Jacob Sands

Combined Chemoradiation as Primary Treatment for Invasive Male Urethral Cancer

PURPOSE We evaluated the efficacy and intermediate term outcomes of a combined chemoradiation protocol for the treatment of primary invasive carcinoma of the male urethra. MATERIALS AND METHODS We retrospectively reviewed the medical records of 29 male patients diagnosed with carcinoma of the urethra between 1991 and 2014. All patients were treated at the same tertiary care referral center, and received a combination chemoradiation protocol consisting of 2 cycles of 5-fluorouracil and mitomycin-C with concurrent external beam radiation therapy to the genitalia, perineum, and inguinal and external iliac lymph nodes. Kaplan-Meier curves were constructed to assess overall, disease specific and disease-free survival. RESULTS A total of 26 patients met inclusion criteria for the study. Median followup was 35.5 months. The histology was squamous cell carcinoma in all but 1 patient with adenocarcinoma. Overall 88% of patients presented with at least T3 disease or metastatic to the lymph nodes and only 10% presented with a well differentiated tumor. Nineteen (79%) patients showed complete response to treatment. Five patients (21%) had no response to treatment and ultimately died of their disease, regardless of salvage therapy. Of the 19 complete responders 8 (42%) had disease recurrence at a median of 12.5 months. The 5-year overall, disease specific and disease-free survival rates were 52% (SE 10.6%), 68.4% (SE 10%) and 43.2% (SE 10.2%), respectively. CONCLUSIONS Male squamous cell carcinoma treated with combination chemoradiation offers the potential for genital preservation and is an alternative therapeutic choice in patients not seeking surgery or considered surgical candidates.

Phase II study of dovitinib in patients progressing on anti-vascular endothelial growth factor therapy

BACKGROUND Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment. METHODS Patients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible. A research tumor biopsy was followed by treatment with dovitinib 500 mg on a 5-day on/2-day off schedule for 28-day cycles. The primary endpoint of tumor response was evaluated every 2 cycles. Secondary endpoints included toxicity and 8-week disease control rate. Intratumor mRNA expression of angiogenic mediators was analyzed using a next generation sequencing based expression array. RESULTS Ten patients treated previously with bevacizumab or ziv-aflibercept enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable patients. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All patients experienced at least one grade ≥ 3 treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. CONCLUSIONS We found no evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway.

Prospective evaluation of low-dose ketoconazole plus hydrocortisone in docetaxel pre-treated castration-resistant prostate cancer patients.

Background:Ketoconazole is a well-known CYP17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200–300 mg three times daily) had PSA response rate (>50% decline) of 21–62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state.Methods:Men with CRPC and performance status 0–3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg orally three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (>50% reduction from baseline) where a rate of 25% was to be considered promising for further study (versus a null rate of <5%); 25 patients were required. Secondary endpoints included PSA response >30% from baseline, progression-free survival (PFS), duration of stable disease and evaluation of adverse events (AEs).Results:Thirty patients were accrued with median age of 72 years (range 55–86) and median pre-treatment PSA of 73 ng ml−1 (range 7–11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the two grade 4 AEs were considered related to treatment.Conclusions:In docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy.

URINE CIRCULATING-TUMOR DNA (ctDNA) DETECTION OF ACQUIRED EGFR T790M MUTATION IN NON-SMALL-CELL LUNG CANCER: AN OUTCOMES AND TOTAL COST OF CARE ANALYSIS

OBJECTIVES Third-generation tyrosine kinase inhibitors (TKIs) have proven effective in patients with the acquired EGFR T790M resistance mutation who progress on prior EGFR TKI therapy. Median progression-free survival (PFS) on a 3rd-gen TKI was 9-10 months for T790M+ patients compared to 2.8 months for T790M- patients. PFS is similar regardless of the specimen used to assess T790M, such as tissue, plasma, or urine ctDNA. This study aimed to assess the total cost of care of a urine-testing strategy (UTS) versus a tissue-testing strategy (TTS) for T790M detection, in patients with EGFR-mutation positive lung adenocarcinoma and progression on prior TKI therapy. MATERIALS AND METHODS Long-term outcomes and economic implications were assessed from a US payer perspective. Endpoints were PFS, overall survival (OS), medical resource use and related costs. DATA SOURCES We included published randomized drug trials and Medicare fee schedules. A state-transition analysis and Markov model tracked patients from stable disease to progression and death. Univariate and multivariate sensitivity analyses were performed to assess the robustness of findings and identify factors that most influenced outcomes and costs. RESULTS UTS increased the rate of detection of patients with T790M mutation eligible for treatment with 3rd generation TKI by 7% compared with TTS; urine ctDNA testing detected T790M mutation in some patients for whom biopsy could not be performed or when tissue testing yielded indeterminate results. Due to enhanced targeting of TKI therapy, UTS increased PFS and OS by 0.44 and 0.35 months, respectively. UTS yields a savings of

Abstract A15: Nasal gene expression for the diagnostic evaluation of indeterminate pulmonary nodules within a screening population

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Single-day HER2neu amplification assessment using chip-based digital PCR in formalin-fixed paraffin-embedded breast carcinoma tissue

1680 per patient due to avoidance of biopsy, potential biopsy-associated complications, and tissue-based molecular testing in approximately 55.6% of patients. Probability of T790M detection by tissue and cost of biopsy procedure were the most influential factors. CONCLUSION UTS prolonged PFS/OS due to increased detection of T790M mutation and decreased biopsies and complication-related costs.

