Clinical Features and Survival Analysis of T1mic, a, bn0m0 Breast Cancer

Original Articles Jpn J Clin Oncol 2012;42(6)471 476 doi:10.1093/jjco/hys046 Advance Access Publication 3 April 2012 Clinical Features and Survival Analysis of T1mic, a, bn0m0 Breast Cancer Junnan Li, Xiaodong Liu and Zhongsheng Tong * Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China *For reprints and all correspondence: Zhongsheng Tong, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin 300060, China. E-mail: tonghang@medmail.com.cn Received September 27, 2011; accepted March 8, 2012 Objective: To analyze the clinicopathological features and prognosis of T1mic, a, bn0m0 breast cancer. Methods: The clinical data and survival status of 4487 cases of operable breast cancer treated in our hospital from 2002 to 2005 were collected, including 372 cases with T1mic, a, bn0m0 breast cancers. These patients were divided into four subtypes: Luminal A, Luminal B, triple-negative and human epidermal growth factor receptor 2-positive. Disease-free survival and risk factors for recurrence were identified. Results: We identified 372 eligible patients. The median follow-up was 78 months (range: 5 106 months). Univariate analysis showed age, adjuvant endocrine therapy, hormonal receptor and human epidermal growth factor receptor 2 were prognostic factors. Multivariate analysis showed that hormonal receptor and human epidermal growth factor receptor 2 were prognostic factors. In the hormonal receptor-positive group, human epidermal growth factor receptor 2-positive patients (Luminal B) had a four times higher recurrence risk than human epidermal growth factor receptor 2 negative (Luminal A) patients. However, there was no statistically significant difference between hormonal receptor-negative groups (triple-negative and human epidermal growth factor receptor 2-positive). Conclusions: Hormonal receptor and human epidermal growth factor receptor 2 were independent factors of 5-year disease-free survival for patients with T1mic, a, bn0m0 breast cancer. The Luminal B group had a worse prognosis than the Luminal A group, but there was no statistically significant difference between triple-negative and human epidermal growth factor receptor 2-positive groups. Key words: breast neoplasms T1mic, a, bn0m0 prognosis INTRODUCTION Breast cancer is a major cause of morbidity and mortality in women worldwide (1). As the use of screening mammography grows, the proportion of invasive breast cancer with tumor size 1 cm is increasing. It is reported that these patients had a favorable prognosis with complete surgical resection of primary tumor, even without systemic adjuvant therapy, and many international multicenter clinical trials also excluded them (2,3). However, according to the data of SEER 1998 2001, 10-year mortality of these patients was 4% (4). If they were not treated with adjuvant chemotherapy, 10 30% (5) of the cases eventually recurred. The 2007 St Gallen criteria divided breast cancer patients into low-, intermediate- and high-risk groups. Tumors with # The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

472 T1mic, a, bn0m0 breast cancer node-negative, size 2 cm, G1, no peritumoral vascular invasion, human epidermal growth factor receptor 2 (HER2)-negative and age 35 years could be low-risk diseases. So, there were several clinical and pathological factors which might play a prognostic role within the group of patients with small tumors and node-negative disease. In this study, we retrospectively investigated the general features, clinicopathological features, treatments and outcomes obtained in 372 T1mic, a, bn0m0 patients followed at our hospital with the diagnosis of breast cancer between 2002 and 2005. PATIENTS AND METHODS We collected the information on 4487 cases operated on from January 2002 to December 2005 at Cancer Institute and Hospital of Tianjin Medical University, and 372 T1mic, a, bn0m0 cases were enrolled. Tumor stage was based on the 6th American Joint Committee on Cancer (AJCC) criteria. Histological type and grading followed the World Health Organization (WHO) classification. The following pathologic information was obtained: tumor size and histological subtype. Immunohistochemical data were also collected for standard prognostic biomarkers [estrogen receptor (ER), progesterone receptor (PR), HER2]. The threshold for ER and PR positivity was 10%. For HER2 assessment, tumors were scored according to the intensity and completeness of cell membrane staining, in a four-tier scale (0: no immunoreactivity, 1þ: weak and incomplete membrane staining or,10% weak but complete membrane staining, 2þ: 10% weak/moderate and complete membrane