Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer
Abstract
:1. Introduction
2. Material and Methods
2.1. Patients
2.2. Evaluation of PD-L1 Expression by Immunohistochemistry
2.3. TILs Assessment
2.4. Assessment of Response to Neoadjuvant Radiotherapy
2.5. Statistical Analyses
3. Results
3.1. Patients, Tumor, and Treatment Characteristics
3.2. Effect of Short-Course versus Long-Course RT on PD-L1+ Cells
3.3. Relation between CD8 TILs Infiltration and PD-L1+ Cells
3.4. Survival and Tumor Regression Grade Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cohort | Pre-Treatment | Post-Treatment | |||||
---|---|---|---|---|---|---|---|
PDL1 ≤ 0.15 | PDL1 > 0.15 | p Value | PDL1 ≤ 0.5 | PDL1 > 0.5 | p Value 4 | ||
Age (Years) | 0.14 | 0.39 | |||||
Mean (SD 1) | 68.1 (10.0) | 66.2 (10.7) | 69.9 (9.0) | 67.0 (11.0) | 69.1 (9.0) | ||
Median [range] | 69.0 [29.0–85.0] | 68.0 [29.0–81.0] | 70.0 [48.0–85.0] | 69.0 [29.0–84.0] | 70.0 [43.0–85.0] | ||
Gender | 0.09 | 0.22 | |||||
Male | 47 (63.5%) | 27 (73.0%) | 20 (54.1%) | 26 (70.3%) | 21 (56.8%) | ||
Female | 27 (36.5%) | 10 (27.0%) | 17 (45.9%) | 11 (29.7%) | 16 (43.2%) | ||
Tumor Distance from Anal Verge (mm) | 0.08 | 0.15 | |||||
N | 72 | 36 | 36 | 37 | 35 | ||
Mean (SD) | 6.2 (3.8) | 6.9 (3.8) | 5.4 (3.8) | 6.5 (3.5) | 5.7 (4.1) | ||
Median [range] | 6.0 [0.0–18.0] | 6.5 [0.0–18.0] | 4.5 [0.0–15.0] | 7.0 [0.0–15.0] | 6.0 [0.0–18.0] | ||
Tumor Distance from Anal Verge (mm) | 0.01 | 0.36 | |||||
<5 cm | 25 (34.7%) | 7 (19.4%) | 18 (50.0%) | 10 (27.0%) | 15 (42.9%) | ||
[5–10] cm | 33 (45.8%) | 22 (61.1%) | 11 (30.6%) | 19 (51.4%) | 14 (40.0%) | ||
≥10 cm | 14 (19.4%) | 7 (19.4%) | 7 (19.4%) | 8 (21.6%) | 6 (17.1%) | ||
Missing | 2 | 1 | 1 | 0 | 2 | ||
Histopathological Subtype | 0.21 | 0.74 | |||||
Poorly differentiated adenocarcinoma | 2 (2.9%) | 2 (5.6%) | 0 (0.0%) | 1 (2.9%) | 1 (2.8%) | ||
Moderately differentiated adenocarcinoma | 36 (51.4%) | 21 (58.3%) | 15 (44.1%) | 20 (58.8%) | 16 (44.4%) | ||
Highly differentiated adenocarcinoma | 30 (42.9%) | 12 (33.3%) | 18 (52.9%) | 12 (35.3%) | 18 (50.0%) | ||
Other | 2 (2.9%) | 1 (2.8%) | 1 (2.9%) | 1 (2.9%) | 1 (2.8%) | ||
Missing | 4 | 1 | 3 | 3 | 1 | ||
cT Stage | 0.59 | 0.70 | |||||
T2 | 2 (3.0%) | 0 (0.0%) | 2 (6.1%) | 1 (3.2%) | 1 (2.9%) | ||
