Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer

The aim of this study was to ascertain if oestrogen receptor (ER) status predicts for pathological complete response (pCR) to neoadjuvant chemotherapy in operable breast cancer, and the effects of pCR on survival. Using a single-institution database, 435 patients were identified, who received neoadjuvant chemotherapy for operable breast cancer and were eligible for the analysis. Patients whose tumours were ER negative were more likely to achieve a pCR than patients who were ER positive (21.6 vs 8.1%, P<0.001). Owing to a strong correlation between ER status and grade, these variables were not shown to be independent predictors of pCR. Overall survival (OS) was better in those patients who achieved a pCR compared to those who did not (5-year OS 91 vs 73%; P=0.02). This was still the case when only patients with ER-negative tumours were examined (5-year OS 90 vs 52%, P=0.005), but not in the subset of patients with ER-positive tumours (5-year OS 93 vs 79%; P=0.3). Therefore, patients with ER-negative tumours were found to be more likely to achieve a pCR to neoadjuvant chemotherapy than those with ER-positive tumours, and pathological response did not have prognostic significance in patients with ER-positive tumours.     

HER2 and response to anthracycline-based neoadjuvant chemotherapy in breast cancer

BackgroundThe predictive role of human epidermal growth factor receptor 2 (HER2) to adjuvant anthracycline-based chemotherapy remains controversial. Here, we investigated the association between HER2 status and pathological response in breast cancer patients who received neoadjuvant anthracycline-based regimens.Patients and methodsWomen (n = 538) with operable primary breast cancer received neoadjuvant anthracycline-based chemotherapy. Pathological complete response (pCR) was defined as no invasive breast tumor cells in breast after completion of neoadjuvant chemotherapy. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core biopsy breast cancer tissue obtained before initiation of neoadjuvant chemotherapy.ResultsIn this cohort of 538 patients, 23.9% of patients achieved a pCR in their breast. HER2-positive tumors had a lower rate of pCR than did HER2-negative tumors (14.7% versus 25.7%, P = 0.013); negative HER2 status remained as an independent favorable predictor of pCR after adjusted for age, estrogen receptor, progesterone receptor, tumor size, chemotherapy cycles, and tumor grade in a multivariate analysis (odds ratio = 3.14; 95% confidence interval = 1.60–6.16, P = 0.001). Furthermore, patients with a pCR had a higher 3-year disease-free survival (DFS) rate than did patients without a pCR (P = 0.007).ConclusionWomen with HER2-negative breast cancers rather than HER2-positive tumors benefit from anthracycline-based neoadjuvant chemotherapy.     

Relationship between oestrogen receptor status and proliferation in predicting response and long-term outcome to neoadjuvant chemotherapy for breast cancer

Oestrogen receptor (ER) negative breast cancers are more likely to achieve a pathological complete response (pCR) to neoadjuvant chemotherapy compared to those with ER positive tumours. ER positive tumours exhibit low proliferation and ER negative cancers high proliferation. The aim of this study was to determine to what extent the better response of ER negative cancers correlates with proliferation rate. A retrospective analysis of a prospectively maintained database identified 175 neoadjuvant chemotherapy patients with tissue available for Ki67 analysis. On univariate analysis, pre-therapy Ki67 (P = 0.04), ER status (P = 0.002), HER2 status (P = 0.004) and grade (P = 0.0009) were associated with a pCR. In a multivariate model, HER2 was the only significant predictor of pCR. No significant relationship between pre-therapy Ki67 and relapse-free and overall survival was demonstrated. Ki67 is not an independent predictor of clinical CR or pCR. Aspects of ER status beyond its inverse relationship with proliferation may contribute to its predictive value for pCR.     

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Background:

Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment.

Methods:

We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed.

