Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment

Background:

The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC).

Methods:

One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively.

Results:

Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ⩽20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ⩽20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS.

Conclusion:

HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.     

PI3K inhibitors in trastuzumab-resistant HER2-positive breast cancer cells with PI3K pathway alterations

The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.     

Expression of truncated HER2 and its prognostic value in HER2-positive breast cancer patients

Purpose

The purpose of this work was to assess the truncated form of human epidermal growth factor receptor 2 (HER2) such as p95-HER2 expression in HER2-positive breast cancer (BC) patients who developed metastatic disease after adjuvant treatment with a trastuzumab-containing regimen.

Risk factors for brain relapse in HER2-positive metastatic breast cancer patients

Brain relapse is a common occurrence in HER2-positive breast cancer patients. However, the factors determining the risk of brain metastasis in these patients remain to be established. The aim of this study was to assess the impact of particular clinical and pathological factors on the risk of brain relapse in HER2-positive advanced breast cancer patients. The study group included 264 consecutive HER-2 positive metastatic breast cancer patients, most of whom (210; 80%) were administered trastuzumab, usually in combination with chemotherapy. Time from the diagnosis to distant relapse ranged from 0 to 142 months (median 16 months). The most common dominant site of metastatic disease was viscera (80%), followed by soft tissue (11%) and bones (10%). After a median follow-up of 3.1 years, the symptomatic brain relapse occurred in 103 patients (39%). Median time from treatment dissemination to brain relapse was 15 months (range, 0–81 months), and the cumulative 1-year, 3-year and 5-year risk of brain relapse was 17, 42 and 55%, respectively. The average annual risk of brain relapse for surviving patients during consecutive 7 years of follow-up was 10.0% (95% CI, 6.6–13.5%). In the univariate analysis the only variable significantly related to the increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03–2.33, P = 0.034). Patients with dominant site of disease in soft tissue or bones tended to have lower risk of relapse (HR = 0.54 and 0.62; P = 0.098 and 0.203, respectively) compared to patients with visceral metastases. Treatment with trastuzumab was not associated with reduced risk of brain relapse (HR = 0.91, 95% CI, 0.47–1.77, P = 0.78). In the multivariate analysis, time from initial diagnosis to distant relapse shorter than 2 years remained the only significant variable related to increased risk of brain relapse (adjusted HR = 1.62, 95% CI, 1.07–2.44; P = 0.022). HER2-positive breast cancer patients remain at high and continuous risk of brain relapse for a prolonged period of time after diagnosis of disease dissemination. Short time from initial diagnosis to distant relapse is related to increased risk of brain relapse. Molecular predictors are sorely needed to better characterize patients with high probability of early brain relapse. Presented in part in oral form at the 2007 European Cancer Conference, Barcelona, Spain.     

Efficacy and safety of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer

Purpose We retrospectively evaluated the efficacy and safety of combination therapy of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer (MBC). Methods Patients with HER2-positive MBC who had been administered the combination therapy between July 2003 and July 2006 at the Cancer Institute Hospital, Tokyo, were retrospectively reviewed. Capecitabine (828 mg/m²) was given twice daily for 3 weeks followed by a 1-week rest period; this was repeated every 4 weeks. Trastuzumab was given at 4 mg/kg as an initial loading dose intravenously, followed by 2 mg/kg weekly. We investigated objective response rate (ORR), clinical benefit rate (CBR), and time-to-treatment failure (TTF) according to the Response Evaluation Criteria in Solid Tumors guidelines. Adverse events were graded according to the National Cancer Institute, Common Toxicity Criteria, version 3.0. Results A total of 49 patients were assessed and median follow-up time of patients was 16.2 months (1.4–43.5 months). ORR was 16% (95% confidence interval: 7–30%) and CBR was 47% (95% confidence interval: 32–62%). Median TTF was 5.4 months. Common adverse effects were hand–foot syndrome, liver dysfunction, and bone marrow suppression. Grade 3 adverse events were observed in nine patients (18%). One patient (2%) suffered from symptomatic chronic heart failure, which improved after discontinuation of trastuzumab. Conclusions The combination therapy of trastuzumab plus capecitabine is effective and tolerable for heavily pretreated patients with HER2-positive MBC.     

