Foundation For Cancer Research Research Articles

Self-Reported Adherence to Capecitabine on XELOX Treatment as Adjuvant Therapy for Colorectal Cancer.

Adherence has become an important issue in modern oncology treatment. Most studies have included heterogeneous target tumor types, regimens, and therapy settings. Our study focused on capecitabine during capecitabine plus oxaliplatin (XELOX) treatment as an adjuvant therapy for colorectal cancer. The main aims of this study were to evaluate real-life adherence to capecitabine and to investigate candidate factors that might decrease adherence. We studied 338 consecutive patients who received XELOX treatment between December 1, 2011, and April 30, 2015, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Our study assessed adherence to capecitabine through patient-reported treatment diaries and interviewed nonadherents to determine the reasons for not taking capecitabine at a pharmaceutical outpatient clinic. We calculated the adherence rate in a cycle as: number of times the patient took capecitabine/28. Relative dose intensities and factors associated with deteriorating adherence to capecitabine were retrospectively surveyed from electronic patient records. Uni- and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence. The study covered 282 patients who received 2,055 cycles of XELOX. Median adherence rate was 94.0% in the first cycle, and median relative dose intensity of capecitabine was 77.8%. The most common reasons for nonadherence were nausea/vomiting and diarrhea. The presence of the following factors was not significantly associated with adherence: ECOG performance status ≥1 (p = 0.715), clinical stage (p = 0.408), primary tumor site (p = 0.576), age ≥70 years at study entry (p = 0.757), female gender (p = 0.504), and not living alone (p = 0.579). The adherence rate from this study was significantly higher than the adherence from metastatic settings. Adherence-enhancing interventions for capecitabine in XELOX treatment as adjuvant therapy comprised management of nausea/vomiting and diarrhea.

Population-Based Assessment of Complications After Surgery for Thyroid Cancer

Context: As thyroid cancer incidence rises, more patients undergo thyroid surgery. Although postoperative complication rates have been reported in single institution studies, population-based data are limited. Objective: To determine thyroid cancer surgery complication rates and identify at-risk populations. Design/Setting/Patients: Using the Surveillance, Epidemiology, and End Results-Medicare database, we evaluated general complications within 30 days and thyroid surgery-specific complications within 1 year in 27,912 patients who underwent surgery for differentiated or medullary thyroid cancer between 1998 and 2011. Multivariable analyses of patient characteristics associated with postoperative complications were performed. Main Outcome Measures: General and thyroid surgery-specific complications. Results: Overall, 1820 (6.5%) patients developed general postoperative complications (fever, infection, hematoma, cardiopulmonary, and thromboembolic events) and 3427 (12.3%) patients developed thyroid surgery-specific complications (hypoparathyroidism/hypocalcemia and vocal cord/fold paralysis). In multivariable analyses, general and thyroid surgery-specific complication rates were significantly higher in patients >65 years (odds ratio [OR] 2.61, confidence interval [95% CI] 2.31, 2.95; OR 3.12, 95% CI 2.85, 3.42), those with a Charlson/Deyo comorbidity score of 1 (OR 2.40, 95% CI 1.66, 3.49; OR 1.88, 95% CI 1.53, 2.31) and ≥2 (OR 7.05, 95% CI 5.33, 9.56; OR 3.62, 95% CI 3.11, 4.25), and those with regional (OR 1.18, 95% CI 1.03, 1.35; OR 1.31, 95% CI 1.19, 1.45) or distant disease (OR 2.83, 95% CI 2.30, 3.47; OR 1.85, 95% CI 1.54, 2.21), respectively. Conclusions: The rates of thyroid cancer surgery complications are higher than predicted, and patients with older age, more comorbidities, and advanced disease are at greatest risk. This has implications for patients undergoing thyroid cancer surgery. Efforts to reduce complications are needed. Acknowledgments: M.P. is funded by the National Institute on Aging of the National Institutes of Health under Award K08 AG049684 and a Career Development Pilot Grant from the Cancer Control and Population Sciences Program at the University of Michigan. M.R.H. is funded by Grant R01 CA201198 from the National Cancer Institute and Grant R01HS024512 from the Agency for Healthcare Research and Quality. The Punya Foundation for Thyroid Cancer Research also provided support for this project. The content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health or Agency for Healthcare Research and Quality. No competing financial interests exist. Runtime of video: 5 mins 23 secs Abstract reproduced from Papaleontiou M, Hughes DT, Cui G, Banerjee M, Haymart MR. Population-Based Assessment of Complications Following Surgery for Thyroid Cancer, Journal of Clinical Endocrinology and Metabolism, 2017, 102(7); 2543–2551, by permission of Oxford University Press and the Endocrine Society.

