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A total of 1,627 patients were diagnosed with early stage BC between January 2011 and December 2015. Of these, 238 patients were excluded due to HER2-positive status, and 390 HER2-negative patients were not included in the study on the basis of exclusion criteria. Ultimately, 999 patients were included in the further analyses. A flowchart depicting the progression of study is shown in Figure 1.
The percentages of HER2-low in the whole cohort, HR-positive group, and HR-negative group were 84.78%, 87.86%, and 72.5%, respectively, as shown in Figure 2.
Figure 2. Distribution of HER2-low in (A) the whole cohort; (B) HR-positive group; (C) HR-negative group. HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry.
The median age of patients at the time of diagnosis was 49.00 years. A total of 55.0% of the patients had a body mass index (BMI) less than 25 kg/m2, and 55.0% of the patients were postmenopausal at the time of diagnosis. The most prevalent histological type was invasive ductal carcinoma (90.0%), with the highest grade being grade 2 (67%). Majority of the patients in our cohort had T1 and T2 disease (97.0%), and more than half of the patients had node-negative disease (60%). ER negativity (37% vs. 19%) and low ER levels (5.9% vs. 4.3%) were more frequently observed in the HER2-IHC0 group than in the HER2-low group. On the other hand, the frequency of ER levels being > 10% was higher in the HER2-low group than in the HER2-IHC0 group (76% vs. 57%, P < 0.001). The rate of PR positivity was also higher in the HER2-low group (77% vs. 61%, P < 0.001). In the context of treatment regimen, a significantly higher proportion of endocrine therapy was observed in the HER2-low group (80% vs. 32%, P < 0.001). No significant differences were found between the HER2-low and HER2-IHC0 groups in terms of age at the time of diagnosis, BMI, menopausal status, histological type, T stage, N stage, Ki-67 index, or TOP2A expression. Details of the clinicopathological factors of the HER2-IHC0 and HER2-low subgroups in the entire cohort are presented in Supplementary Table S1 (available in www.besjournal.com).
Table S1. Demographic characteristics of the HER2−IHC0 and HER2 low groups in the whole cohort
Characteristic Overall
N = 9991HER2 IHC 0
N = 1521HER2 low
N = 8471P value2 Age 49.00 (43.00, 59.00) 49.00 (42.75, 61.25) 50.00 (43.00, 59.00) 0.9 Age group, years 0.070 < 40 138 (14%) 25 (16%) 113 (13%) 40−59 622 (62%) 82 (54%) 540 (64%) > 59 239 (24%) 45 (30%) 194 (23%) BMI, kg/m2 0.7 ≤ 25 553 (55%) 82 (54%) 471 (56%) > 25 446 (45%) 70 (46%) 376 (44%) Menopausal 0.8 premenopausal 549 (55%) 82 (54%) 467 (55%) postmenopausal 450 (45%) 70 (46%) 380 (45%) Histology3 0.13 IDC 903 (90%) 133 (88%) 770 (91%) ILC 33 (3.3%) 4 (2.6%) 29 (3.4%) Others 63 (6.3%) 15 (9.9%) 48 (5.7%) Grade 0.2 1 59 (5.9%) 10 (6.6%) 49 (5.8%) 2 665 (67%) 92 (61%) 573 (68%) 3 275 (28%) 50 (33%) 225 (27%) T > 0.9 1 538 (54%) 83 (55%) 455 (54%) 2 431 (43%) 65 (43%) 366 (43%) 3 30 (3.0%) 4 (2.6%) 26 (3.1%) N > 0.9 0 596 (60%) 89 (59%) 507 (60%) 1 241 (24%) 38 (25%) 203 (24%) 2 102 (10%) 17 (11%) 85 (10%) 3 60 (6.0%) 8 (5.3%) 52 (6.1%) Stage 0.7 Ⅰ 402 (40%) 59 (39%) 343 (40%) Ⅱ 450 (45%) 67 (44%) 383 (45%) Ⅲ 147 (15%) 26 (17%) 121 (14%) ER4 , % < 0.001 0 220 (22%) 56 (37%) 164 (19%) 1−10 45 (4.5%) 9 (5.9%) 36 (4.3%) > 10 734 (73%) 87 (57%) 647 (76%) PR5 < 0.001 negative 256 (26%) 60 (39%) 196 (23%) positive 743 (74%) 92 (61%) 651(77%) Ki67 0.5 < 14% 216 (22%) 36 (24%) 180 (21%) ≥ 14% 783 (78%) 116 (76%) 667 (79%) TOP2A, % 0.8 < 30 866 (87%) 134 (88%) 732 (86%) 30−60 97 (9.7%) 13 (8.6%) 84 (9.9%) > 60 36 (3.6%) 5 (3.3%) 31 (3.7%) Radiotherapy 0.9 No 798 (80%) 122 (80%) 676 (80%) Yes 201 (20%) 30 (20%) 171 (20%) Chemotherapy > 0.9 No 372 (37%) 56 (37%) 316 (37%) Yes 627 (63%) 96 (63%) 531 (63%) Endocrine therapy < 0.001 No 272 (27%) 103 (68%) 169 (20%) Yes 727 (73%) 49 (32%) 678 (80%) Note. 1Median (IQR); n (%); 2Wilcoxon rank sum test; Pearson's Chi−squared test; Fisher's exact test; 3 IDC, invasive ductal carcnoma; ILC: invasive lobular carcinoma; 4ER: estrogen receptor; 5PR: progesterone receptor. T, T stage; N, N stage. We then analyzed these factors based on the HR groups. In the HR-positive group, a higher proportion of Ki-67 was observed in the HER2-low group (75% vs. 66%, P = 0.048), and no significant differences were found between the HER2-IHC0 and HER2-low groups in terms of other clinicopathological characteristics. More number of patients in the HER2-low group received adjuvant endocrine therapy (97% vs. 51%, P < 0.001). However, in the HR-negative group, more number of patients with HER2-low had invasive ductal type BC (94% vs. 84%, P = 0.021) and no differences were observed in terms of other factors, including treatment. Details of the clinicopathological characteristics of the patients stratified by HR status are presented in Table 1.
Table 1. Baseline characteristics of patients stratified by hormone receptor
Characteristics Hormone receptor negative Hormone receptor positive HER2 IHC0
(N = 55)1HER2 Low
(N = 145)1P value2 HER2 IHC0
(N = 97)1HER2 Low
(N = 702)1P value2 Age (years) 48 (41, 59) 51 (43, 59) 0.6 49 (44, 62) 49 (43, 59) 0.500 Age group (years) 0.3 0.200 < 40 12 (22) 23 (16) 13 (13) 90 (13) 40−59 29 (53) 93 (64) 53 (55) 447 (64) > 59 14 (25) 29 (20) 31 (32) 165 (24) BMI (kg/m2) 0.5 0.300 ≤ 25 34 (62) 82 (57) 48 (49) 389 (55) > 25 21 (38) 63 (43) 49 (51) 313 (45) Menopausal 0.6 0.800 0 28 (51) 68 (47) 42 (43) 312 (44) 1 27 (49) 77 (53) 55 (57) 390 (56) Histology 0.021 0.400 IDC 46 (84) 137 (94) 87 (90) 633 (90) ILC 2 (4) 0 (0) 2 (2) 29 (4.1) Other 7 (13) 8 (5.5) 8 (8.2) 40 (5.7) Grade > 0.9 0.500 2 26 (47) 68 (47) 66 (68) 505 (72) 3 29 (53) 77 (53) 21 (22) 148 (21) 1 0 (0) 0 (0) 10 (10) 49 (7) T 0.4 > 0.9 1 28 (51) 64 (44) 55 (57) 391 (56) 2 26 (47) 80 (55) 39 (40) 286 (41) 3 1 (2) 1 (1) 3 (3) 25 (7) N > 0.9 0.800 0 33 (60) 87 (60) 56 (58) 420 (60) 1 10 (18) 30 (21) 28 (29) 173 (25) 2 8 (15) 16 (11) 9 (9) 69 (10) 3 4 (7) 12 (8) 4 (4) 40 (6) Stage 0.2 0.500 Ⅰ 24 (44) 47 (32) 35 (36) 296 (42) Ⅱ 20 (36) 73 (50) 47 (48) 310 (44) Ⅲ 11 (20) 25 (17) 15 (15) 96 (14) ER proportion (%) 0.200 0 55 (100) 145 (100) 1 (1) 19 (3) 1−10 − − 9 (9) 36 (5) > 10 − − 87 (90) 647 (92) PR 0.400 Negative 55 (100) 145 (100) 5 (5) 51 (7) Positive − − 92 (95) 651 (93) ki−67 proportion (%) > 0.9 0.048 < 14 3 (6) 7 (5) 33 (34) 173 (25) ≥ 14 52 (95) 138 (95) 64 (66) 529 (75) Radiotherapy 0.4 0.500 No 42 (76) 118 (81) 80 (82) 558 (79) Yes 13 (24) 27 (19) 17 (18) 144 (21) Chemotherapy > 0.9 0.400 No 12 (22) 32 (22) 44 (45) 284 (40) Yes 43 (78) 113 (78) 53 (55) 418 (60) Endocrine therapy < 0.001 No 55 (100) 145 (100) 48 (49) 24 (3) Yes − − 49 (51) 678 (97) Note. 1Data were represented as median (IQR) or n (%); 2Wilcoxon rank sum test / Pearson's Chi-squared test / Fisher's exact test; BMI, body mass index; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; ER, estrogen receptor; PgR, progesterone receptor; PR, progesterone; HER2, human epidermal growth factor receptor-2; IHC, -immunohistochemistry; T, T stage; N, N stage. -
Survival data were analyzed from November 1, 2022, to December 31, 2022. The median follow-up time for all patients was 105 months (95% CI: 102–107 months), and the survival status was known for 937 (93.8%) patients. During this period, 89 patients died and 119 developed DFS events. The median OS and DFS were not reached. The K-M curves are summarized in Figure 3.
