Summary
Background
There is some controversy regarding the precise role and need for adjuvant therapy in patients with pT1a/pT1bN0 breast cancer, although studies have indicated that a HER2-positive status is one of the most powerful poor prognostic factors.
Patients and Methods
We retrospectively evaluated disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) among 960 patients diagnosed between 2000 and 2008 with T1N0 primary breast cancer treated at 3 German centers, and determined prognostic risk factors. Univariate analysis was used to determine associations with potential risk factors.
Results
With a median follow-up of 23 months, DFS was 94.8%, DDFS 96.3%, and OS 97.5%. Risk factors for decreased 1-year DFS were: peritumoral lymphatic invasion (L1) (p = 0.031), negative hormone receptor status (p = 0.003), non-use of hormonal therapy (p = 0.001), and a positive HER2 status (p = 0.003). Amongst the HER2-positive patients only 2.7% (n = 1/37) of those treated with trastuzumab had a DFS event compared with 20% (n = 10/50) without trastuzumab.
Conclusion
Patients with HER2-positive T1 breast cancer should be considered for inclusion in prospective trials of trastuzumab in combination with chemotherapy to determine the risk-to-benefit ratio and association with other prognostic factors.
Key Words: Trastuzumab, High-risk breast cancer, Adjuvant treatment, HER2/neu, Disease-free survival
Abstract
Zusammenfassung
Hintergrund: Die Bedeutung und der Nutzen einer adjuvanten Therapie bei Patientinnen mit einem pT1a/pT1bN0-Mammakarzinom wird kontrovers diskutiert. In einigen Studien konnte ein positiver HER2-Status als einer der stärksten prognostischen Faktoren nachgewiesen werden. Patientinnen und Methoden: In dieser Studie wurde retrospektiv an 3 deutschen Brustzentren das krankheitsfreie Überleben (DFS), das distant krankheitsfreie Überleben (DDFS) und das Gesamtüberleben (OS) von 960 Patientinnen, die zwischen 2000 und 2008 an einem primären Mammakarzinom < 2 cm (T1N0) erkrankten, ausgewertet. Zusätzlich wurden die prognostischen Faktoren untersucht. Der Zusammenhang mit potentiellen Risikofaktoren wurde durch univariate Analysen untersucht. Ergebnisse: Die mediane Nachbeobachtungszeit betrug 23 Monate, DFS war 94,8%, DDFS 96,3% und OS 97,5%. Risikofaktoren für ein kürzeres 1-Jahres-DFS waren: peritumorale lymphatische Invasion (L1) (p = 0,031), negativer Hormonrezeptorstatus (p = 0,003), keine adjuvante hormonelle Therapie (p = 0,001) und ein positiver HER2-Status (p = 0,003). Bei Patientinnen, die mit Trastuzumab behandelt wurden, trat nur bei 2,7% (n = 1/37) ein DFS-Ereignis auf, bei Patienten ohne Trastuzumab-Therapie war dies bei 20% (n = 10/50) der Fall. Schlussfolgerung: Patienten mit einem HER2-positiven Mammakarzinom < 2 cm sollten in prospektive Studien eingeschlossen werden, um die Bedeutung der Trastuzumab-Therapie in Kombination mit Chemotherapie, das Nutzen-Risiko-Verhältnis und die Bedeutung anderer Riskiofaktoren untersuchen zu können.
