Japanese Foundation For Cancer Research Research Articles

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

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.

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.

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.

Radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome in breast cancer patients is associated with age.

BackgroundRadiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome is a rarely observed phenomenon characterized by infiltration of the lungs outside of the radiation field, differentiating it from radiation pneumonitis (RP).The risk factors for radiation-induced BOOP (RT-BOOP) remain unclear and controversial. We retrospectively analyzed the incidence and risk factors for RT-BOOP associated with radiation therapy (RT) after breast conserving surgery (BCS) and post-mastectomy radiation therapy (PMRT).Methods and materialsWe analyzed 1,176 breast cancer patients treated with RT after BCS or PMRT between March 2005 and September2008 at the cancer institute hospital of the Japanese foundation for cancer research. Chest radiographs were routinely obtained every three to six months for at least 12 months after surgery, as well as when the patients experienced respiratory symptoms or fever.ResultsRT-BOOP syndrome was diagnosed in 16patients (1.4%), including12BCS patients (1.3%) and four PMRT patients (1.8%). An older age (≥52 years old) was significantly associated with the incidence of RT-BOOP syndrome in a univariate analysis (p =0.023). The type of treatment (BCS or PMRT) and irradiated lung volume at 20 Gy (V20) were not significantly associated with the incidence of RT-BOOP syndrome in the entire patient cohort. In the multivariate analysis, age and smoking were the significant factor associated with RT-induced BOOP syndrome (p =0.044 and 0.049, respectively).ConclusionsRT-BOOP syndrome was a rarity, and the incidence for BCT cases was similar to that for PMRT cases. The irradiated lung volume was not significantly associated with RT-BOOP syndrome. An older age can predict the incidence of RT-BOOP syndrome.

Comparison between three oxaliplatin-based regimens with bevacizumab in patients with metastatic colorectal cancer.

BackgroundA previous pivotal Phase III study (NO16966) demonstrated the benefit of the addition of bevacizumab (BV) to oxaliplatin-based regimens in metastatic colorectal cancer (MCRC). Our study evaluated the safety and efficacy of three oxaliplatin-based chemotherapy regimens (FOLFOX4 [intravenous twice-bolus and twice-infusional 5-fluorouracil/folinic acid plus oxaliplatin], mFOLFOX6 [intravenous once-bolus and once-infusional 5-fluorouracil/folinic acid plus oxaliplatin], and XELOX [capecitabine plus oxaliplatin]) plus BV in the first-line treatment of MCRC patients.MethodsPatients with MCRC who started treatment between June 2007 and September 2010 were evaluated in this retrospective cohort study. We also evaluated early objective tumor response (EOTR) within 12 weeks, which was defined as a relative change of ≥30% in the sum of the longest diameters of target lesions when compared with baseline. The primary study endpoints were progression-free survival (PFS) and response rate.ResultsA total of 185 patients received the following chemotherapy: FOLFOX4 + BV (FF4 arm, n=85), mFOLFOX6 + BV (FF6 arm, n=40), and XELOX + BV (XELOX arm, n=60). The overall response rates were 61.2%, 72.5%, and 75.0% (95% confidence interval: 50.6%–71.8%, 58.0%–87.0%, and 63.7%–86.3%). Median PFS was 18.0, 15.5, and 13.7 months, respectively (log-rank: P=0.254; data cut-off: May 2013). Patients with EOTR (n=117) had significantly better PFS than those without-EOTR (n=68) (17.5 versus 12.7 months, P=0.004).ConclusionThis study suggests that these three BV plus oxaliplatin-based treatments might have comparable benefit in terms of tumor response and PFS. Moreover, EOTR may be a predictive factor for PFS in patients with MCRC.

