Gray, Richard J.

131 Background: Research demonstrating a volume-outcome relationship has resulted in regionalization of complex cancer surgery to high volume hospitals. A simultaneous national trend towards improved surgical outcomes brings into question whether the potential benefits of regionalization are still relevant. We hypothesize that the difference in adjusted post-operative mortality between low and high volume hospitals has decreased over time. Methods: The National Cancer Database (NCDB) was used to identify patients with colon, esophageal, and pancreatic cancer undergoing curative intent surgery from 2003-2011. Hospitals were divided into low ( < 25th percentile), medium (25th-75th) and high ( > 75thpercentile) volume groups depending on annual volume of cancer-specific surgery. Year-specific hospital averaged observed/expected (O/E) ratios were calculated for 90-day mortality. Poisson regression was used to model hospital averaged O/E ratios over time. Results: Our study population included 343,929 patients with colon (88%), esophageal (5%) and pancreatic (7%) cancer. There were significant (p < 0.05) improvements in adjusted 90-day mortality from 2003 and 2011 for all volume categories and cancer types, except in high volume hospitals for esophageal cancer. In 2003, high volume hospitals had significantly better outcomes compared to low volume hospitals for all cancer types, as suggested by lower O/E ratios for 90 day mortality (p < 0.05). However, by 2011 the difference in O/E ratios for 90 day mortality was no longer significantly lower for high compared to low volume hospitals (p > 0.05); this was true for all three cancer types (Figure1). Conclusions: During the period of our study, 90-day mortality following gastrointestinal cancer surgery improved in low, medium and high volume hospitals. However, by 2011 the difference in adjusted post-operative mortality between low and high volume hospitals was not significantly different, likely due to global improvements in operative and peri-operative care. This attenuation of the volume-outcome curve has important implications for policy pertaining to regionalization of cancer care in the US.

Background: Patients diagnosed with melanoma of the foot have been reported to have a poor prognosis. We reviewed our experience at a tertiary-care medical clinic to determine the disease course in patients diagnosed with melanoma of the foot. Methods: A retrospective review was performed of 38 patients with a diagnosis of primary or locally recurrent melanoma of the foot treated between January, 1988, and July, 2004. The main outcome measures included methods of diagnosis, clinical and histopathologic features, and patterns of recurrence. Results: The mean age at diagnosis was 61 years; most were women (58%) and Caucasian (95%). The average time to diagnosis was 17 months. Initial clinical diagnosis had been considered benign in 12 (32%). The median Breslow thickness was 1.75 mm, T1 lesions were the most common, and acral lentiginous melanoma accounted for 42%. Thirteen patients (34%) had ulcerated lesions. Sentinel lymph node biopsy specimens of 25 patients identified four (16%) with metastatic disease. Surgical complications occurred in 12 patients, usually after skin graft or soft-tissue flap reconstruction. Systemic recurrence developed in six patients, four of whom also had regional recurrence. Conclusions: Most patients were elderly Caucasian women and most presented with early-stage disease, but diagnosis can be difficult and a subgroup presented with thick melanomas. Reconstructive surgical procedures had a high rate of complications; however, overall functional outcomes were good. Stage of cancer at diagnosis was associated with systemic metastases.

178 Background: Soft tissue sarcoma is a rare disease requiring multidisciplinary care for effective treatment. The National Comprehensive Cancer Network has developed guidelines for surgical resection and adjuvant therapy based on best available evidence. We sought to examine variance from these guidelines in treatment across the United States. Methods: The Surveillance, Epidemiology and End Results cancer registry was queried to identify patients undergoing surgery for extra-abdominal soft tissue sarcoma from 2004-2009. Coded variables signifying radical excision (RE) and the use of radiation therapy (RT) were correlated with stage of the primary tumor. Patients with metastatic disease, unknown size and unknown grade were excluded. Results: A total of 5,600 patients were identified with a median age of 61. Median tumor size was 8cm and most tumors were high grade (57% G3). Stage specific breakdown was as follows; Stage I 24%, Stage II 37% and Stage III 39%. Overall, 54% of patients underwent RE and 50% received RT, mostly in the post-operative setting (83%). The amputation rate was 4%. Although routine radiation therapy is not recommended for Stage IA and IB patients, 24% still underwent RT, whereas only 49% of Stage I patients were noted to have undergone a RE. Even though routine RT is recommended for Stage II and III tumors, 42% of patients did not undergo any RT, and only 58% underwent RE. On multivariate analysis predictors of RE were age <50 (OR 1.3, 95% CI 1.1-1.6), lower extremity tumor (OR 2.2, 95% CI 1.6- 2.8), Stage III, (OR 2.1, 95% CI 1.7- 2.6), and white race (OR 1.4, 95% CI 1.2- 1.8). Variance from guidelines was seen in 64% of patients. Conclusions: Significant heterogeneity and variation in the contemporary treatment for soft tissue sarcoma in the United States exists. Although low rates of RE may be related to coding discrepancies, rates as low as 54% are still a cause for concern. Overuse, and more importantly, underuse of RT is seen for a significant proportion of patients. If these trends are confirmed by further study, more effort will have to be directed towards compliance with appropriate treatment recommendations, perhaps by regionalizing sarcoma care.

