S. Swisher

Adenovirus-Mediated p53 Gene Transfer in Sequence With Cisplatin to Tumors of Patients With Non–Small-Cell Lung Cancer

PURPOSE To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Esophageal cancer dose escalation using a simultaneous integrated boost technique

PURPOSE We previously showed that 75% of radiation therapy (RT) failures in patients with unresectable esophageal cancer are in the gross tumor volume (GTV). We performed a planning study to evaluate if a simultaneous integrated boost (SIB) technique could selectively deliver a boost dose of radiation to the GTV in patients with esophageal cancer. METHODS AND MATERIALS Treatment plans were generated using four different approaches (two-dimensional conformal radiotherapy [2D-CRT] to 50.4 Gy, 2D-CRT to 64.8 Gy, intensity-modulated RT [IMRT] to 50.4 Gy, and SIB-IMRT to 64.8 Gy) and optimized for 10 patients with distal esophageal cancer. All plans were constructed to deliver the target dose in 28 fractions using heterogeneity corrections. Isodose distributions were evaluated for target coverage and normal tissue exposure. RESULTS The 50.4 Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4 Gy 2D-CRT plan. The 64.8 Gy SIB-IMRT plan produced a 28% increase in GTV dose and comparable normal tissue doses as the 50.4 Gy IMRT plan; compared with the 50.4 Gy 2D-CRT plan, the 64.8 Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord). CONCLUSIONS The use of SIB-IMRT allowed us to selectively increase the dose to the GTV, the area at highest risk of failure, while simultaneously reducing the dose to the normal heart, lung, and liver. Clinical implications warrant systematic evaluation.

Validation of a Proliferation-based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma

Purpose: New prognostic markers to guide treatment decisions in early stage non–small cell lung cancer are necessary to improve patient outcomes. In this report, we assess the utility of a predefined mRNA expression signature of cell-cycle progression genes (CCP score) to define 5-year risk of lung cancer–related death in patients with early stage lung adenocarcinoma. Experimental Design: A CCP score was calculated from the mRNA expression levels of 31 proliferation genes in stage I and stage II tumor samples from two public microarray datasets [Directors Consortium (DC) and GSE31210]. The same gene set was tested by quantitative PCR in 381 formalin-fixed paraffin-embedded (FFPE) primary tumors. Association of the CCP score with outcome was assessed by Cox proportional hazards analysis. Results: In univariate analysis, the CCP score was a strong predictor of cancer-specific survival in both the Directors Consortium cohort (P = 0.00014; HR = 2.08; 95% CI, 1.43–3.02) and GSE31210 (P = 0.0010; HR = 2.25; 95% CI, 1.42–3.56). In multivariate analysis, the CCP score remained the dominant prognostic marker in the presence of clinical variables (P = 0.0022; HR = 2.02; 95% CI, 1.29–3.17 in Directors Consortium, P = 0.0026; HR = 2.16; 95% CI, 1.32–3.53 in GSE31210). On a quantitative PCR platform, the CCP score maintained highly significant prognostic value in FFPE-derived mRNA from clinical samples in both univariate (P = 0.00033; HR = 2.10; 95% CI, 1.39–3.17) and multivariate analyses (P = 0.0071; HR = 1.92; 95% CI, 1.18–3.10). Conclusions: The CCP score is a significant predictor of lung cancer death in early stage lung adenocarcinoma treated with surgery and may be a valuable tool in selecting patients for adjuvant treatment. Clin Cancer Res; 19(22); 6261–71. ©2013 AACR.

Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort

BACKGROUND Chemoradiation followed by surgery is the preferred treatment of localized gastroesophageal cancer (GEC). Surgery causes considerable life-altering consequences and achievement of clinical complete response (clinCR; defined as postchemoradiation [but presurgery] endoscopic biopsy negative for cancer and positron emission tomographic (PET) scan showing physiologic uptake) is an enticement to avoid/delay surgery. We examined the association between clinCR and pathologic complete response (pathCR). PATIENTS AND METHODS Two hundred eighty-four patients with GEC underwent chemoradiation and esophagectomy. The chi-square test, Fisher exact test, t-test, Kaplan-Meier method, and log-rank test were used. RESULTS Of 284 patients, 218 (77%) achieved clinCR. However, only 67 (31%) of the 218 achieved pathCR. The sensitivity of clinCR for pathCR was 97.1% (67/69), but the specificity was low (29.8%; 64/215). Of the 66 patients who had less than a clinCR, only 2 (3%) had a pathCR. Thus, the rate of pathCR was significantly different in patients with clinCR than in those with less than a clinCR (P < 0.001). CONCLUSIONS clinCR is not highly associated with pathCR; the specificity of clinCR for pathCR is too low to be used for clinical decision making on delaying/avoiding surgery. Surgery-eligible GEC patients should be encouraged to undergo surgery following chemoradiation despite achieving a clinCR.