Laparoscopic Incisionless Stoma Creation for Patients With Colorectal Malignant Stricture

Minimally invasive techniques have been applied with increasing frequency to stoma creation. A recent focus in the field of minimally invasive surgery is laparoscopic single-site surgery. The aim of this study was to assess whether this procedure is a feasible option compared with other techniques of stoma creation. We introduced laparoscopic surgery to fecal diversion in April 2010 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. This technique was performed on 53 patients, including 15 laparoscopic single-site surgeries, from April 2010 to December 2011. Of these 15 cases, 8 ileostomies and 7 colostomies were created. The mean operative time was 65.9 minutes (range, 32 to 93 min). The estimated volume of blood loss was small in all cases. There were no intraoperative complications. All patients started an oral diet on the second postoperative day with the exception of 1 patient who suffered from prolonged paralytic ileus. A laparoscopic single-site approach to stoma creation may be a feasible option in fecal diversion.

Endoscopic evaluation of clinical response after preoperative chemoradiotherapy for lower rectal cancer: the significance of endoscopic complete response.

The management of rectal cancer is a significant oncologic challenge because rectal cancer has a poor prognosis among the various types of colorectal cancer. There have been several recent reports on a nonoperative approach for advanced lower rectal cancer, and this may be best for local disease control. However, objective evaluation of tumor response after preoperative chemoradiotherapy has not been standardized. The purpose of this study is to evaluate our method of endoscopic evaluation of complete response. This is a retrospective chart review. All patients received a long course of preoperative chemoradiotherapy (5-fluorouracil-based chemotherapy and 45-50.4 Gy) followed by radical surgical resection from May 2005 to March 2012 in The Cancer Institute Hospital of Japanese Foundation for Cancer Research. One hundred fifty-seven patients were reviewed consecutively. Criteria for endoscopic complete response were defined with a focus on the degree of ulcer healing and pit pattern without magnification. Endoscopic CR (E-CR) evaluation with our definitions reflected histopathologic response evaluation with an accuracy of 91.7 %, sensitivity of 27.8 %, specificity of 100 %, positive predictive value (PPV) of 100 %, and negative predictive value (NPV) of 91.4 % (p < 0.001). Our criteria of E-CR led all cases of y-clinical CR (ycCR) to pathological CR. Endoscopic evaluation focused on the degree of ulcer healing, and pit pattern without magnification is useful for judging ycCR.

Long-term prognoses and outcomes of axillary lymph node recurrence in 2,578 sentinel lymph node-negative patients for whom axillary lymph node dissection was omitted: results from one Japanese hospital.

Axillary dissection omission for sentinel lymph node-negative patients has been a practice at Cancer Institute Hospital, Japanese Foundation for Cancer Research since 2003. We examined the long-term results of omission of axillary dissection in sentinel lymph node-negative patients treated at our hospital, as well as their axillary lymph node recurrence characteristics and outcomes. Our study included 2,578 patients with cTis or T1-T3N0M0 primary breast cancer for whom dissection was omitted because they were sentinel lymph node negative. The median observation period was 75 months. In sentinel lymph node-negative patients for whom dissection was omitted, the rates of axillary lymph node recurrence, distant recurrence, and breast cancer mortality were 0.9, 2, and 1 %, respectively. Eighteen patients underwent additional dissection if axillary lymph node recurrence was observed at the first recurrence. Four triple-negative (TN) patients experienced distant recurrence after additional dissection. All four patients were administered anticancer agents after axillary lymph node recurrence and experienced recurrence within 1 year of additional dissection. The axillary lymph node recurrence rate was 0.8 % for luminal and 4.5 % for TN subtypes. The long-term prognoses of patients for whom dissection was omitted owing to negative sentinel lymph node metastases were similar to those reported previously-low recurrence and mortality rates. The frequency of axillary lymph node recurrence and the post-recurrence outcome differed between luminal and TN cases, with recurrence being more frequent in patients with the TN subtype. TN patients also had poorer prognoses, even after receiving additional dissection and anticancer agents after recurrence.