Figure 3. Survival analysis according to HER2 status. OS for HER2 low vs. HER2-IHC0 tumors in (A) the entire cohort; (C) HR-positive group; (E) HR-negative group; DFS for HER2 low vs. HER2-IHC0 tumors in (B) the entire cohort; (D) HR-positive group; (F) HR-negative group. P values were calculated using the stratified log-rank test. OS, overall survival; DFS, disease free survival; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry; HR, hormone receptor.
In the context of whole population, K-M analysis suggested that OS of the HER2-low group improved significantly compared to that in the HER2-IHC0 group (HR: 0.525, 95% CI: 0.33–0.85, P = 0.007). However, no independent role of DFS was observed. In the HR-positive group, we observed slightly enhanced OS and DFS in the HER2-low group compared to that in the HER2-IHC 0 group; however, neither OS nor DFS were significantly different. The same trend was observed in the HR-negative group, with a significantly longer OS in the HER2-low group than in the HER2-IHC0 group (HR: 0.37, 95% CI: 0.173–0.83, P = 0.012); however, no significant survival difference was observed in DFS. Univariate analysis revealed that HER2-low was associated with increased OS (HR: 0.52; 95% CI: 0.33–0.85, P = 0.008). The same trend was observed in the 40–50 years age group along with ER and PR positive groups. However, higher T stage, N stage, clinical stage, Ki-67 ≥ 14%, and radiotherapy were associated with decreased OS. Multivariate analysis showed that HER2-low was an independent prognostic factor for improved OS (HR: 0.54, 95% CI: 0.33–0.89, P = 0.015). Hazard ratios for the COX models of OS are presented in Table 2.
Table 2. Univariate and multivariate COX analyses of OS between HER2 low and HER2−IHC0 groups
Characterisics Univariate Multivariate HR 95% CI P value HR 95% CI P value Age (years) < 40 − − − − − − 40−59 0.59 0.32−1.09 0.095 0.63 0.33−1.20 0.158 > 59 1.49 0.80−2.77 0.204 1.35 0.57−3.19 0.488 BMI (kg/m2) ≤ 25 − − − > 25 1.05 0.69−1.59 0.834 Menopausal postmenopausal − − − − − − premenopausal 0.62 0.41−0.94 0.026 0.82 0.45−1.52 0.535 Histology IDC − − − ILC 0.69 0.17−2.80 0.603 Others 0.88 0.36−2.17 0.784 Grade 1 − − − − − − 2 0.48 0.24−0.99 0.046 0.36 0.17−0.76 0.008 3 0.78 0.37−1.63 0.511 0.38 0.17−0.85 0.019 T 1 − − − − − − 2 2.47 1.58−3.87 < 0.001 1.28 0.70−2.34 0.427 3 1.84 0.56−6.04 0.315 0.53 0.13−2.15 0.374 N 0 − − − − − − 1 2.1 1.28−3.43 0.003 1.12 0.61−2.05 0.708 2 2.24 1.19−4.24 0.013 0.93 0.23−3.77 0.915 3 3.68 1.91−7.09 < 0.001 1.44 0.31−6.75 0.645 Stage Ⅰ − − − − − − Ⅱ 3.19 1.76−5.77 < 0.001 2.34 0.97−5.67 0.06 Ⅲ 5.09 2.65−9.80 < 0.001 3.5 0.70−17.57 0.129 ER Negative − − − − − − Positive 0.65 0.41−1.02 0.06 1.25 0.60−2.61 0.558 PR Negative − − − − − − Positive 0.55 0.36−0.85 0.006 0.56 0.28−1.11 0.098 HER2 0 − − − − − − Low 0.52 0.33−0.85 0.008 0.54 0.33−0.89 0.015 Ki-67 proportion (%) < 14 − − − − − − ≥ 14 3.28 1.51−7.09 0.003 3.01 1.36−6.69 0.007 TOP2A proportion (%) < 30 − − − 30−60 0.75 0.34−1.62 0.458 > 60 1.41 0.57−3.48 0.462 Chemotherapy No − − − Yes 1.19 0.77−1.85 0.43 Radiotherapy No − − − − − − Yes 1.69 1.07−2.69 0.026 1.34 0.81−2.22 0.258 Endocrine therapy No − − − Yes 0.73 0.47−1.13 0.153 Note. BMI, body mass index; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; ER, estrogen receptor; PR, progesterone receptor; HR, hazard ratio; HER2, human epidermal growth factor receptor-2; IHC,-immunohistochemistry; OS, overall survival; T, T stage; N, N stage. We also observed independent prognostic roles of nuclear grade, Ki-67 level, and clinical stage. However, we did not observe an independent prognostic role of HER2-low in the univariate or multivariate COX analyses for DFS. The hazard ratios for the COX in DFS models are presented in Supplementary Table S2 (available in www.besjournal.com).