The Hippo transducer TAZ as a biomarker of pathological complete response in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy

Activation of the Hippo transducer TAZ is emerging as a novel oncogenic route in breast cancer and it has been associated with breast cancer stem cells. Additionally, TAZ expression has been linked with HER-2 positivity. We investigated the association between TAZ expression and pathological complete response in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy. TAZ was assessed in diagnostic core biopsies by immunohistochemistry. To categorize samples with low TAZ and samples with high TAZ we generated a score by combining staining intensity and cellular localization. The pathological complete response rate was 78.6% in patients with low TAZ tumors and 57.6% in patients with high TAZ tumors (p=0.082). In HER2-enriched tumors there was no significant association between TAZ and pathological complete response, whereas in the luminal B subtype the pathological complete response rate was 82.4% in tumors with low TAZ and 44.4% in tumors with high TAZ (p=0.035). This association remained statistically significant when restricting our analysis to triple-positive tumors with expression of both estrogen receptor and progesterone receptor ≥ 50% (p=0.035). Results from this exploratory study suggest that the TAZ score efficiently predicts pathological complete response in Luminal B, HER2-positive breast cancer patients who received neoadjuvant chemotherapy and trastuzumab.     

Long-term survivor characteristics in HER2-positive metastatic breast cancer from registHER

Background:

Data characterising long-term survivors (LTS) with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) are limited. This analysis describes LTS using registHER observational study data.

Methods:

A latent class modelling (LCM) approach was used to identify distinct homogenous patient groups (or classes) based on progression-free survival (PFS), overall survival, and complete response. Demographics, clinicopathologic factors, first-line treatment patterns, and clinical outcomes were described for each class. Class-associated factors were evaluated using logistic regression analysis.

Results:

LCM identified two survivor groups labelled as LTS (n=244) and short-term survivors (STS; n=757). Baseline characteristics were similar between groups, although LTS were more likely to be white (83.6% vs 77.8%) with oestrogen receptor–positive (ER+) or progesterone receptor–positive (PgR+) disease (59.4% vs 50.9%). Median PFS in LTS was 37.2 (95% confidence interval (CI): 32.9–40.5) vs 7.3 months (95% CI: 6.8–8.0) in STS. Factors associated with long-term survival included ER+ or PgR+ disease, metastasis to node/local sites, first-line trastuzumab use, and first-line taxane use.

Conclusions:

Prognostic variables identified by LCM define a HER2-positive MBC patient profile and therapies that may be associated with more favourable long-term outcomes, enabling treatment selection appropriate to the patient''s disease characteristics.     

Human epidermal growth factor receptor 2 (HER2) extracellular domain levels are associated with progression-free survival in patients with HER2-positive metastatic breast cancer receiving lapatinib monotherapy

BACKGROUND:

Changes in serum human epidermal growth factor receptor 2 (HER2) levels associated with clinical outcomes, including objective response rate, progression‐free survival (PFS), and overall survival have been reported in patients with metastatic breast cancer (MBC) receiving trastuzumab and chemotherapy. This study investigated whether baseline or changes in serum HER2 correlated with overall response rate (ORR) and/or PFS in patients with MBC receiving first‐line lapatinib monotherapy.

METHODS:

The EGF20009 study investigated lapatinib monotherapy in 138 HER2‐positive patients with MBC previously untreated for their metastatic disease. Serum was collected and assessed at baseline and every 4 weeks for 16 weeks after treatment initiation. Disease assessment was performed at weeks 8 and 12 and every 12 weeks thereafter. A ≥20% decrease or increase in serum HER2 was defined as a significant change.

RESULTS:

Seventy‐nine percent of patients had elevated baseline serum HER2. Baseline serum HER2 was associated with ORR (P = .043) but not PFS. Patients with a ≥20% decrease from baseline of serum HER2 at weeks 4, 8, 12, and 16 had a significantly increased ORR and prolonged PFS. Conversely, those with a ≥20% increase from baseline had a significantly lower ORR and shorter PFS.

CONCLUSION:

Significant decreases in serum HER2 levels during the first 16 weeks of lapatinib monotherapy were associated with better clinical outcome (longer PFS and increased ORR) in HER2‐positive MBC patients. Cancer 2011;. © 2011 American Cancer Society.     

