bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical application of targeted deep sequencing for predicting responsiveness to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in never-smoking lung adenocarcinomas (NSLA).
Authors: Han Ji-Youn , Lee Yeon-Su , Lee Geon Kook , Hwang Jung-Ah , Hong Seung-Hyun , Yoon Sung Jin , Lee Jin Soo
Published: March 2020

e19019

Background: Most patients with EGFR-mutant lung adenocarcinoma response well to EGFR-TKIs. However, a subset of patients showed primary resistance to EGFR-TKIs. The routine conventional methods have limitation in predicting primary resistance among EGFR mutant lung cancers. We performed targeted deep sequencing to explore the accuracy and additional values in predicting responsiveness to EGFR-TKIs in NSLA. Methods: We performed direct sequencing to identify EGFR mutations in 48 NSLA received gefitinib or erlotinib for their recurrent advanced disease after surgery. The peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) was used to confirm the EGFR mutation status. To exclude well known causes of resistance, we analyzed KRAS, BRAF and PIK3CA mutations by PNA clamp PCR, ALK rearrangement by FISH, and RET and ROS-1 rearrangements by reverse transcriptase (RT)-PCR and quantitative real-time PCR. After screening, Ion Torrent Personal Genome Machine (PGM) was performed in 31 patients harboring EGFR exon 19 deletions (19DEL) or L858R mutations or none of above molecular changes. Results: The conventional screening found 25 EGFR mutations (10 19DEL; 9 L858R, 1 G719X, 4 double EGFR mutations, 1 concomitant L858R and PIK3CA mutations), 4 KRAS mutations, 3 ALK, 2 RET and 2 ROS-1 rearrangements. No mutation was found in 12 patients. After screening, samples were divided into 4 groups; 1) good responders to EGFR-TKIs with only 19DEL or L858R (n=15); 2) non-responder to EGFR-TKI with only 19DEL or L858R (n=4); 3) non-responders to EGFR-TKI without any mutation (n=8); 4) stable disease to EGFR-TKI without any mutations (n=4). With PMG, all conventionally detected mutations were confirmed, and some additional mutations were detected in a subset of samples; two KRAS and one PIK3CA mutations in group 3, one concomitant PIK3CA and L858R mutations in group 3, one PIK3CA mutation in group 2, and one 19DEL mutation in group 4. Conclusions: Targeted deep sequencing may improve the detection of clinically actionable genomic alterations and enable mutation-driven personalized approach in lung cancer patients.
The incidence and clinical impact of bone metastases in non-small cell lung cancer.
Authors: Kuchuk Michael , Kuchuk Iryna , Hutton Brian , Clemons Mark , Wheatley-Price Paul
Published: March 2020

e19024

Background: Non-small cell lung cancer (NSCLC) is the leading global cause of cancer death. Bone metastases (BM) in NSCLC are a common cause of morbidity, but use of bone targeted agents (BTA) is variable. We investigated the incidence and impact of BM in an unselected NSCLC population. Methods: With ethics approval, we performed a retrospective chart review of all patients (pts) with NSCLC seen at our institution in 2007. Baseline demographics, stage and initial treatment goals were recorded. In pts with advanced disease (mNSCLC) metastatic sites were identified. In BM pts, skeletal related events (SRE), interventions and outcomes were recorded. Results: In total, 374 pts were identified. Median age was 68 years (IQR 60-76), 54% female. Histological subtypes were adenocarcinoma (36%), squamous (18%), and other (46%). Overall 91% were current or ex-smokers. At initial diagnosis 37% had stage I-IIIa, 18% IIIb and 46% stage IV disease. A total of 160 pts (43%) were treated with curative intent; 211 (56%) were considered palliative. Of the 160 curative therapy pts, 90 (56%) subsequently relapsed, with a median time from diagnosis to relapse of 14.9 months. Of the 301 pts with mNSCLC, common sites of metastasis were lung/pleura (80%), mediastinal lymph nodes (69%), bone (39%), brain (30%), and liver (24%). In total 116 pts had BM; a higher incidence was observed in pts ≤70 years than pts >70 (36% vs 23%). SREs were observed in 69 pts (59%), the median number of SREs per BM pt was 1 (0-16). The incidence of SREs was radiotherapy (63%), fractures (22%), spinal cord compression (6%) and surgery to bone (5%). Factors associated with ≥2 SREs were smoking status (28% never smokers vs 9% ex/current smoker) and younger age (15% vs 5%). In BM pts, 64% required opioid analgesia, only 6% received BTA. Overall survival (OS) in pts with mNSCLC was 7.3 months (IQR 3.1-20.5). Pts with BM had significantly shorter OS compared to those without BM (5.5 vs. 9.9 months, p=0.02). Median OS in pts with or without SRE were 5.5 and 6.4 months (p=0.58). Conclusions: BM in NSCLC pts are common, and most pts will develop an SRE and/or require opioids. In mNSCLC, the presence of BM is associated with significantly shorter survival, which raises challenging questions around the use of BTA.
Clinical validation of mutational analysis of EGFR and KRAS in fine needle aspiration and small core needle biopsies using a real-time PCR method.
Authors: Lozano Maria D. , Labiano Tania , Echeveste Jose Ignacio , Montanana Myriam , Gomez Nerea , Aguirre Mercedes , Shieh Felice , Ramos Teresa , Zulueta Javier , Gurpide Alfonso , Perez-Gracia Jose Luis , Martin-Algarra Salvador
Published: March 2020

