Is adjuvant chemotherapy necessary for patients with microinvasive breast cancer after surgery?

Introduction

Microinvasive breast cancer (MIBC) has been paid much attention since the term "microinvasive" in breast pathology was introduced by Lagios in 1982¹. Microinvasiveness is characterized by invasion of less than 1 mm size. Various definitions have been used to define MIBC^2–4. In 1997, the fifth edition of the staging manual of the American Joint Committee on Cancer (AJCC) defined MIBC as "the extension of cancer cells beyond the basement membrane into adjacent tissues with no focus more than 0.1 cm in greatest dimension", and AJCC was the first organization to recognize a specific T stage as pT1mic⁵. Although the World Health Organization (WHO) classification of tumors had admitted and supplemented interpretations for the definition by the fifth edition of the AJCC staging manual published in 2003⁶, the definition seemed to have been used generally until the seventh edition of the AJCC staging manual⁷. Moreover, MIBC, which is one of the rare breast carcinomas, has incidence rate ranging from 0.24% to 3.3%^8,9 based on various definitions. Consequently, the clinical characteristics, prognosis, and treatments of MIBC are highly controversial. Current studies focused on the clinical characteristics of MIBC^10–12. However, only a few studies have evaluated the survival and treatment, especially adjuvant chemotherapy after surgery, for patients with MIBC.

The aim of this study was to evaluate the necessity of adjuvant chemotherapy for patients with MIBC, identify risk factors influencing the prognosis of MIBC, and decide the indication for adjuvant chemotherapy.

Materials and methods

Results

We retrospectively collected 19,656 breast cancer patients from January 2006 to June 2013 in Tianjin Medical University Cancer Institute and Hospital. Among the 19,656 patients, 118 women were diagnosed with MIBC according to the definition by the seventh edition of the AJCC staging manual. Ten of the 118 patients diagnosed with MIBC were excluded, because one patient had been previously diagnosed with invasive breast cancer, one patient accepted neoadjuvant chemotherapy before surgery, and eight patients lacked information on follow-up. The rate of loss was appropriately 6.8%. Finally, 108 patients were eligible for analysis.

Among the 108 patients with MIBC, 79 patients were given chemotherapy after surgery, while the remaining 29 did not accept chemotherapy. Table 1 shows the clinical and pathologic characteristics of the chemotherapy and non-chemotherapy groups. Statistical significance was observed in both menopause and estrogen receptor status.

Median follow-up was 33 months (range 13-104 months). Nine patients had positive axillary lymph nodes, and 8 patients had breast-related positive events, such as local recurrence, distant metastasis, and death. The rate of positive events was 7.4%. Table 2 shows the characteristics of the 8 patients with breast-related positive events, 5 of which belonged to the chemotherapy group, and the rest in the non-chemotherapy group. Among the 8 patients, one patient had chest wall relapsed after 43 months from the time of diagnosis, one patient had controlateral breast tumor metastasis 14 months after surgery, one patient manifested metastasis of supraclavicular lymph nodes, and the rest had distant metastasis at 18, 21, 26, 43, or 64 months after the surgical operation. Two patients died from breast-associated causes, such as pulmonary and liver metastasis. Table 2 shows that 6 patients had negative hormonal receptors, whereas 2 had positive hormonal receptor. In addition, only one patient had Ki-67≤20%, and the rest had Ki-67>20%. In addition, 7 of these patients had positive events related to breast cancer within 5 years after surgical operation.

The 5-year DFS rates for patients in the chemotherapy and non-chemotherapy groups were 93.7% and 89.7%, respectively. The OS rate in the chemotherapy group was 97.5%, compared with 100% in the other group. Figures 1 and 2 illustrate the curves of 5-year DFS and OS of both groups. No significant difference in 5-year DFS (P=0.223) or OS (P=0.530) was found between the two groups (Table 3).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Kaplan-Meier plots of 5-year DFS comparing chemotherapy vs. non-chemotherapy for patients with MIBC.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Kaplan-Meier plots of OS comparing chemotherapy vs. non-chemotherapy for patients with MIBC.

