bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical antitumor activity of oral silibinin-meglumine in combination with erlotinib or gefitinib in the treatment of erlotinib- and gefitinib-resistant EGFR-mutant NSCLC mouse xenografts.
Authors: Bosch-Barrera Joaquim , Cufi Silvia , Vazquez-Martin Alejandro , Oliveras-Ferraros Cristina , Corominas-Faja Bruna , Bonavia Rosa , Visa Joana , Martin-Castillo Begoña , Barrajon-Catalan Enrique , Carcereny Enric , Micol Vicente , Menendez Javier A.
Published: March 2020

e19003

Background: Silibinin (SLB), a bioactive flavonolignan isolated from the dried fruits of milk thistle (Silybum marianum), suppresses the resistance to erlotinib (ERL) caused by the EGFR T790M mutation in NSCLC xenograft models. Poor water solubility and low bioavailability might severely limit the efficacy of SLB. The ability of SLB to overcome ERL resistance attributed to mechanisms other than the second-site EGFR mutations remains completely unexplored. Methods: Using PC-9 cells harboring the ERL-sensitizing EGFR exon 19-mutation ΔE746-A750, we developed ERL-refractory derivatives (PC-9 ERL-R) that lacked EGFR T790M mutation. An oral formulation of milk thistle extract enriched (30%) with a water-soluble form of SLB complexed with the excipient amino-sugar meglumine (SLB-m) was explored for its ability to inhibit the growth of PC-9 ERL-R xenografts. Results: In the absence of second-site EGFR mutations or the alternative activation of MET or AXL, acquired cross-resistance to ERL and GEF correlated with enhanced epithelial-to-mesenchymal transition (EMT) features. Single-agent SLB-m significantly decreased the overall tumor volumes of PC-9 ERL-R xenografts, which exhibited enhanced engraftment and faster growth compared with the ERL-/GEF-sensitive PC-9 parental xenografts. Combination treatment with ERL + SLB-m or GEF + SLB-m significantly suppressed tumor growth (> 90%) compared with single-agent treatment. The SLB-m treatment fully inhibited the development of an EMT phenotype in the ERL-/GEF-refractory cells in vitro. Systemic SLB-m treatment significantly affected the expression of EMT-related transcription factors in the ERL-/GEF-refractory xenografts. Conclusions: The oral administration of SLB-m delays tumor progression in ERL-/GEF-refractory EGFR-mutant NSCLC mouse xenografts. Given that the EMT phenomenon is required by a multiplicity of mechanisms of acquired resistance mechanisms to ERL, our data might facilitate the design of clinical trials to test the administration of SLB-m in combination with ERL or GEF in patients with EGFR-mutated tumors that progress to these drugs.
Dynamic treatment regimen analysis to determine which treatment sequence can prolong survival of NSCLC patients.
Authors: Koba Taro , Imamura Fumio , Morita Satoshi , Mori Masahide , Komuta Kiyoshi , Kijima Takashi , Namba Yoshinobu , Nishino Kazumi , Yamamoto Suguru , Takahashi Ryo , Nakazawa Yukie , Minami Seigo , Ogata Yoshitaka , Kumanogoh Atsushi
Published: March 2020

e19010^

Background: We often experience the re-challenge of EGFR-TKI on practice. However, it has not been reported which treatment sequence for EGFR-TKI re-challenge will contributes to long-term survival of NSCLC patients. Methods: We extracted information from retrospective cohort of advanced NSCLC patients with the following inclusion criteria: 1) Japanese patients who were diagnosed by October 2010 and treated with gefitinib after July 2002. 2) Performance status (PS) 0-2. 3) PR, CR, or long SD (6 months or more) by gefitinib. 4) Patients who had not received curative surgical operation or radiation therapy. The primary objective was to evaluate the effects of treatment histories on Overall Survival (OS). We also conducted a “Dynamic Treatment Regimen Analysis (DTRA)”. DTRA can be used to compare multiple treatment strategies/sequences in terms of time-to-event data like overall survival time. Results: A total of 335 NSCLC patient details were extracted. Sixty five patients experienced gefitinib re-challenge. There was a statistical difference in OS between gefitinib re-challenge group and non re-challenge group (median OS was 1272 days vs 774 days; p<0.001). We confirmed this result using DTRA, “Gefitnib-Singlet chemo-Gefitinib” treatment sequence extended survival most out of all treatment sequence. Conclusions: This study suggests that gefitinib re-challenge may have significant affects on OS in long survivors after responding gefitinib treatment. Clinical trial information: UMIN000006913. [Table: see text]
Which do patients prefer as a first-line therapy, EGFR-TKI or chemotherapy, if they have NSCLC harboring EGFR mutation? A Vignettes study (LOGIK0903).
Authors: Sasaki Jiichiro , Tokunaga Shoji , Suetsugu Takayuki , Ebi Noriyuki , Fukuda Minoru , Nagata Nobuhiko , Takayama Koichi , Tsuruta Nobuko , Ishida Masayuki , Nishida Chinatsu , Kashiwabara Kosuke , Akamine Shinji , Komiya Kazutoshi , Nakagaki Noriaki , Kishi Hiroto , Seto Takashi , Saeki Sho , Uchitomi Yosuke , Ichinose Yukito ,   Lung Oncology Group in Kyushu, Japan
Published: March 2020