e19027

Background: About 75% of NSCLC is diagnosed at an advanced stage, thus analysis is often performed from small samples. There is a growing need for multiple biomarker testing when tissue is limited. We evaluated two real-time PCR based assays to assess EGFR and KRAS mutation status in limited tissue specimens and compared results to a lab validated method. Methods: 117 NSCLC patient samples (46 CNB, 71 FNA) were tested for EGFR and KRAS mutations using a single section. DNA was extracted directly from one stained smear in FNA samples (without pre-processing) and one 5-micron section in CNB using the cobas DNA Sample Preparation Kit. Sixty samples were also analyzed for both genes by direct sequencing using the same DNA. Eleven patients had matched CNB and FNA samples. Results: We tested 68 ADCs, 38 SqCCs, 8 NSCLC-NOS, 2 ADCs in situ non-mucinous, and 1 large cell carcinoma (Table). Median DNA concentrations for CNB and FNA were 14.17 ng/ul and 3.75 ng/ul. The failure rate for the cobas were 1.7% (EGFR), 6.8 % (KRAS) in FNA samples, and 0% for CNB. The failure rate for EGFR sequencing was 13.1% (FNA), 16.4% (CNB), and 0% for KRAS. The 11 patients with FNA and CNB showed concordant results between cobas and sequencing. One patient had two mutations; one (L782F) was detected only by sequencing. No discordant findings were seen other than invalid results comparing both systems. Conclusions: Assessment of mutations in limited tissue samples of CNB and FNA using a single section performed on the cobas EGFR and KRAS test is feasible and reliable. There was a lower invalid rate for EGFR testing on cobas test compared to Sanger sequencing. The cobas tests have rapid turnaround time to results, require limited input DNA, and are easier to use compared to sequencing. Still, it is mandatory that pathologists maintain careful quality control of the samples. [Table: see text]
Comparison of the effects of bevacizumab (BV) in combination with chemotherapy (CT) and CT alone on the incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC): A retrospective clinical analysis.
Authors: Du Nan , Li Fang , Jiao Shunchang , Fu Yan , Li Xiaosong , Zhao Hui
Published: March 2020

e19044

Background: The incidence of BM of advanced NSCLC is 20-40%, and there's a lack of effective treatment. This study aims to investigate the value of the angiogenesis marker VEGF in predicting the risk of BM in patients (pts) with NSCLC receiving CT+BV or CT alone and to explore the cumulative risk of BM of NSCLC with high VEGF expression that treated with BV. Methods: Pts with stage IIIB/IV NSCLC underwent CT and/or targeted therapy from 2008-1 to 2010-12 were included. Semi-quantitative detection of VEGF expression was carried out using conventional immunohistochemical staining of lung tissue specimens. Pts experienced BM prior to treatment were excluded. Pts underwent gemcitabine /carboplatin (GC) + BV treatment were included in observation group; pts underwent GC were included in control group. The cumulative risk of BM was calculated using death as a competing risk. Results: 177 pts were included (118 in BV+CT group; 59 in CT group). The median follow-up duration was 18.7 months. Up to 2012-12-31, BM occurred in 15 cases in BV+CT group and 17 in CT group (12.71% vs. 28.81%). 4 cases (33.89%) in BV+CT group survived, and 11 (18.64%) in CT group survived. In BV+CT group, the cumulative risks of BM at 6, 12, and 24 months were 0.86%, 7.52%, and 13.01%, respectively, and 6.74%, 18.88%, and 28.85% in CT group, respectively (P < 0.001). HR of BM in BV+CT group was 0.048 (95% CI: 0.171-0.994) compared to CT group. In BV+CT group, the 6-, 12-, and 24-month cumulative risks of BM were 1.6%, 7.97%, and 12.63% in pts with VEGF(+) and 0, 7.24%, and 12.71% in pts with VEGF(-), respectively; in CT group, the 6-, 12-, and 24-month cumulative risks of BM were 9.35%, 27.04%, and 37.5% in pts with VEGF(+) and 3.52%, 10.71%, and 18.05% in pts with VEGF(-), respectively; there was no significant difference between them. Conclusions: BV+CT can effectively reduce the incidence of BM in pts with advanced NSCLC and improve their prognosis. This small data sample suggests that pts with VEGF(+) are more prone to BM than pts with VEGF(-). The incidence of BM in pts with VEGF(+) is reduced after BV treatment, though its specific mechanism still requires further study.
Retreatment with pemetrexed-based chemotherapy in advanced nonsquamous NSCLC patients.
Authors: Zhuo Minglei , Wang Jie , An Tongtong , Wang Zhijie , Zhao Jun , Wu Meina , Duan Jianchun , Wang Yuyan , Bai Hua , Wang Shuhang
Published: March 2020

e19061^

Background: Retreatment of pemetrexed based chemotherapy (PBC) has been reported in MPM previously, but it is not investigated in non-squamous NSCLC (NS-NSCLC). Methods: We retrospectively enrolled 26 advanced NS-NSCLC patients who had received retreatment of PBC when their response to initial PBC were PR or SD. Chemotherapy regimens administered as retreatment were single pemetrexed (500 mg/m2every 3 weeks) or pemetrexed with a platinum. Response was evaluated according to RECIST. Toxicity was evaluated according to NCI-CTC version 3.0. PFS and OS were computed by Kaplan-Meier. Statistical analyses were performed with SPSS13.0. Results: In retreatment, most adverse effects (AE) were tolerable but doublet regimen was associated with higher AE including bone marrow depression and fatigue. In patients who received retreatment of PBC, objective response rate (ORR) and disease control rate (DCR) was 12% (3/26) and 73% (19/26) respectively. Patient with PFS≥10 months in initial PBC therapy would have a longer PFS in retreatment comparing with those PFS <10 months (6.0 vs 3.1 month, p = 0.004); patients with therapy-free interval (TFI) ≥6 months after initial PBC therapy also have a longer PFS in retreatment comparing with those interval <6 months (7.0 vs 3.0 month, p = 0.001). The OS also tend to be longer but not reach statistic significance. The response of first round PBC therapy (PR vs. SD) was not a factor affecting the PFS in retreatment. Conclusions: Patients with PFS over 10 months or TFI over 6 months after first round of PBC could benefit from retreatment of PBC.
Confirmation of non-small cell lung cancer (NSCLC) diagnosis using ALK testing and genetic profiling in patients presenting with carcinoma of unknown primary site (CUP).
Authors: Penley William Charles , Spigel David R. , Greco F Anthony , Hainsworth John D.
Published: March 2020

