LASSO-Driven Selection of Biochemical and Clinical Markers for Primary Resistance to PD-1 Inhibitors in Metastatic Melanoma
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Data Collection
2.3. Statistical Analysis
2.4. Management of Missing Data
3. Results
3.1. Patient Characteristics
3.2. Markers Selection
3.3. Construction of Nomogram
3.4. Model Performance Metrics
4. Discussion
5. Limitation
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
- Lymphocyte
- Monocyte
- Eosinophil
- Mean Platelet Volume
- Lactate Dehydrogenase
- C-Reactive Protein
- Albumin
- Globulin
- Neutrophil-to-Lymphocyte Ratio (NLR)
- Lymphocyte-to-Monocyte Ratio (LMR)
- Platelet-to-Lymphocyte Ratio (PLR)
- Mean Platelet Volume to Lymphocyte Ratio
- Albumin-to-Globulin Ratio
- Scottish Inflammatory Prognostic Score (SIPS)
- Royal Marsden Hospital (RMH) Prognostic Score
- Global Risk Index Model Score (GRIm-Score)
- Combine Immun Index (CII)
- Haemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score
- MD Anderson Immune Checkpoint Inhibitor Score (MD Anderson Score)
- Prognostic Inflammatory and Nutritional Index (PIV score)
- Pan-Immune Inflammation Value and ECOG (PILE score)
- Prognostic Nutritional Index (PNI)
- Systemic Immune Inflammation Index (SII)
- Systemic Inflammatory Response Index (SIRI)
Appendix B
- Neutrophil-to-Lymphocyte Ratio (NLR): Neutrophil Count/Lymphocyte Count
- Lymphocyte-to-Monocyte Ratio (LMR): Lymphocyte Count/Monocyte Count
- Platelet-to-Lymphocyte Ratio (PLR): Platelet Count/Lymphocyte Count
- Mean Platelet Volume to Lymphocyte Ratio: Mean Platelet Volume (MPV)/Lymphocyte Count
- Albumin-to-Globulin Ratio: Albumin/Globulin
- Scottish Inflammatory Prognostic Score (SIPS):
- If Albumin < 35 g/L and CRP > 10 mg/L, score = 2
- If one is abnormal, score = 1
- If both are normal, score = 0
- Royal Marsden Hospital (RMH) Prognostic Score:
- Albumin < 35 g/L
- Lactate Dehydrogenase (LDH) > Upper Limit of Normal (ULN)
- More than two sites of metastases
- Global Risk Index Model Score (GRIm-Score): Combines Albumin, Haemoglobin, NLR, and BMI.
- Combine Immun Index (CII): (NLR × Platelet Count)/Lymphocyte Count
- Haemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score: (Haemoglobin × Albumin × Lymphocyte Count)/Platelet Count
- MD Anderson Immune Checkpoint Inhibitor Score: Based on specific biomarkers and inflammatory parameters.
- Prognostic Inflammatory and Nutritional Index (PIV score): (Platelet Count × Neutrophil Count)/(Lymphocyte Count × Albumin)
- Pan-Immune Inflammation Value and ECOG (PILE score): ECOG Score + (AST + ALT + Bilirubin)
- Prognostic Nutritional Index (PNI): (Albumin (g/dL) × 10) + (Lymphocyte Count (per mm3) × 0.005)
- Systemic Immune Inflammation Index (SII): (Platelet Count × Neutrophil Count)/Lymphocyte Count
- Systemic Inflammatory Response Index (SIRI): (Neutrophil Count × Monocyte Count)/Lymphocyte Count
Appendix C
Variable | Lambda |
---|---|
PLR | 0.002256649 |
MPV/lymphocyte | 0.020427439 |
PNI | −0.003089101 |
Globulin | −0.284104028 |
ICI before ICI | −0.197677588 |
Metastasis Status | 0.343231699 |
