Citations

Background: An expanded understanding of the biology of breast cancer has led to the identification of the HER-2 receptor as an important growth factor. This receptor possesses intrinsic tyrosine kinase activity and has been associated with aggressive biological behavior and poor clinical outcome. Methods: Data have been reviewed regarding the role of HER-2 expression as a prognostic variable, as a predictive factor for response to chemotherapy and hormonal therapies, and as a directed therapeutic target for breast cancer. Results: Therapy with a humanized monoclonal antibody to HER-2 (trastuzumab) can be effective treatment in some patients with metastatic breast cancer, either given alone or in combination with some chemotherapeutic agents. Cardiac toxicity limits concurrent use with anthracyclines. Clinical trials will further define optimal combination regimens with this agent, and its value in patients with localized or locally advanced stages. Conclusions: Trastuzumab is a significant addition to the armamentarium against breast cancer. Standardization of the optimal method to evaluate for HER-2 overexpression is necessary to better define its role as a prognostic, predictor, and therapeutic target in this disease.

Background: The management of patients with localized and advanced breast cancer continues to evolve. Chemotherapy, endocrine therapy, and trastuzumab are effective therapies but leave considerable room for improvement. As the cellular aberrations inherent to cancer cells in general and breast cancer cells specifically are better understood, therapies to target specific cellular pathways continue to be developed with the goal of expanding available effective therapy through better patient selection. Methods: We conducted a computerized search of the medical literature as well as a manual search of selected meeting abstracts. Results: Several targeted therapies are in phase III clinical trials testing their promise in the treatment of breast cancer. Many other agents are completing phase I and II testing. An overview of the most promising agents in clinical development is discussed herein. Conclusions: Targeted therapy for breast cancer is a reality at this time, and several new agents hold promise for expanding and refining the pool of patients likely to further benefit from this approach in the near future.

Abstract Cancer has been considered a heterogeneous disease, which mainly arises from the accumulation of genetic mutations, leading to a loss of tumor suppressor genes, as well as to an activation of oncogenes. The epigenetic mechanisms, such as DNA and histone modifications, are processes that regulate gene expression, and an alteration of these can contribute to cancer progression. Methylation on histone 3 lysine 9 (H3K9), in particular di-methyl (H3K9me2), is mainly mediated by the nuclear histone lysine methyltransferase G9a. Preliminary data showed that G9a was overexpressed in aggressive and highly metastatic forms of cancer. However, to date, this pathway has remained unstudied in esophageal adenocarcinoma. Interestingly, epigenetic drugs, such as those that target G9a, have the potential to reverse the adverse effects acquired downstream from genetic mutations, which currently cannot be directly repaired or targeted. In the current study, we utilize BRD4770, an S-adenosylmethionine (SAM) mimetic inhibitor of G9a, to determine the benefits of inhibiting this pathway in the context of esophageal adenocarcinoma. We hypothesize that pharmacological targeting of G9a by BRD4770 inhibits esophageal adenocarcinoma cell growth. To examine G9a-mediated dimethyl histone H3K9 levels in esophageal adenocarcinoma, we performed immunohistochemistry on paraffin-embedded esophageal adenocarcinoma tissues with an H3K9me2 antibody. In order to confirm specificity of BRD4770 in regulating the dimethyl histone H3K9 levels, and thus trimethyl H3K9 levels, in esophageal adenocarcinoma, we treated human esophageal adenocarcinoma cells (SKGT-4) with different doses of BRD4770 at various time points for western blot analysis using antibodies against histone H3K9me2 and H3K9me3. Moreover, we found that treatment of SKGT-4 cells with BRD4770 significantly inhibits cell proliferation by MTS assay, as well as clonogenic survival. Therefore, to determine the mechanism(s) by which BRD4770 inhibits the growth of esophageal adenocarcinoma cells, we utilized Caspase-3, Senescence, and Autophagy Assays. Our data shows that inhibition of G9a by BRD4770 does not induce Caspase 3 activity, while it significantly increases senescence and autophagy. Combined, our results suggest that BRD4770 has an important pharmacological role in regulating methyl histone H3K9 levels that may lead to inhibition of esophageal adenocarcinoma cell growth via an increase in senescence and autophagy. Further studies are focused on in vivo models to understand these effects in more detail, however the fact that an anti-G9a drug antagonizes esophageal adenocarcinoma cell growth raises optimism for its potential in the treatment of this malignancy. Note: This abstract was not presented at the meeting. Citation Format: Mabel G. Perez-Oquendo, Gwen A. Lomberk, Raul A. Urrutia, Sarah Kossak, Navtej Buttar, Sounak Gupta. Treatment with the G9a antagonist, BRD4770, inhibits esophageal adenocarcinoma cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-094. doi:10.1158/1538-7445.AM2017-LB-094