Abstract 5584: PHY906(YIV-906), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Immune checkpoint blockade therapy: anti-PDL1, anti-PD1, anti-PD1/CTLA4 against melanoma

Abstract Immune checkpoint blockade therapy has recently been recognized as a breakthrough in cancer treatment. Currently the FDA has approved Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD1) and Nivolumab (anti-PD1), and Atezolizumab (anti-PDL1) for the treatment of several types of cancers, including melanoma. However, colitis and diarrhea are commonly found in these immunotherapies, particularly in anti-PD1/CTLA4 therapy. PHY906(YIV-906) is inspired by the Huang Qin Tang, which was first described in Chinese texts 1800 years ago for the treatment of numerous gastrointestinal symptoms. Consistent preparations of PHY906 could be manufactured apart 10 years. In animal studies, PHY906 can increase the anti-tumor activity of a broad spectrum of chemotherapies while promoting damaged intestinal tissue recovery via mutliple targets. Several clinical results suggest that PHY906 had potential to increase the therapeutic index of cancer treatments (chemotherapy, radiation) by prolonging life and improving patient quality of life. We hypothesize that PHY906 can reduce diarrhea caused by anti-PD-L1, anti-PD1, and/or in combination with CTL4 without compromising their anti-tumor activity. We studied the effect of PHY906 in combination with anti-PDL1, anti-PD1, anti-CTLA4 and anti-PD1/CTLA4, using subcutaneously implanted B16F10 melanoma in Black B16 mice. Results indicated that PHY906 enhanced the anti-tumor activity of anti-PD1, anti-PDL1, or anti-PD1/CTLA4; but not anti-CTLA4 alone, in vivo. In addition, PHY906 did not compromise the action of anti-PD-L1 in brain implanted B16 tumor. PHY906 in combination with all of the antibodies had no impact of body weight change or different type of blood cells counts. PHY906 reduced mRNA expression of several inflammation markers, including TNFa, MCP1, ICAM, IL2, in ileum or colon tissues following anti-PD1 or anti-CTLA4 treatment. In cell culture, PHY906 was found to have modulation effect on Indoleamine 2,3-dioxygenase (IDO) which is a key resistance factor to immune checkpoint blockade therapies. Overall, PHY906 can increase the therapeutic index for anti-PDL1, antiPD1, or anti-PD1/CTLA4 in against melanoma. We are planning to initiate a clincal trial to determine if PHY906 could enhance the therapeutic index of anti-PD1/CTLA4 for the treatment fo melanoma in patient. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA. Citation Format: Wing Lam, Zaoli jiang, Xue han, Shwu-Huey Liu, Lieping Chen, YungChi Cheng. PHY906(YIV-906), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Immune checkpoint blockade therapy: anti-PDL1, anti-PD1, anti-PD1/CTLA4 against melanoma [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 5584. doi:10.1158/1538-7445.AM2017-5584

Abstract 3138: Mechanism based quality control (MBQC) for the four-herb Chinese medicine formulation, PHY906(YIV-906) and other herbal products

Abstract PHY906(YIV-906), a four-herb Chinese medicine formulation, is inspired by an 1800 year-old Chinese formulation called Huang Qin Tang historically used to treat gastrointestinal symptoms. PHY906 can increase the anti-tumor activity of immunotherapy antibodies or chemotherapies while promoting damaged intestinal tissue recovery. Several clinical studies showed that PHY906 had potential to increase the therapeutic index of cancer treatments (chemotherapy, radiation) by prolonging life and improving patient quality of life. When in vivo activities of three different clinical batches (number 6, 10, 11) of PHY906 and F (which is commercial batch of Huang Qin Tang, HQT) was compared to their similarity of chemical profiles, the two set results could not be completely matched. For example, F had very different in vivo activities from PHY906-10 but F clustered closely to PHY906-10 based on their chemical profiles. This information concludes that chemical profile analysis without excluding irrelevant chemicals is not sufficient to evaluate the in vivo activities of a polychemcial mixture. Therefore, we included another two biological platforms based on the in vivo mechanism of action of PHY906 for the quality control. First, we tested the activity of different batches of PHY906 and F on our signaling transduction activity response (STAR) platform which including 18 luciferase reporter cell lines and 2 enzymatic assays. The results of correlation analysis and clustering analysis based on the results from STAR could be matched to in vivo activities of different batches of PHY906 and F. Second, we tested the effect of different batches of PHY906 and F on a set of genes which based on our previous DNA array data in cell culture and the mechanism action of PHY906. Again, the results of correlation analysis and clustering analysis based on qRT-PCR could be matched to to in vivo activities of PHY906 and F. In conclusion, the quality control of a herbal product should be dependent on its usage. Appropriate biological assays based on its mechanism action should be developed for QC for particular usage. Chemical fingerprint has limitation unless irrelevant chemicals had been filter out. Similarity index is only useful when relevant information is used. Mechanism based quality control could be used for other herbal products. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA. Citation Format: Wing Lam, Yongshen Ren, Fulan Guan, Zaoli jiang, William Cheng, Shwu-Huey Liu, YungChi Cheng. Mechanism based quality control (MBQC) for the four-herb Chinese medicine formulation, PHY906(YIV-906) and other herbal products [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 3138. doi:10.1158/1538-7445.AM2017-3138

