Search

This study assessed outcomes of patients with hypopharyngeal carcinoma treated with organ-preservation therapy utilizing intensity-modulated radiation therapy (IMRT).The medical records of 98 patients treated with definitive IMRT +/- chemotherapy from 2001 to 2013 for nonmetastatic hypopharyngeal cancer were retrospectively reviewed.Patients were treated to doses of 66 to 72 Gy. Eighty-three patients (85%) received chemotherapy. With median follow-up of 35 months, 2-year overall survival (OS), locoregional control, progression-free survival (PFS), and laryngectomy-free survival rates were 74%, 77%, 67%, and 65%, respectively. Functional laryngeal preservation rate was 76% at 2 years. N3 disease correlated with worse OS (p.01). Concurrent chemotherapy correlated with improved locoregional control (p = .03) and complete response to induction chemotherapy correlated with improved OS and PFS (p = .02). Actuarial 2-year and 5-year grade 3 treatment toxicities were 17% and 21%, respectively.Favorable disease outcomes and functional laryngeal preservation rates can be achieved with IMRT for patients with hypopharyngeal cancer. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2091-E2099, 2016.

Oral premalignant lesion (OPL) expression of PD-L1 is associated with increased cancer risk. These data suggest that immune evasion is already present at the OPL stage and warrant an evaluation of immune modulatory therapies for cancer prevention. We conducted this preclinical study in a carcinogen-induced mouse model of oral cancer to evaluate the efficacy of multiple immunomodulatory strategies, given at a time point when only OPLs are present, to reduce the incidence of oral squamous cell carcinoma (OSCC). We treated C57BL/6 mice with the carcinogen 4-nitroquinoline 1-oxide (4-NQO) for 8 weeks in drinking water. Eight weeks after discontinuing 4-NQO treatment, a group of mice (N=6) was sacrificed for assessment of invasive and non-invasive tongue lesions. A second group of mice was treated with either anti-PD-1 (N=40), anti-CTLA-4 (N=20), anti-OX40 (N=20), anti-PD-1 + anti-CTLA-4 (N=20), anti-PD-1 + anti-OX40 (N=20) antibodies, or IgG (N=40) for a total of 3 doses every 3 days, initiating 8 weeks after the cessation of 4-NQO. Antibodies used in combination were given on the same day . Mice were sacrificed 56 days after the last dose of treatment. We assessed serial H&E-stained cross sections of the tongues harvested at that same time point for development of OPLs and cancer and measured the OSCC area of each tongue using aperio imagescope software. Mann-Whitney and Fisher's exact tests were used for statistical comparisons between groups. Eight weeks after 4NQO cessation, 100% of mice developed tongue hyperplasia or dysplasia and invasive lesions were not identified, indicating this to be an ideal time point to initiate treatment strategies addressing OPLs. Tongues from mice treated with anti-PD-1 antibody displayed a decrease in the mean OSCC area when compared with mice treated with IgG (mean 3.53 mm2 versus 6.62 mm2, respectively; p= 0.018). At this time point, invasive oral cancers had developed in 75% versus 50% of IgG and anti-PD-1 treated mice, respectively (p=0.03). There were also non-significant decreases in the mean OSCC area in tongues from mice treated with anti-CTLA-4 (mean = 5.07 mm2), anti-OX40 (mean = 3.79 mm2) and anti-PD-1 + anti-CTLA-4 (mean = 3.86 mm2) antibodies when compared to mice treated with IgG (mean = 6.62 mm2) control. In the group treated with anti-PD-1 + anti-OX40 combination therapy, there was an increase in the mean OSCC area when compared to anti-PD-1 monotherapy (mean 3.53 mm2 versus 9.03 mm2), respectively (p= 0.01). Short-term anti-PD-1 immune checkpoint inhibitor therapy in the context of OPLs led to a reduction in the incidence of oral cancer. When comparing the mean area of OSCC in each group, anti-PD-1 monotherapy was superior to IgG and all other treatment strategies. Paradoxically, combining anti-OX40 and anti-PD-1 antibodies created an antagonizing effect on the therapy and increased total tumor burden when compared with anti-PD-1 monotherapy. Citation Format: Jose Augusto Monteiro de Oliveira Novaes, Marlese A. Pisegna, Alissa Poteete, Fahao Zhang, John V. Heymach, William N. William. Anti-PD-1 monotherapy outperforms multiple immunotherapy combination strategies in an oral cancer prevention mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1268.

Introduction: Blockade of immune checkpoints has improved clinical outcomes for patients with metastatic non-small cell lung cancer (NSCLC), but its role in the perioperative setting for early-stage disease is unclear. We generated preclinical models of resectable NSCLC expressing an antigen that permits quantitative assessment of the immune response and compared survival, tumor recurrence, and immune response after neoadjuvant or adjuvant immunotherapy. Experimental Procedures: We transfected murine 344SQ NSCLC cells with an ovalbumin-expression plasmid to generate OVA+ cells that can be identified with an antibody against the peptide SIINFEKL bound to H-2Kb of MHC-I. We implanted 344SQ-OVA+ cells in the flank of syngeneic mice and then randomized mice with established tumors to either 3 doses of neoadjuvant IgG, anti-PD-1, anti-CTLA-4, anti-PD-1+anti-CTLA-4, or to observation. Primary tumors were resected in all mice 2 days after mice in the neoadjuvant group had received their last dose of therapy. Two days post-surgery, mice in the observation group were treated with 3 doses of adjuvant IgG, anti-PD-1, anti-CTLA-4, anti-PD-1+anti-CTLA-4. Mice were euthanized 4 weeks after injection or when moribund and their survival recorded and lung metastases counted. We determined the composition of CD3+CD8+ tumor-infiltrating lymphocytes (TILs) with flow cytometry using tetramers against SIINFEKL-specific T cell receptors and immunohistochemical staining of tumors. Results: Single agent and combined immunotherapy significantly prolonged survival compared to controls in both neoadjuvant and adjuvant groups (p Conclusions: Neoadjuvant combined immune checkpoint blockade is superior to adjuvant immunotherapy at prolonging survival, reducing distal recurrence and inducing anti-tumor immunity in preclinical models of resectable NSCLC. Citation Format: Tina Cascone, Haifa Hamdi, Fahao Zhang, Alissa Poteete, Lerong Li, Courtney W. Hudgens, Leila J. Williams, Qiuyu Wu, Jayanthi Gudikote, Weiyi Peng, Patrick Hwu, Jing Wang, Michael Tetzlaff, William N. William, John V. Heymach. Superior efficacy of neoadjuvant compared to adjuvant immune checkpoint blockade in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1719.

8555Background: Major pathologic response (mPR) in resected NSCLC following neoadjuvant chemotherapy correlates with long-term survival. This phase 1 study assessed the safety and efficacy of N add...

