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High grade neuroendocrine neoplasms (G3 NENs) are rare aggressive tumors with limited treatment options. Twenty-one previously treated patients with metastatic extra-pulmonary G3 NENs were treated with pembrolizumab. Baseline tumor samples were assessed for PD-L1 and tumor infiltrating lymphocytes (TIL). Peripheral blood samples drawn pre-treatment, prior to cycle three, and at disease progression were analyzed by flow cytometry. One patient achieved partial response, two had stable disease, and 18 exhibited progressive disease. The partially responding patient did not progress after 392 days, and the median progression-free survival (PFS) was 59 days. Longer PFS correlated independently with higher pre-treatment peripheral blood T-cell counts and lower pre-treatment activation state (CD69 expression) of naive T cells and NK cells. Peripheral T-cell viability was reduced in patients with greater TILs. Post-treatment, T cells had reduced numbers of CD4+ cells, reduced PD-1 expression, increased activation of effector (CD62L−) cells, and increased expression of TIGIT. Baseline TIGIT expression on peripheral T cells also correlated positively with Ki67 in tumor. Patients with higher baseline T-cell expression of TIM-3 had shorter PFS. Despite limited activity of pembrolizumab, this study highlights the immune phenotype in this rare tumor type before and after treatment. High baseline peripheral T-cell count and reduced activation of T and NK cell subsets were associated with improved outcomes. Furthermore, increased post-treatment TIGIT and elevated baseline TIM-3 expression suggest that these may limit the efficacy of pembrolizumab, providing a rationale for combination immunotherapy (PD-1 with TIGIT and/or TIM-3 antibodies) to treat extra-pulmonary G3 NENs.

Background Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs. Methods Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint. Results Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related. Conclusions Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered. Clinical trial registration number NCT02939651 (10/20/2016).

The NCCN Guidelines for Colon Cancer provide recommendations regarding diagnosis, pathologic staging, surgical management, perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and adjuvant treatment for patients with stage III colon cancer, and treatment of BRAF V600E mutation-positive metastatic colorectal cancer with regimens containing vemurafenib.

Background: The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical. Methods: Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%). Results: A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67

The NCCN Guidelines for Anal Carcinoma provide recommendations for the management of patients with squamous cell carcinoma of the anal canal or perianal region. Primary treatment of anal cancer usually includes chemoradiation, although certain lesions can be treated with margin-negative local excision alone. Disease surveillance is recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is essential for optimal patient care.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer. This portion of the guidelines focuses on the management of localized disease, which involves careful patient selection for curative-intent treatment options that sequence multimodality therapy usually comprised of chemotherapy, radiation, and surgical resection.

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.

Background: Many circulating biomarkers have been reported for the diagnosis of breast cancer, but few, if any, have undergone rigorous credentialing using prospective cohorts and blinded evaluation. Methods: The NCI Early Detection Research Network (EDRN) has created a prospective, multicenter collection of plasma and serum samples from 832 subjects designed to evaluate circulating biomarkers for the detection and diagnosis of breast cancer. These samples are available to investigators who wish to evaluate their biomarkers using a set of blinded samples. The breast cancer reference set is composed of blood samples collected using a standard operating procedure at four U.S. medical centers from 2008 to 2010 from women undergoing either tissue diagnosis for breast cancer or routine screening mammography. The reference set contains samples from women with incident invasive cancer (n = 190), carcinoma in situ (n = 55), benign pathology with atypia (n = 63), benign disease with no atypia (n = 231), and women with no evidence of breast disease by screening mammography (BI-RADS 1 or 2, n = 276). Using a subset of plasma samples (n = 505) from the reference set, we analyzed 90 proteins by multiplexed immunoassays for their potential utility as diagnostic markers. Results: We found that none of these markers is useful for distinguishing cancer from benign controls. However, elevated CA-125 does appear to be a candidate marker for estrogen receptor–negative cancers. Conclusions: Markers that can distinguish benign breast conditions from invasive cancer have not yet been found. Impact: Availability of prospectively collected samples should improve future validation efforts. Cancer Epidemiol Biomarkers Prev; 24(2); 435–41. ©2014 AACR.

Neuroendocrine tumors (NETs) comprise a broad family of tumors that may or may not be associated with symptoms attributable to hormonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors discuss the diagnosis and management of both sporadic and hereditary NETs. This selection from the guidelines focuses on sporadic NETs of the pancreas, gastrointestinal tract, lung, and thymus.

Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship. This portion of the guidelines focuses on the use of systemic therapy in metastatic disease. The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents. Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference.

Neuroendocrine tumors (NET) and gastrointestinal stromal tumors (GIST) are believed to originate from the cells of Cajal that are randomly dispersed along the aerodigestive tract. Despite their distinct morphologic appearance, NET and GIST may share oncogenic mechanisms. Often presenting in the metastatic setting, treatment options for patients with NET are limited. This case report presents a patient with refractory metastatic NET that did not respond conventional chemotherapy. The patient was treated with a KIF11 inhibitor in a phase I clinical trial and experienced a prolonged and clinically meaningful partial response. On progression at 20 months, the patient's tumor was sequenced to reveal a KIT exon 11 mutation. Institution of imatinib therapy achieved a rapid and sustained antitumor effect with profound clinical benefit. Despite previously reported KIT expression in NET, this is the first documented case of an activating KIT mutation in NET and of successful treatment with both a KIF11 inhibitor and imatinib, each of which was elucidated through molecular profiling of the patient's tumor. Imatinib may be a valuable therapy in NET harboring activating KIT mutations.