Introduction
As a result of widespread mammographic screening, there has been an increase in the absolute number and proportion of breast cancer patients being diagnosed with small primary tumors (T1 grading) [1,2]. This shift at presentation in combination with improved techniques for locoregional control (e.g. attention to surgical margins, improved radiotherapy), and better systemic therapy has resulted in mortality reductions in recent decades [2,3]. Patients with node-negative pT1a/pT1b tumors might have a good long-term prognosis with locoregional therapy alone and no systemic adjuvant treatment; 10-year disease-free survival rates exceeding 90% and a 20-year disease-free survival of 86% have been reported [4,5,6]. However patients with pT1a/pT1bN0 breast cancer show a relatively heterogeneous prognosis. Risk factors associated with poor outcome include tumor grade, age at diagnosis (< 50 years), lymphovascular invasion, high Ki67 expression, hormone receptor-negative status, and a human epidermal growth factor receptor 2 (HER2)-positive status [7]. Although there is some degree of controversy concerning the precise role of, and need for, adjuvant therapy in patients with pT1a/pT1bN0 disease [7], the identification of risk factors or combinations of risk factors in patients with pT1a/pT1bN0 disease may assist in identifying patients that are more likely to benefit from adjuvant therapy. Several recent studies indicate that a HER2-postive status is one of the most powerful poor prognostic factors in patients with pT1a/pT1bN0 tumors [8,9,10,11,12]. We retrospectively collected data on patients treated for T1N0 primary breast cancer at 3 German centers. The aims of our study were to evaluate disease-free survival, distant disease-free survival and overall survival, and to determine prognostic risk factors among these patients.
Patients and Methods
Three German breast cancer centers (Heidelberg, Cologne, and Mönchengladbach) provided retrospective data on a total of 960 patients who were diagnosed and treated between 2000 and 2008 for T1N0 breast cancer. Data collected from patient records included demographic and disease characteristics at disease diagnosis, and information on treatment. The Mönchengladbach center did not provide information on Eastern Collaborative Oncology Group (ECOG) performance status (PS) or lymphadenectomy.
A HER2-positive status was defined as a score of HER2 3+ on immunohistochemistry (IHC) assay, or HER2 2+ on IHC assay confirmed as positive with a fluorescence in situ hybridization assay of HER2 gene amplification according to consensus guidelines [13]. All patients gave written informed consent to provide the data used in this study which was conducted in accordance with the Declaration of Helsinki. Ethical committee approval was provided by the University of Heidelberg (reference no. S-522/2010).
1-year disease-free survival, distant disease-free survival, and overall survival were calculated by Kaplan-Meier analysis. Log-rank tests were used to determine associations between potential risk factors and disease-free survival, distant disease-free survival, and overall survival. This time period was used to focus on the direct effect and exclude other factors. Due to the low numbers of events, multivariate analyses were not meaningful.
Results
Demographic and Disease Characteristics
Of the 960 patients with T1N0 breast cancer, 394 were recruited from Heidelberg, 353 from Cologne, and 213 from Mönchengladbach. T subgrouping was pT1a/pT1b in 735 patients (77%) and pT1c in 225 (23%) (table 1). Of the patients recruited from Heidelberg, 44% (n = 175) had pT1a/pT1b disease and 56% (n = 219) had pT1c disease. The majority of the Cologne patients had pT1a/pT1b disease (98%, n = 346), with the remainder having pT1c disease (2%, n = 7). All 213 patients recruited from Mönchengladbach had pT1a/pT1b disease. The demographic and disease characteristics of the whole T1 cohort and the pT1a/pT1b and pT1c subgroups are summarized in table 1. For the whole T1N0 cohort, 11% were HER2-positive. Comparing patients with pT1a/pT1b disease to those with pT1c disease, the pT1a/pT1b cohort showed better ECOG PS (PS 0: 72 vs. 49%), were more likely to have lower tumor grade (G1: 31 vs. 25%), and were less likely to show peritumoral lymphatic infiltration (L1: 3 vs. 10%) (table 1).
Table 1.
