Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis

Introduction

Triple negative breast cancer (TNBC) has a poorer survival, despite a higher response rate to neoadjuvant chemotherapy. The purpose of this study was to identify the predictive or prognostic value of Ki-67 among patients with TNBC treated with neoadjuvant chemotherapy, and the role of Ki-67 in further classification of TNBC.

Methods

A total of 105 TNBC patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were included in the present study. Pathologic complete response (pCR) rate, relapse-free survival (RFS), and overall survival (OS) were compared according to the level of Ki-67.

Results

pCR was observed in 13.3% of patients. TNBC with high Ki-67 expression (≥10%) showed a higher pCR rate to neoadjuvant chemotherapy than TNBC with low Ki-67 expression. None of the low Ki-67 group achieved pCR (18.2% in the high Ki-67 group vs. 0.0% in the low Ki-67 group, P = 0.019). However, a high Ki-67 expression was significantly associated with poor RFS and OS in TNBC, despite a higher pCR rate (P = 0.005, P = 0.019, respectively). In multivariate analysis, high Ki-67 was an independent prognostic factor for RFS in TNBC (hazard ratio = 7.82, P = 0.002). The high Ki-67 group showed a similar pattern of recurrence with overall TNBC, whereas the low Ki-67 group demonstrated a relatively constant hazard rate for relapse.

Conclusions

TNBC with high Ki-67 was associated with a more aggressive clinical feature despite a higher pCR rate. High proliferation index Ki-67 can be used for further classification of TNBC into two subtypes with different responses and prognosis.     

三阴乳腺癌在新辅助化疗中相关预测因子的Meta分析(英文)

Objective: Neoadjuvant chemotherapy (NAC) was increasingly used as a systemic therapy for triple-negative breast cancer (TNBC). The pathological complete response (PCR) rates of neoadjuvant chemotherapy in TNBC were higher than other types of breast cancer with fluctuate data. Predictors to identify which subgroup TNBC was more likely to achieve PCR in neoadjuvant chemotherapy would give us some hints on how to improve outcomes of TNBC patients. The meta-analysis was conducted to contrast the prognostic function of some clinicopathological parameters in the PCR rates of neoadjuvant chemotherapy for TNBC. Methods: Studies were selected from the PubMed database. The relevant parameters to PCR rates in TNBC group were recorded. Review Manager and MIX were used to estimate prognostic function of some biological markers and clinicopathological parameters in PCR rates of TNBC. Results: The analysis included 6 studies with 723 patients, the aggregate PCR rate was 27.9% in TNBC group. The association of lymph nodes metastasis, Ki-67 expression, p53 expression and CK5/6 expression with PCR rate of TNBC was investigated in the analysis, and the odds ratios were 0.50, 9.87, 1.17 and 0.53 respectively. Conclusion: This meta-analysis demonstrated that Ki-67 expression and lymph nodes metastasis were predictors of PCR rate for TNBC in neoadjuvant chemotherapy, while p53 and CK5/6 expression could not be confirmed for the prognostic function.     

激素受体和HER-2及Ki-67预NSL腺癌新辅助化疗疗效价值的分析

目的：探讨乳腺癌组织中雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2（HER-2）及Ki-67的表达状态对新辅助化疗反应的预测作用以及化疗前后其表达差异对疗效的影响。方法：免疫组织化学方法检测新辅助化疗前后118例乳腺癌组织的ER、PR、HER-2及Ki-67的表达情况,并分析其与新辅助化疗疗效的关系。结果：118例新辅助化疗乳腺癌病例中,ER-和PR-组pCR分别为26．1％和27．1％,明显高于ER＋组11．1％和PR＋组6．8％,P-0．003。HER-2和Ki-67的表达对新辅助化疗疗效无显著影响。新辅助化疗前ER、PR与Ki-67的表达呈明显负相关,P〈0．001;新辅助化疗后Ki-67的高表达病例数显著减少,P-0．001。结论：ER-／PR-的患者对新辅助化疗更为敏感,Ki-67在化疗后发生了显著下调,提示新辅助化疗能降低肿瘤的增殖活性。ER、PR及Ki-67可以作为新辅助化疗疗效的预测指标。     

