Patient characteristics
In total, 3133 patients with pT1abN0M0 TNBC were enrolled in this study. The clinicodemographic patient characteristics are shown in Table 1. The median age was 62 years (range, 24-90 years), and most patients were white (75.9%) and married (59.4%). The median tumor size was 7 mm, and most tumors were classified as grade III (62.6%) and ductal carcinoma of no special type (88.8%). Most patients underwent breast-conserving surgery (BCS, 71.5%), and approximately half the cohort was administered chemotherapy (CT, 49.4%) and radiotherapy (RAD, 59.0%). The median follow-up time was 44.0 months (interquartile range, 26.0–62.0 months). By the end of the last follow-up, 133 patients (4.3%) had died, of which 72 (2.3%) died from breast cancer and 61 (2.0%) died from other causes.
Table 1. Patient characteristics (n=3133)
Characteristics
|
Total population
|
Training cohort
|
Validation cohort
|
|
3133 (100)
|
1566 (50.0)
|
1567 (50.0)
|
Age at diagnosis, years
|
|
|
|
18–39
|
107 (3.4)
|
55 (3.5)
|
52 (3.3)
|
40–49
|
411 (13.1)
|
200 (12.8)
|
211 (13.5)
|
50–59
|
813 (25.9)
|
405 (25.9)
|
408 (26.0)
|
60–69
|
998 (31.9)
|
499 (31.9)
|
499 (31.8)
|
70–79
|
605 (19.3)
|
294 (18.8)
|
311 (19.8)
|
80–90
|
199 (6.4)
|
113 (7.2)
|
86 (5.5)
|
Race
|
|
|
|
White
|
2377 (75.9)
|
1198 (76.5)
|
1179 (75.2)
|
Black
|
518 (16.5)
|
251 (16.0)
|
267 (17.0)
|
Othersa
|
225 (7.2)
|
113 (7.2)
|
112 (7.1)
|
Unknown
|
13 (0.4)
|
4 (0.3)
|
9 (0.6)
|
Marital status at diagnosis
|
|
|
|
Not marriedb
|
1120 (35.7)
|
567 (36.2)
|
553 (35.3)
|
Married
|
1862 (59.4)
|
916 (58.5)
|
946 (60.4)
|
Unknown
|
151 (4.8)
|
83 (5.3)
|
68 (4.3)
|
CS tumor size (mm)
|
|
|
|
[1,4]
|
629 (20.1)
|
317 (20.2)
|
312 (19.9)
|
[5,6]
|
643 (20.5)
|
319 (20.4)
|
324 (20.7)
|
[7,8]
|
841 (26.8)
|
419 (26.8)
|
422 (26.9)
|
[9,10]
|
1020 (32.6)
|
511 (32.6)
|
509 (32.5)
|
Histology
|
|
|
|
Ductal carcinoma, NST
|
2781 (88.8)
|
1386 (88.5)
|
1395 (89.0)
|
Other ductal and lobular neoplasms
|
200 (6.4)
|
103 (6.6)
|
97 (6.2)
|
Others
|
151 (4.8)
|
77 (4.9)
|
74 (4.7)
|
Grade
|
|
|
|
I
|
184 (5.9)
|
99 (6.3)
|
85 (5.4)
|
II
|
988 (31.5)
|
499 (31.9)
|
489 (31.2)
|
III
|
1961 (62.6)
|
968 (61.8)
|
993 (63.4)
|
Surgery of the primary sitee
|
|
|
|
BCS
|
2240 (71.5)
|
1121 (71.6)
|
1119 (71.4)
|
CPM
|
140 (4.5)
|
65 (4.2)
|
75 (4.8)
|
Other mastectomies
|
753 (24.0)
|
380 (24.3)
|
373 (23.8)
|
CTf
|
|
|
|
No
|
1585 (50.6)
|
822 (52.5)
|
763 (48.7)
|
Yes
|
1548 (49.4)
|
744 (47.5)
|
804 (51.3)
|
RADg
|
|
|
|
No
|
1178 (37.6)
|
594 (37.9)
|
584 (37.3)
|
Yes
|
1848 (59.0)
|
927 (59.2)
|
921 (58.8)
|
Unknown
|
107 (3.4)
|
45 (2.9)
|
62 (4.0)
|
aOther races include American Indian/AK Native, Asian/Pacific Islander.
bNot married includes single (never married), separated, divorced, unmarried or with a domestic partner, and widowed.
