bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitotic checkpoint gene CHFR methylation in pretreatment serum DNA of docetaxel (doc)/cisplatin (cis)-treated stage IV non-small cell lung cancer (NSCLC) patients (p)
Authors: Isla D. , Salazar F. , Ramirez J. , Sanchez Ronco M. , Cobo M. , Montes A. , Sanchez J. , Catot S. , Taron M. , Rosell R.
Published: March 2020

7056

Background: CHFR (checkpoint with forkhead-associated and ring finger) regulates a prophase delay in cells exposed to agents that disrupt microtubules. Epigenetic inactivation of CHFR is a frequent event in human tumors, leading to impaired checkpoint function and enhanced sensitivity to docetaxel. We hypothesized that serum DNA methylation of CHFR could be a predictor of longer survival in p treated with doc/cis. Methods: Sodium bisulfite modified serum DNAwas used as the template for methylation-specific PCR assay. DNA was obtained from 600 doc/cis-treated stage IV NSCLC p. Results: Preliminary data on 301 p is available. The frequency of CHFR hypermethylation was 32.6%. There was no association between methylation and performance status (PS), age, gender, histology, response, 14–3-3σ serum DNA methylation, polymorphisms in lymphocyte DNA (ERCC1 118 C/T, ERCC1 C8092A, XRCC3 241 ThrMet), or tumor ERCC1 mRNA levels. Overall, there was a tendency to better median survival (MS) for p with methylated CHFR. In p with PS 0, MS was 33 months (m) for 41 p with methylated CHFR and 12 m for 64 p with unmethylated CHFR (P = 0.23). In p >66 years (y), MS was not reached for 31 p with methylated CHFR and 9.6 m for 80 p with unmethylated CHFR (P = 0.01), while in p <66 y, MS was 9.4 m for 67 p with methylated CHFR and 10 m for 123 p with unmethylated CHFR (P = 0.62). p with both 14–3-3σ and CHFR methylation showed a tendency to longer survival. Final data on 600 p will be presented. Conclusions: Early findings indicate that CHFR methylation in elderly p predicts a significant survival benefit in doc/cis-treated NSCLC.

No significant financial relationships to disclose.
EGFR mutation-based phase II multicenter trial of gefitinib in advanced non-small cell lung cancer (NSCLC) patients (pts): Results of West Japan Thoracic Oncology Group trial (WJTOG0403)
Authors: Okamoto I. , Kashii T. , Urata Y. , Hirashima T. , Kudoh S. , Ichinose Y. , Ebi N. , Satoh T. , Tamura K. , Fukuoka M.
Published: March 2020

7073

Background: Recently several retrospective analyses have reported that somatic activating mutations in the EGFR tyrosine kinase domain underlie responsiveness to gefitinib. In the present study, we have prospectively assessed whether these specific mutations in EGFR gene affect the clinical outcomes of NSCLC pts treated with gefitinib. Method: Pts with a histologically confirmed, recurrent or metastatic NSCLC that harbored EGFR mutations were eligible for the study. Direct sequencing using DNA extracted from paraffin-embedded tumor specimens to detect mutations in EGFR (exons 18, 19 and 21) was performed in a central laboratory. Eligible pts with measurable lesions, ECOG PS of 0–2, adequate organ functions and less than 2 prior chemotherapy regimens were treated with gefitinib 250 mg orally once daily. The primary objective of this study was to determine the objective response rate of single-agent gefitinib in NSCLC pts with EGFR mutations. With the target activity level of 50% and the lowest response rate of interest set at 25%, 23 eligible patients were required with an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Allowing for a 10% loss to follow-up rate, a total of 25 patients with EGFR mutations were planned to enroll. Results: Between March 2005 and December 2005, 104 patients were recruited from fifteen study centers in Japan and screened for the presence of EGFR mutations. EGFR mutations were detected in 28 pts (27%). Twenty-five of the 28 pts have been enrolled onto this study; 12 pts had deletional mutations in exon 19 and 13 pts had missense mutations (L858R) in exon 21. Of the 25 pts with EGFR mutations: adenocarcinoma (24), female (17), never smoker (18), and PS 0–1 (22). Median age was 69 years (range, 54 to 89 years). Previous therapy included surgery in 9 pts (36%), chemotherapy in 7 pts (28%), and radiotherapy in 1 pts (4%). Conclusions: Efficacy and safety data will be mature in March 2006 and will be presented at the ASCO meeting. These are the first prospective studies targeted at NSCLC pts harboring EGFR mutations.

No significant financial relationships to disclose.
Phase II study of gefitinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) gene mutations detected by PNA-LNA PCR clamp
Authors: Sutani A. , Nagai Y. , Udagawa K. , Uchida Y. , Murayama Y. , Tanaka T. , Miyazawa H. , Kanazawa M. , Hagiwara K. , Kobayashi K.
Published: March 2020