Topoisomerase II alpha expression and the Ki-67 labeling index correlate with prognostic factors in estrogen receptor-positive and human epidermal growth factor type-2-negative breast cancer

Background

Topoisomerase II alpha (Topo IIa) is involved in DNA replication and is a molecular target for anthracycline-based chemotherapy. The Ki-67 labeling index (LI) is an evaluation of tumor cell proliferation. The objective of this study was to evaluate relationships among Topo IIa expression, the Ki-67 LI, and prognostic factors in estrogen receptor (ER)-positive, human epidermal growth factor type-2 (HER2)-negative breast cancer.

Materials and methods

Seventy-one patients were diagnosed with ER-positive, HER2-negative breast cancer between July 2003 and December 2004. Formalin-fixed, paraffin-embedded tumor specimens were stained for Topo IIa expression and Ki-67 LI. We investigated the correlation of the level of Topo IIa expression and the Ki-67 LI with clinical factors such as age, tumor size, progesterone receptor status, nodal status, nuclear grade, and lymphovascular invasion (LVI).

Results

Statistically significant differences were observed between Topo IIa overexpression, nuclear grade (p?=?0.036), and LVI (p?=?0.029). Topo IIa overexpression was statistically correlated with the Ki-67 LI (p?p?=?0.01). Survival analysis revealed the significant prognostic value of Ki-67 LI in patients with ER-positive, HER2-negative breast cancer (p?=?0.003).

Conclusions

Ki-67 LI is a strong prognostic factor in ER-positive HER2-negative breast cancer. Topo IIa overexpression was significantly correlated with the Ki-67 LI, nuclear grade, and LVI. These findings suggest use of Topo IIa expression as a proliferation marker and a prognostic factor in ER-positive, HER2-negative breast cancer.     

Marked lymphovascular invasion,progesterone receptor negativity,and high Ki67 labeling index predict poor outcome in breast cancer patients treated with endocrine therapy alone

Purpose

Whether postoperative chemotherapy should be added to endocrine therapy or not is an important issue in patients with hormone receptor-positive and human epidermal growth factor receptor (HER)2-negative breast cancer. To identify patients who should be treated with additional chemotherapy, prognostic factors were investigated in breast cancer patients postoperatively treated with endocrine therapy alone.

Patients and methods

Tumor samples and clinicopathological data were collected from patients who underwent curative surgery and were postoperatively treated with endocrine therapy alone between 1999 and 2003 in three different institutes. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and HER2 in primary tumors were centrally retested. Patients with ER-negative and/or HER2-positive tumors and/or with unknown nodal status were excluded from the study subjects. Immunohistochemical analysis of Ki67, HER1, insulin-like growth factor-1 receptor, and aldehyde dehydrogenase-1 was also performed. Prognostic factors were investigated by univariate and multivariate analyses.

Results

A total of 261 patients were the subjects of this study. The median age was 59 years old, the mean tumor size was 1.9 cm, the node-positive rate was 20 %, and 65 % received tamoxifen alone. Distant metastases were observed in 11 patients at a median follow-up of 98 months, and four patients had died of breast cancer at a median follow-up of 99 months. Univariate analysis showed that marked lymphovascular invasion (LVI), PgR negativity, high Ki67 labeling index (LI), and high nuclear grade were significantly worse prognostic factors for distant metastasis. Multivariate analysis revealed that marked LVI [hazard ratio (HR) 21.8] and PgR negativity (HR 10.3) were independently worse prognostic factors for distant metastasis, respectively. Multivariate analysis also revealed that marked LVI (HR 287.3), PgR negativity (HR 25.1), and high Ki67 LI (HR 19.6) were independently worse prognostic factors for breast cancer-specific death, respectively.