Abstract 1882: Tankyrase-binding protein TNKS1BP1 regulates cancer cell invasion

Abstract Tankyrase, a member of poly(ADP-ribose) polymerase (PARP) family, catalyzes addition of long PAR chains onto the acceptor proteins, such as TRF1, a telomere-binding protein, and Axin, a repressor of Wnt/β-catenin signaling. Tankyrase-mediated PARylation of TRF1 and Axin represses the biological functions of these proteins, leading to enhanced telomere elongation by telomerase and upregulation of Wnt/β-catenin signaling, respectively. Thus, tankyrase is a multifunctional protein that supports oncogenic properties of cancer cells. Given that tankyrase has a large protein-protein interaction platform called ANK repeat clusters, and is broadly distributed to various intracellular loci, including telomeres, nucleoplasm, nuclear pore complexes, cytoplasm, Golgi, and spindle poles, this protein seems to have a yet unidentified function. In the present study, we explored the function of a novel tankyrase-binding protein called TNKS1BP1 and elucidated its contribution to regulating cancer cell invasion. Since TNKS1BP1 co-localizes with the actin filaments, we first examined the effect of genetic manipulation of TNKS1BP1 expression on cell invasion. We found that TNKS1BP1 depletion by small interfering RNAs increased the invasive capacity of human fibrosarcoma cells, whereas its overexpression decreased the cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion and lamellipodia ruffling were increased with activation of the ROCK-LIMK-cofilin pathway, which promotes cell motility. Importantly, tankyrase overexpression reproduced the phenotype of TNKS1BP1-depleted cells and enhanced cell invasion in a PARP activity-dependent manner. Under approval by Institutional Review Board of Japanese Foundation for Cancer Research, we performed immunohistochemical analysis of clinical pancreatic cancer. We found that TNKS1BP1 protein expression is decreased in invasive regions of the tumors. Taken together, these observations suggest that the tankyrase-TNKS1BP1 axis constitutes a post-translational modulator of cell invasion and its aberration promotes cancer malignancy. Citation Format: Tomokazu Ohishi, Haruka Yoshida, Masamichi Katori, Toshiro Migita, Yukiko Muramatsu, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Shun-ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya. Tankyrase-binding protein TNKS1BP1 regulates cancer cell invasion [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 1882. doi:10.1158/1538-7445.AM2017-1882

The Tyrosine Phosphatase PRL3 Drives T‐Cell Acute Lymphoblastic Leukemia Progression

T‐cell acute lymphoblastic leukemia (T‐ALL) is a major clinical challenge, representing 15–25% of all acute lymphoblastic leukemias in children and adults. The survival rate for pediatric patients with relapsed T‐ALL is a disheartening <30% in pediatric patients and <10% in adults. Current drugs against T‐ALL include highly cytotoxic chemotherapies, which are generally ineffective against relapse and are particularly hard for young children to receive. These harsh therapies can result in a spectrum of developmental issues and potent side‐effects. Therefore, it is imperative to develop molecularly targeted therapies that can effectively inhibit T‐ALL progression without contributing to the adverse side‐effects of general chemotherapy.We have found that zebrafish T‐ALL cells acquired amplification and high expression of the Protein Tyrosine Phosphatase 4A3 (PRL3) concurrent with evolution of enhanced relapse potential in a transplantation screen involving over 6,000 animals. Further, approximately 50% of human T‐ALL patients have high PRL3 expression. PRL3 has not been associated with leukemia onset or progression, but here we show overexpression of PRL3 leads to increased T‐ALL onset and aggressiveness in an in vivo transgenic zebrafish T‐ALL model. Small molecule inhibitors of PRL3 significantly reduced viability of established cultures of human T‐ALL cells in vitro. Based on these data, we hypothesize that PRL3 plays an important role in T‐ALL cell survival at all stages of leukemia progression. We are currently using fluorescent and confocal microscopy in zebrafish over‐expressing PRL3 to determine the cellular mechanisms by which PRL3 enhances leukemia onset. We are also generating PRL3 knockout lines using a CRISPR‐Cas9 for similar studies. Finally, we are treating zebrafish bearing T‐ALL with two specific, research‐grade PRL inhibitors to determine if blocking PRL3 phosphatase activity prevents leukemia onset and relapse. We have also identified several FDA‐approved, general phosphatase inhibitors that have potent anti‐PRL activity and are capable of killing ALL cells in vitro. Current work is focused on screening these inhibitors in vivo in our zebrafish models.We conclude that PRL3 is a novel gene that may be important for T‐ALL onset and progression. As a phosphatase, it is a unique druggable target. Future directions will focus on identifying the molecular mechanisms by which PRL3 drives leukemia progression, and moving top drug hits from our zebrafish screens into pre‐clinical testing in patient derived xenografts models in mice. We hope that our findings may lead to eventual clinical trials as alternatives to the traditional cytotoxic chemotherapy offered to pediatric T‐ALL patients now.Support or Funding InformationNCI 4R00CA181500NIGMS P30GM110787The V Foundation for Cancer Research

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

Self-reported adherence to regorafenib for metastatic colorectal cancer: A retrospective cohort study.