7076

Background: The responsiveness to gefitinib has been reported to closely link to the presence of EGFR gene mutations. We developed a method, PNA-LNA PCR clamp, capable of detecting EGFR mutations in the presence of 100-fold background of wild type EGFR from normal cells (Can Res. 2005;65:7276). This study was prospectively designed to evaluate 1) the sensitivity and the specificity of the PNA-LNA PCR clamp (sample size > 100 pts) and 2) a phase II study of gefitinib for NSCLC patients (pts) with EGFR gene mutations (sample size > 25 pts to show the lower limit of 95% CI > 50%). Methods: Clinical samples (sputum, pleural effusion, bronchial fluid and paraffin tissue) were obtained from consecutive NSCLC pts with informed consent in our institution, and were tested by the PNA-LNA PCR clamp. After the second informed consent, for PS 0–2, inoperable stage III and IV pts with EGFR mutations, gefitinib (250mg P.O. daily) was given as the second treatment after docetaxel containing chemotherapy. In case of poor PS pts, the first line chemotherapy was omitted. Results: From Sept. ’04 to Oct. ’05, samples from 100 of a total of 107 pts were informative of EGFR mutation status. PNA-LNA PCR clamp detected EGFR mutations in 38 pts (38%) (15 males/23 females; median age:62; adenoca.:33 pts). Exon 19 deletions, L858R and L861Q were found in 25 (66%), 12 (32%) and 1 (2%) patients, respectively. But 62 pts (51 males/11 females; median age:66; Ad:43 pts) were judged to have wild type EGFR. Between positive and negative pts in EGFR mutation, there was significant difference in the distinction of sex (p = 0.00001). Gefitinib was given to 26 pts with EGFR mutations as the first line (4 pts) or the second line treatment (22 pts). One patient and 20 patients showed CR and PRs, respectively, and the response rate was 81% (95% CI: 61–94%). For patients with wild EGFR genes, gefitinib was given to 5 patients and one patient (20%) showed PR. The response rate was significantly different between wild and mutant EGFR genes detected by the PNA-LNA PCR clamp (p = 0.017). Conclusions: PNA-LNA PCR clamp could reliably detect EGFR mutations, indicating the method is useful to detect EGFR mutations in clinical specimens. Updated data will be presented at the meeting.

No significant financial relationships to disclose.
Prospective analysis of the epidermal growth factor receptor gene mutations in non-small cell lung cancer in Japan
Authors: Morikawa N. , Inoue A. , Suzuki T. , Fukuhara T. , Suzuki S. , Kondo T. , Moriya T. , Saijo Y. , Nukiwa T.
Published: March 2020

7077

Background: Previous clinical trials have revealed that gefitinib is more likely to be effective in non-small cell lung cancer (NSCLC) with activating somatic mutations of epidermal growth factor receptor (EGFR). Most of those reports evaluated NSCLC patients who had post-operative recurrence and then received gefitinib retrospectively using their surgical specimens. However, many NSCLC patients are inoperable at diagnosis. Thus we conducted this study to examine EGFR mutation status by diagnostic tumor samples before gefitinib treatment and investigate the correlation between EGFR mutation and the efficacy of gefitinib. Methods: We prospectively evaluated various tumor samples obtained from NSCLC patients who had never received gefitinib for EGFR mutations in exon 18–23. For patients treated with gefitinib after the examination of EGFR mutations, the response to gefitinib was also evaluated. Results: From June 2004 to November 2005, 91 patients with advanced or post-operative recurrent NSCLC enrolled onto this study and 104 tumor samples were obtained from transbronchial biopsies, effusions, as well as surgical specimens. Thirty-two mutations including deletions in exon 19 in 23 patients and L858R in 9 patients were detected among those 91 patients; 30 in 81 adenocaricinoma, 1 in 2 adenosquamous cell carcinoma, and 1 in 5 large cell carcinoma. The mutations were found more frequently in female (51.9%) than male (12.8%), in never smoker (52.0%) than smoker (14.6%). Response rate of gefitinib in patients with EGFR mutations was 65.0% (13 of 20) compared to 37.5% (3 of 8) in patients without mutations. Among 7 patients with EGFR mutations who were examined multiple tumor samples, 3 had the discrepancy of EGFR gene status between different samples obtained at different time points, suggesting genetic heterogeneity of their tumors. The EGFR status of the most recent samples is likely to be correlated to the response to gefitinib. Conclusions: The EGFR mutation analysis was possible not only from surgical specimens but also from daily available diagnostic samples. For patients with EGFR mutations, gefitinib could achieve a promising high response rate. We propose to examine the most recent tumor samples to predict the sensitivity to gefitinib reliably.

No significant financial relationships to disclose.
Dose intensive chemotherapy (Cx) in advanced thymoma: Initial report of Japan Clinical Oncology Group trials (JCOG 9605 and 9606)
Authors: Kunitoh H. , Tamura T. , Fukuda H. , Nakagawa K. , Takeda K. , Nishiwaki Y. , Katagami N. , Yokoyama A. , Noda K. , Saijo N.
Published: March 2020

7080

Background: Thymoma is considered to be sensitive to Cx. Dose intensive Cx might well be suitable for such tumors, especially in combination with local therapy. Objectives of the trials were to evaluate the safety and efficacy of the dose intensive CODE (cisplatin[C]- vincristine[O]- doxorubicin[D]- etoposide[E]) Cx in thymoma. The primary endpoint was progression-free survival time (PFS). Methods: Patients (pts) with 15–70 years of age with histologically documented Cx-naïve thymoma with stage IVa/IVb disease (JCOG 9605) or unresectable stage III disease (JCOG 9606) were eligible. Tumors of other histology, such as thymic carcinoma, carcinoid or lymphoma were excluded; pts were to have ample organ function and ECOG PS of 0–2. Myasthenia was allowed. Signed consent form was obtained. Pts received CODE Cx of 9 weeks (w): C 25 mg/m2 Cx day 1 on each w1–9; O 1mg/m2 d1 on w1,2,4,6,8; D 40 mg/m2 d1 and E 80 mg/m2 d1,2,3 on w 1,3,5,7,9. Cx courses were supported by GCSF. Steroids were used only for antiemesis. Those with stage III disease (JCOG 9606) went on to surgery, if judged to be resectable, and post-operative radiotherapy (RT) of 48Gy; those with unresectable disease received 60Gy RT. Results: From Jul./97 to Apr./05, 53 pts were entered to the studies. Five were found ineligible because of different histology. Pt characteristics and response to the Cx were summarized in the table . Toxicity of the Cx was mainly hematologic and generally well tolerated, with no toxic death; 70% of the pts completed planned 9 weeks. Thirteen pts in JCOG 9606 (stage III) received thoracotomy; tumor was resected in 11 pts, completely in 9 (39% of enrolled pts). Pathologic CR was observed in 3. The median PFS was 9.5m for stage IV and 4.5 y for stage III diseases. Overall survival at 2 & 5 yrs were 82% & 57% for stage IV and 96% & 77% for stage III pts. Conclusions: Short-course, dose intensive Cx was active against thymoma. Although it does not seem to bring long PFS in stage IV pts, it could improve resectability in limited disease.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of weekly cisplatin, etoposide and irinotecan (PE/CPT) for refractory relapsed small cell lung cancer (SCLC)
Authors: Kim Y. , Goto K. , Nishiwaki Y. , Kubota K. , Omatsu H. , Tamura T. , Ohe Y. , Kunitoh H. , Sekine I. , Yamamoto N. , Saijo N.
Published: March 2020

