bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of whole-body FDG-PET in breast cancer screening.
Authors: Nishizawa S. , Kodama H. , Okada H.
Published: February 2017

66

Background: The utility of whole-body FDG-PET for the detection of breast cancers in a screening program is not well investigated.

Methods: We analyzed data from a cancer screening program including whole-body FDG-PET performed for consecutive 2065 asymptomatic women (age: 40 to 80 y.o. with mean ± SD of 56.1 ± 8.6 y.o.) without a previous history of breast cancer. They underwent the initial screening between September 2003 and December 2008. The screening included neither mammography nor ultrasonography of the breast. Final results of cancers and/or follow-up data more than 1 year following the screening were available in 1822 of the 2065 (88.2%: 941 by the following screening and 881 by the response to questionnaires). Data of the second screening in 670 women (age: 55.0 ± 8.0 y.o.) of the 941, who didn’t have cancer at the initial screening and received the second screening by December 2008 and within 2 years of the initial screening were also analyzed. Final results and/or follow-up data more than 1 year were available in 642 of the 670 (95.8%: 573 by a subsequent screening and 69 by the response to questionnaires).

Results: Data were analyzed as of the end of 2010. In 2 years after the initial screening, 57 cancers of a variety of organs including 12 of the breast were confirmed. Nine (stage 0: 1, I: 7 and IIA: 1) of the 12 were proven in 29 women with PET positive results and 3 (stage I: 1, IIA: 1 and not available: 1) in 2036 women with PET negative results. In 2 years after the second screening, 9 cancers including 4 of the breast were confirmed. Three of the 4 (stage 0: 1, I: 1 and IIB: 1) were diagnosed in 9 women with PET positive results and 1 (stage I) in 661 with PET negative results. Two of the 4 PET negative cancers were diagnosed after developing symptoms and the remaining 2 were detected by another screening. Sensitivity, specificity, positive and negative predictive values and false positive rate of the initial screening were 75.0% (9/12), 99.0% (2033/2053), 31.0% (9/29), 99.9% (2033/2036) and 1.0% (20/2053), respectively.

Conclusions: Whole-body FDG-PET had the capability to screen the breast with a very low false positive rate and high positive and negative predictive values, and could detect breast cancers of asymptomatic women at early stages with reasonable sensitivity.
MRI versus breast-specific gamma imaging (BSGI) in the detection of synchronous breast cancer: A prospective head-to-head trial.
Authors: Kirstein L. J. , Keto J. L. , Sanchez D. P. , Fulop T. , Cohen I. , Cohen J. M. , Harshan M. , Boolbol S. K.
Published: February 2017

72

Background: Literature suggests that MRI identifies additional mammographically and sonographically occult cancers in 8-10% of newly diagnosed breast cancer patients. We have reported comparable sensitivity of BSGI to MRI in the detection of the known index cancer. We sought to prospectively compare BSGI to MRI in the identification of additional occult malignancies in newly diagnosed breast cancer patients.

Methods: Patients with newly diagnosed breast cancer from June 1, 2009 through February 4, 2011 were consented for an IRB approved protocol in which they underwent both breast MRI and BSGI. Each imaging study was read by a dedicated breast radiologist, with one reading all MRI, and another reading all BSGI studies. All subsequent biopsies were performed percutaneously under image guidance and reviewed by dedicated pathologists. The identification of additional occult breast cancers by MRI and BSGI was compared.

Results: Eighty-five patients underwent both MRI and BSGI. Twenty-one patients elected to undergo mastectomy without further management of imaging findings and were excluded, leaving 64 eligible patients. No additional lesions were found in 22 patients. Twenty-one patients had benign pathology on biopsied imaging findings. Metastatic axillary lymph nodes, satellite lesions or larger extent of disease was identified in 11 patients. Eleven occult breast cancers were identified in 10 patients (15.6%), 6 on MRI alone (9.4%), 3 on BSGI alone (4.7%), and 2 by both modalities (3.1%). There was no significant difference in the identification of occult cancer between MRI and BSGI (chi-square 0.77, p>0.1; Table).

Conclusions: BSGI has previously been shown to be as sensitive as MRI for detecting known invasive and in situ breast carcinoma. This study shows that BSGI is equally sensitive to MRI in the detection of synchronous mammographically and sonographically occult cancers in newly diagnosed breast cancer patients. Further research is needed to identify the false positive rates of BSGI and the effect on surgical management in comparison to MRI.

[Table: see text]
Stage IV breast cancer in the community hospital setting: Primary tumor extirpation effect on overall survival.
Authors: Tjoe J. A. , Robinson L. A. , Stephenson J. , Marx J. J.
Published: February 2017

90

Background: Publications from academic centers and national cancer databases suggest a survival advantage for women who undergo primary tumor extirpation in the setting of known distant disease. We asked if similar findings exist in a community hospital setting.

Methods: 15,887 patients entered in a longitudinally maintained breast cancer database (encompassing a system network of 13 community hospitals) during 1985-2009 were analyzed for those diagnosed with stage IV disease upon initial presentation. The cohort was divided into those who underwent primary tumor resection, and those who did not. The two subgroups were compared for patient demographics, tumor characteristics, sites of distant metastases, systemic treatment, and overall survival (OS).