783 Background: Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) and it is frequently involved in various adverse events. The clinical factors affecting adherence to regorafenib remain unclear. The aim of this study is to evaluate adherence to regorafenib in patients with mCRC and to identify candidate factors which might have influence on adherence to regorafenib. Methods: We evaluated 106 consecutively enrolled patients with mCRC who received regorafenib between May 18, 2013 and March 2, 2015 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Adherence to regorafenib was checked by pharmacists using a self-reported treatment diary for patients at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of actual intakes per 21 intakes scheduled in each cycle. We retrospectively surveyed median relative dose intensities of regorafenib and the factors deteriorating adherence across three cycles. Univariate analyses were then performed using patient socio-demographic factors and clinical factor. Multivariate analysis was performed using logistic regression. Significance levels for uni- and multivariate analyses were p < 0.2 and p< 0.05, respectively. Results: A total of 81 patients were evaluated in the study analysis. Adherence rates were 64.4% in the first cycle of regorafenib treatment, 77.4% in the second cycle, and 83.8% in the third cycle. The median relative dose intensity was 57.6%. The most common reasons for non-adherence were hand-foot skin reaction (34.3%, 331 instances), and liver dysfunction (15.3%, 148 instances). In multivariate analysis, increased non-adherence to regorafenib was significantly associated with gender (female) [odds ratio (OR) = 0.20; 95% confidence interval (CI): 0.06-0.68, p = 0.01] and adverse events ( ≥ Grade 3) [OR = 3.16; 95% CI: 1.00-9.97, p= 0.04) in the first cycle.] Conclusions: The high frequency of treatment-related hand-foot skin reaction and liver dysfunction is the main factor affecting adherence to regorafenib. Intensive supportive care in the management of these symptoms could assist adequate adherence to regorafenib.

The Efficacy of JAK2 Inhibitor in Heavily Pretreated Classical Hodgkin Lymphoma: A Prospective Pilot Study of Ruxolitinib in Relapsed or Refractory Classical Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma

BackgroundJAK2 expression and activity increased in classical Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL) because both of them were reported to have chromosome 9p24.1/JAK2 amplification. Thus, JAK2 has been suggested as a potential therapeutic target in both disease having similar clinical and genetic features, and a previous in vitro and in vivo study showed cHL and PMBCL with JAK2 amplification were sensitive to JAK2 inhibition. However, the efficacy of JAK2 inhibitor has never been evaluated in clinical trials with cHL and PMBCL patients. We performed a prospective pilot proof of concept study with JAK2 inhibitor, ruxolitinib in relapsed or refractory cHL and PMBCL to evaluate the effect of JAK2 inhibition.MethodsThis study enrolled only relapsed or refractory cHL and PMBCL. Subjects should experience at least two times of relapse or treatment failure before enrollment. We enrolled subjects who were more than 18 years and had at least one lesion of FDG-PET positive measureable disease. Ruxolitinib was administered orally at a dose of 20 mg twice a day of a 28-day cycle. Treatment cycles were repeated up to 16 cycles until disease progression or unacceptable toxicity occurred. The primary objective was to assess the overall disease control rate including the achievement of complete response (CR), partial response (PR) and stable disease (SD). Response evaluation was done according to the 2007 Cheson criteria, and the planned number of subjects was 20. Pathology review was done by the Korean Lymphoma Pathology Review Board after the enrollment was completed. The JAK2 amplification in tumor cells was independently analyzed by the Cancer Institute Hospital of Japanese Foundation for Cancer Research without clinical information. Details of the study were registered at ClinicalTrials.gov (NCT01965119).ResultsWe enrolled 20 patients (median age: 43, range: 19 - 76) including 14 cHL and 6 PMBCL between 2013 and 2015. The median number of prior therapies was four (range: 2 - 10). Eight patients underwent autologous stem cell transplantation, and ten patients received involved field radiotherapy during their treatment period. Four cHL (29%, 4/14) and four PMBCL (67%, 4/6) were primarily refractory to induction treatment. At the time of enrollment, 18 patients were refractory to salvage treatment, and two patients relapsed five years after their last treatment. The first response evaluation after the 2nd cycle showed 40% (7/20) of overall disease control rate (1 CR, 6 PR, and 1 SD). However, one cHL case with PR was excluded from the analysis after the final diagnosis was changed to chronic active EBV infection by the pathology review board. The comparison between cHL and PMBCL showed more efficacy of ruxolitinib in cHL because all patients with PMBCL rapidly progressed after 1st or 2nd cycle whereas disease was controlled in seven patients with cHL (1 CR, 5 PR and 1 SD) out of 13 patients with cHL (54%, 7/13). Although the median number of treatment cycle of all patients was two (range: 1-10), six responders received on the average five cycles of treatment (range: 4-10), and the median duration of response was 5 months (range: 4 - 12+ months). The toxicity was manageable without any grade 3 or 4 hematologic and non-hematologic toxicity. Most non-hematologic toxicities including liver enzyme elevation and abdominal pain were grade 1 or 2. The analysis of JAK2 amplification by FISH was done in 9 patients whose tissue sample was available. Among three patients with high amplification (more than 10 signals), only one SD was observed whereas two patients achieved PR out of six cases with low or absent amplification.ConclusionsThe efficacy of ruxolitinib in heavily pretreated patients with relapsed or refractory cHL suggested JAK2 inhibition might be more effective for the treatment of cHL than PMBCL. A phase I/II study with larger study population should be warranted based on our results of pilot study. DisclosuresKim:Celltrion, Inc.: Consultancy, Honoraria.

