不同分子亚型局部晚期乳腺癌的新辅化疗反应率的临床研究(英文)

Objective: The aim of this study was to evaluate the impact of different molecular subtypes defined by immunohistochemistry (IHC) staining on the response rate for patients with locally advanced breast cancer received neoadjuvant chemotherapy. Methods: One hundred and seven breast cancer patients admitted from 2007 to 2011 who received 4 cycles of docetaxel/epirubicin-combined (TE) neoadjuvant chemotherapy were retrospectively reviewed, the patients were classified into 4 subtypes: luminal A, luminal B, HER-2 and triple negative breast cancer (TNBC) according to different combination patterns of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor-2 (HER-2) expression defined by IHC method. The correlation between response rate and the molecular subtypes were analyzed. Results: The pathological complete response (PCR), clinical complete response (CCR), clinical partial response (CPR), and clinical stable disease (CSD) rate of whole group was 15.89% (17/107), 22.43% (24/107), 63.55% (68/107), 14.02% (15/107), respectively, and the overall response rate (ORR) was 85.98% (92/107). The PCR rate and ORR of luminal A, luminal B, HER-2 and TNBC subtypes was 4.76% and 73.81%; 16.67% and 83.33%;17.65% and 100.00%; 30.00% and 96.67%, respectively. The PCR and ORR rate of HER-2/TNBC subtypes was higher than that of luminal A/B subtypes (P = 0.019, P = 0.002, respectively). Conclusion: Different molecular subtypes display different response rate for patients with locally advanced breast cancer received neoadjuvant TE chemotherapy, HER-2/TNBC subtypes have a higher PCR and ORR rate than that of luminal A/B subtypes.     

不同分子亚型乳腺癌的临床病理特征及预后分析

目的 探讨乳腺癌各分子亚型的临床特点及其预后情况.方法 分析1153例可手术乳腺癌患者的临床病理资料,根据雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)的表达情况将乳腺癌分为4种分子亚型,即Luminal A型、Luminal B型、Her-2过表达型和Basal-like型.分析各分子亚型乳腺癌患者在年龄、肿瘤大小、淋巴结转移状况、临床分期和预后的差异及影响预后的因素.结果 1153例患者中,Luminal A型791例(68.6%),Luminal B型50例(4.3%),Her-2过表达型53例(4.6%),Basal-like型259例(22.5%).各分子亚型在年龄、肿瘤大小、淋巴结转移状况、临床分期的差异均无统计学意义(均P>0.05).有完整随访资料的1006例患者中,Her-2过表达型的远处转移率(17.0%)显著高于其他亚型(P=0.005),而各分子亚型间的局部复发率差异无统计学意义(P>0.05).Kaplan-Meier法分析结果显示,Her-2过表达型患者的7年无病生存率和9年总生存率最低(均P<0.05).单因素和多因素分析结果均显示,淋巴结转移状况和分子分型是影响乳腺癌患者无病生存及总生存的独立预后因素.结论 Her-2过表达型乳腺癌患者的预后最差.乳腺癌的分子分型对判断患者预后可能具有重要临床意义,有望成为今后制订乳腺癌个体化治疗方案的重要依据.

Abstract：

Objective To investigate the clinical characteristics and prognosis of different breast cancer molecular subtypes.Methods Clinicopathological and follow-up data of 1153 cases of operable breast cancer were analyzed retrospectively.Their molecular subtypes were categorized as luminal A, luminal B, Her-2 over-expressing and basal-like subtypes, based on detection of ER, PR, Her-2 expression.The correlation of prognosis of different molecular subtypes with age, tumor size, lymph node status and clinical staging was analyzed.Results Among the 1153 cases, 791 cases (68.6%) were of luminal A subtype, 50 cases (4.3%) luminal B subtype, 53 cases (4.6%) Her-2( + )subtype, and 259 cases (22.5%) basallike subtype.There were no statistically significant differences among different molecular subtypes regarding the age, tumor size, lymph node status, and clinical stage.1006 cases had complete follow-up data and the analysis showed that distant metastasis of Her-2 over-expressing subtype was significantly higher than that in other subtypes ( P = 0.005 ), but the differelices of local recurrence rate in different molecular subtypes was not statistically significant (P >0.05).Kaplan-Meier method was used to analyze the survival prognosis of different molecular subtypes, showing both DFS rate and OS rate of Her-2 over-expressing subtype were the lowest, with a statistically significant difference (Log rank test, P < 0.05 ).Univariate and multivariate analyses showed that molecular typing and lymph node status were independent prognostic factors affecting both DFS and OS.Conclusions Her-2 over-expressing subtype has the worst prognosis.Molecular subtypes may provide important information to predict the prognosis of breast cancer and might be an important basis for individualized treatment of breast cancer in future.     