Lesion localisation | 0.615436046 |
Oligometastasis Status | −0.143845135 |
Metastasis Sites | 1.071470755 |
BRAF mutation | 0.163690698 |
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Resistance Status | ||||
---|---|---|---|---|
Patient Characteristics | Non-Resistant | Resistant | Total | |
Total N (%) | 61 (55.5) | 49 (44.5) | 110 | |
Age | Median (IQR) | 61.0 (48.0–68.0) | 59.0 (46.0–67.0) | 60.0 (47.2–68.0) |
Sex | Male | 34 (55.7) | 24 (49.0) | 58 (52.7) |
Female | 27 (44.3) | 25 (51.0) | 52 (47.3) | |
ECOG PS | Poor (0–1) | 5 (8.2) | 8 (16.3) | 13 (11.8) |
Good (2–3) | 56 (91.8) | 41 (83.7) | 97 (88.2) | |
BRAF/MEKi treatment before PD1 | No | 51 (83.6) | 39 (79.6) | 90 (81.8) |
Yes | 10 (16.4) | 10 (20.4) | 20 (18.2) | |
Chemotherapy Before PD1 | No | 48 (78.7) | 36 (73.5) | 84 (76.4) |
Yes | 13 (21.3) | 13 (26.5) | 26 (23.6) | |
ICI before ICI | No | 40 (65.6) | 35 (71.4) | 75 (68.2) |
İpilimumab | 18 (29.5) | 14 (28.6) | 32 (29.1) | |
PD1 | 3 (4.9) | 0 (0.0) | 3 (2.7) | |
Metastasis Status | De Novo | 28 (45.9) | 15 (30.6) | 43 (39.1) |
Recurrent | 33 (54.1) | 34 (69.4) | 67 (60.9) | |
Anti-PD1 Treatment Line | First | 35 (57.4) | 23 (46.9) | 58 (52.7) |
Second and Beyond | 26 (42.6) | 26 (53.1) | 52 (47.3) | |
Lesion Localization | Non-Acral Cutaneous | 44 (72.1) | 24 (49.0) | 68 (61.8) |
Acral | 9 (14.7) | 15 (30.5) | 24 (21.8) | |
Mucosal | 8 (13.1) | 10 (20.4) | 18 (16.4) | |
Oligometastasis Status | No | 26 (42.6) | 36 (73.5) | 62 (56.4) |
Yes | 35 (57.4) | 13 (26.5) | 48 (43.6) | |
Stage | M1a | 26 (42.6) | 8 (16.3) | 34 (30.9) |
M1b | 14 (23.0) | 10 (20.4) | 24 (21.8) | |
M1c | 17 (27.9) | 24 (49.0) | 41 (37.3) | |
M1d | 4 (6.6) | 7 (14.3) | 11 (10.0) | |
Metastasis Site | <3 | 49 (80.3) | 20 (40.8) | 69 (62.7) |
≥3 | 12 (19.7) | 29 (59.2) | 41 (37.3) | |
BRAF mutation | Wild | 47 (77.0) | 34 (69.4) | 81 (73.6) |
Mutant | 14 (23.0) | 15 (30.6) | 29 (26.4) | |
SIPS | Good | 50 (86.2) | 33 (80.5) | 83 (83.8) |
Poor | 8 (13.8) | 8 (19.5) | 16 (16.2) | |
Royal Marsden Hospital Score | Good | 29 (50.9) | 10 (24.4) | 39 (39.8) |
Poor | 28 (49.1) | 31 (75.6) | 59 (60.2) | |
MD Anderson ICI Score | Good | 17 (28.8) | 5 (11.9) | 22 (21.8) |
Intermediate | 38 (64.4) | 26 (61.9) | 64 (63.4) | |
Poor | 4 (6.8) | 11 (26.2) | 15 (14.9) | |
Lymphocyte | Median (IQR) | 1820.0 (1315.0–2315.0) | 1430.0 (1080.0–1780.0) | 1635.0 (1255.0–2125.0) |
Monocyte | Median (IQR) | 560.0 (440.0–785.0) | 560.0 (439.5–710.0) | 560.0 (440.0–737.5) |
Eosinophil | Median (IQR) | 180.0 (102.5–290.0) | 100.0 (50.0–205.0) | 130.0 (60.0–250.0) |
Albumin | Median (IQR) | 4.3 (4.0–4.6) | 4.1 (3.9–4.4) | 4.2 (3.9–4.5) |
Globulin | Median (IQR) | 2.8 (2.5–3.2) | 2.8 (2.4–3.0) | 2.8 (2.5–3.1) |
CRP | Median (IQR) | 0.2 (0.1–1.1) | 0.5 (0.2–1.4) | 0.3 (0.1–1.4) |
LDH | Median (IQR) | 201.0 (175.0–274.0) | 227.0 (177.0 t–290.0) | 208.5 (175.0–278.2) |
MPV | Median (IQR) | 10.1 (9.6–10.7) | 9.8 (9.2–10.3) | 10.0 (9.5–10.7) |
NLR | Median (IQR) | 2.4 (1.7–3.3) | 3.0 (2.5–3.7) | 2.7 (2.0-3.6) |
LMR | Median (IQR) | 3.0 (2.5–4.2) | 2.6 (2.0–3.3) | 2.9 (2.2- 3.8) |