Results: 643 (4.05%) presented with an intact primary breast malignancy and synchronous distant metastasis. Median age at diagnosis: 66 years (range 22-96). Median OS: 15 months (range 0-249). 264 (41.1%) patients underwent primary tumor resection as part of first course treatment. On Kaplan-Meier univariate analysis, patients who underwent surgical extirpation of the primary tumor demonstrated improved median OS compared to those who did not (26 vs 10 months; p<0.0001, HR 0.52). Age at diagnosis <50 (p=0.0003, HR 0.65) and oligometastasis to bone (p=0.0002, HR 0.72) were statistically significant predictors of improved OS. Race, primary tumor size, and ER status alone did not influence OS. Those ER+ patients who underwent primary tumor excision in addition to chemotherapy and/or hormonal therapy fared significantly better than those treated with systemic therapy alone (32 vs 17 months; p<0.0001). Chemotherapy 16+ weeks prior to surgery improved OS compared to those who had surgery <16 weeks after starting chemotherapy. While there was no difference with regards to type of resection (partial vs simple vs modified radical mastectomy), clear margins were imperative to optimize OS.

Conclusions: Patients with stage IV breast cancer treated at community hospitals also demonstrate improved OS after primary tumor extirpation, especially in the context of a multimodality approach combining chemotherapy and/or hormonal therapy preceding surgery.
A novel staging system for disease-specific survival in patients with breast cancer treated with surgery as the first intervention.
Authors: Yi M. , Mittendorf E. A. , Buchholz T. A. , Sahin A. A. , Kuerer H. M. , Luo S. , Bilimoria K. Y. , Crow J. , Cormier J. N. , Gonzalez-Angulo A. M. , Buzdar A. , Hortobagyi G. N. , Hunt K.
Published: February 2017

92

Background: American Joint Committee on Cancer (AJCC) staging of breast cancer is used to determine prognosis, yet survival of patients within each stage shows wide variation and remains unpredictable. We hypothesized that differences in underlying biology might influence some of this variation and that the addition of biologic markers to current AJCC staging parameters would improve predictions of prognosis.

Methods: We identified an initial cohort of 3,728 patients at our center who underwent surgery as the first intervention between 1997 and 2006. We used a Cox proportional hazards model, with backward stepwise exclusion of factors and stratified on pathologic stage (PS), to test the added significance of modified Black’s nuclear grade (G), the presence of lymphovascular invasion (L), estrogen receptor status (E), progesterone receptor status (P), or combined ER and PR status (EP), or combined receptor subtype (ER+PR+HER2 [M]). We assigned values 0-2 to these disease-specific survival (DSS)–associated factors and then used different combinations to assess different staging systems. Surveillance Epidemiology and End Results (SEER) data was used as the external cohort (n=26,711) to validate the scoring system.

Results: Median follow-up time for the initial cohort was 6.5 years, and the 5-year DSS rate was 97.4%. Six different staging systems were used to predict 5-year patient outcomes: PS, PS+G, PS+GL, PS+EG, PS+GEP, and PS+GM. We compared 5-year DSS rates, Akaike’s information criterion (AIC) and Harrell’s concordance index (C-index) for each staging system. We found that the PS+GEP staging system was most precise with lowest AIC (1927.3) and had the highest C-index (0.80). The ability of the PS+GEP system to stratify outcomes was confirmed in the internal bootstrapping samples and the external validation cohort.

Conclusions: Our results validate a new staging system that incorporates tumor grade, ER and PR status into current AJCC staging for breast cancer. We recommend that biologic markers be incorporated into revised versions of the AJCC staging system for patients undergoing surgery as their first intervention.
Treatment of ductal carcinoma in situ (DCIS) with lumpectomy and accelerated whole breast radiation therapy with concomitant boost (ARTB).
Authors: Chadha M. , Portenoy J. , Boolbol S. K. , Kierstin L. , Baoch-Abaje K. , Harrison L. B.
Published: February 2017

93

Background: The efficacy of accelerated radiation therapy (RT) for treating early stage invasive breast cancer has been established (Whelan T et al: NEJM, February 2010). But the role of accelerated schedules in treating patients with DCIS still needs to be defined. We have previously described the feasibility and low toxicity when using ARTB after lumpectomy (Chadha M et al: Int J Radiat Oncol Biol Phys 2007; 69). The objective of this study is to evaluate early outcomes in patients with DCIS treated with lumpectomy and ARTB, and to compare local recurrence rates of ARTB and conventional fraction (fr) RT with sequential boost (CRT).

Methods: This study includes patients diagnosed to have primary DCIS treated with lumpectomy and RT. Patients with DCIS who had history of contralateral synchronous or metachronous invasive cancer were excluded. We identified 215 patients from our breast cancer database as having met this selection criteria; 54 patients received ARTB on an IRB approved protocol, and 161 patients matched by prognostic factors constituted the comparative CRT group. ARTB delivered 40.5Gy in 15fr to the breast, and with concomitant boost 45Gy in15fr was delivered to the lumpectomy boost volume. CRT delivered 46.8Gy in 26fr with sequential boost of 14Gy in 7fr. The patients were well matched with no significant difference in the distribution of known prognostic factors including age, nuclear grade, margin status, receptor status, and Body Mass Index between the groups.

Results: The overall median follow up was 3.5 years (0.5 years–11.4 years). Actuarial 5-year local relapse-free survival was 95%. The actuarial 3-year local relapse rate was 2% and 0% for CRT and ARTB groups, respectively (p = 0.22). Local recurrence was observed in 9 patients with a median time to failure of 4.3 years (0.5 years to 8.6 years); 4/9 had grade 3 DCIS; 1 patient with grade 3 had close final margin (<1 mm); 5/9 patients received hormone therapy.