Analysis of the Clinicopathologic Features and Prognosis in Triple-Negative Breast Cancer

OBJECTIVE To investigate the clinical and pathological features,as well as prognosis in triple-negative breast cancer patients.METHODS A total of 509 cases of operable breast cancer from January,2002 to June,2002 treated in the Cancer Hospital of Tianjin Medical University were analyzed.The Her-2,ER and PR status was determined using immunohistochemistry.Of the total cases,one group was identifi ed as triple negative breast cancer,ie defi ned as ER,PR and Her-2 negative.The other group was non-triple-negative breast cancer.Clinicopathologic features of the groups were compared and 5-year disease-free survival(DFS) analyzed by the Kaplan-Meier method.RESULTS Of the total cases,21.4%(109/509) of cases were found to be triple-negative while 78.6%(400/509) were non-triple-negative.The triple negative group had higher incidence rates than the non-triple-negative group of the medullary type and Grade Ⅲ tumors(P < 0.05).There was no other difference in the clinicopathologic features between the 2 groups.From follow-up to June,2007,21.1%(23/109) of the triple-negative group and 12.7%(51/400) of the non-triple negative group had a local recurrence or distant metastasis,resulting in a signifi cant difference(P < 0.05).In the triple-negative group and non-triple-negative group,5-year DFS were 78.9% and 87.3% respectively.There was a statistically signifi cant difference between the 2 groups(P = 0.031).CONCLUSION Compared with non-triple-negative breast cancer,triple-negative breast cancer patients have an increased likehood of a local recurrence or distant metastasis and a poorer prognosis.     

Response and long-term effect of patients with triple-negative breast cancer receiving neo-adjuvant anthracycline-based chemotherapy

OBJECTIVE The breast cancer lack of expression of estrogen receptor （ER）, progesterone receptor （PR）, and human epidermal growth factor receptor 2 （HER-2） is defined as the Triple-negative breast cancer （TNBC）. Our purpose is to compare the response and long-term effect of the TNBC and non-TNBC patients receiving neo-adjuvant anthracycline-based chemotherapy, and to investigate the mechanisms of TNBC affecting the survivals. METHODS Data of long-term follow-up （median, 5.4 years） of 326 patients who received neo-adjuvant chemotherapy with anthracycline-based regimen, during a period from 2000 to 2003, were analyzed. Expressions of ER, PR, HER-2, P53, Ki-67 and E-cadherin were determined using immunohistochemical staining method. A multivariate Cox regression analysis was used to analyze independent prognostic factors affecting the relapse-free survival （RFS） and overall survival （OS） rates. Clinical effects of the neo-adjuvant anthracycline-based chemotherapeutic regimen and the RFS and OS rates were compared between the patients with TNBC and non-TNBC, and the correlations among the triplenegative phenotype （TNP）, tumor grading and the expressions of P53, Ki-67 and E-cadherins were analyzed. RESULTS TNP, TNM staging, histological grades, clinical response of the neo-adjuvant chemotherapy and pathological complete remission （pCR） rate were the independent prognostic factors affecting the survival rates. Furthermore, 70 （21.5%） of the 326 patients suffered TNBC. Compared with the subjects in non-TNBC group, the patients with TNBC had a significantly higher pCR rate （P = 0.046） and clinical response rate （P = 0.037）, but also decreased 5-year RFS （P = 0.001） and OS （P = 0.004） rates. The RFS and OS rates were not improved in the TNBC patients who achieved a clinical remission after the neo-adjuvant chemotherapy. The triple-negative phenotype was positively correlated with the level of P53, Ki-67 expression （P = 0.007, P = 0.028）, but negatively correlated with level of E-cadherin （P = 0.034）. CONCLUSION Both clinical remission rate and pCR rate of the TNBC patients receiving neo-adjuvant anthracycline-based chemotherapy are high, however, the long-term effect is poor. The mechanism may relate to a strong potential of proliferation and invasive metastasis, as well as lack of an effective therapeutic target in the TNBC patients.     

Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

Breast cancer has been shown to live in the tumor microenvironment,which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells.Diverse components of the breast cancer microenvironment,such as suppressive immune cells,re-programmed fibroblast cells,altered extracellular matrix (ECM) and certain soluble factors,synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis.Among these components,stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways,whereas the ECM features biochemical and biomechanical changes.However,triple-negative breast cancer (TNBC),the most aggressive subtype of this disease that lacks effective therapies available for other subtypes,is considered to feature a unique microenvironment distinct from that of other subtypes,especially compared to Luminal A subtype.Because these changes are now considered to significantly impact breast cancer development and progression,these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC.In this review,we focus on the composition of the TNBC microenvironment,concomitant distinct biological alteration,specific interplay between various cell types and TNBC cells,and the prognostic implications of these findings.     

Cutting the root: the next generation of T cells engagers against cancer stem cells to overcome drug resistance in triple-negative breast cancer

<正>Triple-negative breast cancer(TNBC) is the most difficult type of breast cancer to treat. TNBC is defined by the lack of expression of three receptors: estrogen receptor(ER); progesterone receptor(PR); and human epidermal growth factor receptor 2(HER2). Chemotherapy is currently first-line treatment for TNBC; however, due to the high heterogeneity of TNBC,     

Clinico-pathological significance of extra-nodal spread in special types of breast cancer

Objective： To investigate the significance of extra-nodal spread in special histological sub-types of breast cancer and the relationship of such spread with prognostic parameters.Methods： A total of 303 breast cancer cases were classified according to tumor type, and each tumor group was subdivided according to age, tumor diameter, lymph node metastasis, extra-nodal spread, vein invasion in the adjacent soft tissue, distant metastasis, and immunohistochemical characteristics [estrogen receptor（ER）, progesterone receptor（PR） existence, p53, c-erbB-2, and proliferative rate（Ki-67）]. The 122 cases with extra-nodal spread were clinically followed up.Results： An extra-nodal spread was observed in 40%（122 cases） of the 303 breast cancer cases. The spread most frequently presented in micro papillary carcinoma histological sub-type（40 cases, 75%）, but least frequently presents in mucinous carcinoma（2 cases, 8%）. Patients with extra-nodal spread had a high average number of metastatic lymph nodes（8.3） and a high distant metastasis rate（38 cases, 31%） compared with patients without extra-nodal spread.Conclusion： The existence of extra-nodal spread in the examined breast cancer sub-types has predictive value in forecasting the number of metastatic lymph nodes and the disease prognosis.     

Expression of HIF-1α in breast cancer and precancerous lesions and the relationship to clinicopathological features简