13 Background: A Memorial Sloan Kettering Cancer Center (MSKCC) nomogram predicts disease−specific survival (DSS) following R0 resection for gastric adenocarcinoma using patient and tumor factors, with predictive ability superior to that of the current AJCC staging system. However, validation has only been performed in high−volume, specialized institutions. The goal of this study is to compare nomogram-predicted survival with actual survival by using a population database with the largest sample size reported to date. Methods: A retrospective review of all gastric cancer patients from Surveillance, Epidemiology and End Results (SEER) registry data from 1988 to 2000 was conducted. Data for patient age, tumor size, gender, primary location of tumor, Lauren histology, depth of tumor invasion, and % (+) and (-) lymph nodes was entered into the nomogram calculator for each patient. Nomogram-derived 5−year DSS was compared with actual DSS survival using Cox proportional hazards regression and Kaplan-Meier estimates. Results: 4,700 patients were identified. Mean patient age was 68.7 years (SD 12.3), and mean tumor size was 4.8 cm (SD 2.7). The commonest tumor location was the body/middle third of stomach (1519, 32%), followed by the gastro−esophageal junction (1381, 29%) and the antrum (1376, 29%). The majority of patients (76%) had intestinal histology. The estimated proportion of patients surviving 5 years was 23%, 48%, 58%, and 82% for survival groups defined by nomogram likelihoods of 5−year DSS of 0−25%, 26−50%, 51−75%, and 76−100%, respectively. Relative to patients in the 76−100% 5−year nomogram group, patients in the 0−25%, 26−50%, and 51−75% group had significantly higher likelihood of death with hazard ratios of 7.0 (95% CI 6.1−8.0), 3.3 (95% CI 2.8−4.0), and 2.6 (95% CI 2.2−3.0), respectively (all p<0.001). Median follow-up was 9.1 years (range, 0−18). The concordance index (c−index) for the 5−year nomogram score was 0.68 (95% CI 0.67−0.69). Conclusions: There is good discrimination of survival between nomogram-predicted survival groups. Our results validate the use of the MSKCC nomogram in the setting of the general population, outside of specialized institutions, for predicting DSS following resection of gastric adenocarcinoma.

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]

IntroductionHyperthermic isolated limb perfusion (HILP) has an established role in the management of melanoma, but its role for Merkel cell carcinoma (MCC) is less well defined.MethodsRetrospective review of our institutional experience with HILP for MCC was conducted (2009–2015). Literature search was performed through 04/2015 and 10 studies met inclusion criteria.ResultsFour patients underwent HILP for MCC at our institution. There were no major complications and complete response was achieved in all patients. Early metastatic recurrence developed in two patients. The remaining two had no evidence of disease at last follow‐up (36 months) or death (39 months). Systematic review identified an additional 12 pts that underwent HILP for MCC, for a total of 16 cases. Median age was 73 [IQR 69–78] years and 56% were men. Of the patients with reported follow‐up, 12 (86%) had complete response, 1 had stable disease, and 1 partial response. Four patients developed local–regional recurrence and six distant metastases, all within 6 months. Overall median follow‐up time was 15 [7–36] months.ConclusionAmong a highly selective group of patients, regional perfusion for MCC is safe and has a high complete response rate. HILP is an acceptable therapeutic modality for obtaining durable loco‐regional control but early distant metastatic disease remains a significant cause of mortality. J. Surg. Oncol. 2016;114:187–192. © 2016 Wiley Periodicals, Inc.