Conclusions: With the follow up to date, we observed excellent outcomes in patients with DCIS treated by lumpectomy and RT. These preliminary results suggest comparable local control between ARTB and CRT. Additional studies and longer follow-up are needed.
Cosmetic outcome 1, 2, 3, and 4 years after intraoperative radiotherapy or external beam radiotherapy for early breast cancer: An objective assessment of patients from a randomized controlled trial.
Authors: Keshtgar M. R. , Williams N. R. , Corica T. , Saunders C. , Bulsara M. , Joseph D. J. ,   on behalf of the TARGIT Trialists' Group
Published: February 2017

94

Background: The randomized controlled TARGIT Trial was designed to determine noninferiority between the novel technique of TARGIT [intra-operative radiotherapy with Intrabeam (Carl Zeiss, Germany)] and conventional external beam radiotherapy (EBRT) in women with early breast cancer. The main outcome objective is risk of local relapse within the treated breast. We report here data from a subprotocol assessing cosmesis in 114 women over 50 years old participating in the TARGIT Trial from one center (Perth, Australia).

Methods: Frontal view digital photographs from were assessed, blind to treatment, using specialist software (BCCT.core 2.0, INESC Porto, Portugal) that produces an objective composite score based on symmetry, color, and scar. Data on patient and tumor characteristics were obtained from hospital notes. Statistical analysis was by generalized estimating equations (GEE) on all data, and logistic regression analysis at year 1 only.

Results: Photographs were taken at baseline (before surgery) and 1, 2, 3, and 4 years after initial breast-conserving surgery; none of the 114 patients had subsequent breast surgery. Median age at randomization was 62 years (IQR 56 to 68). The composite scores were dichotomized into Excellent and Good (EG), and Fair and Poor (FP). There was a nonsignificant 45% increase in the odds of having an outcome of EG for patients in the TARGIT group relative to the EBRT group (OR=1.45, 95%CI 0.78 – 2.69, p=0.245) after adjusting for tumour size. The results were similar when adjusted for tumor grade and age of the patient. For year 1 there was a statistically significant 2.35 fold increase in the odds of having an outcome of EG for patients in the TARGIT group relative to the EBRT group (OR=2.35, 95%CI 1.02 – 5.45, p=0.047) after adjusting for age of the patient, tumor size, and grade.

Conclusions: These results confirm a significantly better cosmetic outcome with TARGIT compared to EBRT in the first year after surgery.
The impact of breast reconstruction on the decision to undergo contralateral prophylactic mastectomy.
Authors: McGhan L. J. , Pockaj B. A. , Gray R. J. , Bagaria S. P. , McLaughlin S. A. , Casey W. J. , Rebecca A. M. , Wasif N.
Published: February 2017

96

Background: In the last decade there has been an increase in the incidence of contralateral prophylactic mastectomy (CPM) for unilateral breast cancer. Although many factors have been proposed to explain this trend, the impact of breast reconstruction on the decision to undergo CPM has not been extensively studied.

Methods: A retrospective review of breast cancer patients from Surveillance, Epidemiology and End Results (SEER) registry data (2004-2008) was conducted. Characteristics of patients undergoing CPM were evaluated.

Results: 71,176 patients with a diagnosis of stage I-III infiltrating ductal or lobular breast cancer underwent mastectomy for their primary lesion. Among these, 10,558 patients (15%) underwent a CPM. A significantly higher proportion of women undergoing CPM had reconstruction performed (44%) than those patients not undergoing CPM (13%), p<0.001. On multivariate analysis (Table), significant variables predicting CPM included age <50 years (OR 10.12), breast reconstruction (OR 3.58), and lobular histology (OR 1.41), all p<0.001. Of the 12,466 patients (18%) who underwent reconstruction, 4,636 (37%) had implant reconstruction, 4,498 (36%) had tissue reconstruction, and 1,122 (9%) had combined tissue/implant reconstruction (no data for 18%). On multivariate analysis, predictors of reconstruction included age <50 years (OR 20.5; CI 18.5-22.7), year of surgery (2008 vs. 2004; OR 1.60; CI 1.49-1.71), low tumor grade (OR 1.19; CI 1.13-1.25) and ER+ status (OR 1.16; 95% CI 1.10-1.23). The use of radiation therapy was associated with a lower likelihood of pursuing reconstruction (OR 0.61; CI 0.58-0.65).

Conclusions: Apart from age, the factor most strongly associated with CPM is the decision to have reconstructive surgery performed. This suggests that CPM may not be purely associated with risk-reduction but also with treatment factors such as cosmesis.

[Table: see text]
The use of trastuzumab in Japanese patients with HER2-positive advanced or metastatic gastric cancer.
Authors: Sawaki A. , Ohashi Y. , Omuro Y. , Satoh T. , Hamamoto Y. , Boku N. , Miyata Y. , Takiuchi H. , Ohtsu A. ,   the ToGA Trial Japanese Investigators
Published: February 2017

102

Background: The Trastuzumab for Gastric Cancer (ToGA) study showed the efficacy of trastuzumab for HER2-positive gastric cancer (HGA). The aim of this study is to evaluate the benefit of trastuzumab for Japanese HGA patients.

Methods: ToGA was an open-label, international, phase III, randomized controlled trial undertaken in 122 centers in 24 countries. Median overall survival (OS) was 13.8 months in those assigned to trastuzumab plus chemotherapy (C+T) compared with 11.1 months in those assigned to chemotherapy alone (C) with hazard (HR) ratio of 0.74. Subgroup analyses of patients enrolled from Japan were undertaken to estimate the hazard ratio (HR) for OS in the Japanese population. Based upon the prescribed protocol for Japan, we calculated HR using multiple Cox regression model with prespecified covariates in the ToGA study in order to make up for the small number of Japanese patients and reduce the bias in the baseline characteristics between two groups.