T3 | 58 (87.9%) | 30 (90.9%) | 28 (84.8%) | 26 (83.9%) | 32 (91.4%) | ||
T4 | 6 (9.1%) | 3 (9.1%) | 3 (9.1%) | 4 (12.9%) | 2 (5.7%) | ||
Missing | 8 | 4 | 4 | 6 | 2 | ||
cN Stage | 0.88 | 0.37 | |||||
N0 | 34 (55.7%) | 17 (56.7%) | 17 (54.8%) | 19 (61.3%) | 15 (50.0%) | ||
N+ | 27 (44.3%) | 13 (43.3%) | 14 (45.2%) | 12 (38.7%) | 15 (50.0%) | ||
Missing | 13 | 7 | 6 | 6 | 7 | ||
cM Stage | 1.00 | 1.00 | |||||
M0 | 66 (95.7%) | 33 (97.1%) | 33 (94.3%) | 34 (94.4%) | 32 (97.0%) | ||
M+ | 3 (4.3%) | 1 (2.9%) | 2 (5.7%) | 2 (5.6%) | 1 (3.0%) | ||
Missing | 5 | 3 | 2 | 1 | 4 | ||
Radiation Dose Per Fraction (Gy) | 0.46 | 0.22 | |||||
≤2 | 47 (63.5%) | 25 (67.6%) | 22 (59.5%) | 26 (70.3%) | 21 (56.8%) | ||
>2 | 27 (36.5%) | 12 (32.4%) | 15 (40.5%) | 11 (29.7%) | 16 (43.2%) | ||
Chemotherapy | 0.11 | 0.88 | |||||
No | 44 (60.3%) | 19 (51.4%) | 25 (69.4%) | 22 (59.5%) | 22 (61.1%) | ||
Yes | 29 (39.7%) | 18 (48.6%) | 11 (30.6%) | 15 (40.5%) | 14 (38.9%) | ||
Missing | 1 | 0 | 1 | 0 | 1 | ||
Neoadjuvant Chemotherapy | |||||||
No | 68 (100.0%) | 34 (100.0%) | 34 (100.0%) | 33 (100.0%) | 35 (100.0%) | ||
Missing | 6 | 3 | 3 | 4 | 2 | ||
Concurrent Chemotherapy | 0.73 | 0.46 | |||||
No | 52 (73.2%) | 25 (71.4%) | 27 (75.0%) | 25 (69.4%) | 27 (77.1%) | ||
Yes | 19 (26.8%) | 10 (28.6%) | 9 (25.0%) | 11 (30.6%) | 8 (22.9%) | ||
Missing | 3 | 2 | 1 | 1 | 2 | ||
Type of Concurrent Chemotherapy | 0.82 | 0.92 | |||||
5FU 2 | 1 (5.3%) | 0 (0.0%) | 1 (11.1%) | 1 (9.1%) | 0 (0.0%) | ||
Xeloda | 3 (15.8%) | 2 (20.0%) | 1 (11.1%) | 2 (18.2%) | 1 (12.5%) | ||
Folinic acid + 5FU | 12 (63.2%) | 7 (70.0%) | 5 (55.6%) | 7 (63.6%) | 5 (62.5%) | ||
Folfox | 1 (5.3%) | 0 (0.0%) | 1 (11.1%) | 0 (0.0%) | 1 (12.5%) | ||
Cisplatine + 5FU | 2 (10.5%) | 1 (10.0%) | 1 (11.1%) | 1 (9.1%) | 1 (12.5%) | ||
Adjuvant Chemotherapy | 0.20 | 0.78 | |||||
No | 55 (76.4%) | 26 (70.3%) | 29 (82.9%) | 27 (75.0%) | 28 (77.8%) | ||
Yes | 17 (23.6%) | 11 (29.7%) | 6 (17.1%) | 9 (25.0%) | 8 (22.2%) | ||
Missing | 2 | 0 | 2 | 1 | 1 | ||
Type of Adjuvant Chemotherapy | 1.00 | 0.56 | |||||
Folinic acid + 5 FU | 9 (52.9%) | 6 (54.5%) | 3 (50.0%) | 5 (55.6%) | 4 (50.0%) | ||
Folfox | 4 (23.5%) | 2 (18.2%) | 2 (33.3%) | 1 (11.1%) | 3 (37.5%) | ||
Other | 4 (23.5%) | 3 (27.3%) | 1 (16.7%) | 3 (33.3%) | 1 (12.5%) | ||
