Response of Triple Negative Breast Cancer to Neoadjuvant Chemotherapy: Correlation between Ki-67 Expression and Pathological Response

Elnemr, Gamal M,El-Rashidy, Ahmed H,Osman, Ahmed H,Issa, Lotfi F,Abbas, Osama A,Al-Zahrani, Abdullah S,El-Seman, Sheriff M,Mohammed, Amrallah A,Hassan, Abdelghani A Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.2

Triple-negative breast cancers constitute about 15% of all cases, but despite their higher response to neoadjuvant chemotherapy, the tumors are very aggressive and associated with a poor prognosis as well as a higher risk of early recurrence. This study was retrospectively performed on 101 patients with stage II and III invasive breast cancer who received 6-8 cycles of neo-adjuvant chemotherapy. Out of the total, 23 were in the triple negative breast cancer subgroup. Nuclear Ki-67 expression in both the large cohort group (n=101) and triple negative breast cancer subgroup (n=23) and its relation to the pathological response were evaluated. The purpose of the study was to identify the predictive value of nuclear protein Ki-67 expression among patients with invasive breast cancers, involving the triple negative breast cancer subgroup, treated with neoadjuvant chemotherapy in correlation to the rate of pathological complete response. The proliferation marker Ki-67 expression was highest in the triple negative breast cancer subgroup. No appreciable difference in the rate of Ki-67 expression in triple negative breast cancer subgroup using either a cutoff of 14% or 35%. Triple negative breast cancer subgroup showed lower rates of pathological complete response. Achievement of pathological complete response was significantly correlated with smaller tumor size and higher Ki-67 expression. The majority of triple negative breast cancer cases achieved pathological partial response. The study concluded that Ki-67 is a useful tool to predict chemosensitivity in the setting of neoadjuvant chemotherapy for invasive breast cancer but not for the triple negative breast cancer subgroup.

조기 유방암에서 삼중복 음성군의 임상 병리학적 특징 및 예후

안재석(Jae Seok Ahn),조지형(Jihyoung Cho),권선영(Sun Young Kwon),강선희(Sun Hee Kang) 대한외과학회 2009 Annals of Surgical Treatment and Research(ASRT) Vol.77 No.1

Purpose: Triple negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2/neu negative) is associated with high risk of recurrence and poor prognosis. We investigated the characteristics and prognosis of triple negative early-stage breast cancer. Methods: We reviewed the records of 821 early-stage breast cancer patients treated at our hospital from 1995 to 2005. We studied the differences between a triple negative group compared with a non-triple negative group. Results: Of 821 early-stage breast cancer patients, 200 (24.4%) were classified as triple negative. Large tumors (>2 cm) in the triple negative group were significantly more than those in the non-triple negative group (P=0.042). Histologic and nuclear grade of the triple negative group were significantly higher than those of the non-triple negative group (P<0.001). The median follow-up time is 50 months (1∼135). There have been 50 local recurrences, 98 distant metastases, and 65 deaths. There were high rates of local recurrence in the triple negative group but no difference in 5-year disease free survival rates (P=0.178). The 5-year overall survival rate showed 85% in the triple negative group but 92.8% in the non-triple negative group (P=0.008). The relative risk for overall survival was 1.93 times higher in the triple negative group. Conclusion: Triple negative breast cancer patients in early stages have poor pathologic findings and prognoses. Careful treatment and follow-up are important and further investigation is necessary for triple negative breast cancer.