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation

BACKGROUND Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a <clinCR (Suzuki A, Xiao LC, Hayashi Y et al. Prognostic significance of baseline positron emission tomography and importance of clinical complete response in patients with esophageal or gastroesophageal junction cancer treated with definitive chemoradiotherapy. Cancer 2011; 117: 4823-4833; Cheedella NK, Suzuki A, Xiao L et al. Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort. Ann Oncol 2013; 24: 1262-1266; Ajani JA, Correa AM, Hofstetter WL et al. Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 2012; 23: 2638-2642). We hypothesized that the initial standardized uptake value (iSUV) of positron emission tomography will define novel subsets of clinCR patients. METHODS We analyzed 323 EAC patients, from our prospective database, who achieved a clinCR. Various statistical methods were used to assess the influence of iSUV on patient outcome. RESULTS The median follow-up of 323 patients was 40.8 months [95% confidence interval (CI) 35.6-47.3 months]. Two hundred six (63.8%) patients had TMT and 117 (36.2%) had BMT. If iSUV was ≥6, TMT patients had a longer median OS (94.8 months; 95% CI 66.07-NA) than BMT patients (31.4 months; 95% CI 21.7-42.1; P ≤ 0.001). However, if iSUV was <6, the median OS of TMT and BMT patients was similar (P = 0.62). iSVU did not influence the pathologic complete response rate in TMT patients (P = 0.85). CONCLUSION clinCR patients with iSUV of <6 are identified as a new subset that fared equally well when treated with TMT or BMT. Future esophageal preservation strategy may be best suited for this newly identified subset of EAC patients.

Biomarker-Integrated Neoadjuvant Dasatinib Trial in Resectable Malignant Pleural Mesothelioma

Introduction: Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. Methods: We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419. Results: For all patients, the median progression‐free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p‐SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5–110), and the median posttreatment score was 41.9 (interquartile range 4.2–60) (p = 0.004). A decrease in p‐SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p‐SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet‐derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p‐PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher‐than‐median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. Conclusions: In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet‐derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

P3.01-109 Real-World Patient-Reported Outcome Assessment of Patients with Metastatic Non-Small Cell Lung Cancer

1 72/Male Blood No No No treatment Not applicable Not applicable 2 62/Male Tissue No KRAS p.G12A, STK11 p.D53Gfs*110 Chemotherapy Not available Not available 3 62/Male Tissue No EGFR p.L747_T751del (EX19del) Gefitinib PR 20+ 4 63/Female Tissue No EGFR p.L858R (EX21) Gefitinib PR 5+ 5 75/Female Tissue No EGFR p.L858R (EX21) Icotinib SD 11+ 6 63/Male Blood Icotinib EGFR p.L858R (EX21),CHEK2 c.4451G>A Combined gefitinib and bevacizumab SD 6+

Factors associated with membrane carbonic anhydrase IX (mCAIX) immunohistochemistry (IHC) in non-small cell lung cancer (NSCLC).