We assessed the relationship between biological features and breast-associated positive events using the log-rank and Cox proportional regression analysis. Ki-67 and ER/PR were the most significant prognostic factors for MIBC in both univariate (Table 4) and multivariate analyses (Table 5). Cumulative survival of patients with tumors bearing low Ki-67 was 98.2%, compared to 86.5% for patients with tumors bearing high Ki-67 (Figure 3). Hazard ratio (HR) for patients with high Ki-67 was 16.585 [95% confidence interval (CI), 1.969-139.724; P=0.010]. Patients with high Ki-67 (>20%) still had a significantly poorer survival, compared with patients with lower Ki-67 (≤20%, P=0.021). Meanwhile, patients with ER(-)PR(-) tumors had cumulative survival of 79.3%, whereas those with ER(+)/PR(+) tumors had 97.5% (Figure 4). HR for patients with ER(-)/PR(-) tumors was 19.149 (95% CI, 3.702–9.057; P<0.001). Figure 4 shows that patients tested negative for both hormonal receptors had significantly poorer survival (P=0.001).

• Download figure
• Open in new tab
• Download powerpoint

Figure 3

Kaplan-Meier plots of cumulative survival comparing elevated Ki-67 (>20%) vs. low Ki-67 (≤20%) for patients with MIBC.

• Download figure
• Open in new tab
• Download powerpoint

Figure 4

Kaplan-Meier plots of cumulative survival comparing ER(-) PR(-) vs. ER(+)/PR(+) for patients with MIBC.

We conducted subgroup analysis to evaluate the impact of chemotherapy on Ki-67 and the status of hormonal receptors. Table 6 shows that chemotherapy could improve the outcomes of ER(-)/PR(-) patients (P=0.014), but not those who overexpress Ki-67 (P=0.105).

Discussion

MIBC is reported to be a distinct entity from pure ductal carcinoma in situ (DCIS) and represents the interim stage in the progression from DCIS to invasive ductal carcinoma (IDC)^12,13. However, MIBC accounts for less than 1%^12,14 of all newly diagnosed breast cancers according to the criteria of the fifth edition of AJCC staging manual⁵. MIBC accounted for 0.56% of all patients recruited in our study.

Controversy on MIBC is related to the limited information available on the prognosis of this disease¹⁵. The rate of axillary metastases at diagnosis was 8.3% in our study, which was within the 6-11% rate of axillary metastases reported in other MIBC studies^9,14,16. Long-term DFS ranging between 91% and 100% had been reported^3,17. Factors related to good prognosis were low-grade¹² and ER(+) disease¹⁷. However, these studies suffered from small sample size. In the current study, we collected 108 patients with MIBC according to the definition of the seventh edition of AJCC. The 5-year DFS was 92.6%, and OS was 98.1%. Elevated expression of Ki-67 was found to be one of the significant predictors of poor outcome. HR for patients with high Ki-67 tumors was 16.585 (95% CI 1.969-139.724, P=0.010) with cumulative survival of only 86.5%. The role of Ki-67 was reported in a study with 425 assessable patients with pT1a and pT1b, where the value of Ki-67 overexpression was significantly correlated with poor outcome¹⁸, similar to this study. These results indicated a possible role of Ki-67 in the identification of high-risk patients. Alternative poor prognostic factor was the characteristic of having both negative hormonal receptors. HR for patients with negative hormonal receptors was 19.149 (95% CI, 3.702-99.057; P<0.001), whose cumulative survival was only 79.3%. The role of status for hormonal receptors was commonly reported. However, previous studies reported that the status of single hormonal receptor (ER or PR) was related to the outcome¹⁹. We found for the first time that ER(-)/PR (-) patients with MIBC had poorer prognosis compared with patients with MIBC who were either ER (+) or PR (+). This characteristic was primarily due to the fact that patients of MIBC with ER(+) or PR(+) and ER(+)PR(+) were provided with adjuvant endocrinotherapy. By contrast, ER(-)/PR(-) patients with MIBC were not administered endocrine treatment, indicating the function of endocrinotherapy.