e19016

Background: Treatment decision-making is associated with potential decisional conflict of patients. Aim of this study was to determine the preferences of advanced NSCLC patients for EGFR-TKI or chemotherapy as first-line therapy if they were in the situation of having a lung cancer harboring EGFR mutation, and to investigate the variables considered important to that preference. Methods: Three vignettes were designed to assess the patients’, the physicians’ or medical staff members’ preferences for treatment decision-making and the reasons classified into five category such as “evidence level”, “type of drug administration”, “therapeutic efficacy”, “adverse events”, and “influence to ordinary life” behind the decision. HADS, FACT-L and characteristics of participants including gender, age, and performance status (PS) are also investigated in this analysis. Results: Total 377 individuals containing 100 patients, 100 physicians, and 177 medical staff members were analyzed in this study, and 322 participants (85.4%) preferred to EGFR-TKI than chemotherapy as a first-line therapy. Preference rate of EGFR-TKI in patients was statistically significantly lower than those in physicians and medical staffs, 73%, 88% and 91%, respectively. Among the reasons we investigated, “therapeutic efficacy” was the only marginal significant reason for preference in patients (odds ratio: 3.88, p=0.06). In addition to “therapeutic efficacy”, “type of drug administration” and “influence to ordinary life” was the significant reasons for their preference in physicians (odds ratio: 11.57, 22.57 and 20.5, respectively). In pre-planned analysis, we found the difference of value between the patients and the physicians in “influence to ordinary life”. Conclusions: If the patients have an advanced lung cancer with EGFR mutation, they may prefer EGFR-TKI as a first-line therapy to chemotherapy as well as physicians and medical staff members. However the reasons of those preferences among them may be different. We should consider continuation of patients’ ordinary life when we discuss about treatment decision-making with patients. Clinical trial information: UMIN000003532.
Phase II, open-label study of erlotinib (ERL) in patients with NSCLC with activating mutations of the EGFR identified on tissue samples, plasma DNA, and CTC-trigger.
Authors: Crino Lucio , Santoro Armando , Chella Antonio , Barbieri Fausto , Venturino Paola , Marchetti Antonio , Milella Michele , Brandes Ariela , De Pas Tommaso
Published: March 2020

e19020

Background: Patients (pts) with advanced NSCLC and activating mutations of EGFR represent a biologically distinct disease that shows exquisite sensitivity to the reversible EGFR-TK inhibitors (TKIs) as ERL, demonstrated in phase III randomized studies. Unfortunately, tumor tissue needed for mutation analysis is in some cases insufficient for an accurate molecular characterization of the tumor before treatment and re-biopsies after treatment are challenging. Therefore it is crucial to develop new diagnostics techniques. Methods: Pts with histologically or cytologically confirmed stage IIIB/IV NSCLC, previously untreated with chemotherapy who present activating mutations of EGFR received ERL 150 mg/d until PD. The primary endpoint was 12-month PFS. Secondary endpoints included: ORR; OS; correlation between EGFR testing results obtained from basal tumor biopsies, from circulating tumor cells (CTC), from plasma DNA and by immunoistochemical detection; primary and secondary resistances and correlation to response and safety and tolerability. Results: Between 03-2011 and 11-2012, a total of 50 pts were enrolled from 7 centers. Median age was 63 years; 98% had adenocarcinoma, 54% had never smoked and 68% were female. Exon 19 deletions were more common (70%) than exon 21 (30%). EGFR screening methods applied at a site level were different: pyrosequencing (41%), Sanger (29%), SSCP (8%), Pyrosequencing and DNA melting (4%) and others (18%). Central evaluation confirmed the presence of an EGFR mutation in all cases. EGFR testing from CTC and from plasma DNA resulted feasible. EGFR mutations were identified by next generation sequencing in CTC preparations from 31 (84%) of 37 pts so far examined, corresponding to those present in matching tumor tissue. Treatment discontinuation was observed in 25 pts, mainly due to PD (30%) and death (10%). Results of plasma DNA and of immunoistochemical detection at baseline are ongoing as well as analysis on CTC and plasma DNA at progression. Conclusions: This trial confirms the feasibility of new diagnostics techniques and will help in improving understanding in the resistance mechanisms to EGFR TKIs. Clinical trial information: EudraCT Number: 2010-023892-24.
Phase II study of bevacizumab (Bv) in combination with paclitaxel-carboplatin (PC) as first-line chemotherapy for nonsquamous (SQ) non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE).
Authors: Tamiya Motohiro , Hirashima Tomonori , Tamiya Akihiro , Okamoto Norio , Suzuki Hidekazu , Yamadori Tadahiro , Morishita Naoko , Shiroyama Takayuki , Otsuka Tomoyuki , Kitai Kanako , Yasue Tomomi , Asami Kazuhiro , Minomo Shojiro , Sonobe Syoko , Nakao Keiko , Kawaguchi Tomoya , Atagi Shinji , Kawase Ichiro
Published: March 2020

e19021

Background: Vascular endothelial growth factor (VEGF) plays an important role in NSCLC with MPE, but the evidence regarding the efficacy of Bv with PC for treatment of NSCLC with MPE is lacking. Therefore, we prospectively evaluated the efficacy and safety of Bv and PC in non-SQ NSCLC pts. Methods: Chemotherapy-naive non-SQ NSCLC pts with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. The treated pts received PC without Bv in the first cycle to prevent Bv-induced delayed wound healing after chest drainage. Subsequently, they received 2–6 cycles of PC with Bv. Patients who completed more than 3 cycles of PC and Bv without disease progression or severe toxicities continued to receive Bv alone as a maintenance therapy. The primary endpoint was overall response, although an increase in MPE was allowed in the first cycle. The plasma and MPE VEGF levels were measured at baseline and the plasma VEGF levels after 3 cycles of chemotherapy. Results: Between September 1, 2010 and June 30, 2012, 23 pts were enrolled. The overall response rate was 60.8%, and the disease control rate was 87.0%. No pts showed complete response, 14 showed partial responses, 6 showed stable disease, 2 showed disease progression, and 1 died in the first cycle. Sixteen pts received maintenance therapy, following a median of 3 cycles. The median progression-free survival period for all pts was 200 days (95% CI, 156–263 days), whereas the median overall survival was 328 days (95% CI, 206–415 days). All pts experienced high levels of hematological toxicities, with most pts experiencing neutropathic toxicities above grade 3. However, none of the pts experienced severe bleeding events. The median baseline MPE VEGF level was 1798.6 (range, 223.4–35,633.4) pg/mL. The plasma VEGF levels showed a significant decrease after 3 chemotherapy cycles (baseline, 513.6 ± 326.4 pg/mL; post-chemotherapy: 25.1 ± 14.1 pg/mL; p < 0.01), regardless of the degree of efficacy. Conclusions: The combination of PC with Bv was confirmed to be effective and reasonably well-tolerated in chemotherapy-naïve non-SQ NSCLC pts with MPE. Clinical trial information: UMIN000005284.
Pharmacogenetic study of Japanese patients with advanced nonsquamous non-small cell lung cancer treated with pemetrexed plus cisplatin.
Authors: Imai Hisao , Serizawa Masakuni , Takahashi Toshiaki , Mori Keita , Ono Akira , Akamatsu Hiroaki , Taira Tetsuhiko , Nakamura Yukiko , Kenmotsu Hirotsugu , Naito Tateaki , Murakami Haruyasu , Koh Yasuhiro , Endo Masahiro , Nakajima Takashi , Yamamoto Nobuyuki
Published: March 2020