BackgroundA Memorial Sloan Kettering (MSKCC) nomogram predicts disease specific survival (DSS) for gastric adenocarcinoma. The goal of this study is to use a cancer registry to compare nomogram predicted survival with actual survival in the general population.MethodsAll patients undergoing surgery for gastric adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database (1988–2012) were studied.Results6954 patients were identified. Majority of cancers were in the antrum (30.2%), and had intestinal histology (73.7%). Median follow‐up was 8.2 years. Five year DSS for nomogram risk groups (0–25%, 26–50%, 51–75%, and 76–100%) was 23%, 48%, 57%, and 81% respectively. Actual DSS was 7–15% lower than nomogram predicted DSS. Relative to patients in the 76–100% 5‐year DSS risk group, patients in the 0–25%, 26–50%, and 51–75% groups had significantly higher risks of death with hazard ratios of 6.84 (95%CI 6.12–7.65), 3.30 (95%CI 2.83–3.86), and 2.64 (95%CI 2.30–3.03), respectively (all P < 0.001). The concordance index for 5‐year nomogram predicted DSS was 0.68 (95%CI 0.67–0.69).ConclusionsThe MSKCC gastric cancer nomogram over‐estimates DSS from gastric cancer in the general population and has a moderate concordance index. Predictive tools generated at specialized institutions may not perform as well in the general population. J. Surg. Oncol. 2015; 112:377–380. © 2015 Wiley Periodicals, Inc.

Abstract INTRODUCTION Next generation sequencing (NGS) of patients has significantly changed our ways to study cancer genomics as it provides precise estimates of gene expression, fusion transcripts, expressed single nucleotide variants (eSNVs), splice variants and copy number variants. The Breast Cancer Genome Guided Therapy (BEAUTY) is an ongoing clinical study in which RNA sequencing (RNAseq) and whole exome sequencing (WES) are performed prior to, during and after neoadjuvant chemotherapy. Here we report the use of these sequencing technologies to investigate gene expression levels and mutational profiles in a triple negative breast cancer (TNBC) patient enrolled in BEAUTY whose disease did not respond to neoadjuvant paclitaxel and anthracycline/cycphosphamide. METHODS Computational approaches were used to integrate WES and RNAseq data obtained before therapy (V1T), after 12 weekly paclitaxel treatments (V2T) and after anthracycline-based regimen at surgical resection (V3T) to study a single patient with persistent TNBC disease after neoadjuvant chemotherapy. RESULTS Using RNA-Seq data, we identified an inter-chromosomal fusion transcript between chromosome 20 and 22 (GNAS-TTC38) that was highly expressed at V1T, V2T and V3T. We also identified intra-chromosomal fusion transcripts that were expressed at two time points, such as fusion transcript (KANSL1-ARL17A) on chromosome 17 for V1T and V2T and fusion transcript (RBM12B-LINC00535) on chromosome 8 for V2T and V3T time points. Several gene expression changes were also observed. Gene expression analysis of V1T, V2T and V3T tumors was performed. Differential temporal gene expression profiles of 9884 genes that were significant and varying at different time points were obtained for pathway analysis. Pathway analysis of 9884 genes identified up regulation and down regulation of several transcription factors with a fold change of 2x or more. When compared to blood, DNA tumor and RNA-Seq data, we identified 81 common somatic eSNVs that were expressed in both V1T and V2T time points and we are in the process of investigating V3T data. We found alterations of key transporter domains (CD225, Coatamer_beta_C, DUF2435, Dynamitin, EI24, GLTP, LMF1, Porin_3, V-ATPase_C) in our V1T and V2T SNV data. Similar to gene expression analysis, we are in the process of obtaining the list of mutations at various time points to identify driver and passenger mutation candidate genes for this specific TNBC patient. CONCLUSIONS Our initial time-series analysis of eSNV, fusion transcripts and gene expression data demonstrate that intensive analysis for individual patients is feasible. Further investigation of drug transporters and transcription regulators may help develop personalized treatment strategies for patients with disease resistant to current regimens. Citation Format: Krishna R. Kalari, Xiaojia Tang, Kevin J. Thompson, Douglas W. Mahoney, Poulami Barman, Jason P. Sinnwell, Hugues Sicotte, Peter Vedell, Steven N. Hart, Travis J. Dockter, Katie N. Jones, Amy L. Conners, Ann M. Moyer, Daniel W. Visscher, Jia Yu, Bowen Gao, Sarah A. McLaughlin, John A. Copland, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard J. Gray, Vera J. Suman, Jeanette E. Eckel Passow, Jean-Pierre A. Kocher, Eric D. Wieben, Gianrico Farrugia, Cloann G. Schultz, James N. Ingle, Richard Weinshilboum, Matthew P. Goetz, Liewei Wang, Judy C. Boughey. Analysis of sequencing data to identify potential drug targets for an individual newly diagnosed with basal breast cancer who failed to respond to current standard neoadjuvant chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4185. doi:10.1158/1538-7445.AM2014-4185