292 Background: Few studies have characterized the molecular drivers of NET growth and mechanisms differentiating poorly differentiated (PD) and well differentiated (WD) NETs. We explored the role of dysregulated transcriptome as the principal molecular mechanism of NETs with the goal to identify novel targets and biomarkers of differentiation. Methods: With IRB approval, de-identified, formalin fixed NET samples were used to extract total RNA for transcriptome analysis. All pathology specimens were centrally reviewed. Gene expression profiles of 774 genes were obtained using nCounter platform (PanCancer pathway panel, Nanostring TechnologiesTM). The resulting count data was voom normalized and differentially expressed genes between PD and WD NETs were identified using linear modeling methods available in R-Bioconductor LIMMA package. Candidate genes with potential therapeutic implications were validated in tissue microarrays by immunohistochemistry (IHC). Results: Analysis of gene count data between 16 PD and 23 WD NETs resulted in 154 differentially expressed genes on the 774 gene panel (FDR < 10% and 2 fold change (FC) up- or down-regulated), some of which may be potential drug targets (Figure 1). E.g. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for transcriptional repression, and CHK1, a G2/M cell cycle regulator, were upregulated in PD compared to WD NETs (2.7 and 3.1 FC, respectively) and serine/threonine-protein kinase PAK 3, involved in cytoskeleton reorganization, was upregulated in WD NETs (3.4 FC). IHC staining also suggested overexpression of EZH2 and its enzymatic substrate H3K27me in PD NETs (p < 0.001). PAK 3, another novel therapeutic candidate overexpressed in WD NETs (p < 0.001) was confirmed using IHC, validating the transcriptome analysis at protein level. Conclusions: These findings, combined with previously reported pathway analysis (Vijayvergia et.al 2017)], highlight biological differences between PD and WD NETs and serve as a platform for future research. They also support investigation of novel drugs that inhibit activity of EZH2 (e.g. EPZ6438) in PD NETs and PAK3 (e.g FRAX597) in WD NETs.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions surrounding metastatic colorectal cancer for the 2013 update of the guidelines. Importantly, changes were made to the continuum of care for patients with advanced or metastatic disease, including new drugs and an additional line of therapy.

Purpose Practice guidelines recommend that patients who receive neoadjuvant chemotherapy and radiation for locally advanced rectal cancer complete postoperative adjuvant systemic chemotherapy, irrespective of tumor downstaging. Patients and Methods The National Comprehensive Cancer Network (NCCN) Colorectal Cancer Database tracks longitudinal care for patients treated at eight specialty cancer centers across the United States and was used to evaluate how frequently patients with rectal cancer who were treated with neoadjuvant chemotherapy also received postoperative systemic chemotherapy. Patient and tumor characteristics were examined in a multivariable logistic regression model. Results Between September 2005 and December 2010, 2,073 patients with stage II/III rectal cancer were enrolled in the database. Of these, 1,193 patients receiving neoadjuvant chemoradiotherapy were in the analysis, including 203 patients not receiving any adjuvant chemotherapy. For those seen by a medical oncologist, the most frequent reason chemotherapy was not recommended was comorbid illness (25 of 50, 50%); the most frequent reason chemotherapy was not received even though it was recommended or discussed was patient refusal (54 of 74, 73%). After controlling for NCCN Cancer Center and clinical TNM stage in a multivariable logistic model, factors significantly associated with not receiving adjuvant chemotherapy were age, Eastern Cooperative Oncology Group performance status ≥ 1, on Medicaid or indigent compared with private insurance, complete pathologic response, presence of re-operation/wound infection, and no closure of ileostomy/colostomy. Conclusion Even at specialty cancer centers, a sizeable minority of patients with rectal cancer treated with curative-intent neoadjuvant chemoradiotherapy do not complete postoperative chemotherapy. Strategies to facilitate the ability to complete this third and final component of curative intent treatment are necessary.