MiR-18b-5p对大肠癌PTEN/PI3K/Akt2信号通路的调控

目的:探讨miR-18b-5p对大肠癌PTEN/PI3K/Akt2信号转导通路的调控。方法:qRT-PCR方法检测33例大肠癌患者癌组织中miR-18b-5p表达水平,将患者临床病理特征与癌组织miR-18b-5p表达水平进行独立样本t检验和多元线性回归分析。应用microrna.org预测miR-18b-5p靶基因,miR-18b-5p 类似物、抑制物转染肠癌细胞SW480及HCT116,qRT-PCR检测细胞PTEN、PI3K、Akt2 mRNA表达水平。结果:在大肠癌患者癌组织中,miR-18b-5p表达水平显著增高,为癌旁组织的3.6倍(P<0.01 ),其表达水平与肿瘤分化程度、淋巴结转移及TNM分期相关。Microrna.org预测PTEN可能是miR-18b-5p的靶基因,大肠癌细胞转染类似物后PTEN含量明显降低,其下游基因PI3K、Akt2表达增高。结论:miR-18b-5p下调抑癌基因PTEN表达,诱导PI3K/Akt2信号转导通路持续活化,促进了大肠癌的发生发展。     

Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway.

The PTEN protein is a lipid phosphatase with putative tumor suppressing abilities, including inhibition of the PI3K/Akt signaling pathway. Inactivating mutations or deletions of the PTEN gene, which result in hyper-activation of the PI3K/Akt signaling pathway, are increasingly being reported in human malignancies, including breast cancer, and have been related to features of poor prognosis and resistance to chemotherapy and hormone therapy. Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the PI3K/Akt signaling pathway becomes a fundamental proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore further this hypothesis in breast cancer cells. To this end, we have determined the growth response to inhibition of the PI3K/Akt signaling pathway in a series of breast cancer cell lines with different PTEN levels. The PTEN-negative cell line displayed greater sensitivity to the growth inhibitory effects of the PI3K inhibitor, LY294002 and rapamycin, an inhibitor of the PI3K/Akt downstream mediator mTOR, compared with the PTEN-positive cell lines. To determine whether or not these differences in response are specifically due to effects of PTEN, we developed a series of cell lines with reduced PTEN protein expression compared with the parental cell line. These reduced PTEN cells demonstrated an increased sensitivity to the anti-proliferative effects induced by LY294002 and rapamycin compared with the parental cells, which corresponded to alterations in cell cycle response. These findings indicate that inhibitors of mTOR, some of which are already in clinical development (CCI-779, an ester of rapamycin), have the potential to be effective in the treatment of breast cancer patients with PTEN-negative tumors and should be evaluated in this setting.     

Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Background:

Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed.

Methods:

We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation.

Results:

We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P⩽0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P⩽0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P⩽0.019; Cox analysis).

Conclusion:

Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.     

PI3K在复发乳腺癌中的表达及意义

目的：探讨磷脂酰肌醇3激酶（PI3K）在复发乳腺癌中的表达及其意义。方法收集复发乳腺癌患者52例及原发乳腺癌患者50例的手术标本,采取免疫组织化学法进行PI3K标记。结果 PI3K在复发性乳腺癌中的阳性率（78.8%）,高于原发乳腺癌（36.0%）;高级别组织学分型的乳腺癌PI3K阳性例数高于低级别组织学分型乳腺癌;原发乳腺癌中有淋巴结转移的PI3K阳性例数高于无淋巴结转移,而复发乳腺癌中无明显差异;原发及复发乳腺癌中基底样型和HER-2阳性型PI3K阳性率均低于Luminal型。结论 PI3K可能是乳腺癌肿瘤细胞侵袭、转移、耐药及复发的一个重要标志物。     

Molecular alterations and poziotinib efficacy,a pan-HER inhibitor,in human epidermal growth factor receptor 2 (HER2)-positive breast cancers: Combined exploratory biomarker analysis from a phase II clinical trial of poziotinib for refractory HER2-positive breast cancer patients