Table S2. Univariate and multivariate Cox analyses of DFS between the HER2 low and HER−IHC0 groups
Characteristics Univariate Multivariate HR 95% CI P value HR 95% CI P value Age, years < 40 − − − − − − 40−59 0.42 0.28−0.62 < 0.001 0.47 0.32−0.70 < 0.001 > 59 0.69 0.44−1.06 0.088 0.81 0.52−1.25 0.334 BMI, kg/m2 ≤ 25 − − − > 25 0.91 0.66−1.25 0.555 Menopausal postmenopausal − − − premenopausal 0.90 0.66−1.23 0.502 histology IDC − − − ILC 0.76 0.28−2.06 0.594 Others 0.90 0.46−1.77 0.769 Grade 1 − − − 2 0.86 0.45−1.65 0.653 3 1.35 0.69−2.64 0.383 T 1 − − − − − − 2 1.86 1.35−2.57 < 0.001 1.35 0.85−2.15 0.201 3 1.41 0.57−3.52 0.457 0.70 02.6−1.91 0.488 N 0 − − − − − − 1 1.7 1.17−2.47 0.005 1.13 0.70−1.80 0.62 2 2.06 1.29−3.31 0.003 0.87 0.31−2.46 0.791 3 3.44 2.11−5.61 < 0.001 1.23 0.39−3.84 0.726 Stage Ⅰ − − − − − − Ⅱ 1.91 1.30−2.83 0.001 1.25 0.66−2.36 0.502 Ⅲ 3.42 2.20−5.31 < 0.001 2.1 0.64−6.94 0.222 ER Negative − − − Positive 0.79 0.56−1.13 0.202 PR Negative − − − Positive 0.76 0.54−1.06 0.105 HER2 0 − − − Low 0.81 0.54−1.20 0.295 Ki67, % < 14 − − − ≥ 14 2.33 1.41−3.85 < 0.001 2.07 1.24−3.43 0.005 TOP2A, % < 30 − − − 30%−60 1.09 0.67−1.78 0.732 > 60 1.11 0.52−2.37 0.796 Chemotherapy No − − − Yes 1.35 0.97−1.89 0.078 Radiotherapy No − − − Yes 2.3 1.66−3.21 < 0.001 1.81 1.27−2.60 0.001 Endocrine therapy No − − − Yes 0.86 0.62−1.21 0.383 Note. T, T stage; N, N stage. -
Patients in our cohort were divided into four groups according to their ER status: 0%, 1%–10%, 10%–50%, and > 50%; and the rates of HER2-low in these four groups were 74.54%, 75.51%, 81.76%, and 88.57%, respectively. The correlation between HER2-low and ER status is shown in Figure 4.
Figure 4. Positive correlation between ER levels and percentage of HER2 low (Mantel-Haenszel χ2 test, P < 0.001, Pearson’s R = 0.159, P < 0.001). ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry.
The distribution of HER2-low increased with increasing ER levels in each group (Mantel-Haenszel χ2 test, P < 0.001; Pearson’s R = 0.159, P < 0.001). It can be concluded that HER2-low was enriched in the ER high-expression groups, whereas HER2-IHC0 was concentrated in the ER-negative and ER-low groups. We further explored the survival differences between the HER2-IHC0 and HER2-low groups, and the results were presented using K-M curves (Supplementary Figure S1 and Supplementary Figure S2, available in www.besjournal.com). The HER2-low group showed a longer OS than the ER 0 and ER 10%–50% groups (ER: 0% group: HR = 0.319, 95% CI: 0.132–0.776, P = 0.0117; ER: 10%–50% group: HR = 0.2183, 95% CI: 0.06159–0.7737, P = 0.0291), whereas in the ER 1%–10% group, the HER2-low group showed the opposite trend; however, no significant difference was observed. No significant differences were observed between the groups in terms of DFS.