e19062

Background: Emerging data suggest real-time reverse transcriptase-polymerase chain reaction (RT-PCR) tumor profiling can predict the primary site in CUP. We report on CUP patients (pts) predicted to have NSCLC by RT-PCR, in whom detection of ALK rearrangements provided further diagnostic support. Methods: 4 pts were diagnosed with CUP based on standard clinical, radiographic, pathologic evaluation with immunohistochemistry (IHC), and bronchoscopy/endoscopy where indicated. All pts had a RT-PCR assay (CancerTYPE ID, bioTheranostics, Inc.) performed on tumor specimens for the purpose of predicting a primary site. Tissue was also tested for ALK by FISH using a break-apart probe. Results: Pt characteristics are shown (Table). RT-PCR results prompted ALK testing in Pts 2 and 3. ALK testing and RT-PCR testing were performed concurrently in Pts 1 and 4. Each specimen was diagnosed as lung adenocarcinoma (AC) by RT-PCR gene profiling, and also tested positive for an EML4-ALKrearrangement. All pts are being followed for clinical outcome. Conclusions: Gene expression profiling in CUP diagnosed lung AC in 4 pts who also had ALK rearrangements supporting the diagnosis. Identifying ALK-positive NSCLC among pts who present with CUP improves the site-specific treatment options. [Table: see text]
EGFR mutation testing, from bench to practice: A single Irish institute experience.
Authors: Shikhrakab Hassan , O'Brien Cathal , Osman Nemer , O'Byrne Kenneth John
Published: March 2020

e19064

Background: Epidermal growth factor receptor (EGFR) gene mutations determine the treatment and prognosis in lung adenocarcinoma. Exon 19 and exon 21 (L858R) deletions represent the most common recognised mutations detected. To date, no figures regarding the prevalence of EGFR mutations in the Irish population have been published. Methods: The prevalence of EGFR mutations was retrospectively analysed for all patient samples tested since the introduction of EGFR testing routinely (Mar to Dec 2012) in a single Irish institute. The presence of 41 known treatment linked EGFR mutations in exons 18, 19, 20 and 21 of the EGFR gene was tested in 209 Irish patients. Resection, core biopsy or FNA samples were analysed using a commercially available CE-IVD marked multiplex real-time PCR assay. Samples were included from patients of curative and palliative treatment intent. Results: 30 out of 209 patients with lung adenocarcinoma tested had an EGFR mutation (13%, 95% CI 8.4-17.6%). Of the mutations detected relative frequency was as follows: exon 19 deletion 63.3% (n=19, 95% CI 46.1-80.6%), exon 21 (p.L858R) 16.7% (n=5, 95% CI 3.3-30.0%), exon 20 insertions 13.3% (n=4, 95% CI 1.2-25.5%) and exon 18 (p.G719X) and exon 20 (p.T790M) both at 3.3% (n=1, 95% CI 0-9.8%). Of those patients tested 51.2% were male (n=107) and 48.8% (n=102) female. The incidence of mutations was higher in females than in males; 63.3% of those with an EGFR mutation were female (n=19, 95% CI 46.1-80.6%). Reciprocally, the male percentage was 36.7% (n=11, 95% CI 19.4-53.9). The mean age at testing was 67 years. Complete smoking data was unavailable for this study. All samples tested were formalin fixed paraffin embedded tissue or cell preparations. Turn around time (TAT) for EGFR mutation processing substantially improved over ten month period, from over five weeks to less than four working days. Conclusions: This group of patients represent the largest cohort of patients tested for EGFR mutation in a single institute in Ireland in less than 12 months. The incidence of EGFR mutations in this patient population is comparable to current European estimates. The gender bias was notable amongst those tested, with female patients being nearly twice as likely to harbour an EGFR mutation.
Paclitaxel/carboplatin (PC) intercalated with gefitinib or paclitaxel/carboplatin (PC) for advanced non-small cell lung cancer (NSCLC) in selected population who were smoker or wild-type EGFR: Randomized phase II study.
Authors: Choi Yoon Ji , Kim Sang-We , Lee Dae Ho , Choi Chang-Min , Lee Jung Shin
Published: March 2020

e19079

Background: The introduction of EGFR inhibitors to standard chemotherapy is an attractive approach to improved outcome. However, the tumor cells which were driven to G0/G1 phase by gefitinib may not sensitive to cytotoxic chemotherapy which is active to G2M arrested tumor cells. This randomized phase II study compared the efficacy of PC intercalated with gefitinib versus PC, as first-line treatment in a clinically selected population of advanced NSCLC patients. Methods: Eligible patients were chemotherapy-naïve advanced NSCLC patients with good ECOG PS of 0 or 1. Non-smoking patients with adenocarcinoma or patients with activating EGFR mutation were excluded because they could benefit from gefitinib alone. They were randomized to either one of the treatments; standard chemotherapy alone (control arm, 46 pts) of paclitaxel (175 mg/m2) and carboplatin (AUC 5) on day 1; or the same chemotherapy plus gefitinib 250 mg/day on day 2 through 15 (study arm, 44 pts). The treatment was repeated every 3 weeks for maximum 4 cycles without maintenance. The primary endpoint included the response rate (RR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 90 patients (male 85.6%, median age 59, adenocarcinoma 63.3%, smoker 90.0%, wild-type EGFR 24.4%, unknown EGFR status 75.6%) were included. There was no difference in terms of RR (the study arm, 40.9% [95% CI 27.3-56.8%] vs. the control arm, 37.0% [95% CI 23.8-51.2%], p=0.701). There was also not difference in terms of PFS (the median PFS; 4.13 vs. 4.13, HR=0.941 [95% CI 0.61-1.45], p=0.781) and OS (the median OS; 9.33 vs. 10.53, HR=0.95 [95% CI 0.58-1.54], p=0.827). Safety analyses showed a similar incidence of drug-related grade 3/4 toxicity in study group (20.9%) compared with control group (23.3%), while mild rash (58% vs. 9%) and diarrhea (14% vs. 7%) were more common in the study arm. Conclusions: PC chemotherapy intercalated with gefitinib did not improved RR, PFS, and OS compared to PC chemotherapy alone in clinically selected population of advanced NSCLC patients who were smoker or wild-type EGFR. Clinical trial information: NCT01196234.
A practical decision-making strategy based on clinical triple features for EGFR-TKIs to treat advanced non-small cell lung cancer patients with unknown EGFR mutation status.
Authors: Zheng Di , Wang Jiying , Lu Bing
Published: March 2020