Patient demographic and disease characteristics
| Characteristicsa | All T1 patients (n = 960) | T1ab(n = 735) | T1c(n = 225) |
|---|---|---|---|
| Age, n (%) | |||
| < 35 years | 6 (< 1) | 3 (< 1) | 3 (2) |
| 35–50 years | 221 (23) | 163 (22) | 58 (26) |
| 51–65 years | 452 (47) | 352 (48) | 100 (44) |
| > 65 years | 281 (29) | 217 (30) | 64 (28) |
| Median bodyweight (range), kg | 68 (41–162) | 68 (41–162) | 67 (46–115) |
| Median height (range), cm | 165 (147–190) | 165 (147–182) | 165 (147–190) |
| ECOG performance status, n (%)b | |||
| 0 | 487 (50) | 377 (51) | 110 (49) |
| 1 | 257 (27) | 145 (20) | 112 (50) |
| ≥ 2 | 3 (< 1) | 0 (0) | 3 (1) |
| Menopausal status, n (%) | |||
| Premenopausal | 205 (22) | 145 (20) | 60 (27) |
| Postmenopausal | 737 (78) | 575 (80) | 162 (73) |
| Tumor size, n (%) | |||
| T1a | 194 (20) | – | – |
| T1b | 541 (56) | – | – |
| T1c | 225 (23) | – | – |
| Metastatic status, n (%) | |||
| 0 | 958 (99.8) | 733 (99.8) | 225 (100) |
| 1 | 2 (0.2) | 2 (0.2) | 0 |
| Histological type, n (%) | |||
| Ductal | 567 (80) | 395 (80) | 172 (78) |
| Non-ductal | 145 (20) | 97 (20) | 48 (22) |
| Tumor grade, n (%) | |||
| G1 | 289 (30) | 233 (31) | 56 (25) |
| G2 | 553 (57) | 429 (58) | 124 (55) |
| G3 | 117 (12) | 72 (10) | 45 (20) |
| GX | 1 (< 1) | 1 (< 1) | 0 |
| Peritumoral lymphatic infiltration, n (%)b | |||
| L0 | 605 (95) | 405 (97) | 200 (90) |
| L1 | 34 (5) | 13 (3) | 21 (10) |
| ER status, n (%) | |||
| Positive | 823 (86) | 637 (87) | 186 (83) |
| Negative | 136 (14) | 97 (13) | 39 (17) |
| PR status, n (%) | |||
| Positive | 751 (78) | 579 (79) | 172 (76) |
| Negative | 208 (22) | 155 (21) | 53 (24) |
| HER2 status, n (%) | |||
| Positive | 106 (11) | 77 (11) | 29 (13) |
| Negative | 846 (89) | 650 (89) | 196 (87) |
Data missing for some patients and not included in denominator for percent calculations.
Data not supplied by the Mönchengladbach center.
ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor.
Treatment
Treatment for the whole T1N0 cohort and the pT1a/pT1b and pT1c subgroups is summarized in table 2. For the whole cohort, 19% received adjuvant chemotherapy and 2% neo-adjuvant chemotherapy, and 4% received trastuzumab. Compared to patients with pT1c disease, those with pT1a/pT1b disease were more likely to undergo breast-conserving surgery (80 vs. 72%) or sentinel node lymphadenectomy (73 vs. 63%), and less likely to receive chemotherapy (14 vs. 37%) or trastuzumab (3 vs. 10%).
Table 2.
Treatments received
| Treatmenta | All T1 patients (n = 960) | T1ab (n = 735) | T1c (n = 225) |
|---|---|---|---|
| Surgery, n (%) | |||
| Mastectomy | 212 (22) | 149 (20) | 63 (28) |
| Breast-conserving | 748 (78) | 586 (80) | 162 (72) |
| Lymphadenectomy, n (%)b | |||
| Axillary | 226 (30) | 143 (27) | 83 (37) |
| Sentinel | 521 (70) | 379 (73) | 142 (63) |
| Radiotherapy, n (%) | |||
| Yes | 727 (77) | 556 (77) | 171 (76) |
| No | 223 (23) | 169 (23) | 54 (24) |
| Chemotherapy, n (%) | |||
| Yes | 182 (19) | 98 (14) | 84 (37) |
| No | 740 (79) | 606 (85) | 134 (60) |
| Neoadjuvant | 16 (2) | 10 (1) | 6 (3) |
| Hormonal therapy, n (%) | |||
| Yes | 822 (87) | 632 (88) | 190 (84) |
| No | 125 (23) | 90 (12) | 35 (16) |
| Trastuzumab, n (%) | |||
| Yes | 43 (4) | 20 (3) | 23 (10) |
| No | 916 (96) | 714 (97) | 202 (90) |
Data missing for some patients and not included in denominator for percent calculations.