Conclusions

The results of this multi-institute cohort study indicated that endocrine therapy alone could not prevent distant metastasis in breast cancer patients with PgR-negative tumors and/or with tumors showing marked LVI or high cell proliferation. These patients may need postoperative adjuvant chemotherapy in addition to endocrine therapy.     

PIK3CA-activating mutations and chemotherapy sensitivity in stage II–III breast cancer

Introduction

In vitro evidence suggests that PIK3CA (phosphatidylinositol 3-kinase, catalytic, alpha polypeptide) activation may be associated with altered chemotherapy sensitivity in cancer.

Methods

Tumor DNA from 140 patients with stage II–III breast cancer undergoing neoadjuvant chemotherapy was sequenced for PIK3CA mutations on exons 1, 9, and 20. Mutation status was correlated with clinical/pathological parameters and chemotherapy response as (a) pathological complete response (pCR) versus residual cancer or (b) quantitative residual cancer burden (RCB) scores, including stratification for estrogen receptor (ER) expression status, type of chemotherapy, and by exons.

Results

Twenty-three patients (16.4%) harbored a PIK3CA mutation, with 12, 11, and 0 mutations located in exons 9, 20, and 1, respectively. PIK3CA exon 9 mutations were more frequent among node-negative (52% versus 25%; P = 0.012) than node-positive tumors, particularly among ER-positive tumors. pCR rates and RCB scores were similar among patients with the wild-type and mutant PIK3CA genes, even after stratification by ER status, chemotherapy regimen (anthracycline versus anthracycline plus paclitaxel), or exon.

Conclusion

PIK3CA mutations are not associated with altered sensitivity to preoperative anthracycline-based or taxane-based chemotherapies in ER-positive and ER-negative breast tumors. In this study, PIK3CA mutation was associated with a decreased rate of node-positive disease, particularly among ER-positive tumors.     

T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers

Introduction

Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.

Methods

Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed.

Results

A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy.

Conclusions

Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.     

Ki-67 as a Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer Patients

Purpose

The objectives of this study were to assess the potential value of Ki-67 in predicting response to neoadjuvant chemotherapy in breast cancer patients and to suggest a reasonable cutoff value for classifying Ki-67 expression.

Methods

This study included 74 breast cancer patients who underwent surgery after anthracycline-based neoadjuvant chemotherapy between 2007 and 2012. We analyzed the clinical and immunohistochemical characteristics using core biopsy specimens obtained before neoadjuvant chemotherapy to determine their correlations with the response to chemotherapy.

Results

A clinical complete response was observed in 6 patients (8.1%); a clinical partial response, in 44 patients (59.5%); and clinical stable disease, in 24 patients (32.4%). A pathologic complete response (pCR) was observed in 10 patients (13.5%). In univariate analysis, estrogen receptor (ER) negativity (p=0.031), human epidermal growth factor receptor 2 (HER2) positivity (p=0.040), and high Ki-67 expression (p=0.036) were predictive factors for a pCR. In multivariate analysis, Ki-67 was the only independent predictor of a pCR (p=0.049). The analysis of Ki-67 values revealed that 25% was a reasonable cutoff value for predicting the response to chemotherapy. In subgroup analysis, a higher Ki-67 value (≥25%) was a significant predictive factor for the response to neoadjuvant chemotherapy, especially in ER-negative and HER2-positive breast cancer patients.

Conclusion

Ki-67 expression in breast cancer tissue may be an effective factor for predicting the response to neoadjuvant chemotherapy. We suggest that a 25% level of Ki-67 expression is a reasonable cutoff value for predicting a response to chemotherapy. Moreover, Ki-67 is a useful predictive factor for pCR, especially in patients with ER-negative and HER2-positive breast cancer.     