e19050

Background: Pemetrexed (PEM) inhibits multiple enzymes in the folate (F) pathway. Several studies show that genetic polymorphisms in these enzymes influence the efficacy and toxicity of PEM. We aimed to investigate the relationship between genetic polymorphisms associated with the F pathway and clinical outcomes of Japanese patients with advanced non-squamous non-small cell lung cancer (NSQ-NSCLC) treated with PEM plus cisplatin (CIS). Methods: We analyzed 38 polymorphisms in 15 genes associated with the F pathway in NSQ-NSCLC patients treated with PEM plus CIS: ABCC11, ADA, ATIC, CBS, DHFR, ERCC1, FPGS, GGH, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS. These polymorphisms were compared with clinical outcomes such as response, toxicity, and progression-free survival (PFS) using Pearson’s χ2 test and the log-rank test. Results: All 56 patients were Japanese, with a median age of 62 years; 57.1% were male, 96.4% had an Eastern Cooperative Oncology Group Performance Status of 0–1, 96.4% had stage IV disease, and 94.6% had adenocarcinoma. The response rate, disease control rate, and median PFS were 32.2%, 78.6%, and 4.7 months, respectively. Of the 38 polymorphisms tested, none were associated with response or toxicity, but 2 single nucleotide polymorphisms (SNPs) (in the gamma-glutamyl hydrolase [GGH 452C>T] and methionine synthase [MTR 2756A>G] genes) were significantly associated with PFS. Patients harboring the GGH-C452C variant had significantly longer PFS (5.6 vs 2.8 months; p < 0.0001) than those with the C452T or T452T variants. Further, patients harboring the MTR-A2756A variant had significantly longer PFS (5.3 vs 3.7 months; p = 0.036) than those with the A2756G variant. In addition, among patients with the GGH-C452C variant, those harboring the MTR-A2756A variant had significantly longer PFS (5.9 vs 4.3 months; p = 0.044) than those with the A2756G variant. Conclusions: SNPs in GGH and MTR seem to predict differences in PFS in NSQ-NSCLC patients treated with PEM plus CIS, and a combination of these 2 SNPs may predict differences in PFS more accurately. These results should be validated in larger, adequately designed prospective studies.
Comparison of clinical outcome between gefitinib and erlotinib treatment in patients with non-small cell lung cancer harboring an epidermal growth factor receptor exon 19 or exon 21 mutations.
Authors: Lim Sung Hee , Lee Ji Yoon , Sun Jong-Mu , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju
Published: March 2020

e19051

Background: Gefitinib and erlotinib are small-molecule kinase inhibitors that inhibit signaling via EGFR and both agents showed dramatic response rate and prolonged PFS in patients harboring activating EGFR mutation. We investigated the clinical outcomes between gefitinib- and erlotinib-treated patients with recurrent or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations. Methods: A total 375 patients with recurrent or metastatic NSCLC who had either an exon 19 deletion or L858R mutation on exon 21 and received gefitinib (n=228) or erlotinib (n=147) therapy between August 2007 and December 2011 were retrospectively reviewed. By using a matched-pair case-control study design, 121 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, smoking history, ECOG performance status, and types of EGFR mutation. Results: The median age of all patients was 58 years (range, 30-84) and more than half of patients were never smokers (63.6%). Most patients had adenocarcinoma (98.3%) and good ECOG performance status (0, 1) (90.9%). Of 242 patients, 64 (26.4%) received an EGFR TKI as first line therapy. The overall response rates and disease control rates in the gefitinib-treated and erlotinib-treated groups were 85.5% versus 79.8 % (p=.375) and 94.0% versus 89.1%, respectively (p=.242). There was no statistically significant difference noted with regard to OS (median, 38.9 vs 37.5; p=.642) and PFS (median, 12.9 vs 10.1; p=.135) between the gefitinib-treated and erlotinib-treated groups. For a subgroup which patients were treated with TKI as first line therapy, the overall response rates were higher than those of patients who had progressed on prior chemotherapy (90.3% vs 79.9%; p=.063). However, there was no significant difference in PFS (median, 13.3 vs 10.3; p=.134) between subjects with first line TKI therapy and more than second line treatment. Conclusions: Both gefitinib and erlotinib showed similar effective activity in selected population of NSCLC that harbored an EGFR mutation and further studies are needed to evaluate the efficacy of EGFR TKI as first line treatment.
Survival versus intrinsic and acquired resistance in advanced non-small cell lung cancer.
Authors: Stewart David J. , Saintigny Pierre , Goss Glenwood D. , Lu Charles
Published: March 2020