Figure S1. OS of HER2 low and HER2-IHC0 in different ER levels. (A) ER: 0%; B. ER: 1%–10%; (C) ER: 10%–50%; (D) ER > 50%. HER2 low group showed a longer OS in ER 0 and ER 10%–50% groups [ER: 0% group: HR = 0.319 (95% CI: 0.132–0.776), P = 0.0117; ER: 10%–50% group: HR = 0.2183 (95% CI: 0.06159–0.7737), P = 0.0291]. P-values were calculated using the stratified log-rank test.
Figure S2. DFS for HER2 low and HER2-IHC0 in different ER levels. (A) ER: 0%; (B) ER: 1%–10%; (C) ER: 10%–50%; (D) ER > 50%. HER2 low group showed a longer OS than the ER 0 and ER 10%–50% groups. No significant differences were found between the HER2-IHC0 and HER2 low groups. P-values were calculated using the stratified log-rank test.
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During the follow-up period, 119 (11.9%) patients developed relapse or metastatic disease, of whom 57 (47.89%) had matched biopsy samples. The most advanced settings were: bone (37/119, 31.1%), lungs (20/119, 16.80%), lymph nodes (17/119, 14.3%), liver (15/119, 12.6%), pleura (11/119, 9.24%), breast (7/119, 5.89% local recurrence and 4/119, 3.37% de novo metastasis), brain (5/119, 4.20%), and mediastinum (3/119, 2.52%). The differences in the distributions are shown in Figure 5.
Figure 5. Distribution of first-advanced settings including bone (37/119, 31.1%), lungs (20/119, 16.80%), lymph nodes (17/119, 14.28%), liver (15/119, 12.6%), pleura (11/119, 9.24%), breast (including 7/119, 5.89% local recurrence and 4/119, 3.37% de novo metastasis), brain (5/119, 4.20%), and mediastinum (3/119, 2.52%).
A total of 42.85% of the cases were visceral biopsies, while 57.15% were non-visceral. There was a significant difference between HER2-IHC0 and HER2-low cases, with a higher rate of visceral metastatic disease in HER2-low cases (38.1% vs. 13.6%, P = 0.028). Among the patients who underwent matched biopsy, 75.43% (43/57) of the primary tumors and 68.42% (39/57) of the relapsed and metastatic lesions were HER2-low BC. The discordance rate of HER2 IHC score was 38.59% (22/57) (K = 0.194, 95% CI: 0.168–0.219), including 45.45% HER2-IHC0 cases and 54.54% HER2-low cases. In the HER2-IHC0 group, 57.14% (8/14) of the cases showed a switch from HER2-IHC0 to HER2-low. On the other hand, in the HER2-low group, 13.95% (6/43) of patients showed an increasing trend. Figure 6 summarizes the dynamic evolution of HER2 IHC scores from primary sites to the matched relapsed and metastatic sites.
doi: 10.3967/bes2024.014
Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer: A Single-Institution Study
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Abstract:
Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2 (HER2)-low early breast cancer (BC) and HER2-IHC0 BC. Methods Patients diagnosed with HER2-negative BC (N = 999) at our institution between January 2011 and December 2015 formed our study population. Clinicopathological characteristics, association between estrogen receptor (ER) expression and HER2-low, and evolution of HER2 immunohistochemical (IHC) score were assessed. Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes (5-year follow-up) between the HER2-IHC0 and HER2-low groups. Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor (PgR) positivity than HER2-IHC0 BC group (P < 0.001). The rate of HER2-low status increased with increasing ER expression levels (Mantel-Haenszel χ2 test, P < 0.001, Pearson’s R = 0.159, P < 0.001). Survival analysis revealed a significantly longer overall survival (OS) in HER2-low BC group than in HER2-IHC0 group (P = 0.007) in the whole cohort and the hormone receptor (HR)-negative group. There were no significant differences between the two groups in terms of disease-free survival (DFS). The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%. Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles. -
Key words:
- HER2 /
- HER2-low /
- Breast cancer /
- Estrogen receptor /
- Trastuzumab deruxtecan
The authors have no relevant financial or non-financial interests to disclose.
This study was conducted in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of the General Hospital of the Chinese People’s Liberation Army (hospital ethics no. S2023-307-1). The need for informed consent was waived by the Review Board due to the retrospective nature of the study.
注释:1) AUTHOR CONTRIBUTIONS: 2) COMPETING INTERESTS: 3) ETHICS APPROVAL AND CONSENT TO PARTICIPATE: -
Figure 3. Survival analysis according to HER2 status. OS for HER2 low vs. HER2-IHC0 tumors in (A) the entire cohort; (C) HR-positive group; (E) HR-negative group; DFS for HER2 low vs. HER2-IHC0 tumors in (B) the entire cohort; (D) HR-positive group; (F) HR-negative group. P values were calculated using the stratified log-rank test. OS, overall survival; DFS, disease free survival; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry; HR, hormone receptor.