staining or 30% strong and complete membrane staining, 3þ: 30% strong and complete membrane staining). Tumors scored 3þ were considered as overexpressing HER2. The immunohistochemical classification was as follows: Luminal A (ERþ or PRþ) and (HER2 0/þ/þþ); Luminal B (ERþ or PRþ) and (HER2 þþþ); HER2-positive: (ER2 and PR2) and(her2þþþ); and triple-negative (ER2 and PR2) and(her20/þ/þþ). The Mantel Haenszel x 2 test for trend was used to assess the association between, respectively, categorical and ordinal variables. The endpoints were the incidence of disease-free survival (DFS). DFS was defined as the time from randomization to the first of any of the following events: recurrence of the disease at a local, regional or distant site; a new invasive cancer in the contralateral breast; any second (non-breast) cancer; or death without a previous cancer event. Univariate analysis and survival plots of different subtype were drawn using the Kaplan Meier method. The log-rank test was used to assess survival difference between strata. The Cox regression was applied for multivariate prognostic analysis. Statistical significance was considered at P, 0.05. All analyses were carried out with the SPSS16.0 software. RESULTS In 372 (8.3%) eligible cases, 63 (16.9%) patients were classified as T1mic, 121 (32.5%) as T1a and 188 (50.5%) as T1b. The median follow-up was 78.00 months (range: 5 106 months). Table 1 shows the baseline characteristics of Table 1. Comparison of clinical features between T1mic, a, bn0m0 and other breast cancers [n (%)] Characteristics Stage x 2 P value T1mic, a, bn0m0 (n ¼ 372) Others (n ¼ 4115) Age (years),35 14 (3.8%) 206 (5.0%) 1.130 0.288 35 358 (96.2%) 3909 (95.0%) Tumor grade G1 47 (12.6%) 156 (3.8%) 1645 0.000** G2 250 (67.2%) 3167 (77.0%) G3 12 (3.2%) 570 (13.9%) unknown 63 (16.9%) 222 (5.4%) ER Positive 234 (62.9%) 2364 (57.4%) 4.165 0.041* Negative 138 (37.1%) 1751 (42.6%) PR Positive 202 (54.3%) 2276 (55.3%) 0.140 0.708 Negative 170 (45.7%) 1839 (44.7%) HR ERþ and/or PRþ 254 (68.3%) 2579 (62.7%) 4.607 0.032* ER2PR2 118 (31.7%) 1536 (37.3%) HER2 Positive 111 (29.8%) 1119 (27.2%) 1.200 0.273 Negative 261 (70.2%) 2996 (72.8%) Surgery Mastectomy 334 (89.8%) 3851 (93.6%) 7.845 0.005** Breast-conserving surgery 38 (10.2%) 264 (6.4%) Adjuvant chemotherapy Yes 330 (88.7%) 3934 (95.6%) 34.309 0.000** No 42 (11.3%) 181 (4.4%) Adjuvant radiotherapy Yes 36 (9.7%) 2789 (67.8%) 4938 0.000** No 336 (90.3%) 1326 (32.2%) Adjuvant endocrine therapy Yes 240 (64.5%) 2513 (61.1%) 1.709 0.191 No 132 (35.5%) 1602 (38.9%) ER, estrogen receptor; PR, progesterone receptor; HR, hormonal receptor; HER2, human epidermal growth factor receptor 2. *P, 0.05. **P, 0.01.

Jpn J Clin Oncol 2012;42(6) 473 T1mic, a, bn0m0 and other breast cancers. We could conclude that the T1mic, a, bn0m0 group always presented a lower grade, but higher ER and hormonal receptor (HR)-positive rate (all P, 0.05), and these patients tended to undergo more breast-conserving surgery (BCS), less Table 2. Monofactorial analysis of prognosis with early-stage breast cancer Total number Number of evens Five-year disease-free survival rate x 2 P value Tumor size T1mic 63 2 96.7 1.340 0.247 T1a 121 5 96.6 T1b 188 13 94.5 Age (years),35 14 3 77.4 8.306 0.004** 35 358 17 96.2 Tumor grade G1 47 4 93.4 0.003 0.959 G2 250 12 96.2 G3 12 2 83.3 Surgery Mastectomy 334 19 95.3 0.524 0.469 BCS 38 1 96.9 ER Positive 234 9 96.4 2.725 0.099 Negative 138 11 93.9 PR Positive 202 11 94.8 0.011 0.918 Negative 170 9 96.3 HR ER2PR2 118 13 91.0 10.866 0.001** ERþ and/or 254 7 97.5 PRþ HER2 Positive 111 13 89.8 13.148 0.000** Negative 261 7 97.9 Adjuvant chemotherapy Yes 330 19 95.3 0.673 0.412 No 42 1 97.6 Adjuvant radiotherapy Yes 36 1 97.1 0.476 0.490 No 336 19 95.3 Adjuvant endocrine therapy Yes 240 7 97.4 8.169 0.004** No 132 13 92.0 **P, 0.01. adjuvant chemotherapy and radiotherapy. We also analyzed differences in the characteristics among T1mic, T1a and T1b tumors, and got a conclusion that larger size tumors always accompanied a higher grade, lower ER and HR expression, and higher rate of chemotherapy (data not shown). In these 372 cases, 14 HR-positive patients did not receive adjuvant endocrine therapy, and extra 5 cases did not receive adjuvant radiotherapy after breast conservation surgery. Table 2 shows the univariate analysis results. Young age (,35 years), HR, HER2 and endocrine therapy were risk factors of recurrence. The 5-year cumulative DFS rate for all patients was 94.6%, and the overall survival rate was 98.1%. During the follow-up period, three patients died, one belonged to T1bN0M0 and the other two were T1aN0M0. In addition, breast cancer recurred in 20 