Recommending treatment for patients with MIBC who had insufficient information caused by small sample size and varying definitions is quite difficult. Adjuvant chemotherapy plays a very important role in breast cancer treatment, especially for triple-negative breast cancer^20,21. However, chemotherapy is considered synonymous to cytotoxic treatment. Tumor cells are wiped out, but normal cells are also injured, in chemotherapy which leads to various adverse reactions. Thus, risk–benefit balance of chemotherapy should be considered to avoid widespread use of aggressive treatments for patients with MIBC.

To our knowledge, only a few studies have provided information on adjuvant treatment received by patients with MIBC. Our study is unique since we were the first to select patients with MIBC to review the necessity of adjuvant chemotherapy after surgical operation. We found no statistical significance on the 5-year DFS or OS between chemotherapy and non-chemotherapy groups. However, 5-year DFS was superior, but OS was inferior, in the chemotherapy group compared with the other group. This result indicates that chemotherapy may have short-term benefits for patients with MIBC. However, long-term chemotherapy may produce side effect on patients with MIBC caused by adverse events. Therefore, selecting the best implication of adjuvant chemotherapy for MIBC is important. According to our subgroup analysis, ER(-)/PR(-)patients had the best implication, which is reported for the first time.

In addition, difference was found in the menopause and estrogen receptor status between the chemotherapy and non-chemotherapy groups. This result implies that the proportion of ER(+) and post-menopause was higher in non-chemotherapy than chemotherapy group in our study. On one hand, the diversity may be attributed to empirical therapy of clinicians who tend to provide chemotherapy for patients with negative hormonal receptors. On the other hand, the majority of postmenopausal patients were old women with some medical diseases. These patients were not advised to accept chemotherapy by oncologists considering the risk of chemotherapy. However, despite the above difference, our conclusions that menopause and estrogen receptor status were neither connected with the outcome of MIBC were rational (Tables 4 and 5).

Thus, adjuvant chemotherapy should be cautiously administered to patients with MIBC. Adjuvant chemotherapy can be considered to patients with negative hormonal receptors when costs and benefits of adjuvant chemotherapy are weighed accurately. These patients have substantial risk of relapse within the first 5 years after surgical operation, contrary to that reported by Rosner². The report of Rosner published in Cancer indicated that MIBC was an entirely curable disease when treated by mastectomy alone, without the need for adjuvant therapy, regardless of the status of other prognostic factors, such as tumor size, histologic differentiation, age, or steroid receptor status through mean follow-up of 57 months. The difference in results may have been caused by several reasons, such as small sample and short follow-up time. However, the most important reason was different diagnostic criteria. The diagnosis of MIBC in Rosner’s study followed the principles elucidated by Schwartz that DCIS had limited microscopic stromal invasion below the basement membrane in one or several ducts, but not invading more than 10% of the surface of the histologic sections examined⁴. In other words, the definition by Schwartz, which is beyond the definition by the seventh edition of the AJCC staging manual, should include part of IDC classified as pT1a or pT1b according to TNM staging in the seventh edition of AJCC Staging Manual published in 2010²².

However, our study has limitations. We cannot establish firm conclusions because of the small sample size and short follow-up period.

Conclusions

Patients with MIBC have the good prognosis. However, patients who overexpress Ki-67 and with negative hormonal receptors have relatively substantial risk of relapse within the first 5 years after surgical operation. Adjuvant chemotherapy can only improve the outcomes of patients with negative hormonal receptors, but not those who overexpress Ki-67. Further studies with prolonged follow-up of large cohort are warranted to assess the prognostic significance and treatment of this lesion.