Abstract Background: Trastuzumab (H), a monoclonal antibody against HER2, has revolutionized the treatment for HER2-positive breast cancer. Besides inhibiting downstream signaling of HER2, several studies showed that H also exerts its anti-tumor activity via immune-related mechanisms. While H is quite effective in preventing recurrence, significant numbers of patients still develop recurrence despite adjuvant H-based chemotherapy. In this study, we analyzed immune-related genes that were associated with poor outcome in N9831. Methods: NanoStringTM technology was used to quantify mRNA of immune-related genes in baseline samples from 1,280 patients in N9831. In N9831, patients in arm A were treated with chemotherapy alone (AC-T), arm B received chemotherapy followed by sequential H (AC-T-H), and arm C received H concurrently with chemotherapy (AC-TH). Cox proportional hazard ratio (HR) was used to determine the association of each immune-related gene with recurrence free survival (RFS). Different immune subset signatures, including CD45, CD8, cytotoxic-cells, and T-cells were analyzed using algorithms developed by NanoString. Results: With the median follow up of 10.6 years, we identified a total 77 genes that were associated with improved outcome in arm C. Among these 77 genes, there were 20 tumor necrosis factor (TNF)-related genes. Of those, only OX40 (TNFRSF4) and its ligand TNFSF4 have interaction p < 0.10. Interestingly, we found uneven distribution of OX40 expression in the N9831 specimens. Approximately, 9.5% of HER2-positive breast cancer expressed OX40 at distinctly low level. Low expression of OX40 was significantly associated with HR positivity (OX40 low 61% vs. OX40 high 51%, p 0.003) and larger tumor size but not patients’ age, tumor grade, and lymph node status. Low expression of OX40 was significantly associated with low mTIL-CD45, CD8, cytotoxic-cells, and T-cells immune signature scores. Tumors with low OX40 expression had significantly lower levels of CTLA4 (p 9.11e-71) and PD-L1 expressions (p 2.49e-92). Low expression of OX40 is associated with poorer outcome among patients treated with H in both sequential (HR 0.88, 95% CI 0.79-0.98, p 0.022) and concurrent arms (HR 0.86, 95%CI 0.76-0.98, p 0.027) but not in chemotherapy only arm (HR 0.9, 95%CI 0.90-1.09, p 0.8). Similar findings were observed with its ligand TNFSF4 in arm A (HR 1.02, 95%CI 0.92-1.15, p 0.68), arm B (HR 0.87, 95%CI 0.76-0.99, p 0.04), and arm C (HR 0.81, 95%CI 0.68-0.95, p 0.01). Conclusion: Our study suggests that pre-existing expression of OX40 and its ligand TNFSF4 are prognostic and may also be predictive of adjuvant H benefit. Patients with distinctly low level of OX40 had poor outcome despite adjuvant H-based adjuvant chemotherapy. Our study provides a rationale to further evaluate the strategy to increase immune activation to improve outcome in this group of patients. Citation Format: Saranya Chumsri, Daniel J. Serie, Afshin Mashadi-Hossein, Sarah Warren, Alvaro Moreno-Aspitia, Geraldo Colon-Otero, Keith L. Knutson, Edith A. Perez, E. Aubrey Thompson. Correlation of immune co-stimulatory molecule OX40 and outcome in trastuzumab treated HER2-positive breast cancer patients in the NCCTG-N9831 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1682. doi:10.1158/1538-7445.AM2017-1682

Abstract LIN28 is well known as a RNA-binding protein and a suppressor of microRNA biogenesis, by selectively blocking the processing of let-7 precursors. It plays diverse functions in cellular reprogramming, development, metabolism and tumorigenesis. Many of these functions are executed through its ability to inhibit let-7 maturation. However, little is known about its function independent of let-7. Here we made zebrafish transgenic lines expressing high levels of either wild-type or mutant LIN28B (does not block the maturation of let-7) in the peripheral sympathetic nervous system driven by the dopamine beta-hydroxylase promoter. We bred these lines with a transgenic zebrafish line overexpressing the MYCN oncogene in these cells. Either wild-type or mutant LIN28B overexpression accelerated the onset and increased the penetrance of MYCN-induced neuroblastoma, despite the fact that only wild-type LIN28B blocked let-7 maturation compared to MYCN-only tumors. Mechanistically, both wild-type and mutant LIN28B overexpression enhanced MYCN-induced hyperplasia by increasing cell proliferation in the sympathoadrenal lineage. Further studies revealed that overexpression of either wild-type or mutant LIN28B resulted in hyperphosphorylation of AKT on both Ser473 and Thr308 in zebrafish tumors and also serum-deprived human neuroblastoma cell lines. Both wild-type and mutant LIN28B interacted with IGF2BP1, a known interactor that increases stability and translation of a subset of RNAs. We found IGF2 RNA levels to be increased in response to either form of LIN28B. Coincident with IGF2 overexpression, IGF1R was phosphorylated, providing an explanation for PI3K-AKT activation in LIN28B overexpressing cells. Finally, overexpression of a constitutively active, myristoylated murine Akt2 (myr-mAkt2) alone in zebrafish induced ganglioneuroma in the interregnal gland (the zebrafish equivalent of the human adrenal medulla), without a requirement for MCYN overexpression. Thus, our studies indicate that overexpression of LIN28B leads to AKT activation mediated through its interaction with IGF2BP1 and subsequent upregulation of IGF2. This pathway provides a mechanism underlying enhanced transformation in LIN28B overexpressing neuroblastomas, which is independent of the inhibitory activity of LIN28B on let-7 maturation. Citation Format: Ting Tao, John T. Powers, Hui Shi, Pavlos Missios, Antonio R. Perez-Atayde, Shizhen Zhu, George Q. Daley, Thomas A. Look. LIN28B-mediated let-7 independent activation of AKT promotes neuroblastoma pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1040. doi:10.1158/1538-7445.AM2017-1040

