Purpose Positive margins dominate clinical outcomes after surgical resections in most solid cancer types including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that epidermal growth factor receptor (EGFR) can be targeted for safe and specific real-time localization of cancer. Experimental design A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n=12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days post-infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology. Results There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathological analysis of tissues ex-vivo. Fluorescence levels positively correlated with EGFR levels. Conclusion We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology.

In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.

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IMPORTANCE Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES Safety and tolerability and efficacy measured by objective response rate. RESULTS Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02319044

Purpose: To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients.Experimental Design: Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics.Results: Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving ≥15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the doselimiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease ≥4 months. PD-0325901 exposure was generally dose proportional. Doses ≥2 mg BID consistently caused ≥60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (≥50%) in Ki-67.Conclusions: PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use. Clin Cancer Res; 16(6); 1924-37. ©2010 AACR.The RAS-mitogen-activated protein kinase (MAPK) pathway has emerged as a critical signaling network involved in the regulation of cell growth and survival. The RAS-MAPK cascade mediates proliferative and antiapoptotic signaling from growth factors and oncogenic factors (such as gain-of-function RAS and RAF mutant phenotypes) that promote tumor growth, progression, and metastasis. The RAS-MAPK pathway is constitutively active in several solid tumor types (1-4).MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) occupies a pivotal position in the RAS-MAPK pathway and serves as a focal point for several mitogenic signaling pathways activated by known oncogenes (e.g., BRAF, ErbB, and RAS; refs. 5-7). Although MEK has not been identified as an oncogene itself, constitutively active MEK has been shown in >30% of primary tumor cell lines tested (including colon, lung, breast, pancreas, ovary, and kidney; ref. 2). Constitutively active MEK shows transforming ability and has resulted in highly tumorigenic cell lines in vitro (6, 7). MEK is a dual-specificity kinase and phosphorylates its only known substrates, ERK1/2 (MAPK), on both a tyrosine and threonine residue. Note: This article is part of a two-part st...

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NCCN Categories of Evidence and Consensus Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus. Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus. Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement). Category 3: The recommendation is based on any level of evidence but reflects major disagreement. All recommendations are category 2A unless otherwise noted. The Breast Cancer Clinical Practice Guidelines presented here are the work of the members of the NCCN Breast Cancer Clinical Practice Guidelines Panel. Categories of evidence were assessed and are noted on the algorithms and in the text. Although not explicitly stated at every decision point of the Guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer. The full breast cancer guidelines are not printed in this issue of JNCCN, but can be accessed online at www.nccn.org. Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Please Note These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way. These guidelines are copyrighted by the National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of the NCCN © 2009. Disclosures for the NCCN Breast Cancer Guidelines Panel At the beginning of each NCCN guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member. Individual disclosures for the NCCN Breast Cancer Guidelines Panel members can be found on page 192. (To view the most recent version of these guidelines and accompanying disclosures, visit the NCCN Web site at www.nccn.org.) These guidelines are also available on the Internet. For the latest update, please visit www.nccn.org.

Remaining the most common cancer in women through the 21(st) century, breast cancer and the development of treatment strategies continue to highlight advances made in our understanding of the pathogenesis of cancer development and resistance to therapies. Despite significant progress in the treatment of breast cancer, resistance to chemotherapeutic agents remains a consistent obstacle in terms of treatment success. Anthracyclines, first used over 30 years ago, and the more recent addition of taxanes to the treatment armamentarium are integral components for both newly diagnosed and recurrent breast cancer. Unfortunately, along with other constituents of combination chemotherapy for metastatic breast cancer, these agents ultimately become ineffective in controlling disease. With the emergence of a resistant phenotype, tumors are deemed to be drug resistant - frequently multidrug resistant (MDR). A number of processes have been identified that can underlie clinical drug resistance; observations stemming largely from in vitro laboratory-based studies in human cancer cell lines. Recognized mechanisms of resistance include altered expression of the adenosine triphosphate-binding cassette (ABC) superfamily of transporters, alteration in DNA repair pathways, mutations in cellular targets, resistance to initiation of the apoptotic pathway and the development of constitutively activated signaling pathways. As our understanding of mechanisms of resistance expands, the ability to select specific drugs or drug combinations specific to the phenotype of the cancer will become more specific. Illustrative of these advancements are the reported benefits from the use of newer microtubule-targeting agents in triple negative breast cancer, such as eribulin and ixabepilone; drugs which may be less susceptible to common pathways of drug resistance. Likewise, the combination usage of agents which intersect in receptor crosstalk, such as between the estrogen receptor and the mammalian target of rapamycin (mTOR), have demonstrated synergy in antitumor effects. The recent report of exemestane used in combination with everolimus, have shown great promise in this regard. For patients with HER2 positive disease, a combination approach with trastuzumab and investigational agents such as pertuzumab appear to result in a more complete blockage of HER2 signaling, and improved progression free survival. Thus, as our understanding of the interconnectedness of signaling pathways in breast cancer improves, the ability to rationally design appropriate chemotherapy regimens and delay emerging resistance will improve.