PLR | Median (IQR) | 153.3 (112.2–196.9) | 196.4 (127.0–294.2) | 162.9 (113.8–236.8) |
MPV/Lymphocyte | Median (IQR) | 5.4 (4.6–7.5) | 6.5 (5.7–8.8) | 6.0 (4.7–8.3) |
HALP Score | Median (IQR) | 39.1 (26.8–50.3) | 26.4 (16.0–49.2) | 34.3 (19.9–50.2) |
PIV Score | Median (IQR) | 383.3 (206.1–651.0) | 474.0 (276.6–936.6) | 438.1 (225.7–822.8) |
PNI Score | Median (IQR) | 51.6 (46.5–54.7) | 48.7 (44.5–51.6) | 50.2 (45.6–54.4) |
SII Score | Median (IQR) | 676.0 (421.2–982.4) | 889.7 (526.4–1365.1) | 724.2 (465.3–1123.7) |
Primary Resistance | No | Yes | OR (Univariable) | OR (Multivariable) | |
---|---|---|---|---|---|
MPV/lymphocyte | Mean (SD) | 6.4 (2.8) | 7.8 (3.8) | 1.16 (1.01–1.35, p = 0.043) | |
PNI | Mean (SD) | 51.9 (5.8) | 48.7 (5.8) | 0.91 (0.84–0.98, p = 0.015) | |
ICI before ICI | No | 40 (53.3) | 35 (46.7) | - | |
Yes | 21 (60) | 14 (40) | 0.59 (0.22–1.47, p = 0.264) | ||
Metastasis Status | Denovo | 28 (65.1) | 15 (34.9) | - | |
Recurrent | 33 (49.3) | 34 (50.7) | 2.28 (0.97–5.63, p = 0.065) | ||
Oligometastasis Status | No | 49 (71.0) | 20 (29.0) | - | |
Yes | 12 (29.3) | 29 (70.7) | 0.30 (0.12–0.72, p = 0.008) | ||
Lesion Localisation | Non Acral | 44 (64.7) | 24 (35.3) | - | |
Acral + Mucosal | 17 (40.5) | 25 (59.5) | 2.32 (0.99–5.53, p = 0.055) | 3.82 (1.16–12.6, p = 0.027) | |
BRAF Mutation | Wild | 28 (65.1) | 15 (34.9) | - | - |
Mutant | 33 (49.3) | 34 (50.7) | 1.78 (0.69–4.65, p = 0.234) | 5.22 (1.31–20.82, p = 0.019) | |
Metastasis Grup | <3 | 47 (58.0) | 34 (42.0) | - | |
≥3 | 14 (48.3) | 15 (51.7) | 5.75 (2.35–14.90, p < 0.001) | 11.4 (3.43–37.55, p < 0.001) | |
PLR | Mean (SD) | 164.2 (72.5) | 223.7 (118.3) | 1.01 (1.00–1.01, p = 0.006) | 1.007 (1.01–1.01, p = 0.019) |
Globulin | Mean (SD) | 2.9 (0.7) | 2.8 (0.5) | 0.75 (0.36–1.49, p = 0.429) | 0.35 (0.14–0.88, p = 0.027) |
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© 2025 by the authors. Published by MDPI on behalf of the Lithuanian University of Health Sciences. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Yuksel, H.C.; Acar, C.; Sahin, G.; Celebi, G.; Tunbekici, S.; Karaca, B.S. LASSO-Driven Selection of Biochemical and Clinical Markers for Primary Resistance to PD-1 Inhibitors in Metastatic Melanoma. Medicina 2025, 61, 1559. https://doi.org/10.3390/medicina61091559
Yuksel HC, Acar C, Sahin G, Celebi G, Tunbekici S, Karaca BS. LASSO-Driven Selection of Biochemical and Clinical Markers for Primary Resistance to PD-1 Inhibitors in Metastatic Melanoma. Medicina. 2025; 61(9):1559. https://doi.org/10.3390/medicina61091559
Chicago/Turabian StyleYuksel, Haydar C., Caner Acar, Gokhan Sahin, Gulcin Celebi, Salih Tunbekici, and Burcak S. Karaca. 2025. "LASSO-Driven Selection of Biochemical and Clinical Markers for Primary Resistance to PD-1 Inhibitors in Metastatic Melanoma" Medicina 61, no. 9: 1559. https://doi.org/10.3390/medicina61091559
APA StyleYuksel, H. C., Acar, C., Sahin, G., Celebi, G., Tunbekici, S., & Karaca, B. S. (2025). LASSO-Driven Selection of Biochemical and Clinical Markers for Primary Resistance to PD-1 Inhibitors in Metastatic Melanoma. Medicina, 61(9), 1559. https://doi.org/10.3390/medicina61091559