Abstract Previous studies have implicated estrogen as a regulator of epidermal growth factor receptor (EGFR) expression in breast tumors. We therefore speculated that estrogen might modulate serologic soluble EGFR (sEGFR) concentrations in breast cancer patients. Accordingly, we measured serum sEGFR concentrations in postmenopausal women with metastatic breast cancer (MBC) treated with letrozole, an aromatase inhibitor that blocks estrogen synthesis. Serum specimens were obtained prior to and following 1 and 3 months of letrozole therapy. We report that sEGFR concentrations do not differ between MBC patients prior to letrozole treatment and age- and postmenopause-matched healthy women (P = 0.468). In contrast, however, sEGFR concentrations decreased significantly in 76% of MBC patients after both 1 month (P = 0.006) and 3 months (P = 0.003) of letrozole therapy versus pretreatment concentrations. Within the limitations of this study, we found no evidence for an association between pretreatment sEGFR concentrations or decreased treatment sEGFR concentrations and either progression-free or overall survival. Nonetheless, we conclude that future prospective studies are warranted to determine if baseline and/or longitudinal serum sEGFR concentrations may be useful for predicting disease progression and survival, and/or for monitoring responsiveness to aromatase inhibitors or other endocrine therapies in breast cancer patients.

In this study, we present a simple and effective process that integrates hydrogels with drugs + ceramics via physical crosslinks resulting in improved mechanical properties. These cryogels have the potential for controlled drug release and stimulus responsive behavior. The hydrogels were produced from polyvinyl alcohol (PVA) and polyacrylic acid by varying the molecular weight of the polymers, via freeze‐thawing technique. The cryogels were combined with two ceramics: (1) a combination of beta‐tricalcium phosphate, wollastonite, magnesium silicate and (2) titanium dioxide nanopowder. Theophylline, a model drug, was incorporated into the structure to analyze the drug release behavior. A layered structure was produced by adding both hydrogels + ceramics into a mold where a PVA dried film acted as a barrier and reinforcing structure. The results showed that the barrier integrated between both hydrogels by a physically crosslinking mechanism. This adhesion was demonstrated using Fourier‐transform infrared spectroscopy and scanning electron microscopy. Swelling of this composite showed the profile of drug release from both hydrogels + ceramics while simultaneously releasing the drug independently without diffusing via the opposite layer. Finally, mechanical properties were improved with the addition of the ceramics, which demonstrates the potential approach in terms of modification of weak hydrogel systems. POLYM. COMPOS., 39:E210–E220, 2018. © 2017 Society of Plastics Engineers

Abstract Background VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first-line treatment regimen for patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co-infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co-infused, followed by vinorelbine. Patients and Methods During cycle 1, patients with HER2-positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m2) on days two and nine. From cycle 2 onwards, patients received a co-infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30–35 mg/m2) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS) and safety. Results Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0–73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3–15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade ≥3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure. Conclusion These results support the feasibility of pertuzumab and trastuzumab co-infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160–1168

ABSTRACTBackground and Objectives: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy.Methods: Dynamic PET scans were obtained for 70 minutes after the bolus injection of [11C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region.Results: In comparison to the control group, PSP subjects showed specific uptake of [11C]PBB3 in putamen, midbrain, GP, and SN. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. A DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and GP. In SNCA duplication carriers, there was a significant increase of [11C] PBB3 binding in GP, putamen, thalamus, ventral striatum, SN, and pedunculopontine nucleus. The MSA case showed increased binding in frontal lobe, GP, midbrain, parietal lobe, putamen, temporal lobe, SN, thalamus, and ventral striatum.Conclusions: All PSP patients showed increased retention of the tracer in the basal ganglia, as expected. Binding was also present in asymptomatic SNCA duplication carriers and in an MSA case, which are not typically associated with pathological tau deposition. This suggests the possibility that [11C]PBB3 binds to alpha‐synuclein. © 2017 International Parkinson and Movement Disorder Society