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Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan–Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL . In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97–3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups.

INTRODUCTION Neoadjuvant chemotherapy is standard treatment for locally advanced (LABC) or inflammatory breast cancer (IBC). We hypothesized adding sunitinib, a tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2 negative LABC or IBC. PATIENTS AND METHODS We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2 negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly x12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the Clinical-pathologic scoring + estrogen receptor (ER) and grade (CPS+EG) score. RESULTS Seventy patients enrolled and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple negative disease). When defining response as pCR and/or CPS+EG score ≤ 2, 47% were responders. In ER+ patients, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR. However, 47% were responders using pCR and/or CPS+EG score ≤2. ER+ patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for ER+ patients.

Introduction Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC. Patients and Methods We conducted a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC. During induction, the patients received nab-paclitaxel 100 mg/m2 intravenously (days 1, 8, and 15) and bevacizumab 10 mg/kg intravenously (days 1 and 15) every 28 days for 6 cycles. Patients free of progression at 24 weeks received maintenance therapy with bevacizumab 10 mg/kg intravenously every 2 weeks and oral erlotinib 150 mg/d until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were best overall response, overall survival (OS), and adverse events. We explored the measurement of circulating tumor cells as a prognostic marker. Results A total of 55 evaluable patients were enrolled. The median PFS and OS for the cohort was 9.1 months (95% confidence interval, 7.2-11.1) and 18.1 months (95% confidence interval, 15.6-21.7), respectively. Of the 53 patients with measurable disease, 39 (74%) had experienced a partial response and 10 (19%) had stable disease using the Response Evaluation Criteria In Solid Tumors. The most common toxicities were uncomplicated neutropenia, fatigue, and neuropathy. Decreased circulating tumor cells from baseline to the first assessment correlated with longer PFS and OS. Conclusion Nab-paclitaxel and bevacizumab, followed by maintenance targeted therapy with bevacizumab and erlotinib, resulted in PFS similar to that of other trials. Most patients experienced a partial response (74%). Most patients received maintenance therapy (55%), providing a break from cytotoxic chemotherapy.

Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2-positive breast cancer with coexisting PIK3CA(H1047R). Induction of PIK3CA(H1047R) expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CA(H1047R) expression. Strikingly, although these Her2(+) PIK3CA(H1047R)-initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CA(H1047R), a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2-positive cancers with coexisting PIK3CA-activating mutations.

567 Background: MACC1, part of the HGF-MET pathway, drives proliferation and regulation of MET expression in vitro. In vivo, MACC1 is associated with tumor progression and studies suggest greater MACC1 expression is associated with resistance to platinum-based chemotherapy. We hypothesized that MACC1 may be a prognostic biomarker in colorectal cancer (CRC). Methods: MACC1 expression was evaluated by immunohistochemistry on tumor microarrays (N = 428). Patients were stage I-III CRC who received an oxaliplatin-based regimen (either with 5-FU (FOLFOX) or capecitabine (XELOX)) within the HeCOG 6C/08 observational study. MACC1 expression was assessed by a blinded GI pathologist using a scale ranging from 0 (no staining) to 3+ (strong expression). Each patient had at least 3 samples and the strongest result was used for the final score. MACC1 positivity was defined as ≥2+ expression and 0-1+ as MACC1-. Cox regression models were used to estimate hazard ratios (HR) for the association of MACC1 expression with patient characteristics, disease-free (DFS), and overall survival (OS). Results: 400/428 CRC tumors were evaluable: 322 (80.5%) were MACC1+ and 78 (19.5%) MACC1-. Mucinous features were less likely in MACC1+ patients (24% vs. 38%, p = 0.02). Other unfavorable features including grade, lymphovascular invasion, perineural invasion, and tumor mutational burden were not significantly different. There was no difference for stage, microsatellite instability, BRAF, KRAS, or NRASstatus between MACC1+/- cancers. There was a trend towards worse survival in MACC1+ patients regardless of treatment (DFS HR 1.55 [95% CI: 0.87, 2.76], OS HR 1.59 [95% CI 0.74, 3.4]). This difference was not statistically significant for OS (p = 0.26) or DFS (p = 0.08) even when stratified by clinicopathologic variables. Conclusions: Patients with MACC1+ CRC tumors who received adjuvant oxaliplatin-based therapy were less likely to have mucinous histology. They had a trend toward independently worse survival that was not significant when accounting for stage and clinicopathologic variables. Studies focused on the predictive role of MACC1 and oxaliplatin in stage III CRC are in progress.

Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated phosphatidylinositol 3-kinase (PI3K)/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors. Cancer Res; 74(1); 15–23. ©2013 AACR.

Loss of Pten expression and mutational inactivation of p53 are frequent molecular events in liver cancer associated with advanced disease stage and poor prognosis. The tumor suppressor PTEN is a phosphoinositide phosphatase that antagonizes the class IA PI3K-engaged oncogenic signaling by dephosphorylating PtdIns(3,4,5)P(3); however, the specific roles of class IA PI3K isoforms, p110a and p110b, have not been assessed in genetically engineered mouse models of liver cancer with Pten inactivation. Furthermore, effective treatment strategies for Pten and p53 deficient liver malignancy remain to be defined. In this study, we showed that combined deletion of Pten and p53 in liver led to rapid development of hepatocellular carcinoma and cholangiocellular carcinoma, the two most common types of liver cancer, with complete penetrance. While a single ablation of p110a or p110b markedly reduced the tumor burden, inactivation of both p110a and p110b completely blocked the liver tumorigenesis. Although liver tumors driven by inactivation of Pten and p53 showed a good response to GDC-0941, a pan-PI3K inhibitor, the combined treatment with both GDC-0941 and Rad001, an mTOR inhibitor or single-agent BEZ235, a dual pan-PI3K and mTOR inhibitor, led to marked tumor regression. These studies suggest that Pten and p53 cooperate to constrain the PI3K/mTOR pathway activation and inhibitors targeting both PI3K and mTOR may effectively treat Pten and p53 deficient liver cancers. Citation Format: Pixu Liu, Hailing Cheng, Lynn Symonds, Erbo Xu, Sauveur-Michel Maira, Emmanuelle di Tomaso, Thomas Roberts, Jean Zhao. The Pten and p53 tumor suppressors cooperate to constrain the PI3K/mTOR pathway activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2013-2713