S1. OS of HER2 low and HER2-IHC0 in different ER levels. (A) ER: 0%; B. ER: 1%–10%; (C) ER: 10%–50%; (D) ER > 50%. HER2 low group showed a longer OS in ER 0 and ER 10%–50% groups [ER: 0% group: HR = 0.319 (95% CI: 0.132–0.776), P = 0.0117; ER: 10%–50% group: HR = 0.2183 (95% CI: 0.06159–0.7737), P = 0.0291]. P-values were calculated using the stratified log-rank test.
S2. DFS for HER2 low and HER2-IHC0 in different ER levels. (A) ER: 0%; (B) ER: 1%–10%; (C) ER: 10%–50%; (D) ER > 50%. HER2 low group showed a longer OS than the ER 0 and ER 10%–50% groups. No significant differences were found between the HER2-IHC0 and HER2 low groups. P-values were calculated using the stratified log-rank test.
Figure 5. Distribution of first-advanced settings including bone (37/119, 31.1%), lungs (20/119, 16.80%), lymph nodes (17/119, 14.28%), liver (15/119, 12.6%), pleura (11/119, 9.24%), breast (including 7/119, 5.89% local recurrence and 4/119, 3.37% de novo metastasis), brain (5/119, 4.20%), and mediastinum (3/119, 2.52%).
S1. Demographic characteristics of the HER2−IHC0 and HER2 low groups in the whole cohort
Characteristic Overall
N = 9991HER2 IHC 0
N = 1521HER2 low
N = 8471P value2 Age 49.00 (43.00, 59.00) 49.00 (42.75, 61.25) 50.00 (43.00, 59.00) 0.9 Age group, years 0.070 < 40 138 (14%) 25 (16%) 113 (13%) 40−59 622 (62%) 82 (54%) 540 (64%) > 59 239 (24%) 45 (30%) 194 (23%) BMI, kg/m2 0.7 ≤ 25 553 (55%) 82 (54%) 471 (56%) > 25 446 (45%) 70 (46%) 376 (44%) Menopausal 0.8 premenopausal 549 (55%) 82 (54%) 467 (55%) postmenopausal 450 (45%) 70 (46%) 380 (45%) Histology3 0.13 IDC 903 (90%) 133 (88%) 770 (91%) ILC 33 (3.3%) 4 (2.6%) 29 (3.4%) Others 63 (6.3%) 15 (9.9%) 48 (5.7%) Grade 0.2 1 59 (5.9%) 10 (6.6%) 49 (5.8%) 2 665 (67%) 92 (61%) 573 (68%) 3 275 (28%) 50 (33%) 225 (27%) T > 0.9 1 538 (54%) 83 (55%) 455 (54%) 2 431 (43%) 65 (43%) 366 (43%) 3 30 (3.0%) 4 (2.6%) 26 (3.1%) N > 0.9 0 596 (60%) 89 (59%) 507 (60%) 1 241 (24%) 38 (25%) 203 (24%) 2 102 (10%) 17 (11%) 85 (10%) 3 60 (6.0%) 8 (5.3%) 52 (6.1%) Stage 0.7 Ⅰ 402 (40%) 59 (39%) 343 (40%) Ⅱ 450 (45%) 67 (44%) 383 (45%) Ⅲ 147 (15%) 26 (17%) 121 (14%) ER4 , % < 0.001 0 220 (22%) 56 (37%) 164 (19%) 1−10 45 (4.5%) 9 (5.9%) 36 (4.3%) > 10 734 (73%) 87 (57%) 647 (76%) PR5 < 0.001 negative 256 (26%) 60 (39%) 196 (23%) positive 743 (74%) 92 (61%) 651(77%) Ki67 0.5 < 14% 216 (22%) 36 (24%) 180 (21%) ≥ 14% 783 (78%) 116 (76%) 667 (79%) TOP2A, % 0.8 < 30 866 (87%) 134 (88%) 732 (86%) 30−60 97 (9.7%) 13 (8.6%) 84 (9.9%) > 60 36 (3.6%) 5 (3.3%) 31 (3.7%) Radiotherapy 0.9 No 798 (80%) 122 (80%) 676 (80%) Yes 201 (20%) 30 (20%) 171 (20%) Chemotherapy > 0.9 No 372 (37%) 56 (37%) 316 (37%) Yes 627 (63%) 96 (63%) 531 (63%) Endocrine therapy < 0.001 No 272 (27%) 103 (68%) 169 (20%) Yes 727 (73%) 49 (32%) 678 (80%) Note. 1Median (IQR); n (%); 2Wilcoxon rank sum test; Pearson's Chi−squared test; Fisher's exact test; 3 IDC, invasive ductal carcnoma; ILC: invasive lobular carcinoma; 4ER: estrogen receptor; 5PR: progesterone receptor. T, T stage; N, N stage. Table 1. Baseline characteristics of patients stratified by hormone receptor