Importance Compared with white American (WA) women, African American (AA) women have a 2-fold higher incidence of breast cancers that are negative for estrogen receptor, progesterone receptor, andERBB2(triple-negative breast cancer [TNBC]). Triple-negative breast cancer, compared with non-TNBC, likely arises from different pathogenetic pathways, and benign breast disease (BBD) predicts future non-TNBC. Objective To determine whether AA identity remains associated with TNBC for women with a prior diagnosis of BBD. Design, Setting, and Participants This study is a retrospective analysis of data of a cohort of 2588 AA and 3566 WA women aged between 40 and 70 years with a biopsy-proven BBD diagnosis. The data—obtained from the Pathology Information System of Henry Ford Health System (HFHS), an integrated multihospital and multispecialty health care system headquartered in Detroit, Michigan—include specimens of biopsies performed between January 1, 1994, and December 31, 2005. Data analysis was performed from November 1, 2015, to June 15, 2016. Main Outcomes and Measures Subsequent breast cancer was stratified on the basis of combinations of hormone receptor andERBB2expression. Results Case management, follow-up, and outcomes received or obtained by our cohort of 2588 AA and 3566 WA patients were similar, demonstrating that HFHS delivered care equitably. Subsequent breast cancers developed in 103 (4.1%) of AA patients (mean follow-up interval of 6.8 years) and 143 (4.0%) of WA patients (mean follow-up interval of 6.1 years). More than three-quarters of subsequent breast cancers in each subset were ductal carcinoma in situ or stage I. The 10-year probability estimate for developing TNBC was 0.56% (95% CI, 0.32%-1.0%) for AA patients and 0.25% (95% CI, 0.12%-0.53%) for WA patients. Among the 66 AA patients who developed subsequent invasive breast cancer, 16 (24.2%) developed TNBC compared with 7 (7.4%) of the 94 WA patients who developed subsequent invasive breast cancers and had complete biomarker data (P = .01). Conclusions and Relevance This study is the largest analysis to date of TNBC in the context of racial/ethnic identity and BBD as risk factors. The study found that AA identity persisted as a significant risk factor for TNBC. This finding suggests that AA identity is associated with inherent susceptibility for TNBC pathogenetic pathways.

The workup and management of squamous cell anal carcinoma, which represents the most common histologic form of the disease, are addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma. These NCCN Guidelines Insights provide a summary of major discussion points of the 2012 NCCN Anal Carcinoma Panel meeting. In summary, the panel made 4 significant changes to the 2012 NCCN Guidelines for Anal Carcinoma: 1) local radiation therapy was added as an option for the treatment of patients with metastatic disease; 2) multifield technique is now preferred over anteroposterior-posteroanterior (AP-PA) technique for radiation delivery and the AP-PA technique is no longer recommended as the standard of care; 3) PET/CT should now be considered for radiation therapy planning; and 4) a section on risk reduction was added to the discussion section. In addition, the panel discussed the use of PET/CT for the workup of anal canal cancer and decided to maintain the recommendation that it can be considered in this setting. They also discussed the use of PET/CT for the workup of anal margin cancer and for the assessment of treatment response. They reaffirmed their recommendation that PET/CT is not appropriate in these settings.

Pancreatic adenocarcinoma impinging the portal and/or superior mesenteric vein (PV-SMV) is classified as borderline resectable, and preoperative chemoradiation is recommended to increase the margin-negative resection rate. There is no consensus about what degree of venous impingement constitutes borderline resectability.All patients undergoing potentially curative pancreatectomy for pancreatic adenocarcinoma were reviewed. Venous involvement was classified by preoperative computed tomography according to Ishikawa types: (I) normal, (II) smooth shift without narrowing, (III) unilateral narrowing, (IV) bilateral narrowing, (V) bilateral narrowing with collateral veins.From 1990-2009, 109 patients underwent resection of pancreatic adenocarcinoma involving the PV-SMV. Seventy-four patients received preoperative chemoradiation, whereas 35 did not. Patients who received preoperative therapy had a significantly longer median overall survival rate of 23 months compared with 15 months for patients without preoperative therapy (P = 0.001). Preoperative chemoradiation was associated with higher R0 resection rate and negative lymph nodes (both P 0.0001) but did not affect the need for vein resection. When stratified by Ishikawa types, preoperative therapy was associated with improved overall survival among patients with types II and III but not types IV and V. Similarly, the correlation between preoperative therapy and R0 resection rate was observed only among patients with Ishikawa types II and III.Preoperative therapy for borderline resectable pancreatic adenocarcinoma is associated with higher margin-negative resection and survival rates in patients with Ishikawa type II and III tumors, defined as a smooth shift or unilateral narrowing of the PV-SMV. Patients with bilateral venous narrowing were less likely to benefit from preoperative treatment.

Lessons Learned Rate of progression-free survival at a particular point in time, i.e., a landmark analysis, is a difficult endpoint for a heterogenous malignancy such as neuroendocrine cancer. Landmark analyses can also be complicated by evolution in the standard of care during the conduct of a clinical trial. Improvements in biomarker development would be useful in developing future clinical trials in NET to better tailor individualized therapies and assess for possible efficacy endpoints. Background Neuroendocrine tumors (NETs) are rare malignancies of the gastrointestinal (GI) tract that are highly vascularized and overexpress vascular-endothelial growth factor (VEGF). Sunitinib has demonstrated efficacy in the pancreatic subset of NET. This study explored the activity of another oral VEGF inhibitor, AMG 706 or motesanib, a multikinase inhibitor that targets receptor tyrosine kinases, including VEGFR1, VEGFR2, VEGFR3, KIT, RET, and PDGFR (IC50s = 2, 3, 6, 8, 59, and 84 nM, respectively). Methods This was a single-arm, first-line, phase II study run through the Eastern Cooperative Oncology Group. Patients with low-grade NET (as defined by central confirmation of Ki-67 of 0%–2%) were administered a flat dose of 125 mg per day orally combined with octreotide long acting-repeatable (LAR) for patients who had been on a stable dose. The primary objective was to determine the 4-month progression-free survival (PFS). Results Forty-four patients were evaluated per protocol. The 4-month PFS was 78.5%. The partial response rate was 13.6% (6/44), stable disease was 54.5% (24/44), 9.1% (4/44) had progressive disease, and 10/44 were not evaluable for response. Common toxicities included fatigue, hypertension, nausea, and headache, and most were grade 1–2. Median PFS was 8.7 months, and overall survival was 27.5 months. Conclusion Motesanib (AMG 706) demonstrated a 4-month PFS that met the per-protocol definition of efficacy. Fatigue and hypertension were the most common toxicities, and few grade 3–4 toxicities were encountered. The progression-free survival of 8.7 months in all NETs merits further study.