T1-2 림프절 음성 삼중음성유방암의 예후인자

유지영 ( Ji Young You ),이혜윤 ( Hye Yoon Lee ),이은숙 ( Eun Sook Lee ),배정원 ( Jeoung Won Bae ),우상욱 ( Sang Uk Woo ),박경화 ( Kyong Hwa Park ) 대한임상종양학회 2011 Korean Journal of Clinical Oncology Vol.7 No.2

배경: 삼중음성유방암은 비삼중음성유방암군에 비해 조기라 해도 더 나쁜 예후를 보이는 걸로 알려져 있다. 따라서 삼중음성유방암의 초기 치료를 위해서 정확한 예후인자를 찾는 것이 중요하다. 본 연구에서는, T1-2 림프절 음성인 삼중음성유방암의 나쁜 예후와 관련된 예후인자를 찾아 보고자 하였다. 방법: 1995년부터 2006년까지 고려대학교 의료원 안암병원에서 유방암으로 근치절제술을 시행받은 환자 중 림프절 전이나 원격전이가 없는 환자를 대상으로 하였다. 이 중에서 호르몬 수용체 및 HER2 수용체 여부에 대한 기록이 있는 환자들만을 포함시켰다. 의무기록의 후향적 분석을 통해 삼중음성유방암 및 비삼중음성유방암 환자들의 임상병리적 특징이 분석되었다. 결과: 79명 (22.9%) 의 환자들이 삼중음성유방암군으로 분류되었다. 삼중음성유방암군에서 p53 양성 환자군에서 p53 음성 환자군보다 더 낮은 무병생존율을 보였다 (p=0.028). 다변량 회귀분석에서는 35세 이하의 낮은 연령이 삼중음성유방암과 관련된 독립적인 예후인자로 나타났으며, Ki-67은 단변량 회귀분석에서 삼중음성유방암과 통계적으로 유의하게 관련성을 보였다. 결론: 본 연구에서, T1-2 림프절 음성인 삼중음성유방암에서 연령은 독립적인 예후인자이고 어릴수록 나쁜 예후와 연관됨을 알 수 있었고, Ki-67 은 통계적으로 증명되지는 않았지만, 삼중음성유방암의 예후인자가 될 수 있을 것으로 생각된다. Purpose Triple-negative breast cancer typically results in poorer prognoses compared to non-triple negative breast cancer, even in early stages. The initial management of triple negative breast cancer patients and detection of clear prognostic factors are therefore of great importance. We aimed to identify specific prognostic factors associated with unfavorable outcomes of triple negative breast cancer in T1-2 node-negative breast cancer. Materials and Methods We analyzed breast cancer patients without lymph node metastasis or distant metastasis who underwent curative surgery at the Anam Hospital of the Korea University Medical Center between 1995 and 2006. Among them, patients were eligible for analysis, only if the reports about hormone receptor and human epidermal growth factor receptor-2 status were available. Clinico-pathological features were reviewed by retrospective examination and comparison of medical records of triple negative breast cancer and non-triple negative breast cancer patients. Results Seventy-nine patients (22.9%) were categorized to the triple negative breast cancer group. The disease-free survival rate of TNBC p53-positive patients was significantly lower than that of p53-negative patients (p =0.028). In multivariate analysis, young age was an independent prognostic factor for disease-free survival of the triple negative breast cancer group. High Ki-67 expression was a significant prognostic factor in univariate analysis in triple negative breast cancer, but it was not significant in multivariate analysis. Conclusion We suggest that age is an independent prognostic factor of triple negative breast cancer in T1-2 and node-negative patients and that Ki-67 could also be a prognostic factor in these patients.

Clinical Usefulness of Cytokeratin 5/6 as an Immunohistochemical Marker to Predict Prognosis in Triple-negative Breast Cancer

Woo-Sik Choi,Dong-Won Ryu,Chung-Han Lee 고신대학교 의과대학 2010 고신대학교 의과대학 학술지 Vol.25 No.2