A pilot study of the effects of short-term tamoxifen therapy on Ki-67 labelling index in women with primary breast cancer

In this study we demonstrate the change in estrogen receptor (ER) level and cell proliferation in human breast cancer after a short-term tamoxifen therapy. Ten pre- and post-treatment breast tumor samples were examined immunohistochemically using ER and Ki-67 antibodies. Before tamoxifen treatment, six (60%) of ten patients were positive for ER. Tamoxifen increased the ER level in one patient and decreased the level in 4 patients. There was no significant change in ER level by tamoxifen therapy. On the other hand, Ki-67 labelling index (LI) significantly decreased after tamoxifen treatment. When Ki-67 LI was analyzed according to ER level, there was no difference between pre- and post-tamoxifen treatment in ER-negative patients, however, a significant decrease of Ki-67 LI by tamoxifen treatment was seen in ER-positive patients. Patients who showed down-regulation of ER expression tended to show a decrease of Ki-67 LI after tamoxifen therapy. In conclusion, short-term tamoxifen therapy decreased the proliferation of breast cancer, in ER-positive breast tumor samples.     

Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer

Introduction

Although the prognostic significance of proliferation in early invasive breast cancer has been recognized for a long time, recent gene-expression profiling studies have reemphasized its biologic and prognostic value and the potential application of its assessment in routine practice, particularly to define prognostic subgroups of luminal/hormone receptor-positive (HR⁺) tumors. This study aimed to assess the prognostic value of a proliferation assay by using Ki-67 immunohistochemistry as compared with mitotic count scores.

Method

Proliferation was assessed by using Ki-67 labeling index (Ki-67LI) and mitotic scores in a large (n = 1,550) and well-characterized series of clinically annotated primary operable invasive breast cancer with long-term follow-up. Tumors were phenotyped based on their IHC profiles into luminal/HR⁺, HER2⁺, and triple-negative (TN) classes. We used a split-sample development and validation approach to determine the optimal Ki-67LI cut-offs.

Results

The optimal cut-points of Ki-67LI were 10% and 50% for the luminal class. Both Ki7LI and MS were able to split luminal tumors into subgroups with significantly variable outcomes, independent of other variables. Neither mitotic count scores nor Ki-67LI was associated with outcome in the HER2⁺ or the TN classes.

Conclusions

Assessment of proliferation by using Ki-67LI and MS can distinguish subgroups of patients within luminal/hormone receptor-positive breast cancer significantly different in clinical outcomes. Overall, both Ki-67 LI and mitotic-count scores showed comparable results. The method described could provide a cost-effective method for prognostic subclassification of luminal/hormone receptor-positive breast cancer in routine clinical practice.     

Clinicopathological features of young patients (<35 years of age) with breast cancer in a Japanese Breast Cancer Society supported study

Background

To clarify the clinicopathological features of breast cancer in young females, surveillance data of the Registration Committee of the Japanese Breast Cancer Society were analyzed.

Methods

The clinicopathological characteristics were compared between young (<35) patients and non-young (≥35) patients among 109,617 records registered between 2004 and 2009.

Results

The numbers of young and non-young patients were 2,982 (2.7 %) and 106,295 (97.0 %), respectively. The young patients had more cases of a familial history of breast cancer, more subjective symptoms, fewer bilateral tumors, lower BMIs, larger tumors, more positive lymph nodes, fewer instances of an ER-positive status, more instances of an HER2-positive status, more triple-negative tumors and more advanced TNM stages. The young patients more frequently received neoadjuvant chemotherapy and breast-conserving therapy (BCT) compared with the non-young patients. Eighty percent of all patients received adjuvant therapy. The young patients were more frequently treated with chemotherapy, molecular targeted therapy and radiation therapy than the non-young patients.

Conclusions

In this study, young patients with breast cancer were diagnosed at more advanced stages and had more endocrine-unresponsive tumors than non-young patients. Further prognostic analyses should be conducted in this cohort.     

Clinical response after two cycles compared to HER2, Ki-67, p53, and bcl-2 in independently predicting a pathological complete response after preoperative chemotherapy in patients with operable carcinoma of the breast

Introduction

To investigate the predictive value of clinical and biological markers for a pathological complete remission after a preoperative dose-dense regimen of doxorubicin and docetaxel, with or without tamoxifen, in primary operable breast cancer.