e19082

Background: EGFR mutated lung cancers are strongly associated with clinical characteristics of never- smoking history and adenocarcinoma histology type, and tended to develop multiple pulmonary metastases.Whether multiple pulmonary metastatic lung adenocarcinomas with never-smoking history would respond to EGFR-TKIs as those harboring EGFR active mutation remains unclear. Methods: 223 consecutive metastatic non-small cell lung cancer (NSCLC) patients with unknown EGFR status who received EGFR-TKIs as salvage therapy after failure of previous platinum-based chemotherapy in Shanghai Pulmonary hospital between 2009 and 2011 were included to the study. Available CT scans, routinely performed at baseline and one month after the start of EGFR-TKIs therapy, were reviewed independently by two investigators. For the purposes of this study, diffuse pulmonary metastatic nodules were defined as multiple nodules distributed diffusely throughout the whole lung with at least 20 nodules within the unilateral lung field. Paraffin embedded tissues were available for 45 of 223 patients for EGFR gene mutation test. Results: Of 134 never-smokers with lung adenocarcinoma,70 patients responded to EGFR-TKIs with an objective response rate (ORR) of 52.2% (70/134), and the ORR for the 62 patients with diffuse pulmonary metastatic nodules was 79% (49/62). Among the 20 patients with confirmed EGFR mutation (based on the available 45 archived specimen), the ORR was 75% (15/20). The multivariate analyses showed that the presence of diffused multiple pulmonary metastatic nodules, activating EGFR mutation and female are independent predictive factors of the response to EGFR-TKIs. Conclusions: Patient selection based on specific clinical features to recieve EGFR-TKI treatment yield high response rate comparable to that selected by EGFR mutation status. It is practical to consider EGFR-TKI as salvage therapy in non-smoking patients with lung adenocarcinoma characterized by diffuse pulmonary nodules when EGFR mutation testing is a challenge.
Tyrosine kinase inhibitors (TKI) treatment of non-small cell lung cancer (NSCLC) patients (p) based on EGFR mutations (m) status in serum only.
Authors: Capdevila Laia , Carcereny Enric , de Aguirre Itziar , Cros Sara , Queralt Cristina , Moran Teresa , Buges Cristina , Mijangos Erika , Pardo Nuria , Rosell Rafael
Published: March 2020

e19088

Background: Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy. However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless, so far, no data exists for NSCLC p treated according to EGFR m status in serum alone. Methods: We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue. We analyzed p treated with an EGFR TKI for whom EGFR m status was known in serum only (status in tissue unknown due to insufficient material). At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters: PFS, ORR and overall survival (OS). EGFR m analysis was performed in cell free circulating DNA (cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit. Results: 9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo). Conclusions: Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.
Predicting significance of EGFR mutation existing in tissues and plasma concuurrently or alone to EGFR–tyrosine kinase inhibitors (EGFR-TKIs) for advanced non-small cell lung cancer.
Authors: Wang Yuyan , Wang Jie , Bai Hua , Wang Zhijie , Duan Jianchun , An Tongtong , Zhao Jun , Zhuo Minglei , Wu Meina , Wang Shuhang
Published: March 2020

e19091

Background: To investigate predicting significance of EGFR mutations existing in tissues couples with plasma or either sample alone to EGFR–tyrosine kinase inhibitors (EGFR-TKIs) treatment for advanced non–small-cell lung cancer (A-NSCLC). Methods: Two hundred-eighty-seven A-NSCLC patients met following criteria were included into this study: 1) had received EGFR-TKIs as first- or second-line therapy; 2) had sufficient tissue and plasma samples for EGFR mutation analysis. All patients were divided into four subgroups which were wild-type EGFR in both of specimens (B-/T-), mutated in both of specimens (B+/T+), mutated only in one specimen (B+/T- and B-/T+). EGFR mutation was screened by denaturing high performance liquid chromatograph (DHPLC) and confirmed by ARMS. Objective response rate (ORR) and progression-free survival (PFS) were compared among four subgroups. Results: Of all 287 patients, 101 patients carried EGFR mutation both in tissue and plasma, 103 patients carried mutation only in tissue (65 cases) or plasma (38 cases). Median PFS was 9.2 months (95% CI, 6.3 to 12.1) and 2.0 months (95% CI, 1.3 to 2.7) in B+/T+ and B-/T- group, respectively. For single mutated group, mPFS were 7.87 month for B-/T+ group (95% CI, 5.1 to 10.6) and 11.87 months for B+/T- group (95% CI, 3.3 to 20.5) (P=0.001). For ORR, 53.0% for B+/T+ group, 15.8% for B-/T- group, 40.0% for B-/T+ group and 28.9% for B+/T- group (P=0.000). EGFR-TKIs therapeutic line could not change trend which B+/T- or B+/T+ group had better PFS than B-/T+ group. Conclusions: Detection of EGFR mutation in tissue and plasma may have different significance in predicting response of EGFR-TKIs.
Efficacy and safety results of pemetrexed administration in non-small cell lung cancers, a multicenter study of the Association of Anatolian Medical Oncology.
Authors: Yasar Nurgul , Unal Olcun Umit , Geredeli Caglayan , Inal Ali , Berk Veli , Sari Ebru , Durnali Ayse , Suner Ali , Ozdemir Nuriye , Budakoglu Burcin , Demirci Umut , Gumussoy Ozge , Uncu Dogan , Boruban Cem Melih , Oztop Ilhan , Ozkan Metin , Gumus Mahmut , Elkiran Tamer ,   Anatolian Medical Oncology
Published: March 2020