9035Background: RET fusions (RET+) occur in 1-2% of NSCLCs. Tumors eventually become refractory to multi-kinase RET inhibitor monotherapy. We evaluated the pre-clinical and clinical activity of the...

Objectives: Combination chemotherapy with third-generation, nonplatinum agents (ie, gemcitabine, vinorelbine, taxanes, or camptothecins) represents a well-tolerated frontline treatment option for metastatic non―small-cell lung cancer and might play a role as salvage therapy as well. The aim of this phase 2 study was to investigate the use of docetaxel and vinorelbine in the frontline and second-line setting in patients with incurable non―small-cell lung cancer. Patients and Methods: Seventy-eight patients (42 untreated, 36 previously treated) were administered vinorelbine (20 mg/m 2 ) on days 1 and 8 and docetaxel (75 mg/m 2 for untreated patients; 60 mg/m 2 for previously treated patients for cycle 1, increased to 75 mg/m 2 for the subsequent cycles in the absence of grade 3 fever/neutropenia) on day 8, repeated every 21 days, with routine filgrastim support. Results: The most common grade 3 to 4 nonhematologic toxicities were diarrhea, dyspnea, fatigue, and nausea/vomiting (5% each). Grade 3 to 4 granulocytopenia occurred in 55% of the patients, however only 5% experienced febrile neutropenia. Response rates were 13% in the chemotherapy-naive cohort and 9% in previously treated patients. Median time to progression was 2.9 and 3.0 months and median overall survival was 15.0 and 6.2 months, for the frontline and second-line patients, respectively. Conclusions: Compared with historical controls, in the first-line setting, the combination of docetaxel and vinorelbine did not demonstrate increased efficacy advantages over platinum- or other nonplatinum-based doublets. In the second-line setting, single agent chemotherapy is as effective as, and less toxic than the docetaxel-vinorelbine combination, and the former remains the cytotoxic treatment of choice.

PD-L1 expression occurs in OPLs in humans and is associated with increased cancer risk (William et al., ASCO 2017). These data suggest a contribution of the PD-1/PD-L1 axis to immune evasion of OPLs, and warrant evaluation of anti-PD-1 immunotherapy for cancer prevention. We conducted this preclinical study in a carcinogen-induced mouse model of oral cancer to test the hypothesis that a short course of anti-PD-1 therapy, given at a time point when only OPLs are present (and before invasive cancer development), could lead to enhanced and sustained immune responses. We treated C57BL/6 mice with the carcinogen 4-nitroquinoline 1-oxide (4-NQO) for 8 weeks in drinking water. Eight weeks after 4-NQO discontinuation, a group of mice (N=6) was sacrificed for assessment of invasive and noninvasive tongue lesions. A second group of mice was treated with either anti-PD-1 antibody (N=10) or IgG (N=10) for a total of 3 doses every 3 days initiating 8 weeks after the cessation of 4-NQO. We sacrificed these animals 56 days after the last dose of treatment, harvested cervical lymph nodes, and prepared and stained cell suspensions with fluorochrome-labeled antibodies against CD45, CD3, CD8, Granzyme B (GZB), PD-1, TIM-3, Lag-3, ZombieNirt (live/dead discrimination) for flow cytometric evaluation. We also assessed serial H&E-stained cross-sections of the tongues harvested at that same time point for development of OPLs and cancers. Student’s t-test and Fisher's exact test were used for statistical comparisons between groups. At 8 weeks after 4NQO cessation, 6 out of 6 mice developed tongue hyperplasia or dysplasia. No invasive lesions were identified, indicating this to be an ideal time point to study/initiate treatment strategies addressing OPLs. Anti-PD-1 therapy led to a sustained increase in the proportion of CD8+|GZB+ cytotoxic T lymphocytes (CTLs) when compared to IgG (mean 26.9% ± 4.4% versus 14.4% ± 2.3%, respectively; p= 0.025) in cervical lymph nodes harvested 56 days after treatment discontinuation. We also observed an increase in the proportion of CD8+|PD-1+ CTLs (mean 22.3% ± 2.08% versus 13.3% ± 1.42%, respectively; p= 0.0026) and a trend towards an increase in CD8+|TIM-3+|LAG-3+ CTLs (mean 5.9% ± 1.5% versus 2.5% ± 0.7%, respectively; p= 0.0733). This immune profile is indicative of activated CTLs with limited/no signs of exhaustion. At this late sacrifice time point, frankly invasive oral cancers had developed in 70% vs 40% of IgG and anti-PD1-treated mice, respectively (p=0.36). Short-term anti-PD-1 immune checkpoint inhibitor therapy in the context of OPLs led to a sustained increase in the population of granzyme B+ CTLs in cervical lymph nodes, accompanied by a trend towards a reduction in the incidence of oral cancer. These results suggest that immune checkpoint-targeted therapy can reverse immune suppression already present at the preinvasive stage, and support the ongoing Immune Prevention of Oral Cancer (IPOC) clinical trial evaluating pembrolizumab in high-risk OPLs (NCT02882282). Additional preclinical studies are under way to assess if an immune response to anti-PD1 therapy can occur at earlier time points, and lead to pronounced prevention of oral cancers at a stage when the (irreversible) malignant transformation process induced by the potent 4-NQO carcinogen is not yet far advanced. Citation Format: Jose Augusto Monteiro de Oliveira Novaes, Taghreed Hirz, Marlese A. Pisegna, Patrick Hwu, John V. Heymach, William N. William. Sustained immune response to anti-PD-1 therapy for oral premalignant lesions (OPLs) in a carcinogen-induced oral cancer mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A077.

Purpose To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) consisting of six weekly cycles of paclitaxel 135 mg/m2 and carboplatin (area under the curve = 2) with cetuximab 400 mg/m2 in week 1 and then 250 mg/m2 (PCC). Patients and Methods Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis. Results After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046). Conclusion ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis.

Background The purpose of this population-based study is to provide a detailed analysis of survival outcome of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) enrolled in the Surveillance, Epidemiology and End Results (SEER) program. Methods We retrieved, from the SEER database, data on demographics, disease extension (size, extent of primary tumor, and nodal status), histology, primary treatment modality, and survival time of NSCLC cases diagnosed between 1998 and 2003 (n = 138,063). Cases were reclassified into separate T4 (satellite, invasive, or pleural effusion) and M1 (ipsilateral, contralateral, or distant) categories based on the extent of the primary tumor and the location of metastatic disease. Univariate and multivariate analyses were performed to assess the effects of each variable on survival. Results For stage IIIB NSCLC, T4 satellite had the best prognosis (comparable to T2 lesions), followed by T4 invasive and T4 pleural effusion. For stage IV, M1 ipsilateral had the best prognosis, followed by M1 contralateral and M1 distant. Nodal status remained a powerful determinant of survival, particularly for patients with T4 satellite, T4 invasive, M1 ipsilateral, and, to a less extent, M1 contralateral. Other prognostic variables were identified within each subgroup. Conclusions In this report, we present the most comprehensive analysis performed to date of patients with stage IIIB and IV NSCLC enrolled in the SEER program. The survival trends observed here suggest that T4 satellite lung cancer cases should be redefined as T2b, and not T3 as recently proposed for the upcoming TNM classification, seventh edition.