4104Background: There is currently no standard therapy for metastatic HG-NENs after progression on platinum based therapy and available chemotherapy is of limited benefit. Given the promising activ...

The establishment of a reliable method for using RNA from formalin-fixed, paraffin-embedded (FFPE) tissue would provide an opportunity to obtain novel gene expression data from the vast amounts of archived tissue. A custom-designed 22,000 oligonucleotide array was used in the present study to compare the gene expression profile of colonic epithelial cells isolated by laser capture microdissection from FFPE-archived samples with that of the same cell population from matched frozen samples, the preferred source of RNA. Total RNA was extracted from FFPE tissues, amplified, and labeled using the Paradise Reagent System. The quality of the input RNA was assessed by the Bioanalyzer profile, reverse transcriptase-polymerase chain reaction, and agarose gel electrophoresis. The results demonstrate that it is possible to obtain reliable microarray data from FFPE samples using RNA acquired by laser capture microdissection. The concordance between matched FFPE and frozen samples was evaluated and expressed as a Pearson's correlation coefficient, with values ranging from 0.80 to 0.97. The presence of ribosomal RNA peaks in FFPE-derived RNA was reflected by a high correlation with paired frozen samples. A set of practical recommendations for evaluating the RNA integrity and quality in FFPE samples is reported.

This study examined the rate of smoking among 399 cancer patients in Russia and assessed correlates of tobacco use and readiness to quit smoking. The results indicated that (a) 41.6% of patients were smokers; and (b) smokers were likely to be male, have lung or colorectal cancer, exhibit low levels of knowledge concerning the negative effects of smoking, report a low level of advantages to quitting smoking and a high level of disadvantages to quitting smoking, show low perceived risk for the adverse effects of smoking, and exhibit high fatalistic beliefs. Though certain findings converge well with data collected from U.S. samples of cancer patients, these results can guide the development of smoking interventions that address the specific needs of Russian cancer patients. In sum, this study fills a critical gap in knowledge concerning the epidemic of tobacco use in Russia and broadens research regarding tobacco use by cancer patients from the United States to the Russian Federation.

The goal of this study was to examine the degree to which Russian oncologists are trained in providing smoking cessation counseling to patients and to assess physician smoking cessation practices and attitudes about providing smoking cessation treatment. Sixty-three oncologists at a large cancer center in Moscow completed a brief survey. The results showed that Russian oncologists: (a) lack training in smoking interventions; (b) rarely offer cessation treatment; (c) exhibit beliefs about smoking that may serve as barriers to providing cessation counseling; and (d) desire training in cessation counseling. These results can be used to guide the development of smoking cessation training programs for Russian physicians.

OBJECTIVE To pilot a worksite smoking intervention. METHODS Following baseline assessment, participants (N=6378) received cancer risk feedback; 2 annual evaluations were conducted. RESULTS Using all data, smoking dropped from 13.7% to 8.4% and 9.3%, and smoker's readiness to quit increased. Using complete data, smoking initially increased from 5.7% to 6.7%, but subsequently decreased to 5.3%; the increase in smoker's readiness to quit remained. Being male, younger, and with lower education and self-efficacy predicted smoking. Lower age and higher self-efficacy predicted readiness to quit smoking. CONCLUSIONS These findings support a formal evaluation of a worksite smoking intervention using cancer risk feedback.

Background The purpose of this study was to examine sociodemographic and psychosocial correlates of intention to undergo prophylactic oophorectomy among women with a family history of ovarian cancer. Methods Participants were 76 women enrolled in a familial cancer risk assessment program. Psychosocial assessments were collected upon entry into the program and included measures of perceived risk of developing ovarian cancer, perceived benefits and limitations of prophylactic oophorectomy, and psychological distress. In addition, respondents were asked whether they intended to undergo prophylactic oophorectomy in the following 12 months. Results Thirty-four percent reported intention to have surgery within 12 months. Logistic regression analyses indicated that intention to undergo surgery was associated with several psychosocial factors including greater perceived risk of developing ovarian cancer and greater perceived benefits of surgery. Conclusions Women who have heightened risk perceptions and who perceive there to be many benefits of surgery may be more inclined to undergo the procedure, possibly without fully considering the potential limitations and consequences of surgery. These findings suggest the need for education and risk counseling designed to facilitate informed decision making among not only high-risk women, but also women who perceive themselves to be at increased risk.