Time between End of Radiotherapy and Surgery (Days) | 0.92 | 0.11 | |||||
N | 74 | 37 | 37 | 37 | 37 | ||
Mean (SD) | 43.4 (35.3) | 46.6 (48.8) | 40.2 (11.0) | 42.9 (13.2) | 43.9 (48.5) | ||
Median [Range] | 40.0 [4.0–319.0] | 42.0 [4.0–319.0] | 40.0 [19.0–65.0] | 42.0 [15.0–77.0] | 39.0 [4.0–319.0] | ||
Conservative Surgery | 0.07 | 0.18 | |||||
No | 32 (43.8%) | 12 (33.3%) | 20 (54.1%) | 13 (36.1%) | 19 (51.4%) | ||
Yes | 41 (56.2%) | 24 (66.7%) | 17 (45.9%) | 23 (63.9%) | 18 (48.6%) | ||
Missing | 1 | 1 | 0 | 1 | 0 | ||
Margins | 1.00 | 0.35 | |||||
R0 | 69 (94.5%) | 34 (94.4%) | 35 (94.6%) | 36 (97.3%) | 33 (91.7%) | ||
R1 | 4 (5.5%) | 2 (5.6%) | 2 (5.4%) | 1 (2.7%) | 3 (8.3%) | ||
Missing | 1 | 1 | 0 | 0 | 1 | ||
pN+ | 0.11 | 0.67 | |||||
No | 49 (67.1%) | 21 (58.3%) | 28 (75.7%) | 24 (64.9%) | 25 (69.4%) | ||
Yes | 24 (32.9%) | 15 (41.7%) | 9 (24.3%) | 13 (35.1%) | 11 (30.6%) | ||
Missing | 1 | 1 | 0 | 0 | 1 | ||
ypT Stage | 0.69 | 0.40 | |||||
0 | 4 (5.4%) | 2 (5.4%) | 2 (5.4%) | 3 (8.1%) | 1 (2.7%) | ||
1 | 3 (4.1%) | 1 (2.7%) | 2 (5.4%) | 1 (2.7%) | 2 (5.4%) | ||
2 | 16 (21.6%) | 7 (18.9%) | 9 (24.3%) | 5 (13.5%) | 11 (29.7%) | ||
3 | 46 (62.2%) | 23 (62.2%) | 23 (62.2%) | 25 (67.6%) | 21 (56.8%) | ||
4 | 5 (6.8%) | 4 (10.8%) | 1 (2.7%) | 3 (8.1%) | 2 (5.4%) | ||
ypN Stage | 0.29 | 0.43 | |||||
0 | 49 (68.1%) | 22 (61.1%) | 27 (75.0%) | 23 (63.9%) | 26 (72.2%) | ||
1 | 15 (20.8%) | 8 (22.2%) | 7 (19.4%) | 7 (19.4%) | 8 (22.2%) | ||
2 | 8 (11.1%) | 6 (16.7%) | 2 (5.6%) | 6 (16.7%) | 2 (5.6%) | ||
Missing | 2 | 1 | 1 | 1 | 1 | ||
TRG 3 | 0.58 | 0.21 | |||||
1 | 4 (5.5%) | 2 (5.6%) | 2 (5.4%) | 3 (8.1%) | 1 (2.8%) | ||
2 | 18 (24.7%) | 9 (25.0%) | 9 (24.3%) | 11 (29.7%) | 7 (19.4%) | ||
3 | 24 (32.9%) | 9 (25.0%) | 15 (40.5%) | 11 (29.7%) | 13 (36.1%) | ||
4 | 23 (31.5%) | 13 (36.1%) | 10 (27.0%) | 12 (32.4%) | 11 (30.6%) | ||
5 | 4 (5.5%) | 3 (8.3%) | 1 (2.7%) | 0 (0.0%) | 4 (11.1%) | ||
Missing | 1 | 1 | 0 | 0 | 1 |
≤2 Gy | >2 Gy | p Value 4 | |
---|---|---|---|
PD-L1+ Cells Rate on Biopsy | 0.56 | ||
n1 | 47 | 27 | |
Mean (SD 2) | 1.1 (2.9) | 1.1 (1.5) | |
Median [range] | 0.1 [0.0–17.0] | 0.2 [0.0–4.8] | |
Median PD-L1+ Cells Rate on Biopsy | 0.46 | ||
≤0.15 | 25 (53.2%) | 12 (44.4%) | |
>0.15 | 22 (46.8%) | 15 (55.6%) | |
PD-L1+ Cells Rate on Surgical Specimen | 0.33 | ||