Objective: This phase I trial was designed to determine the maximal tolerated dose (MTD) of the combination of topotecan and gemcitabine given in a weekly schedule. Materials and Methods: In this single-arm, open label, dose-escalation study, we administered topotecan (0.75–1.5 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks to 25 patients with advanced solid tumors. Results: The topotecan MTD, when combined with gemcitabine, was 1.25 mg/m2/wk. Dose-limiting toxicities consisted of febrile granulocytopenia in 2 patients at the highest dose level. At the MTD, no episodes of granulocytopenia were observed, whereas 2/9 patients exhibited grade 3 thrombocytopenia. Other common grades 3–4 adverse events across all cohorts included non-neutropenic infections, fatigue, skin reactions, vomiting, and fever. One partial response and 2 stable diseases were observed in patients with nasopharyngeal carcinoma. Disease stabilization was also observed in patients with squamous cell carcinoma of the head and neck (3), nonsmall cell lung cancer (1), and thymoma (1). Conclusions: Topotecan and gemcitabine combined in a weekly schedule exhibit a favorable toxicity profile. Efficacy results support the further evaluation of this regimen in patients with head and neck cancer (particularly nasopharyngeal carcinoma).

Introduction Motexafin gadolinium is a novel antineoplastic drug that disrupts cancer cell antioxidant systems, thus contributing to cellular death. In patients with lung cancer, motexafin gadolinium has been shown to increase the time to neurologic progression when given in combination with whole-brain radiotherapy in randomized phase III studies. Preclinical data suggest that this drug might also enhance the antineoplastic effects of chemotherapy. Methods In this one-arm, open label, phase I, dose-escalation study, we administered docetaxel (75 mg/m 2 ), cisplatin (75 mg/m 2 ), and motexafin gadolinium every 3 weeks to patients with metastatic non-small cell lung cancer. Twenty-one patients were treated at one of four motexafin dose levels. Results The maximal tolerated motexafin dose was 10 mg/kg on day 1 of a 3-week cycle. Dose-limiting toxicities consisted of febrile neutropenia, hypertension, myocardial ischemia, and pneumonitis/pulmonary infiltrates. Other common grade 3–4 adverse events across all cohorts that did not appear to be exacerbated by motexafin gadolinium included granulocytopenia, fatigue, dehydration, nausea, and vomiting. Two episodes of myocardial ischemia and one sudden death of unknown cause were observed. Response rates were partial response (10%), stable disease (60%), and disease progression (30%). Conclusions The regimen studied was tolerable and showed activity in patients with metastatic non-small cell lung cancer. The recommended doses for future phase II trials are motexafin gadolinium 10 mg/kg, docetaxel 75 mg/m 2 , and cisplatin 75 mg/m 2 intravenously on day 1 every 3 weeks. Caution is advised in patients with a history of cardiovascular disease.

Background. Late complications of novel organ preservation multimodal protocols for the treatment of locally advanced head and neck cancer may be underreported in the literature. Methods and Results. We present the case of a 64-year-old man with T4 N0 M0 squamous cell carcinoma of the oropharynx, who enrolled on an organ-preservation protocol at our institution. He received 2 cycles of neoadjuvant chemotherapy with capeci- tabine, docetaxel, and carboplatin, followed by 2 more identical cycles given concurrently with radiotherapy. Nine months later, he was admitted to the hospital with Streptococcus pyogenes necrotizing fasciitis of the cervical region, leading to rapidly pro- gressive septic shock. Conclusions. Severe infectious complications of chemora- diation for locally advanced head and neck cancer may occur months after completion of treatment. The recognition of these late side effects is crucial so as to accurately ascertain the long- term morbidity and benefits of organ-preservation protocols in this setting. V C 2007 Wiley Periodicals, Inc. Head Neck 29: 700-704, 2007

Purpose To assist in determining barriers to an oncology career incorporating cancer prevention, the American Society of Clinical Oncology (ASCO) Cancer Prevention Workforce Pipeline Work Group sponsored surveys of training program directors and oncology fellows. Methods Separate surveys with parallel questions were administered to training program directors at their fall 2013 retreat and to oncology fellows as part of their February 2014 in-training examination survey. Forty-seven (67%) of 70 training directors and 1,306 (80%) of 1,634 oncology fellows taking the in-training examination survey answered questions. Results Training directors estimated that ≤ 10% of fellows starting an academic career or entering private practice would have a career focus in cancer prevention. Only 15% of fellows indicated they would likely be interested in cancer prevention as a career focus, although only 12% thought prevention was unimportant relative to treatment. Top fellow-listed barriers to an academic career were difficulty in obtaining funding and lower compensation. Additional barriers to an academic career with a prevention focus included unclear career model, lack of clinical mentors, lack of clinical training opportunities, and concerns about reimbursement. Conclusion Reluctance to incorporate cancer prevention into an oncology career seems to stem from lack of mentors and exposure during training, unclear career path, and uncertainty regarding reimbursement. Suggested approaches to begin to remedy this problem include: 1) more ASCO-led and other prevention educational resources for fellows, training directors, and practicing oncologists; 2) an increase in funded training and clinical research opportunities, including reintroduction of the R25T award; 3) an increase in the prevention content of accrediting examinations for clinical oncologists; and 4) interaction with policymakers to broaden the scope and depth of reimbursement for prevention counseling and intervention services.

DNA promoter methylation of tumor suppressor genes and global DNA hypomethylation are common features of head and neck cancers. Our goal was to identify early DNA methylation changes in oral premalignant lesions (OPL) that may serve as predictive markers of developing oral squamous cell carcinoma (OSCC). Using high-throughput DNA methylation profiles of 24 OPLs, we found that the top 86 genes differentially methylated between patients who did or did not develop OSCC were simultaneously hypermethylated, suggesting that a CpG island methylation phenotype may occur early during OSCC development. The vast majority of the 86 genes were nonmethylated in normal tissues and hypermethylated in OSCC versus normal mucosa. We used pyrosequencing in a validation cohort of 44 patients to evaluate the degree of methylation of AGTR1, FOXI2, and PENK promoters CpG sites that were included in the top 86 genes and of LINE1 repetitive element methylation, a surrogate of global DNA methylation. A methylation index was developed by averaging the percent methylation of AGTR1, FOXI2, and PENK promoters; patients with a high methylation index had a worse oral cancer–free survival (P = 0.0030). On the other hand, patients with low levels of LINE1 methylation had a significantly worse oral cancer–free survival (P = 0.0153). In conclusion, AGTR1, FOXI2, and PENK promoter methylation and LINE1 hypomethylation may be associated with an increased risk of OSCC development in patients with OPLs. Cancer Prev Res; 8(11); 1027–35. ©2015 AACR.