An increased risk of prostate cancer associated with a family history of prostate cancer has been documented in multiple published reports. Risk has been shown to vary by degree of relationship and age of onset of disease in the affected relative. Several studies, using various designs, have estimated the relative risk (RR) for these associations. The purpose of our study was to identify and summarize published reports on the relationship between risk of prostate cancer and family history, which is defined as having a father, brother, any first- or second-degree relative or other relative affected with prostate cancer. A Medline and manual search from 1982 to 2000 identified 24 studies that reported RR and confidence intervals (CI) and satisfied inclusion criteria. Pooled RR estimates based upon a weighted average model were as follows: any affected family member RR = 1.93, CI 1.65-2.26; affected first-degree relative RR = 2.22, CI 2.06-2.40; affected second-degree relative RR = 1.88, CI 1.54-2.30; father with prostate cancer RR = 2.12, CI 1.82-2.51; and brother with prostate cancer RR = 2.87, CI 2.21-3.73). Statistical comparison of pooled data demonstrated that the RR is significantly higher for affected brother than for affected father (p < 0.03). A sensitivity analysis demonstrated that these results are robust with respect to population bias. This meta-analysis confirms that risk of prostate cancer is associated with family history of disease and improves the quantification of this risk.

Patients diagnosed with early-stage prostate cancer not only have to cope with the impact of the cancer diagnosis, but also need to interpret complicated medical information to make an informed treatment decision. We report initial results from an ongoing longitudinal investigation examining treatment decision making among men diagnosed with early stage prostate cancer. Men (N = 654) were recruited into the assessment study after an initial treatment consultation with a urologic surgeon or radiation oncologist. Patients were, on average, 66 years old, married (85%), had at least a high school education (45%), were retired (58%), and were Caucasian (91%) or African American (7%). Guided by a cognitive-affective theoretical framework, we assessed treatment and disease-relevant beliefs and affects in addition to clinical variables. The majority of patients decided on external beam radiation therapy (52%), followed by brachytherapy (25%), prostatectomy (17%), and watchful waiting (6%). Patients who decided on prostatectomy were significantly younger (mean age, 58 yr) than patients who received radiation therapy (mean age, 67 yr) and brachytherapy (mean age, 66 yr). When asked for the most important reason influencing their treatment decision, patients indicated physician recommendation (51%), advice from friends and family (19%), information obtained from books and journals (18%), or the Internet (7%). Among cognitive variables, patients who decided on surgery perceived prostate cancer as being significantly more serious (P

217 Background: Physical activity (PA) interventions – including low-intensity, home-based walking programs – can lead to improvements in quality of life (QOL) and symptoms among patients with cancer. Despite the evident benefits, no PA interventions have been evaluated in patients with pancreatic cancer, perhaps due to concerns that these patients are too ill to participate. We assessed the feasibility and safety of implementing a PA intervention among patients with advanced pancreatic cancer. Methods: Patients with unresectable locally advanced or metastatic disease were randomized to a 12-week walking program (intervention; n = 19) or usual care (UC; n = 18). All patients met with a health educator to complete baseline assessments of QOL, symptoms, and physical functioning. Intervention participants were also instructed on how to complete the walking program and received a program booklet, a walking log, and a pedometer. Both intervention and UC patients were contacted every 4 weeks by phone to assess symptoms and changes in medical status. At 12-weeks post-baseline (intervention end), all patients completed assessments again. Results: 70 patients were approached; 37 enrolled on study (53% acceptance rate). Patients’ mean age was 63.5 years; 49% were male. There were no differences in overall QOL, symptoms, or functioning between groups at baseline. 25 of 37 patients completed the study (68%); 11 in the Intervention group and 14 in UC. Primary reason for study drop-out was declining health. Compared to UC, the intervention group reported a significant increase in average duration of physical activity from baseline (11 min/day) to follow-up (35 min/day) (p < 0.05), and improvement in symptoms as assessed by the FACT-Hep (p = 0.06). Importantly, no adverse events were reported among study participants. Conclusions: Despite advanced disease, patients with pancreatic cancer are willing and interested in participating in a PA intervention. Preliminary results suggest that intervention participants increased their PA and reported symptom improvement. Recruitment is ongoing, and clinical outcomes will be explored. In sum, this pilot study suggests that a home-based walking program is feasible and safe among patients with advanced pancreatic cancer. Clinical trial information: NCT02442323.