Results: Sixteen institutes participated and 102 patients were enrolled, of which 101 patients were evaluable for this research. The median OS was 15.9 months in C+T arm versus 17.7 months in C arm. The HR for OS was 1.00 [95% CI: 0.59-1.69]. However, the HR for OS adjusted for the above covariates was estimated to be 0.68 [95% CI: 0.36-1.27]. There were differences between C+T arm and C arm in some baseline characteristics. Higher frequencies were seen in C arm as follow: intestinal type, prior gastrectomy, and smaller number of metastatic sites. For HER2 status, the percentage of patients with IHC0/FISH+ was lower in C+T arm (5.9%) than in C arm (18.0%), while that of patients with HER2 status IHC2+/FISH+ was higher in C+T arm (35.3%) than in C arm (26.0%).

Conclusions: Although ToGA's overall OS HR = 0.74 (p = 0.0046), in the Japan patient subgroup, the unadjusted hazard ratio was 1.00. However, there was an imbalance of the baseline characteristics between the treatment arms in Japanese population. When adjusted for these characteristics, the HR was 0.68 which is similar to those in the ToGA study. Adding trastuzumab to chemotherapy in Japanese population appears to confer a similar magnitude of benefit compared to the whole population enrolled in the ToGA study.

[Table: see text]
Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: Literature-based analysis of 36 randomized trials.
Authors: Shitara K. , Ikeda J. , Mizota A. , Kondo C. , Nomura M. , Yokota T. , Takahari D. , Ura T. , Muro K. , Matsuo K.
Published: February 2017

103

Background: We evaluated the potential of progression-free survival (PFS) and time to progression (TTP) to act as surrogates of overall survival (OS) in clinical trial settings by a comprehensive literature-based analysis.

Methods: Randomized trials of systemic chemotherapy for advanced gastric cancer were identified by comprehensive electronic and manual search. Correlations between PFS/TTP and OS were evaluated.

Results: Thirty-six trials with a total of 83 treatment arms and 10,484 patients were selected for analysis. The nonparametric Spearman rank correlation coefficient (p) between median PFS/TTP and OS was 0.70 (95% CI, 0.59 to 0.82) and the correlation coefficient between hazard ratios in PFS/TTP and OS was 0.80 (95% CI, 0.68 to 0.92). Correlation tended to be higher in non-Asian (p = 0.80; 0.61-0.98) than Asian trials (p = 0.67; 0.39-0.94), higher in trials reporting PFS (p = 0.85; 0.72-0.97) than in those reporting TTP (p = 0.60; 0.24-0.97), and higher in trials in patients with measurable lesions only (p = 0.91; 0.77-1.00) than in those including non-measurable lesions (p = 0.71; 0.50-0.93), albeit that none of these differences was significant.

Conclusions: Our results indicate that improvements in PFS/TTP in advanced gastric cancer strongly correlate with improvements in OS. PFS/TTP may be an appropriate surrogate for OS in clinical trials for advanced gastric cancer.

No significant financial relationships to disclose.
Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients (pts) with untreated advanced gastric cancer (AGC).
Authors: Nakajima T. E. , Satoh T. , Muro K. , Yamada Y. , Shimada Y. , Takahari D. , Hayashi H. , Taku K. , Shi X. , Boku N.
Published: February 2017

111

Background: Cediranib (AZD2171) is an oral, highly potent inhibitor of VEGF signalling with activity versus all three VEGFRs and c-Kit. Combination therapy with cisplatin + oral fluoropyrimidine is commonly used as first-line treatment for AGC. This phase I study assessed cediranib in combination with cisplatin/S-1 or cisplatin/capecitabine in Japanese pts with previously untreated AGC.

Methods: Eligible pts received cediranib 20 mg/day and either cisplatin 60 mg/m2 iv, day 1 + S-1 40–60 mg bd, days 1–21, q5w (Arm A) or cisplatin 80 mg/m2 iv, day 1 + capecitabine 1000 mg/m2 bd, days 1–14, q3w (Arm B). The primary endpoint was safety and tolerability. Secondary endpoints included assessment of steady-state pharmacokinetics (PK) of cediranib and chemotherapy alone and in combination. Preliminary efficacy was an exploratory objective. Adverse events (AEs) were evaluated according to CTCAE v3.0.

Results: Between Aug–Dec 2009, 14 pts (median age, 60.5 [27–72] years; male, n = 9; PS 0/1, n = 7/7) were recruited to Arm A (n = 6) or Arm B (n = 8). The safety profile in both arms was consistent with that of the individual agents. There were no unexpected toxicities. All pts experienced ≥1 AE. Dose-limiting toxicities were reported in 1 pt in Arm A (decreased appetite) and 1 pt in Arm B (decreased appetite, fatigue, hyponatremia). The most common AEs in Arm A were decreased appetite, fatigue, nausea, diarrhoea, decreased weight and neutropenia (all n = 5; 83%), and decreased appetite, fatigue, nausea (all n = 8; 100%) and constipation (n = 7; 88%) in Arm B. Five (83%) pts in Arm A and 6 (75%) in Arm B experienced grade ≥ 3 AEs. Grade 3 AEs in > 1 pt were neutropenia (n = 3) in Arm A and hypokalaemia (n = 3), neutropenia, hyponatraemia and fatigue (all n = 2) in Arm B. Grade 4 syncope was reported in 1 pt in Arm A; this resolved on the same day it was observed. Preliminary efficacy and PK data will be presented.

Conclusions: Cediranib 20 mg plus cisplatin/S-1 or cisplatin/capecitabine was generally well tolerated and considered suitable for further evaluation in pts with AGC. The safety profile of each regimen was comparable with the individual agents. No new toxicities were identified.

[Table: see text]
Adjuvant chemotherapy for gastric cancer: Less drug, same efficacy.
Authors: Liu T. , Li W. , Sun Y. , Shen K.
Published: February 2017

114

Background: Adjuvant chemotherapy is proved to improve survival in gastric cancer by meta-analyses. However, no evidence showed the best regimen. We conducted a retrospective analysis to compare triplets with doublets in the adjuvant setting.