Context Dexamethasone is often used to treat dyspnea in cancer patients, but evidence is lacking. Objectives We determined the feasibility of conducting a randomized trial of dexamethasone in cancer patients and estimated the efficacy of dexamethasone in the treatment of dyspnea. Methods In this double-blind, randomized, controlled trial, patients with dyspnea ≥4 were randomized to receive either dexamethasone 8 mg twice daily × four days then 4 mg twice daily × three days or placebo for seven days, followed by an open-label phase for seven days. We documented the changes in dyspnea (0–10 numeric rating scale), spirometry measures, quality of life, and toxicities. Results A total of 41 patients were randomized and 35 (85%) completed the blinded phase. Dexamethasone was associated with a significant reduction in dyspnea numeric rating scale of −1.9 (95% CI −3.3 to −0.5, P = 0.01) by Day 4 and −1.8 (95% CI −3.2 to −0.3, P = 0.02) by Day 7. In contrast, placebo was associated with a reduction of −0.7 (95% CI −2.1 to 0.6, P = 0.38) by Day 4 and −1.3 (95% CI −2.4 to −0.2, P = 0.03) by Day 7. The between-arm difference was not statistically significant. Drowsiness improved with dexamethasone. Dexamethasone was well tolerated with no significant toxicities. Conclusion A double-blind, randomized, controlled trial of dexamethasone was feasible with a low attrition rate. Our preliminary data suggest that dexamethasone may be associated with rapid improvement in dyspnea and was well tolerated. Further studies are needed to confirm our findings. Trial Registration ClinicalTrials.gov NCT01670097.

BackgroundPericardial effusion (PE) is common in cancer patients, but the optimal therapeutic approach is not well defined. Percutaneous pericardiocentesis is less invasive than surgery, but its long-term effectiveness and safety have not been well documented.ObjectivesThe goal of this study was to evaluate outcomes of cancer patients undergoing percutaneous pericardiocentesis for PE and assess the procedure’s safety in patients with thrombocytopenia.MethodsCancer patients who underwent percutaneous pericardiocentesis for PE between November 2009 and October 2014 at the MD Anderson Cancer Center were included. Procedure-related complications, effusion recurrence rate, and overall survival were analyzed.ResultsOf 1,645 cancer patients referred for PE, 212 (13%) underwent percutaneous pericardiocentesis. The procedure was successful in 99% of the cases, and there were no procedure-related deaths. Four patients had major procedure-related bleeding that did not vary by platelet count 65 years), lung cancer, platelet count

There is a lack of data from phase III randomized studies to support an ideal approach for locally advanced oral cavity cancer patients. In general, surgery, radiotherapy and chemotherapy are valid treatment options, and combined approach is usually indicated given poor clinical outcomes with single modality therapy. The aim of this study is to review the current status and future perspectives of induction chemotherapy for locally advanced oral cavity cancer patients.

Background Locoregionally advanced oral cavity cancers are aggressive tumours with high risk of relapse after definitive treatment. This study was performed to assess the effectiveness and safety of induction chemotherapy prior to surgery for untreated oral cavity cancer patients. Material and methods Only prospective phase III randomised studies comparing induction chemotherapy followed by surgery with or without postoperative radiotherapy (Chemo Group) compared with surgery with or without postoperative radiotherapy (Control Group) were eligible. Two of the authors independently selected and assessed the studies regarding eligibility criteria and risk of bias. Results Two studies were selected. A total of 451 patients were randomly assigned to Chemo Group (n = 226) versus Control Group (n = 225). Most patients had tumours at clinical stages III/IV (89.1%). Both trials were classified as having low risk of bias. No significant overall benefit in favour of induction chemotherapy was found regarding loco-regional recurrence, disease-free survival and overall survival. A subgroup analysis of individual data from cN2 patients showed statistically significant overall survival benefit in favour of induction chemotherapy. The included studies did not directly compare toxicity between the groups and no statistical analysis was performed regarding safety outcomes. Conclusions Based on the available studies, induction chemotherapy when administered before surgery with curative intent did not improve clinical outcomes in locoregionally advanced oral cavity cancer patients. Clinically assessed N2 patients might benefit from induction chemotherapy.

Purpose To review our experience treating patients with the Hedgehog pathway inhibitor, vismodegib, in patients with orbital or periocular locally advanced or metastatic basal cell carcinoma (BCC) or basal cell nevus syndrome. Design Retrospective interventional case series. Methods We reviewed all patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome treated with the Hedgehog pathway inhibitor, vismodegib, at a comprehensive cancer center from 2009 through 2015. Reviewed data included age; sex; American Joint Commission on Cancer tumor, node, metastasis staging system designation; type and grade of drug-related side effects; response to treatment; duration of follow-up, and status at last follow-up. Results The study included 10 white men and 2 white women; the median age was 64.5 years. Ten patients had locally advanced BCC; 2 had basal cell nevus syndrome. Among the patients with locally advanced BCC, 5 had T3bN0M0 disease at presentation; 1 each had T3aN0M0, T3bN1M0, T2N1M1, T4N1M1, and T4N2cM1 disease. Overall, 3 patients had a complete response, 6 had a partial response, and 3 had stable disease at last follow-up. Two patients developed progressive disease after a complete response for 38 months and stable disease for 16 months, respectively. All patients developed grade I drug-related adverse effects, most commonly muscle spasms (12 patients), weight loss (10), dysgeusia (9), alopecia (9), decreased appetite (5), and fatigue (4). Five patients developed grade II adverse effects. At last follow-up, none of the 5 patients presenting with T3bN0M0, nor the patient with T3bN1M0 disease, had required orbital exenteration. Conclusion Hedgehog pathway inhibition produces a significant clinical response in most patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome and can obviate orbital exenteration in some patients. Drug-related adverse effects are manageable in most patients.

Oral pre-malignant lesions (OPLs) are usually clinically characterized as leukoplakia or erythhroplakia, and confer an increased risk of oral cancer. Despite decades of clinical investigations with candidate chemopreventive agents such as 13-cis-retinoic acid, beta-carotene, fenretinide, green-tea extract, celecoxib, erlotinib, among others, a standard-of-care chemoprevention strategy for oral cancers has not yet been developed. Importantly, OPLs and oral cavity cancers are not related to HPV, thus HPV vaccines are not expected to be effective in this setting. One of the greatest challenges in managing patients with OPLs is determining risk for malignant transformation and need for intervention. To that end, retrospective and prospective studies have been completed by our group and others and demonstrate that LOH profiles (primarily at 13p14 and/or 9p21) in OPLs are associated with higher incidence of oral cancers. LOH is now considered the most robust prognostic marker of cancer risk in this setting, and these data now set the stage for development of clinical trials focused on molecularly-defined high risk groups of OPLs. Immune checkpoint blockade with antibodies directed at programmed cell death protein 1 (PD-1) has recently been successfully developed for the management of advanced head and neck squamous cell carcinomas, validating the importance of immune modulation in the progression of these invasive tumors. Given the favorable toxicity profile, there is interest in studying these agents for prevention of oral cancers in patients with high risk OPLs. In this presentation, we will review the data that support a role for immune surveillance and immune editing in the development of oral cancers, and describe the rationale and clinical trial design of the Immunoprevention of Oral Cancer (IPOC) study, the first randomized trial to evaluate the PD-1 inhibitor pembrolizumab for oral cancer prevention in patients with molecularly-defined high-risk OPLs. Citation Format: William N. William, Jr. Immunoprevention of oral cancers [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA05.