Objective： The aim of this study was to observe the expressions and clinical significance of HIF-1a in breast cancer and precancerous lesions, and analyze the relationship between the expressions and clinicopathological features in breast cancer. Methods： We analyzed the HIF-1a expression in 128 cases of invasive ductal carcinomas, 146 precancerous lesions patients including 89 cases of ductal carcinoma in situ and 57 cases of atypical ductal hyperplasia. 53 cases of usual ductal hyperplasia breast tissues were selected as a control group. The specimens were evaluated for HIF-1a, estrogen receptor （ER） ＆ progesterone receptor （PR）, epidermal growth factor receptor type 2 （HER2/neu） and Ki-67. Immunoreactivity was semi-quantitatively evaluated in at least 1000 cells examined under the microscope at 40 x magnification and recorded as the percentage of positive tumor cells over the total number of cells examined in the same area. The percentage scores were subsequently categorized. The express of HIF-1a and their relationship with multiple biological parameters including ER ＆ PR, HER2/neu and Ki-67, the biomarkers levels of CA153, CA125 TSGF, and CEA in blood serum and nipple discharge, histological grade, region lymph node metastasis, distant metastasis and recurrence on files were also assessed. Results： Compared with usual ductal hyperplasia, the positive expression rate of HIF-1a in atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinomas group was significantly increased （P 〈 0.01）. The positive rates of HIF-1a in invasive ductal carcinomas were 68.75%, which were significantly higher than that in ductal carcinoma in situ （43.8%）, atypical ductal hyperplasia （31.6%）, usual ductal hyperplasia （9.4%; X2 = 13.44, 22.27, 52.79, respectively, P 〈 0.01）. Statistical analysis showed that difference of abnormal expression rate of HIF-1a between ductal carcinoma in situ and usual ductal hyperplasia （X2 = 18.37, P = 0.00）, atypical ductal hyperplasia and usual ductal hyperplasia （x2 = 8.14, P = 0.00） was significant （P = 0.00）. However, no significant difference in the positive expression rate of HIF-1a was found between atypical ductal hyperplasia and ductal carcinoma in situ tissue （X2 = 2.19, P = 0.14）. There was a significantly difference in the mean HIF-1a frequency between ER ＆ PR positive invasive ductal carcinomas group and negative group, epidermal growth factor receptor type 2 （HER2/neu） positive and negative groups, Ki-67 proliferation index 〈 14% and 〉 14% groups, histological grade （I ＋ II） and grade III invasive ductal carcinomas groups, with lymph node metastasis, distant metastasis and recurrence groups （P 〈 0.05） and without groups （P 〈 0.05）. However, there was not difference in the mean HIF-1a between age （〈 50 years vs 〉 50 years）, tumor diameter （〈 2 cm vs 〉 2 cm; P 〉 0.05）. The nipple discharge and serum levels of CA153, TSGF, CA125 and CEA in invasive ductal carcinomas HIF-1a positive patients were significantly higher than those in the negative patients （P 〈 0.05）. Conclusion： In breast cancer, HIF-1a expressibn was abnormally increased. The aberration of HIF-1a may play a key role during oncogenesis （atypical ductal hyperplasia or ductal carcinoma in situ） and promote breast cellular transformation into malignancy, a finding useful for further understanding of tumorigenesis. The abnormal expression of HIF-1a may be as an early event in the development of breast tumor. The over-expression of HIF-1a might be important biological markers for invasion, metastasis and recurrence of breast cancer.     

The significance of minimally invasive core needle biopsy and immunohistochemistry analysis in 235 cases with breast lesions

OBJECTIVE To evaluate core needle biopsy （CNB） as a minimally invasive method to examine breast lesions and discuss the clinical significance of subsequent immunohistochemistry （IHC） analysis. METHODS The clinical data and pathological results of 235 patients with breast lesions, who received CNB before surgery, were analyzed and compared. Based on the results of CNB done before surgery; 87 out of 204 patients diagnosed as invasive carcinoma were subjected to immunodetection for p53, c-erbB-2, ER and PR. The morphological change of cancer tissues in response to chemo- therapy was also evaluated. RESULTS In total of 235 cases receiving CNB examination, 204 were diagnosed as invasive carcinoma, reaching a 100% consistent rate with the surgical diagnosis. Sixty percent of the cases diagnosed as non-invasive carcinoma by CNB was identified to have the presence of invading elements in surgical specimens, and similarly, 50% of the cases diagnosed as atypical ductal hyperplasia by CNB was confirmed to be carcinoma by the subsequent result of excision biopsy. There was no significant difference between the CNB biopsy and regular surgical samples in positive rate of immunohistochemistry analysis （p53, c-erbB-2, ER and PR; P 〉 0.05）. However, there was significant difference in the expression rate of p53 and c-erbB-2 between the cases with and without morphological change in response to chemotherapy （P 〈 0.05）. In most cases with p53 and c-erbB-2 positive, there was no obvious morphological change after chemotherapy. CONCLUSION CNB is a cost-effective diagnostic method with minimal invasion for breast lesions, although it still has some limitations. Immunodetection on CNB tissue is expected to have great significance in clinical applications.     