302 Background: NETs lack mutations in the “classical” signaling pathways but share mutations in regulators of gene expression (Jiao; 2011). We compared gene expression in PD & WD NETs to identify novel targets and biomarkers of differentiation. Methods: High quality RNA, extracted from paraffin blocks of deidentified NETs under an IRB-approved protocol, was profiled using a 770 gene panel (nCounter PanCancer pathway, Nanostring Technologies). The resulting data was used to identify the differentially expressed genes between PD and WD NETs using limma software (Ritchie; 2015). Gene Set Enrichment Analysis (Subramanian; 2005) identified differential pathway enrichment by calculating a Normalized Enrichment Score (NES). Results: Analysis of 16 PD and 23 WD NET samples identified 154 genes as extreme outliers ( > 2 fold up/downregulation between the subtypes). Compared to WD NETS, drug targets of interest overexpressed in PD NETs were histone lysine methyltransferase EZH2, and a cell cycle regulator CHEK1 (6.5x and 8.1x, respectively, p < 0.001). In contrast, serine/threonine protein kinase PAK 3 was upregulated in WD (10.6x, p < 0.001). These and other biomarkers will be further validated by immunolabeling of tissue sections. We also found differential enrichment of canonical pathways in PD versus WD NETs (table). Conclusions: Extreme outlier transcripts identified in PD & WD NETs support investigation of inhibitors of EZH2 (e.g. EPZ6438) and CHEK1 (e.g. LY2606368) in PD and PAK3(e.g. FRAX597) in WD NETs. Genes involved in cell cycle regulation and DNA repair in PD NETs and calcium / G protein coupled receptor signaling in WD NET account for biological differences between the 2 molecular subtypes and warrant future investigation as classifiers for NETs. Our findings provide mechanistic insights into the biology of NET and targets for therapy with direct clinical implications.[Table: see text]

Purpose: This study was designed to test the feasibility of conducting routine quality assessment within community medical oncology practices. Description of study: Eleven medical oncologists practicing within the Fox Chase Network were surveyed over an 8-month period, using a standardized 10-item checklist. Eight of the items (ie, board certification, continuing education, office procedure manual for chemotherapy, chemotherapy flow sheets, body surface area calculations, adherence to guidelines for follow-up of breast cancer, adjuvant hormones in women with estrogen receptor-positive breast cancer, and patient satisfaction survey) were chosen because they measure structural and process variables particularly relevant to the high-volume clinical services seen in private practice oncology. The authors also calculated two rates (protocol accrual and neutropenic complications of chemotherapy) to test as putative indicators of quality. Results: The authors found a high level of both physician interest in developing the audit measures and compliance with the survey process. Overall quality of care, as measured by structure and process variables, was excellent with negligible internal variability. Derived rates of protocol accrual (0.003–0.373; mean 0.11, SD 0.11) and neutropenic sepsis (0.004–0.014; mean 0.007, SD 0.004) show considerable variability, however, and are only minimally correlated (r = −.36). These are both potential indicators of quality that should be further evaluated. Clinical implications: The authors have demonstrated the feasibility of conducting quality assessment within private medical oncology practices and have identified two easily calculated rates that merit further study as potential indicators of quality.

The purpose of the present study was to systematically compare the psychological and screening profiles of first-degree relatives (FDRs) of prostate cancer patients versus non-FDRs. FDRs (n = 56) and non-FDRs (n = 100), recruited through prostate cancer index cases and newspaper advertisements, completed questionnaires via mail. FDRs reported feeling at greater risk for prostate cancer, estimated that they were at higher average lifetime risk for the disease, agreed more strongly that prostate cancer is inherited, and that less can be done to prevent the development of the disease. Increased age, but not FDR status, was associated with more frequent screening behavior. Taken together, the results indicate that FDRs are characterized by greater perceived vulnerability to prostate cancer and lower expectations about disease prevention. Yet, they are no more likely to be screened than non-FDRs. These findings underscore the importance of developing, and evaluating, evidence-based health communication protocols to promote screening adherence among at-risk patients.

Despite steady decreases in the cancer burden in industrialized countries, its rapid increase in the developing world means that the number of cancer cases and deaths will likely more than double worldwide over the next two decades ([1][1]). Already a leading cause of death around the globe, cancer

Fox Chase Cancer Center developed a format for affiliation with community providers in 1986. Fox Chase Network was formed to establish hospital-based community cancer centers to increase access to patients involved in clinical research. Under this program, the Fox Chase Network now contributes 500 patients per year to prevention and clinical research studies. As relationships with community providers form, patient referrals have increased at Fox Chase Cancer Center and for each Fox Chase Network member. A dedicated staff is required to operate the central office on a day-to-day basis as well as at each affiliate. We have found this to be a critical element in each program's success. New challenges in the cancer business—increasing volumes with declining revenue—have caused us to reconfigure the services offered to affiliates, while maintaining true to our mission: to reduce the burden of human cancer.

A clear benefit of increased hospital procedure volume or teaching hospital status on outcomes of rectal cancer surgery has yet to be shown. Few have examined treatment differences that may lead to varying outcomes. This study assessed the impact of hospital procedure volume and teaching status on both treatment and outcome measures of rectal cancer surgery in a large general population. Data were obtained for 1072 incident cases of rectal adenocarcinoma diagnosed in 1990 from Ontario, Canada, and treated with a major resection. Hospitals were classified by teaching status and procedure volume. Pathology reports were examined for 418 procedures. Abdominoperineal resections accounted for 3 1.0% of all procedures. There were no clinically significant differences in treatment measures, operative mortality, and long-term survival among the hospital groups according to both univariate and multivariate analyses. In conclusion, the absence of a hospital volume or teaching status effect on treatment and outcome measures suggests that for rectal cancer surgery in Ontario, centralization of procedures into high-volume or teaching centers is unlikely to improve surgical quality.

