bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFR genomic gain in Japanese non-small cell lung cancer patients treated with gefitinib
Authors: Varella-Garcia M. , Mitsudomi T. , Yatabe Y. , Kosaka T. , Nakajima E. , Franklin W. , Bunn P. A. , Hirsch F. R. 
Published: March 2020

7164 Background: Increased EGFR gene copy numbers evaluated by fluorescence in situ hybridization (FISH) is excellent predictor of clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) in Caucasian non small-cell lung cancer (NSCLC) patients. This study was performed to verify how this marker performs in Oriental patients. Methods: A cohort of 59 Japanese patients with recurrent NSCLC after surgery was treated with gefitinib 250 mg daily. The cohort included 46% of females, 47% of never-smokers, 68% of patients had prior chemotherapy and 59% had stage III-IV at the time of surgery. Adenocarcinoma was the most common histology (85%). FISH was performed using EGFR /CEP 7 and PathVysion probes (Vysis/Abbott). Specimens were classified as FISH+ when showing gene amplification or high polysomy (≥4 copies of the gene in ≥40% of tumor cells). Effectiveness of gefitinib was concluded when there was 30% tumor shrinkage in imaging studies and/or elevated CEA level decreased to <50% of baseline. Results: FISH results were available in 51 tumors: 35 (69%) were EGFR+ and 29 (57%) were HER2+. There was a significant association between EGFR+ and HER2+ (p = 0.012) and between EGFR FISH+ and of EGFR mutations (p = 0.003). All 9 tumors exhibiting clustered EGFR gene amplification harbored mutations. Response rate assessed in 43 patients was 59% in EGFR+ and 33% in EGFR- (p = 0.11). Gefitinib treatment produced response in 5 (83%) cases with gene amplification and 12 (52%) cases with high polysomy. Response rate was 77% in 22 cases positive for FISH and mutation and 100% in 5 cases with EGFR mutation/FISH- cases. No responses were observed in EGFR WT patients, neither in 9 FISH+ nor in 10 FISH- cases. Survival was not significantly impacted by EGFR (p = 0.42) or HER2 (p = 0.40) FISH status, while EGFR mutation was significantly associated with longer survival (p = 0.005). Conclusion: Patients in this Japanese cohort had more frequently FISH+ status than in the Caucasian populations, which may contribute to higher sensitivity to EGFR TKIs. However, the predictive power of EGFR FISH status for TKI sensitivity seems to be lower supporting significant differences in the mechanisms of EGFR pathway activation in Oriental and Caucasian populations. [Table: see text]
Associations between chromosome 7 aneusomy and EGFR copy number with survival and response to gefitinib in NSCLC
Authors: Morrison L. E. , Jewell S. S. , Jacobson K. K. , Kaiser K. , Gale M. , Muzzafar T. , Mauer A. M. , Villaflor V. M. , Bonomi P. , Coon J. S. 
Published: March 2020

7171 Background: EGFR, the presumed target of gefitinib and erlotinib, has been studied (expression, gene copy number, & mutations) for predicting response to these tyrosine kinase inhibitors (TKI), in non-small cell lung cancer (NSCLC). ’High polysomy’ and ’amplification’ of the EGFR gene, as defined by Cappuzzo et al. JNCI 97:643, using fluorescence in situ hybridization (FISH), showed significant association with objective response (Resp) and survival. We also measured EGFR and chromosome 7 (C7) copy numbers by FISH in 81 gefitinib-treated NSCLC patients (12 Resp). Using Cappuzzo’s FISH± parameter alone we saw similar trends but no statistical significance in the 81 patient group. Therefore we sought to optimize FISH parameters for these patients. Methods: FISH was performed (paraffin sections) using a 2-color probe set (Vysis LSI EGFR/CEP 7), median 80 cells per specimen. >50 parameters were derived from the data (e.g. mean EGFR/cell, C7/cell etc) and compared, using different threshold values, to Resp and survival. Results: The best single parameter associated with survival was the average C7/cell. Applying upper and lower thresholds of 3.6 and 2.0 C7/cell to delineate moderate from extreme ratios yielded median survival of 177 and 465 d, respectively (Kaplan-Meier, p < .002). A single threshold of 3.6, separating low from high, yielded survival of 201 and 522 d, respectively (p < .01). For these thresholds C7/cell was not associated with Resp, however, thresholds could be found for which both survival and Resp were significant. The best single parameter associated with Resp was average EGFR/cell. Of the 70 patients with EGFR/cell≤6.0, 63 (90%) did not respond while 5 of 11 patients (45%) with EGFR/cell >6.0 responded (p < .01). No EGFR/cell threshold could be found for which both survival and Resp were significant. Many 2-parameter combinations provided significant associations with both survival and Resp. Conclusions: Several FISH-derived parameters were significantly associated with either survival or Resp to gefitinib and a subset were associated with both. These parameters must be tested on independent data sets to determine their value in directing TKI therapy. [Table: see text]
Detection of epidermal growth factor receptor mutation in transbronchial aspiration cytology of non-small cell lung cancer
Authors: Horiike A. , Kimura H. , Nishio M. , Ohyanagi F. , Satoh Y. , Okumura S. , Nishio K. , Ishikawa Y. , Nakagawa K. , Horai T. 
Published: March 2020