Expression of Immunohistochemical Markers before and after Neoadjuvant Chemotherapy in Breast Carcinoma,and Their Use as Predictors of Response

Purpose

For patients with breast carcinoma, immunohistochemical markers are important factors in determining the breast cancer subtype and for establishing a therapeutic plan, including the use of neoadjuvant chemotherapy (NACT). However, it is not clear whether the expression of certain markers changes after NACT.

Methods

We assessed estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, p53, and Bcl-2 expression in specimens from 345 breast cancer cases before and after NACT. We analyzed the association between response to NACT and the expression of the markers in pre-NACT specimens. We also compared the expression between pre- and post-NACT specimens.

Results

ER and PR expression was negatively associated with pathological complete response (pCR). HER2 was associated with pCR in all cases, but the association was lost when the cases were subdivided according to hormone receptor status. The pre-NACT tumor size of cases with pCR after NACT was smaller than that of cases with residual disease. HER2-enriched and triple-negative breast cancers were more likely to achieve pCR than luminal A type cancers. PR expression and the Ki-67 index decreased after NACT. A decrease in the Ki-67 index was also demonstrated in hormone receptor positive and HER2-enriched subtypes, but no similar tendency was observed in the triple-negative subtype.

Conclusion

A patient with breast cancer scheduled for NACT should be assessed for the breast cancer subtype, as this will influence the treatment plans for the patient. The expression of PR and Ki-67 after NACT should be interpreted carefully because NACT tends to reduce the expression of these molecules.     

Metabolic interaction between cancer cells and stromal cells according to breast cancer molecular subtype

Introduction

The aim of this study was to investigate the differential expression of markers related to metabolic, mitochondrial and autophagy status in different molecular subtypes of breast cancer.

Methods

Using tissue microarray sections generated from 740 cases of breast cancer, we performed immunohistochemical staining for Glut-1, CAIX, MCT4, ATP synthase, glutaminase, BNIP3, Beclin-1, LC3A, LC3B and p62. Based on the immunohistochemical expression of estrogen receptor (ER), progesterone (PR), HER2, and Ki-67 labeling index, the cases were classified into luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC). We further classified metabolic phenotypes of tumors according to glycolytic status by assessing Glut-1 and CAIX expression as follows: Warburg type: tumor (glycolysis type), stroma (nonglycolysis type); reverse Warburg type: tumor (nonglycolysis type), stroma (glycolysis type); mixed type: tumor (glycolysis type), stroma (glycolysis type); and null type: tumor (nonglycolysis type), stroma (nonglycolysis type).

Results

Expression of Glut-1, MCT4 and LC3A was highest in TNBC and lowest in luminal A type (P < 0.001). Tumors were classified into 298 Warburg type (40.3%), 54 reverse Warburg type (7.3%), 62 mixed type (8.4%) and 326 null type (44.0%). The mixed type had a higher histologic grade, ER negativity, PR negativity and Ki-67 index, whereas the null type showed lower histologic grade, ER positivity, PR positivity and Ki-67 index (P < 0.001). TNBC constituted the major portion of Warburg and mixed types, and luminal A consisted mainly of reverse Warburg and null types (P < 0.001).

Conclusion

Breast cancer is heterogeneous in its metabolic status, and therefore it can be classified into various metabolic phenotypes. Specifically, the Warburg and mixed types had strong associations with TNBC, whereas reverse the Warburg and null types had associations with the luminal type, suggesting a correlation between metabolic phenotype and the biology of breast cancer.     

Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index

Introduction

Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes.

Methods

Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14), luminal B (ER + and/or PR+, HER2-, Ki-67 ≥14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER-, PR-, HER2-, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2-, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2-, Ki-67 ≥14, any CK 5/6, any EGFR), HER2-enriched (ER-, PR-, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER-, PR-, HER2-, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER-, PR-, HER2-, any Ki-67, CK 5/6-, EGFR-). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki-67 ≥14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value.