Introduction: Immunotherapy with single agent anti-PD-1 antibody confers modest overall survival benefits in patients with recurrent/metastatic HNSCCs. Combined immune checkpoint targeting has shown promising results for melanomas and other solid tumors. Thus, evaluation of combination immunotherapy in animal models specific to HNSCCs could inform prioritization and design of human clinical trials for this disease. We conducted this pre-clinical study to test the hypothesis that combining anti-PD-1 with either anti-CTLA-4 or co-stimulatory immune checkpoint agonist antibodies would be more effective than anti-PD-1 monotherapy in a mouse model of oral carcinoma. We also aimed at identifying the combination regimen with highest anti-tumor activity. Methods: C57BL/6 mice were subcutaneously grafted with 2x106 mouse oral cancer 1 (MOC1) cells derived from a carcinogen-induced tumor molecularly similar to human HNSCC. After 25 days, mice were randomized into one of 12 treatment groups (IgG, or antibodies targeting PD-1, CTLA-4, CD40, OX-40, GITR, 4-1BB, PD-1+CTLA-4, PD1+CD40, PD-1+OX-40, PD-1+GITR, or PD-1+4-1BB), N=8-9 mice/group. Antibodies were administered every 4 days for 3 doses. Tumors were measured twice per week. The primary endpoint was overall survival. Mice were sacrificed when tumor diameter was >2 cm or tumor ulceration was >5 mm. Survival curves were computed using the Kaplan-Meier method and compared using the log-rank (Mantel-Cox) test. Results: In analogy to human clinical trials, anti-PD-1 therapy led to a modest improvement in survival compared to IgG [HR=0.41; 95%CI 0.06-0.53; P=0.015], indicating that this model recapitulates, in part, the effects of immunotherapy in HNSCC patients; none of the animals survived long term. Monotherapy with anti-CTLA-4, anti-CD40, anti-OX-40, or anti-4-1BB also improved survival compared to IgG (P=0.0001, 0.003, 0.02, and 0.003, respectively), but were not more effective than anti-PD-1 alone (P=0.09, 0.12, 0.72, and 0.77, respectively). Combination therapy did not prolong survival compared to anti-PD-1 alone, with the exception of anti-PD-1+ anti-CTLA4 [HR=0.36; 95% CI 0.07-0.6; P=0.016], and anti-PD-1+ anti-CD40 [HR=0.125, 95% CI 0.02-0.24; P=0.0003]. Notably, 50% of mice receiving anti-PD-1+ anti-CD40 antibodies had complete tumor eradication and are alive and disease-free 120 days after tumor grafting. Conclusions: Single agent immunotherapy targeting PD-1, CTLA-4, CD40, OX-40 and 4-1BB modestly improved survival in a mouse model of oral cancer. Combination with anti-PD-1+ anti-CTLA4 and anti-PD-1+ anti-CD40 antibodies outperformed anti-PD-1 monotherapy. Complete responses were exclusively seen with PD-1+CD40 dual targeting. This regimen should be prioritized for evaluation in HNSCC clinical trials. Citation Format: Jose Augusto Monteiro de Oliveira Novaes, Alissa R. Poteete, Marlese A. Pisegna, Uma Giri, Fahao Zhang, Patrick Hwu, John V. Heymach, William N. William. Combined immune checkpoint targeting with anti-PD-1 plus anti-CD40 antibodies as the most effective approach to eradicate head and neck squamous cell carcinomas (HNSCCs) in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5648. doi:10.1158/1538-7445.AM2017-5648

1545 Background: We previously demonstrated that high-risk loss of heterozygosity (LOH) profiles (i.e., 3p14/9p21 LOH) and EGFR gene copy number gain (CNG) in OPLs were associated with inferior oral cancer-free survival (OCFS) in patients enrolled in the randomized EPOC trial. Herein, we performed comprehensive immune profiling of OPLs and correlated the findings with molecular features and outcomes, using the prospectively collected and clinically annotated EPOC biobank. Methods: We evaluated OPL specimens by multiplex immunofluorescence using the Opal 7-color fIHC Kit and the Vectra multispectral microscope / inForm Cell Analysis software. Markers included AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD8, and CD68. Wilcoxon rank-sum and Fisher’s exact tests were used to assess the associations between binary markers and continuous and categorical variables, respectively. Cox model was used to investigate associations of markers with OCFS. Results: The cohort included 188 OPL patients with hyperkeratosis/hyperplasia (18%), mild/moderate (44%), or severe dysplasia (5%); 65% had high-risk LOH profiles. The 5-year OCFS was 72.3% (median follow-up of 50 months). PD-L1 expression in > 1% of epithelial cells occurred in 28% of OPLs. Intraepithelial CD3+, CD3+/CD8+, CD68+, and CD68+/PD-L1+ cells were detected in 100%, 88%, 88%, and 54% of the samples, respectively. OPLs with high-risk LOH profiles had increased epithelial PD-L1 expression (P = 0.007), intraepithelial CD68+/PD-L1+ cells (P = 0.002), and a trend towards more CD3+/CD8+ cells in the stroma (P = 0.06) but not in the epithelium (P = 0.97), compared with low-risk LOH OPLs. Increased epithelial PD-L1 expression was associated with inferior OCFS on univariate (P = 0.023), and multivariate analysis including LOH status and EGFR CNG as co-variates (P = 0.018). Conclusions: High-risk OPLs defined by LOH profiles had increased PD-L1 expression in epithelial cells and intraepithelial macrophages, as well as stromal CD3+/CD8+ immune infiltration. Higher PD-L1 expression was associated with increased oral cancer risk. The findings may support evaluation of (PD-1-targeted) immunoprevention strategies in high-risk OPLs.