Objective. Women with a family history of ovarian cancer are confronted with difficult decisions regarding the management of their risk status. Currently, the main preventive option available is prophylactic oophorectomy. The objective of the present paper is to review research and theory on psychological factors that influence decision making about preventive surgery and discuss the implications for patient management. Methods. Guided by a cognitive–social framework, the literature on decision making about preventive surgery is reviewed and integrated. Results. The available studies show that women are more likely to opt for surgery if they feel more vulnerable to cancer, believe that surgery will prevent cancer, and are worried about developing cancer. Further, the response to ovarian risk is influenced by the individual's characteristic psychological style: monitors (who typically scan for and amplify threatening cues) tend to feel more vulnerable to cancer and more distressed about their cancer risk than blunters (who typically distract from threatening cues) do. Conclusion. On the basis of prior research, monitors may be more likely to choose surgical intervention to reduce their distress, without fully anticipating the psychological and medical consequences of that decision. In order to facilitate informed decision making, counseling protocols should be designed to enable the patient to understand and take account of the psychological consequences of the available medical options. Future studies are needed to systematically extend and explore the proposed theory-based relationships.

We previously demonstrated that nipple aspirate fluid (NAF) can be obtained from virtually all non-Asian women between the ages of 30 and 72. The focus of this report is to (1) determine the association of candidate markers of breast cancer risk in NAF obtained from fresh mastectomy specimens with residual breast carcinoma, and (2) evaluate the association of the markers with breast tumour progression. Nipple aspiration was performed on 97 specimens. Cytology, DNA index (including % hypertetraploid cells), cell cycle parameters (S phase fraction, % cells in G2/M), prostate-specific antigen (PSA), epidermal growth factor (EGF), testosterone, carcinoembryonic antigen (CEA) and prostaglandin D synthase (PGDS) were evaluated in NAF for their association with (1) residual ductal carcinoma in situ (DCIS) or invasive cancer, and (2) pathologic tumour size. NAF was obtained from 99% (96/97) of specimens. Atypical and malignant NAF cytology were significantly associated with residual DCIS or invasive cancer (P = 0.001) and with larger tumours (P = 0.004). One hundred per cent and 88% of subjects with malignant and atypical NAF cytology, respectively, had residual carcinoma. The percentage of cells in G2/M and DNA index were associated both with risk of residual carcinoma (P = 0.01 for each) and larger tumour size (DNA index, P = 0.03; G2/M, P = 0.05), although neither biomarker improved the ability of NAF cytology, to predict residual breast cancer. Higher DNA index was associated with atypical cytology (P = 0.0001). In summary, atypical and malignant NAF cytology are associated with larger tumour size, and are highly predictive of residual carcinoma after needle or excisional biopsy of the breast. © 1999 Cancer Research Campaign

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

Genetic testing for inherited cancer susceptibility, based on the recently identified. BRCA1 and BRCA2 genes, will soon be available on a large scale. However, at present, genetic test results do not lead to clearly indicated diagnostic or preventive measures, and the nature of the psychological impact of BRCA1/2 testing is still largely unknown. This uncertainty, combined with preliminary evidence suggesting significant individual differences in reactions to genetic susceptibility feedback, constitutes a unique challenge for any individual contemplating such testing. We outline the nature of this challenge and then propose an intervention strategy designed to help individuals make deeply processed and psychologically well-informed decisions with regard to their genetic susceptibility. The intervention is guided by recent research findings and theory on the cognitive–emotional processing of cancer-risk information. Specifically, the goal is to prepare the individual for genetic testing by (1) cognitively and emotionally activating, or “preliving,” the individual's potential reactions to testing feedback; (2) facilitating accurate appraisal of the individual's cognitive–emotional reactions; and (3) enabling the individual to process these reactions through the use of well-established clinical techniques.

To evaluate the feasibility of nipple aspiration and to identify intermediate markers of breast cancer risk, nipple aspirate fluid (NAF) was collected from 177 subjects using a modified breast pump. The first 33 subjects demonstrated that we could obtain NAF quickly, reliably and repeatedly. Specimens from the remaining 144 subjects were collected to evaluate promising cellular biomarkers. NAF was obtained in 167 out of 177 (94%) subjects overall and in 99% of the 144 most recent subjects. Sufficient NAF was obtained to evaluate cytology in 160 out of 167 (96%) cases and specimens were sufficiently cellular to analyse DNA markers in 53% of cases. Among the last 144 subjects, menopausal status did not influence the ability to obtain NAF. NAF cytology correlated with increased breast cancer risk (P = 0.002). Using computerized image analysis of NAF epithelial cells, DNA index (P = 0.0002), percentage of cells in G2M (P = 0.05) and percentage of cells with hypertetraploidy (P = 0.002) increased as cytology became more abnormal. Our data indicate that NAF can be obtained in essentially all eligible subjects; that breast epithelial cells are evaluable in > 95% of NAF samples for cytology and in over half of NAF samples for DNA index (ploidy) and cell cycle analysis; and that abnormal NAF cytology correlates with increased breast cancer risk. This suggests that biomarkers identified in nipple aspirate fluid may prove useful either as an adjunct to currently accepted breast cancer screening methods, or to evaluate response to a chemopreventive agent. Images Figure 1

The NCCN Clinical Practice Guidelines in Oncology for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions regarding the treatment of localized disease for the 2013 update of the guidelines.