e21125 Background: CAIX reduces cell acidity, is upregulated by HIF1a, and correlates with HIF1a and with poor prognosis in some cancers but not others. We found in multivariate analysis that mCAIX but not cytoplasmic (c) CAIX (cCAIX) correlated with relapse in stage I-II NSCLC (Proc AACR, 2010). METHODS In 308 resected NSCLCs (stage I, II, III, IV in 188, 61, 46 and 9 patients) we used IHC to assess CAIX and other markers of hypoxia, proliferation, etc. IHC scores (0-300) were calculated by multiplying stain intensity (0-3) by % cells staining. We used nonparametric statistics to assess factors correlating with mCAIX scores. RESULTS Median mCAIX scores were lower in adeno vs squamous NSCLC (5 vs 65, p<0.0001) and correlated inversely with % papillary adeno present (r -0.17, p 0.02). mCAIX correlated with tumor diameter (r 0.19, p 0.0008) but not with node stage (N0 vs N1-2, 30 vs 20, p 0.93). mCAIX correlated with nuclear (n) Ki67 (r 0.20, p 0.0005), mitoses (r 0.18, p 0.001) and necrosis (r 0.20, p 0.0006) but not apoptosis (r 0.05, p 0.38). mCAIX did not correlate with nHIF1a (r -0.01, p 0.84) and paradoxically correlated inversely with cHIF1a (r -0.14, p 0.02) and cVEGF (r -0.13, p 0.03), but did correlate with the hypoxia-induced transcription factor cSHARP2 (r 0.18, p 0.002). cCAIX did correlate with cHIF1a, but only in tumors < 5 cm (r 0.14, p 0.04) and N0 patients (r 0.17, p 0.01). mCAIX was higher with EGFR wild type vs mutant (20 vs 0, p 0.006) and Notch amplified vs not (120 vs 21.25, p 0.0006), and did not vary with KRAS mutation (5 vs 15.83, p 0.76). There was a trend to lower mCAIX in well vs moderately/poorly differentiated tumor (5 vs 30, p 0.06). mCAIX correlated negatively with the tumor suppressors cRB (r -0.13, p 0.03), cP16 (r -0.12, p 0.03), nP16 (r -0.13, p 0.03) and nP14 (-0.12, p 0.04). CONCLUSIONS In NSCLC mCAIX expression correlates with tumor type, subtype, size, proliferation and necrosis, and varies inversely with tumor suppressor genes. mCAIX did not correlate with HIF1a. cCAIX only correlated with cHIF1a in small and N0 tumors. Variable findings between studies with respect to CAIX importance may depend on tumor type, size and stage, and on whether mCAIX is assessed separately from cCAIX. Support: DoD # W81XWH-07-1-0306.

Treatment for superior sulcus tumors (SST): Effect of surgery first followed by adjunct concurrent chemoradiotherapy on survival of patients with marginally resectable SST.

7026 Background: The role of preoperative treatment for locally advanced SST (LA-SST) has not been well defined. We compared two IRB-prospective phase II trials of patients (pts) with LA-SST (T3-4 N0-3 M0) treated at The University of Texas M.D. Anderson Cancer Center. Methods: Trial A (16 pts, 1988 to 1997) was induction chemotherapy consisting of cyclophosphamide (500 mg/m2 i.v.), VP-16 (100 mg /m2 i.v.) and cisplatin (80 mg/m2 i.v.)×2-3 cycles followed by en bloc resection, then post operative radiotherapy (RT) with 60-66Gy/30-33 Fx depending on the surgical margin. Trial B (32 pts, 1992 to 2007) was immediate en bloc resection followed by concurrent chemoradiotherapy (CCRT). The RT was 1.2 Gy/Fx, bid, with 60 Gy/50 Fx or 64.8 Gy/54 Fx depending the surgical margin status. Concurrent chemotherapy consisted of cisplatin (50 mg/m2 i.v.) and VP-16 50 mg, p.o. given on the day 1 and 8 RT, repeated every 29 days ×4 cycles. Results: Median follow-up was 41 months (range, 2-155 months). Median age was 55 (ran...

Association of activated transcription factor NF-kappaB with chemo-radiotherapy resistance and poor outcome in esophageal adenocarcinoma

4029 Background: The incidence of esophageal/gastroesophageal junction adenocarcinoma (E/GEJAC) is rapidly rising in Western countries. Chemo-radiotherapy (CT-XRT) followed by surgery has been used for localized E/GEJAC. However, while 30% of patients achieve a pathologic complete response (pCR), most patients present with radioresistant residual, highly aggressive tumor. Thus there is a need to identify and target new molecular pathways associated with cancer resistance. Through microarray gene expression profiles we identified differentially expressed transcription factor NF-kappa B (NF-κB) associated signaling pathway in CT-XRT non-responders group. To validate our findings, we examined activated NF-κB protein expression, CT-XRT response and clinical outcome. Methods: Pre-treatment tumor biopsies and post-treatment resected residual tumor were obtained from patients enrolled in a phase II trial of pre-operative induction chemotherapy and CT-XRT for potentially resectable E/GEJAC. Activated (p65 nuclear...