Methods

Patients with a histologically confirmed diagnosis of previously untreated, operable, and measurable primary breast cancer (tumour (T), nodes (N) and metastases (M) score: T2-3(≥ 3 cm) N0-2 M0) were treated in a prospectively randomised trial with four cycles of dose-dense (bi-weekly) doxorubicin and docetaxel (ddAT) chemotherapy, with or without tamoxifen, prior to surgery. Clinical and pathological parameters (menopausal status, clinical tumour size and nodal status, grade, and clinical response after two cycles) and a panel of biomarkers (oestrogen and progesterone receptors, Ki-67, human epidermal growth factor receptor 2 (HER2), p53, bcl-2, all detected by immunohistochemistry) were correlated with the detection of a pathological complete response (pCR).

Results

A pCR was observed in 9.7% in 248 patients randomised in the study and in 8.6% in the subset of 196 patients with available tumour tissue. Clinically negative axillary lymph nodes, poor tumour differentiation, negative oestrogen receptor status, negative progesterone receptor status, and loss of bcl-2 were significantly predictive for a pCR in a univariate logistic regression model, whereas in a multivariate analysis only the clinical nodal status and hormonal receptor status provided significantly independent information. Backward stepwise logistic regression revealed a response after two cycles, with hormone receptor status and lymph-node status as significant predictors. Patients with a low percentage of cells stained positive for Ki-67 showed a better response when treated with tamoxifen, whereas patients with a high percentage of Ki-67 positive cells did not have an additional benefit when treated with tamoxifen. Tumours overexpressing HER2 showed a similar response to that in HER2-negative patients when treated without tamoxifen, but when HER2-positive tumours were treated with tamoxifen, no pCR was observed.

Conclusion

Reliable prediction of a pathological complete response after preoperative chemotherapy is not possible with clinical and biological factors routinely determined before start of treatment. The response after two cycles of chemotherapy is a strong but dependent predictor. The only independent factor in this subset of patients was bcl-2.

Trial registration number

NCT00543829     

Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER-negative/progesterone receptor-positive breast cancers

We examined estrogen receptor (ER) mRNA expression and molecular subtypes in stage I–III breast cancers that are progesterone receptor (PR) positive but ER and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization. The ER, PR, and HER2 status was determined by IHC as part of routine clinical assessment (N = 501). Gene expression profiling was done with the Affymetrix U133A gene chip. We compared expressions of ESR1 and MKI67 mRNA, distribution of molecular subtypes by the PAM50 classifier, the sensitivity to endocrine therapy index, and the DLDA30 chemotherapy response predictor signature among ER/PR-positive (n = 223), ER-positive/PR-negative (n = 73), ER-negative/PR-positive (n = 20), and triple-negative (n = 185) cancers. All patients received neoadjuvant chemotherapy with an anthracycline and taxane and had adjuvant endocrine therapy only if ER or PR > 10 % positive. ESR1 expression was high in 25 % of ER-negative/PR-positive, in 79 % of ER-positive/PR-negative, in 96 % of ER/PR-positive, and in 12 % of triple-negative cancers by IHC. The average MKI67 expression was significantly higher in the ER-negative/PR-positive and triple-negative cohorts. Among the ER-negative/PR-positive patients, 15 % were luminal A, 5 % were Luminal B, and 65 % were basal like. The relapse-free survival rate of ER-negative/PR-positive patients was equivalent to ER-positive cancers and better than the triple-negative cohort. Only 20–25 % of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers. In this rare subset of patients (i) a second RNA-based assessment may help identifying the minority of ESR1 mRNA-positive, luminal-type cancers and (ii) the safest clinical approach may be to consider both adjuvant endocrine and chemotherapy.     

Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Introduction

We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy.

Methods

Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX^® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0–2.5, 0–5, 5-10 years.

Results

In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0–2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results.

Conclusions

Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.     