6017 Background: In a single-arm, phase 2 study, we previously demonstrated that in pts with R/M HNSCC, cisplatin, docetaxel and E improved progression-free survival (PFS) compared to historical data (Kim et al., ASCO 2006). Herein, we evaluated this regimen in a single center, randomized, phase 2 trial. Methods: Pts with R/M HNSCC, with a performance status (PS) 0-2, were randomized (1:1) to receive up to 6 cycles of first-line chemotherapy with cisplatin 75 mg/m2 (or carboplatin AUC 6) and docetaxel 75 mg/m2 i.v. on day 1 every 21 days, plus placebo (P) vs. E 150 mg p.o. daily, followed by maintenance P or E until disease progression. The primary endpoint was PFS. With 120 pts, the study had 80% power to detect an improvement in median PFS from 3.0 to 4.9 months with a two-sided type I error rate of 0.1. Results: From 05/2010 to 07/2015, 120 pts were randomized to the P (N = 60) or E (N = 60) groups. All pts but one initiated treatment and were eligible for evaluation of the primary endpoint – 92 males; median age 62 years; 52 oropharynx, 40 oral cavity, 19 larynx, 8 hypopharynx cancer pts; 86 current/former smokers; 43 with recurrence within 6 months of completion of local treatment; 27 with prior exposure to EGFR inhibitors. Median PFS was 4.4 vs. 6.1 months for the P and E groups, respectively (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.42-0.95 months, p = 0.026). Response rates were 44% vs. 56% for P vs. E (p = 0.21). Median overall survival (OS) for P- and E-treated pts was 13.7 vs. 17.0 months (HR = 0.67, 95% CI 0.43-1.04, p = 0.07). Benefits from E on PFS and OS were more pronounced in pts with oropharyngeal tumors (p≤0.05 for interaction). In the E group, first-cycle rash grade 2-4 (34% pts) was associated with longer OS (HR = 0.40, p = 0.02). E-treated pts experienced a higher incidence of grade 3-4 adverse events (33.9 vs. 53.3%), including diarrhea (3 vs.17%), dehydration (5 vs. 15%), nausea (5 vs. 14%), rash (0 vs. 12%). Conclusions: This study met its primary endpoint. Addition of E to first-line platinum/docetaxel improved PFS and OS. This regimen may warrant further evaluation in randomized, phase 3 trials. Clinical trial information: NCT01064479.

8570 Background: Histopathology, largely determined by morphology, plays a critical role in choosing appropriate treatment for lung cancer. The understanding of molecular determination of lung cancer histology is rudimentary. Our recently published data (Zhang, Science, 2014 and Liu, Nature Communications, 2016) have demonstrated that within the same patients with identical genetic background and identical exposure, tumor regions with different morphologic appearances may have very similar genomic profiles while tumors with the same morphology may have distinct genomic landscape. Methods: We collected 12 lung cancers of mixing histology with 2 to 4 histologic components within each tumor. In total, 26 tumor regions including 9 adenocarcinomas, 6 large-cell neuroendocrine carcinoma, 6 small cell carcinomas and 4 squamous cell carcinomas and one poorly differentiated lung carcinoma were microdissected and subjected to whole exome sequencing. Results: A substantial number of identical mutations were shared between different histologic components within the same tumor in all 12 patients. However, the proportion of shared mutations varies in different patients ranging from as little as 4% to as much as 99%. Mutation spectrum is also similar between different histologic components within the same tumors suggesting similar mutational process in place. Identical canonical cancer gene mutations including TP53, KRAS, PIK3CA, SOS1 and STK11 are generally shared between different histologic components within the same tumors. Canonical mutations in FBXW7 and MTHFR were detected in squamous component, but not small-cell component in one patient. Conclusions: Different histologic components of lung cancers of mixing histology are likely derived from the same progenitor cells, but the molecular timing of branch separation of subclones giving rise to different histologic components varies in different tumors. Although genomic aberrations may play a role in a subset of tumors, histologic features may not be determined at genomic level for most lung cancers. Gene expression and methylation analyses from these tumors are underway.

e14557 Background: In immuno-oncology (IO), the correlation between clinical trial endpoints, specifically, objective response rate (ORR), disease control rate (DCR) or progression free survival (PFS), and overall survival (OS) is poorly understood. The effect of IO agents as opposed to chemotherapy, is not on tumor cells, but on immune cells and OS benefit has been observed in absence of PFS benefit. However, decisions on registration trials often rely on PFS from Phase II trials. Methods: We conducted a systematic literature review with PubMed and Embase (Jan. 2005–Nov. 2016), supplemented with oncology conference proceedings (2014–2016). Eligible studies were randomized controlled trials (RCT) that investigated ≥1 immune checkpoint blockers (CBs) targeting programmed death proteins (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and reported their relative effect on OS and on ≥1 of the clinical endpoints, DCR, ORR, and PFS. Log-transformed hazard ratios were fitted using weighted regression models to determine the power of relative effects on clinical endpoints to predict OS effects, with correlation coefficients estimated and presented with adjusted R2 (high values indicating better goodness-of-fit). Results: This analysis included 18 RCTs involving 7140, patients. Most studies (10/18) evaluated the efficacy of CBs vs conventional chemotherapy, whereas 8 studies compared the efficacy of ≥1 CB. Among trials that evaluated anti-CTLA-4, the adjusted R2 for the relative efficacy of CBs on DCR, ORR, PFS, and relative efficacy of CBs on OS were 0.160 ( P= 0.156), 0.016 ( P= 0.332), and 0.000 ( P= 0.623) respectively. Among trials that evaluated either anti-PD-1 or anti-PD-L1, the adjusted R2 were 0.038 ( P= 0.401), 0.066 ( P= 0.251), and 0.432 ( P= 0.032), for DCR, ORR and PFS respectively. Among trials that evaluated CBs in melanoma, the adjusted R2 were 0.030 ( P= 0.267), 0.028 ( P= 0.279), and 0.192 ( P= 0.154), for DCR, ORR, and PFS respectively. Conclusions: No clear correlations were observed between relative effects of conventional clinical endpoints and OS for CBs. New surrogate endpoints may be needed to better predict OS benefit for CBs and other forms of cancer immunotherapy.

8545 Background: Our previous study has suggested that complex genomic intratumor heterogeneity (gITH) was associated with an increased risk of relapse in patients with localized lung adenocarcinomas (LUAD). We have launched a study to investigate molecular and immune profile ITH of Stage IA NSCLC (a patient population with no optimal biomarker to guide postsurgical therapy) to understand the molecular evolution during early carcinogenesis and to identify biomarkers for early detection and intervention. Here, we report the preliminary analysis on gITH. Methods: We performed multiregion whole exome sequencing on 30 Stage IA LUAD and matched normal lung tissue to a median sequencing depth of 494x. 15 patients have relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are 1:1 matched for the key prognostic factors including tumor size, smoking status, age, gender, ethnicity and lobectomy or wedge resection. Shannon diversity index (SDI) was used to quantify ITH in each individual tumor. Kaplan-Meier method was used to evaluate the relationship between ITH and disease-free survival (DFS) as well as overall survival (OS). Results: Consistent with our previous study, 108 of 110 (98.2%) canonical cancer gene mutations were shared events by all regions of individual tumor. Compared to non-relapsed controls, tumors from relapsed cases demonstrated significantly higher degree of ITH (SDI of 1.78 in cases vs 1.58 for controls, p = 0.016). Higher degree of gITH was associated with shorter DFS (p = 0.008) and shorter OS (p = 0.0153). Significantly higher mutation burden was observed in tumors from relapsed patients (median of 10.86 mutations per MB in cases vs 7.45 mutations per MB in controls, p = 0.03). Analysis of gITH on a larger cohort and on predicted neoantigen, methylation, gene expression and immune profiles are in progress. Conclusions: Majority of cancer gene mutations are clonal events during early carcinogenesis of LUAD. Complex gITH may be associated with more aggressive biology and inferior clinical outcome in patients with Stage IA LUAD, therefore, may be evaluated as a potential biomarker.