P1-21-7 - Myelodysplastic Syndrome is Often Associated with Solid Cancer, but Treatable: 21 Mds Cases at a Single Institution

Introduction: 5-azacitidine (AZA) is an analogue of pyrimidine nucleoside cytidine, which prolongs overall survival of high-risk myelodysplastic syndrome (MDS) patients (pts.) and was approved in Japan in 2011. We here evaluate the response, safety, and feasibility of AZA.Methods: We retrospectively reviewed 21 MDS patients who have started AZA therapy from July 2011 to December 2013 at the Cancer Institute Hospital of Japanese Foundation for Cancer Research and assessed the efficacy and severe adverse event (SAE). All the bone marrow samples were reviewed by expert hematopathologists.Results: The baseline pts. characteristics included 14 male, 7 female, median age was 72.3 (68.0-88.9), 18 pts. with past history of cancer, in which 10 pts. with the experience of chemotherapy, and 3 pts. with radiotherapy. Five patients had past history of MDS overt acute myeloid leukemia (AML) and had received CAG (cytarabine, acracinon, G-CSF) therapy. AZA was administered intravenously or subcutaneously at daily dose of 75 mg/m2 for 5 or 7 days at every 28 day. Nineteen pts. received AZA 5 days per cycle, and 2 patients received 7 days. Median treatment cycle was 5 (range 1-14). Hematological improvement (HI) was seen in 19 pts.; neutrophil improved in 10 pts., hemoglobin improved in 12 pts., and platelet improved in 7 pts.. At a median follow-up of 12.8 months (range 0.5-23.5), the 1-year progression free survival (PFS) and overall survival (OS) rates were 61.9% and 57.1%, respectively. Five pts. after CAG therapy for AML have been treated with AZA as median treatment cycle 8 (2-11), and their PFS and OS rates were 60.0% and 80.0%, respectively. They have been able to continue the therapy as outpatients.Conclusions: AZA is safe for elderly patients and we recognized HI. Administrating AZA for the patients after CAG therapy for MDS overt leukemia is effective, and it is possible to continue AZA as outpatients. We need to follow their therapeutic procedure and evaluate the outcome.

Numbers and Percentages Of Peripheral Monocytes Is a Prognostic Marker For CNS Involvement In Diffuse Large B-Cell Lymphoma