e19066

Background: While advanced NSCLC responds to platinum-based therapy (PBT), intrinsic and acquired resistance limits efficacy. We assessed impact of resistance patterns on overall survival (OS). Methods: Using serial measurements of tumor diameters from 130 NSCLC patients on PBT, we calculated % incremental change in tumor size compared to the most recent prior scan and % overall change from pre PBT. Results: 98/130 (75%) had measurable tumor shrinkage (TS) at 1st repeat scan (RS) post 2 cycles, of whom 81 had a 2nd RS post 4 cycles. Of these, 20 (25%) had tumor growth (TG) at the 2nd RS. Only 1 had initial TG then followed by TS. Of 41 with a 3rd RS <4 weeks post cycle 6, 13/41 (32%) had TG. The greatest % incremental TS (compared to most recent prior scan) was seen early (at 1st RS) for 76% of patients. Rate of TS decreased with later cycles in these patients. 11 patients had rapid TS on 1st RS, then gradual further shrinkage over >3 subsequent scans, while 15 had progressive gradual TS over >4 scans without initial rapid TS. By Spearman coefficients, maximum % TS from pre PBT over all scans correlated with OS (r=0.46, p<0.0001), time to progression (TTP) (r=0.69, p<0.0001) and post-progression survival (PPS) (r=0.30, p=0.001). TTP also correlated with OS (r=0.63, p<0.0001), TTP correlated with PPS (r=0.44, p<0.0001), and OS correlated with PPS (r=0.95, p<0.0001). Median OS (11.0 months for all patients) varied with TS pattern (p<0.0001): OS for patients with first TG at 1st, 2nd, 3rd and 4th RS was 5.9, 10.8, 10.5 and 15.1 months. OS was 18.2 months in patients with most TS at 1st RS followed by gradual further TS over later scans, and was 30.5 months with progressive gradual TS without rapid TS at 1st RS. OS with RECIST partial response (23% of patients), minor TS (52%), minor TG (13%) and RECIST progressive disease (13%) was 16.9, 12.4, 9.8 and 4.0 months (p<0.0001). Conclusions: OS, TTP and PPS correlate strongly with response (degree of TS/TG) and with resistance pattern. OS is longest with progressive further TS over multiple scans. Within this group, partial acquired resistance (decreased TS rate after initial rapid TS) has shorter OS than with sustained incremental TS. The underlying biological factors driving clinical resistance remain undefined.
SUV max of the most intense lesion on fdgpet/CT scan at baseline as a potential prognostic factor in stage IV (NSCLC): A retrospective review.
Authors: Kodali Manga Devi , Takalkar Amol , Shi Runhua , Peddi Prakash , Mills Glenn Morris , Jafri Syed Hasan Raza
Published: March 2020

e19070

Background: Lung cancer is the leading cause of mortality in United States and worldwide. Stage IV lung cancer has poor prognosis with 5-year survival of 2%. Limited numbers of factors are known to predict survival in stage IV NSCLC (Non Small Cell Lung Cancer) including stage at diagnosis, Performance Status (PS), genomic expression profile. Earlier studies have found SUV max (Maximum Standardized Uptake Value) of primary lung tumor on FDGPET/CT (Fluoro Deoxy Glucose –Positron Emission Tomography/Computed Tomography) correlates with tumor doubling time and survival. However prior studies included stage I-IV NSCLC patients and SUVmax of primary lung tumor. Hence we performed this study with only clinical stage IVNSCLC who underwent FDGPET/CT scan at baseline to determine whether SUVmax value of most intense lesion has any prognostic significance. Methods: Retrospective review identified 46 patients (September 2004- September 2011) that were diagnosed with stage IV NSCLC at our institution. SUVmax of most intense lesion on FDG PET/CT scan was determined utilizing an automated program on a dedicated PET/CT workstation by a single nuclear medicine specialist. Cox regression analysis and Log-rank test were used to analyze data. Results: Descriptive statistics: Median age 61.6 (43.8-77.8), Females 17 (36%), African Americans 26 (56%), Performance status 0-1=36 (80%), number of metastatic sites 1-2=30 (65%), Adenocarcinoma 32 (70%), Chemotherapy 31 (61%), SUV max- primary (65%), other sites (35%). The patient population was subdivided into two groups using the median SUVmax of 17.8. The median survival of patients having SUV max ≤17.8 and SUVmax > 17.8 was 13.4 months and 4.5 months respectively (P =0.0269). Multivariate analysis indicated PS (HR=2.8), any chemotherapy (HR=2.56) and SUV max ≤ 17.8 (HR=1.98, P=0.04) predicted survival. Conclusions: SUV max of the most intense lesion at the time of presentation predicts worse outcome in stage IVNSCLC and needs to be validated in a prospective study. PETCT may be able to predict the areas that harbor resistant clones of cells, described in previous studies as tumor heterogeneity, which may confer prognostic significance.
Clinical impact of EGFR mutation fraction and tumor cellularity in EGFR mutation positive NSCLC.
Authors: Martin Petra , Shiau Carolyn Jane , Pasic Maria D , Tsao Ming Sound , Kamel-Reid Suzanne , Le Lisa , Higgins Brian Patrick , Cheng Susanna Y. , Burkes Ronald L. , Ng Matilda , Arif Saroosh , Roxana Tudor , Lin Stephanie Chen Xing , Ellis Peter Michael , Hubay Stacey , Kuruvilla Sara , Laurie Scott Andrew , Li Jing , Shepherd Frances A. , Leighl Natasha B.
Published: March 2020