Data not supplied by the Mönchengladbach center.
Disease-Free Survival, Distant Disease-Free Survival, and Overall Survival
With an overall median follow-up of 23 months (range 0-192 months), the 1-year disease-free survival was 94.8% (42 events) (fig. 1), distant disease-free survival was 96.3% (30 events), and overall survival was 97.5% (21 deaths). Potential risk factors affecting 1-year disease-free survival, distant disease-free survival, and overall survival were examined by univariate analysis (table 3). Significant negative prognostic factors for 1-year disease-free survival were: peritumoral lymphatic invasion (L1) (p = 0.031), negative hormone receptor status (p = 0.003), and non-use of hormonal therapy (p = 0.001). The following were significant negative prognostic factors for 1-year distant disease-free survival: ECOG performance status ≥ 1 (p = 0.008), peritumoral lymphatic invasion (L1) (p = 0.009), negative hormone receptor status (p = 0.004), non-use of hormonal therapy (p = 0.003), and prior mastectomy versus breast-conserving surgery (p = 0.046). The following were significant negative prognostic factors for 1-year overall survival: ECOG PS ≥ 1 (p = 0.001), no signs of peritumoral lymphatic invasion (L1) (p = 0.004), negative hormone receptor status (p = 0.008), sentinel lymphadenectomy (p = 0.016), and non-use of hormonal therapy (p = 0.008). 1-year disease-free survival and distant disease-free survival were also significantly decreased by a HER2-positive status (p = 0.003 and p = 0.004, respectively) (table 3). Of the 106 HER2-positive patients, disease-free survival data were only available for 87 individuals. 12.6% (11/87) of patients with HER2-positive disease had a disease-free survival event compared to only 4.5% (31/684) of those with HER2-negative disease (fig. 2). Of the 87 patients with HER2-positive disease, 42.5% (n = 37) had received adjuvant trastuzumab therapy, and of those 37 patients only 1 had a disease-free survival event compared to 20% (n = 10/50) of HER2-positive patients who did not receive trastuzumab treatment. Information on trastuzumab treatment was present for all of the 87 patients with HER2-positive breast cancer.
Fig. 1.
Kaplan-Meier plot of disease-free survival for patients with T1N0 breast tumors.
Table 3.
Prognostic risk factors affecting survival outcomes
| Variablea | 1-year DFS | 1-year DDFS | 1-year OS | |||
|---|---|---|---|---|---|---|
| % (95% CI) | p | % (95% CI) | p | % (95% CI) | p | |
| Overall (n = 960) | 98.4 (97.1–99.1) | 98.8 (97.7–99.4) | 99.5 (98.6–99.8) | |||
| Age (n = 960) | ||||||
| < 50 years | 99.4 (95.7–99.9) | 99.4 (95.7–99.9) | 99.4 (95.7–99.9) | |||
| 51–65 years | 99.0 (97.0–99.7) | 99.7 (98.2–99.9) | 100 | |||
| > 65 years | 96.6 (93.3–98.3) | 0.285 | 97.0 (93.8–98.6) | 0.355 | 98.7 (96.0–99.6) | 0.256 |
| ECOG performance status (n = 747)b | ||||||
| 0 | 99.4 (97.5–99.8) | 99.5 (97.9–99.9) | 99.7 (98.1–99.9) | |||