n | 47 | 27 | |
Mean (SD) | 1.8 (4.3) | 1.4 (1.6) | |
Median [range] | 0.5 [0.0–27.5] | 0.6 [0.0–5.9] | |
Median PD-L1+ Cells Rate on Surgical Specimen | 0.22 | ||
≤0.5 | 26 (55.3%) | 11 (40.7%) | |
>0.5 | 21 (44.7%) | 16 (59.3%) | |
Delta PD-L1 3 | 0.52 | ||
N | 47 | 27 | |
Mean (SD) | 0.7 (4.9) | 0.4 (1.8) | |
Median [range] | 0.2 [-17.0–25.9] | 0.1 [-4.1–3.1] |
PD-L1 Biopsy ≤ 0.15 (n = 27) | PD-L1 Biopsy > 0.15 (n = 26) | p Value 3 | |
CD8 TILs 1 on Biopsy | 0.65 | ||
Mean (SD 2) | 47.4 (32.3) | 68.8 (70.4) | |
Median [range] | 44.5 [1.3–113.0] | 42.8 [0.3–290.7] | |
Intraepithelial CD8 TILs on Biopsy | 0.62 | ||
Mean (SD) | 10.5 (13.4) | 14.8 (19.4) | |
Median [range] | 6.0 [0.0–50.9] | 6.0 [0.0–87.2] | |
Stromal CD8 TILs on Biopsy | 0.69 | ||
Mean (SD) | 36.9 (23.9) | 54.1 (54.3) | |
Median [range] | 37.8 [1.3–87.3] | 34.2 [0.3–203.5] | |
PD-L1 Surgery ≤ 0.5 (n = 37) | PD-L1 Surgery > 0.5 (n = 36) | p Value | |
CD8 TILs on Surgical Specimen | 0.99 | ||
Mean (SD) | 63.6 (49.2) | 71.0 (71.6) | |
Median [range] | 55.8 [1.7–273.7] | 51.5 [4.0–392.8] | |
Intraepithelial CD8 TILs on Surgical Specimen | 0.17 | ||
Mean (SD) | 6.6 (10.9) | 11.2 (15.6) | |
Median [range] | 1.6 [0.0–49.2] | 4.4 [0.0–65.9] | |
Intraepithelial CD8 TILs on Surgical Specimen | 0.82 | ||
Mean (SD) | 57.0 (44.5) | 59.8 (60.9) | |
Median [range] | 49.2 [1.7–251.8] | 46.9 [2.8–353.6] |
Univariate Analysis | Multivariate Analysis | ||||||
---|---|---|---|---|---|---|---|
HR 3 | 95% CI 4 | p Value 5 | HR | 95% CI | p Value 5 | ||
Gender | n = 74 | 0.93 | |||||
Female vs Male | 1.025 | [0.542–1.940] | |||||
Age (Years) | n = 74 | 0.97 | |||||
>69 vs ≤69 | 1.012 | [0.543–1.884] | |||||
Tumor Distance from Anal Verge (cm) | n = 72 | 0.37 | |||||
≥10 cm vs <5 cm | 1.398 | [0.570–3.427] | |||||
[5,6,7,8,9,10] cm vs <5 cm | 1.667 | [0.811–3.425] | |||||
Histological Subtype | n = 70 | 0.79 | |||||
Highly differentiated vs Poorly or Moderately differentiated adenocarcinoma | 0.827 | [0.428–1.597] | |||||
Other vs Poorly or Moderately differentiated adenocarcinoma | 1.211 | [0.284–5.170] | |||||
cN Stage | n = 61 | 0.39 | |||||
N+ vs N0 | 1.346 | [0.678–2.674] | |||||
Radiation Dose Per Fraction (Gy) | n = 74 | 0.10 | |||||
>2 vs ≤2 | 1.686 | [0.899–3.163] | |||||
Chemotherapy | n = 73 | 0.82 | |||||