Results

Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 ≥14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 ≥14% show sharp peak at nearly 18 months.

Conclusions

Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients.     

Analysis of clinically relevant values of Ki-67 labeling index in Japanese breast cancer patients

Background

It has become important to standardize the methods of Ki-67 evaluation in breast cancer patients, especially those used in the interpretation and scoring of immunoreactivity. Therefore, in this study, we examined the Ki-67 immunoreactivity of breast cancer surgical specimens processed and stained in the same manner in one single Japanese institution by counting nuclear immunoreactivity in the same fashion.

Methods

We examined 408 Japanese breast cancers with invasive ductal carcinoma and studied the correlation between Ki-67 labeling index and ER/HER2 status and histological grade of breast cancer. We also analyzed overall survival (OS) and disease-free survival (DFS) of these patients according to individual Ki-67 labeling index.

Results

There were statistically significant differences of Ki-67 labeling index between ER positive/HER2 negative and ER positive/HER2 positive, ER negative/HER2 positive or ER negative/HER2 negative, and ER positive/HER2 positive and ER negative/HER2 negative groups (all P < 0.001). There were also statistically significant differences of Ki-67 labeling index among each histological grade (P < 0.001, respectively). As for multivariate analyses, Ki-67 labeling index was strongly associated with OS (HR 39.12, P = 0.031) and DFS (HR 10.85, P = 0.011) in ER positive and HER2 negative breast cancer patients. In addition, a statistically significant difference was noted between classical luminal A group and “20 % luminal A” in DFS (P = 0.039) but not between classical luminal A group and “25 % luminal A” (P = 0.105).

Conclusions

A significant positive correlation was detected between Ki-67 labeling index and ER/HER2 status and histological grades of the cases examined in our study. The suggested optimal cutoff point of Ki-67 labeling index is between 20 and 25 % in ER positive and HER2 negative breast cancer patients.     

Biological characteristics of luminal subtypes in pre- and postmenopausal estrogen receptor-positive and HER2-negative breast cancers

Background

Estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negetive breast cancers can be divided into luminal A and luminal B subtypes based on Ki67 expression levels. However, the biological differences in ER and progesterone receptor (PR) expression levels between these luminal subtypes are not clear.

Methods

We examined immunohistochemical expression levels of ER, PR, and Ki67 in 180 ER-positive/HER2-negative breast cancers while taking menopausal status into account. Breast cancers were divided according to ER and PR levels (H: >50%, L: ≤50%), and luminal A and B were classified by the Ki67 labeling index (A: Ki67 <14%, B: Ki67 ≥14%).

Results

When breast cancers were classified based on ER and PR levels, the distribution of pre- and postmenopausals was significantly different for luminal A (P < 0.0001), but not for luminal B cancers. As for luminal A, ER-H/PR-L cancers were rare among premenopausals (8%), but frequent among postmenopausals (54%). Correlation between ER and PR levels among luminal A cancers was strong in premenopausals but weak in postmenopausals. Since crosstalk with growth factor signaling is unlikely in luminal A, we speculate that intratumoral estrogen insufficiency contributed to the characteristics of postmenopausal ER-H/PR-L cancers.

Conclusion

We speculate that the biological characteristics of luminal A cancers are influenced by the estrogen environment, but its influence on luminal B cancers may be limited. We believe these considerations constitute useful information for a better understanding of the biology of ER-positive-HER2-negetive breast cancers.     

Triple negative breast cancer in Korea-distinct biology with different impact of prognostic factors on survival