e19077

Background: We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival in advanced EGFR mutation positive NSCLC patients. Methods: From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutation. Patients with EGFR mutation positive samples were identified, tumour cellularity, mutation fraction (percent tumour cells mutated) and clinical outcome data collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour cellularity and sample type on clinical outcomes. Results: Of 173 patients identified to date, 153 received EGFR TKI and are included in this analysis, with median follow up of 10.6 months (range 0-44). Most are female (73%), never smokers (65%), have exon 19 deletions (55%; 45% exon21 L858R), and median age 64 years (range 34 to 95). Tumour specimens tested include resection (36%), cytology (32%), and core biopsy samples (32%). Median EGFR mutation fraction is 30% (range 1% to 96%); 18% had a low (<10%) mutation fraction. Responses (any reduction) were seen in 66%, mixed response or stable disease in 28%, and progression in 7%. Median TTF of EGFR TKI therapy is 13.8 months. Median OS from TKI start is 24.1 months, with 1-, 2- and 3-year rates of 75%, 51% and 42%. In multivariable analysis, increasing mutation fraction was associated with EGFR TKI response (OR 2.5, p<0.01), but not TTF or OS. Female sex was associated with TTF (HR 0.49, p=0.007), and testing of larger samples (lobectomy, wedge, excision) was associated with TTF and OS (HR 0.45, p=0.007; HR 0.26, p=0.0002). Exon 19 deletions are associated with a higher risk of death (HR 2.41, p=0.02) and a lower probability of response than L858R (OR 0.31, p=0.004). Conclusions: Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, specimen tested and mutation type. Validation of the use of EGFR mutation fraction in clinical decision-making is ongoing.
Extensive surgical resection in stage IV non-small cell lung cancer patients after tailored chemotherapy.
Authors: Guo Huiqin , Zhao Yu , Lu Jiangyang , Christiani David C. , Lin Xihong , Wang Zhaoxi
Published: March 2020

e19080

Background: The treatment of stage IV non-small cell lung cancer patients is a problem for thoracic surgeons and the optimal treatment is discussed controversially. ERCC1, class III β-tubulin, p53, and RRM1 are predictive molecular biomarkers reported for neoadjuvant chemotherapy. Here we report a prospectively enrolled case series that patients were treated with extensive surgical resection after personalized chemotherapy tailored by these 4 markers. Methods: Patients with previously untreated stage IV NSCLC, ECOG PS of 0-2 were enrolled. The expression of ERCC1, class III β-tubulin, p53, and RRM1 was tested with IHC staining method for the tumor samples by bronchoscopy biopsy or percutaneous lung biopsy. Patients were treated with 2 of four drugs including cisplatin, taxol, gemcitabine and vinorelbine, selected by the expression of ERCC1, class III β-tubulin, RRM1 and p53, respectively. Then patients received surgical resection after evaluation with continuing adjuvant chemotherapy. A follow-up CT was performed after every 2 cycles chemotherapy and every 3 months post chemotherapy. PFS and OS were estimated by the Kaplan-Meier method. Results: 26 patients were included from May 2008 to Dec 2011 with a follow-up period 12–58 months till Nov 2011. 8 (30.8%) patients died within Follow-up period. The overall response (CR+PR) rate of tailored neoadjuvant chemotherapy was 88.5% with 23 PR. A complete resection (R0) was achieved in 24 (92.3%) patients and R1 in 2 (7.7%) patients. Median PFS was 27.0 months (95% CI: 21.0–32.9 months) and median OS was 41.6 months (95% CI: 23.1–60.0 months). Conclusions: Our study suggest extensive surgical resection in stage IV non-small cell lung cancer patients after tailored chemotherapy should be performed because it may improve survival dramatically over conservative chemotherapy. Surgery within multimodality approach will be a promise treatment option in the future.
Bevacizumab (Bv) in non small cell lung cancer (NSCLC) patients ≥75 years old with pre-existing cardiovascular disease (CVD): Experience at a tertiary referral center.
Authors: Strimpakos Alexios S , Vassos Demetrios , Panagiotarakou Meropi , Syrigos Konstantinos N.
Published: March 2020

e19087

Background: Bv is a novel anti-angiogenic agent used in many advanced solid tumours, including non-squamous NSCLC. In contrast to clinical studies where enrolled pts are fit, many elderly NSCLC pts suffer from co-morbidities and often have history of a CVD. Methods: Medical records of 2,672 pts diagnosed with NSCLC between 2001-2012 were screened. We identified and examined pts ≥75 yrs old treated with Bv, for their demographics, clinical data and treatment (Tx) details. We focused on those elderly pts with stable pre-existing cardiovascular disease. Results: 356/2672 NSCLC pts received Bv at any Tx line. 33/356 (9.2%) were ≥75 yrs old. Of those, 29 had various co-morbidities including 19 pts with stable CVD on medical Tx. In the 19 pts with CVD the male:female ratio was 17:2 and median age 76 yrs (range 75-86). 8/19 pts had impaired renal function. All pts were of Performance Status ECOG 0/1. Median number of Bv cycles was 5 (range 2-11). 17/19 pts experienced ≥1 side effects (11 epistaxis and haemoptysis, 5 proteinuria, 4 hypertension) which led to treatment discontinuation in 5 pts. No major/fatal adverse events were noted. 8/19 pts (42%) showed radiological partial response and 5 (19%) stable disease (total disease control rate 61%). Median survival from initiation of Bv till death/last follow up was 7 months (range 2-28, 95% CI 5.14-12.55). Conclusions: Treatment with Bevacizumab seems to be safe and effective in elderly NSCLC patients with controlled pre-existing cardiovascular disease and good PS. These patients might benefit from participation in clinical trials similarly to younger NSCLC patients.
Effectiveness of erlotinib in lung adenocarcinomas with classic and alternative EGFR mutations detected by Roche 454 GS-FLX next-generation sequencing (NGS).
Authors: Ostoros Gyula , Sarosi Veronika , Mandoky Laszlo , Pinter Ferenc , Schwab Richard , Petak Istvan , Urban Laszlo
Published: March 2020