Results:

pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P<0.0001). DFS also differed significantly between patients receiving adjuvant trastuzumab or not (hazard ratio=4.84, 95% CI (2.52; 9.31), P<0.001). We analysed 199 patients given neoadjuvant and adjuvant trastuzumab. Multivariate analysis identified older age and hormone receptor-negative tumours as independent predictors of pCR. T stage (hazard ratio=2.55, 95% CI (1.01; 6.48), P=0.05) and strict pCR (hazard ratio=9.15, 95% CI (1.22; 68.83), P=0.03) were independent predictors of DFS. The latter association was significant in the HR-negative subgroup (P=0.02) but not in the HR-positive subgroup (P=0.12).

Conclusions:

Major pCR and DFS gains in HER2-positive BC were observed since ‘trastuzumab'' era. Further improvements rely on the enrollment of accurately selected patients into clinical trials.     

Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer

BackgroundAlthough 1% has been used as cut-off for estrogen receptor (ER) positivity, several studies have reported that tumors with ER < 1% have characteristics similar to those with 1% ≤ ER < 10%. We hypothesized that in patients with human epidermal growth factor 2 (HER2)-negative breast cancer, a cut-off of 10% is more useful than one of 1% in discriminating for both a better pathological complete response (pCR) rate to neoadjuvant chemotherapy and a better long-term outcome with adjuvant hormonal therapy. Our objectives were to identify a percentage of ER expression below which pCR was likely and to determine whether this cut-off value can identify patients who would benefit from adjuvant hormonal therapy.Patients and methodsPatients with stage II or III HER2-negative primary breast cancer who received neoadjuvant chemotherapy followed by definitive surgery between June 1982 and June 2013 were included. Logistic regression models were used to assess the association between each variable and pCR. Cox models were used to analyze time to recurrence and overall survival. The recursive partitioning and regression trees method was used to calculate the cut-off value of ER expression.ResultsA total of 3055 patients were analyzed. Low percentage of ER was significantly associated with high pCR rate (OR = 0.99, 95% CI = 0.986–0.994,P<0.001). The recommended cut-off of ER expression below which pCR was likely was 9.5%. Among patients with ER ≥ 10% tumors, but not those with 1%≤ER < 10% tumors, adjuvant hormonal therapy was significantly associated with long time to recurrence (HR = 0.24, 95% CI = 0.16–0.36,P<0.001) and overall survival (HR = 0.32, 95% CI = 0.2–0.5,P<0.001).ConclusionStage II or III HER2-negative primary breast cancer with ER < 10% behaves clinically like triple-negative breast cancer in terms of pCR and survival outcomes and patients with such tumors may have a limited benefit from adjuvant hormonal therapy. It may be more clinically relevant to define triple-negative breast cancer as HER2-negative breast cancer with <10%, rather than <1%, of ER and/or progesterone receptor expression.     

Impact of clinicopathological characteristics on the efficacy of neoadjuvant therapy in patients with human epidermal growth factor receptor‐2‐positive breast cancer

Neoadjuvant therapy has become increasingly common in human epidermal growth factor receptor‐2 (HER2)‐positive breast cancer. In this study, we examined the impact of different clinicopathological characteristics on pathological complete response (pCR) in patients treated with anti‐HER2 agents. The PubMed and Embase databases were searched from inception through April 2017 to identify studies that met pre‐specified criteria. The odds ratios (ORs) and 95% confidence intervals (CIs) were extracted directly or were calculated with other available information. Eleven randomized controlled trials (RCTs) that involved 3,269 HER2‐positive women were included in this meta‐analysis. Patients with hormone receptor (HR)‐negative breast cancer benefited more from anti‐HER2 therapy than did patients with HR‐positive tumours (OR, 2.25; 95% CI, 1.93‐2.62). Furthermore, this improvement in pCR was independent of anti‐HER2 agents, phase, combined chemotherapy, neoadjuvant duration, year the trials started and region where the trials were conducted. Patients with small tumours achieved greater benefits than patients with large tumours (OR, 1.25; 95% CI, 1.00‐1.55). Age did not predict an additional benefit from anti‐HER2 neoadjuvant treatment (OR, 1.02; 95% CI, 0.73‐1.45). The impact of nodal status on pCR was dependent on the anti‐HER2 agents. In conclusion, for HER2‐targeted neoadjuvant treatment in breast cancer, greater benefits were achieved in patients with small HR‐negative tumours compared with patients with large HR‐positive tumours. These results may improve drug development and treatment strategies, economic analyses and the design and interpretation of clinical trials.     