e19107

Background: In this study, the efficacy and safety of pemetrexed chemotherapy was evaluated retrospectively in patients who were non-responders to or who have demonstrated progression after the first and/or second line treatments in local advanced and metastatic NSCLC. Methods: 175 patients (139 males, 36 females) were assessed in years 2008 – 2012. Patients were given pemetrexed 500 mg/m2, and the ones receiving combined treatment were given pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 once in every 21 days. Supplementary steroid and vitamin treatment were administered to all patients. Age, gender, performance status (PS), stage, single agent or combined administration of treatment, progression-free survival (PFS) and overall (OS) were investigated. Patients were assessed in terms of treatment efficacy and toxicity. Results: Median follow-up period was 6 months (1 - 25), and median age was 55 years (28 - 83). In 82% of patients, PS was 0 – 1. 73% of patients were at stage 4. 71% of the patients received single agent pemetrexed, and 14% received platinum - pemetrexed combination treatment. 93% of patients received pemetrexed treatment as second line. Median 3 cycles of treatment (1 – 12) were administered. In side effect assessment, while side effects (grade 1 – 4) were observed in 62% of the patients, the most frequently observed side effects were anemia (18%) and nausea-vomiting (15%). Febrile neutropenia was detected in 6 patients (3.4%).In assessment of the response, the disease control ratio was 50% (21% partial response, 29% stable disease). 1- and OS rates were respectively 14% and 41%. Median OS was 10 months (SE:1, 95% CI: 7-12) and median PFS was 3 months (SE:1, 95% CI: 2-4). In multivariate analysis, PS of 0 – 1 and response to treatment were found as factors with prognostic significance (p=0.047, p=0.014, respectively). Conclusions: It is observed that chemotherapy regimen containing pemetrexed in NSCLC treatment is a treatment approach, which provides an efficient disease control with a manageable side effect profile, in patients especially with good performance status and with no platinum resistance, who can receive treatment in combination form.
Adrenalectomy for low-tumor-burden metastatic lung cancer: Results of a single institution experience.
Authors: López-Picazo José María , Martin-Romano Patricia , Zubiri Oteiza Leyre , Gurpide Alfonso , Gil-Bazo Ignacio , Perez-Gracia Jose Luis , Fusco Juan Pablo , Moreno-Jiménez Marta , Carranza Omar Esteban , Martin-Algarra Salvador
Published: March 2020

e19114

Background: Adrenal gland is a common site of metastasis in lung cancer. Adrenal metastasis (AM) can occur at the time of diagnosis (synchronous AM) or later (metachronous AM). When an AM appears as an isolated site of dissemination it is considered a good-prognosis metastatic disease. Nevertheless few data are available about the prognosis and the optimal management of these patients. Methods: Retrospective analysis of the historical series of adrenalectomies in patients treated of lung cancer at our institution. Results: From April 2002 to April 2011, 30 patients (27m/3f) diagnosed of AM of lung cancer (16 non-squamous, 8 squamous, 6 small-cell; 21 metachronous AM, 9 synchronous AM) were treated with adrenalectomy (26 laparoscopic, 4 open surgery). Median age was 55 years old (range: 42-71). Median size of the AM was 35 mm (range: 12-140). There were no severe complications of surgery in any patient. All the patients had received radical treatment for the primary tumour and for other metatatic sites (8 patients brain metastases, 3 patients other sites) before adrenalectomy. Median overall survival (OS) and disease-free survival from adrenalectomy for the entire group were 44 (95% CI: 10-78) and 15 (95%CI: 7,6-22.3) months respectively. We found an statistical trend (p=0.087) of better OS from adrenalectomy for patients with non-squamous histology compared with squamous histology: 57 (95%CI: 38.4-75.6) and 21 (18.3-23.8) months respectively. The percentage of alive patients at 2 and 5 years was 59.1% and 36% respectively. Conclusions: These results add new data about the prognosis of patients with adrenal metastases into the context of low-tumor-burden metastatic lung cancer. Adrenalectomy is a tolerable procedure which plays a role in the management of these patients.
Plasma microRNA signatures to predict EGFR-TKI resistance in EGFR-mutant advanced NSCLC patients.
Authors: Wang Shuhang , Wang Jie , Bai Hua , An Tongtong , Zhao Jun , Wang Zhijie , Duan Jianchun , Zhuo Minglei , Wang Yuyan , Wu Meina
Published: March 2020