Abstract Background Cancer genomic investigations have identified recurrent genomic aberrations critical for cancer initiation, progression, and metastases. However, these investigations are typically performed in isolation, and the effects of treatment on the clonal selection of tumor cells are mostly unknown. We hypothesized that molecular profiling of residual tumors after neoadjuvant chemotherapy (NAC) would identify new drug targets/pathways in patients at high risk for disease recurrence. To better identify clonal populations of resistant breast cancer cells, we utilized DNA content-based flow sorting of nuclei to identify and isolate clonal populations for aCGH and next generation sequencing (NGS) both before and after NAC. Methods The Breast Cancer Genome Guided Therapy Study (BEAUTY) (NCT 02022202) is a prospective study of patients with high-risk breast cancer treated with neoadjuvant 12 weekly paclitaxel (T) +/- trastuzumab followed by 4 cycles of anthracycline based chemotherapy. Tumor tissue from baseline, residual disease from surgery, distant metastases, and patient derived xenografts (PDX) are obtained for cell sorting by DNA ploidy, aCGH, RNA and exome sequencing. Results: 140 patients have been enrolled, 104 have completed surgery and 30 unique PDX have been established corresponding to 26 patients prior to chemotherapy and 4 from residual disease at surgery. Baseline exome and RNA sequencing is complete in 140. Currently, genomic analyses of flow sorted matched baseline, surgical, PDX, and distant disease samples are available in 6 patients. Substantial genomic variation was observed in the surgical sample compared to the primary tumor including gain of oncogenic drivers (EGFR) and loss of negative regulators (ATG5) (Table). The PDX recapitulated these events with excellent fidelity compared to the corresponding human tumor. In patients with TNBC, RNA seq obained from matched samples demonstrated changes in immune related pathways. Evaluation of drug targets/pathways identified in the resistant tumors are ongoing using the PDX and sequencing of the remaining matched baseline/surgical disease will be reported. Clonal changes occurring over time in patients with residual disease or disease recurrence after NACTumor SubtypeResidual Cancer BurdenDisease StatusClonal Aberration Changes (baseline and post NAC)TNBC (AR subtype)3Contralateral lymph node recurrence at 150 days2p25.2 - p25.1 amplicon lost at recurrence; 6p21.32 -p21.31 amplicon lost at recurrenceTNBC (BL 1)3Bone/liver/lymph node recurrence at 135 days5q11.2 amplicon gained at surgery; 12p13.33 - p13.2 amplicon gained at surgeryTNBC (BL 1)3Disease-free at day 1506q21 amplicon lost at sugeryTNBC (BL 2)0Brain recurrence at 390 daysChr 2 chromothripsis at surgeryLuminal B3Progression during chemotherapy7p12.1 - p11.2 amplicon gained at surgeryLuminal HER23Disease-free at day 3609q33.2 amplicon lost at surgery; 15q13.1 - q13.3 amplicon lost at surgery; 15q22.2 - q24.1 amplicon lost at surgery Conclusions: We observed substantial evolutionary changes in residual breast tumors remaining after NAC. Our findings suggest that a comprehensive assessment of the mutational landscape that has evolved during NAC can inform drug development in high risk breast cancer patients. Citation Format: Matthew P Goetz, Michael T Barrett, Krishna R Kalari, Vera J Suman, Sarah A McLaughlin, Alvaro Moreno-Aspitia, Ann M Moyer, Donald W Northfelt, Richard J Gray, Jason Sinnwell, Douglas Mahoney, Poulami Barman, Peter Vedell, Xiaojia Tang, Kevin Thompson, Travis Dockter, Katie Jones, Sara J Felten, Amy Conners, Jeanette Eckel-Passow, Hughes Sicotte, Steven N Hart, Jia Yu, Daniel W Visscher, Eric D Wieben, Cloann Schultz, Minetta C Liu, James N Ingle, Liewei Wang, Richard W Weinshilboum, Judy C Boughey. Impact of neoadjuvant chemotherapy on the clonal composition of breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD3-3.