e20042 Background: The widespread use of CT for lung cancer screening and other reasons has resulted in a dramatic increase in the number of indeterminate ground glass opacities (GGOs). While many of GGOs can be resected with minimal morbidity, the cost has been called into question. Furthermore, multifocality is a relatively common, which makes decisions on extent of surgical resection and potential benefit less clear. Chemoprevention is a theoretically appealing approach to reduce lung cancer incidence and mortality. However, randomized trials have been disappointing to date. This may be due to the constellation of many factors including lack of reliable biomarkers to identify high-risk patients, lack of appropriate molecular targets and appropriate drugs because of our rudimentary knowledge on early carcinogenesis of lung cancers. It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that can progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, the biology of these lesions is poorly understood and the definition and management of these lesions remain controversial. Methods: Study on early carcinogenesis is hampered by the small size of lesions and challenge of obtaining longitudinal samples at different stages of disease progression. Multiregion sequencing can depict genomic events relative to molecular time with early events ubiquitously present in all regions and late mutations confined to spatially separated regions of lesions. Using this approach, our recent work has reported that 20/21 canonical cancer gene mutations were early genetic events. Results: With intent to delineate the pivotal molecular events driving early carcinogenesis of lung cancer, we have collected 154 resected GGOs with including AAH (N = 40), AIS (N = 39), MIA (N = 55) and ADC (N = 20) based on the IASLC/ATS/ERS classification from 89 patients including 38 patients presenting with multifocal GGOs and 18 patients carry more than one type of pathology. Two to five spatially separated regions from each of the 154 lesions are subjected to whole exome sequencing. Conclusions: The data will be ready to present at the meeting.

e20077 Background: Intra-tumor heterogeneity (ITH) may be present in all molecular levels. Genomic ITH at the exome level has been reported in many cancer types, but comprehensive gene expression ITH has not been well studied. Methods: We collected 35 samples from 10 NSCLC patients (3 or 4 regions/tumor) including lung adenocarcinoma (n = 6), squamous cell carcinoma (n = 2), large cell carcinoma (n = 1) and pleomorphic carcinoma (n = 1). Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for each sample. Diverse gene expression signatures associated with clinical outcomes were tested for ITH. Results: Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of ITH. The analysis of various clinically relevant gene expression signatures including molecular subtype, EMT and immunotherapy response signatures also revealed heterogeneity between different regions of the same tumor. The gene expression ITH we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Conclusions: Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression ITH.

9083 Background: Overall response rates (ORR) to 2nd-line SACTx in NSCLC have consistently not exceeded 15%. Exploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in ORR to CTx after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if SACTx (3rd-line or beyond) would yield improved ORR when given after exposure to programmed-death-(ligand)1 inhibitors (PD1i) in metastatic NSCLC. Methods: Eligibility criteria - patients registered in the Thoracic GEMINI database of MD Anderson treated between 06/12 and 11/16 who received at least one SACTx as 3rd-line or beyond, following progression after platinum-based CTx and PD1i. We computed efficacy outcomes to each therapy, including ORR by RECIST v1.1, progression-free survival (PFS) and overall survival (OS). Results: Of 306 PD1i-treated patients registered in the database, 28 met eligibility criteria - 54% were male, median age 66 years, 82% adenocarcinoma, 29% never smokers. The PD1i and SACTx most commonly used were nivolumab (82%) and docetaxel (54%). ORR to SACTx after exposure to PD1i was 39% (11/28 patients, 8 confirmed). In contrast, ORR to 1st-line CTx in this cohort was 30% (Table). Liver metastasis and pembrolizumab as the PD1i of choice were the only factors associated with response to SACTx on univariate analysis (p < 0.05). Conclusions: In NSCLC patients, ORR to SACTx after immunotherapy exposure was higher compared to historical data from the pre-PD1i era, and approached ORR to 1st-line platinum-based CTx. Further investigation of a possible chemosensitization effect by immunotherapy is warranted. [Table: see text]

6089 Background: We previously reported that activating NOTCH1 mutations occurs in approximately 20% of ACCs and drive a phenotype with solid histology, liver and bone metastases, poor prognosis, and potential responsiveness to Notch1 inhibitors; however the impact of NOTCH1mutations on responsiveness to systemic therapy in ACC is unknown. The aim of this study was to evaluate the ORR and median PFS (mPFS) to systemic therapy in patients with metastatic ACC according to their Notch1 status. Methods: We identified 20 ACC patients with measurable disease that underwent treatment at MDACC and had tumor molecular profile. A radiologist blinded to the patient’s NOTCH1status performed review of all images. Measurement of target lesions was captured by a quantitative imaging analysis tool for ORR assessment by RECIST 1.1. PFS was estimated by Kaplan-Meier method. Comparisons of PFS between groups were performed using log-rank test. P≤0.05 was considered statistically significant. Results: Out of 20 patients, 4 (20%) were NOTCH1 mutant. Notch1 pathway activation status by immunohistochemistry (NICD) was available for 15 patients, 10 were positive. The median number of therapy lines was 2 (range 1-6). Best ORR among 49 treatment plans across all lines of systemic therapy including chemotherapy (15), anti-EGFR (10), anti-VEGFR (11), and others (13) was PR in 2 (4%), SD in 29 (59%), and PD in 18 (37%). During first line treatment, patients with NOTCH1 mutations had significantly shorter mPFS compared to NOTCH1 wild-type (2.97 vs. 6.92 months, P = 0.02). The PFS rate at 3 months was 25% for NOTCH1mutants vs. 81% for wild-type. A trend towards shorter PFS was seen in NICD positive vs. negative (3.58 vs. 6.74 months, P = 0.2). Conclusions: NOTCH1 mutations in ACC are associated with shorter PFS during first-line treatment. Validation of these findings is warranted in larger patient cohorts.

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations. Cancer Res; 75(7); 1527–36. ©2015 AACR.