e19136

Background: EGFR mutation is a strong predictor of EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitor) therapy in advanced NSCLC. However, 20-30% of patients with EGFR mutation are resistant to EGFR-TKIs, suggesting that other determinants of outcome beyond EGFR mutation might exist. We hypothesized that plasma microRNA (miRNA) might play a role. Methods: Training group: 20 advanced NSCLC patients treated with EGFR-TKIs as first-line therapy with EGFR 19 deletion mutation were enrolled, 10 of whom responded dramatically while other 10 are resistant. Matched plasma were collected for miRNA profile detection using TaqMan Low-Density (TLDA). Testing group: Real-time PCR were employed to identify the level of miRNAs found significant differently expressed in training step; bioinformatics was applied to find related miRNAs possibly account for resistance. Validation group: Another cohort with EGFR 19 deletion mutation present dramatically different response to EGFR-TKI was used to analyze the difference of miRNAs expression between responding and resistant group. Results: Training group: 153 miRNAs were found differently expressed between responding and resistant group. Testing group: 3 miRNAs (miR-21, AmiR-27a, and miR-218) were verified significantly higher (P=0.004, A0.009, A0.041, respectively) in resistant group than responding group. Validation group: expression level of these 3 miRNAs was validated to be significantly different (P=0.011, A0.011, A0.026, respectively) between 17 couples advanced NSCLC patients with different response to EGFR-TKI. Conclusions: Higher expression level of miR-21, AmiR-27a, and miR-218 might play the role in the resistance to EGFR-TKI for advanced NSCLC patients who had an EGFR exon 19 deletion mutation treated with EGFR-TKI, which needs further validation.
Phase I dose escalation study of pemetrexed and carboplatin in chemotherapy-naive elderly patients with advanced nonsquamous non-small cell lung cancer.
Authors: Yamada Kazuhiko , Takeoka Hiroaki , Zaizen Yoshiaki , Shimamatsu Fumie , Azuma Koichi , Hoshino Tomoaki
Published: March 2020

e19137

Background: The subgroup analyses in several phase III trials have suggested that overall survival after platinum-doublet chemotherapy in elderly patients with non-small cell lung cancer (NSCLC) can be similar to those in younger patients. The combination of carboplatin (CBDCA) with pemetrexed (PEM) is expected as a suitable treatment for carefully selected elderly patients with advanced non-squamous (non-Sq) NSCLC. Methods: Patients with ≥75 years, PS of 0-1, chemotherapy-naïve advanced non-Sq NSCLC were enrolled in this study. They received escalated doses of CBDCA at AUC 4 (cohort 1) or AUC 5 (cohort 2) and PEM 500 mg/m2 every 3 weeks for six cycles. Dose escalation was decided by dose-limiting toxicity (DLT) occurred in the first cycle of chemotherapy. Study protocol stipulated that additional number of patients, up to maximum of 20 patients, was enrolled to receive the recommended dose of study treatment. The primary objectives were to evaluate feasibility and determine the recommended dose of this combination. Results: A total of 20 patients (6 patients in cohort 1, 14 patients in cohort 2) were enrolled in this study. Median age was 77 (range 75-83). No DLTs were observed in the patients with cohort 1 and the first 6 patients of cohort 2 during the first cycle of chemotherapy, thus the combination of PEM 500 mg/m2 plus CBDCA at AUC 5 was determined as the recommended dose. Median number of cycles was 4 (range 1-6). The major toxicities were neutropenia, thrombocytopenia, anemia. During the entire period of study, 2 and 5 patients needed to have platelet transfusion and RBC transfusion, respectively. Liver dysfunction, fatigue and anorexia were also common, but these were generally manageable. Six partial responses and 9 stable diseases were observed, giving an overall response rate of 30% and a disease control rate of 75%. Median progression-free survival time was 4.8 months (95% CI, 4.1 – 5.4 months). Conclusions: The combination of PEM 500 mg/m2 plus CBDCA at AUC 5 was determined as the recommended dose. This combination therapy is generally tolerable, and may have encouraging antitumor activity in chemotherapy-naïve elderly patients with advanced non-Sq NSCLC. Clinical trial information: UMIN000003231.
First-line chemotherapy (CT) with pemetrexed (PEM) + cisplatin (CIS) + bevacuzimab (BEV) followed by maintenance PEM+BEV for advanced nonsquamous non-small cell lung cancer (NS-NSCLC): Final results of a single-arm phase II study.
Authors: Hillerdal Gunnar N , Sorensen Jens Benn , Hoeffken Gert , Favaretto Adolfo , Perez-Carrion Ramon , Visseren-Grul Carla , Ameryckx Sophie , Soldatenkova Victoria , Bourayou Nawel , Santoro Armando
Published: March 2020

e19148

Background: 1st line PEM+CIS induction CT followed by PEM maintenance and 1st line BEV-based CT followed by BEV maintenance offer clinical benefit (PFS, OS) in NS-NSCLC. This study explored efficacy and safety of 1st line induction PEM+CIS+BEV followed by maintenance PEM+BEV. Methods: Pts with advanced NS-NSCLC and ECOG 0-1 were planned to receive 4 cycles PEM 500 mg/m2, CIS 75 mg/m2, BEV 7.5 mg/kg, q3w. In absence of PD and with ECOG 0-1, pts could continue on PEM+BEV until PD or unacceptable toxicity. All pts received vitamin supplementation as per PEM label. Primary endpoint was PFS; secondary were OS, response rate, toxicity. Results: 109 pts were enrolled in 5 countries. Characteristics: median age 61 yrs, males/females 59/41%, ECOG 0/1 54/46%, IIIB/IV 9/91%, adenocarcinoma 91%. 72 pts (66%) had maintenance CT. Overall median (max) no of cycles were 6 (34) for PEM+BEV and 2 (4) for CIS. Median PFS was 6.9 m (90% CI 5.7, 8.3). The table gives efficacy and G3/4 AE data. 2 pts died from study-drug related toxicity (GI hemorrhage, pneumonia aspiration; during induction). Conclusions: In this study of PEM+CIS+BEV induction followed by PEM+BEV maintenance median PFS was 6.9 m. Main G3/4 toxicities included neutropenia and fatigue, hypertension was less common. Clinical trial information: NCT01004250. [Table: see text]
Risk of interstitial lung disease and other pulmonary related adverse events among patients taking EGFR inhibitors: A meta-analysis of randomized controlled trials.
Authors: Garcia Salvador Ricardo , Donath Elie , Ortega-Parra Camilo A. , Jacobson Robert J.
Published: March 2020

