Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patient Selection and Data Collection
2.2. Statistics
3. Results
3.1. Patient Characteristics
3.2. Univariable Analysis on NLR and Survival Outcomes
3.3. Univariable Analysis on BMI and Studied Outcomes
3.4. Total Number of Disease Sites, Adverse Drug Events and ECOG Score on NLR
3.5. Multivariable Analysis on Baseline Patient Characteristics and Survival Outcomes at Treatment Start
3.6. Multivariable Analysis of NLR at Treatment Start, 6 Weeks and 12 Weeks of Therapy
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patient Characteristics | NLR 1 < 5 | NLR ≥ 5 | NLR N/A 2 | Total |
---|---|---|---|---|
Age at Diagnosis | ||||
<65 | 46 | 23 | 4 | 73 |
≥65 | 42 | 17 | 5 | 64 |
Gender | ||||
Male | 19 | 14 | 2 | 35 |
Female | 69 | 26 | 7 | 102 |
Race | ||||
White | 53 | 26 | 7 | 86 |
Asian | 9 | 3 | 0 | 12 |
Black/African American | 20 | 8 | 2 | 30 |
Other | 4 | 1 | 0 | 5 |
More than one | 1 | 0 | 0 | 1 |
Not reported | 1 | 2 | 0 | 3 |
Smoking Status | ||||
Never | 41 | 17 | 4 | 62 |
≤15 pack years | 30 | 12 | 2 | 44 |
>15 pack years | 17 | 10 | 3 | 30 |
Former (not counted) | 0 | 1 | 0 | 1 |
Baseline BMI 3 | ||||
≤18.5 | 0 | 2 | 0 | 2 |
>18.5 to ≤25 | 36 | 23 | 3 | 62 |
>25 to ≤30 | 31 | 10 | 3 | 44 |
>30 | 20 | 5 | 3 | 28 |
Not available | 1 | 0 | 0 | 1 |
Number of Metastatic Sites | ||||
1 | 8 | 1 | 1 | 10 |
2 | 29 | 1 | 3 | 33 |
3 | 25 | 14 | 3 | 42 |
4 | 16 | 11 | 1 | 28 |
5 | 8 | 8 | 0 | 16 |
6 | 0 | 1 | 0 | 1 |
7 | 2 | 4 | 1 | 7 |
CNS 4 Metastases | ||||
Present | 25 | 21 | 1 | 47 |
Not present | 63 | 19 | 8 | 90 |
Histology | ||||
Adenocarcinoma | 86 | 40 | 9 | 135 |
Mixed/poorly differentiated NSCLC 5 | 2 | 0 | 0 | 2 |
Baseline Mutations | ||||
Exon 19 Deletion (Total with All Co-mutations) | 49 | 21 | 2 | 72 |
Exon 19 alone | 46 | 21 | 2 | 69 |
+T790M | 2 | 0 | 0 | 2 |
+EGFR 6 amplification | 1 | 0 | 0 | 1 |
+L858R | 1 | 0 | 0 | 1 |
L858R (Total with All Co-mutations) | 30 | 15 | 2 | 47 |
L858R alone | 24 | 14 | 2 | 40 |
+T790M | 4 | 1 | 0 | 5 |
+Exon 19 | 1 | 0 | 0 | 1 |
+L833V | 1 | 0 | 0 | 1 |
T790M (Total with All Co-mutations) | 6 | 1 | 0 | 7 |
+Exon 19 | 2 | 0 | 0 | 2 |
+L858R | 4 | 1 | 0 | 5 |
G719X (Total with All Co-mutations) | 6 | 3 | 0 | 9 |
G719A alone | 1 | 1 | 0 | 2 |
G719A + L833_V834delinsFL | 1 | 0 | 0 | 1 |
G719A + S768I | 1 | 0 | 0 | 1 |
G719C + S768I | 1 | 0 | 0 | 1 |
G719A + E709A | 1 | 0 | 0 | 1 |
G719S + G709A | 1 | 0 | 0 | 1 |
G719S + E709A | 0 | 2 | 0 | 2 |
S768I (Total with All Co-mutations) | 3 | 0 | 1 | 4 |
S768I alone | 1 | 0 | 1 | 2 |
S768I +G719X | 2 | 0 | 0 | 2 |
L861Q Alone | 1 | 0 | 1 | 2 |
Others | ||||
Exon 18 del p.E709_T710delinsD | 0 | 0 | 1 | 1 |
LUL: Exon 19; RUL: pT790M and L861Q | 0 | 0 | 1 | 1 |
EGFR amplification and E709_T710 > D; | 0 | 0 | 1 | 1 |
Not known | 1 | 1 | 0 | 2 |
First-line TKI 7 | ||||
Erlotinib | 48 | 21 | 7 | 76 |
Osimertinib | 26 | 9 | 1 | 36 |
