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P2.03b-038 The Diagnostic and Prognostic Value of CSF Cyfra 21-1 in Patients with Leptomeningeal Metastasis of Non-Small Cell Lung Cancer
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Background: In 2013, recommendations for 1st line treatment in advanced NSCLC included a platinum based chemotherapy (pCT) with or without bevacizumab (BEVpCT), an EGFR-TKI, or a non-platinum based CT (nonpCT) depending on clinical, pathological and molecular characteristics. Molecular testing for KRAS, EGFR and ALK, is routinely performed in France for advanced nonsquamous NSCLC. However, the prognostic impact of the molecular status knowledge before beginning 1st line treatment is unknown.
Journal of Thoracic Oncology
Vol. 12 No. 1S
BEVA-pCT regimen, especially in patients with KRAS+ and WT tumor. Keywords: non-small cell lung cancer (NSCLC), KRAS, EGFR, bevacizumab
P2.03b-038 The Diagnostic and Prognostic Value of CSF Cyfra 21-1 in Patients with Methods: After a cross-validation study, KRAS, EGFR Leptomeningeal Metastasis of and ALK molecular status were assessed in 843 Non-Small Cell Lung Cancer consecutive patients (pts) with previously untreated advanced NSCLC (all histologic subtypes) and categorized as: EGFR/ALK+, KRAS+, wild-type (WT), undetermined (UD) and not done (ND). Treatments from the 1st to 3rd line were separated into 4 groups: p-CT, BEVA-pCT, EGFR/ALK TKI and non-pCT. Demographic, clinical and pathological characteristics were collected and pts were followed-up until death. Overall survival (OS) and progression-free survival (PFS) for each line were determined. Prognostic factors including treatment categories (p-CT as reference) and biomarkers status (WT as reference) were studied by Cox model. Results: Treatments were analyzed in 767 (91.0%) of the 843 pts enrolled between 01/2013 and 02/2014. Pts were 93.1% Caucasians, 66.2% males. Median age was 62.4 yr (28-92). 13.4% were never smokers. PS 2 were 21.4% and 90.3% were stage IV. 76.5% had adenocarcinoma, 14.5% squamous cell carcinoma and 9% others with WT¼40.4%, KRAS+¼23.1%, EGFR/ALK+¼10.2%, UD¼5.1%, ND¼21.2%. 1st line treatments were: p-CT¼75.9%, BEVA-pCT¼14.2%, EGFR/ALK TKI¼7.8% and non-pCT¼2.1%. With a 30.3 months (mo) median of follow-up, median OS and PFS were 10.7 mo and 5.3 mo, respectively. Factors independently associated with shorter OS were PS2 (HR¼2.08, p<.0001), KRAS+, UD and ND mutation status (HR¼1.40, p¼.002; 1.53, p¼.02; 1.29, p¼.02), and non-pCT as 1st line treatment (HR¼1.92, p¼.01), while EGFR/ALK+ (HR¼.38, p<.0001) and BEVA-pCT (HR¼.54, p<.001) were associated with better survival. There was no interaction effect between biomarkers status and OS treatment groups. However, BEVA-pCT in 1st line therapy in KRAS+ and WT NSCLC (p<.0001 and <.0003, respectively) was associated with longer survival compared to p-CT, while giving a TKI or p-CT in 1st line therapy in EGFR/ALK+ NSCLC did not affect OS. Conclusion: Results from the IFCT-PREDICT.amm study suggest that prognosis of advanced NSCLC might be optimized in 1st line setting by the knowledge of EGFR/ ALK molecular status and the opportunity to give a