e19090^

Background: Next generation sequencing (NGS) detects all possible mutations with a higher sensitivity than Sanger sequencing. EGFR mutations are important predictors of sensitivity and resistance to EGFR tyrosine kinase inhibitors including erlotinib. The clinical significance of alternative (“rare”) EGFR mutation types, and mutation present in a small fraction of tumor cells detected by NGS is less known. Methods: For the present retrospective analysis, 100 lung adenocarcinoma tumor samples were collected from patients who participated in a previous observational cohort study of erlotinib (MOTIVATE). In this study only patients with advanced (IIIb/IV) K-RAS wild type tumors refractory to one or two previous chemotherapy were enrolled. Four exons (18, 19, 20, 21) of EGFR gene were PCR amplified and sequenced by Roche 454 GS FLX sequencer. Differences in overall survival (OS), and progression free survival (PFS) were statistically analyzed (Log Rank). Results: 47 mutations of the EGFR tyrosine kinase domain were detected in the 35 out of 100 tumors. 14 mutations were present in less than 10% of alleles. 16 tumors contained known („classic”) sensitizing mutations: nine deletions in exon 19, five L858R, one L861Q mutation in exon 21, one G719A mutation in exon 18 and one known resistance mutation D770_N771insY in exon 20. 18 tumors contained only alternative mutations with unknown functional relevance. The median PFS of patients with tumors harbouring EGFR wild type gene, classic EGFR mutations and alternative mutations were 2.9 months, 13.2 months (p<0.001) and 3.0 months (P=0.43) respectively. The median OS of patients with tumors containing wild type EGFR tumors, and alternative mutations was 7.2 and 5.5 months respectively (P=0.68). The median OS of patients harbouring classic EGFR mutations was not reached. The mean OS of these patients was 29.0 months. Conclusions: NGS is a sensitive and reliable diagnostic method to detect EGFR mutations with known functional significance. Alternative mutations need further one by one functional interpretation and analytical validation before being used as positive predictors in clinical decisions.
Gefitinib combined biologic therapy for advanced lung adenocarcinoma.
Authors: Li Baoping , Zhang Lei
Published: March 2020

e19098

Background: Gefitinib is an effective treatment for non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations. However, due to the limited genetic testing methods and other constraints, a large proportion of patients did not benefit from it. In order to overcome the limitation of genetic testing and other constraints, we use gefitinib with the immune-biotherapy to treatment advanced lung adenocarcinoma. Methods: From February 2011 to December 2012, we use gefitinib combined with immune-therapy to treat 59 cases with advanced lung adenocarcinoma. These patients completes at least one cycle of therapy. The efficacy and quality of life were investigated. The prognostic factors were analyzed using Cox regression model. Results: CRF0, PR:46, SD:13, the PD:0. The overall response rate = 77.97%. FACT-L: 100%. The response rate and scores of quality of life are higher than the reported data. COX regression analysis showed that the complete remission after the treatment is significant factor(P <0.01), but the factors such as the disease control status, gender, tumor stage, smoking history were not significant. Conclusions: Gefitinib and biological therapy combined, can significantly improve short-term effect of advanced lung adenocarcinoma. Its possible mechanism of gefitinib to reduce interstitial fluid pressure may increase immunocompetent cells into the tumor tissues, thereby enhancing efficacy.
Erlotinib as a salvage treatment for patients with advanced non-small cell lung cancer after failure of gefitinib treatment: Is there a rationale for a clinical trial?
Authors: Salesi Nello , Di Cocco Barbara , Calabretta Francesca , Ciorra Alida Armida , Cirino Crescenzo , Cauchi Carolina , Pistillucci Giorgio , Sciacca Venerina , Rossi Rosalinda , Veltri Enzo
Published: March 2020

e19099

Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated pts resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Methods: Retrospective review of 5 EGFR mutated (exon 19 deletions) patients that were given gefitinib and subsequently erlotinib. Results: All pts responded to gefitinib with median progression-free survival of 13 months (95% confidence interval, 4-16). After gefitinib resistance, 60% (3 of 5) of these pts displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). These pts acquired the T790M mutation. 2 gefitinib-resistant pts with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. In literature doesn’t exist a prospective study about the stratification of pts ordered by PS, age, gender, smoker/non-smoker, which could test the efficiency of the erlotinib after gefitinib in pts with different EGFR mutations. We only have at our disposal few studies control-case in non-selected pts which show a potential efficiency of erlotinib after the failure of the gefitinib, nevertheless, without an evident increase of the overall survival. Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most pts. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.
EGFR-activating mutations and treatment with tyrosine-kinase inhibitors (TKI) to revert poor-prognosis (PP) associated with liver metastases (LM) in stage IV non-small cell lung cancer (NSCLC) patients (pts).
Authors: Castanon Eduardo , Lozano Maria D. , Fusco Juan Pablo , Arevalo Estefania , Carranza Omar Esteban , López-Picazo José María , Perez-Gracia Jose Luis , Gurpide Alfonso , Gil-Bazo Ignacio
Published: March 2020