Characteristics Hormone receptor negative Hormone receptor positive HER2 IHC0
(N = 55)1HER2 Low
(N = 145)1P value2 HER2 IHC0
(N = 97)1HER2 Low
(N = 702)1P value2 Age (years) 48 (41, 59) 51 (43, 59) 0.6 49 (44, 62) 49 (43, 59) 0.500 Age group (years) 0.3 0.200 < 40 12 (22) 23 (16) 13 (13) 90 (13) 40−59 29 (53) 93 (64) 53 (55) 447 (64) > 59 14 (25) 29 (20) 31 (32) 165 (24) BMI (kg/m2) 0.5 0.300 ≤ 25 34 (62) 82 (57) 48 (49) 389 (55) > 25 21 (38) 63 (43) 49 (51) 313 (45) Menopausal 0.6 0.800 0 28 (51) 68 (47) 42 (43) 312 (44) 1 27 (49) 77 (53) 55 (57) 390 (56) Histology 0.021 0.400 IDC 46 (84) 137 (94) 87 (90) 633 (90) ILC 2 (4) 0 (0) 2 (2) 29 (4.1) Other 7 (13) 8 (5.5) 8 (8.2) 40 (5.7) Grade > 0.9 0.500 2 26 (47) 68 (47) 66 (68) 505 (72) 3 29 (53) 77 (53) 21 (22) 148 (21) 1 0 (0) 0 (0) 10 (10) 49 (7) T 0.4 > 0.9 1 28 (51) 64 (44) 55 (57) 391 (56) 2 26 (47) 80 (55) 39 (40) 286 (41) 3 1 (2) 1 (1) 3 (3) 25 (7) N > 0.9 0.800 0 33 (60) 87 (60) 56 (58) 420 (60) 1 10 (18) 30 (21) 28 (29) 173 (25) 2 8 (15) 16 (11) 9 (9) 69 (10) 3 4 (7) 12 (8) 4 (4) 40 (6) Stage 0.2 0.500 Ⅰ 24 (44) 47 (32) 35 (36) 296 (42) Ⅱ 20 (36) 73 (50) 47 (48) 310 (44) Ⅲ 11 (20) 25 (17) 15 (15) 96 (14) ER proportion (%) 0.200 0 55 (100) 145 (100) 1 (1) 19 (3) 1−10 − − 9 (9) 36 (5) > 10 − − 87 (90) 647 (92) PR 0.400 Negative 55 (100) 145 (100) 5 (5) 51 (7) Positive − − 92 (95) 651 (93) ki−67 proportion (%) > 0.9 0.048 < 14 3 (6) 7 (5) 33 (34) 173 (25) ≥ 14 52 (95) 138 (95) 64 (66) 529 (75) Radiotherapy 0.4 0.500 No 42 (76) 118 (81) 80 (82) 558 (79) Yes 13 (24) 27 (19) 17 (18) 144 (21) Chemotherapy > 0.9 0.400 No 12 (22) 32 (22) 44 (45) 284 (40) Yes 43 (78) 113 (78) 53 (55) 418 (60) Endocrine therapy < 0.001 No 55 (100) 145 (100) 48 (49) 24 (3) Yes − − 49 (51) 678 (97) Note. 1Data were represented as median (IQR) or n (%); 2Wilcoxon rank sum test / Pearson's Chi-squared test / Fisher's exact test; BMI, body mass index; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; ER, estrogen receptor; PgR, progesterone receptor; PR, progesterone; HER2, human epidermal growth factor receptor-2; IHC, -immunohistochemistry; T, T stage; N, N stage. Table 2. Univariate and multivariate COX analyses of OS between HER2 low and HER2−IHC0 groups
