BACKGROUND: Breast cancer is associated with a relatively good prognosis. Prognostic factors examined to date are related to early recurrence while those related to late recurrence and their countermeasures remain unclear. Therefore, we examined the factors related to late recurrence. PATIENTS AND METHODS: From January 1980 to August 2012, 4,774 patients who underwent primary treatment and estrogen (ER) and progesterone receptor (PgR) assessment were enrolled in this study. The patients were divided into two groups, those with a follow-up period <10 years and those without any recurrence at 10 years but who continued follow-up examinations. Recurrence occurred in 711 patients followed up for <10 years and in 51 patients for ≥10 years. RESULTS: The overall 10-year cumulative disease-free survival rate was 79.5%, and the recurrence rate at ≥10 years was 5.8%. A multivariate analysis revealed that the factors related to late recurrence were PgR positivity and positive nodes. This result differed from that for early recurrence in terms of ER/PgR, Ki-67 index and p53 overexpression. CONCLUSION: PgR positivity and lymph node metastases significantly correlated with late recurrence. Therefore, it is important to evaluate appropriate measures such as treatment period and treatment regimen for hormone-sensitive patients.
The choice of adjuvant systemic therapy is based on targeted therapy in line with the St. Gallen Consensus meeting. In addition to the traditional parameters, the panel recommended the use of proliferation markers and multigene assays. The purpose of the present study was to evaluate the clinical significance of proliferative activity using the Ki-67 index as a prognostic marker and as a predictor of recurrence time in breast cancer patients. The Ki-67 index was measured in 3,652 cases with primary breast cancer from 1987 to 2009. Out of these patients, 2,638 cases were evaluated simultaneously for estrogen receptor, progesterone receptor and HER2 from 1997, and these were analyzed as a prognostic factor according to their subtypes. The Ki-67 index exhibited a wide range of 1-99%, with a median of 20%, and cases were divided into 2 or 3 index groups; <20% and ≥20% (and ≥50%). The median Ki-67 index of tumors with luminal A was 17%, and that of luminal B type tumors was 29%. The Ki-67 index of HER2 tumors was 40% and that of triple negative tumors was 50%. A higher Ki-67 index significantly correlated with a higher grade of malignancy. Patients with a higher Ki-67 index had significantly lower disease-free survival (DFS) and overall survival rates. Moreover, there was a significant difference in the recurrence time. Multivariate analysis revealed that the Ki-67 index was a significant factor for DFS, irrespective of nodal status, and that Ki-67 was a significant marker only in luminal A type tumors. Furthermore, luminal A type cases with high Ki-67 had a similar DFS as the luminal B type cases. A higher Ki-67 index (≥20%) significantly correlated with other biological markers, poorer prognosis and early recurrence, particularly in luminal A type tumors. It is important to take the Ki-67 index into consideration in the treatment and follow-up of breast cancer patients.
// Hitomi Mori 1, * , Makoto Kubo 1, * , Rin Yamaguchi 2 , Reiki Nishimura 3 , Tomofumi Osako 3 , Nobuyuki Arima 4 , Yasuhiro Okumura 5 , Masayuki Okido 6 , Mai Yamada 1 , Masaya Kai 1 , Junji Kishimoto 7 , Yoshinao Oda 8 , Masafumi Nakamura 1 1 Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 2 Department of Pathology, Kurume University Medical Center, Kurume, Japan 3 Breast Center, Kumamoto Shinto General Hospital, Kumamoto, Japan 4 Department of Pathology, Kumamoto Shinto General Hospital, Kumamoto, Japan 5 Department of Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan 6 Department of Surgery, Hamanomachi Hospital, Fukuoka, Japan 7 Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan 8 Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan * These authors have contributed equally to this work Correspondence to: Makoto Kubo, email: mkubo@tumor.med.kyushu-u.ac.jp Keywords: programmed cell death ligand-1, tumor-infiltrating lymphocytes, triple-negative breast cancer, biomarker, prognosis Received: August 02, 2016 Accepted: December 27, 2016 Published: January 17, 2017 ABSTRACT This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD-L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs-low tumors ( P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival ( P = 0.0018) and overall survival ( P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies.
BACKGROUND: In breast cancer, ER/PgR, HER2, and Ki-67 are important biological markers for predicting prognosis and making effective treatment decisions. In addition, changes in markers due to relapse are also clinically experienced; however, the frequency and clinical significance are still not fully understood. Thus, changes in markers and their correlations with prognosis were investigated. PATIENTS AND METHODS: Out of the patients with relapse from 1997 to March 2011, there were 97 consecutive patients from whom the lesion was resected and evaluated by immunostaining. The biopsy sites were chest wall, lymph node, ipsilateral breast tumor recurrence, lungs, bones, ovaries and brain. The markers sought were ER, PgR, HER2, p53 and Ki-67. RESULTS: The hormone receptor positive rate from the primary tumor to recurrence decreased from 63.9% to 57.7% and from 56.7% to 43.3% for ER and PgR, respectively. Changes in the positive/negative evaluation were seen at the rate of 10.3% and 25.8% for ER and PgR, respectively. The Ki-67 index increased significantly from a mean of 29.1% at primary tumor to 36.3% at relapse. When divided into 2 groups (< 50% and ≥50%), changes were seen in 24.7%. On the other hand, the rates of changes in HER2 and p53 positivity were 14.4% and 12.4%. The changes in subtypes were seen in 25%, however, the lowest rate of change was seen in the triple negative cases. Although there was no notable difference in the rate of change between disease-free interval (DFI) and PgR, Ki-67, p53 and HER2, there was a significant difference in the change rates in the ER. A multivariate analysis revealed that the status of distant metastasis and PgR level at relapse, and Ki-67 levels at primary tumor were all significant factors. CONCLUSION: Estrogen receptor and PgR decreased while Ki-67 increased due to relapse; however, the rate of change was high for PgR and Ki-67. Change in the subtypes was seen in 25%. In addition, PgR at relapse and Ki-67 at primary tumor were significant factors for post-relapse prognosis while PgR becoming negative was a poor prognostic factor. These findings are important for making effective treatment decisions.