7088

Background: There is no standard treatment for relapsed SCLC. Irinotecan and etoposide has been studied in several phase II trials as active agents for relapsed SCLC. We reported the efficacy and tolerability of irinotecan combined with weekly cisplatin and etoposide (PE) in patients (pts) with sensitive relapsed SCLC (Goto, et al. Br J Cancer 2005). Methods: We conducted a phase II study to evaluate the efficacy and toxicity of PE/CPT regimen in pts with refractory relapsed SCLC, who had relapsed within 8 weeks after completion of first-line therapy. Pts must have measurable or assessable disease, age of 75 years or younger, performance status of 0 to 2 (ECOG), and adequate organ function. PE/CPT regimen consisted of cisplatin 25 mg/m2 on day 1 at one-week intervals for 9 weeks (at least 6 weeks), etoposide 60 mg/m2 on days 1–3 on week 1, 3, 5, 7, 9 (at least on week 1, 3, 5), and irinotecan 90 mg/m2 on day 1 on weeks 2, 4, 6, 8 (at least on week 2, 4, 6). After day 1 on week 2, G-CSF was administered on days when cytotoxic drugs were not given. Results: From May 2000 to January 2005, 30 pts were enrolled in this study. Pt characteristics were median age 64 years (range 44–75); 23 male and 7 female; 3 LD and 27 ED. Prior chemotherapy included PE in 13 pts, cisplatin and irinotecan in 7, carboplatin and etoposide in 5, and others in 5. 23 pts (77%) completed 6 or more weeks of chemotherapy. 2 CR and 19 PR were observed and the overall response rate was 70% (95% CI 50.6–85.3%). Grade 3/4 neutropenia, anemia and thrombocytopenia were observed in 60%, 73% and 47%, respectively. Grade 3/4 diarrhea was observed in only 7%. Coclusions: PE/CPT regimen was active and well tolerated for refractory relapsed SCLC.

No significant financial relationships to disclose.
Gemcitabine (G) plus carboplatin (C) at AUC 5 demonstrates reduced grade 4 thrombocytopenia rate compared to AUC 5.5 in first line therapy of patients with advanced stage NSCLC
Authors: Treat J. , Belani C. P. , Schiller J. , Monberg M. J. , Cunneen J. , Chen R. , Ye Z. , Obasaju C. K.
Published: March 2020

7130

Background: GC is a commonly used regimen in first-line therapy of advanced stage NSCLC. Various dosing of carboplatin in the GC regimen produces different toxicity profiles. This report summarizes three recent large clinical trials, including the Coalition Trial, using GC regimens that had comparable efficacy to other modern doublets. Methods: Three trials using GC as first-line treatment for advanced NSCLC with recent best response and toxicity data were selected. Pt populations were similarly defined, including measurable or evaluable Stage IIIB (with pleural effusion) or IV disease. All utilized similar 21-d regimens of G 1000 mg/m2 d 1,8 and C AUC 5.5 or 5.0 d1. Results: Despite a grade 4-thrombocytopenia rate of 12% in Trial 1 (Coalition) there was no difference in serious bleeding events compared to the other arms (paclitaxel/carboplatin and paclitaxel/gemcitabine). Discussion: In these three trials, 1126 pts with advanced NSCLC were treated with first-line GC. This database of 743 patients assessed for safety suggests that GC AUC 5 results in a 4.7% (95% CI: 3.3–6.5%) grade 4-thrombocytopenia rate with similar anti-tumor efficacy. The regimen of G 1000 mg/m2 on d1, 8 with C AUC 5 on d1 of a 21-d cycle may be optimal for treatment of advanced NSCLC.

[Table: see text]

[Table: see text]
Dual blockade of epidermal growth factor receptor (EGFR) and cyclooxygenase 2 (COX 2) may be dependent upon the EGFR mutational status in non-small cell lung cancer (NSCLC) cell lines
Authors: Gadgeel S. M. , Ali S. , Philip P. , Wozniak A. , Sarkar F.
Published: March 2020

7170

Background: Recent data has shown that the benefit of EGFR TKIs (tyrosine kinase inhibitors) in NSCLC is in patients with tumors that have EGFR mutations and /or gene amplification. Even among these patients, the median survival with EGFR TKIs is only 22 months. Pre-clinical data has shown that dual blockade of EGFR and COX 2 pathways may be beneficial. A recent clinical trial conducted at our center suggested that this combination primarily impacted NSCLC tumors that have the EGFR biomarkers. We therefore hypothesized that the EGFR biomarker status determines the outcome of dual blockade of these pathways in NSCLC. Methods: Three different cell lines with varying biomarker status and sensitivities to EGFR TKIs were used- H3255 (L858R; gene amplified), H1650 (del E746-A750; gene amplified), H1781 (wild type). Cells were treated with erlotinib, EGFR TKI- 10nM-100nM or celecoxib, COX 2 inhibitor- 5 μM and with the combination of two drugs. Cell survival was determined by a standard MTT assay and apoptosis was measured by ELISA method. Western blot analysis was conducted to assess COX 2, EGFR and pAkt levels. Results: Celecoxib by itself had no effects on any of the cell lines. Erlotinib showed a concentration dependent growth inhibition of both H3255 (IC50–41.72nM; surviving fraction at 50nM was 52%) and H1650 (IC50 > 100nM; Surviving fraction at 50nM was 70%) but had no effect on H1781. Celecoxib added to erlotinib significantly enhanced the growth inhibition of H3255 (p = 0.001) and H1650 (p = 0.014) as well as apoptosis (H3255- p = 0.016; H1650- p = 0.011) at all concentrations of erlotinib but had no effect in H1781 cells. In western Blot analysis the combination significantly reduced levels of COX-2, EGFR and pAkt compared to baseline and either agent alone in H3255 cells. Conclusions: The addition of celecoxib to erlotinib has a differential effect in NSCLC cell lines based on their EGFR biomarker status. This beneficial effect of celecoxib addition may be through improved inhibition of each pathway.