(PR) and human epidermal growth factor receptor 2. Negative staining for all three markers defines the ‘triple-negative’ phenotype. By adding markers for cytokeratin 5/6 and epidermal growth factor receptor, triple-negative breast cancers can be divided into ‘basal-like’ and ‘non-basal-like’ subgroups. The aim of this study is to asscess the usefulness of cytokeratin 5/6 as a distinguishable marker in the basal-like subgroup of triple-negative breast cancers. Methods : We examined, by immunohistochemistry, the expression of biological markers cytokeratin 5/6 in triple-negative breast cancers. We classified triple-negative breast cancerpatients into two groups as cytokeratin 5/6-positive and cytokeratin 5/6-negative. The clinicopathological features, such as disease free survival (DFS) and overall survival (OS) for patients with cytokeratin 5/6-positive were compared with those of the cytokeratin 5/6-negative patients. Results : In the 131 cases of operable triple-negative breast cancer, cytokeratin 5/6-positive group was detected in 15 (11.5%) and cytokeratin 5/6-negative group was detected in 116 (88.5%). Significant correlation was observed between cytokeratin 5/6-positive groupwith tumor size, pathologic lymph-node metastasis and American Joint Committee on Cancer staging (pT, pN and stage, P = 0.001). No association was detected between cytokeratin 5/6-positive cancerand other biological markers. Patients with cytokeratin 5/6-positive showed shorter disease-free survival (P = 0.031) and overall survival (P = 0.018) than patients with cytokeratin 5/6-negative. Conclusion : Our results show that cytokeratin 5/6 is important markers that can be used to predict prognosis in triple-negative breast cancer. But, there is a need for larger number of cases, more immunohistochemical markers and gene investigation to observe more accurate disease free survivaland overall survival rate

Outcomes of Triple-Negative Versus Non-Triple-Negative Breast Cancers Managed with Breast-Conserving Therapy

Bhatti, Abu Bakar Hafeez,Khan, Amina Iqbal,Siddiqui, Neelam,Muzaffar, Nargis,Syed, Aamir Ali,Shah, Mazhar Ali,Jamshed, Arif Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.6

Background: Triple negative breast cancer is associated with aggressive behavior and high risk of local and regional failure. Aggressive surgical intervention is considered suitable. This makes role of breast conserving therapy (BCT) debatable in these patients. The objective of this study was to compare outcome of BCT for triple negative versus non-triple negative breast cancer. Materials and Methods: Medical records of patients who underwent breast conserving therapy from 1999 to 2009 at Shaukat Khanum Cancer Hospital and had complete receptor status information were extracted. Patients were divided into triple negative breast cancer (TNBC) and non-TNBC. Patient characteristics, medical treatment modalities and adverse events were compared. Expected five year locoregional recurrence free, disease free and overall survival was calculated. The Cox proportional hazard model was used to identify independent predictors of outcome. Results: A total of 194 patients with TNBC and 443 with non-TNBC were compared. Significant difference was present for age at presentation (p<0.0001), family history (p=0.005), grade (p<0.0001) and use of hormonal therapy (p<0.0001). The number of locoregional failures, distant failures and mortalities were not significantly different. No significant difference was present in 5 year locoregional recurrence free (96% vs 92%, p=0.3), disease free (75% vs 74%, p=0.7) and overall survival (78% vs 83%, p=0.2). On multivariate analysis, tumor size, nodal involvement and hormonal treatment were independent predictors of negative events. Conclusions: Breast conserving therapy has comparable outcomes for triple negative and non-triple negative breast cancers.

The expression of Rab5 and its effect on invasion, migration and exosome secretion in triple negative breast cancer

Lei Qiao,Chao Dong,Jiaojiao Zhang,Gang Sun 대한약리학회 2023 The Korean Journal of Physiology & Pharmacology Vol.27 No.2