| ≥ 1 | 96.7 (93.3–98.4) | 0.114 | 96.7 (93.3–98.4) | 0.008 | 98.5 (95.5–99.5) | 0.001 |
| Menopausal status (n = 942) | ||||||
| Premenopausal | 99.3 (95.4–99.9) | 99.3 (95.4–99.9) | 99.3 (95.4–99.9) | |||
| Postmenopausal | 98.0 (96.5–98.9) | 0.151 | 98.6 (97.3–99.3) | 0.182 | 99.5 (98.4–99.8) | 0.178 |
| Tumor size (n = 960) | ||||||
| T1a | 97.3 (92.9–99.0) | 98.7 (94.8–99.7) | 99.4 (95.9–99.9) | |||
| T1b | 98.6 (96.8–99.4) | 98.8 (97.2–99.5) | 99.5 (98.0–99.9) | |||
| T1c | 99.0 (95.6–99.7) | 0.928 | 99.0 (96.0–99.7) | 0.868 | 99.5 (96.2–99.9) | 0.561 |
| T1ab | 98.2 (96.7–99.0) | 98.8 (97.4–99.4) | 99.5 (98.3–99.8) | |||
| T1c | 99.0 (95.6–99.7) | 0.913 | 99.0 (96.0–99.7) | 0.602 | 99.5 (96.2–99.9) | 0.283 |
| Histological type (n = 712) | ||||||
| Ductal | 98.5 (96.8–99.3) | 98.5 (96.9–99.3) | 99.6 (98.3–99.9) | |||
| Non-ductal | 99.1 (93.8–99.9) | 0.413 | 99.1 (93.8–99.9) | 0.509 | 99.1 (93.8–99.9) | 0.604 |
| Tumor grade (n = 959) | ||||||
| G1 | 98.0 (94.6–99.2) | 99.5 (96.3–99.9) | 99.5 (96.3–99.9) | |||
| G2 | 98.4 (96.8–99.3) | 98.5 (96.8–99.3) | 99.3 (97.9–99.8) | |||
| G3 | 98.7 (91.4–99.8) | 0.273 | 98.7 (91.4–99.8) | 0.209 | 100 | 0.149 |
| Peritumoral lymphatic infiltration (n = 639) | ||||||
| L0 | 98.3 (96.6–99.2) | 98.9 (97.5–99.6) | 99.6 (98.3–99.9) | |||
| L1 | 96.8 (79.2–99.5) | 0.031 | 96.8 (79.2–99.5) | 0.009 | 100 | 0.004 |
| Hormone receptor status (n = 959) | ||||||
| Positive | 98.6 (90.4–99.8) | 100 | 100 | |||
| Negative | 98.3 (97.0–99.1) | 0.003 | 98.7 (97.4–99.3) | 0.004 | 99.4 (98.4–99.8) | 0.008 |
| HER2 status (n = 952) | ||||||
| Positive | 97.1 (88.8–99.3) | 98.5 (89.9–99.8) | 100 | |||
| Negative | 98.5 (97.2–99.2) | 0.001 | 99.8 (97.7–99.4) | 0.002 | 99.4 (98.4–99.8) | 0.008 |
| Positive + trastuzumab | 100 | 100 | 100 | |||
| Positive + no trastuzumab | 95.7 (83.9–98.9) | 0.002 | 97.9 (86.1–99.4) | 0.005 | 100 | 0.022 |
| Surgery (n = 960) | ||||||
| Mastectomy | 97.6 (93.8–99.1) | 97.6 (93.7–99.1) | 98.9 (95.5–99.7) | |||
| Breast-conserving | 98.6 (97.2–99.3) | 0.053 | 99.2 (98.0–99.7) | 0.046 | 99.6 (98.6–99.9) | 0.062 |
| Lymphadenectomy (n = 747)b | ||||||
| Axillary | 98.8 (95.5–99.7) | 98.8 (95.5–99.7) | 100 | |||
| Sentinel | 98.2 (96.2–99.1) | 0.277 | 98.3 (96.4–99.2) | 0.07 | 99.0 (97.2–99.6) | 0.016 |
| Radiotherapy (n = 950) | ||||||
| Yes | 98.4 (96.9–99.2) | 99.0 (97.7–99.5) | 99.6 (98.5–99.9) | |||
| No | 98.3 (94.7–99.4) | 0.273 | 98.3 (94.7–99.4) | 0,388 | 98.9 (95.7–99.7) | 0.377 |
| Chemotherapy (n = 938) | ||||||
| Yes | 99.4 (95.8–99.9) | 99.4 (95.8–99.9) | 100 | |||
| No | 98.0 (96.5–98.9) | 0.248 | 98.6 (97.2–99.3) | 0,132 | 99.3 (98.1–99.7) | 0.115 |
| Hormonal therapy (n = 947) | ||||||
| Yes | 98.6 (97.2–99.3) | 98.6 (97.7–99.5) | 99.7 (98.7–99.9) | |||
| No | 96.8 (90.3–99.0) | 0.001 | 98.0 (92.1–99.5) | 0,003 | 98.0 (92.1–99.5) | 0.008 |
Denominators apply for calculation of risk factors for disease-free survival and may vary by one or two patients for overall survival and distant disease-free survival analysis.