[Table: see text]
EGFR mutation and intron 1 CA repeat polymorphism as predictive markers of gefitinib responsiveness in non-small cell lung cancer (NSCLC)
Authors: Han S. W. , Kim T. Y. , Lee K. W. , Oh D. Y. , Lee S. H. , Kim D. W. , Chung D. H. , Im S. A. , Heo D. S. , Bang Y. J.
Published: March 2020

7173

Background: EGFR mutation is significantly associated with objective response and prolonged survival in NSCLC patients treated with gefitinib. However, presence of mutant nonresponses and nonmutant responses mandates investigation of other molecular markers for more effective prediction of gefitinib sensitivity in NSCLC. It is unclear whether low CA repeat number in EGFR intron 1 has such a predictive role. Methods: Advanced NSCLC patients received gefitinib 250mg/day. EGFR mutation in exons 18 - 21 were identified by direct sequencing of PCR products of DNA extracted from archival paraffin embedded tissue. Number of CA repeat in intron 1 of EGFR was determined by GeneScan with tumoral DNA. Baseline characteristics, mutational status, CA repeat number and efficacy of gefitinib were analyzed in respect to each other. Results: To date, 73 patients were evaluable for EGFR mutation, CA repeat and gefitinib responsiveness. 14 patients (19.2%) harbored EGFR mutation (7 deletion in exon 19, 4 L858R, 1 L861Q, 1 G719A, and 1 insertion in exon 20). Most common CA repeat genotype was 20/20 repeat (31 patients) followed by 16/20 repeat (15 patients). Patients were classified as having either low CA repeat (sum of both allele ≤ 37 repeats) or high CA repeat (≥ 38 repeats). 34 patients (46.6%) had low repeat, whereas 39 patients (53.4%) had high repeat. Patients with EGFR mutation showed better objective response (response rate [RR] 57.1% vs. 10.2% in wild type [WT], p < 0.001), time-to-progression (TTP) (p = 0.031, median 5.1 vs. 1.9 months in WT), and overall survival (OS) (p = 0.051, median14.5 vs. 7.4 months in WT). In the whole study population, low CA repeat was not associated with RR (p = 0.38), TTP (p = 0.15), or OS (p = 0.51). However, in the 59 patients without an EGFR mutation, patients with low CA repeat tended to have better objective response (RR 17.2% [5/29] in low repeat vs. 3.3% [1/30] in high repeat, p = 0.10) and significantly better TTP (p = 0.019, median 2.2 months in low repeat vs. 1.2 months in high repeat). Conclusions: Our results suggest that low number of CA repeats in EGFR intron 1 may have possible role in prediction of gefitinib responsiveness when analyzed together with EGFR mutational status.

[Table: see text]
Epidermal growth factor receptor (EGFR) mutation testing in non-small cell lung cancer (NSCLC) patients (pts)
Authors: Sequist L. V. , Joshi V. A. , Jänne P. A. , Fidias P. , Muzikansky A. , Meyerson M. , Haber D. A. , Kucherlapati R. , Johnson B. E. , Lynch T. J.
Published: March 2020

7177

Background: Somatic mutations in EGFR are associated with response to therapy and prolonged overall survival (OS) of NSCLC pts treated with tyrosine kinase inhibitors (TKI). We began EGFR mutation screening in 2004 with a CLIA certified test. We determined the characteristics of pts tested, EGFR mutations identified, and analyzed response to therapy and OS. Methods: We performed a retrospective cohort study of all NSCLC pts referred for EGFR testing over 1 year. Samples underwent direct sequence analysis of EGFR exons 18–24. We used multivariable logistic regression models to examine associations between mutation and pt characteristics. We used chi-square tests to assess differences in response to therapy by EGFR status and analyzed OS with Cox proportional hazard models, adjusting for age, gender and stage. Results: We screened 269 NSCLC pts for EGFR mutations, including 188 (71%) with unresectable disease and 245 (91%) with adenocarcinoma. Mutations were identified in 62 (23%) pts. 15 samples (6%) yielded insufficient DNA for testing. Mutation was more likely in the 59 never-smokers compared to the 185 ever-smokers [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.5–9.2]. Each added pack-year of smoking history lowered the odds of mutation by 5% (OR 0.95, 95% CI 0.94–0.97). Mutation was more likely in the 12 Asians than in the 212 of all other races (OR 3.7, 95% CI 1.1–12.0). In multivariable analyses, pack-years of smoking remained predictive of mutation (OR 0.96, 95% CI 0.94–0.99). Among 44 pts with unresectable disease undergoing subsequent TKI therapy, the 20 EGFR positive pts had an increased response rate (RR) compared to the 24 EGFR negative pts (60% v. 4%, p < 0.0001). In 27 pts given subsequent chemotherapy, RR was 33% and did not differ by EGFR status. Median follow-up was 9.8 months (mo) (range 0.2–135.8 mo). Among pts with unresectable disease, median OS is estimated to be 22.7 mo in EGFR negative pts and is not reached in EGFR positive pts (HR 0.22, 95% CI 0.80–0.63). Conclusions: Sequencing EGFR for somatic mutations is feasible in routine care of NSCLC pts. 23% of screened pts tested positive, and never smoking was the strongest predictor of mutation. Among patients with unresectable disease, EGFR mutation was associated with an increased RR to TKI therapy and OS.