Methods: We collected data from January 2004 to December 2008 from patients performed radical surgery and adjuvant chemotherapy. Doublets were defined as 5-FU 750 mg/m2 (d1- 5) or capecitabine 1,000 mg/m2 (d1-14) plus cisplatin 60 mg/m2 (d1) or oxaliplatin 130 mg/m2 (d1), while triplets had epirubicin 50 mg/m2 (d1) added. Chemotherapy was initiated within 6 weeks after surgery, repeated every three weeks and planned for 6 cycles. Patients were followed up in the outpatient clinic until death or April 30, 2010. Cox proportional-hazard model and chi-square test were used to test statistical difference.

Results: A total of 316 patients (210 in doublets, 106 in triplets) had a median follow-up time of 47 months. 77 patients died at the end of follow-up (3-year survival of 67.4%).Two groups were well balanced except age (median age of 57 in doublets, 51 in triplets, p < 0.001). All the patients tolerated well, with few grade 3/4 side effects (21.9% in doublets, 30.2% in triplets, p = 0.107). Two groups had similar disease-free survival (median DFS, 16 months vs. 23 months, p = 0.656) and overall survival (3-year survival rate, 59.6% vs. 64.8%, p = 0.293). Subgroup analysis showed the same benefit on survival between the two groups.

Conclusions: Our study suggested doublets and triplets had the same efficacy as the adjuvant chemotherapy. Furthermore, doublets seem more cost-effective.

[Table: see text]

No significant financial relationships to disclose.
Comparison of the 6th and 7th editions of the UICC TNM staging system for gastric cancer: Results of a Chinese single-institution study of 1,503 patients.
Authors: Wang W.
Published: February 2017

117

Background: To evaluate the prognostic efficacy of the 7th edition TNM classification compared to the 6th edition in gastric cancer patients.

Methods: A total of 1,503 gastric cancer patients undergoing surgical resection were staged using the 6th and 7th edition staging systems. Homogeneity, discriminatory ability, and monotonicity of gradients of the two systems were compared using linear trend X2, likelihood ratio X2 statistics, and Akaike information criterion (AIC) calculations.

Results: Significant differences in five-year survival rates were observed for the “T,” “N,” and “M” subgroups using the 7th edition system, except for stage N2 and N3 patients in the 6th edition system. There were no significant differences in survival between IB and IIA in the 7th edition system. Patients with stage IV disease due to T4/N3 in the 6th edition system who were downstaged to stage III in the 7th edition system had significantly better survival than those who remained at stage IV. The 7th edition system had higher linear trend and likelihood ratio X2 scores, and smaller AIC values compared with those for the 6th edition, which represented the optimum prognostic stratification.

Conclusions: Our study suggested that the 7th edition system performs superior to the 6th edition in several aspects.

No significant financial relationships to disclose.
Impact of c-kit mutations, including codons 557 and/or 558, on the recurrence-free survival after curative surgery in patients with GIST.
Authors: Watanabe T. , Cho H. , Yoshikawa T. , Tsuburaya A. , Kobayashi O.
Published: February 2017

12

Background: Recently, c-kit exon 11 deletions, including codons 557 and/or 558, have been reported to predict a worse prognosis in GIST patients. However, it is difficult to prove the correlation between genotype and tumor aggressiveness in the imatinib- adjuvant era because exon 11 mutations respond well to imatinib. In this study, we evaluated the impact of c-kit mutational status on recurrence-free survival (RFS) after resection of primary GIST.

Methods: Clinical and pathological characteristics of 89 GIST patients in our single institution study were retrospectively analyzed. Tumors were categorized into 4 subgroups based on their mutational locations; A1: mutated codons including neither 557 nor 558, A2: either 557 or 558, B1: only 557 and 558, B2: both 557 and 558. All of the patients underwent curative surgery, and none received adjuvant imatinib. The median duration of follow-up was 49 months.

Results: Tumors originated from the stomach (n=75/89, 84%), small intestine (n=10), and colorectum (n=4). Mutation subgroup B was associated with both Fletcher and Miettinen high-risk categories. The 2-year recurrence free survival rate for A1, A2, B1, B2, was 84.9%, 85.7%, 50%, 57%, respectively. Group B2 had a significantly worse RFS than groups A1 (p=0.0004) and A2 (p=0.0014). Multivariate analysis for RFS indicated that only the mutational subgroup was a significant prognostic factor (p=0.03, HR=2.42).

Conclusions: C-kit mutations, including both 557 and 558, affected the RFS of GIST patients after curative surgery, but those including either 557 or 558 did not. Our results indicate that the locations of c-kit mutations are associated with PFS, and they may therefore affect the selection of candidates with GIST for adjuvant imatinib.

No significant financial relationships to disclose.
Nationwide trends in diagnosis and outcomes of gastrointestinal stromal tumors in the era of targeted therapy.
Authors: Witkowski E. R. , Smith J. K. , Ng S. , McDade T. P. , Shah S. A. , Al-Refaie W. B. , Tseng J. F.
Published: February 2017

121

Background: Gastrointestinal stromal tumors (GISTs) have historically been inconsistently categorized in tumor registries. Discovery of c-kit expression in 1998 allowed for more precise diagnosis, and use of tyrosine kinase inhibitors for GIST in 2000 marked a new era in management. We examined nationwide trends in the diagnosis, management, and outcomes of GIST in this post-imatinib era.

Methods: Patients ≥ 18 years old with GIST were identified in the SEER database 1998-2007, using the GIST-specific ICD-O-3 code. After a period of steady increase, incidence stabilized after 2001. Trends from 2002 to 2007 were examined. Univariate and multivariate analyses were performed. This cohort was further divided into 2002-2004 and 2005-2007 for survival analysis by Kaplan-Meier methods and Cox proportional-hazard ratios.