e19155

Background: Epidermal growth factor receptor (EGFR) inhibitors are suspected of being a potential cause of interstitial lung disease (ILD). This speculation is based largely on case reports and series in which it is difficult to establish causality. In this meta-analysis we evaluated randomized controlled trials (RCTs) involving EGFR inhibitors to verify if a relationship exists between exposure to EGFR inhibitors and development of ILD and other pulmonary-related events. Methods: EMBASE and Medline were searched for all RCTs evaluating cetuximab, gefitinib or erlotinib in non-small cell lung cancer (NSCLC). Studies were disqualified if the control contained any EGFR inhibitor or drug known to cause ILD. Thirty-one RCTs with 15,736 patients were identified. The primary outcome was ILD incidence. ILD is poorly defined and there is overlap with other pulmonary related outcomes including pneumonia, acute respiratory failure (ARF) and pneumonitis, and these were therefore secondary outcomes of interest. For all outcomes, a fixed-effects meta-analysis was performed. Results: For the primary outcome, there is a 173% increased risk of ILD among patients given EGFR inhibitors (RR 2.73, 95% CI: 1.74-4.23, p<0.001) across 15 RCTs that report on ILD incidence. Among secondary endpoints, there is an 86% increased risk of pneumonia (RR 1.86, 95% CI 1.36-2.53, p<0.001), a 19% increased risk of pneumonitis (RR 1.19, 95% CI: 0.62-2.27, p=0.59) and a 33% increased risk of ARF (RR 1.33, 95% CI: 0.65-2.72, p=0.44) among patients given EGFR inhibitors. There is minimal heterogeneity across trials for all above outcomes. Conclusions: EGFR inhibitors play a direct role in causing or contributing to ILD progression in patients with NSCLC who are susceptible to alveolar damage from prior chemoradiation therapy. Additionally, EGFR inhibitors seem to be associated with an increased risk for other pulmonary related events.This research suggests that caution should be undertaken in administering EGFR inhibitors to patients with poor baseline lung function or pre-existing pulmonary disease.
Variables impacting the number of palliative chemotherapy lines administered to patients with advanced non-small cell lung cancer (NSCLC) in a common daily practice setting.
Authors: Roa-Garcia Diana Marcela , Muñoz Silvia , Baste Neus , Holguin Francia , Sais Elia , Urbano Cristina , Quer Nuri , Guerra Silvia , Cufi Silvia , Vazquez-Martin Alejandro , Oliveras-Ferraros Cristina , Corominas-Faja Bruna , Menendez Javier A. , Brunet Joan , Garcia-Velasco Adelaida , Izquierdo Angel , Porta Rut , Bosch-Barrera Joaquim
Published: March 2020

e19159

Background: Palliative chemotherapy (CT) can increase survival and quality of life for advanced non-small cell lung cancer (NSCLC) patients (pts). It has been observed in phase III clinical trials that not all pts are able to receive second or further lines of CT. We have analyzed the number of CT lines that pts with advanced NSCLC do in our institution and factors that could have an impact on it. Methods: All pts treated during 2010 for advanced NSCLC in our institution were analyzed (n=124). Quantitative data were compared by Student’s t test. Overall survival (OS) was estimated by Kaplan-Meier analysis and differences were assessed with the log-rank test. Results: Most pts (75.8%) were men. Median age was 66 years. The 67.7% of patients received up to 2 lines of CT, 38.7% 3 lines, 15.3% 4 lines, 8% 5 lines, and 2.4% received up to 6 lines. The higher the number of lines of CT were administered, the higher the median of OS obtained from one line of CT to up to six lines respectively (4.4 vs 10.9 vs 15.6 vs 19.2 vs 31.1 vs 54.3 months, p<0.0001). Women presented a higher median of OS than men (18.7 vs 12.1 months, p=0.015), but without a significant higher number of CT lines (2.6 vs 2.17, p=0.159). Adenocarcinoma pts (54.0%) received greater numbers of CT lines than squamous cell carcinoma pts (26.6%) (2.54 vs 1.58, p=0.007), with a trend towards significant increase in the median OS (14.7 vs 11.6 months, p=0.072). Pts receiving cisplatin-based CT as first line (40.3%) received more lines of treatment than carboplatin-based (46.0%) (2.88 vs 2.04, p=0.001) and were also younger (59.6 vs 65.8 years, p=0.003), but these differences did not have a statistically significant impact on median OS (14.0 vs 11.6 months, p=0.375). Conclusions: In our series, pts with adenocarcinoma histology and cisplatin-based first line treatment received a higher number of lines of CT. Women had better median OS. The number of lines of CT received may have an impact on median OS.
Single institution experience of brentuximab vedotin (SGN-35) impact on allogeneic transplant in patients with relapsed/refractory CD 30 positive lymphoma.
Authors: Parsons Benjamin Marshall , Stiff Patrick J. , Smith Scott E.
Published: March 2020