Predictive factors for the effectiveness of neoadjuvant chemotherapy and prognosis in triple-negative breast cancer patients

Purpose

Triple-negative breast cancers (TNBCs) do not derive benefit from molecular-targeted treatments such as endocrine therapy or anti-HER2 therapy because they lack those molecular targets. On the other hand, TNBCs have been shown to respond to neoadjuvant chemotherapy (NAC). In this study, we analyzed TNBC patients who were treated with NAC at Osaka National Hospital over a recent 5-year period to clarify the predictive factors for NAC and prognostic factors.

Patients and methods

Thirty-three TNBC patients underwent sequential NAC with anthracycline (FEC100: 5FU 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m²/q3w, 4 courses) and taxanes (paclitaxel 80 mg/m²/qw, 12 courses or docetaxel 75 mg/m²/q3w, 4 courses) from May 2003 to July 2008. Pre-therapeutical and surgical specimens were studied for expressions of ER, PgR, HER-2, EGFR, cytokeratin 5/6, Ki-67, p53 and androgen receptor by immunohistochemistry (IHC). We analyzed clinicopathological factors and molecular markers in regard to the response to NAC and prognosis.

Results

Pathological complete response (pCR) was achieved in 12 TNBC patients (36%). The pCR rate in the basal-like phenotype was significantly lower than in the non-basal-like phenotype (23 vs. 64%, respectively: P = 0.02). High pre-operative expressions of Ki-67 (≥50%) and HER-2 (2+) were considered as predictive factors for a better response from NAC. Pre-operative Ki-67 expression showed a significant correlation with disease-free survival (DFS) and a lower expression of Ki-67 (<50%) after NAC was favorable for DFS among non-pCR patients.

Conclusions

A non-basal-like phenotype and higher expressions of Ki-67 and HER-2 (2+) were favorable factors for NAC. However, a higher expression of Ki-67 on the surgical specimen after NAC was also a poor prognostic factor.     

Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes

BACKGROUND: Uncertainty about prognosis and treatment of axillary lymph node-negative patients with estrogen receptor (ER)-negative or ER-positive invasive breast tumors of 1 cm or less prompted the analysis of data from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. METHODS: Two hundred thirty-five patients with ER-negative tumors and 1024 patients with ER-positive tumors were identified in these trials. Patients with ER-negative tumors received surgery alone or surgery and chemotherapy. Patients with ER-positive tumors received surgery alone; surgery and tamoxifen; or surgery, tamoxifen, and chemotherapy. End points were relapse-free survival (RFS), event-free survival, and overall survival. A result was considered to be statistically significant with a P value of.05 or less; all statistical tests were two-sided. RESULTS: The 8-year RFS of women with ER-negative tumors who received surgery alone or with chemotherapy was 81% and 90%, respectively (P = .06). Survival was similar in both groups (93% and 91%; P = .65). The 8-year RFS of women with ER-positive tumors was 86% after surgery alone, 93% when tamoxifen was added (P = .01), and 95% after the addition of tamoxifen and chemotherapy (P = .07 compared with tamoxifen). Survival in the three groups was 90%, 92% (P = .41), and 97%, respectively. The difference between the latter two groups was significant (P = .01). Regardless of ER status or treatment, overall mortality was 8%; one half of the deaths were related to breast cancer. Several covariates affected the risk of recurrence in ER-negative and ER-positive patients. Risk was greater in women with tumors of 1 cm than in those with tumors of less than 1 cm, in women aged 49 years or younger than in those aged 50 years or older, and in women with infiltrating ductal or lobular carcinoma than in those with other histologic tumor types. CONCLUSIONS: Chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes.     

Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers

Background

Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined.

Methods

A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically.

Results

Ki67 expression levels after NAC (median 5 %, range 0–70 %) were significantly reduced compared with before NAC (25, 1–80 %, P < 0.0001), but only in patients who attained clinical response. This significant suppression of Ki67 in clinical responders was consistently observed in breast cancers from the ER-positive subset, but not the ER-negative subset in the total test set (n = 120). These observations were also made in the validation set (n = 63). Among premenopausal, but not postmenopausal patients, a significant decrease in PgR expression levels was detected in breast cancers of patients who attained clinical response (pre-NAC 50, 0–100 %, post-NAC 5, 0–20 %; P = 0.0003).