Topic: Biomarkers Jae-Won Hyun, Su-Hyun Kim, Sang-Hyun Hwang, Ho-Shin Gwak, Ho Jin Kim National Cancer Center, Goyang/Korea, Republic of Background: Cyfra 21-1, belonging to the intermediate filament protein, is responsible for the mechanical integrity of the cell and celluar processes such as cell division. Cyfra 21-1 in cerebrospinal fluid (CSF) has been proposed as a diagnostic and prognostic marker in patients with leptomeningeal carcinomatosis. We aimed to evaluate the diagnostic and prognostic value of CSF cyfra 21-1 in patients with leptomeningeal metastasis (LM) of non-small cell lung cancer (NSCLC). Methods: CSF cyfra 21-1 was measured by chemiluminescence immunoassay in cerebrospinal fluid (CSF) samples of LM patients with NSCLC (n ¼ 36) and other neurological diseases (n¼209, OND, multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barre syndrome, headache) from National Cancer Center in Korea. Diagnosis of LM was made via positive CSF cytology and/or MRI scans showing LM. Upper normal limit (UNL) was calculated by two times of mean value plus two standard deviation (3.46 ng/ml). Overall survival was defined as the time elapsed from the start of intra-thecal chemotherapy to death and survival curves were analyzed according to the Kaplan-Meier method. Results: CSF cyfra 21-1 (22 ± 83 vs. 1.4 ± 0.1 ng/ml, p<0.001) was significantly higher in LM patients with NSCLC than patients with OND. Diagnostic sensitivity, specificity, positive and negative predictive values for LM with NSCLC were estimated 41%, 100%, 100% 91% in CSF cyfra 21-1 and 67%, 100%, 100%, 95% in CSF cytology, respectively. Two of 12 cytology-negative patients showed high CSF cyfra 21-1 (over 3.46 ng/ml). CSF cyfra 21-1 was significantly higher in cytologypositive LM patients than cytology-negative LM patients (31.4 ± 101 vs. 3.1 ± 3.5 ng/ml, p¼0.004). The median overall survival was longer in LM patients with low CSF cyfra 21-1 than those with high CSF cyfra 21-1, although
January 2017
Abstracts
it did not reach statistical significance (median 5 vs. 2 months, p¼0.163). Conclusion: These findings suggested that CSF cyfra 21-1 could be used as an additional diagnostic and prognostic biomarker for LM of NSCLC. Keywords: NSCLC, Leptomeningeal biomarker, CYFRA 21-1
Metastasis,
P2.03b-039 Cell-Free (cf) DNA and cfRNA levels in Plasma of Lung Cancer Patients Indicate Disease Status and Predict Progression Topic: Biomarkers Luis Raez,1 Kathleen Danenberg,2 Brian Hunis,1 Aurelio Castrellon,1 Yolanda Jaimes,2 Michel Velez,1 Joshua Usher,2 Cheryl Habaue,1 Peter Danenberg2 1 Florida International University, Memorial Cancer Institute, Pembroke Pines/FL/United States of America, 2 Liquid Genomics, Torrance/CA/United States of America Background: Cell-free circulating tumor DNA (ctDNA) and RNA (ctRNA) can be extracted from plasma of cancer patients (pts). Measuring dynamic changes in gene expression, allele-fractions of mutations and levels of nucleic acids per ml of plasma in metastatic patients has shown great potential for monitoring disease state and predicting outcome to antitumoral therapy in advance of imaging. Methods: We designed a clinical trial to measure gene levels of plasma ctDNA and ctRNA in metastatic pts with NSCLC, breast, and GI malignancies under treatment and correlate the levels with CT scans done assessing response for one-year clinical trial. CtDNA/ctRNA were extracted from plasma separated from patient wholeblood draws shipped at ambient temperature. CtRNA was reverse transcribed with random primers to cDNA. Levels of ctDNA/ctRNA were determined by real-time qPCR. Results of ctDNA/ctRNA tests were compared with responses (CR, PR, SD or PD) as determined by the CT scans. Levels of PD-L1 expression relative to beactin were determined by qPCR. Results: We have enrolled 39 pts and we are presenting data from 15 pts with NSCLC. The first-line treatments were Carboplatin (40%, 6/15), Opdivo (26.7%, 4/15), Afatinib (13.3%, 2/15), Ceritinib (6.7%, 1/15), Crizotinib (6.7%, 1/15), and Taxotere/Cyramza (6.7%, 1/15). Histological subtypes were 73.3% (11/15) adeno, 20% (3/15) squamous, and 6.7% (1/15) other. The majority of patients were Caucasian (66.7%, 10/15), Hispanic (26.7%, 4/15), and African American (6.7%, 1/15).