patients. Among them, three cases were,35 years, 11 cases with HR-negative, 13 cases with HER2-positive and 11 cases developed systemic recurrence. Table 3 shows the multivariate analysis results. The Cox proportional hazard regression model was constructed using the variables of age, tumor size, grade, adjuvant chemotherapy, adjuvant radiotherapy, HR and HER2 status. The independent prognostic factors of recurrence were HR and HER2 status. The Kaplan Meier estimated that the percentage of patients who remained disease free at 5 years was 98.9% of the Luminal A group, 92.9% of the Luminal B group, 95.0% of the triple-negative group and 86.3% of the HER2-positive group (Fig. 1). Patients of the Luminal A group had a better prognosis than other three groups, and statistical significance was achieved, especially when Luminal A subtype was compared with HER2-positive subtype. However, no statistical significance was achieved among the other three subtypes (Table 4). We also made a further analysis of 5-year recurrence risk (data not shown). Overall, in the HR-positive group, the hazard ratio (HR) associated with HER2 overexpression was 4.995 [95% confidence interval (CI), 1.113 22.424]. In contrast, it was 2.791 (95% CI, 0.859 9.064) in the HR-negative group. Table 3. Multivariate Cox s regression prognostic analysis of all breast cancer in 5-year DFS P value HR 95% CI for HR Age (,35 years) 0.120 3.408 0.725 16.015 Tumor size 0.497 1.434 0.507 4.059 Grade 0.457 0.654 0.214 2.001 HR 0.047 2.824 1.013 7.869 HER2 0.009 3.941 1.401 11.08 Adjuvant chemotherapy 0.830 0.800 0.104 6.143 Adjuvant radiotherapy 0.383 2.545 0.312 20.767 DFS, disease-free survival; HR, hazard ratio; CI, confidence interval.

474 T1mic, a, bn0m0 breast cancer DISCUSSION Patients with node-negative, tumor size 1 cm belonged to the early stage. The literature showed that even without systemic adjuvant chemotherapy, they could get an excellent prognosis after mastectomy (6). For patients with microinvasive breast cancer, which was defined as tumor foci of 0.1 cm or less, the recurrence risk and mortality were even lower. However, according to the 2007 St Gallen criteria for low-, medium- and high-risk group classification, the evaluation indicators were more than these two factors. Therefore, we summarized the clinical and pathological features of T1mic, a, bn0m0 patients and analyzed the prognosis to provide more references. Our study elucidated that these patients had a favorable prognosis. Among 376 patients, 3 patients died during the follow-up period, 20 patients experienced recurrence of disease and 5-year DFS was 94.6%. Previously to our study, Kwon et al. (7) analyzed 375 Korean women of T1a, bn0m0 breast cancer. One patient died and 12 recurred. In addition, 10-year outcomes in a population-based cohort study (5), including 430 cases, revealed that patients with Figure 1. Comparison of 5-year disease-free survival between the four subtypes. Grade 3 tumor had shorter 10-year recurrence-free survival, and the difference was statistically significant (74 vs. 82%, P ¼ 0.007). Our research indicated that the large tumor size was always associated with a higher grade, and the differences were significant (P ¼ 0.000). Although the difference in 5-year recurrence rate in each grade was not significant (P ¼ 0.959), Grade III patients had a higher recurrence rate than the other two. Univariate analysis illustrated that age,35 years, endocrine therapy, HR and HER2 were prognostic factors. In the meantime, multivariate analysis represented that HR and HER2 status were associated with a shorter 5-year DFS. It was reported that age,35 years breast cancer always had a poor prognosis than older counterparts. Nevertheless, our study did not support that opinion, which may be relevant to a small number of cases. However, the influence of young age could not be ignored, especially for Asian women, facing a higher morbidity than Western countries (8 10). Among 38 (10%) cases who received BCS, 5 cases, belonging to T1mic and T1a, did not accept post-operative radiotherapy. In these 38 cases, only one case developed into systemic recurrence but not local recurrence during the 5-year follow-up. So, the short-term follow-up indicated the importance of the necessity of adjuvant radiotherapy after BCS. Kwon et al. (7) also showed that patients with T1mic disease had a higher proportion of HER2-positive disease but a very low potential of systemic metastasis of recurrence. In our study, HER2 expression rates in T1mic, T1a and T1b were 34.9, 28.1 and 29.3% (P ¼ 0.600), respectively. The trend was similar to other literatures, but it was still unclear why T1mic accompanied