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and current therapeutic strategies are limited in their effectiveness. The expressions of Rab5 and the M2 tumor-associated macrophage marker CD163 in tissues were detected by Western blot. The migration and invasion of cells were determined using a Transwell assay. The expressions of the exosome markers were evaluated by Western blot. The polarization of human macrophages (THP-1) was determined by incubation of THP-1 cells with conditioned medium or exosomes collected from MDA-MB-231 cells with indicated transfections or by a coculture system of THP-1 and MDA-MB-231 cells. The M1 and M2 macrophage markers were evaluated by qRT-PCR. The expression of Rab5 in TNBC was significantly higher than that in normal breast tissue. Rab5 expressions in triple-negative and luminal A breast cancer were higher than those in other molecular subtypes. Higher CD163 expression was observed in triple-negative breast cancer and in triple-negative and luminal B subtypes. Rab5 knockdown suppressed but Rab5 overexpression promoted the migration and invasion capacity of MDA-MB-231 cells. The levels of CD63 and CD9 in the medium of Rab5 knockdown cells were lower than those in control cells, whereas higher levels of CD63 and CD9 were observed in Rab5 overexpression cells. Rab5 knockdown decreased the excretion but did not alter the diameter of the exosomes. Knockdown of Rab5 facilitated the anti-tumor polarization of macrophages, which was partially reversed by Rab5 overexpression. Therefore, Rab5 is expected to be a potential therapeutic target for triple-negative breast cancer.

Clinical significance of morphologic characteristics in triple negative breast cancer

Dong Won Ryu,Min Jung Jung,Woo Sik Choi,Chung Han Lee 대한외과학회 2011 Annals of Surgical Treatment and Research(ASRT) Vol.80 No.5

Purpose: No clinically useful target molecule has been identified for triple-negative (TN) breast cancer, i.e., estrogen receptor- negative, progesterone receptor-negative, human epidermal growth factor receptor-2-negative phenotype, and its prognosis is poor. The aim of this study is to clarify the clinical and pathologic characteristics of triple negative breast cancer (TNBC). Methods: The study subjects, 87 women with TNBC, were a subset of patients operated at Kosin University Gospel Hospital from January 2000 to December 2005. We examined pathologic characteristics such as tumor necrosis, infiltrating border, lymphocytic infiltration, prominent nucleoli in TNBC. And we studied the correlation between TNBC and several factors related to pathologic morphology. Chi-squared tests were used for statistical analysis. Kaplan-Meier estimates are presented for the survival function, and differences in survival were analyzed using the log rank test. Results: Tumor necrosis was found in 51 patients (58.3%) in TNBC. And infiltrating border was found in 71 patients (81.0%). Also continuous lymphocytic distribution and prominent nucleoli was found in 31 patients (35.7%), 52 patients (59.7%), respectively. No association was detected between pathologic characteristics and other biological markers. Patients with tumor necrosis positive for TNBC didn’t show shorter disease-free survival (P = 0.4490) or overall survival (P = 0.979) than patients without tumor necrosis. Conclusion: These findings suggest that pathologic characteristics cannot be used to classify triple-negative breast cancer into only two subtypes with differing prognoses. But because our study is small size study, more abundant patients’ dates will be needed to evaluate the morphologic characteristics’ predictive role.

Overexpression of Cell Cycle Progression Inhibitor Geminin is Associated with Tumor Stem-Like Phenotype of Triple-Negative Breast Cancer

Maurizio Di Bonito,Monica Cantile,Francesca Collina,Giosuè Scognamiglio,Margherita Cerrone,Elvira La Mantia,Antonio Barbato,Giuseppina Liguori,Gerardo Botti 한국유방암학회 2012 Journal of breast cancer Vol.15 No.2

Purpose: Triple-negative breast cancer, has a significant clinical relevance being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. For this reason, identifying the molecular pathways associated with increased aggressiveness, for example the presence of stem cell populations within the tumor and alteration of genes associated with cell cycle regulation represents an important objective in the clinical research into this neoplasm. Methods: To investigate the role of cell cycle progression inhibitor Geminin in triple-negative breast cancers and its potential correlation with stem-like phenotype of this neoplasm, we used tissue microarray technology to build a specific triplenegative breast cancer tissue micro-array. Geminin and cancer stem cell marker CD133 expression was further investigated at the mRNA level for selected breast tumor samples through realtime polymerase chain reaction quantification. Results: Our results showed that CD133 expression was significantly associated to high Geminin expression (p=0.017), a strong association between Ki-67 and tumor grade (p=0.020) and an inverse association between Geminin expression and lymphonode metastases (p=0.058), and a trend of statistically significance between Geminin marker expression and survival of triple-negative breast cancer patients (p=0.076). Conclusion: The strong association between the expression of CD133 and Geminin could be useful in molecular stratification of breast tumors and in particular of triple-negative breast cancers.