Results: 3,604 patients were identified. There was a dramatic increase in diagnoses from 1998 to 2001 (109 to 376 cases, p < 0.0001), but no significant change from 2002 to 2007 (p = 0.572). During this period of stable incidence (2002-2007), the proportion of patients recommended for surgery continued to decrease (85.2% to 80.1%, p = 0.0006), while utilization of radiation (which dropped to 1.1% by 2001) remained relatively constant (p = 0.101). Anatomic distribution remained stable (p = 0.529), with stomach (52.9%) and small bowel (29.3%) predominating. There was also no change in stage distribution (p = 0.811). Late stage, black race, and advanced age were predictive of not receiving resection. Female sex, younger age, local disease, later year of diagnosis, and resection were associated with lower risk of death. Survival for patients diagnosed in 2005-2007 improved over 2002-2004 for both unresected (p = 0.027) and resected (p = 0.0998) groups. Resection was an independent predictor of survival in both periods (p < 0.0001).

Conclusions: Incidence of GIST as identified in the SEER database has stabilized 2002-2007, likely reflecting more accurate diagnosis. Survival for both resected and unresected patients has improved since the introduction of imatinib, and continues upward. These population-level findings confirm the significant benefit of surgical therapy beyond clinical trials.

No significant financial relationships to disclose.
Treatment patterns for locoregional esophageal carcinoma according to race/ethnicity, histology, and insurance.
Authors: Cox D. D. , Fedewa S. , Chen A. , Virgo K. S. , Ward E. M.
Published: February 2017

128

Background: Esophageal carcinoma (EC) is a disease with a poor prognosis. There has been a rise in incidence of EC in many western countries, including the United States. African Americans (AA) have a higher mortality rate from EC than any other ethnic group in the U.S. We investigated if there were differences in treatment and clinical characteristics in AA patients with locoregional EC compared to whites.

Methods: We used the National Cancer Data Base (NCDB), a national hospital-based cancer of registry to study 20,056 adults diagnosed with locoregional EC from 2004-2007. Treatment and outcome data were obtained from the NCDB. Multivariate log binomial models were used to estimate relative risk ratios (RR) and 95% confidence intervals (CI) of receiving surgery, surgery plus systemic treatment vs. surgery alone, and margin status among patients undergoing surgery.

Results: Compared to whites, AA were younger, more likely to have proximal tumors and squamous cell carcinoma, and to be uninsured. AA patients had a lower likelihood of surgery compared to whites (RR = 0.71, 95% CI = 0.66-0.77). Patients who were uninsured, Medicaid insured or younger Medicare patients had a lower likelihood of surgery. Other important predictors of surgical treatment included age, tumor location, size and histology type. Facility level factors impacted surgical treatment as well. Among patients receiving surgery, there were no differences in receipt of systemic treatment by race/ethnicity and insurance status. Younger Medicare patients and uninsured patients were more likely to have positive margins while there was no difference by race/ethnicity.

Conclusions: AA patients were less likely than whites with locoregional EC to receive surgery, however, there were no treatment disparities among AA receiving surgery. Tumor characteristics, patient, provider and/or institutional factors that may influence lower receipt of surgical treatment and survival among AA should be further explored.

No significant financial relationships to disclose.
Treatment outcome and safety of docetaxel as the third-line chemotherapy in advanced gastric cancer after progression or after failure of FOLFOX and FOLFIRI-based sequential chemotherapy.
Authors: Hwang I. , Kang J. , Park B. , Park S. , Jang M. , Kim S.
Published: February 2017

133

Background: We performed multicenter retrospective study to evaluate the activity and the safety of a docetaxel as the third-line chemotherapy in advanced gastric cancer (AGC) patients who had undergone oxaliplatin (FOLFOX) and irinotecan (FOLFIRI)-based chemotherapy regimens.

Methods: Thirty-eight patients with AGC previously treated were eligible for this study. Patients received docetaxel 30 mg/m2 +/- cisplatin 30 mg/m2 IV on day 1, 8 or docetaxel 60 mg/m2 +/- cisplatin 60 mg/m2 IV on day 1 every 3 weeks until disease progression, and responses were assessed after every two cycles according to RECIST criteria and toxicity was evaluated by NCI-CTC.

Results: Thirty-two out of 38 patients were evaluable for response. A total of 95.1 cycles of chemotherapy (median 2, range 0.5–7) were administered. Relative dose intensities of docetaxel and cisplatin were 93.4% and 87.8%, respectively. The overall response rate was 15.6% and the disease control rate was 50%. With a median follow-up duration of 3.1 months (range 0.3-14.3 months), 36 patients had disease progression, and 34 patients had died at the time of analysis. The median progression-free survival was 1.8 months (95% CI, 1.3–2.3 months). The median overall survival was 3.1 months (95% CI, 2.3–3.9 months). Grade 3 or 4 hematologic toxicities included neutropenia in thirteen patients (38.3%), febrile neutropenia in four patients (11.7%). and thrombocytopenia in one patient (2.9%). Other grade 3 or 4 toxicities included neuropathy in three patients (8.8%) and mucositis in two patients (5.9%). There were three treatment-related deaths (8.8%) caused by infection associated with neutropenia.

Conclusions: Salvage docetaxel chemotherapy in AGC patients failed in oxaliplatin and irinotecan-based treatment is not recommend routinely. However, selected patients with good performance status and sufficient albumin levels may have derived some survival benefits from salvage chemotherapy.