A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients

Purpose

HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients.

Methods

We selected clinical trials of neoadjuvant chemotherapy?±?anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR.

Results

Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy?±?anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher’s exact test p?=?0.015). The area under the ROC curve (AUC) was 0.62 (p?=?0.005). In the 303 ER-negative (ER?)/HER2+ patients treated with chemotherapy?±?anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group.

Conclusions

Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy?±?anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.

     

SerpinB3, a new prognostic tool in breast cancer patients treated with neoadjuvant chemotherapy

It is unclear which patients with breast cancer benefit from anthracycline-based neoadjuvant chemotherapy and whether taxanes increase survival. Hsp70 and serpinB3 inhibit a lysosomal cell death pathway induced in anthracycline and taxane treated cells, which may be critical for breast cancer cell survival. Thus we evaluated serpinB3 and Hsp70 as putative prognostic biomarkers in breast cancer patients treated with neoadjuvant chemotherapy. SerpinB3 and Hsp70 were measured by immunohistochemistry in residual breast tumours of patients without a complete pathological response [pCR] (n = 250), from a retrospective cohort of 296 patients treated with anthracycline-based chemotherapy with or without sequential docetaxel prior to surgical resection. SerpinB3 (P = 0.02) and Hsp70 (P = 0.008) positivity in residual tumour were associated with a poor pathological response and serpinB3 was an independent prognostic biomarker (HR 2.1 (95% CI 1.2–3.8), P = 0.02). Docetaxel significantly improved overall survival of breast cancer patients treated with neoadjuvant chemotherapy. Furthermore, serpinB3 positivity predicted poor survival in patients treated with anthracycline-based chemotherapy alone (P = 0.02), but those with serpinB3 negative tumours had as equally good survival as those also treated with docetaxel (P = 0.7). Survival was independent of serpinB3 expression in patients who received sequential docetaxel. The Nottingham prognostic index (NPI), calculated at surgical resection, predicted overall survival in these neoadjuvantly treated patients (P < 0.001) and serpinB3 status segregated patients with a moderate NPI into distinct prognostic subgroups. The use of clinical (NPI) and molecular (serpinB3) biomarkers measured at surgical resection to provide accurate prognostication in patients who do not achieve a pCR following neoadjuvant chemotherapy could facilitate optimal post-operative clinical management of these patients and is of significant clinical value. Furthermore, serpinB3 status in residual tumour is a biomarker of neoadjuvant docetaxel benefit in patients not achieving a pCR and use of serpinB3 molecular subtyping for adjuvant docetaxel treatment planning warrants further investigation.     

Semi-quantitative evaluation of estrogen receptor expression is a strong predictive factor of pathological complete response after anthracycline-based neo-adjuvant chemotherapy in hormonal-sensitive breast cancer