e19106

Background: LM appear in 20-30% of pts diagnosed with NSCLC and they confer PP. However, whether the clinical outcome of NSCLC pts with LM harboring molecular alterations in EGFR, KRAS and EML4-ALK genes is substantially different depending on their distinct status is still unknown. Methods: A total of 268 consecutive stage IV NSCLC pts were included. The tumor molecular analysis for EGFR, KRAS and EML4-ALK was available in 205 pts (76.5%), 136 pts (50.7%) and 31 pts (11.6%), respectively. An EGFR mutation was observed in 32 pts (15.6%), KRAS was mutated in 28 pts (20.6%) and EML4-ALK gene rearrangement was observed in 3 pts (9.6%). We aimed to determine whether the molecular status of EGFR, KRAS and EML4-ALK has an impact on the clinical outcome of stage IV NSCLC pts. Results: Most of the pts were men (71.3%). The most common histology was adenocarcinoma (59.3%). Overall, 34% of the pts showed LM at any time of the disease course. Among the whole cohort, median OS for LM pts was 16 months vs 42 months for pts with metastases other than LM (p<0.001). Among pts with LM and EGFR mutations, the one-year survival rate was 85.7% vs 54.3% for pts with LM and EGFR wild-type (p=0.03). We analyzed whether pts received EGFR TKI or standard chemotherapy (SC). For the subgroup of pts carrying EGFR mutations and receiving TKI, the 18-month survival rate was 75% for those showing LM vs 80% (p=0.44) for those without LM. In contrast, for the subgroup of EGFR wild-type pts receiving SC, the 18-month survival rate was 32.4% for those showing LM vs 74.9% for those without LM (p<0.001). No impact of KRAS or EML4-ALK molecular alterations on OS of pts with LM was observed. Conclusions: The presence of LM at any time of the disease curse negatively impacts on the clinical outcome of NSCLC pts. However, the presence of EGFR activating mutations significantly improves the OS of those with liver spread, reaching a similar OS to subjects with no LM. Pts with EGFR mutations and LM may revert the PP associated to LM when an EGFR TKI is prescribed.
VEGF-A 165 family of isoforms as predictive biomarkers in patients with nonsquamous non-small cell lung cancer (NSCLC) treated with bevacizumab.
Authors: Garcia-Foncillas Jesus , Domine Manuel , Rojo Federico , Hernandez Tatiana , Zazo Sandra , Serrano Gloria , Chamizo Cristina , Carames Cristina , Carvajal Nerea , Moreno Irene , Perez-Gonzalez Nuria , Leon Ana , Auz Carmen Laura , Martin-Valades Jose Ignacio , Madoz Juan , Lobo Francisco
Published: March 2020

e19109

Background: Bevacizumab is a recombinant monoclonal humanized antibody to vascular endothelial growth factor (VEGF) that improves Time to Progression (TTP) in patients with advanced non-squamous NSCLC in combination with a doublet of platins, but currently no proven predictive markers exist. The VEGF-A 165 splice variant has been described as the most abundant and active isoform in cancer. Exon 8 splice modifications of VEGF 165 generates the VEGF-A 165a family of isoforms, which has a pro-angiogenic effect, and VEGF-A 165b family, with an anti-angiogenic activity. This study is aimed to explore the role of VEGF165a and VEGF165b expression in tumors as predictive biomarkers of efficacy in patients with NSCLC treated with platins plus bevacizumab. Methods: 22 patients were included (20 adenocarcinomas and 2 large cell carcinomas): 5 received carboplatin-taxol-bevacizumab, 14 carboplatin-taxotere-bevacizumab and 3 cisplatin-gemcitabine-bevacizumab. Total RNA was isolated by RNeasy FFPE procedure. VEGF165a and VEGF165b expression was analyzed by RT-qPCR using appropriate specific primers and probes. Individual VEGF165a and VEGF165b family of isoforms expression was calibrated to normal tissue and the ratio between both isoforms was calculated. Results: VEGF165a overexpression was detected in 14 (63.6%) cases and VEGF165b overexpression in 15 (68.2%). Individual overexpression for each family of isoforms was not predictive of benefit to bevacizumab therapy (p=0.933 and 0.166). However, the ratio between VEGF165a and VEGF165b was associated with TTP, correlating a predominant expression of pro-angiogenic VEGF165a with a significant benefit compared with cases with predominant VEGF165b expression (median TTP, 15 vs. 8 months respectively, p=0.005). The expression of both isoforms did not impact on OS (p=0.477). Conclusions: The overexpression of VEGF165a and low expression of VEGF165b family of isoforms correlated with benefit to anti-angiogenic therapy in NSCLC patients, supporting a potential use as predictive biomarkers for bevacizumab treatment in stage IV non-squamous NSCLC.
Thymidylate synthase (TS) polymorphisms (Pol) in buffy coat-derived genomic DNA as a clinical outcome predictor in non-Asian stage III/IV non-small cell lung cancer (NSCLC) patients (pts) receiving pemetrexed (Pem).
Authors: Arevalo Estefania , Lopez Ines , Fotuño Maria Antonia , Castanon Eduardo , Collado Victor , Rodriguez Maria , Olarte Alicia , Andueza Maria Pilar , Perez Gracia Jose Luis , Patiño-García Ana , Gil-Bazo Ignacio
Published: March 2020