Yes vs No | 1.074 | [0.577–1.996] | |||||
Concurrent Chemotherapy | n = 71 | 0.88 | |||||
Yes vs No | 0.949 | [0.470–1.915] | |||||
Adjuvant Chemotherapy | n = 72 | 0.24 | |||||
Yes vs No | 1.499 | [0.763–2.945] | |||||
Time between End of Radiotherapy and Surgery (Days) | n = 74 | 0.24 | |||||
>40 vs ≤40 | 1.437 | [0.775–2.663] | |||||
Conservative Surgery | n = 73 | 0.61 | |||||
Yes vs No | 1.175 | [0.626–2.205] | |||||
pN+ | n = 73 | 0.14 | |||||
Yes vs No | 1.613 | [0.845–3.080] | |||||
ypT Stage | n = 74 | 0.0045 | 2.64 | [1.160–6.031] | 0.02 | ||
3–4 vs 0–2 | 3.27 | [1.444–7.404] | |||||
ypN Stage | n = 72 | 0.29 | |||||
1–2 vs 0 | 1.419 | [0.740–2.719] | |||||
TRG 1 | n = 73 | 0.21 | |||||
3–5 vs 1–2 | 1.579 | [0.771–3.235] | |||||
Median PD-L1 Biopsy | n = 74 | 0.10 | |||||
>0.15 vs ≤0.15 | 0.596 | [0.317–1.119] | |||||
Median PD-L1 Surgery | n = 74 | 0.05 | |||||
>0.5 vs ≤0.5 | 0.542 | [0.287–1.022] | |||||
Delta PD-L1 2 | n = 74 | 0.90 | |||||
>0.2 vs ≤0.2 | 0.962 | [0.521–1.777] | |||||
Evolution of PD-L1+ Cells Rate | n = 74 | 0.07 | |||||
High-to-high vs low-to-low | 0.329 | [0.127–0.856] | |||||
High-to-low vs low-to-low | 1.154 | [0.513–2.594] | |||||
Low-to-high vs low-to-low | 1.007 | [0.450–2.251] | |||||
High-to-high vs other | 0.317 | [0.132–0.758] | 0.0098 | 0.33 | [0.136–0.811] | 0.01 | |
PD-L1 Biopsy | n = 74 | 0.0065 | |||||
>0.08 vs ≤0.08 | 0.422 | [0.227–0.786] |
Univariate Analysis | Multivariate Analysis | ||||||
---|---|---|---|---|---|---|---|
Variable | HR 3 | 95% CI 4 | p Value 5 | HR | 95% CI | p Value 5 | |
Gender | n = 74 | 0.83 | |||||
Female vs Male | 0.937 | [0.508–1.728] | |||||
Age (Years) | n = 74 | 0.85 | |||||
>69 vs ≤69 | 0.945 | [0.522–1.710] | |||||
Tumor Distance from Anal Verge (cm) | n = 72 | 0.21 | |||||
≥10 cm vs <5 cm | 1.628 | [0.684–3.874] | |||||
[5,6,7,8,9,10] cm vs <5 cm | 1.878 | [0.929–3.798] | |||||
Histological Subtype | n = 70 | 0.81 | |||||
Highly differentiated vs Poorly or Moderately differentiated adenocarcinoma | 0.824 | [0.442–1.538] | |||||
Other vs Poorly or Moderately differentiated adenocarcinoma | 1.056 | [0.249–4.484] | |||||
cN Stage | n = 61 | 0.17 | |||||
N+ vs N0 | 1.571 | [0.815–3.029] | |||||
Radiation Dose Per Fraction (Gy) | n = 74 | 0.30 | |||||
>2 vs ≤2 | 1.373 | [0.752–2.507] | |||||