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Levels of ctDNA and ctRNA were significantly correlated with one another across patient blood draws (r ¼ 0.5781, p < 0.0001). After the first 2 cycles of therapy, 9 of the 15 patients achieved SD, of whom 8 were analyzed for ctDNA/ctRNA levels. In 7/8 of pts who had SD indicated by CT scan, CtDNA/ctRNA levels were stable, while the 2 PD pts showed significant increases in levels of ctDNA/ctRNA 4.8 weeks prior to progression. In the 2 SD pts treated with Opdivo, PD-L1 expression was stable during the cycles when CT scans also indicated an SD status. Conclusion: In almost 90% of the pts, constant ctDNA/ ctRNA levels correlated with stable disease status as seen by CT; moreover, in 2 pts changes in the levels of both ct nucleic acids predicted progression about 5 weeks before CT scans. Importantly, the concordance between cDNA and cfRNA suggest that cfRNA can just as effective as cfDNA as a prognostic tool, while adding the extra dimension of gene expression. Keywords: cfDNA, cfRNA, plasma, liquid biopsies
P2.03b-040 NANOG Predicts Poor Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy Topic: Biomarkers Seung Hyeun Lee,1 Myung Jae Park,1 So Young Park,1 Kwang Ho In,2 Chul Hwan Kim3 1Department of Internal Medicine, Kyung Hee University Medical Center, Seoul/Korea, Republic of, 2Department of Internal Medicine, Korea University College of Medicine, Seoul/ Korea, Republic of, 3Department of Pathology, Korea University College of Medicine, Seoul/Korea, Republic of Background: NANOG is a master transcription factor that regulates embryonic stem cell pluripotency and cellfate specification though complex interaction with a myriad of factors in signaling pathways. Cumulating evidence suggests that it has oncogenic potential correlating with cell proliferation, clonogenic growth, tumorigenicity and invasiveness. Increased NANOG expression has been reported to be related with poor survival in several human malignancies including hepatic, breast, ovarian and colorectal cancers. However, clinical significance of NANOG overexpression in lung cancer has been scarcely evaluated, and correlation between NANOG expression and prognosis in advanced non-small cell lung cancer (NSCLC) has not been studied. The aim of this study is to investigate whether NANOG expression is
Background: In 2013, recommendations for 1st line treatment in advanced NSCLC included a platinum based chemotherapy (pCT) with or without bevacizumab (BEVpCT), an EGFR-TKI, or a non-platinum based CT (nonpCT) depending on clinical, pathological and molecular characteristics. Molecular testing for KRAS, EGFR and ALK, is routinely performed in France for advanced nonsquamous NSCLC. However, the prognostic impact of the molecular status knowledge before beginning 1st line treatment is unknown.
Journal of Thoracic Oncology
Vol. 12 No. 1S
BEVA-pCT regimen, especially in patients with KRAS+ and WT tumor. Keywords: non-small cell lung cancer (NSCLC), KRAS, EGFR, bevacizumab
P2.03b-038 The Diagnostic and Prognostic Value of CSF Cyfra 21-1 in Patients with Methods: After a cross-validation study, KRAS, EGFR Leptomeningeal Metastasis of and ALK molecular status were assessed in 843 Non-Small Cell Lung Cancer consecutive patients (pts) with previously untreated advanced NSCLC (all histologic subtypes) and categorized as: EGFR/ALK+, KRAS+, wild-type (WT), undetermined (UD) and not done (ND). Treatments from the 1st to 3rd line were separated into 4 groups: p-CT, BEVA-pCT, EGFR/ALK TKI and non-pCT. Demographic, clinical and pathological characteristics were collected and pts were followed-up until death. Overall survival (OS) and progression-free survival (PFS) for each line were determined. Prognostic factors including treatment categories (p-CT as reference) and biomarkers status (WT as reference) were studied by Cox model. Results: Treatments were analyzed in 767 (91.0%) of the 843 pts enrolled between 01/2013 and 02/2014. Pts were 93.1% Caucasians, 66.2% males. Median age was 62.4 yr (28-92). 