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Introduction: In the phase 3 KEYNOTE-048 trial (NCT02358031) in R/M HNSCC, first-line pembrolizumab (P) monotherapy vs EXTREME (E; chemotherapy [C] + cetuximab) improved overall survival (OS) in PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 populations and led to noninferior OS in the total population with favorable safety; first-line P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety. Outcomes in CPS Table.Efficacy in subgroups of patients with PD-L1 CPS Citation Format: Barbara Burtness, Danny Rischin, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Joy Ge, Ramona Swaby, Burak Gumuscu, Kevin Harrington. Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score

Background: Metastatic breast cancer patients have many options for therapy and may be at risk for late or absent hospice referrals. Previous studies suggest that late referrals to palliative care make meaningful improvements in symptoms and quality of life difficult to achieve. We examined hospice utilization, status of patients on hospice admission, and quality of care documentation in patients treated for metastatic breast cancer at Roswell Park Cancer Institute (RPCI) from 1999–2010. Methods: Analysis of breast cancer cases through the RPCI database identified 182 cases with deaths resulting from breast cancer eligible for services through The Buffalo Center for Hospice and Palliative Care (HB) (residence in Erie County, NY). Cases were cross-matched to the HB database for information on hospice utilization and outcome, and patient symptoms/status on admission to hospice. Date of last chemotherapy, opiate use, anxiolytic use, documentation of advance directive and palliative care discussion, and place of death were collected through chart abstraction. Results: 182 patients eligible for HB services expired from breast cancer during the study period. 122 (67%) utilized hospice services; 60(33%) did not. 117 patients received chemotherapy as their last treatment for metastatic breast cancer; patients referred to hospice received their last dose of chemotherapy a median of 31 days (14.1−47.9) prior to death; non-hospice patients 16 days (0-44.1) p=0.071. Patients subsequently admitted to hospice were significantly more likely to have a discussion of advance directives by their oncology team (30% vs. 5% p= Conclusion: Despite the recognition of the importance of high-quality end of life care, including end of life decision-making, advance directives, pain and symptom management, and hospice care, 33% of metastatic breast cancer patients at our institution died without hospice referral. Those patients referred to HB were significantly more likely to have an advance directive discussion, and to die at home. However, patients referred to HB had a median LOS of 17 days, and poor PPS. Efforts to enhance discussion of palliative care earlier in the treatment of MBC are critical to improved patient care. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-13-02.

Background: The etiology, optimal management, and long term outcome of osteonecrosis of the jaw (ONJ) is not well understood. Large trials have suggested that the combination of bevacizumab and bisphosphonates (BPs) does not significantly increase the incidence of ONJ. Because healing after mucosal trauma or dental surgery requires revascularization, it is possible that bevacizumab use could influence dental outcomes. Theoretically, the combination of bevacizumab and BPs may affect the time to development of ONJ and/or the response to dental therapy. Dental management of ONJ has not changed over time in our center, but increased recognition and screening may impact the dental outcome. Methods: We reviewed all cases of ONJ in metastatic breast cancer patients treated with BPs and with or without bevacizumab at Roswell Park Cancer Institute between October 2002 and April 2010. All patients diagnosed with ONJ discontinued BP therapy, while 3/7 (42%) continued bevacizumab until breast cancer progression. Type of BP, duration of treatment, total dose of BPs and bevacizumab dosing were recorded. All patients were treated in the department of dentistry with a combination of antibiotics, debridement, and chlorhexidine scrub. We evaluated the time to diagnosis of ONJ after the initiation of BP therapy, total dose of BP and dental treatment outcomes. Statistical analysis was performed using t-test and log-rank analysis. Results: See tables. 27 ONJ patients with a median age of 57 years (range 40-68) were analyzed. Patients were treated with zoledronic acid (95%), pamidronate (20%), or both (15%). 2 patients were excluded from dental response analysis due to lost follow up. Overall median time to ONJ treatment response was 5.0 months (range 1.3-67.5). Conclusions: The addition of bevacizumab to BP treatment did not significantly alter the time to the development of ONJ, the number of BP doses administered prior to diagnosis, or the response to dental treatment. However, ONJ response rates (complete and partial) to dental therapy have improved from 38% prior to 2007 to 58% after 2007, likely reflecting improved recognition and earlier treatment. Table.1 Time to ONJ and number of BP doses Table 2 ONJ response to dental treatments Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-13-03.