Trisenox: a paradigm shift in APL therapy, an interview with Francesco Lo-Coco.

Francesco Lo-Coco speaks to Sebastian Dennis-Beron, Commissioning Editor: Francesco Lo-Coco is currently a full professor of hematology and head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases at the Department of Biomedicine and Prevention of the University Tor Vergata of Roma. He obtained his MD degree from the University of Pisa in 1981, and his specialization in clinical and laboratory hematology is from the University La Sapienza of Rome in 1985. From 1992 to 1994, he has trained on molecular genetics of lymphomas at Columbia University, New York. His main scientific interest and research activities include genetic characterization, monitoring and treatment of hematologic tumors, particularly acute myeloid leukemia and acute promyelocytic leukemia (APL). He has published over 390 internationally peer-reviewed articles, mainly focused on molecular diagnosis and follow-up of leukemia as well as on treatment of APL. He chairs at present the APL subcommittee of the Italian National Cooperative Group, GIMEMA. He served as president of the Italian Society of Experimental Hematology, chairman of the Education Committee of the European Hematology Association, board member of the Italian Foundation for Cancer Research, member of the Committe on Health Research of the Italian Ministry of Health and member of the Editorial Board of the journals Leukemia, Journal of Clinical Oncology and Haematologica.

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer

BackgroundMetastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. MethodsIn this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. FindingsSIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. InterpretationThe discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. FundingThis work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

Abstract B34: Integrated Approaches to Treating Lung Adenocarcinoma Resistant to Targeted Therapy

Abstract Mutations in the EGFR gene or transcript fusion involving EML4-ALK result in oncogenic activation of these oncogenes driving lung adenocarcinoma growth in tumors carrying such an alteration. For lung adenocarcinoma with these genetic changes, small-molecule tyrosine kinase inhibitors have been highly effective at reducing tumor burden and improve the outcome of the patients. Unfortunately, drug resistance eventually develops in these tumors and challenges remain in controlling lung cancer recurrence after targeted therapy. To overcome recurrence, we initiated a prove-of-principle study to evaluate the feasibility of an integrated strategy utilizing genomic profiles of the tumor and patient-specific tumor xenografts derived (PDX) from biopsies for ex vivo evaluation of antitumor drugs to help guide personalized treatment of lung cancer in patients who have developed resistance to targeted therapy drugs. Our study has three main objectives. 1) Use tumor biopsies obtained at the time of recurrence for oncogene mutation and RNAseq analyses to identify molecular changes in oncogenes and gene pathways that can be potentially targeted. 2) Evaluate drug efficacy and optimize personalized therapy for each patient using PDX models. 3) Assess clinical feasibility and our experience using integrated approaches for lung cancer patients who failed targeted therapy. This study was approved by the Mayo Clinic Institutional Review Board (IRB) and utilizes both clinical and research biopsies. A dedicated nurse study coordinator reviews clinical patient list and history on weekly basis and informs the study team of each potential candidate patient. A total of 30 patients having ALK positive lung cancers have been identified and followed up from nearly 500 potentially ALK positive cases between April 2014 to Sept. 2015. Most patients were never smokers but six were former smokers and two were current smokers. Age at diagnoses ranged from 27-78 years (median = 61). Seven patients (23%) were 45 years or younger at the time of diagnosis. A total of 22 patients are currently being treated with crizotinib while eight are on ceritinib or alectinib. For each biopsy, tumor tissues are obtained using a 20 gauge needle, transferred on ice in preserving media and implanted within one hour into 6-8 week old NOD/SCID mice. Many patients have been on treatment for 2-3 years with stable disease so they do not require biopsy. Using a similar strategy, we also obtained biopsies from patients with EGFR gene mutations in their tumors and have progressed while on targeted therapy. A total of seven cases have been implanted. We will report our experiences in patient selection, clinical follow up, patient consent, PDX development, time from biopsy to tumor establishment, and the results of molecular analyses. Our study enabled us to gain new insights regarding the molecular changes associated with recurring tumors after they have failed targeted therapy as well as clinical experiences on how to utilize state-of-the art approaches and comprehensive genomic information to further improve cancer patient care upon disease progression. Acknowledgements: This work is supported in part by the Hillsberg Award from the National Foundation for Cancer Research and by the Biomarker Discovery Program at the Mayo Clinic Center for Individualized Medicine. Citation Format: Jin Jen, Aaron Mansfield, Patrick W. Eiken, Shawn Stoddard, Karlyn Pierson, Xiaonan Hou, Hong Zheng Ren, Julian Molina, Joanne Yi, Ping Yang. Integrated Approaches to Treating Lung Adenocarcinoma Resistant to Targeted Therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B34.