We analyzed breast cancer subtypes using Korean Breast Cancer Society Registration Program data to compare clinical features and prognosis for triple-negative breast cancer (TNBC). A cohort of 26,767 breast cancer patients were divided in four groups: luminal A (ER+ and/or PR+, HER2−), luminal B (ER+ and/or PR+ HER2+), HER2+ (ER−, PR−, HER2+), and triple-negative (ER−, PR−, HER2−). Clinicopathologic factors were evaluated. The luminal A (14,437 patients, 53.9%) subtype was the largest in our study. Compared with luminal A subtype, TNBC correlated with younger age, more aggressive characteristics and poor overall survival and breast cancer-specific survival. The hazard rate showed a peak at 24 months for the TNBC subtype, but after 60 months, risk was similar to that of the luminal A subtype. Higher T, N stage and histologic grade, and lymphatic and vascular invasion showed poor prognosis in TNBC patients, but on multivariate analysis only histologic grade and ki-67 status were related. Young age was related to poor prognosis in the luminal A subtype, however, age was not related to prognosis in the TNBC subtype. Of the 5,586 TNBC patients, 282 patients (7.11%) expired within 3 years of diagnosis. T and N stage and grade were significantly associated with prognosis on multivariate analysis. TNBC subtype is characterized by younger age with poorer outcome. However, younger age is not related to prognosis, and mortality risk decreases to that of the luminal A subtype, which is known to have the best prognosis after a few years.     

Differences in subtype distribution between screen-detected and symptomatic invasive breast cancer and their impact on survival

Purpose

Stage shift is considered a major reason for more favorable outcomes in patients with screen-detected breast cancer. However, even after adjusting for clinical stage, unresolved issues concerning the reasons for a survival benefit associated with screening programs remain. This study aims to evaluate differences in subtype distribution and outcomes among patients with screen-detected and symptomatic invasive breast cancer and assess whether variations in subtype distribution could explain differences in prognosis.

Methods

Survival analysis was performed to estimate the likelihood of distant recurrence and death in 1132 patients. Subtypes were defined as luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)?, and Ki67 low], luminal B (HER2?) (ER+ and/or PR+, HER2?, and Ki67 high), luminal B (HER2+) (ER+ and/or PR+ and HER2+), HER2 overexpressing (ER?, PR?, and HER2+), and triple negative (ER?, PR?, and HER2?).

Results

Screen-detected cancers had favorable clinicopathological characteristics, such as smaller tumor size and a lower frequency of lymph node involvement. Women with screen-detected cancers had a survival advantage. Subtype distribution differed significantly among women with screen-detected and symptomatic cancer. Screen-detected cancers were more likely to be luminal A and less likely to be HER2 overexpressing or triple negative cancer compared with symptomatic cancers (luminal A 61.3 vs. 44.2%, HER2 overexpressing 4.0 vs. 8.0%, triple negative 8.0 vs. 15.9%). Node status, mode of detection, and subtype were independent prognostic factors in the multivariate analysis.

Conclusions

Differences in subtype distribution between screen-detected and symptomatic cancer could partially explain differences in outcomes.

     

Management of small T1a/b breast cancer by tumor subtype

Background

The treatment of patients with small (T1a/b) breast cancer is based on retrospective analysis. The influence of intrinsic tumor subtypes on patients’ outcome and treatment decision remains unclear.

Patients and methods

This is a prospective cohort register study including 1008 patients with small T1a/b breast cancer treated between 2003 and 2011. Tumors were grouped by biological characteristics into four different subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC).

Results

The median follow-up time was 6.5 years. From 919 eligible patients, 408 (44.4%) were classified as luminal A, 246 (26.8%) as luminal B, 183 (19.9%) as HER2 enriched, and 82 (8.9%) as TNBC. A total of 305 (34.2%) patients were treated with systemic therapy. Patients receiving systemic therapy were significantly younger and had lymph node metastasis, higher tumor grade, negative HR, and positive HER2 status. Patients with luminal A tumors demonstrated the best survival rate which improved with systemic therapy. The survival rate of patients with luminal B cancer, HER2-enriched tumors, and TNBC improved by addition of systemic treatment. The effect of systemic treatment was significant in luminal B (p = 0.040) and HER2 overexpressing tumors (p = 0.016). The treatment effect of systemic therapy in HER2-enriched tumors remained significant even after adjustment of other prognostic factors (HR 0.43, CI 0.19–0.98; p = 0.047). Notably, tumor size was not associated with patients’ survival and treatment decision.

Conclusion

The treatment decision of small breast cancer should be made by biological subtype and not by tumor size or lymph node status.