Background: Recent studies suggest that older women derive the same benefits from adjuvant systemic chemotherapy (AST) as younger women. In older women, the ability to successfully complete chemotherapy may be complicated by other health conditions and performance status. This study examines the frequency of inability to complete planned AST and factors associated with difficulty administering AST in older women. Methods: We performed a retrospective analysis of breast cancer patients (age≥65) who received adjuvant/neoadjuvant chemotherapy at Roswell Park Cancer Institute from 9/1997 to 1/2010. Endpoints considered collectively as “difficulty “ in delivering AST were delay in treatment, hospitalization, dose reduction and discontinuation of AST. Factors defined a priori that could affect these outcomes were creatinine clearance (CCr), obesity (BMI ≥30), cardiac disease, hypertension, psychiatric disorders, diabetes, cerebrovascular disease, previous malignancy, COPD/asthma, Charlson comorbidity index, and use of anthracycline-based chemotherapy. The Pearson chi-squared test was used to identify the significant categorical factors associated with each of the five binary responses indicating difficulty administering AST. Logistic regression was used to obtain crude and adjusted odds ratios to further examine the relationships. Kaplan-Meier methods were used to estimate survival distributions, progression free and overall survival. The log-rank test was used for comparison between women experiencing difficulty with treatment and those with no difficulty with treatment. A 0.05 nominal significance level was used in all testing. Statistical analysis and plots were completed using SAS, version 9.2, statistical software (SAS Institute Inc., Cary, NC). Results: 193 women age 65 and over received AST (median age of 70 years - range 65-86). Median follow up was 40.9 months. 73% received anthracycline-based AST. Factors associated with difficulty, delay, dose reduction, hospitalization, or failure to complete planned AST are shown in the Table. Women who completed planned AST had better OS than those who did not complete AST (p=0.01). Women who completed therapy with difficulty had no difference in outcome compared to those without difficulty [DFS (p=0.07) and OS (p=0.18)]. Conclusions: Age, cardiac disease, diabetes, hypertension, CCr, obesity, CCI, and sum of comorbidity significantly impact the ability to deliver and complete AST in older women with BC. Completing planned chemotherapy is associated with improved survival. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-08.

Toll-like Receptor 5 (TLR5) is a type 1 transmembrane receptor involved in the first line of defense against invading bacterial pathogens expressing flagellin. TLR5 is expressed on a wide variety of tumors and induction of TLR5 signaling exhibits anti-tumor activities via mobilization of innate and subsequent adaptive antitumor immune response. Entolimod, a pharmacologically optimized flagellin of Salmonella, is the first TLR5 agonist to enter clinical trials. This agent binds to TLR5 and activates NF-kB and other signaling pathways to elicit antitumor activity. The antitumor activity of entolimod has been shown to be dependent on the expression of functional TLR5 on tumors. Since TLR5 is genetically polymorphic, we hypothesized that variations in the gene would alter responses to therapy with entolimod. We therefore characterized genetic variants of TLR5. Expression constructs for nine naturally occurring human TLR5 variants namely Thr82Ile (Ile82): c.245C>T [rs764535]; Asn143Thr (Thr143): c.428A>C [rs5744167]; Arg149Cys (Cys149): c.445C>T [rs201906412]; Gln387Ter (Ter387 or 387*): c.1159C>T [rs147164861]; Arg392Ter (Ter392 or 392*): c.1174C>T [rs5744168]; Leu487Ile (487Ile): c.1459C>A [rs5744171]; Asn592Ser (Ser592): c.1775A>G [rs2072493]; Phe616Leu (Leu616): c.1846T>C [rs5744174] and Glu731Asp (Asp731): 2193A>T [rs148986834], were created from C-terminal FLAG-tagged wild type (WT) TLR5. All constructs together with a construct with no TLR5 insert (empty vector) were transfected in cos-1 cells. In vitro translation of the constructs in rabbit reticulocyte lysates (RRL) were also performed. Cos-1 cells transfected with constructs were also treated with flagellin and entolimod and with proteasome and autophagy inhibitors. Recombinant and synthesized proteins were examined by western blot analysis and NF-kB activity was measured using a Dual-Glo Luciferase Assay. The molecular weight of the recombinant proteins was approximately 100kD. There were variations in expression levels of immunoreactive proteins (10-80% of WT) and the NF-kB activity induced was lower or similar to WT. The Ile82 variant showed a significant reduction in levels of immunoreactive protein (10% of WT) which correlated with decreased NF-kB activity compared to WT, after stimulation. All proteins synthesized in RRL had similar molecular weight except Ter387 and Ter392 which expressed truncated proteins of approximately 40kD and had no NF-kB activity compared to the WT. The Ile82 protein was degraded primarily through the autophagy pathway. The mRNA and cytokine levels of the variant constructs will be reported. These results suggest that genetic variations in the TLR5 gene may be predictive of response to entolimod. This predictive biomarker will be explored in the ongoing phase I study of entolimod. Citation Format: Andrzej J. Wierzbicki, Araba A. Adjei, Nuttapong Ngamphaiboon, Thanyanan Reungwetwattana, Andrei V. Gudkov, Alex A. Adjei. Functional characterization of human toll-like receptor 5 (TLR5) genetic variants. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5492. doi:10.1158/1538-7445.AM2015-5492