BackgroundIn the rituximab era, there are several studies that have reported the risk factors for central nervous system (CNS) involvement in non-Hodgkin lymphoma, but the same factors emerge, such as high international prognostic index (IPI) score, >1 extranodal site, elevated lactate dehydrogenase (LDH) level, poor performance status (PS), advanced stage, bone marrow involvement. Macrophages are an important component of the tumor microenvironment and the immune response to malignancy. Recently, elevated peripheral blood monocyte counts have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. Patients and methodsWe reviewed data from a total of 1238 lymphoma patients(1185 non-Hodgkin lymphoma, 53 Hodgkin lymphoma) at our institution between February 2005 and May 2013. Of these, 42 patients (3.4%) developed CNS complications during the clinical course. Thirty patients out of these 42 (71.4%) were diagnosed with diffuse large B-cell lymphoma (DLBCL). Therefore, we focused on DLBCL. In this study, we retrospectively analyzed data from a total of 557 DLBCL patients, 30 patients (5.4%) who developed CNS involvement and 527 patients with DLBCL but without CNS involvement. This study was approved by the Institutional Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The clinical features of all 557 DLBCL patients, including 30 patients with CNS involvement, are summarized in Table 1. CNS involvement was defined by the presence of at least one histologically confirmed CNS involvement; neuroimaging findings compatible with CNS involvement with lymphoma, in conjunction with consistent clinical presentation; and the absence of other clinically feasible diagnosis or positive cerebrospinal fluid (CSF) (lymphoma cells detected by cytology). The absolute monocyte counts (AMC) and monocyte ratio were derived from pre-treatment complete blood counts.Table 1Characteristics of DLBCL patients with or without CNS involvementCharacteristicsDLBCL with CNS involvement n=30, n (%)DLBCL without CNS involvement n=527, n (%)PGender; male21 (70)295 (56.0)0.1840Age ≤60 years16 (53.3)172 (32.6)0.0277Stage III-IV23 (76.7)208 (39.5)<0.0001IPI score 3-519 (63.3)175 (33.2)0.0013PS 2-412(40.0)47 (8.9)<0.0001Elevated LDH level18 (60)231 (43.8)0.0916Elevated soluble IL-2R level28 (93.3)380 (72.1)0.0096Monocyte count ≥0.6 (×109/L)12 (40)117 (22.2)0.0420Monocyte ratio ≥8 (%)17 (56.7)192 (36.4)0.0325 Pathological studiesImmunohistochemical analysis was carried out using mAbs against CD68 at our institution. ResultsThe incidence of CNS involvement was 5.4%, 1.3% having CNS involvement at diagnosis with DLBCL. Intriguingly, absolute monocyte counts (AMC) ≥0.6 (×109/L) at diagnosis were significantly frequent in 30 DLBCL patients (p=0.0420) with CNS involvement, compared with in 527 DLBCL patients without CNS involvement. Furthermore, the monocyte ratio ≥8% in peripheral blood at diagnosis was significantly frequent in 30 DLBCL patients (p=0.0325) with CNS involvement, compared with in 527 DLBCL patients without CNS involvement. DLBCL patients with CNS involvement showed age ≤60 years, stage III-IV, IPI score ≥3, and PS ≥2, elevated soluble IL-2 receptor levels was significantly frequent, compared with in DLBCL patients without CNS involvement. Neither gender, elevated LDH level, white blood cell counts (WBC) differed significantly in the two groups. With regard to pathological immunohistochemistry, the numbers of CD68 positive cells in or around lymphoma samples did not differ in the 14 DLBCL patients with CNS involvement that we were able to analyze, compared with DLBCL patients without CNS involvement. CNS involvement free survival rate in DLBCL patients was significantly lower in AMC ≥0.6 (×109/L) and/or the monocyte ratio ≥8% (Log-rank test, P=0.0102) in peripheral blood at diagnosis, compared with in AMC less than 0.6 (×109/L) and the monocyte ratio less than 8%. ConclusionsThese results suggest that in DLBCL patients, AMC and monocyte ratios in peripheral blood at diagnosis are closely correlated with the risk of eventual CNS involvement. AMC and monocyte ratios in peripheral blood at diagnosis in DLBCL patients could be a useful prognostic marker for the risk of CNS involvement during the clinical course. Disclosures:Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy.

Abstract 1214: RET fusion gene: translation to the therapy of lung adenocarcinoma.

Abstract A considerable proportion of lung adenocarcinomas, the most common histological type of lung cancer that comprises 40% of the total cases, develops through activation of oncogenes, for example, somatic mutations in EGFR or KRAS or fusion of ALK, in a mutually exclusive manner. Tyrosine kinase inhibitors targeting the EGFR and ALK proteins are effective in the treatment of lung adenocarcinomas that carry EGFR mutations and ALK fusions, respectively. We performed whole-transcriptome sequencing (RNA sequencing) of 30 lung adenocarcinoma specimens from Japanese individuals to identify new chimeric fusion transcripts that could be targets for therapy. Then, we identified KIF5B (kinesin family 5B)-RET fusion gene, as another druggable oncogene that is present in 2% (6/319) of lung adenocarcinomas (Kohno et al., Nat Med, 2012). The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation segregating from mutations or fusions in EGFR, KRAS, HER2 and ALK. The RET fusion has preferentially been detected in well or moderately differentiated tumors of never smokers. The RET fusion in lung adenocarcinoma was also identified by three other groups: Dr. Ju et al of Seoul National University, Dr. Takeuchi et al of Japanese Foundation for Cancer Research, and Dr. Lipson et al of Foundation Medicine, USA. A clinical trial to address the therapeutic efficacy of a RET tyrosine kinase inhibitor, vandetanib, will be started in 2013 by Dr. Koichi Gotoh (kgoto@east.ncc.go.jp) of National Cancer Center Hospital East, Japan. Citation Format: Takashi Kohno, Hitoshi Ichikawa, Koji Tsuta, Tatsuji Mizukami, Yoko Shimada, Mamoru Kato, Hiromi Sakamoto, Katsuya Tsuchihara, Shun-ichi Watanabe, Hiroshi Nokihara, Koichi Goto, Jun Yokota, Teruhiko Yoshida, Tatsuhiro Shibata. RET fusion gene: translation to the therapy of lung adenocarcinoma. [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 1214. doi:10.1158/1538-7445.AM2013-1214