Characterisics Univariate Multivariate HR 95% CI P value HR 95% CI P value Age (years) < 40 − − − − − − 40−59 0.59 0.32−1.09 0.095 0.63 0.33−1.20 0.158 > 59 1.49 0.80−2.77 0.204 1.35 0.57−3.19 0.488 BMI (kg/m2) ≤ 25 − − − > 25 1.05 0.69−1.59 0.834 Menopausal postmenopausal − − − − − − premenopausal 0.62 0.41−0.94 0.026 0.82 0.45−1.52 0.535 Histology IDC − − − ILC 0.69 0.17−2.80 0.603 Others 0.88 0.36−2.17 0.784 Grade 1 − − − − − − 2 0.48 0.24−0.99 0.046 0.36 0.17−0.76 0.008 3 0.78 0.37−1.63 0.511 0.38 0.17−0.85 0.019 T 1 − − − − − − 2 2.47 1.58−3.87 < 0.001 1.28 0.70−2.34 0.427 3 1.84 0.56−6.04 0.315 0.53 0.13−2.15 0.374 N 0 − − − − − − 1 2.1 1.28−3.43 0.003 1.12 0.61−2.05 0.708 2 2.24 1.19−4.24 0.013 0.93 0.23−3.77 0.915 3 3.68 1.91−7.09 < 0.001 1.44 0.31−6.75 0.645 Stage Ⅰ − − − − − − Ⅱ 3.19 1.76−5.77 < 0.001 2.34 0.97−5.67 0.06 Ⅲ 5.09 2.65−9.80 < 0.001 3.5 0.70−17.57 0.129 ER Negative − − − − − − Positive 0.65 0.41−1.02 0.06 1.25 0.60−2.61 0.558 PR Negative − − − − − − Positive 0.55 0.36−0.85 0.006 0.56 0.28−1.11 0.098 HER2 0 − − − − − − Low 0.52 0.33−0.85 0.008 0.54 0.33−0.89 0.015 Ki-67 proportion (%) < 14 − − − − − − ≥ 14 3.28 1.51−7.09 0.003 3.01 1.36−6.69 0.007 TOP2A proportion (%) < 30 − − − 30−60 0.75 0.34−1.62 0.458 > 60 1.41 0.57−3.48 0.462 Chemotherapy No − − − Yes 1.19 0.77−1.85 0.43 Radiotherapy No − − − − − − Yes 1.69 1.07−2.69 0.026 1.34 0.81−2.22 0.258 Endocrine therapy No − − − Yes 0.73 0.47−1.13 0.153 Note. BMI, body mass index; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; ER, estrogen receptor; PR, progesterone receptor; HR, hazard ratio; HER2, human epidermal growth factor receptor-2; IHC,-immunohistochemistry; OS, overall survival; T, T stage; N, N stage. S2. Univariate and multivariate Cox analyses of DFS between the HER2 low and HER−IHC0 groups
Characteristics Univariate Multivariate HR 95% CI P value HR 95% CI P value Age, years < 40 − − − − − − 40−59 0.42 0.28−0.62 < 0.001 0.47 0.32−0.70 < 0.001 > 59 0.69 0.44−1.06 0.088 0.81 0.52−1.25 0.334 BMI, kg/m2 ≤ 25 − − − > 25 0.91 0.66−1.25 0.555 Menopausal postmenopausal − − − premenopausal 0.90 0.66−1.23 0.502 histology IDC − − − ILC 0.76 0.28−2.06 0.594 Others 0.90 0.46−1.77 0.769 Grade 1 − − − 2 0.86 0.45−1.65 0.653 3 1.35 0.69−2.64 0.383 T 1 − − − − − − 2 1.86 1.35−2.57 < 0.001 1.35 0.85−2.15 0.201 3 1.41 0.57−3.52 0.457 0.70 02.6−1.91 0.488 N 0 − − − − − − 1 1.7 1.17−2.47 0.005 1.13 0.70−1.80 0.62 2 2.06 1.29−3.31 0.003 0.87 0.31−2.46 0.791 3 3.44 2.11−5.61 < 0.001 1.23 0.39−3.84 0.726 Stage Ⅰ − − − − − − Ⅱ 1.91 1.30−2.83 0.001 1.25 0.66−2.36 0.502 Ⅲ 3.42 2.20−5.31 < 0.001 2.1 0.64−6.94 0.222 ER Negative − − − Positive 0.79 0.56−1.13 0.202 PR Negative − − − Positive 0.76 0.54−1.06 0.105 HER2 0 − − − Low 0.81 0.54−1.20 0.295 Ki67, % < 14 − − − ≥ 14 2.33 1.41−3.85 < 0.001 2.07 1.24−3.43 0.005 TOP2A, % < 30 − − − 30%−60 1.09 0.67−1.78 0.732 > 60 1.11 0.52−2.37 0.796 Chemotherapy No − − − Yes 1.35 0.97−1.89 0.078 Radiotherapy No − − − Yes 2.3 1.66−3.21 < 0.001 1.81 1.27−2.60 0.001 Endocrine therapy No − − − Yes 0.86 0.62−1.21 0.383 Note. T, T stage; N, N stage. -
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