No significant financial relationships to disclose.
Gastric HER2 testing study (GaTHER): Evaluation of gastric cancer testing accuracy in Australia.
Authors: Kumarasinghe M. P. , Morey A. , Bilous M. , Fox S. B. ,   GaTHER Study Group
Published: February 2017

15

Background: Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) has been reported in 6%-33% of advanced gastric cancers (GC), and trastuzumab, an anti-HER2 monoclonal antibody, has been shown to provide a survival benefit in HER2-positive disease. Thus accurate testing will be critical to ensure HER2 utility as a predictive marker in GC. HER2 in situ hybridisation (ISH) testing is currently undertaken for all breast cancer in Australia as part of a national program, however pathologists have limited experience with GC tissue. This study evaluated testing methods and determined inter-laboratory reproducibility of HER2 scoring in GC across 9 Australian reference laboratories.

Methods: A tissue microarray (TMA) comprising 100 pre-screened gastric or gastro-oesophageal junction (GOJ) adenocarcinoma samples with a range of HER2 positivity was prepared from 1-mm cores. Each laboratory assessed TMA HER2 status by both immunohistochemistry (IHC) (n=9) and ISH [chromogenic (n=3), silver (n=6), fluorescent (n=1)], using its validated testing methods and applying GC scoring criteria. Inter-laboratory agreement on HER2 ISH scoring, using both HER2 copy number and HER2:chr17 ratio, and agreement on IHC scoring (ToGA method), was calculated (kappa statistics).

Results: There was only moderate agreement between laboratories on IHC scoring (κ = 0.46). Agreement on CISH/SISH scoring was good/very good when HER2 copy number, stratified into negative, equivocal and positive for amplification, was used (κ = 0.68-0.86), but was reduced when HER2:chr17 ratio was used (κ = 0.59-0.70). Agreement between CISH/SISH and FISH using HER2 copy number was excellent (κ = 0.88-0.91) but was again reduced when HER2:chr17 ratio was used (κ = 0.84-0.86). Good/very good agreement between IHC and FISH (κ = 0.85) or CISH/SISH (κ = 0.72-0.87) was also achieved when HER2 copy number was used.

Conclusions: Good concordance across laboratories can be achieved with FISH, or single-probe CISH or SISH, scored using HER2 copy number, with use of chr17 probe in chromogenic assays best restricted to equivocal cases. HER2 IHC alone is not recommended for determining HER2 status in gastric and GOJ cancers.

[Table: see text]
First interim results of the global investigation of therapeutic decisions in hepatocellular carcinoma (HCC) and of its treatment with sorafenib (GIDEON) study: Use of sorafenib (Sor) by oncologists and nononcologists in the management of HCC.
Authors: Venook A. P. , Lencioni R. , Marrero J. A. , Kudo M. , Nakajima K. , Ye S.
Published: February 2017

157

Background: GIDEON is an ongoing, global, prospective, non-interventional registry study of patients (pts) with unresectable HCC (uHCC) receiving Sor under real-life practice settings. From January 2009 to September 2010, over 2,200 pts have been enrolled from 32 countries. Per protocol, the first planned interim analysis was triggered when 500 enrolled pts were followed for at least 4 mos; the primary safety and efficacy results were reported in October 2010. A preplanned subset analysis of treatment patterns across MD specialities is reported here.

Methods: Demographics, medical, disease and treatment history are recorded at enrolment; Sor dose, concomitant treatments, performance status, liver function are noted at follow-up. Standard efficacy measures and adverse events (AEs) are captured. Preplanned subanalysis by MD specialty was conducted.

Results: Of the 141 treating MDs, 69 (49%) were hepatologists/gastroenterologists (Hep/GIs), 55 (39%) were medical oncologists (Oncs) and 17 (12%) were other specialties. Descriptive statistics of differences in pts' HCC stage, Sor treatment and AEs by the main specialties are shown for the 479 pts evaluable for safety (Table).

Conclusions: Interim data from the GIDEON study suggests differential use of Sor by MD specialties. It appears that Oncs tend to treat with lower doses of Sor and for a somewhat shorter duration than Hep/GIs. If these data persist, it will be important to explore the reasons for these differences in Sor usage between Oncs and Hep/GIs and potential impact on patient outcomes.

[Table: see text]

No significant financial relationships to disclose.
Efficacy of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) versus doxorubicin in advanced HCC: Updates on the EACH study.
Authors: Thongprasert S. , Qin S. , Lim H. , Bhudhisawasdi V. , Yin X. , Gang W. , Kim B. , Jian Z. , Yang T. , Rau K.
Published: February 2017

160

Background: In Asia, where hepatitis B is very common, patients often present with locally advanced or metastatic hepatocellular carcinoma (HCC), and their prognosis is poor. The EACH study was designed to evaluate the efficacy and safety of FOLFOX4 vs. doxorubicin as palliative systemic chemotherapy in advanced HCC.

Methods: The open-label, randomized, multicenter phase III study was conducted in 371 patients in China, Taiwan, Korea and Thailand, who had locally advanced or metastatic HCC and were ineligible for resection. Patients were randomized 1:1 to receive either FOLFOX4 (oxaliplatin 85 mg/m2 i.v. d1; LV 200 mg/m2 i.v. h0–h2 d1 and d2; 5FU 400 mg/m2 i.v. bolus h2, then 600 mg/m2 over 22 hours d1 and d2 q2w) or doxorubicin (50 mg/m2 i.v. q3w). The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rate (RR) by RECIST and safety. Data from final and follow-up analyses of the intent-to-treat (ITT) population and selected subgroup analyses are presented.