Abstract INTRODUCTION Patient derived xenografts (PDX) may better reflect individual patient (pt) tumor biology; however, the feasibility of collecting PDX from percutaneous tumor biopsies (PTB) in the neoadjuvant setting is unknown. Furthermore, drug response phenotypes observed in PDX have not been prospectively compared to the corresponding pt clinical outcomes. METHODS The Breast Cancer Genome Guided Therapy Study (BEAUTY) is a prospective Mayo study of pts with high-risk breast cancer treated with neoadjuvant weekly paclitaxel (T) +/- trastuzumab followed by anthracycline based chemotherapy. PTB (at baseline) and residual surgical tissue (after all chemotherapy) are obtained for next generation sequencing (NGS) and PDX. Tumor biopsies (1-2 cores from 14 gauge needle) were implanted with Matrigel &lt;1 hour of collection in the flanks of NOD-SCID or NSG mice. Low dose estradiol was supplemented in the drinking water. Primary outgrowth rate was defined as PDX tumor volume &gt;50 mm3. Take rate was defined as development of at least 1 stably transplantable xenograft line/pt. To determine whether clinical T response assessed by MRI corresponded with in vivo T response, pretreatment PDX from 5 pts were injected into NOD-SCID mice (20 mice per pt PDX) and when tumors reached 100-200mm3, mice were randomized to no treatment vs T (20 mg/kg, ip. every 3-4 days). Two of these 5 patients had a MRI response defined as &gt;30% decrease in longest lesion. RESULTS Pretreatment PTB from 81 unique pts were implanted in 251 mice (2-4 mice/pt). PDX outgrowth rates were 33.3% (27/81 pts) and 22 stable PDX were established (overall take rate 27.2%). Take rates were as follows: triple negative breast cancer (46%; 13/28); HER2 (27%; 6/22), Luminal B (13%; 3/22), and luminal A (0%; 0/9). Residual surgical tumor (after all treatment) from 17 pts was injected into 85 mice (average 5 mice/pt) and the initial outgrowth rate was 23% (4/17) with 3 stably transplantable lines established. PDX, derived from pretreatment PTB of 5 pts (2 responders and 3 non-responders), were assessed for in vivo T response. The size of the T treated group was significantly smaller than the no treatment group for the PDX derived from the 2 clinical responders, with complete disappearance of tumor by 18 days. In contrast, the PDX derived from the 3 clinical non-responders had no evidence for T response. CONCLUSIONS We have demonstrated the feasibility of using PTB to establish PDX in a prospective neoadjuvant clinical study and have demonstrated similar T drug response phenotypes in in the PDX as seen in the corresponding pt. These data suggest that PDX generated prospectively may be useful for biomarker validation and the development and individualization of new drug therapy. Funded by the Mayo Clinic Center for Individualized Medicine and the Mayo Clinic Cancer Center Citation Format: Jia Yu, Ping Yin, Bowen Gao, Jason P. Sinnwell, Ann M. Moyer, Daniel W. Visscher, Amy L. Conners, Travis J. Dockter, Krishna R. Kalari, Xiaojia Tang, Kevin J. Thompson, Hugues Sicotte, Douglas W. Mahoney, Steven N. Hart, Peter T. Vedell, Poulami Barman, Katie N. Jones, Sarah A. McLaughlin, John A. Copland, Alvaro Moreno Aspitia, Donald W. Northfelt, Richard J. Gray, Vera J. Suman, Jeanette E. Eckel Passow, Eric D. Wieben, James N. Ingle, Zhenkun Lou, Gianrico Farrugia, Richard Weinshilboum, Matthew P. Goetz, Judy C. Boughey, Liewei Wang. Feasibility of using percutaneous tumor biopsies from a prospective neoadjuvant breast cancer study to develop patient derived xenografts and assess in vivo chemotherapy sensitivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1195. doi:10.1158/1538-7445.AM2014-1195