Background. This prospective study assessed combined modality therapy of patients with International Union Against Cancer classification T1-4 NO MO anal cancer. Methods. Protocol therapy consisted of a dose of 4000 cGy to the pelvis, anus, and perineum, followed by a 1000-1300 cGy boost. Infusions of 5-fluorouracil and mitomycin-C were administered when radiation therapy began. A second infusion of 5-fluorouracil was administered 28 days later. Biopsy was performed 6-8 weeks after completion of treatment. Positive biopsy findings resulted in abdominal-perineal resection. Results. Survival at 7 years for 50 eligible patients was 58%. White patients and those with favorable performance status had significantly better survival. Of the 46 patients evaluable for response, 34 had a complete response, 11 had a partial response, and I had no response. Seven-year survival for partial responders was 53%. Freedom from locoregional progression was 80% at 7 years. Conclusion. Treatment with a combination of chemotherapy and radiation therapy is effective for patients with anal cancer. The investigation of methods of improving therapy is warranted. Cancer 1995; 76:1731–6.

Purpose : The incidence of adenocarcinoma of the esophagus is increasing, but the optimal treatment for this disease is unknown. We evaluated the efficacy of chemoradiation and chemoradiation followed by esophagectomy as treatment for adenocarcinoma of the esophagus in sequential prospective nonrandomized phase II studies. Methods and Materials : Between May 1981 and June 1992, all previously untreated patients (N = 35) with potentially resectable adenocarcinoma of the esophagus (clinical Stage I or II) were treated with curative intent in sequential prospective Phase II studies. From May 1981 to August 1987, 11 patients (median age 66) were treated with concurrent chemotherapy [mitomycin C, and 5-fluorouracil (5-FU)] and radiotherapy to a median dose of 60 Gy (CRT group). From September 1987 to June 1992, 24 patients (median age 65) were treated with the same regimen of chemoradiation followed by planned esophagectomy (CRT + PE group). Of these, 12 patients (median age 62) actually underwent esophagectomy (CRT + E subgroup). Results : The median overall survival was 19 months for the CRT group and 15 months for the CRT + PE group. For the CRT + E subgroup, the median overall survival was 33 months. The 3-year actuarial overall survival for the CRT and the CRT + PE groups were 36 and 28% (p = 0.949). The subset of patients treated with chemoradiation followed by esophagectomy had a 3-year actuarial overall survival of 33% (p = 0.274). The 3-year actuarial freedom from local failure rates were similar : 62% in the CRT group vs. 58% in the CRT + PE group. Of the 12 patients who underwent esophagectomy (CRT + E group), 9 (75%) were free of local failure. Four of 12 (33%) patients had no pathologic evidence of malignancy in their surgical specimen. Six of 11 patients (55%) in the CRT group were free of local failure at the time of analysis. Two of five patients in this group who had local recurrence at 2 and 10 months underwent surgical salvage with subsequent survivals of 20 and 100 months, respectively. Treatment-related mortality was 0 out of 11 in the CRT group and 2 out of 24 in the CRT + PE group. Dysphagia relief was similar in the CRT group vs. the CRT + E subgroup ; however, a greater percentage of patients treated with chemoradiation alone had normal long-term swallowing function when compared to those patients also undergoing esophagectomy (100% vs. 73%). Conclusion : High-dose chemoradiation alone appears to provide similar survival and relief of dysphagia compared with high-dose chemoradiation followed by esophagectomy for patients with potentially resectable esophageal adenocarcinoma. Local failure may be higher in patients undergoing chemoradiation compared to chemoradiation followed by esophagectomy, but surgical salvage is possible, thus providing similar overall local control. However, because of the small number of patients in each group, these treatment modalities need to be further evaluated in a prospective randomized Phase III study.

e23284Background: MEN1, DAXX and ATRX are frequently mutated in pNET. Their associations with chromosomal aberrations, disease progression, and efficacy of targeted therapy have not been establishe...

Sixty-three patients were treated with a program of preoperative radiotherapy (RT) and two 96-hour infusions of 5-fluorouracil (1,000 mg/m2/day, days 2–5 and 29–32) and a single bolus of mitomycin C (10 mg/m2) on day 2. Those who had no evidence of distant disease nor local unresectability underwent pancreatic resection (16 Whipple resections, 7 total pancreatectomies, 2 distal pancreatectomies). Thirty-eight percent of the patients had grade 3 or 4 toxicity from the chemoradioth-erapy (CTRT). One patient died during CTRT of biliary sepsis. Operative mortality for the 25 patients with potentially curative (PC) resections was 4%. One of the four patients with palliative resection died postoperatively. Two other patients with PC resection had major postoperative morbidity. Median survival for those with PC resections was 22 months, while 5-year survival was 20%. Recurrence was noted in 20 patients, primarily in the liver (50% of patients). Follow-up is 25 months for 7 patients remaining alive (range 16–77 months). We conclude that this technique is relatively safe, and can produce local cancer control in most patients and prolonged survival in a few with truly localized disease. It is still unclear whether this method of treatment sequencing is any better than postoperative CTRT. © 1995 Wiley-Liss, Inc.