[Table: see text]
Prognostic significance of immunohistochemical markers in non-small cell lung cancer
Authors: Renouf D. , Wood-Baker R. , Ionescu D. , Leung S. , Massoudi H. , Gilks B. , Laskin J.
Published: March 2020

7211

Background: The purpose of this study is to use a large patient population to identify immunohistochemical (IHC) biomarkers to enable improved prognostication in patients with non-small cell lung cancer (NSCLC). Methods: A tissue microarray was constructed using duplicate 0.6 mm cores of formalin-fixed paraffin embedded tissue blocks from 609 patients with NSCLC. IHC was used to detect 11 biomarkers including EGFR, HER2, HER3, p53, p63, Bcl-1, Bcl-2, TTF-1, CEA, Ch, and SNP. A clinical database was created prospectively at the time of tissue collection. Survival outcomes were obtained from a Provincial Cancer Registry database. Results: Male to female ratio was 400:209; median age 63yrs (range 35–82); median survival 3.5yrs (mean 5.7). All specimens were reviewed: 243 adenocarcinoma (ACA), 272 squamous cell carcinoma (SCC), 35 large cell carcinoma, 32 non-small cell carcinoma NOS, and 6 other (giant cell carcinoma). 21 patients with other histologies were excluded. Survival data for 535 cases was available. As of June 2005, 429 patients (80%) had died; of these 286 (54%) died of lung cancer, 117 (22%) died of other known causes, and for 26 (5%) the cause of death was not available. Bcl-2 (p = 0.007) was the only biomarker to predict better overall survival (OS). Bcl-2 (p = 0.021) and p63 (p = 0.025) were significant for disease specific survival (DSS) in all NSCLC. Analysis of the subgroups indicated that p63 was significant (p = 0.039) for DSS in squamous cell carcinoma (SCC) but not for adenocarcinoma (ACA) (p = 0.81). Bcl-2 was not significant for DSS in either subgroup (p = 0.28 for SCC, p = 0.112 for ACA). EGFR expression was associated with improved DSS in SCC (p = 0.012) but not for ACA. Co-expression of EGFR-HER3 was more likely in SCC then in ACA (p = 0.033). There was no correlation between outcome and any combination or clustering of biomarkers. Conclusions: The biomarkers p63 and Bcl-2 are predictive of DSS in NSCLC. EGFR expression is predictive of DSS in SCC. Sub-classification of NSCLC by histopathology is important as the relevance of some biomarkers (EGFR) would be lost if pooled. p63, Bcl-2, and EGFR may be used as prognostic markers in patients with NSCLC. Co-expression of EGFR-HER3 is more likely in SCC then in ACA. This may help explain the differential response to EGFR inhibitors in SCC versus ACA.

No significant financial relationships to disclose.
The role of F-18 FDG PET within randomized multicenter phase III trials for multi-modality treatment of non-small cell lung cancer stage III
Authors: Schmuecking M. , Schneider C. P. , Scheithauer M. , Presselt N. , Leonhardi J. , Hoeffken K. , Baum R. P. , Wendt T. G. , Mueller K. M. , Bonnet R.
Published: March 2020

7213

Background: To evaluate the role of F-18 FDG PET within clinical trials for staging, therapy management, molecular radiation treatment planning (MRTP), early therapy response and its effect on survival as compared to histopathologic tumor response, findings in 156 patients with NSCLC are analyzed prospectively in a randomized, open, multicenter phase III trial (LUCAS-MD). Methods: Inclusion criteria: histologically confirmed NSCLC stage IIIA/IIIB. ECOG PS 0–1, adequate hematologic, renal, hepatic function. Primary end points: OS, DFS. Secondary end points: TTP, QoL, RR. Neoadjuvant treatment: 2–3 cycles of chemotherapy with paclitaxel/carboplatin and a block of chemoradiation (45Gy, 1.5Gy b.i.d., concomitant paclitaxel/carboplatin) followed by surgery. Randomization: early vs. late chemoradiation. Staging: PET in addition to CT and/or MRI after randomization. Second PET after completion of neoadjuvant therapy. Assessment of standardized uptake values (SUV) in primary tumor (PT) and all metastatic lymph nodes (LN). Documentation of involved LN as detected by PET and LN sampling during surgery according to Naruke/ATS-LCSG classification. Image fusion of PET with CT data followed by molecular radiation treatment planning. Evaluation of histological regression grade (RG) and correlation with PET for PT and each LN. Statistical analyses: Wilcoxon-, chi-square-, Mantel-Haenszel-test, Kaplan-Meier-method, multivariate Cox-regression. Results: Upstaging in 11 pts. due to distant metastases. Downstaging in 5 pts. Complete vs. incomplete metabolic remission after 48 months: 60% vs. 34% (p = 0.0058). RG III/IIb (no/less than 10% of vital tumor cells) vs. RGIIa/I (more than 10% vital tumor cells) after 48 months: 59% vs. 27% (p = 0.0006). Multivariate Cox-regression for SUV: p > 0.05. Statistical power of the tests: 75% so far. Due to PET findings, the planning target volume for MRTP was reduced substantially in 23%, increased in 10%. Conclusions: Integration of PET in clinical trials enables a more accurate MRTP and therapy management (10% stage migration). Histological regression grade correlates well with metabolic remission as detected by PET. F-18 FDG PET may predict (long term) therapeutic outcome in stage III NSCLC.