Absence of hormonal receptors (HR) expression is a predictive factor of high pathologic complete response (pCR) rate after neo-adjuvant chemotherapy. However, HR-positive tumors are less chemosensitive. In the present study, we evaluated the predictive value of estrogen (ER) and progesterone (PgR) semi-quantitative expression in patients with HR-positive tumors treated uniformly with antracycline-based neoadjuvant chemotherapy without hormonal treatment. Value of HR expression as a predictive factor was then evaluated in a multivariate analysis with tumor grade, Ki67 index and HER2 expression. From January 2000 and December 2006, 177 patients with HR-positive breast ductal invasive carcinoma ≥2 cm in its largest diameter were treated with six cycles of an anthracycline-based neo-adjuvant chemotherapy. Tumor grade, ER, PgR, HER2 status and Ki67 index were determined on microbiopsy performed before chemotherapy. A semi-quantitative evaluation of ER and PgR expression by IHC was performed using the Barnes’score. pCR rate was significantly different (P < 0.001) according to the ER expression score. pCR rate was 28% for low score, 9% for medium score and 3% for high score. On the contrary, pCR rate was not significantly different (P = 0.49) according to the PgR expression score. In the multivariate analysis, ER expression score (P = 0.0002) and Ki67 index (P = 0.02) were the only predictive factors of response for HR-positive tumors. pCR after anthracycline-based chemotherapy is significantly correlated with the ER expression score.     

HER2 expression and efficacy of preoperative paclitaxel/FAC chemotherapy in breast cancer

Purpose We examined the correlation between HER2 expression and pathologic complete response (pCR) to paclitaxel/FAC (T/FAC) preoperative chemotherapy in breast cancer. Patients and Methods Retrospective analysis of data including 534 patients treated with preoperative T/FAC was performed. Gene expression results were available from two datasets of 132 and 286 patients, and were used to examine the co-expression of HER2 and topoisomerase II α (TOP2A) and microtubule associated protein tau (MAP-Tau). Results Of the 534 patients, 105 (20%) had HER2-overexpressing breast cancer. The pCR rates were 33% and 15% for patients with HER2+ and HER2- tumors (P < 0.001). The 5-year relapse-free survival rates were 94% and 70% in HER2+ tumors with and without pCR (P = 0.009). HER2 overexpression (odds ratio 2.3, 95%CI: 1.3–3.9, P = 0.004), estrogen receptor (ER) status, grade and weekly schedule of paclitaxel were each significantly and independently associated with pCR in multivariate analysis. When patients were stratified by ER status, the pCR rates were 50% for HER2+/ER−, 30% for HER2−/ER−, 19% for HER2+/ER+, and 6% for HER2−/ER+ tumors. HER2 overexpression was associated with lower expression of MAP-tau (P = 0.001 and P < 0.001) and higher expression of TOP2A mRNAs (P = 0.048 and P = 0.001) in patients with ER+ disease. ER− cancers had low MAP-tau expression regardless of HER-status. Conclusion HER2 overexpression is associated with higher rate of pCR to preoperative T/FAC chemotherapy regardless of ER status. HER2 overexpression also correlates with increased TOP2A and decreased MAP-tau expression in ER-positive cancers.     

Clinical validation of the EndoPredict test in node-positive,chemotherapy-treated ER+/HER2? breast cancer patients: results from the GEICAM 9906 trial

Introduction

EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2− BC patients in the GEICAM 9906 trial.

Methods

The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor–positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression.

Results

The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2− cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant.

Conclusions

EP is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone.     

Prognostic and therapeutic implications of distinct kinase expression patterns in different subtypes of breast cancer

Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 7 in HER2(+), and 28 in ER(-)/HER2(-) cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER(-)/HER2(-) cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER(+)/HER2(-) cancers, but not in ER(-)/HER2(-) or HER2(+) cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER(+)/HER2(-) and HER2(+) tumors and also predicted higher probability of pCR in HER2(+) cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype.     

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.     

Long-term outcome of the REMAGUS 02 trial,a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status

BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.     