A clinico-pathological study on cancer in sclerosing adenosis

Cancer in sclerosing adenosis includes the following 2 types: cancer genuinely arising from sclerosing adenosis and cancer arising near a sclerosing adenosis lesion and infiltrating into it. This study aimed to elucidate the features of the former by comparing both types. This study included 28 lesions in 27 cases of cancer in sclerosing adenosis for which surgery was performed during a 2-year period from January 2006 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We determined the proportions of cancer in sclerosing adenosis relative to the overall lesion of ductal carcinoma in situ. They were compared for 13 clinico-pathological factors by dividing the lesions into 2 groups: those involving cancer in 50 % or more (cancer in sclerosing adenosis predominant type-inner type) and those involving cancer in less than 50 % (cancer out of sclerosing adenosis predominant type-outer type). There were 20 lesions (71 %) of the inner type and 8 lesions (29 %) of the outer type. The comparison between the 2 types revealed significant differences in the following 3 factors. Bilateral breast cancer was observed in 5 cases (26 %) of the inner type and in none (0 %) of the outer type, indicating that there were significantly more cases of bilateral breast cancer for the inner type (p = 0.04). Regarding the subtypes of ductal carcinoma in situ, there were significantly more cases of the non-comedo type for the inner type (p = 0.002). Significantly fewer cases were positive for human epidermal growth factor receptor type 2 (HER2) for the inner type (p = 0.007). The results of this study suggest that cancer genuinely arising in sclerosing adenosis may often have biological features of bilateral breast cancer, non-comedo type in subtype, and being negative for HER2.

O2-034 - Detection and HER2 Expression of Circulating Tumor Cells in Advanced Gastric Cancer Patients

ABSTRACT Purpose This study was aimed at detecting and HER2-expressiong circulating tumor cells (CTC) in peripheral blood of chemo-naive or chemo-resistant patients with advanced gastric cancer. Materials and methods All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital in the Japanese Foundation for Cancer Research and provided informed consent. The study population consisted of patients of aged 18 years or older with histologically proven advanced gastric cancer. A total of 140 patients with advanced gastric cancer were enrolled into a prospective study. We used CellSearch system for the detection and HER2 expression for CTC. Results We detected more than or equal to 1 CTC/7.5 ml in 80 of 140 patients (57.1%). HER2-positive CTC were observed in 19 of 80 CTC-positive patients (23.8%), including six patients with HSR2-negative primary tumors. Twenty-one patients with HER2-positive primary tumors administered trastuzumab in combination with chemotherapy (Xeloda + cisplatin; 15, weekly paclitaxel; 5). We detected more than or equal to 1 CTC/7.5 ml at the baseline in 11 of 20 patients with trastuzumab treatment. HER2-positive CTCs were observed in 6 of 11 CTC-positive patients (54.5%). Patients with HER2-positive CTC at the baseline were shorter PFS than those with HER2-negative CTC at the baseline. Conclusion HER2 expression on CTC was associated with chemoresistance. Information on the HER2 status of CTC might be helpful for stratification of HER2-directed therapies.