No significant financial relationships to disclose.
Low expression of bax predicts poor prognosis in resected non-small cell lung cancer patients with nonsquamous histology
Authors: Choi J. , Lim H. , Kang S. , Jung Y. , Kim H. , Oh Y. , Choi H. , Hwang S. , Park K. , Han J.
Published: March 2020

7215

Background: Both p53 and bax proteins are known to promote apoptosis, and decreased expression of bax and mutation of p53 have been associated with poor progosis in several malignancies. Methods: We investigated the expression of these proteins and their association with clinicopatholgic characteristics including disease-free survival (DFS) and overall survival (OS) in 209 non-small cell lung cancer (NSCLC) patients (pts) who underwent surgical resection (stage I: 97, II: 46, IIIA: 45, IIIB: 17, IV: 4) using immunohistochemistry. Ninety-one pts (44%) received adjuvant treatment (chemotherapy: 9, radiotherapy: 24, both: 58). Results: While 82 pts (39%) had overexpression of p53 (>50% tumor cells positive), low expression of bax (no or weak staining in intensity) was observed in 159 pts (76%), which was significantly associated with male gender (p < 0.0001), squamous cell carcinoma (p < 0.0001), and overexpression of p53 (p = 0.028). With a median follow-up of 65 months (34–133 months) in survivors, 5-year DFS and OS of total pts were 38% and 46%, respectively, excluding 7 deaths from postoperative complications. Neither overexpression of p53 nor low expression of bax was associated with poor DFS (p = 0.728, p = 0.335) and OS (p = 0.927, p = 0.261). However, in pts with nonsquamous histology (111 pts), low expression of bax was significant independent predictor of poor DFS (p = 0.004) in addition to advanced stage (p < 0.0001) and large primary tumor size (>4 cm) (p = 0.005) in multivariate analysis. Furthermore, low expression of bax was associated with poor OS (p = 0.048) along with advanced stage (p = 0.01) and pneumonectomy (p = 0.003). Conclusions: Low expession of bax was significantly associated with poor prognosis in NSCLC pts with nonsquamous histology.

No significant financial relationships to disclose.
MDM2 polymorphism and recurrence-free and overall survival in early stage non-small cell lung cancer (NSCLC)
Authors: Suk Heist R. , Zhou W. , Cogan-Drew T. , Liu G. , Su L. , Neuberg D. , Lynch T. J. , Wain J. C. , Christiani D. C.
Published: March 2020

7221

Background: MDM2 is a negative regulator of p53. A T->G polymorphism in the promoter region of MDM2 has been described, where the G/G genotype is associated with higher MDM2 mRNA and protein levels. Overexpression of MDM2 is thought to interfere with p53-mediated apoptosis and growth inhibition, leading to cancer progression. We hypothesized that the MDM2 G/G genotype may be associated with worse survival outcomes in early stage lung cancer. Methods: We evaluated the relationship between MDM2 polymorphism status and overall survival (OS) and recurrence-free survival (RFS) among 385 Stage I and II NSCLC patients treated with surgical resection at Massachusetts General Hospital from 1992 to 2000. The MDM2 polymorphism was genotyped using the 5’-nuclease assay (Taqman). Kaplan-Meier methods and the log-rank test were used to compare survival by polymorphism status. Cox proportional hazards models were used to adjust for possible confounding variables. Results: Median age was 69, and 48% were female. 52% were Stage IA, 29% Stage IB, 4% Stage IIA, and 15% Stage IIB. 49% had adenocarcinoma, 29% squamous cell, 12% BAC, and 10% other NSCLC. The genotype frequencies for the MDM2 polymorphism were: T/T 161 (42%), T/G 156 (40%), G/G 68 (18%). Genotype was not associated with age, sex, stage, histology, or smoking status. Median follow-up time was 5.79 years. After adjusting for age, sex, stage, histology, and pack-yrs of smoking, the G/G genotype appeared to be associated with worse RFS and OS (AHR 1.60 (95% CI 1.10–2.34), p = 0.01; AHR 1.56 (95% CI 1.03–2.38), p = 0.04; respectively). In subset analysis, patients with squamous cell cancer and current-smokers had significantly worse survival with the G/G genotype, while there was no significant difference by genotype among adenocarcinomas and non-current smokers. (For squamous cell, 5-yr OS for T/T 59%, T/G 52%, G/G 7%, p = 0.0001; for current smokers, 5-yr OS for T/T 67%, T/G 49%, G/G 27%, p = 0.04). Conclusions: Our findings suggest that the G/G genotype of the MDM2 polymorphism is associated with worse survival among early stage NSCLC patients, particularly those with squamous cell histology and current smokers. Supported by NIH grants CA074386, CA092824, CA090578, FAMRI Young Clinical Scientist Award, Doris Duke Foundation.

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FDG uptake as a predictor of outcome in stage I non-small cell lung cancer
Authors: Viswanathan A. K. , Pillot G. , Goodgame B. , Yang Z. , Shriki J. , Gao F. , Dehdashti F. , Siegel B. A. , Govindan R.
Published: March 2020

7224

Background: Lung cancer is the leading cause of cancer-related mortality in both men and women in the United States. Over 80% of patients are diagnosed with non-small cell lung cancer (NSCLC) and approximately 30% of patients with NSCLC present with resectable disease. Nearly 40–50% of patients with resected stage I NSCLC develop recurrent disease. Currently there are no clinical, radiological, or molecular markers to predict outcomes following surgery in early stage NSCLC. Positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (FDG-PET) is used commonly in the staging work up of NSCLC. The standardized uptake value (SUV) is a semiquantitive measure of FDG uptake that correlates with tumor doubling time. We studied the relationship between the maximum preoperative tumor SUV (SUVmax) for FDG and disease-free survival (DFS) in patients with resected stage I NSCLC. Methods: We identified 153 consecutive patients diagnosed with stage I NSCLC between 1999 and 2003 who had undergone FDG-PET before curative surgical resection. Data were collected regarding stage distribution, histology, recurrence and survival. No patient in this cohort received adjuvant chemotherapy or radiotherapy. SUVmax above and below the median was correlated with DFS. Results: Of 153 patients with stage I NSCLC, 90 (59%) had T1 and 63 (41%) had T2 tumors. The mean and median follow-up time for the cohort was 2.9 and 3.1 years respectively. The mean and median SUVs were 7.0 and 6.0 respectively. The 5-year DFS categorized by SUVmax < 6 vs. SUVmax ≥ 6 was 62% vs. 46 (p = 0.0036) for the entire cohort; 64% vs. 54% (p = 0.20) for the T1 subset; and 60% vs. 40% (p = 0.07) for the T2 subset. Conclusions: High SUVmax (≥ 6) on preoperative FDG-PET is a predictor of poor outcome in resectable stage I NSCLC.