The Case to Case Comparison of Hormone Receptors and HER2 Status between Primary Breast Cancer and Synchronous Axillary Lymph Node Metastasis

Background: Nowadays, the adjuvant treatment for breast cancer patients chosen depends on immunohistochemical pattern of Estrogen receptor(ER), Progesterone receptor(PR) and HER2 status of primary breast tumor. Several retrospective studies showed significant discordance in receptor expression between primary and metastatic tumors. The objective of this research was to determine discordant rate of ER, PR and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis of individual breast cancer patients in Thammasat University Hospital. Methods: A prospective observational study of all breast cancer patients who have axillary metastasis and underwent surgery at Thammasat Hospital between January 2011 to December 2015. Tumor staging, ER, PR, and HER2 status on primary breast tumor were recorded. Synchronous axillary lymph node metastasis was evaluated with immunohistochemistry for ER, PR, and HER2. Results: The ER-positive rate from primary tumor to synchronous axillary lymph node metastasis decreased from 74.7% to 71.7%; the HER2 overexpression rate was decreased from 26% to 24%. In contrast, PR positive rate were 71% in both primary tumor and synchronous axillary lymph node metastasis. In case to case comparison, discordance rate of ER, PR and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis were 11.1%, 20.2% and 10.1%, respectively. Furthermore, the tumor staging was not significant associated with discordance of ER, PR and HER2. Conclusion: ER, PR and HER 2 biomarkers showed significant concordance between primary tumor and synchronous axillary lymph node metastasis. Hence, if we cannot assess the ER, PR and HER2 status in primary tumor, then synchronous axillary lymph node metastasis can be studied instead. However, the repeat of biomarker testing in node-positive breast cancer patients may be beneficial for tailored adjuvant therapy, especially for patients with negative hormone receptor and/or HER2 profile on primary tumor.     

Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21 755 patients from the Japanese breast cancer registry

BackgroundWe investigate rates of pathologic complete response (pCR) and tumor expression of ER, PgR, HER2 discordance after neoadjuvant chemotherapy using Japanese breast cancer registry data.Patients and methodsRecords of more than 300 000 breast cancer cases treated at 800 hospitals from 2004 to 2013 were retrieved from the breast cancer registry. After data cleanup, we included 21 755 patients who received neoadjuvant chemotherapy and had no distant metastases. pCR was defined as no invasive tumor in the breast detected during surgery after neoadjuvant chemotherapy. HER2 overexpression was determined immunohistochemically and/or using fluorescence in situ hybridization.ResultspCR was achieved in 5.7% of luminal tumors (n = 8730), 24.6% of HER2-positive tumors (n = 4403), and 18.9% of triple-negative tumors (n = 3660). Among HER2-positive tumors, pCR was achieved in 31.6% of ER-negative tumors (n = 2252), 17.0% of ER-positive ones (n = 2132), 31.4% of patients who received trastuzumab as neoadjuvant chemotherapy (n = 2437), and 16.2% of patients who did not receive trastuzumab (n = 1966). Of the 2811 patients who were HER2-positive before treatment, 601 (21.4%) had HER2-negative tumors after neoadjuvant chemotherapy, whereas 340 (3.4%) of the 9947 patients with HER2-negative tumors before treatment had HER2-positive tumors afterward. Of the 10 973 patients with ER-positive tumors before treatment, 499 (4.6%) had ER-negative tumors after neoadjuvant chemotherapy, whereas 519 (9.3%) of the 5607 patients who were ER-negative before treatment had ER-positive tumors afterward.ConclusionWe confirmed that loss of HER2-positive status can occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer. We also confirmed that in practice, differences in pCR rates between breast cancer subtypes are the same as in clinical trials. Our data strongly support the need for retest ER, PgR, HER2 of surgical sample after neoadjuvant therapy in order to accurately determine appropriate use of targeted therapy.     