7175 Background: Somatic mutations of epidermal growth factor receptor (EGFR) strongly associate with objective response to EGFR tyrosine kinase inhibitors. There are some problems to practically use it as prognostic markers. Since it is difficult to obtain sufficient tumor samples from non-small cell lung cancer (NSCLC) patients, they are often diagnosed by cytological procedure alone. Therefore, it is very useful if EGFR mutations are able to be detected in cytological samples. The aims of this study are to detect EGFR mutations in the samples of transbronchial aspiration cytology (TBAC) by using direct sequencing and Scorpion ARMS method, and to compare the sensitivities of these methods. Patients and Methods: 94 patients diagnosed as NSCLC in our institute were enrolled in this study, consisting of 63 males and 31 females with a median age of 66. In cytologic diagnosis, they were adenocarcinoma in 58, squamous carcinoma in 24, and the others in 12. DNA was extracted from the TBAC samples, and EGFR mutations were analyzed using direct sequencing (exon 19 and exon 21) and Scorpion ARMS method (E746-A750del and L858R). Results: The mutations were detected in 31patients (33%). 13 mutations (14%) (E746-A750del; 6 patients, L858R; 7 patients) were detected by direct sequencing. 27 mutations (29%) (E746-A750del; 16 patients, L858R; 11 patients) were detected by Scorpion ARMS method. Conclusion: EGFR mutations were able to be detected in TBAC samples by both methods. Scorpion ARMS method is more sensitive for the detection of EGFR mutations than direct sequencing. No significant financial relationships to disclose.
EGFR mutation analysis in histologic and cytologic specimens of non-small cell lung cancer
Authors: Sakai H. , Akagi K. , Sudoh J. , Yoneda S. , Komagata H. , Kurimoto F. , Hommura Y. 
Published: March 2020

7176 Background: Recent studies have suggested that EGFR mutations can be used to predict tumor sensitivity to gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor) in patients with non-small-cell lung cancer (NSCLC). Most previous studies of EGFR mutations have used direct sequencing to analyze surgically resected specimens. More rapid, accurate, and simple techniques for analysis of EGFR mutations in histologic or cytologic specimens (i.e., transbronchial biopsy, bronchial washing, pleural effusion, lymph node aspiration) are needed to improve outcomes. Methods: DNA was extracted from histologic or cytologic specimens of NSCLC obtained from March through October 2005. The major mutations of the EGFR gene (exons 18–21) were analyzed by our original technique for fragment analysis and polymerase-chain-reaction-restriction-fragment-length polymorphism analysis. Results: About 2 days were required for mutation analysis. Pathological analysis indicated that 64 (5 histologic and 59 cytologic specimens) of 90 specimens (11 histologic and 79 cytologic specimens) were adenocarcinomas. EGFR mutations were found in 22 of these specimens (2 histologic and 20 cytologic specimens; ex19:del 13, ex19:ins 2, ex21:L858R 7). An EGFR mutation (ex19:del) was also found in a patient with large cell carcinoma. Conclusions: Our method can efficiently detect EGFR mutations in small samples of lung cancer cells obtained from histologic or cytologic specimens. This method is useful for the identification of EGFR mutations in patients with unresectable NSCLC in whom sufficient tissue specimens are difficult to obtain. No significant financial relationships to disclose.
Erlotinib as single agent in patients (p) with advanced or metastatic NSCLC: A multivariate analysis in a prospective study
Authors: Pallares C. , Paz-Ares L. , López-Picazo J. , Pérez-Carrión R. , Montes A. , López-Vivanco G. , De Castro J. , Cobo M. , García Velasco A. , Regueiro P. , Massutí B. 
Published: March 2020