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Increased risk of thrombosis with lenalidomide in combination with dexamethasone and erythropoietin
Authors: Niesvizky R. , Spencer A. , Wang M. , Weber D. , Chen C. , Dimopoulos M. A. , Yu Z. , Yu Z. , Delap R. , Zeldis J. , Knight R. D.
Published: March 2020

7506

Background: Lenalidomide (Len) is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against multiple myeloma (MM) and additive effects when combined with dexamethasone (Dex). At the interim analysis of MM-009/010, lenalidomide/dexamethasone achieved a significant benefit over dexamethasone, providing a longer median time to progression (TTP), higher response rates, and higher CR rates. Aim: This subgroup analysis of MM-009/010 was performed to evaluate thrombosis in patients receiving Len/Dex vs Dex. Thrombotic events included the following adverse event terms: thrombosis, deep venous thrombosis, thromboembolism, and pulmonary embolism. Methods: Patients (pts) with relapsed or refractory MM were randomized to either receive oral Len (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on Days 1–4, 9–12, 17–20 every 4 weeks for 4 months, then 40 mg on Days 1–4 every cycle thereafter) or placebo plus Dex. Results: Thrombotic events were reported in 39 (11.3%) of 346 pts treated with Len/Dex compared to 13 (3.8%) of 346 pts treated with Dex alone (p < 0.001). Multivariate analysis identified Len/Dex treatment and erythropoietic treatment to be independently correlated with thrombosis (Table). Older age, lower plasma cell percentage in marrow, and better ECOG performance status had a weaker association with thrombosis. Thrombosis occurred more frequently among pts with prior history of thrombosis, although that was not a significant predictor in the multivariate anlaysis. None of 23 pts who used aspirin or salicylate during the first month of treatment developed thrombosis and all events occurred in pts with rising M-paraprotein levels at baseline. Conclusions: The current study findings suggest that the administration of erythropoietic agents should be minimized in MM pts receiving Len/Dex. Prophylactic antithrombotic therapy should also be considered.

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High CR and near-CR rate with bortezomib incorporated into up-front therapy of multiple myeloma with tandem transplants
Authors: Barlogie B. , Anaissie E. , Bolejack V. , Zangari M. , Van Rhee F. , Shaughnessy J. , Hollmig K. , Pineda-Roman M. , Crowley J. , Tricot G.
Published: March 2020

7519

Background: Tandem autotransplants have increased complete response (CR) rates and extended event-free survival (EFS) and overall survival (OS) in multiple myeloma (MM). Because of its remarkable efficacy in end-stage disease and to further increase CR and thereby improving EFS and OS, bortezomib (Velcade, V) was incorporated into Total Therapy 3 (TT3), both with DT-PACE combination chemotherapy (dex, thalidomide, cis-platin, adriamycin, cyclophosphamide, etoposide) as induction prior to and consolidation after transplant. Methods: TT3 has accrued 247 of a target population of 300 patients; median follow-up is 16 months. Twenty-seven percent of patients were 65 yr and older; cytogenetic abnormalities (CA) were present in 31% and inter-phase FISH-based deletion 13 in 42%. Results: Median times to 1st and 2nd transplants were 3 mo and 5 mo, with projected completion rates of 95% and 82%. The cumulative frequency of CR plus near-CR was 50% at 6 mo, 75% at 12 mo, reaching 80% at 18 mo. Blood stem cells were readily procured, yielding ≥20 million CD34 cells/kg in > 95%. At 12 mo, 91% are alive and 89% event-free. Relapse has occurred in 29 patients, whose distinguishing features included age ≥ 65 yr (48% vs 24%, p = .005), abnormal cytogenetics (CA, 48% vs. 29%, p = .03) and LDH > ULN (48% vs 23%, p = .004). Among 21 deaths, baseline features were: creatinine >4 mg/dL in 4; age ≥ 65 yr in 11; PS > 3 in 5 and PS > 2 in 4; CRP > 10 mg/L in 9 patients. Conclusions: Introducing V in TT3 as part of combination chemotherapy is safe, permits robust stem cell collection and induces remarkably high CR plus near-CR rates. High-risk MM features such as CA and LDH, defined in Total Therapies 1 and 2, also appeared detrimental with TT3.

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Comparison of lenalidomide in combination with dexamethasone to dexamethasone alone in patients who have received prior thalidomide in relapsed or refractory multiple myeloma
Authors: Wang M. , Knight R. , Dimopoulos M. , Siegel D. , Rajkumar S. V. , Facon T. , Yu Z. , Zeldis J. , Olesnyckyj M. , Weber D. M.
Published: March 2020