e19511

Background: Case series to date (Chen and Gopal) have reported safety and efficacy of b. vedotin prior to allo-SCT. We report our experience using b. vedotin prior to allo-SCT. Methods: Patients were treated with b. vedotin through Seattle Genetics trials and identified retrospectively using a registry of b. vedotin use and subsequent allo-HCT. Patients were treated per study protocol and received 1.8 mg/kg b. vedotin administered every 3 weeks for up to 16 cycles. Patients were followed for response, survival/disease status and subsequent therapy. Results: 7 patients were identified with a median of 5.7 prior therapies. Of these patients 5 had HL histology and 2 had ALK+, ALCL histology. The median age was 37.0 years. The median time since initial diagnosis was 60.4 months. All 7 patients had previously received an autologous SCT. Patients with primary refractory disease accounted for 42% of patients. Patients received a median of 8.6 cycles of b. vedotin and 86% of patients achieved an objective response; best response was CR for 3 patients and PR for 3 patients. Median maximum tumor reduction was 43%. Median time from b. vedotin to transplant was 7.6 months. Three patients received additional chemotherapy post b.vedotin and prior to allo-SCT. The PFS and OS are 86% with 6 patients alive and without relapse in follow-up post allo-SCT. There was 1 transplant related death at induction which did not appear related to b. vedotin. The median follow up is 17.5 months. The median time to neutrophil engraftment was 12.3 days. The median time to platelet engraftment was 21.6 days. Their were no episodes of aGVHD and 33% of patients developed cGVHD all Grade I/II. No increase in infections was observed. Conclusions: Treatment with b.vedotin provided significant decrease in tumor volume in patients with relapsed CD30+ lymphoma, and allowed for allo-SCT. There was no evidence of a delay in engraftment, aGVHD, cGVHD, or post transplant infectious complications. Our results add to prior reports that b. vedotin is a safe and effective option for reducing tumor burden to facilitate a potentially curative allo-SCT and warrants further study.
Evaluation of protocol mandated testing in E4A03, a randomized phase III study of CC-5013 plus dexamethasone versus CC-5013 plus low-dose dexamethasone in multiple myeloma (MM).
Authors: Callander Natalie Scott , Jacobus Susanna J. , Weiss Matthias , Kumar Shaji , Fonseca Rafael , Siegel David Samuel DiCapua , Katz Michael S. , Abonour Rafat , Williams Michael E. , Greipp Philip R. , Rajkumar Vincent ,   Eastern Cooperative Oncology Group
Published: March 2020

e19517

Background: Investigators cite complicated test (T) schedules as barriers to the conduct of clinical trials, especially T that do not contribute to outcome or pt safety. In MM protocols, some T are prone to being done inaccurately (e.g. UPEP, 24 hour urine collections), or are not useful (e.g. uric acid, AST/ALT) in determination of response (R) or safety. These T lead to increased cost, protocol violations, and do not enhance outcome. Methods: We analyzed data submitted for pts on E4A03 to examine frequency of missing data for R T: serum and urine (U) PEP, immunofixation (IFE) bone surveys (BS), and safety labs for C1-4. Results: Table outlines % pts with completed T. Most had T for serum M protein, as well as heme T but serum and U PEP, and IFE dropped off by C4. Other T e.g. uric acid were completed in 77%. Only 79% of pts had a BS repeated at C4. Incorrect or missing U data led to categorization of 16/445 (3.6%) pts as ineligible and was most frequent reason for ineligibility (69%). Missing U data led to 13/26 pts not evaluable. Analysis of SAE during the C1-4 revealed no SAE for hyperuricemia and < 5 SAE for AST/ALT. Only 5% of pts had lab-based SAE filed in 4 C. Conclusions: Required U T and BS to assess R in E4A03 were missing or completed inadequately and caused pts to be ineligible and or not evaluable. Such T need to be eliminated or replaced. Strategies to monitor data submission in real time may reduce subject loss due to T error. The requirement for routine T should be reassessed to create simpler trial design. Clinical trial information: NCT00098475. [Table: see text]
Retrospective analysis of treatment-induced peripheral neuropathy (TIPN) in multiple myeloma (MM).
Authors: Martin Thomas , Panjabi Sumeet , Imani Robert , Anum Emmanuel , Lubeck Deborah P.
Published: March 2020

e19530

Background: Peripheral neuropathy (PN) is commonly present at MM diagnosis and exacerbated or induced by MM treatments. TIPN poses significant morbidity, and may result in therapy modifications (TM). We examined the “real-life” onset and severity of TIPN in newly diagnosed patients (pt) receiving anti-MM therapies. Methods: Medical records from a US community oncology network were reviewed. Newly diagnosed MM pt treated between 1/1/08 and 7/1/10, ≥18 years, and followed for ≥24 months were eligible. The protocol pre-defined inclusion of an equal number of TIPN and non-TIPN cases. Regimen-related TIPN was based on clinician judgment and/or correspondence of TIPN with regimen start/end dates. Uni- and multi-variate (MV) analyses examined association of demographic and regimen characteristics with TIPN, TIPN severity, and TM. Results: In all, 716 MM records were screened; 367 were deemed ineligible or incomplete. Of 349 eligible records, 229 were abstracted, 10 had unusable data, and 219 formed the analytic set; 120 records were excluded since the accrual target (N=225) had been met. Average age of pts was 67.0 years, 49.3% were female, 57.5% Caucasian, and 36.0% African-American (AA). A majority (56.6%) had 1 regimen prior to 1st disease progression, 26.0% had 2 and 17.4% had >2 regimens. Overall, 138/219 (63.0%) developed PN, 123/219 (53.7%) with documented TIPN. TIPN developed during 1st line therapy in the majority 110/123 (89.4%). Univariate analysis revealed that TIPN pt were younger, more likely to be AA, and treated more frequently with bortezomib-based regimens BTZ-BR (63.3 v 9.3%). MV analysis showed TIPN was associated with BTZ-BR (OR=14.5, 95% CI=6.5-32.2), but not age, race, gender, and diabetes. BTZ-BR compared to non BTZ-BR were associated with severe and grade 3/4 TIPN (79.3 v 20.7%; χ2=5.36, p=0.02), and TM (65.7 v 34.3%, χ2=5.57, p=0.02). Notable TM included dose reductions (66.7 v 33.3%) and delays (83.3 v 16.7%). Conclusions: In this study of newly diagnosed MM pt, TIPN developed frequently during 1st line therapy. BTZ-BR were associated with TIPN that was severe and resulted in greater TM. While this analysis represents a small pt population, the results are provocative and warrant further study.