Adjuvant chemotherapy has become the standard of care treatment for good performance status patients after resection of locally advanced, non-small-cell lung cancers (NSCLCs), based on the results of large, randomized, phase 3 clinical trials. The absolute benefit in survival at 5 years conferred by adjuvant cisplatin-based chemotherapy is estimated at 5.4 %, as described in a metaanalysis including 5 trials with 4584 patients. Efforts to improve outcomes by intensifying systemic therapy with the use of molecular targeted agents, for example, are currently being proposed in cooperative group settings (Alchemist Trial), but challenges exist because adjuvant clinical trials often call for large sample sizes and require a long time to evaluate objective end points such as survival. By the time a conclusive adjuvant trial is completed with novel agents, the knowledge obtained may have become obsolete. Furthermore, only a small number of drugs can be tested in the adjuvant setting, from the vast number of potential therapeutics currently under development. One approach to overcome the limitations of adjuvant NSCLC trials is the use of preoperative (neoadjuvant) rather than a postoperative (adjuvant) therapy strategy for drug development in resectable NSCLCs. The metaanalysis by the NSCLC Meta-Analysis Collaborative Group has recently demonstrated that preoperative chemotherapy confers an absolute improvement in overall survival at 5 years of 5 % compared with surgery up front. Although the metaanalysis does not compare adjuvant versus preoperative therapy, the benefit observed is in the same order of magnitude of what has been demonstrated with an adjuvant approach, thus suggesting that either preoperative or adjuvant cytotoxic treatments could be used to improve outcomes in patients with locally advanced NSCLCs. As discussed elsewhere, one potential advantage of preoperative therapy is the opportunity to evaluate response as a surrogate marker of benefit from treatment and to use this parameter as an end point for systemic therapy trials for patients with resectable NSCLCs. We envision a strategy according to which novel systemic agents can be evaluated in small to medium-sized preoperative trials to screen for activity in selected or unselected patient populations. Such studies would use response to treatment as the primary end point, which can be determined within a few weeks of initiating therapy. This obviates the need to follow patients long term after surgical resection to asses recurrence or death, thus reducing the number of resources necessary to complete such trials. Agents that demonstrate promising activity in preoperative (neoadjuvant) trials can then be evaluated in larger, definitive adjuvant phase 3 studies using survival as an end point. The use of response to treatment to screen for efficacy of investigational drugs is dependent on the ability of response to predict long-term recurrence-free and overall survival, thus serving as a valid surrogate/intermediate marker. Hence, refining the method for response evaluation will become key for the successful implementation of preoperative-based drug development strategies. We have recently demonstrated that a major pathologic response (as defined by B10 % viable tumor cells in the surgical specimen after preoperative systemic therapy) is strongly correlated with long-term recurrence-free survival and overall survival. These findings have been reproduced by other groups, thus leading to the recommendation of use Society of Surgical Oncology 2014

BackgroundHIV-infected individuals have a higher incidence of head and neck cancer (HNC).MethodsCase series of 94 HIV-infected HNC patients (HIV-HNC) at 6 tertiary care referral centers in the US between 1991 and 2011. Clinical and risk factor data were abstracted from the medical record. Risk factors for survival were analyzed using Cox proportional hazard models. Human papillomavirus (HPV) and p16 testing was performed in 46 tumors. Findings were compared with Surveillance Epidemiology and End Results HNC (US-HNC) data.ResultsThis study represents the largest HIV-HNC series reported to date. HIV-HNC cases were more likely than US-HNC to be male (91% vs. 68%), younger (median age, 50 vs. 62 years), nonwhite (49% vs. 18%), and current smokers (61% vs. 18%). Median HIV-HNC survival was not appreciably lower than US-HNC survival (63 vs. 61 months). At diagnosis, most cases were currently on highly active antiretroviral therapy (77%) but had detectable HIV viremia (99%), and median CD4 was 300 cells per microliter (interquartile range = 167-500). HPV was detected in 30% of HIV-HNC and 64% of HIV-oropharyngeal cases. Median survival was significantly lower among those with CD4 counts ≤200 than >200 cells per microliter at diagnosis (16.1 vs. 72.8 months, P < 0.001). In multivariate analysis, poorer survival was associated with CD4

Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients with cancer with biomarker detection. To investigate the prognostic and predictive values of cyclin D1 expression in patients with oral squamous cell carcinoma (OSCC) who were treated in a prospective, randomized, phase III trial evaluating standard treatment with surgery and postoperative radiotherapy preceded or not by induction docetaxel, cisplatin, and 5-fluorouracil (TPF), immunohistochemical staining for cyclin D1 was conducted in pretreatment biopsy specimens of 232 out of 256 clinical stage III/IVA OSCC patients randomized to the clinical trial. Cyclin D1 index was estimated as the proportion of tumor cells with cyclin D1 nuclear staining. A low cyclin D1 expression predicted significantly better overall survival (OS; P = 0.001), disease-free survival (P = 0.005), locoregional recurrence-free survival (P = 0.003), and distant metastasis-free survival (DMFS; P = 0.002) compared with high cyclin D1 expression. Cyclin D1 expression levels were not predictive of benefit from induction TPF in the population overall. However, patients with nodal stage cN2 whose tumors had high cyclin D1 expression treated with TPF had significantly greater OS (P = 0.025) and DMFS (P = 0.025) when compared with high cyclin D1 cN2 patients treated with surgery upfront. Patients with low cyclin D1 level or patients with cN0 or cN1 disease did not benefit from induction chemotherapy. This study indicates that cN2 OSCC patients with high cyclin D1 expression can benefit from the addition of TPF induction chemotherapy to standard treatment. Cyclin D1 expression could be used as a biomarker in further validation studies to select cN2 patients that could benefit from induction therapy. Mol Cancer Ther; 12(6); 1112–21. ©2013 AACR.

The purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance.Erlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated.All 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib.Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line.

6085Background: ATC is an aggressive disease requiring rapid diagnosis. Targeted therapeutics provide ATC patients (pts) with previously unavailable treatment options. Development of high throughpu...

9004Background: We performed a randomized study to assess the effect of aggressive LCT in patients with oligometastatic NSCLC who did not progress after IST. Methods: This study was performed at MD...

Small-cell lung cancer (SCLC) is a disease with a poor prognosis and limited treatment options. Over the past 30 years, basic and clinical research have translated to little innovation in the treatment of this disease. The Study of Picoplatin Efficacy After Relapse (SPEAR) evaluated best supportive care with or without picoplatin for second-line SCLC treatment and failed to meet its primary end point of overall survival. As the largest second-line, randomized study in patients with SCLC, SPEAR provides an opportunity to critically examine the drug development model in this disease. In this Review, we discuss the current standard approach for the management of SCLC that progresses after first-line therapy, analyze the preliminary data that supported the evaluation of picoplatin in this setting, and critically evaluate the SPEAR trial design and results. Lastly, we present advances in the understanding of the molecular biology of SCLC that could potentially inform future clinical trials and hopefully lead to the successful development of molecular targeted agents for the treatment of this disease.