7180 Background: Erlotinib is the first orally available selective EGFR tyrosine-kinase inhibitor that improves survival in 2nd and 3rd line therapy for NSCLC. This non-randomised, phase II trial evaluated the efficacy and safety of erlotinib in patients with advanced or metastatic NSCLC. Methods: Patients with previously treated advanced or metastatic NSCLC or patients that were not suitable for first line conventional chemotherapy, stage IIIB/IV, PS 0–2 were enrolled to receive erlotinib 150 mg/day until disease progression or withdrawal. The primary endpoint of the study was time to progression (TTP) in the intent to treat (ITT) population. A multivariate analysis (Cox-model) was performed. Results: 416 patients were enrolled from June 04 to March 05. Demographics: M 78%/F 22%; median age 64 y [range 28–100]; stage IV 91.6%; PS 0/1/≥2: 65 (16%)/227 (55%)/105 (25%); adeno histology 178p (43%), SCC 121p (29%), BAC 3p (0.7%), LLC 2p (20%), other 29p (7%); smoking status: yes 349 p (84%) no 62 p (15%). 1st line: 60p (14.4%); 2nd line 181p (43.5%) and ≥ 3rd line 175p (42%). 230 patients had measurable disease and were evaluable for response: 1CR, 30 PR (ORR: 13.4%), 98 SD, and 101 PD. Toxicity was predictable (mainly rash, and diarrhoea). In the ITT population the median TTP was 3.2 m [95% CI 2.8–3.6]. For evaluable population median TTP was 4.6 m in 1st line, 3.23 m in 2nd line, and 2.8 m in 3rd line. Exploratory analysis showed that ORR was associated with gender, smoking history, previous treatment and histology. The multivariate analysis for TTP showed that no smoking history (p < 0.005), adeno histology (p < 0.0001), and erlotinib as 1st line treatment (p < 0.02) correlated with better TTP. Conclusions: Erlotinib is an active and very well tolerated treatment in patients with advanced NSCLC untreated or that have previously failed to conventional chemotherapy. Our data suggest that non smoking history, adeno histology and erlotinib as 1st line treatment are associated with better TTP. The study is ongoing. [Table: see text]
EGFR mutations (muts), IHC and FISH status, and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer (NSCLC) patients (pts) treated with gefitinib (GEF)
Authors: Villaflor V. M. , Buckingham L. , Gale M. , Coon J. , Mauer A. M. , Muzzafar T. , Kaiser K. , Shannon M. , Morrison L. , Bonomi P. 
Published: March 2020

7182 Background: EGFR and pAkt expression by immunohistochemistry (IHC), muts, and FISH status have been identified as possible molecular predictors for GEF efficacy in NSCLC (Cappuzzo, et. al, JNCI, 2005). The goal of this study was to independently evaluate these findings regarding survival (surv), and to assess the predictive value of mean chromosome 7 copy number/cell (C7). Methods: 150 consecutive Expanded Access Trial pts with >1 week GEF therapy were included for analysis. IHC (present vs not detected) was performed for 87 pts, and 58 pts were analyzed for muts by SSCP, mut-specific PCR, and sequencing. Tissue from 81 pts was evaluated for EGFR and C7 gene copy numbers by fluorescence in situ hybridization (FISH). Results: 150 pts (77 female, 73 male; median (md) age 67; 85 adenocarcinoma) received GEF; md follow-up was 5.8 months (mo). Overall response was 8% (2 CR, 10 PR); 56 pts had stable disease. Md Kaplan-Meier surv was 5.9 mo. IHC revealed that 47/87 pts (54%) had EGFR+, and 36/75 pts (48%) had pAkt + tumors. pAkt+ pts had significantly (sig) longer surv than pAkt− pts (11.4 vs 5.8 mo, p < .05). High polysomy was seen in 36/81 pts (44%) who were designated FISH+; 45 pts were FISH−. EGFR IHC and FISH positivity were not sig associated with surv. C7 was defined as low (<3.6, 63 pts) or high (≥3.6, 18 pts); md surv was 6.6 and 17.1 mo, respectively, p < .01. Muts were found in 17/58 tumors (29%). Md surv for pts with and without muts was 23.8 and 7.9 mo, respectively, p < .07. EGFR IHC− pAkt− pts (18 pts) had sig shorter surv than 57 pts with any pos value (4.7 vs 8.8 mo, p < .02). Double-positive pts had sig longer surv than pts with any neg value. Conclusions: These findings resemble but do not duplicate those reported by Cappuzzo, et al. Additionally, high C7, alone or combined with pAKT, may be an important predictor for GEF efficacy in NSCLC. Further studies of C7, a technically simple and reproducible FISH assay, are warranted. [Table: see text] [Table: see text]
Phase II study of the efficacy of gefitinib in patients with non-small cell lung cancer with the EGFR mutations
Authors: Sunaga N. , Yanagitani N. , Kaira K. , Tomizawa Y. , Iijima H. , Otani Y. , Tanaka S. , Suga T. , Dobashi K. , Mori M. 
Published: March 2020

