Impacts of pembrolizumab therapy on immune phenotype in patients with high-grade neuroendocrine neoplasms.

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 naïve 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.

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials.

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).

Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

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.

Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

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.

NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018.

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.

NCCN Guidelines Insights: Colon Cancer, Version 2.2018.

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.

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, KRAS/NRAS mutational status, and patient comorbidities and preferences. Location of the primary tumor, the BRAF mutation status, and tumor microsatellite stability should also be considered in treatment decisions.

Association Between Benign Breast Disease in African American and White American Women and Subsequent Triple-Negative Breast Cancer.

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, and ERBB2 (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 and ERBB2 expression. 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.

Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study.

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 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003). CONCLUSIONS: Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.

Rectal Cancer, Version 2.2015.

The NCCN Guidelines for Rectal 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, posttreatment surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Rectal Cancer Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize major discussion points from the 2015 NCCN Rectal Cancer Panel meeting. Major discussion topics this year were perioperative therapy options and surveillance for patients with stage I through III disease.

Neuroendocrine tumors, version 1.2015.

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.

Colon cancer, version 3.2014.

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.

A phase II trial of the proteasome inhibitor bortezomib in patients with advanced biliary tract cancers.

BACKGROUND: Patients with advanced biliary tract cancers have limited therapeutic options. Preclinical data suggest that proteasome inhibition may be an effective therapeutic strategy. We thus evaluated the clinical efficacy of bortezomib in advanced biliary tract cancers. PATIENTS AND METHODS: Patients with locally advanced or metastatic cholangiocarcinoma or gallbladder adenocarcinoma who had received 0 to 2 previous therapies received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 of a 21-day cycle. The primary end point was objective response rate. A Simon 2-stage design was used (null response rate of < 5% and response rate of ≥ 20% of interest). RESULTS: Twenty patients enrolled (bile duct/gallbladder cancer [14/6] and previous treatments 0/1/2 [10/6/3]). The trial was discontinued early because of lack of confirmed partial responses. No unanticipated adverse events were noted. There was 1 unconfirmed partial response. Ten patients achieved stable disease as best response. Median time to progression was 5.8 months (95% confidence interval [CI], 0.7-77.6 months). Median survival was 9 months (95% CI, 4.6-18.5 months). The 6-month and 1-year survival rates were 70% and 38%, respectively. There was no difference in survival based on primary disease site. CONCLUSION: Single-agent bortezomib does not result in objective responses in biliary tract cancers. However, the rate of stable disease and time to progression benchmark is encouraging. Further development of bortezomib in combination with other therapies in this disease setting should be considered.

Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines.

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.

Metastatic colon cancer, version 3.2013: featured updates to the NCCN Guidelines.

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.

Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis.

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.

Genetic analysis of polymorphisms in dopamine receptor and transporter genes for association with smoking among cancer patients.

BACKGROUND: Smoking among Russian cancer patients may be related to variations in the DRD2/ANKK1 (Taq1), DRD4 (exon III VNTR), and SLC6A3 genes. METHODS: Seven hundred fifty patients provided smoking history and DNA. RESULTS: Current smokers were more likely to be DRD2 A2 allele carriers versus nonsmokers (former/never smokers; 69 vs. 56%; OR = 1.69; 95% CI 1.13-2.53, p = 0.01) and former smokers (69 vs. 59%; OR = 1.54; 95% CI 0.97-2.46, p = 0.07). Ever smokers (current/former smokers) were more likely to be DRD2 A2 allele carriers versus never smokers (65 vs. 55%; OR = 1.50; 95% CI 1.00-2.27, p = 0.05). The risk of current smoking among DRD2 A2 allele carriers was present if the DRD4 short allele was also present (OR = 1.76; 95% CI 1.12-2.78, p = 0.02), and the risk of ever smoking among DRD2 A2 allele carriers was present if the DRD4 short allele was also present (OR = 1.62; 95% CI 1.02-2.55, p = 0.04). DRD2 A2 allele carriers had a shorter period of previous abstinence versus DRD2 A1 carriers (p = 0.02). Effects were not statistically significant when controlling for multiple comparisons. CONCLUSIONS: The DRD2 A2 allele may increase the risk of smoking among cancer patients, convergent with studies using non-Western samples. However, additional replication is needed.

Rectal cancer.

These NCCN Clinical Practice Guidelines in Oncology provide recommendations for the management of rectal cancer, beginning with the clinical presentation of the patient to the primary care physician or gastroenterologist through diagnosis, pathologic staging, neoadjuvant treatment, surgical management, adjuvant treatment, surveillance, management of recurrent and metastatic disease, and survivorship. This discussion focuses on localized disease. The NCCN Rectal Cancer Panel believes that a multidisciplinary approach, including representation from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology, is necessary for treating patients with rectal cancer.

Neuroendocrine tumors.

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.