超声及钼靶对乳腺癌新辅助化疗后腋窝淋巴结状态的诊断价值评估

目的:评估乳腺癌新辅助化疗(neoadjuvant chemotherapy,NAC)后腋窝淋巴结的变化,探讨超声及钼靶在NAC疗效评价中的应用价值。方法:对我院176例经穿刺病理证实为腋窝淋巴结转移的乳腺癌患者行NAC,所有患者NAC前后均行彩超与钼靶检查,对比两种检查的灵敏度、特异度及准确率。评价NAC后腋窝淋巴结的状态,并评估临床缓解与病理完全缓解（pathological complete response,pCR）的相关性。结果:NAC后超声、钼靶及两者联合评估的灵敏度分别为:79.4%、76.6%、86.5%;特异度分别为:68.6%、51.4%、71.4%;准确率分别为:77.3%、71.6%、83.5%;较NAC前超声、钼靶及两者联合评估的灵敏度、特异度及准确率明显下降,阳性预测价值最高的为两者联合检查（92.4%）。NAC后超声图像评估44例达到临床完全缓解,其中25（25/44,56.8%）例患者经病理证实达到pCR,NAC后超声检查评估pCR的灵敏度为71.4%,特异度为86.5%,准确率为83.5%。结论:超声诊断NAC后腋窝淋巴结转移较钼靶诊断灵敏度、特异度及准确率高,具有重要的临床诊断价值,但尚存局限性,对手术及术后治疗的指导性仍需进一步研究。     

TOP2A amplification in breast cancer is a predictive marker of anthracycline-based neoadjuvant chemotherapy efficacy

Anthracycline is a DNA topoisomerase 2-α (TOP2A) inhibitor and its concomitant over expression with Human Epidermal Growth Factor Receptor 2 (HER2) was investigated of being predictive for the response to anthracycline-based chemotherapies in breast cancer. 309 early and local advanced breast cancer patients were treated with anthracycline-based neoadjuvant chemotherapies in intense dose dense (IDD) (CE, Cyclophosphamide?+?Epirubicin) or conventional (TE, Paclitaxel?+?Epirubicin) regimens. HER2 proteins were qualitatively analyzed by immunohistochemistry (IHC) of primary tumor core biopsies, and TOP2A gene amplification levels of HER2 over-expressing cases were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Overall pathological complete response rate (pCR) was achieved in 14.3?%. HER2 was over expressed in 80/309 (25.9?%) cases, of which 61/80 cases have been tested for their TOP2A status. Over expression of HER2 was significantly positively correlated with higher pCR rates compared to low HER2 expression (27.5?% vs. 9.6?%, P?相似文献   

Neoadjuvant chemotherapy in ER+ HER2− breast cancer: response prediction based on immunohistochemical and molecular characteristics

A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy in estrogen receptor-positive (ER+) HER2-negative (HER2−) tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be spared neoadjuvant chemotherapy, we tested standard pathology and molecular markers in ER+ HER2− breast tumors. Pretreatment biopsies were available from 211 ER+ HER2− tumors, who had been treated with neoadjuvant chemotherapy (adriamycin/cyclophosphamide). mRNA expression data were available for 132 tumors. We determined progesterone receptor expression (PR), endocrine sensitivity, HER2 expression, histology, proliferation, and molecular subtypes. We correlated these data to chemotherapy response using pCR rates and the previously published neoadjuvant response index (NRI). PR-negative tumors (n = 65, 30.8%) and luminal B type tumors (n = 43, 20.4%) responded significantly better to chemotherapy than other tumors. These associations remained significant in multivariate analysis. However, even in the subgroup of patients with the lowest response rate, comprising tumors that had both a positive-PR expression and the luminal A subtype (n = 58, 44%), the majority of the patients had downstaging because of chemotherapy. For histology (lobular vs. ductal), endocrine sensitivity, and proliferation, no associations with chemotherapy response were observed. Gene expression array analysis resulted in 28 significant genes (FDR < 0.1). PR expression and luminal B status are associated with a better response to neoadjuvant chemotherapy. However, both markers had only weak response predictive power, and it was not possible to identify a subgroup with no or only minimal chemotherapy benefit. Therefore, the decision to refrain from neoadjuvant chemotherapy to ER+ HER2− breast tumors should not be based on predictive markers, but exclusively on estimates of prognosis.