Results: At the final analysis, median OS with FOLFOX4 (N = 184) was 6.40 months (95% CI: 5.30, 7.03) vs. 4.97 months (95% CI: 4.23, 6.03) with doxorubicin [N = 187; p = 0.0695 using a stratified log-rank test; statistical significance (p = 0.0425) was achieved at the post hoc follow-up analysis conducted 7 months later]. Median PFS with FOLFOX4 was 2.93 months (95% CI: 2.43, 3.53) vs. 1.77 months with doxorubicin (95% CI: 1.63, 2.30; p = 0.0002). The RR was 8.2% vs. 2.7% of patients with FOLFOX4 and doxorubicin, respectively (p = 0.0233), and the disease control rate (DCR) was 52.2% vs. 31.6% (p < 0.0001). In the Chinese sub-population, OS, PFS, RR and DCR were significantly improved with FOLFOX4 vs. doxorubicin at both the final and follow-up analyses. In the other subgroups analyzed, the OS and PFS benefits of FOLFOX4 vs. doxorubicin were generally consistent.

Conclusions: In the ITT population, median OS was greater with FOLFOX4 than doxorubicin throughout the study and statistical significance was achieved after continued follow-up. FOLFOX4 can benefit patients with advanced HCC, as it significantly increases median OS, PFS, RR and DCR compared with doxorubicin.

[Table: see text]
An miRNA assay for the classification of benign and neoplastic lesions in pancreatic fine-needle aspirates.
Authors: Labourier E. , Lloyd M. , Andruss B. , Adai A. , Schwarzbach A.
Published: February 2017

163

Background: Improved diagnosis of pancreatic ductal adenocarcinoma (PDAC) versus benign pancreatic lesions is an urgent clinical need. We previously reported a laboratory-developed test based on the differential expression of two miRNAs, miR-196a and miR-217, with a sensitivity and specificity of 95% in formalin-fixed, paraffin-embedded (FFPE) specimens with ≥60% tumor content. Here, we report the development and validation of an miRNA-based research test optimized for low % tumor specimens and fine needle aspirates (FNA).

Methods: RNA was extracted using methods developed and validated by the Asuragen Services Laboratory from frozen, FFPE or FNA pancreatic specimens. One to three endoscopic ultrasonography-guided FNAs were collected, stored, and shipped in RNARetain, an RNA stabilization solution formulated in 1 mL single-use vials. Expression levels of up to 12 miRNAs were interrogated using TaqMan qRT-PCR assays.

Results: A set of 211 specimens, including 94 PDAC, 96 chronic pancreatitis, and 21 normal, was used to develop a miRNA classifier to discriminate benign and low tumor content PDAC. Training on 95 FFPE specimens showed that expression analysis of miR-196a, -210, and -375 improved by 2- to 3-fold the detection rate of PDAC in specimens with 5-88% tumor. The classifier performance was further verified on 4 independent sets of specimens (n=116): frozen with high tumor content (80-100%), FFPE with high tumor content (60-95%), FFPE with low tumor content (10-60%), and FNA. The signature is now being evaluated in a multisite prospective study using FNAs collected in RNARetain; 110 specimens have been analyzed to date and we will report the relative performance of the 2- and 3-miRNA classifiers.

Conclusions: Benign lesions and PDAC can be accurately classified based on the expression level of a few miRNAs in specimens with 5-100% tumor and in FNA. Testing of preoperative FNAs collected in RNARetain as part of routine clinical evaluation could in the future improve the differential diagnosis of PDAC and potentially reduce the rate of indeterminate or false-negative calls.

[Table: see text]
Potential predictors of pancreatic cancer: A population-based screen.
Authors: Ragulin-Coyne E. , Smith J. K. , Ng S. , McDade T. P. , Shah S. A. , Tseng J. F.
Published: February 2017

164

Background: Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in the U.S. Unfortunately, PC is usually diagnosed at late stages. We hypothesized that certain diagnoses may precede PC diagnosis and assist in early identification of pancreatic cancer patients.

Methods: SEER-Medicare 1991-2005 was used to identify PC patients. PC and prePC diagnoses were identified using ICD9 codes. We then examined pre-pancreatic cancer (prePC) diagnoses and compared the frequency of those diagnoses by PC stage at time of cancer diagnosis. Stepwise logistic regression was used to assess potential PrePC diagnoses. Risk factors were compared by stage at diagnosis using Kruskal-Wallis test, stratified univariate analysis and logistic regression. Time to diagnosis was calculated for each PrePC diagnosis.

Results: 19,801 PC patients were identified. Significant (p<0.05) prePC diagnoses included acute pancreatitis, chronic pancreatitis, cyst/pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, hepatomegaly. Median time (months) and interquartile range percentiles (25th-75th) before PC diagnosis were as follows: acute pancreatitis 0.97 (0.33-8.6), chronic pancreatitis 1.56 (0.37-11), cyst/pseudocyst 0.83 (0.3-3.5), other pancreatic disease 0.47 (0.2-1.2), bile duct obstruction 0.4 (0.17- 0.83), diabetes 30.6 (11.3-59.8), weight loss 1.16 (0.43-5.1), jaundice 0.43 (0.2-0.8), abdominal pain 16 (1.07-55.5), hepatomegaly 1.06 (0.33-1.07). Patients diagnosed at AJCC stage 0 had a mean of 3.53 prePC diagnoses (±SD 1.42); stage IA, 2.80 (1.68); stage IB, 2.42 (1.57); stage IIA, 2.44 (1.63); stage IIB, 2.46 (1.64); stage III, 2.33 (1.59); and Stage IV, 1.79 (1.40) (p<0.001).

Conclusions: PC patients who presented at later stages were less likely to have prePC claims identified prior to PC diagnosis compared with patients diagnosed at earlier stages. This analysis of potential prePC diagnoses suggests that access to care and earlier identification of PC related conditions may factor into the stage at which this lethal disease is identified. Further studies need to be conducted to identify and analyze additional predictors of PC and better screen individuals at risk.

No significant financial relationships to disclose.