Total Synthesis and Biological Evaluation of Auripyrones A and B

Abstract The total synthesis of auripyrones was achieved by using a novel aldol-type reaction of γ-pyrone as a key step. From this synthetic work, we have established the stereostructure and absolute configuration of auripyrone B. Furthermore, the cytotoxicities of auripyrones against a panel of 39 human cancer cell lines (termed JFCR39) at the Japanese Foundation for Cancer Research were investigated. The patterns of the differential cytotoxicities of auripyrones were COMPARE negative, suggesting that they inhibit cancer cell proliferation through a novel mechanism.

Detection and HER2 expression of circulating tumor cells in advanced gastric cancer patients.

10541 Background: This study was aimed at detecting and HER2-expressiong circulating tumor cells (CTC) in peripheral blood of chemo-naïve or chemo-resistant patients with advanced gastric cancer. Methods: All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital in the Japanese Foundation for Cancer Research and provided informed consent. The study population consisted of patients of age 18 years or older with histologically proven advanced gastric cancer. A total of 140 patients with advanced gastric cancer were enrolled into a prospective study. We used CellSearch system for detection and HER2 expression for CTC. Results: We detected ≥1 CTC/7.5ml in 80 of 140 patients (57.1%). HER2-positive CTC were observed in 19 of 80 CTC-positive patients (23.8%), including 6 patients with HSR2-negative primary tumors. 21 patients with HER2-positive primary tumors administered trastuzumab in combination with chemotherapy (Xeloda+cisplatin; 15, weekly Paclitaxel; 5). We detected ≥1 CTC/7.5ml at the baseline in 11 of 20 patients with trastuzumab treatment. HER2-positive CTCs were observed in 6 of 11 CTC-positive patients (54.5%). Patients with HER2-positive CTC at the baseline were shorter PFS than those with HER2-negative CTC at the baseline. Conclusions: HER2 expression on CTC was associated with chemo-resistance. Information on the HER2 status of CTC might be helpful for stratification of HER2-directed therapies.

Abstract 1872: Identification of novel single-nucleotide polymorphisms associated with anticancer drug effects using the SNPChip384 platform

Abstract The identification of genetic factors associated with anticancer drug efficacy is an important challenge for optimising chemotherapy and developing personalised treatments. One of the difficulties lies in the absence of preclinical models for identifying reliable tracks that could be translated to the clinics. We have used in vitro models to identify relationships between the presence of a given polymorphic variation and the cytotoxicity of anticancer drugs: the National Cancer Institute (NCI) and the Japanese Foundation for Cancer Research (JFCR) cell line panels, which had been used for the primary screening of thousands of potential anticancer drugs. In order to discover new SNPs of potential interest, high-throughput screening could be an option, but genome-wide studies cannot be used because of the relatively small number of cell lines (105) and the high false-discovery rate that would result. As an intermediate option, we have established a tool (SNPChip384) allowing the simultaneous determination of 384 SNPs in a single DNA sample. The SNPs have been chosen among DNA repair genes, phase I and II drug metabolism genes, drug transport genes and genes involved in oncogenesis, signal transduction and oxidative stress. Genotyping of the 60 cell lines from the NCI panel and the 45 cell lines from the JFCR panel was carried out using the SNPChip384. The concordance between this multiplexed approach and the individual previous determinations was around 95% (0-3 discordances in the 60 cell lines of the NCI panel and 0-2 discordances in the 45 cell lines of the JFCR panel). We first confirmed the significant relationships we had already observed and published concerning MDM2, MTHFR, CYP1B1, ATIC and ERCC2 gene polymorphisms. In addition, we identified novel SNPs involved in the in vitro cytotoxicity of anticancer drugs. The NCI panel was used for establishing these associations and the JFCR panel for validating them independently. The Benjamini-Hochberg correction for multiple testing was used in order to minimize the false-discovery rate. In the NCI panel, ten gene polymorphisms successfully passed this stringent filter (the p values indicated are those obtained after correction): AHR R554K was significantly associated with irofulven cytotoxicity (p=0.0001); APC Y486Y with SN-38 cytotoxicity (p=0.007); ATP7B K832R with carmustine, busulfan and melphalan cytotoxicity (p=0.004 to 0.036); BRCA1 E1038G with geldanamycin cytotoxicity (p=0.01); CASP9 Q221R with the cytotoxicity of a taxol analogue (p=0.03); CDC25C R70C with vinblastine cytotoxicity (p=0.04); CDH1 with spiromustine cytotoxicity (p=0.02); CYP2E1 F421F with irofulven cytotoxicity (p=0.007); PARP4 G1280R with thioguanine cytotoxicity (p=0.04); TLR4 D299G with doxorubicin cytotoxicity (p=0.03). These associations open new tracks for identifying novel determinants of anticancer drug activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1872. doi:1538-7445.AM2012-1872

