Table 4.
Hazard Ratios for Melanoma-Specific Death According to Tumor BRAF and NRAS Mutational Status Among 892 Patients with Primary Melanoma
| Cox Proportional Hazards Model | Proportional Subdistribution
Hazards Model for Competing-Risks |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Censored | Melanoma Death |
Death from Other Cause |
Partially Adjustedb | Fully Adjustedc | Partially Adjustedb | Fully Adjustedc | |||||
| Characteristic | No. (%) | No. (%) | No. (%) | HR (95% CI) | P | HR (95% CI) | P | sHR (95% CI) |
P | sHR (95% CI) | P |
| All primary melanomasa | |||||||||||
| All stage melanomas | (n=750) | (n = 62) | (n=80) | ||||||||
| NRAS/BRAF Status | |||||||||||
| Wildtype (NRAS−/BRAF−) | 420 (84) | 31 (6) | 51 (10) | Reference | .19 | Reference | .27 | Reference | .18 | Reference | .28 |
| NRAS+ | 94 (77) | 14 (11) | 14 (11) | 1.8 (0.9–3.4) | 1.7 (0.8–3.4) | 1.8 (1–3.5) | 1.7 (0.8–3.6) | ||||
| BRAF+ | 236 (88) | 17 (6) | 15 (6) | 1.3 (0.7–2.4) | 1.5 (0.8–2.9) | 1.3 (0.7–2.4) | 1.6 (0.8–3.2) | ||||
| Stratified by AJCC Stage | |||||||||||
| Stage T1a/T1b/T2a | (n=667) | (n = 26) | (n=55) | ||||||||
| NRAS/BRAF Status | |||||||||||
| Wildtype (NRAS−/BRAF−) | 374 (88) | 16 (4) | 36 (8) | Reference | .84 | Reference | .65 | Reference | .83 | Reference | .67 |
| NRAS+ | 77 (87) | 4 (4) | 8 (9) | 1.1 (0.4–3.4) | 0.9 (0.3–3.0) | 1.2 (0.4–3.5) | 0.9 (0.3–2.9) | ||||
| BRAF+ | 216 (93) | 6 (3) | 11 (5) | 0.8 (0.3–2.1) | 0.6 (0.2–1.7) | 0.8 (0.3–2) | 0.6 (0.2–1.7) | ||||
|
Stage T2b/T3a/T3b/T4a/T4b |
(n=83) | (n = 36) | (n=25) | ||||||||
| NRAS/BRAF Status | |||||||||||
| Wildtype (NRAS−/BRAF−) | 46 (61) | 15 (20) | 15 (20) | Reference | .13 | Reference | .04 | Reference | .09 | Reference | .02 |
| NRAS+ | 17 (52) | 10 (30) | 6 (18) | 1.7 (0.8–3.9) | 2.9 (1.1–7.7) | 1.8 (0.8–4.2) | 3 (1.1–8.2) | ||||
| BRAF+ | 20 (57) | 11 (31) | 4 (11) | 2.3 (1.0–5.1) | 3.1 (1.2–8.5) | 2.4 (1.1–5.3) | 3.6 (1.3–9.5) | ||||
| Primary melanomas limited to NRAS codon 61 and BRAF V600E mutant and wildtype melanomas | |||||||||||
| All stage melanomas | (n=685) | (n = 57) | (n=67) | ||||||||
| NRAS/BRAF Status | |||||||||||
| Wildtype (NRAS−/BRAF−) | 420 (84) | 31 (6) | 51 (10) | Reference | .12 | Reference | .17 | Reference | .11 | Reference | .19 |
| NRAS codon 61+ | 90 (79) | 13 (11) | 11 (10) | 1.9 (1.0–3.6) | 1.9 (0.9–4.0) | 1.9 (1–3.7) | 1.9 (0.9–4.2) | ||||
| BRAF V600E+ | 175 (91) | 13 (7) | 5 (3) | 1.6 (0.8–3.0) | 1.7 (0.8–3.5) | 1.6 (0.8–3.2) | 1.8 (0.8–4) | ||||
| Stratified by AJCC Stage | |||||||||||
| Stage T1a/T1b/T2a | (n=607) | (n = 25) | (n=45) | ||||||||
| NRAS/BRAF Status | |||||||||||
| Wildtype (NRAS−/BRAF−) | 374 (88) | 16 (4) | 36 (8) | Reference | .92 | Reference | .87 | Reference | .91 | Reference | .89 |
| NRAS codon 61+ | 74 (88) | 4 (5) | 6 (7) | 1.3 (0.4–3.8) | 1.1 (0.3–3.6) | 1.3 (0.4–3.7) | 1.1 (0.4–3.4) | ||||
| BRAF V600E+ | 159 (95) | 5 (3) | 3 (2) | 1.0 (0.4–2.8) | 0.8 (0.3–2.3) | 1 (0.4–2.8) | 0.8 (0.2–2.5) | ||||
|
Stage T2b/T3a/T3b/T4a/T4b |
(n=78) | (n = 32) | (n=22) | ||||||||
| NRAS/BRAF Status | |||||||||||
| Wildtype (NRAS−/BRAF−) | 46 (61) | 15 (20) | 15 (20) | Reference | .13 | Reference | .04 | Reference | .10 | Reference | .03 |
| NRAS codon 61+ | 16 (53) | 9 (30) | 5 (17) | 1.7 (0.7–3.9) | 3.2 (1.1–9.7) | 1.8 (0.7–4.2) | 3.3 (1.1–10.1) | ||||
| BRAF V600E+ | 16 (62) | 8 (31) | 2 (8) | 2.4 (1.0–6.0) | 3.8 (1.2–11.8) | 2.6 (1–6.6) | 4.3 (1.3–14.8) | ||||
Abbreviations: AJCC, American Joint Committee on Cancer; HR, hazard ratio; sHR, subdistribution hazard ratio; TIL, tumor infiltrating lymphocyte.
Of the 912 patients who entered the study with first primary melanoma, 40 developed a second melanoma during the ascertainment period and were treated as time-dependent and the BRAF/NRAS mutational status and pathologic characteristics of their thicker melanoma was utilized in the survival analysis. Excluded from this analysis wee 20 participants with missing AJCC tumor stage or TIL grade for their melanoma. In the cox models death from other causes were considered as censored.
The Cox models /proportional subdistribution hazards models were adjusted for age (continuous), sex, and study center.
The Cox models/proportional subdistribution hazards models were adjusted for age (continuous), sex, anatomic site (trunk/pelvis, scalp/neck, face/ears/other, upper extremities, lower extremities), AJCC tumor stage (T1a, T1b/T2a, T2b/T3a, T3b/T4a, T4b), TIL grade, and study center.