13.4% were never smokers. PS 2 were 21.4% and 90.3% were stage IV. 76.5% had adenocarcinoma, 14.5% squamous cell carcinoma and 9% others with WT¼40.4%, KRAS+¼23.1%, EGFR/ALK+¼10.2%, UD¼5.1%, ND¼21.2%. 1st line treatments were: p-CT¼75.9%, BEVA-pCT¼14.2%, EGFR/ALK TKI¼7.8% and non-pCT¼2.1%. With a 30.3 months (mo) median of follow-up, median OS and PFS were 10.7 mo and 5.3 mo, respectively. Factors independently associated with shorter OS were PS2 (HR¼2.08, p<.0001), KRAS+, UD and ND mutation status (HR¼1.40, p¼.002; 1.53, p¼.02; 1.29, p¼.02), and non-pCT as 1st line treatment (HR¼1.92, p¼.01), while EGFR/ALK+ (HR¼.38, p<.0001) and BEVA-pCT (HR¼.54, p<.001) were associated with better survival. There was no interaction effect between biomarkers status and OS treatment groups. However, BEVA-pCT in 1st line therapy in KRAS+ and WT NSCLC (p<.0001 and <.0003, respectively) was associated with longer survival compared to p-CT, while giving a TKI or p-CT in 1st line therapy in EGFR/ALK+ NSCLC did not affect OS. Conclusion: Results from the IFCT-PREDICT.amm study suggest that prognosis of advanced NSCLC might be optimized in 1st line setting by the knowledge of EGFR/ ALK molecular status and the opportunity to give a
Topic: Biomarkers Jae-Won Hyun, Su-Hyun Kim, Sang-Hyun Hwang, Ho-Shin Gwak, Ho Jin Kim National Cancer Center, Goyang/Korea, Republic of Background: Cyfra 21-1, belonging to the intermediate filament protein, is responsible for the mechanical integrity of the cell and celluar processes such as cell division. Cyfra 21-1 in cerebrospinal fluid (CSF) has been proposed as a diagnostic and prognostic marker in patients with leptomeningeal carcinomatosis. We aimed to evaluate the diagnostic and prognostic value of CSF cyfra 21-1 in patients with leptomeningeal metastasis (LM) of non-small cell lung cancer (NSCLC). Methods: CSF cyfra 21-1 was measured by chemiluminescence immunoassay in cerebrospinal fluid (CSF) samples of LM patients with NSCLC (n ¼ 36) and other neurological diseases (n¼209, OND, multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barre syndrome, headache) from National Cancer Center in Korea. Diagnosis of LM was made via positive CSF cytology and/or MRI scans showing LM. Upper normal limit (UNL) was calculated by two times of mean value plus two standard deviation (3.46 ng/ml). Overall survival was defined as the time elapsed from the start of intra-thecal chemotherapy to death and survival curves were analyzed according to the Kaplan-Meier method. Results: CSF cyfra 21-1 (22 ± 83 vs. 1.4 ± 0.1 ng/ml, p<0.001) was significantly higher in LM patients with NSCLC than patients with OND. Diagnostic sensitivity, specificity, positive and negative predictive values for LM with NSCLC were estimated 41%, 100%, 100% 91% in CSF cyfra 21-1 and 67%, 100%, 100%, 95% in CSF cytology, respectively. Two of 12 cytology-negative patients showed high CSF cyfra 21-1 (over 3.46 ng/ml). CSF cyfra 21-1 was significantly higher in cytologypositive LM patients than cytology-negative LM patients (31.4 ± 101 vs. 3.1 ± 3.5 ng/ml, p¼0.004). The median overall survival was longer in LM patients with low CSF cyfra 21-1 than those with high CSF cyfra 21-1, although
January 2017
Abstracts
it did not reach statistical significance (median 5 vs. 2 months, p¼0.163). Conclusion: These findings suggested that CSF cyfra 21-1 could be used as an additional diagnostic and prognostic biomarker for LM of NSCLC. Keywords: NSCLC, Leptomeningeal biomarker, CYFRA 21-1
Metastasis,