Data not supplied by the Mönchengladbach center.
DFS = Disease-free survival; DDFS = distant disease-free survival; OS = overall survival; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group
Fig. 2.
Kaplan-Meier plot of disease-free survival for patients with T1N0 breast tumors according to HER2 status: HER2-negative (green) and HER2-positive (red).
Discussion
Among 960 patients with (T1N0) breast cancer, we found peritumoral lymphatic invasion, a negative hormone receptor status, and use of hormonal therapy to be significant prognostic factors for 1-year disease-free survival, with some of these factors also remaining significant prognostic indicators for 1-year distant disease-free survival and overall survival. These are generally recognized risk factors in T1N0 breast cancer [7].
HER2-positivity was also a significant risk factor for 1-year disease-free survival and distant disease-free survival in our patients with T1N0 disease. Other retrospective studies have shown that a HER2-positive status is a powerful poor prognostic factor in patients with pT1a/pT1bN0 tumors [8,9,10,11,12]. In a study of 852 patients with T1N0 disease [8], patients showing HER2 gene amplification had a lower 9-year distant disease-free survival as compared to HER2-negative patients (72 vs. 88%). Univariate analysis showed that a HER2-positive status (p < 0.001) was one of the most powerful prognostic factors for 9-year disease-free survival along with tumor grade (p < 0.001) and tumor size (p = 0.01), and more powerful than progesterone receptor status (p = 0.012), histological type (p = 0.01), and Ki-67 (p = 0.01) and p53 (p = 0.043) expression.
In another study of 965 patients with pT1a/pT1bN0 breast cancer who had received neither systemic adjuvant therapy nor trastuzumab [10], a HER2-positive status was associated with significantly lower 5-year disease-free survival (77 vs. 94%; p < 0.001) and distant disease-free survival (86 vs. 97%; p < 0.001); furthermore, patients with HER2-positive tumors had 5.09 times the rate of recurrences (95% confidence interval (CI) 2.56-10.14; p < 0.001) and 7.81 times the rate of distant recurrences (95% CI 3.17-19.22; p < 0.001) at 5 years compared with patients who had hormone receptor-positive tumors.
Of the 106 patients with HER2-positive disease in our study, follow-up and information regarding trastuzumab therapy was available for only 87 patients. Of these patients, 37 (42.5%) had received adjuvant trastuzumab therapy and only 1 of these patients had a disease-free survival event compared to 20% (n = 10/50) of HER2-positive patients who did not receive trastuzumab treatment. This suggests introducing adjuvant trastuzumab confers a significant benefit in reducing the risk of relapse in HER2-postive T1N0 breast cancer. This corroborates a recently published retrospective report into adjuvant trastuzumab therapy in women with HER2-positive T1N0 breast cancer, where 4-year recurrence and death rates were lower amongst those who received trastuzumab (n = 155) compared with those who did not receive trastuzumab (n = 106). The results were respectively: locoregional invasive recurrence-free survival event (1.3 vs. 7.5%); contralateral invasive recurrence-free survival event (0 vs. 1.9%); distant recurrence-free survival (0 vs. 5.7%); and death (0.7 vs. 2.8%) [14].
