Table 3.
(Subdistribution) hazard ratios for 15-year clinical outcomes according to BRCA1 status, based on multiple-imputed data
| OS, HR (95% CI) | OS with additional adjustment for second primary tumorsd, HR (95% CI) | DRFS, HR (95% CI) | Second primary tumorse, sHR (95% CI) | |
|---|---|---|---|---|
| Univariable | ||||
| BRCA1-non-alteration | 1.00 (referent) | NA | 1.00 (referent) | 1.00 (referent) |
| gBRCA1m 0–3 yearsa | 0.73 (0.36–1.47) | NA | 1.29 (0.79–2.11) | 4.00 (2.34–6.86) |
| gBRCA1m 4–15 yearsa | 2.00 (1.15–3.47) | NA | ||
| sBRCA1m | 1.17 (0.51–2.67) | NA | 1.52 (0.67–3.44) | 0.49 (0.07–3.41) |
| Tumor BRCA1-PM | 0.72 (0.45–1.15) | NA | 0.77 (0.47–1.27) | 0.46 (0.21–1.02) |
| Multivariableb | ||||
| BRCA1-non-alteration | 1.00 (referent) | 1.00 (referent) | 1.00 (referent) | 1.00 (referent) |
| gBRCA1m 0–3 yearsa | 0.75 (0.36–1.53) | 0.60 (0.29–1.27) | 1.34 (0.78–2.28) | 4.04 (2.29–7.13) |
| gBRCA1m 4–15 yearsa | 2.11 (1.18–3.75) | 1.43 (0.77–2.66) | ||
| sBRCA1m | 0.96 (0.42–2.21) | 1.02 (0.44–2.38) | 1.30 (0.55–3.06) | 0.49 (0.07–3.47) |
| Tumor BRCA1-PM | 1.19 (0.65–2.16) | 1.25 (0.68–2.28) | 0.88 (0.51–1.51) | 0.42 (0.19–0.95) |
| sTILs (every 10% increment) | 0.84 (0.78–0.90) | 0.82 (0.76–0.89) | 0.74 (0.68–0.80) | 1.11 (1.03–1.19) |
| sTILs by tumor BRCA1-PM statusc | 0.82 (0.68–0.98) | 0.83 (0.69–1.00) | NA | NA |
Abbreviations: OS, overall survival; DRFS, distant recurrence-free survival; HR, hazard ratio; sHR, subdistribution hazard ratio; CI, confidence interval; BRCA1-non-alteration, without germline BRCA1 mutation, without somatic BRCA1 mutation, and without tumor BRCA1 promoter methylation; gBRCA1m, germline BRCA1 mutation; sBRCA1m, somatic BRCA1 mutation; tumor BRCA1-PM, tumor BRCA1 promoter methylation; sTILs, stromal tumor-infiltrating lymphocytes; NA, not applicable
aHazard ratios for germline BRCA1 mutation were estimated for the first 3 years and from the fourth year onwards separately for overall survival because of non-proportional hazards
bMultivariable models were adjusted for stromal tumor-infiltrating lymphocytes (unit of 10%), tumor size (≤ 20 mm/ > 20 mm), tumor grade (grade 1 or 2/grade 3), histological subtype (carcinoma of no special type/metaplastic carcinoma/other subtypes), lymphovascular invasion (yes/no), and treatment (lumpectomy with radiotherapy/mastectomy alone/other treatments). Results of other covariates are summarized in Additional files 7–9: Table S5–S7
cFor overall survival, a significant interaction term between stromal tumor-infiltrating lymphocytes (unit of 10%) and tumor BRCA1 promoter methylation was added. Interaction terms between other BRCA1 status and stromal tumor-infiltrating lymphocytes were not significant; thus, they were not included in the final model for overall survival. None of the interaction terms was significant in the models for distant recurrence-free survival or cumulative incidence of second primary tumors
dSecond primary tumors (yes/no) was a time-varying covariate, i.e., with the value of 0 until the time when a second primary tumor occurred and with the value of 1 after that time
eFine and Gray competing risk models were used to calculate subdistribution hazard ratios. Second primary tumors were the events of interest, and death and distant recurrence were competing events