Data are presented as no. of patients (%).
Abbreviations: NST, no special type; BCS, breast-conserving surgery; CPM, contralateral prophylactic mastectomy; CT, chemotherapy; RAD, radiation therapy
Overall survival
The results of the univariate and multiple regression analyses in the training cohort based on a Cox proportional-hazards model are presented in Supplemental tables 2 and 3. Several variables, including age (≥ 70 years, hazard ratio, HR = 2.42, P < 0.001), surgery (mastectomies other than contralateral prophylactic mastectomy [CPM] HR = 2.00, P = 0.008), and chemotherapy (HR = 0.52, P = 0.016), showed a significant correlation with OS. All significant factors were then included in multiple regression models, and age (≥ 70 years HR = 1.99, P = 0.023), marital status (married HR = 0.64, P = 0.049), tumor size (every 1 mm increase: HR = 1.14, P = 0.024), and surgery (mastectomies other than CPM HR = 2.43, P = 0.026) were identified as independent factors.
Breast cancer-specific survival
The results of univariate and multiple regression analyses of BCSS, along with estimates of probabilities of death resulting from breast cancer, are listed in Supplemental tables 2, 3, and 4. In univariate analysis, surgery (CPM: HR = 3.62, P = 0.041; mastectomies other than CPM: HR = 3.07, P = 0.001) significantly correlated with BCSS. All factors were then subjected to multiple regression analysis. As expected, surgery remained significantly associated with BCSS (CPM: HR = 9.19, P = 0.004; mastectomies other than CPM: HR = 6.23, P < 0.001).
Overall, the 3- and 5-year probabilities of death from breast cancer were .02 and .03 (Supplemental table 4). Consistent with regression analyses, surgery remained significantly associated with breast cancer-specific death; CPM had the highest incidence (5-year rate: 0.09), whereas breast-conserving surgery had the lowest incidence (5-year rate: 0.02).
Nomogram validity
Nomograms and their point assignment are presented in Figure 1 and Supplemental table 1. Tumor size, histology, grade, and surgery were included in both nomograms, while age, marital status, and CT were applied solely for OS. In the OS nomogram, surgery (CPM: 78) exhibited the strongest influence, followed by age (66) and tumor size (11 for every 1 mm increase). In contrast, surgery remained the most significant factor influencing BCSS (CPM: 100). By adding all points and locating them on the bottom scales, we could calculate the estimated 3- and 5-year survival probabilities.
Calibration and validation of the nomograms
The calibration plots for the OS and BCSS nomograms in the training cohort and validation cohort are shown in Figure 2 and Supplemental figure 2. Most mean predicted values and their 95% confidence intervals covered the actual survival rate, further indicating concordance between the predicted and observed survival. Harrell’s C-indices of the OS and BCSS nomograms were 0.702 [standard error (SE): 0.034] and 0.680 (SE: 0.045), respectively, in the validation cohort. These were similar to those of the training cohort: 0.701 (SE: 0.024) for OS and 0.691 (SE: 0.031) for BCSS. All C-indices were higher than 0.680, indicating that these two nomograms were satisfactorily accurate and suitable for prognosis prediction. In addition, these values significantly exceeded those of the traditional TNM staging system (OS: 0.503 (SE: 0.007), P < 0.001; BCSS: 0.506 (SE: 0.011), P < 0.001), as indicated by 99.7% of the patients having stage IA disease following the AJCC 7th Edition guidelines.