Abstract 3377: Bevacizumab-improved distribution of paclitaxel in ovarian cancer xenografts potentiates antitumor efficacy

Abstract Angiogenesis inhibitors have shown antitumor efficacy when combined with chemotherapy. It has been proposed that this potentiation is related to better drug delivery to the tumor due to improved vessel functionality. This work combined classical pharmacokinetics and imaging analysis to study the delivery and distribution of paclitaxel after bevacizumab in ovarian cancer. The study was conducted on ovarian cancer models (A2780-1A9 and IGROV-1) xenografted orthotopically under the bursa of the nude mouse ovary. Mice bearing tumors in the ovary, treated with bevacizumab (150μg/mouse) and 24 hours later with paclitaxel (60mg/kg), were sacrificed and tumor excised for analysis, or monitored for anti-tumor activity. Paclitaxel spatial distribution after bevacizumab was analyzed by MALDI-Mass Spectrometry Imaging (MALDI-MSI) on frozen tumor slices, and compared with adjacent histochemical images stained for CD31 (vessel analysis) and Ki-67 (proliferation/necrosis); total paclitaxel in tumor homogenates, liver and plasma was evaluated by high-performance liquid chromatography (HPLC). Tumor growth of A2780-1A9 and IGROV-1, carrying the firefly luciferase gene luc2, was monitored by Bioluminescence imaging (BLI) and survival recorded. Bevacizumab decreased tumor vessel number/size compared to vehicle treated mice, but potentiated the antitumor activity of paclitaxel in both models. MALDI-MSI showed that after bevacizumab, paclitaxel was more homogenously distributed and mainly in actively proliferating areas of the tumor where vessels were uniformly diffused, despite paclitaxel concentration did not increase after antiangiogenic drug. No changes in paclitaxel systemic exposure was found in normal tissue. These findings suggest that a more uniform distribution of paclitaxel in the tumor of the mouse ovary is responsible for the better antitumor activity of the combination. A.D. and I.F.N. are the recipients of a fellowship from the Italian Foundation for Cancer Research (FIRC). Citation Format: Marta Cesca, Lavinia Morosi, Alexander Berndt, Ilaria Fuso Nerini, Alessandra Decio, Massimo Zucchetti, Raffaella Giavazzi. Bevacizumab-improved distribution of paclitaxel in ovarian cancer xenografts potentiates antitumor efficacy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3377.

Abstract SY03-01: Macrophage PI3Kgamma drives cancer immune suppression

Abstract Innate immune cells can switch from a proinflammatory state that defends against pathogens and to an anti-inflammatory state that repairs damaged tissue. Proinflammatory myeloid cells activate cytotoxic T cells to eliminate pathogens, but anti-inflammatory myeloid cells inhibit T-cell-mediated immunity, stimulate angiogenesis, and stimulate fibrosis, all of which promote tumor progression. The predominant isoform of PI(3)Kinase in myeloid cells, PI3Kgamma, controls this switch between immune stimulation and immune suppression during inflammation and cancer. Myeloid cell PI3Kgamma and its effectors Akt1, mTor, and S6Kinase stimulate C/EBPbeta-dependent expression of immunosuppressive factors, including Arginase and TGFbeta, while also suppressing NFkappaB-dependent expression of proinflammatory cytokines such as IL12 and IFNgamma, thereby inducing tumor immune suppression and consequent tumor growth and metastasis. In contrast, inhibition of PI3Kgamma activity by genetic or pharmacological means suppresses C/EPBbeta-mediated transcription of anti-inflammatory factors and stimulates NFkappaB-mediated transcription of the proinflammatory cytokines IL12 and IFNgamma, thereby restoring CD8+ T-cell-dependent cytotoxicity that inhibits tumor growth and metastasis. Therefore, inhibitory targeting of PI3Kgamma indirectly restores cytotoxic T-cell immune responses that elicit tumor suppression without unwanted side effects. Our studies highlight the strong therapeutic potential of targeting this kinase to control inflammation and cancer. This work was supported by grants to JAV from the NIH (5R01CA126820), the Landon Foundation-AACR (12-60-27-VARN), the Lustgarten Foundation for Pancreatic Research and the Whitworth Foundation for Cancer Research. Citation Format: Judith A. Varner. Macrophage PI3Kgamma drives cancer immune suppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY03-01.

Abstract 718: Macrophage PI3Kgamma signaling promotes cancer immune suppression

Abstract Innate immune cells can switch from a pro-inflammatory state that defends against pathogens and to an anti-inflammatory state that repairs damaged tissue. Pro-inflammatory myeloid cells activate cytotoxic T cells to eliminate pathogens, but anti-inflammatory myeloid cells inhibit T cell mediated immunity, stimulate angiogenesis, and stimulate fibrosis, all of which promote tumor progression. The predominant isoform of PI(3)Kinase in myeloid cells, PI3Kgamma, controls the switch between immune stimulation and immune suppression during inflammation and cancer. Myeloid cell PI3Kgamma and its effectors Akt1, mTor, and S6Kinase stimulate C/EBPbeta-dependent expression of immunosuppressive factors, including Arginase and TGFbeta, but suppress NFkappaB-dependent expression of pro-inflammatory cytokines such as IL12 and IFNgamma, thereby inducing tumor immune suppression and consequent tumor growth and metastasis. In contrast, inhibition of PI3Kgamma activity by genetic or pharmacological means suppresses C/EPBbeta-mediated transcription of anti-inflammatory factors and stimulates NFkappaB-mediated transcription of the pro-inflammatory cytokines IL12 and IFNgamma, thereby restoring CD8+ T cell-dependent cytotoxicity that inhibits tumor growth and metastasis. Therefore, inhibitory targeting of PI3Kgamma indirectly restores cytotoxic T cell immune responses that elicit tumor suppression without unwanted side effects. Our studies highlight the strong therapeutic potential of targeting this kinase to control inflammation and cancer. This work was supported by grants to JAV from the NIH (5R01CA126820), the Landon Foundation-AACR (12-60-27-VARN), the Lustgarten Foundation for Pancreatic Research and the Whitworth Foundation for Cancer Research. Citation Format: Megan M. Kaneda, Judith A. Varner. Macrophage PI3Kgamma signaling promotes cancer immune suppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 718.