A novel metformin derivative, HL010183, inhibits proliferation and invasion of triple-negative breast cancer cells

Koh, M.,Lee, J.C.,Min, C.,Moon, A. Elsevier/Pergamon 2013 Bioorganic & medicinal chemistry Vol.21 No.8

Mounting evidence suggests that metformin (N,N-dimethylbiguanide), a widely prescribed drug for the treatment of type II diabetes, exerts an anti-tumor effect on several cancers including breast cancer. Breast cancer has been estimated as one of the most commonly diagnosed types of cancer among women. In particular, triple-negative breast cancers are associated with poor prognosis and metastatic growth. In the present study, we synthesized a novel metformin derivative 5 (HL010183) and metformin salts, 9a, 9b, and 9c (metformin gamma-aminobutyric acid (GABA) salt, metformin pregabalin salt and metformin gabapentin salt), which exerted more potent inhibitory effects on the proliferation and invasiveness of Hs578T triple-negative breast carcinoma cells than metformin. Importantly, 5 showed approximately 100-fold more potent effects compared to metformin. In a triple-negative breast cancer xenograft model, 5 showed a comparable degree of inhibitory effect on in vivo tumor growth at the 100mg/kg dose to that of metformin at 500mg/kg. Our results clearly demonstrate that 5 exerts a potent anti-tumor effect both in vitro and in vivo, paving the way for a strategy for treatment of triple-negative breast cancer.

Clinicopathologic and Demographic Evaluation of Triple-Negative Breast Cancer Patients among a Turkish Patient Population: a Single Center Experience

Somali, Isil,Ustaoglu, Bahar Yakut,Tarhan, Mustafa Oktay,Yigit, Seyran Ceri,Demir, Lutfiye,Ellidokuz, Hulya,Erten, Cigdem,Alacacioglu, Ahmet Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.10

Background: To evaluate the clinicopathologic and demographic characteristics of triple-negative breast cancer (TNBC) patients and to determine differences from non-triple-negative cases. Materials and Methods: A detailed review of the medical records of 882 breast cancer (BC) patients was conducted to obtain information regarding age, menopausal status, height and weight at the time of diagnosis, presence of diabetes or hypertension, and pathologic characteristics of the tumor (tumor size, lymph node status, histologic grade, ER status, PR status, HER2 status, p53 mutation). Body mass index (BMI) was calculated and a value of ${\geq}30$ was considered as indicative of obesity. Results: 14.9% (n=132) of the patients had TNBC. There was no difference among the patients in terms of median age, comorbid conditions and menopausal status. The proportion of medullary, tubular and mucinous carcinomas was significantly higher (15.9%) in the triple-negative (TN) group, while invasive lobular histology was more frequent (8.2%) among non-triple negative (NTN) cases (p<0.001). Grade 3 (G3) tumors were more frequent in the triple-negative group (p<0.001). The rate of p53 mutation was 44.3% in TN tumors versus 28.2% in the NTN group (p<0.001). The two groups were similar in terms of LN metastasis. In the NTN group, the rate of patients with BMI ${\geq}30$ was 53% among postmenopausal patients, while it was 36% among premenopausal women, and the difference was statistically significant (p<0.001). No significant difference was observed in terms of BMI between postmenopausal and premenopausal patients in the TN group (p=0.08). Conclusions: TNBC rates and clinicopathologic characteristics of the Turkish patient population were consistent with the data from Europe and America. However, no relationship between obesity and TNBC was observed in our study. The association between TNBC and obesity needs to be evaluated in a larger patient population.