Factors Exacerbating Peripheral Neuropathy Induced by Paclitaxel Plus Carboplatin in Non-small Cell Lung Cancer

No established supportive therapy to prevent and treat chemotherapy-induced peripheral neuropathy (PN) is available. Minimizing the severity of PN is therefore critical in clinical use. We aimed to determine when and how often PN occurs in association with paclitaxel plus carboplatin (PC therapy), a regimen used to treat non-small cell lung cancer, and factors that exacerbate this condition. Patients who received PC therapy for non-small cell lung cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between May 20, 2009, and November 30, 2010, were included. PN was evaluated by the study pharmacist using specific questions based on the Common Terminology Criteria for Adverse Events Version 3.0. Univariate analysis was used to compare a group with no, Grade 1, or Grade 2 PN (non-serious) and a group with Grade 3 PN (serious). Analyses were conducted using the Cox proportional hazard model with patient characteristics having p < or = 0.20 when assessed as independent variables. Of 50 patients, 38 (76.0%) developed PN by day 6 of the first course of anticancer treatment. Grade 3 PN had an incidence of 25.0% in the fourth course. In multivariate analysis with the Cox proportional hazard model, pack-year [hazard ratio = 1.029; 95% confidence interval (CI): 1.009-1.050, p = 0.005] and creatinine clearance (hazard ratio = 0.957; 95% CI: 0.920-0.996, p = 0.031) were significant factors. A high pack-year and a low creatinine clearance exacerbated PN in patients treated with PC. PN must be carefully evaluated in patients with exacerbating factors.

Effect of moisturizers on prevention of hand-foot syndrome associated with capecitabine plus oxaliplatin.

681 Background: Capecitabine plus oxaliplatin (XELOX) has been established as first-line treatment for patients with metastatic colorectal cancer. Hand-foot syndrome (HFS) is the most common toxicity associated with capecitabine, and the mechanism of which remains to be clarified. Appropriate management of HFS for continuing treatment is needed to ensure improved survival. In this study, we evaluated the efficacy of our candidate moisturizers for HFS, considering its compliance in each patient at a single institute. Methods: Patients who received XELOX for metastatic colorectal cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between Apr 1 2010 and Apr 30 2011 were included in this study. Pharmacists conducted the skin care for HFS using moisturizers: heparinoid ointment, a mixture of vitamin A oil and white petrolatums (1:1). All HFS events were graded according to NCI–CTC, version 4.0. The relationship between accumulated dose of capecitabine and incidence of HFS events stratified by frequency of daily moisturizers application was analyzed by using the Kaplan-Meier method. P value of &lt;0.05 was considered significant. Results: Moisturizers were applied two or more times a day in 45 patients (Good compliance group) and once a daily in 28 patients (Poor compliance group). In terms of incidence of grade ≥1 HFS, no significant differences were observed between good compliance group and poor compliance group (p = 0.764). Incidence of grade ≥2 HFS was observed slightly higher in the poor compliance group than in the good compliance group, though the differences were not statistically significant (p = 0.286). Conclusions: The onset of capecitabine-associated HFS is independent of frequency of using moisturizers. However, more frequent application of moisturizers appeared to have a possibility to prevent severe HFS. Assessment for compliance with the moisturizers is important as well as patient-compliance-instruction by pharmacist.