Therapeutic effect of taxanes on metastatic breast cancer of various immunohistochemical subtypes.

Taxane drugs play a central role in chemotherapy for breast cancer. However, previous studies have reported that taxanes are relatively ineffective in patients with operable luminal breast cancer compared with other subtypes. Between January 2000 and August 2008, 293 patients with metastatic breast cancer were treated with taxanes in The Cancer Institute Hospital of The Japanese Foundation for Cancer Research and were included in the present study. The patients were divided into 4 subtypes based on the immunohistochemically evaluated estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status. The clinicopathological features, response rate (RR) and time to progression (TTP) were analyzed retrospectively. In total, 159 patient tissues were classified as luminal type (ER+ and/or PgR+ and HER2-), 28 patient tissues were classified as luminal-HER2 type (ER+ and/or PgR+ and HER2+), 57 patient tissues were classified as HER2 type (ER-, PgR- and HER2+), and 49 patient tissues were classified as triple-negative type (ER-, PgR- and HER2-). Among the 4 subtypes, the clinical benefit rate was 51.6, 78.6, 71.9 and 40.8%, respectively. There were significant differences in TTP between subtypes (median TTP, 8.3 months in luminal, 14.1 months in luminal-HER2, 10.6 months in HER2, and 4.2 months in triple-negative; P<0.001). Patients with luminal type tumors had a significantly longer TTP than patients with triple-negative type tumors. The present data suggested that the immunohistochemical subtypes were associated with the therapeutic effect of taxanes for metastatic breast cancer and that taxanes yielded an acceptable RR and TTP in luminal metastatic breast cancer. Additional investigations are required to elucidate the predictive markers of taxane therapy for patients with metastatic breast cancer in each immunohistochemical subtype.

Frederick W. Alt received the 2015 Szent-Györgi Prize for Progress in Cancer Research.

The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)—a leading cancer research charitable organization in the United States that is committed to supporting scientific research and public education relating to the prevention, early diagnosis, better treatments, and ultimately, a cure for cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher, nominated by colleagues or peers, who has contributed outstanding, significant research to the fight against cancer, and whose accomplishments have helped improve treatment options for cancer patients. The Prize also promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. This report highlights the pioneering work led by the 2015 Prize winner, Dr. Frederick Alt. Dr. Alt’s work in the area of cancer genetics over four decades has helped to shape the very roots of modern cancer research. His work continues to profoundly impact the approaches that doctors around the globe use to diagnose and treat cancer. In particular, his seminal discoveries of gene amplification and his pioneering work on molecular mechanisms of DNA damage repair have helped to usher in the era of genetically targeted therapy and personalized medicine.

The Presence of M Protein Is Strongly Associated with Very Poor Prognosis in Patients with Extranodal Diffuse Large B-Cell Lymphoma

IntroductionSeveral studies concerning extranodal diffuse large B-cell lymphoma (DLBCL) have been reported sporadically. However, no new, valuable prognostic factors have been reported since several risk factors, such as a high international prognostic index (IPI) score, elevated lactate dehydrogenase (LDH) level, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), advanced stage, and extranodal sites ≥2, were identified.MethodsTo identify new and valuable prognostic factors, we reviewed the medical records of patients with nodal and extranodal DLBCL who were newly diagnosed at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from February 2005 to September 2014, and retrospectively analyzed the data of a total of 463 consecutive DLBCL patients. The cases were nodal DLBCL in 237 patients and extranodal DLBCL in 226 patients. We investigated the relationships between overall survival (OS), progression-free survival (PFS), and age, gender, LDH level, beta-2 microglobulin level (b2MG), performance status (PS), stage, extranodal sites ≥2, Ki-67 index, and M protein in serum protein fraction electrophoresis at diagnosis. Univariate and multivariate analyses of estimated risk factors for OS and PFS in extranodal DLBCL patients were performed using the log-rank test and Cox proportional hazard regression analysis.ResultsIn patients with extranodal DLBCL, the median age was 67 years (range, 20-89 years). The median follow-up was 41 months (range, 1-115 months). A serum electrophoresis study detected M protein in 7 patients (3.1%). To adjust the impact of age, gender, LDH level, b2MG, PS, stage, extranodal sites ≥2, Ki-67 index, and the presence of M protein in serum protein fraction electrophoresis at diagnosis for other significant factors for OS, we identified the following risk factors in extranodal DLBCL by univariate analysis: elevated LDH level, elevated b2MG level, stage ≥3, extranodal sites ≥2, and the presence of M protein. Then, we performed multivariate analyses by using all of these factors in the Cox proportional hazard model. M protein (HR 6.78, 95% CI 2.19-20.96, P<0.001) and extranodal sites ≥2 (HR 3.71, 95% CI 1.77-7.80, P<0.001) were identified as independent significant prognostic factors for OS in extranodal DLBCL. Furthermore, we also identified M protein (HR 3.81, 95% CI 1.25-11.60, P=0.019) and extranodal sites ≥2 (HR 2.98, 95% CI 1.45-6.14, P=0.003) as independent significant prognostic factors for PFS by multivariate analysis. Four out of seven patients with M protein died due to lymphoma progression. Median overall survival in patients with extranodal DLBCL with M protein was 12 months (range, 2-114 months) compared with 44 months without M protein (range, 1-115 months, P=0.0038). On the other hand, in patients with nodal DLBCL, M protein (n=10) was not significantly associated with poor OS and PFS.ConclusionsThese results suggest that the presence of M protein in serum protein fraction electrophoresis is significantly associated with very poor OS and PFS in patients with extranodal DLBCL, but not nodal DLBCL. Extranodal DLBCL with M protein is a rare and very poor prognostic subset of DLBCL. [Display omitted] DisclosuresYokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Mishima:Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Semi-synthetic preparation, structural elucidation and pharmacological study of nitrogen-containing ecdysteroid analogs