Afatinib | 13 | 10 | 1 | 24 |
Gefitinib | 1 | 0 | 0 | 1 |
TKI Began 1+ Years after Advanced Stage Diagnosis | ||||
Yes | 7 | 3 | 0 | 10 |
No | 81 | 37 | 9 | 127 |
Other Systemic Treatment for Metastatic Disease before Starting TKI | ||||
Yes | 28 | 8 | 0 | 36 |
No | 60 | 32 | 9 | 101 |
ECOG 8 Score | ||||
0 | 30 | 9 | 5 | 44 |
1 | 49 | 23 | 4 | 76 |
2 | 6 | 6 | 0 | 12 |
3 | 2 | 2 | 0 | 4 |
Not reported | 1 | 0 | 0 | 1 |
Toxicity Grade | ||||
Grade 0–2 | 62 | 31 | 5 | 98 |
Grade 3–4 | 25 | 8 | 4 | 37 |
Grade 5 | 1 | 1 | 0 | 2 |
TKI | Therapy Start | 6 Weeks | 12 Weeks | |||
---|---|---|---|---|---|---|
Drug | NLR < 5 | NLR ≥ 5 | NLR < 5 | NLR ≥ 5 | NLR < 5 | NLR ≥ 5 |
Afatinib | 15% | 15% | 19% | 12% | 19% | 15% |
Erlotinib | 54.50% | 32% | 50% | 69% | 59% | 50% |
Gefitinib | 1% | 0% | 1% | 0% | 1% | 0% |
Osimertinib | 29.50% | 53% | 30% | 19% | 21% | 35% |
Outcome | NLR | Measurement Time | n | Median (Months) | 95% CI | p-Value |
---|---|---|---|---|---|---|
OS | <5 | Treatment Start | 88 | 58 | (45.5, 75.3) | 0.0024 |
OS | ≥5 | Treatment Start | 40 | 27.6 | (21.3, 47.3) | |
OS | <5 | 6 weeks after Treatment Start | 104 | 59.7 | (44.2, 75.3) | 0.015 |
OS | ≥5 | 6 weeks after Treatment Start | 27 | 39.1 | (24.3, 47.3) | |
OS | <5 | 12 weeks after Treatment Start | 89 | 59.7 | (47.3, 73.8) | 0.00083 |
OS | ≥5 | 12 weeks after Treatment Start | 21 | 25.2 | (10.2, 39.1) | |
PFS | <5 | Treatment Start | 88 | 17.2 | (13.3, 23.3) | 0.0029 |
PFS | ≥5 | Treatment Start | 40 | 14 | (9.8, 16.7) | |
PFS | <5 | 6 weeks after Treatment Start | 104 | 17.4 | (14.9, 20.5) | 0.037 |
PFS | ≥5 | 6 weeks after Treatment Start | 27 | 12.1 | (6.3, 15.4) | |
PFS | <5 | 12 weeks after Treatment Start | 89 | 18.4 | (15.4, 24.3) | 0.0003 |
PFS | ≥5 | 12 weeks after Treatment Start | 21 | 5.8 | (3.4, 14.0) | |
OS | <5 | Progression | 71 | 33.4 | (25.2, 42.5) | 0.00022 |
OS | ≥5 | Progression | 31 | 10.2 | (3.7, 17.9) |
OS | PFS | ||||||
---|---|---|---|---|---|---|---|
Group | HR 1 | 95% CI | p | Group | HR | 95% CI | p |
NLR (pre-treatment) | NLR (pre-treatment) | ||||||
≥5 (vs. <5) | 1.935 | (0.911, 4.106) | 0.086 | ≥5 (vs. <5) | 1.077 | (0.602, 1.925) | 0.803 |
Age | Age | ||||||
≥65 (vs. <65) | 1.107 | (0.574, 2.135) | 0.7615 | ≥65 (vs. <65) | 0.902 | (0.558, 1.456) | 0.672 |
Gender | Gender | ||||||
Male (vs. Female) | 0.892 | (0.410, 1.942) | 0.773 | Male (vs. Female) | 16.7 | (14.5, 20.0) | 0.052 |
Race | Race | ||||||
Asian (vs. White) | 4.274 | (1.399, 13.064) | 0.011 | Asian (vs. White) | 0.951 | (0.418, 2.167) | 0.906 |
Black (vs. White) | 0.998 | (0.424, 2.305) | 0.978 | Black (vs. White) | 0.72 | (0.384, 1.348) | 0.304 |
Other (vs. White) | 5.169 | (1.191, 22.428) | 0.028 | Other (vs. White) | 1.413 | (0.492, 4.061) | 0.521 |
Smoking History | Smoking History | ||||||
≤15 pack years (vs. never) | 2.036 | (0.884, 4.688) | 0.095 | ≤15 pack years (vs. never) | 1.452 | (0.801, 2.632) | 0.219 |