e19112

Background: TS is the main biological target of the antifolate Pem. Some TS Pol may confer a short survival and a poor response to antifolate-treated colo-rectal cancer pts. Whether TS genotype has an independent prognostic/predictive impact on non-Asian advanced NSCLC pts treated with Pem is unknown. Methods: Twenty-five non-Asian advanced NSCLC pts treated with Pem-based regimens (1st, 2nd or 3rd line) were included. Genomic DNA was isolated from periferal blood prior to treatment. The variable number of tandem repeat (VNTR) Pol, the G>C single nucleotide Pol (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) Pol were analyzed and correlated with response rate (RR), progression-free survival (PFS), overall-survival (OS) and toxicity (Tx). Results: Regarding the VNTR Pol, most of the pts showed 2R/2R or 3R/2R Pol (17 pts; 68%), and 8 pts (32%) showed 3R/3R or 3R/4R Pol. A SNP (G>C) in VNTR was observed in 18 pts (72%). The Pol found in the 3´UTR region were +6/+6 in 12 pts (48%), +6/-6 in 11 pts (44%) and -6/-6 in 2 pts (8%). In the subgroup of T3-T4 pts, there was a higher RR among those showing 3R/3R Pol than those with 2R/2R Pol (100% vs 83.8%; p=0.029). The genotype +6/+6 predicted a higher RR among active/former smokers (A/FS) compared to +6/-6 (100% vs 37.5%; p=0.026). A 3R/3R Pol followed by 2R/2R and 2R/3R Pol predicted a superior RR in pts with EGFR mutations (p=0.018). Overall, a trend towards a better PFS in pts showing 2R/2R Pol was found (p=0.076). The cohort’s median overall survival (OS) was not reached during follow-up. The most frequent Tx was grade (G)1 anemia (28%) and nausea (20%) and G2 leucopenia (40%). G3-4 anemia (4%), leucopenia (16%), neutropenia (4%), astenia (8%) and dyspnea (4%) were uncommon but more frequent in pts with 2R/2R Pol (p=0.545). Conclusions: In this cohort of NSCLC pts 3R/3R Pol among T3-T4 pts and EGFR mutant pts and +6/-6 bp among A/FS significantly predicted a higher RR to Pem and may aid in treatment selection. Tx was not significantly correlated with a specific TS genotype. These interesting preliminary data warrant further validation in larger series.
Thyroid transcription factor 1 (TTF-1) and overall survival in wild type EGFR patients treated with erlotinib.
Authors: Fidler Mary J. , Basu Sanjib , Hensing Thomas A. , Buckingham Lela , Pool Mark , Mahon Brett , Batus Marta , Walters Kelly Kaiser , Bonomi Philip D.
Published: March 2020

e19113

Background: TTF-1 is a transcription factor involved in regulating epithelial to mesenchymal transition. TTF-1 has a favorable prognosis in early stage lung adenocarcinoma, although it’s prognostic value in erlotinib treated patients remains unknown (Somaiah ASCO 2011). The goal of this study was to validate the relationship between TTF-1 expression and clinical outcomes in wild-type (WT) stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib. Methods: Pts that received erlotinib were retrospectively analyzed by IHC for TTF-1 expression (positive = greater than 5% of tumor cells with moderate (2+) or strong (3+) nuclear staining). Pts’ tumors were considered WT if no mutations were detected in Exon 19 or L858R (Exon 21) using single-strand conformation polymorphism and sequence-specific polymerase chain reaction (PCR). Log Rank was used to correlate TTF-1 positivity with outcomes. Results: 216 pts were analyzed. EGFR activating gene mutations were found in 11.6% of cases. TTF-1 positivity was strongly correlated with the presence of an activating EGFR mutation (p=.0006, negative predictive value=97.7%). Of WT pts: median age was 65, 61% female, 15% never smokers. TTF-1 was positive in 8% of squamous cell and 71% of adenocarcinoma pts. In EGFR WT pts, the median progression free survival (PFS) in TTF-1 positive and negative pts was 2.1 vs. 1.6 months respectively, p=.255. TTF-1 strongly correlated with prolonged overall survival (OS) on erlotinib therapy in WT pts (6.2 vs. 3.2 months, log rank p=.004). After excluding for squamous cell histology, in TTF-1 positive EGFR WT pts there was still a highly significant correlation with prolonged OS on erlotinib (6.2 vs. 2.8 months, p=.001) and a trend toward prolonged PFS (2.2 vs. 1.4 months, p=.05). Conclusions: TTF-1 is related to the presence of exon 19 and 21 EGFR mutations in this group of NSCLC pts, and, similar to early stage lung cancer, TTF-1 appears to be at least a prognostic indicator for OS in stage IV WT EGFR NSCLC pts treated with erlotinib. Exploration of the potential predictive value of this readily available marker should be considered in pts with EGFR WT tumors treated with erlotinib.
Quality of life and safety profile of pemetrexed-platinum doublet in Indian adult chemo-naive NSCLC patients.
Authors: Gota Vikram , Kavathiya Krunal Vasant , E Damodaran S , Joshi Amit , Noronha Vanita , Prabhash Kumar
Published: March 2020

e19118

Background: Pemetrexed in combination with cisplatin or carboplatin is commonly recommended for the first-line treatment of patients with locally advanced or metastatic NSCLC of adenocarcinoma histology. The present study explores the safety and the impact of this doublet on the quality of life in adult Indian NSCLC patients. Methods: Patients were enrolled from a single tertiary care cancer hospital in India. Patients were administered pemetrexed 500 mg/m2, cisplatin 75 mg/m2or carboplatin AUC 5 every 3 weekly. All patients received standard folate and Vitamin B12 supplementation. Premedication included dexamethasone, granisetron and ranitidine. Quality of Life (QoL) data was collected at baseline and at completion of 3 cycles using EORTC QLQ-C30 (version 3) and QLQ- LC13 questionnaires. Toxicity was graded using CTCAE v. 4.03. Results: Twenty seven patients were enrolled on the study since July 2012.Twenty received carboplatin and seven received cisplatin. Mean age of the participants was 54.7 years (SD=9.58) with stage (IV=25; III A/B=2) and ECOG performance status (0=1; 1=17; and 2=9). Pemetrexed–platinum doublet caused significant improvement in Global Health Status and dyspnea score at 3 cycles compared to baseline (Table). The treatment also caused marked improvement in the physical function, emotional function, cognitive function and insomnia scales, although not statistically significant (Table). No significant difference compared to baseline was observed for other parameters. Grade 3/4 toxicities include anemia (3), neutropenia (3), hyponatremia (6), vomiting), diarrhea, and dyspnea (1 each). Conclusions: Pemetrexed-platinum doublet was well tolerated and markedly improved the global health status and dyspnoea at the end of three cycles. A higher incidence of hyponatreemia was observed in our cohort that needs to be investigated further. [Table: see text]