Conclusion

The impact of Ki67 suppression on clinical response seems to be restricted to ER-positive breast cancers. Since PgR expression levels of premenopausal ER-positive cancers were significantly reduced in clinical responders, inhibition of estrogen signaling due to chemotherapy-induced amenorrhea may be involved in this association.

     

A genome-wide association scan on estrogen receptor-negative breast cancer

Introduction

Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.

Methods

We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.

Results

Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer.

Conclusions

ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers.     

Classical markers like ER and ki-67, but also survivin and pERK, could be involved in the pathological response to gemcitabine, adriamycin and paclitaxel (GAT) in locally advanced breast cancer patients: results from the GEICAM/2002-01 phase II study

Introduction

The identification and validation of biomarkers of chemotherapy sensitivity is critical in order to individualise therapy in breast cancer. We evaluated pathological complete response (pCR) to GAT, and its correlation with tumour biomarkers before and after neoadjuvant chemotherapy.

Materials and methods

Stage III (and stage II with T??5 cm) breast cancer patients were included. Treatment consisted of adriamycin (40 mg/m²) day 1, and paclitaxel (150 mg/m²) followed by gemcitabine (2000 mg/m²) day 2, every 14 days for six cycles. Tissue from pre-treatment biopsy and surgery was evaluated for biologic markers by immunohistochemistry. Two XPD single nucleotide polymorphisms (SNP) were also analysed.

Results

Forty-six patients entered the trial. Median age was 49.5 years (range 31?C72); 25 patients (54%) were pre-menopausal; 12 (26%) were ER-PgR-negative; pCR was observed in 17% (95% CI: 6.4?C28.4) of patients. Significant differences in marker expression (mean±SD) in correlation to pathological response were only found in Ki-67. After treatment, tumours showed lower Ki-67-, surviving- and pERK-positive cells. No correlation between XPD polymorphisms and pCR was found. The overall response rate was 89% (95% CI: 80.1?C98.1). Fifteen patients (33%) underwent breast-conserving surgery. The most frequent grade 3 or 4 toxicities were neutropenia (with one febrile neutropenia) and asthenia.

Conclusion

These results show an effective regimen with acceptable tolerability. Our data suggest that not only classical markers (ER, Ki-67), but also survivin and pERK could be involved in the response to GAT, which may contribute to therapy individualisation in future study designs.     

Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment

Introduction

Circulating tumor cells (CTCs) represent an independent predictor of outcome in patients with metastatic breast cancer (MBC). We assessed the prognostic impact of CTCs according to different first-line systemic treatments, and explored their potential predictive value in MBC patients.

Methods

We retrospectively evaluated 235 newly diagnosed MBC patients, treated at the University of Texas MD Anderson Cancer Center. All patients had a baseline CTC assessment performed with CellSearch^®. Progression-free survival and overall survival were compared with the log-rank test between groups, according to CTC count (< 5 vs. ≥ 5) and type of systemic therapy. We further explored the predictive value of baseline CTCs in patients receiving different treatments.

Results

At a median follow-up of 18 months, the CTC count was confirmed to be a robust prognostic marker in the overall population (median progression-free survival 12.0 and 7.0 months for patients with CTC < 5 and ≥ 5, respectively; P < 0.001). Conversely, in patients with human epidermal growth factor receptor-2-overexpressed/amplified tumors receiving trastuzumab or lapatinib, the baseline CTC count was not prognostic (median progression-free survival 14.5 months for patients with CTC < 5 and 16.1 months for those with CTC ≥ 5; P = 0.947). Furthermore, in patients with human epidermal growth factor receptor-2 normal tumors, a baseline CTC count ≥ 5 identified subjects who derived benefit from more aggressive treatments, including combination chemotherapy and chemotherapy plus bevacizumab.

Conclusions

This analysis suggests that the prognostic information provided by CTC count may be useful in patient stratifications and therapeutic selection, particularly in the group with positive CTCs, in which various therapeutic choices may procure differential palliative benefit.