Application of the nomogram in identifying patients for chemotherapy
To further assess the usefulness of the nomograms in identifying patients who will benefit from adjuvant chemotherapy, we calculated the OS prediction scores for patients in the training cohort. A 50% cutoff was used to divide them into two risk groups (low risk: < 213; high risk: ≥ 213). The risk score was significantly associated with survival in both the training cohort (OS: HR= 0.34, 95% CI=0.197-0.863, P < 0.001; BCSS: HR= 0.49, 95% CI=0.24-0.99, P =0.043) (Figure 3A and B) and the validation cohort (OS: HR= 0.29, 95% CI=0.15-0.73, P < 0.001; BCSS: HR= 0.47, 95% CI=0.23-0.97, P = 0.040) (Figures 3C and D). The high-risk group showed lower 5-year OS (93.06% vs 97.03%) and BCSS (96.98% vs 98.70%) than the low-risk group.
The STEPPs of the 5-year OS according to the nomogram prediction score demonstrated distinct patterns of absolute chemotherapeutic effect (Figure 4). In the low-risk patients, the 5-year OS was 98.0% independent of chemotherapy administration (P = 0.840 in the training cohort and P = 0.900 in the validation cohort, Figure 4A and C). There was no apparent pattern across the prediction score spectrum, further indicating no clinically relevant improvement in 5-year OS with respect to chemotherapy. For high-risk patients who did not receive chemotherapy, the 5-year OS was 91.8%. A consistent benefit of chemotherapy was evident across the continuum of prediction scores (P < 0.001 in both the training and validation cohorts, Figure 4B and D). With the average survival benefit being 3.7%, the pattern of treatment effect according to prediction score distribution was also noticeable. Among subpopulations with the highest prediction score, the smallest absolute improvement of survival from chemotherapy was 2%. Meanwhile, the chemotherapeutic absolute improvement reached 6.5% in subpopulations with approximately 250 points, and patients administered chemotherapy achieved a median 5-year OS of 95% (Figure 4B). Similar chemotherapeutic effects in high-risk patients in the validation cohort were observed (Figure 4D).
To confirm the effect of chemotherapy, we delineated OS and BCSS curves for each prediction score category in both cohorts (Figure 5 and Supplemental figure 3). As expected, chemotherapy did not improve the OS and BCSS (HR = 1.07, P = 0.911 for both; all deaths were breast cancer specific) in low-risk patients (Figure 5A and C). In contrast, chemotherapy significantly improved the OS (HR = 2.10, 95% CI = 1.08-8.21, P = 0.032) and BCSS (HR = 2.96, 95% CI =1.23-7.77, P = 0.028) in high-risk patients (Figure 5B and D). The association between chemotherapy and survival was further verified in the validation cohort (low-risk group: OS: HR = 0.83, 95% CI = 0.28-2.49, P = 0.743; BCSS: HR = 0.64, 95% CI = 0.17-2.49, P = 0.521 [Supplemental figure 3A and C]; high-risk group: OS: HR = 1.94, 95% CI = 1.05-3.62, P = 0.040; BCSS: HR = 2.71, 95% CI = 1.18-6.17, P = 0.019 [Supplemental figure 3B and D]).
We further evaluated the relationship between T1a/b classification and nomogram score categorization. Although T1b patients have generally higher risks than T1a patients (Supplemental table 5, P < 0.001), approximately half of them (46.6%) were classified into the low-risk category according to our nomogram score cutoff. This indicated that chemotherapy may not be necessary. However, a significant proportion of pT1a patients (42.0%) were included in the high-risk subgroup. Thus, we subdivided the T1a and T1b patients according to the OS score cutoff (213) and analyzed survival differences associated with chemotherapy (Figure 6, Supplemental figure 4). Patients with a low score did not have an OS benefit from chemotherapy regardless of tumor size (T1a: HR = 1.28, 95% CI = 0.26-6.35, P = 0.762; T1 HR = 0.766, 95% CI = 0.29-2.05, P = 0.595 [Figure 6A and C]). However, both T1a and T1b high-risk patients showed a significant OS benefit from chemotherapy (T1a: HR = 7.25, 95% CI = 1.01-53.57, P = 0.050; T1b: HR = 1.94, 95% CI = 1.18-3.19, P = 0.009 [Figure 6B and D]). Similar trends were observed in the BCSS analyses (Supplemental figure 4). Collectively, nomogram score categorization, which combined tumor size with other clinicopathologic characteristics, could better identify patients who are likely to benefit from chemotherapy compared with the traditional T1a/b classification.