7522

Background: Lenalidomide (len), an analog of thalidomide (thal) is a novel, oral immunomodulatory agent that is effective against multiple myeloma (MM). Two randomized, Phase III trials (MM009 and MM010) have recently demonstrated superior responses and overall survival (OS) for patients (pts) treated with len and dexamethasone (dex) in comparison with dex-placebo. This is a prospective subgroup analysis to assess the impact of prior therapy with thal on the sensitivity of MM to subsequent lenalidomide. Methods: We evaluated 692 pts from both trials (MM009 and MM010). The pts had relapsed/refractory MM, were not refractory to dex and were randomized to receive either len (25 mg daily for 3 weeks (wks) every 4 wks) plus dex (40 mg on days 1–4, 9–12, 17–20 every 4 wks for 4 cycles, then 40 mg on days 1–4 every subsequent cycle) or placebo plus dex. Standard criteria were used to evaluate response and TTP. Results: Pooled data from 692 pts showed superior median TTP (48.1 vs 20.1 wks) and OR (59.2% vs 22.5%) in pts treated with len/dex compared to dex-placebo (p <0.001). Although subgroup analysis of pts with prior thal therapy revealed that pts who received len/dex had significantly improved OR, PR CR and median TTP than pts who received dex-placebo, OR, CR and TTP were highest in len/dex pts not previously treated with thal. Multivariate analysis indicates that after controlling for the treatment factor and baseline disease characteristics, whether or not pt had prior exposure to thal is a marginally significant variable to predict TTP. The risk of deep venous thrombosis and pulmonary embolism in these subgroups will be updated on further analysis. Conclusions: Lenalidomide in combination with dexamethasone is more effective than dexamethasone-placebo regardless of prior thalidomide in relapsed/refractory multiple myeloma.

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A phase II trial of lenalidomide for patients with AL amyloidosis
Authors: Sanchorawala V. , Wright D. G. , Rosenzweig M. , Finn K. T. , Skinner M. , Seldin D. C.
Published: March 2020

7524

Introduction: A phase II trial was designed to evaluate the toxicity and response rate of lenalidomide (Revlimid, CC-5013), alone and in combination with dexamethasone in patients with AL amyloidosis. Patients with this plasma cell disorder have organ dysfunction that makes them more susceptible to drug toxicity. Methods: Planned enrollment, 35 patients. Regimen: 3 cycles of lenalidomide at 25 mg/d for 21d, with dexamethasone 10 mg bid for 4 days, 3 times a month, every other month, for those patients not responding to lenalidomide alone. Toxicity and responses were evaluated after 1, 3, 6, 9, and 12 months of treatment. Hematologic responses were based upon qualitative and quantitative measures of clonal plasma cell disease. Organ responses were scored according to published criteria. Results: 24 patients have been enrolled to date, age range is 47–76, M:F 18:6, κ:λ 7:17. Organ involvement: 75% renal, 38% cardiac, 18% hepatic or gastrointestinal, 17% neuropathy, 13% soft tissue or lymph node. 22 had been treated previously, and 12 had undergone treatment with HDM/SCT. After none of the first 6 patients tolerated 3 treatment cycles at 25 mg/day, the starting dose was reduced to 15 mg/day. A total of 112 cycles have been administered (1–14 cycles per patient). 2 patients were removed from study because of rashes; one because of gout and severe fatigue; one by choice; and one patient died in the first treatment cycle, apparently due to complications of the underlying disease. Grade 3 toxicities observed included fatigue (33%), hypoalbuminemia (29%), worsening performance status (29%), neutropenia (21%), rash (21%), dizziness (13%), gout (13%), dyspnea (8%), muscle weakness (8%), and pneumonia (8%). One patient (4%) had a DVT on lenalidomide and dexamethasone. 8 out of 13 have had a measureable hematologic response, of which 3 were complete or near complete. 8 patients had elevated free light chains (FLC) with a skewed κ:λ ratio, and 4 of these had ≥50% reduction in FLC level. 4 of 14 patients with proteinuria improved. Conclusion: Lenalidomide is reasonably well-tolerated in patients with AL amyloidosis, and alone or in combination with dexamethasone, can induce excellent hematologic responses and improvement in organ disease.

No significant financial relationships to disclose.
Phase I/II results of a second-generation humanized anti-CD20 antibody, IMMU-106 (hA20), in NHL
Authors: Morshhauser F. , Leonard J. P. , Coiffier B. , Petillon M. , Coleman M. , Bahkti A. , Teoh N. , Wegener W. A. , Goldenberg D. M.
Published: March 2020

7530

Background: The humanized anti-CD20 antibody, IMMU-106 (hA20), has similar murine CDRs to rituximab, but the remaining framework is identical to humanized anti-CD22 IgG1 antibody, epratuzumab, whose safety and short infusion times have been reported. Methods: An open-label, multicenter, phase I/II, dose escalation study was conducted in adult patients with recurrent NHL to establish the safety, tolerance, PK, and immunogenicity (HAHA) of hA20 administered weekly x 4. Thirty-four patients have now received hA20 at 120 (n = 7), 200 (n = 6), 375 (n = 18) or 750 mg/m2 (n = 3). These were predominantly stage III/IV patients (n = 27) with follicular lymphoma (N = 23) who received 1–7 prior treatments (median, 2), including 1 (N = 22) or more (N = 9) rituximab regimens (without progression within 6 months). Results: Thirty-three patients completed all 4 hA20 infusions. Median infusion times at 375 mg/m2 were 3.1 h for 1st infusion, 2.0–2.3 h for subsequent infusions, and were generally shorter at lower doses. Fourteen patients (14%) had transient events, predominantly grade 1–2 events at 1st infusion. Antibody levels increased with hA20 dose; at 375 mg/m2, mean serum half-lives after 1st and 4th infusions were 3.4 ± 1.7 and 12.3 ± 3.9 days, respectively. With median follow-up now 3–6 months, peripheral blood B-cell depletion persists, HAHA evaluations are negative, and 14/23 patients (61%) with response assessments have objective responses by Cheson criteria. All 6 CR/CRu’s (23%) were in follicular lymphoma, occurred at all dose levels even at 120 mg/m2 (including patients with 2–4 prior rituximab-containing regimens ), and with 5/6 continuing. Conclusions: The tolerability, relatively short infusion times, and CR/CRu’s in patients with follicular lymphoma who relapsed after rituximab-containing regimens is encouraging. This study is continuing to assess response durability and to determine the optimal hA20 dose for subsequent studies.

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