7183 Purpose: Recent studies have indicated that the mutations of epidermal growth factor receptor (EGFR) were associated with sensitivity of non-small cell lung cancer (NSCLC) to gefitinib, an EGFR tyrosine kinase inhibitor. The clinical objective of this study was to prospectively evaluate the efficacy of gefitinib in patients with stageIII/IV NSCLC that had the EGFR mutations. Methods: Genomic DNA was extracted from tumor specimens and EGFR mutations in exon 19 and 21 were analyzed by direct sequencing. Patients with stageIII/IV NSCLC who had the EGFR mutations were treated with gefitinib (250mg) orally. Response, survival data and toxicity were assessed. Results: From Nov. 2004 to Dec 2005, 14 patients with the EGFR mutations received gefitinib (median age: 67 years; 2 males, 12 females; 1 smokers, 13 non-smokers; all adenocarcinomas). Two patients discontinued gefitinib and came off study because of interstitial pneumonitis (grade 3) and acne (grade 3), respectively. Response data are available for 12 patients. Two achieved a complete response (CR), seven exhibited a partial response (PR) and three had stable disease (SD). Response rate and disease control rate were 75% and 100%, respectively. There were no grade 3/4 toxicities in these 12 patients. All patients were alive during median follow-up period of 8 months (range 1–13 months). Conclusions: The EGFR mutations could be an excellent predictor of response to gefitinib in NSCLC. No significant financial relationships to disclose.
IFCT0401 trial: Phase II study of gefitinib administered as first line treatment in non-resectable, pneumonic-type adenocarcinoma (P-ADC)
Authors: Cadranel J. , Quoix E. , Debove P. , Moro-Sibilot D. , Brãchot J. M. , Souquet P. J. , Soria J. C. , Morin F. , Milleron B. 
Published: March 2020

7186 Background: P-ADC is a peripheral lung ADC with a pneumonic radiological presentation, most often containing the bronchioloalveolar carcinoma variant in the 2004 classification. In this setting, EGF receptor tyrosine kinase inhibitors have shown promise. We therefore conducted a prospective multicentric phase II trial to evaluate gefitinib (G) (250 mg/d) as first line treatment in non-resectable P-ADC. Methods: Inclusion criteria: previously untreated, non-resectable cyto/pathologically proven P-ADC with > 3-month expected survival. Primary objective: disease control rate (DCR) - objective response (OR) plus stable disease (SD) for 3 months. Secondary objectives: tolerance, quality-of-life, time-to-progression (TTP), survival, and identification of clinical, pathological and biological markers associated with DC. Results: From 04/04 to 06/05, 88/90 enrolled patients were eligible. All had stage IV disease, with pulmonary (n = 86) and/or extra-thoracic metastasis (n = 10). After review by the clinical trial panel 85/88 were evaluable for response. Tissue-biopsies were collected for central pathological review and molecular analyses. Patients: all Caucasians, median age 64 yrs (27–84), PS <2 in 80.7%, 48 females (54.5%), 33 never (38.6%), 49 former, and 5 current smokers. At 3 months, DC was achieved in 25/85 patients (DCR: 29.4%, CI = [20–39]), including 11 OR (13%, CI = [6–20]) and 14 with SD (16.5% CI = [9–24]). The longest duration of OR is 19.5+ months (4+ to 19.5+) and SD 18+ (5 to 18+). Median TTP is 2.9 months (CI = [2.5–3.3]) but median survival time was not achieved after a 12-month follow-up median time. No death-related toxicity was observed. Only 1 patient stopped G because of skin toxicity (GIII). DC was associated with female gender (p = 0.095, and 0.002 for OR), non-mucinous tumor (p < 0.001, and 0.006 for OR) and absence of rales (p = 0.009) but not with smoking (except for OR, p = 0.024), PS, bronchorrhea, hypoxemia, extra-thoracic metastasis, or Tx presentation. Conclusions: Gefitinib is active and well-tolerated as first-line treatment of non-resectable P-ADC in a Caucasian population, with a 13% OR rate and a 30% DCR. Interestingly, DC was maintained on a long term under G, maybe resulting in improved survival time. [Table: see text]
Clinical factors affecting the late resistance to gefitinib in patients with non-small cell lung cancer (NSCLC)
Authors: Segawa Y. , Hotta K. , Umemura S. , Fujiwara Y. , Shinkai T. , Ueoka H. , Takigawa N. , Tabata M. , Kiura K. , Tanimoto M. 
Published: March 2020