a higher HER2 expression. Multivariate analysis exhibited that HR and HER2 were independent prognosis factors. So, we made a further analysis by dividing all tumors into four intrinsic subtypes. Patients of the Luminal A group had a better prognosis than other three groups, and statistical significance was achieved in comparison, especially when the Luminal A subtype was compared with the HER2-positive subtype. However, no statistical significance was achieved among the other three subtypes. With the Cox regression analysis, we found that in the HR-positive group, HER2-positive (Luminal B) patients had a four times higher recurrence risk than HER2-negative Table 4. Comparison of 5-year DFS among the four subtypes Immunohistochemical classification Luminal A Luminal B Triple-negative HER2-positive x 2 P value x 2 P value x 2 P value x 2 P value Luminal A 5.429 0.020 4.000 0.046 22.688 0.000 Luminal B 5.429 0.020 0.016 0.900 2.454 0.117 Triple-negative 4.000 0.046 0.016 0.900 3.186 0.074 HER2-positive 22.688 0.000 2.454 0.117 3.186 0.074

Jpn J Clin Oncol 2012;42(6) 475 (Luminal A) patients (hazard ratio ¼ 4.995; 95% CI 1.113 22.424). However, there was no difference in HR-negative groups (hazard ratio ¼ 2.791; 95% CI 0.859 9.064). In recent years, many researches joined in the discussion about whether HER2 overexpression was an independent factor of recurrence for early breast cancer. In the 2008 St Antonio conference, experts had referred that HER2 overexpression was a poor prognostic factor. One study (11) investigated patients with node-negative and pt1a-b breast cancer, and results showed that in patients with HR-positive disease, HER2 overexpression was associated with a worse DFS (hazard ratio ¼ 5.1, 95% CI 1.0 25.7), but no difference was found in HR-negative disease. A retrospective cohort study to assess the value of 10 prognostic factors in pt1n0m0 patients (12) analyzed 852 T1N0M0 cases, 313 cases with tumor size,1 cm. HER2-positive diseases had a higher recurrence risk than HER2-negative disease (hazard ratio ¼ 2.56; 95% CI 1.05 6.23; P ¼ 0.04). Another study about HER2-positive patients (13) summarized the data of 965 pt1a, bn0m0 cases, and the results were that the 5-year DFS rate was 77.1% for HER2-positive disease and 93.7% for HER2-negative disease. The difference was statistically significant (P, 0.001). Now several randomized, controlled trials (RCTs) (2,4) have demonstrated significant improvements in breast cancer recurrence and death associated with the addition of trastuzumab to chemotherapy in the adjuvant setting. All these trials excluded patients with tumors 1 cm in diameter. However, there was no hint from any of the RCTs that the efficacy of trastuzumab, endocrine therapy or chemotherapy would depend on the tumor size (14,15). Therefore, they are expected to benefit from these therapies. The National Comprehensive Cancer Network considered trastuzumab as an option for HER2-positive tumors between 0.6 and 1 cm. However, the cardiotoxicity of trastuzumab was idiosyncratic, was unrelated to dose, displayed a wide range of severity and was reversible in most cases but not all cases (16), and the long-term safety data were still absent (17 19). So whether to add trastuzumab must be balanced with all these things. Our study also had some limitations. First, there were no immunohistochemical results of ER, PR and HER2 for a little portion of patients. Some patients could not be contacted and their survival status could not be included in the analysis. As a result, datum cannot be 100% complete. Secondly, ER- and PR-positive were defined as 10% in our study, but in recent studies if 1% or more of tumor nuclei were stained, they were classified as HR-positive. So, there may be a possibility that tumors with positive staining of ER and PR between 1 and 9% may be defined as HR-negative. Thirdly, some cases only had a short-term follow-up. If it could be prolonged, we could further analyze the relations between the recurrence rate and time. In conclusion, breast cancer with T1mic, a, bn0m0 always had favorable prognosis. HR and HER2 status were independent factors for these patients. Especially in HR-positive groups, the HER2-positive disease recurrence rate was higher than HER2-negative disease. These findings suggested that these patients may benefit from anti-her2 therapy. From the epidemiological standpoint, small tumors are an emerging problem mainly due to screening programs. More International multicenter clinical trials should be carried out so that concrete, effective and personalized treatments could be formulated for these patients. 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