P2.03b-039 Cell-Free (cf) DNA and cfRNA levels in Plasma of Lung Cancer Patients Indicate Disease Status and Predict Progression Topic: Biomarkers Luis Raez,1 Kathleen Danenberg,2 Brian Hunis,1 Aurelio Castrellon,1 Yolanda Jaimes,2 Michel Velez,1 Joshua Usher,2 Cheryl Habaue,1 Peter Danenberg2 1 Florida International University, Memorial Cancer Institute, Pembroke Pines/FL/United States of America, 2 Liquid Genomics, Torrance/CA/United States of America Background: Cell-free circulating tumor DNA (ctDNA) and RNA (ctRNA) can be extracted from plasma of cancer patients (pts). Measuring dynamic changes in gene expression, allele-fractions of mutations and levels of nucleic acids per ml of plasma in metastatic patients has shown great potential for monitoring disease state and predicting outcome to antitumoral therapy in advance of imaging. Methods: We designed a clinical trial to measure gene levels of plasma ctDNA and ctRNA in metastatic pts with NSCLC, breast, and GI malignancies under treatment and correlate the levels with CT scans done assessing response for one-year clinical trial. CtDNA/ctRNA were extracted from plasma separated from patient wholeblood draws shipped at ambient temperature. CtRNA was reverse transcribed with random primers to cDNA. Levels of ctDNA/ctRNA were determined by real-time qPCR. Results of ctDNA/ctRNA tests were compared with responses (CR, PR, SD or PD) as determined by the CT scans. Levels of PD-L1 expression relative to beactin were determined by qPCR. Results: We have enrolled 39 pts and we are presenting data from 15 pts with NSCLC. The first-line treatments were Carboplatin (40%, 6/15), Opdivo (26.7%, 4/15), Afatinib (13.3%, 2/15), Ceritinib (6.7%, 1/15), Crizotinib (6.7%, 1/15), and Taxotere/Cyramza (6.7%, 1/15). Histological subtypes were 73.3% (11/15) adeno, 20% (3/15) squamous, and 6.7% (1/15) other. The majority of patients were Caucasian (66.7%, 10/15), Hispanic (26.7%, 4/15), and African American (6.7%, 1/15).
S959
Levels of ctDNA and ctRNA were significantly correlated with one another across patient blood draws (r ¼ 0.5781, p < 0.0001). After the first 2 cycles of therapy, 9 of the 15 patients achieved SD, of whom 8 were analyzed for ctDNA/ctRNA levels. In 7/8 of pts who had SD indicated by CT scan, CtDNA/ctRNA levels were stable, while the 2 PD pts showed significant increases in levels of ctDNA/ctRNA 4.8 weeks prior to progression. In the 2 SD pts treated with Opdivo, PD-L1 expression was stable during the cycles when CT scans also indicated an SD status. Conclusion: In almost 90% of the pts, constant ctDNA/ ctRNA levels correlated with stable disease status as seen by CT; moreover, in 2 pts changes in the levels of both ct nucleic acids predicted progression about 5 weeks before CT scans. Importantly, the concordance between cDNA and cfRNA suggest that cfRNA can just as effective as cfDNA as a prognostic tool, while adding the extra dimension of gene expression. Keywords: cfDNA, cfRNA, plasma, liquid biopsies
P2.03b-040 NANOG Predicts Poor Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy Topic: Biomarkers Seung Hyeun Lee,1 Myung Jae Park,1 So Young Park,1 Kwang Ho In,2 Chul Hwan Kim3 1Department of Internal Medicine, Kyung Hee University Medical Center, Seoul/Korea, Republic of, 2Department of Internal Medicine, Korea University College of Medicine, Seoul/ Korea, Republic of, 3Department of Pathology, Korea University College of Medicine, Seoul/Korea, Republic of Background: NANOG is a master transcription factor that regulates embryonic stem cell pluripotency and cellfate specification though complex interaction with a myriad of factors in signaling pathways. Cumulating evidence suggests that it has oncogenic potential correlating with cell proliferation, clonogenic growth, tumorigenicity and invasiveness. Increased NANOG expression has been reported to be related with poor survival in several human malignancies including hepatic, breast, ovarian and colorectal cancers. However, clinical significance of NANOG overexpression in lung cancer has been scarcely evaluated, and correlation between NANOG expression and prognosis in advanced non-small cell lung cancer (NSCLC) has not been studied. The aim of this study is to investigate whether NANOG expression is