The lack of a firm recommendation for trastuzumab in pT1a/pT1bN0 breast cancer is due to there being no prospective data on the use of trastuzumab in this setting [15] as patients with tumor size ≤ 1 cm were excluded from adjuvant trials [16,17,18,19]. However in the Herceptin Adjuvant (HERA) trial [20], patients with the best prognosis (pT1cN0) had similar benefit with respect to 3-year disease-free survival improvement to the overall cohort. This strongly implies that tumor size was not a criterion for response to trastuzumab.
In a recently reported retrospective study of 96 patients with pT1a/pT1bN0 HER2-positive breast cancer [21], 43% (n = 41) received adjuvant chemotherapy mostly with trastuzumab (n = 37). At 25 months median follow-up, there was no invasive recurrence among the 40 patients treated with trastuzumab, whereas 5 of the 56 patients who received no adjuvant chemotherapy or trastuzumab had local or metastatic recurrence including 1 fatality.
Current National Comprehensive Cancer Network guidelines for the treatment of breast cancer do not recommend the use of adjuvant chemotherapy plus trastuzumab in HER2-positive T1aN0 disease, but instead suggest the use of adjuvant chemotherapy plus trastuzumab in patients with HER2-positive pT1b/pT1cN0 disease, particularly in those with other negative prognostic factors, despite the lack of empirical data from prospective clinical trials [15].
We believe that patients with HER2-positive T1N0 breast cancer should be considered for inclusion in prospective trials of adjuvant trastuzumab in combination with chemotherapy. The relative contribution of adjuvant chemotherapy and/or trastuzumab might be difficult to distinguish because of low event rates. However it has been suggested that consideration of adjuvant trastuzumab plus chemotherapy should be limited to patients with HER2-positive stage pT1b or larger cancer as the risk-to-benefit ratio may be too high for patients with stage pT1mic or pT1a disease, although it might be worth considering short-term adjuvant chemotherapy/trastuzumab combinations that have better tolerability but still impact recurrence risk [22].
Our study was designed to assess disease-free survival, distant disease-free survival, and overall survival in patients treated for T1N0 primary breast cancer. These aims were met with HER2-positivity being determined as a significant prognostic risk factor in this cohort, and in particular as one of the significant negative prognostic factors for 1-year disease-free survival. Of the HER2-positive patients, those treated with adjuvant trastuzumab had a lower likelihood of a disease-free survival event compared to those who did not receive trastuzumab.
One of the limitations of this study is the short follow-up period and low event rate. 1-year disease-free and distant disease-free survival were chosen because it was shown that in the first year after evidence of disease many events could be seen. In the NCCTG-9831 study, many events occurred in the first 18 months [23]. In the investigated group, the prognosis of those patients is good, therefore not many events are expected. The overall survival is difficult to interpret because there are not many events in the overall survival expected and the statistical interpretation is not sufficient.
There are no existing prospective studies examining the use of the combination of chemotherapy and trastuzumab in patients with nodal-negative primary breast cancer < 1 cm. The best available data giving a strong indication that patients with HER2-positive T1N0 tumors have excellent outcomes following adjuvant trastuzumab only come from retrospective studies. This leads us to the conclusion that this cohort should be considered for inclusion in prospective trials of adjuvant trastuzumab in combination with chemotherapy, and that it should ultimately be determined if guidelines need to be updated.
Disclosure Statement
No financial disclosures were reported by the authors of this paper.
Acknowledgement
Roche Pharma AG provided support for the collection, analysis, and interpretation of data. Support for third-party editorial assistance for this manuscript was provided by Roche Pharma AG.
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