, reasons for early treatment discontinuation were : PD 25 pts, toxicity 38 pts in CT arm, PD 82 pts, toxicity 2 pts in ET ram. The median PFS was 52 weeks(95% CI 23.2-80.8 weeks) and 48 weeks(95% CI 38.9-57.0 weeks) for CT arm and ET arm(P = 0.589),respectively. The median TTF was 20 weeks and 48 weeks for CT arm and ET arm,respectively(P = 0.025). Response rate was 63% and 22% for CT arm and ET arm,respectively(P&lt;0.001). But clinical benefit rate(CR+PR+SD≥6months) was 67% and 69% for CT arm and ET arm,respectively(P = 0.333). Subgroup analysis showed TTF were 48 weeks in ET arm and 15 weeks in CT arm(p = 0.038) for patients who had more than 2 years DFS. TTF results also indicated significant difference in single metastatic site pts and non-visceral metastatic pts between two arms. ET arm was superior to CT arm. Conclusions: Our results indicate first-line chemotherapy has higher response rate than first-line endocrine therapy for HR-positive meatstatic breast cancer, but chemotherapy has shorter maintaining therapy time. First-line endocrine therapy was more suitable than first-line chemotherapy for pts with DFS≥2y, single metastatic site and non-visceral metastatic. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-05.

Background: In recent years, several clinical trials showed that fulvestrant (Ful), alone or in combination with an aromatase inhibitor (AI), is more effective than an AI alone. PACT01 is a randomized neoadjuvant trial of Anastrazole (Ana) alone or in combination with Ful in ER+/HER2- breast cancer. Methods: Patients with newly diagnosed ER+/HER2- breast cancers, 2 cm or larger in size, were randomized to 16 weeks of Ana (1 mg orally every day) alone or in combination with Ful (500mg IM days 1, 15, 29, and every 28 days thereafter) for 16 weeks. Patients then proceeded to surgery. Tumor tissue was collected at baseline, day 28 (D28), and at the time of surgery. Primary endpoint was the reduction of Ki67 in tumor tissue between baseline and D28. Baseline and D28 samples were stained for ER, PR, HER2, and Ki67. ER and PR were scored for intensity and percentage (H-score), HER2 was scored for intensity of membrane staining; and Ki67 was scored as percentage. Data were summarized descriptively. Changes in biomarkers from baseline to D28 were calculated and compared by Wilcoxon signed rank test. Results: PACT01 trial enrolled 72 patients. Three of them did not start treatment. Baseline samples were collected from the remaining 69 patients, and D28 samples from 60 patients (5 refused, 2 withdrew, 1 lost to follow up, 1 unknown). Samples from 18 patients had no tumor (5 at baseline, 9 at D28, 4 at both). Of the 42 patients with paired samples, 20 received Ana and 22 received Ana+Ful. All cases except one were centrally confirmed to be ER+, and all were HER2-. Table 1 summarizes median expression of Ki67, ER, and PR. Both treatment regimens led to a significant reduction in Ki67 between baseline and D28. However, Ana+Ful did not reduce Ki67 more effectively than Ana alone. Ki67 was reduced to &lt;10% in 60% of the Ana arm and 68% of the Ana+Ful, which was not statistically significant.PR was similarly reduced in both treatment arms. ER was significantly reduced at D28 in the Ana+Ful arm (p=0.0004) but not in the Ana alone arm. Safety profile of both treatment arms was consistent with package insert and published studies. Median expression of Ki67, ER and PR in Anastrazole and Anastrazole + Fulvestrant Arms at Baseline and Day 28ARMTimepointNKi67 (%)ER H-scorePR H-scoreAnaBaseline2024.8182.5100.3 Day 28205.6*170.025.0Ana + FluBaseline2225.6198.120.5 Day 28225.1*117.50.0* p=0.0004. Other comparisons were not stastistically significant Conclusions:In this small neoadjuvant trial, the addition of Ful to Ana did not increase Ki67 suppression at D28. This may be due to untreated primary tumors being exquisitely sensitive to Ana and that fulvestrant may not add to it. It is also possible that the effect of Ful may be noted later in the course of treatment. Further biomarker data on tissue collected at the end of treatment will be presented at the meeting. Citation Format: Dhamne S, Nagi C, Wang T, Pavlick AC, Reusser B, Schiff R, Julie N, Niravath P, Silberfein EJ, Sedgwick EL, Sepulveda KA, Gutierrez C, Hilsenbeck SG, Chang JC, Osborne CK, Rimawi MF. Biomarkers of response to neoadjuvant endocrine therapy with anastrozole (Ana) alone or in combination with fulvestrant (Ful) in ER-positive (ER+) HER2-negative (HER2-) breast cancer (PACT01 trial) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-15-05.