Prospective evaluation of low-dose ketoconazole plus hydrocortisone (HC) in chemotherapy-pretreated castration-resistant prostate cancer (CRPC) patients.

Introduction: Lung cancer remains the leading cause of cancer-related death due to the limited ability to detect the disease at an early and potentially curable stage. CT lung screening (CTLS) of high-risk patients improves mortality. However, the high proportion of false-positive tests, the majority of which are indeterminate pulmonary nodules (IPNs), has limited widespread adoption of this life-saving screening modality. Since screen-detected IPNs contribute to the overall cost of screening and potential morbidity due to the need for further diagnostic testing, there is an urgent need for accurate tools to stratify patients with screen-detected nodules for routine follow-up or additional intervention. Prior work from our group has identified alterations in nasal epithelial cell gene expression in individuals undergoing bronchoscopy, which are associated with lung cancer. In this study, we are evaluating the ability of nasal epithelial gene expression to identify patients with lung cancer among CTLS patients with IPNs. Methods: Nasal epithelial brushings were collected from a screening cohort at Lahey Hospital & Medical Center (LHMC) with CTLS IPNs (6-20mm; n=38) that had been followed prospectively for up to 2 years (19 lung cancers; 19 benign disease). We performed total RNA sequencing on the nasal samples using the Illumina TruSeq Stranded Total RNA Sample Preparation kit. Reads were aligned to the human assembly Genome Reference Consortium Human Build 37 to identify a gene signature associated with cancer status. To evaluate the signature in an independent IPN cohort, nasal epithelial brushings were collected from current and former smokers (n=67; age>45, pack-year>20) undergoing diagnostic workup for IPNs (7-30 mm) at military and VA hospitals within the DECAMP consortium. Subjects were followed prospectively for up to two years after sample collection until a final diagnosis of lung cancer (n=38) or benign disease (n=29) was made. Results: Using a generalized linear model correcting for smoking status, we identified 39 differentially expressed genes (DEGs, FDR-q Conclusion: Our findings suggest that there are nasal gene expression alterations associated with lung cancer diagnosis among CTLS patients with indeterminate pulmonary nodules. These alterations may be leveraged to develop a nasal biomarker for the early detection of lung cancer in high-risk smokers. Citation Format: Katrina Steiling, Jiarui Zhang, Jacob Sands, Travis Sullivan, Ehab Billatos, Elizabeth Moses, Gang Liu, Carla Lamb, Brady McKee, Marc Lenburg, Avrum Spira, Kimberly Rieger-Christ. Nasal gene expression for the diagnostic evaluation of indeterminate pulmonary nodules within a screening population [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A15.

Phase II study of dovitinib in patients (Pts) progressing on anti-vascular endothelial growth factor (VEGF) therapy.

Introduction Human epidermal growth factor receptor 2 (HER2) amplification is present in almost 15%–20% of breast cancer tumors, making it an important parameter for testing. The present study was designed to evaluate a chip-based digital PCR (dPCR) system for assessing HER2 amplification from formalin-fixed paraffin-embedded breast carcinoma tissue and to compare this system with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Materials and methods A total of 84 breast carcinoma tissue samples were analyzed by IHC, FISH, and chip-based dPCR in a blinded manner. Results All nine IHC-positive and 35 IHC-negative samples had equivalent results with dPCR, taking an amplification ratio threshold of 1.8 as a positive result. Of the 40 IHC equivocal samples, 10 were assessed as positive, 27 as negative, and three as equivocal by dPCR. Conclusion These results demonstrate that chip-based dPCR is suitable for HER2 amplification detection in formalin-fixed paraffin-embedded samples in a clinical setting, providing the advantages of superior turnaround time, cost-effectiveness, and increased precision with absolute quantification compared with conventional tests such as FISH and IHC. This methodology was especially beneficial in tissue samples with low DNA concentration.

P3.02b-010 Urine Detection of EGFR T790M Mutation in Non-Small-Cell Lung Cancer: An Outcomes and Total Cost of Care Analysis: Topic: EGFR Biomarkers

227 Background: Ketoconazole (keto), a known CYP17 inhibitor, is a traditional systemic treatment for CRPC. However, most of the published data has been in the pre-chemo setting; its efficacy in the post-chemo setting has not been as widely reported. Chemo-naive patients treated with attenuated doses of keto (200-300 mg TID) had prostate specific antigen (PSA) response rate (> 50% decline) ranges from 21%-62% and treatment was well tolerated. We hypothesized that low dose keto would likewise possess efficacy and tolerability in the CRPC post-chemo state. Methods: CRPC patients with ECOG PS 0-3, adequate end organ function, who had received at least one chemo were treated with low-dose keto (200 mg PO TID) and HC (20 mg PO q AM and 10 mg PO q PM) until progression, as defined by either RECIST or PSA rise > 50% from nadir or baseline. Primary endpoint was PSA response rate (> 50% reduction from baseline). A Simon minimax design was used. PSA response of > 25% was to be considered promising for further study...