>15 pack years (vs. never) | 4.574 | (1.835, 11.401) | 0.001 | >15 pack years (vs. never) | 1.754 | (0.816, 3.771) | 0.15 |
BMI Therapy Start | BMI Therapy Start | ||||||
<18.5 (vs. 18.5 to ≤25) | 3.85 | (0.575, 25.762) | 0.165 | <18.5 (vs. 18.5 to ≤25) | 1.601 | (0.263, 9.751) | 0.61 |
>25 to ≤30 (vs. 18.5 to ≤25) | 1.205 | (0.563, 2.577) | 0.631 | >25 to ≤30 (vs. 18.5 to ≤25) | 1.314 | (0.766, 2.253) | 0.321 |
>30 (vs. 18.5 to ≤25) | 0.487 | (0.177, 1.337) | 1.625 | >30 (vs. 18.5 to ≤25) | 1.155 | (0.597, 2.234) | 0.669 |
Number of Disease Sites (continuous) | 1.825 | (1.328, 2.507) | 0.0002 | Number of Disease Sites (continuous) | 1.473 | (1.172,1.851) | 0.0009 |
TKI | TKI | ||||||
Afatinib (vs. osimertinib) | 1.123 | (0.310, 4.006) | 0.86 | Afatinib (vs. osimertinib) | 2.267 | (0.958, 5.363) | 0.063 |
Erlotinib (vs. osimertinib) | 1.562 | (0.586, 4.162) | 0.372 | Erlotinib (vs. osimertinib) | 2.925 | (1.501, 5.699) | 0.0016 |
TKI Began 1+ Years after Stage IV Diagnosis | 0.529 | (0.126, 2.224) | 0.385 | TKI Began 1+ Years after Stage IV Diagnosis | 0.643 | (0.238, 1.739) | 0.385 |
Received Other Systemic Treatment before TKI | 2.253 | (0.976, 5.203) | 0.058 | Received Other Systemic Treatment before TKI | 1.491 | (0.815, 2.727) | 0.195 |
ECOG Score | ECOG Score | ||||||
2–3 (vs. 0–1) | 4.39 | (2.037, 9.458) | 0.0002 | (2–3 vs. 0–1) | 3.435 | (1.779, 6.634) | 0.0002 |
Highest Toxicity Grade | Highest Toxicity Grade | ||||||
3–5 (vs. 0–2) | 1.475 | (0.748, 2.909) | 0.262 | 3–5 (vs. 0–2) | 0.837 | (0.500, 1.400) | 0.497 |
CNS Metastases | 0.526 | (0.235, 1.177) | 0.118 | CNS Metastases | 0.784 | (0.452, 1.358) | 0.385 |
Baseline Mutation | Baseline Mutation | ||||||
Exon 19 | 0.213 | (0.048, 0.948) | 0.042 | Exon 19 | 0.339 | (0.090, 1.309) | 0.117 |
L858R | 1.44 | (0.331, 6.270) | 0.627 | L858R | 0.732 | (0.186, 2.889) | 0.656 |
T790M | 0.337 | (0.101, 1.125) | 0.077 | T790M | 0.714 | (0.280, 1.822) | 0.481 |
G719X | 6.239 | (1.026, 37.931) | 0.047 | G719X | 1.014 | (0.201, 5.110 | 0.987 |
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Yun, N.K.; Rouhani, S.J.; Bestvina, C.M.; Ritz, E.M.; Gilmore, B.A.; Tarhoni, I.; Borgia, J.A.; Batus, M.; Bonomi, P.D.; Fidler, M.J. Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy. Cancers 2021, 13, 1426. https://doi.org/10.3390/cancers13061426
Yun NK, Rouhani SJ, Bestvina CM, Ritz EM, Gilmore BA, Tarhoni I, Borgia JA, Batus M, Bonomi PD, Fidler MJ. Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy. Cancers. 2021; 13(6):1426. https://doi.org/10.3390/cancers13061426
Chicago/Turabian StyleYun, Nicole K., Sherin J. Rouhani, Christine M. Bestvina, Ethan M. Ritz, Brendan A. Gilmore, Imad Tarhoni, Jeffrey A. Borgia, Marta Batus, Philip D. Bonomi, and Mary Jo Fidler. 2021. "Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy" Cancers 13, no. 6: 1426. https://doi.org/10.3390/cancers13061426