7191 Background: The mechanism of late resistance of NSCLC to gefitinib is unclear. In this study, we assessed clinical factors affecting the late resistance in patients with NSCLC. Methods: Between 2000 and 2004, 197 consecutive patients with NSCLC underwent treatment with gefitinib in our institutions. Of those, 56 patients who had received a prior chemotherapy and continued treatment with gefitinib during at least 6 months were included in this study. The characteristics of these patients were as follows: median age, 62.5 years (range, 28 to 77 years); male/female, 22/34 patients; PS 0/1/2/3/4, 15/31/8/0/2 patients; and adeno/nonadenocarcinoma, 52/4 patients. Thirty-two patients never smoked and 24 were former or current smokers. Nineteen patients underwent surgical resection of NSCLC. Numbers of chemotherapy regimens were one in 31 patients, two in 18, three in 6, four in 1, respectively. Results: Of 56 patients, three achieved a CR and 39 attained a PR, with an overall response rate of 75% (95% CI, 69.2 to 80.8%). The remaining 14 patients had a long SD. At a median follow-up time of 21.6 months (range, 7.7 to 59.7 months), median time to progression was 19.5 months, with progression-free survival rates of 68.5% at 1-year, 33.6% at 2-year, and 21.2% at 3-year, respectively. In a univariate analysis regarding progression-free survival, presences of metastasis to brain (p = 0.008), bone (p = 0.025), liver (p = 0.046), and adrenal (p = 0.008), decreased levels of hemoglobin (p = 0.021) and albumin (p = 0.017), and use of multiple chemotherapy regimens prior to treatment with gefitinib (p = 0.026) were significant factors. In a multivariate analysis using Cox proportional hazard model, presence of brain metastasis was a significant factor clinically affecting the late resistance to gefitinib (hazard ratio, 2.14; 95% CI, 1.10 to 4.17, p = 0.025). In addition, decreased hemoglobin level (p = 0.074) and prior multiple chemotherapy regimens (p = 0.069) were tended to be significant. Conclusions: In patients undergoing treatment with gefitinib, presence of brain metastasis was an important factor indicative of the emergence of late resistance in this study. It is needed to confirm this finding in a large cohort of patients with NSCLC. No significant financial relationships to disclose.
Factors impacting survival of patients with post-surgical disease recurrence in non-small cell lung cancer (NSCLC)
Authors: Banerji S. , Nugent Z. , Demers A. , Navaratnam S. 
Published: March 2020

7223 Background: There are no standard recommendations for follow-up of NSCLC patients post surgery. To be of value, follow-up should detect disease recurrence early enough to allow timely initiation of effective treatment leading to clinical benefit. Methods: Patients diagnosed with NSCLC in Manitoba, Canada, who underwent a surgical procedure at the two teaching hospitals between January 1996 and December 2001, were identified using the Cancer Registry. We included 435 patients who underwent complete surgical resection of pathologic Stage IA to IIB disease. To date, a detailed retrospective chart review has been completed on 249 of these patients. Median follow-up of this population was 3.45 years. Results: The median age was 66.4 years and 51% were male. 68% had Stage I disease. Lobectomy (73%) was more commonly performed over wedge resection (14%) and pneumonectomy (13%). The most frequent histological diagnosis was adenocarcinoma (52%) followed by squamous cell (29%) and bronchoalveolar carcinoma (13%). Disease recurred in 68% of patients. Recurrence was detected in 52 patients by routine imaging during follow-up. 117 had symptoms suggestive of disease recurrence prompting additional investigation. Median time to recurrence was 1.2 and 1.5 years (NS) respectively for the symptomatic and asymptomatic group. The median overall survival of the asymptomatic patients (4.19 years) was significantly (p = 0.007) greater than the symptomatic patients (2.66 years). Similarly, the median survival from the time of recurrence was greater for the asymptomatic patients (1.6 vs. 0.7 years, p = 0.004). A multivariate analysis identified symptoms (p = 0.02) at the time of recurrence and stage (p = 0.01) of the disease at the initial presentation as significant independent factors impacting overall survival. Only the absence of symptoms had a significant association (p = 0.006) with improved survival after diagnosis of recurrent disease. Conclusions: The diagnosis of recurrence while patients are asymptomatic resulted in better survival. This may suggest that routine post-surgical follow-up of patients with early NSCLC is justified. No significant financial relationships to disclose.