Chemotherapy | n = 73 | 0.71 | |||||
Yes vs No | 1.119 | [0.617–2.030] | |||||
Concurrent Chemotherapy | n = 71 | 0.89 | |||||
Yes vs No | 1.048 | [0.536–2.051] | |||||
Adjuvant Chemotherapy | n = 72 | 0.12 | |||||
Yes vs No | 1.658 | [0.869–3.163] | |||||
Time between End of Radiotherapy and Surgery (Days) | n = 74 | 0.34 | |||||
>40 vs ≤40 | 1.329 | [0.739–2.392] | |||||
Conservative Surgery | n = 73 | 0.63 | |||||
Yes vs No | 1.159 | [0.633–2.123] | |||||
pN+ | n = 73 | 0.13 | |||||
Yes vs No | 1.611 | [0.866–2.995] | |||||
ypT Stage | n = 74 | 0.0092 | |||||
3–4 vs 0–2 | 2.656 | [1.274–5.537] | 2.223 | [1.055–4.684] | 0.03 | ||
ypN Stage | n = 72 | 0.36 | |||||
1–2 vs 0 | 1.336 | [0.715–2.494] | |||||
TRG 1 | n = 73 | 0.16 | |||||
3–5 vs 1–2 | 1.63 | [0.823–3.229] | |||||
Median PD-L1 Biopsy | n = 74 | 0.03 | |||||
>0.15 vs ≤0.15 | 0.512 | [0.279–0.938] | |||||
Median PD-L1 Surgery | n = 74 | 0.14 | |||||
>0.5 vs ≤0.5 | 0.645 | [0.355–1.171] | |||||
Delta PD-L1 2 | n = 74 | 0.84 | |||||
>0.2 vs ≤0.2 | 1.062 | [0.591–1.907] | |||||
Evolution of PD-L1+ Cells Rate | n = 74 | 0.06 | |||||
High-to-high vs low-to-low | 0.344 | [0.141–0.842] | |||||
High-to-low vs low-to-low | 0.914 | [0.411–2.032] | |||||
Low-to-high vs low-to-low | 1.158 | [0.546–2.456] | |||||
High-to-high vs other | 0.338 | [0.150–0.760] | 0.0087 | 0.402 | [0.177–0.916] | 0.03 | |
PD-L1 Biopsy | n = 4 | 0.0037 | |||||
>0.08 vs ≤0.08 | 0.414 | [0.229–0.751] |
© 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
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Boustani, J.; Derangère, V.; Bertaut, A.; Adotevi, O.; Morgand, V.; Charon-Barra, C.; Ghiringhelli, F.; Mirjolet, C. Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer. Cells 2020, 9, 2071. https://doi.org/10.3390/cells9092071
Boustani J, Derangère V, Bertaut A, Adotevi O, Morgand V, Charon-Barra C, Ghiringhelli F, Mirjolet C. Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer. Cells. 2020; 9(9):2071. https://doi.org/10.3390/cells9092071
Chicago/Turabian StyleBoustani, Jihane, Valentin Derangère, Aurélie Bertaut, Olivier Adotevi, Véronique Morgand, Céline Charon-Barra, François Ghiringhelli, and Céline Mirjolet. 2020. "Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer" Cells 9, no. 9: 2071. https://doi.org/10.3390/cells9092071