Ecdysteroids are specific hydroxysteroids that exert a wide a range of biological functions in the flora and the fauna. Our group has recently described that less polar ecdysteroid derivatives can strongly sensitize various cancer cell lines to certain chemotherapeutics, which can be observed both in multi-drug resistant (MDR) and drug susceptible cancer cells [1 – 2]. Recent studies also revealed that oxime groups can increase the antitumor activity of certain steroid derivatives [3], but ecdysteroid oximes have previously not been studied from this point of view. In our current work, we aimed to synthesize C6 ecdysteroid oximes of 20-hydroxyecdysone 2,3;20,22-diacetonide, optimizing the previously available methods [4]. Rotational planar chromatographic, analytical and preparative RP-HPLC and centrifugal partition chromatographic methods were developed for the purification. The diacetonides of two 14,15-anhydro ecdysteroid oxime isomers (E/Z-oximes) were obtained, and Beckmann rearrangement of the new 14,15-anhydro E-oxime yielded another new derivative containing a seven-membered lactam B-ring [5]. The ecdysteroid oximes were tested for their activity against L5178 mouse T-cell lymphoma cells (non-MDR) and their sub-cell line transfected with pHa MDR1/A retrovirus overexpressing the human ABCB1 efflux pump (MDR cell line). Each oxime was found to be a promising modulator of resistance on the MDR cell line, and the E-oxime could also sensitize the non-MDR cells to doxorubicin. Our preliminary SAR study also revealed, that the antitumor activity of ecdysteroid diacetonides follow the ecdysteroid < Z-oxime < E-oxime order. Acknowledgement: Szeged Foundation for Cancer Research.

Abstract IA12: Collaborators to the Sovereigns: Learning from history to make new chapters in research with American Indians and Alaska Natives

Abstract Purpose/Objective(s): Cancer death rates in the US have declined. However, this trend is not true for American Indians and Alaska Natives (AI/AN) where rates have remained unchanged. Further, AI/ANs have experienced the poorest five-year cancer survival rates of all racial and ethnic groups. The presentation will touch upon the historical traumas and contemporary resiliencies which have had influences on health behaviors, lifestyles, and the investigations of disparities among AI/AN Peoples and communities. The objectives will include 1) the movement of tribes exerting research sovereignty; 2) sharing the state of the science about bio-ethics in the landscapes of Indigenous Peoples; and 3) how cancer centers and academic institutions are becoming effective partners in the research process. Newsworthy exemplars of research in Indian Country will be shared. Materials/Methods: This multifaceted presentation will share 1) research sovereignty through a tribal protocol and recommendations from the US Health and Human Services, AI/AN Research Advisory Council; 2) experiences gained from work with cancer and bio-ethics projects with an AI/AN urban population; 3) how legal cases such as Havasupai vs. Arizona State University have shaped new chapters in research with AI/AN Nations and lastly, 4) a showcase of challenges and resiliencies of Native Nations and their response to various types of health disparity research. Summary: The literature discussed provides a foundation for understanding cancer and health disparity research from a historical perspective that should inform future practices. This includes the importance of building relationships, community based participation, tribally driven research agendas, the sharing of sovereign philosophies, and the highlighting of resiliencies. Conclusions: The development of respectful relationships is important to solidify trust in AI/AN communities where researchers intend to collaborate. This is especially true in sensitive research fields such as genetics, bio-specimen, and cancer and health disparity clinical trials. Community based participatory research should be implemented from the beginning with the community in an effort to jointly build research agendas that are both scientifically novel and beneficial to AI/AN landscapes. Citation Format: Rodney C. Haring. Collaborators to the Sovereigns: Learning from history to make new chapters in research with American Indians and Alaska Natives. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA12.