We aimed to investigate the impact of genetic alterations on the efficacy of poziotinib in a phase II clinical trial of patients with heavily treated HER2-positive metastatic breast cancer (BC). We performed targeted ultra-deep sequencing with a customized cancer gene panel and RNA expression assay using BC specimens. Of 106 patients, biomarker data were available for 85. Copy number (CN) amplifications of HER2 were observed in 72 patients (85%), and CN >8 in 50 (59%). Single nucleotide variants (SNVs) of HER2 were found in 16 patients (19%). Genetic alterations of PIK3CA pathway were found in 40 patients (47%). Median progression free survival (PFS) of the biomarker analysis group was 3.61 months. In terms of PFS, HER2 with CN >8 prolonged (hazard ratio (HR) 0.61, 95% CI: 0.38, 0.97, p = 0.037) and alteration of PIK3CA pathway shortened the duration of survival (HR 2.25, 95% CI: 1.39, 3.63, p = 0.001). SNVs of HER2 increased survival duration, but the effect was not significant (HR: 0.58, 95% CI: 0.31, 1.08, p = 0.085). In addition, SNVs in the ERBB3 cytoplasmic domain decreased poziotinib response (HR: 4.58, 95% CI: 2.02, 10.37, p < 0.001). In multigene analysis, BC with HER2 CN >8 and intact PIK3CA pathway had significantly longer PFS compared to others (HR: 0.37, 95% CI: 0.21, 0.66, p = 0.001), while SNVs in the ERBB3 cytoplasmic domain predicted poor prognosis (HR: 4.28, 95% CI: 1.71, 10.71, p < 0.001). In conclusion, HER2 CN amplification, PIK3CA pathway alteration, and ERBB3 cytoplasmic mutation showed predictive roles on clinical outcomes of HER2-positive MBC treated with poziotinib.     

Long-term remission under Disitamab Vedotin (RC48) in HR-positive/HER2-positive metastatic breast cancer with brain meningeal,and bone marrow involvement: A case report

Breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) is closely associated with an elevated risk of multiple distant metastases and unfavorable prognosis. Disitamab Vedotin (RC48) is a newly developed antibody-drug conjugate targeting HER2, which is comprised of hertuzumab coupled to monomethyl auristatin E via a cleavable linker. Pre-clinical studies indicated its strong anti-tumor activity in HER2-positive and low HER2 expression models of BC. The present study reported on the case of a 60-year-old postmenopausal female who suffered from fatigue and was diagnosed with a right-sided BC tumor. The diagnosis was stage IV (cT4N3M1) hormone receptor (HR)-positive and HER2-positive invasive ductal carcinoma with systemic metastases (brain included). The patient initially responded well to 26 cycles of the first-line anti-HER2 targeted therapy plus chemotherapy (trastuzumab+pertuzumab+nab-paclitaxel) combined with whole-brain radiotherapy. However, both extracranial and intracranial lesions achieved progressive disease (PD), which eventually occurred during 5 sequential cycles of maintenance therapy. Subsequently, 4 cycles of second-line treatment (trastuzumab + pyrotinib + capecitabin) were continued until the levels of blood tumor markers CEA, CA15-3 and CA125 were elevated, and systemic PD was able to be attained (the brain metastases were rated as stable disease). Finally, the patient received RC48 as the third-line therapy and achieved a durable and effective clinical response. To date, the patient has benefited from 12 cycles of RC48 without any severe adverse effects. The overall survival was >3 years. The present study showcased that RC48 was effective and tolerable for a patient with HR- and HER2-positive BMBC.     

PI3K/AKT信号通路相关蛋白在乳腺癌中的表达及其临床意义

目的：研究PI3K/AKT信号转导通路中PTEN、PI3K、AKT蛋白在乳腺癌中的表达及其与疾病发生发展、预后的关系。方法用免疫组化SP法检测45例乳腺癌患者病理组织（观察组）和其中15例患者癌旁正常组织（对照组）中PTEN、PI3K、AKT表达情况,采用单因素回归分析对PTEN、PI3K、AKT蛋白在乳腺癌组织中阳性表达的相关因素进行分析。结果 PI3K、AKT在乳腺癌中的表达率分别为73.3%、75.5%,高于癌旁正常乳腺组织的33.3%、40%,差异具有统计学意义（P﹤0.05）;PTEN在乳腺癌中表达率为22.2%,低于癌旁正常乳腺组织的53.3%,但差异无统计学意义（P﹥0.05）;单因素回归分析结果显示,患者发病年龄对PTEN、PI3K、AKT在乳腺癌组织中阳性表达无关（P﹥0.05）;组织学分级、临床分期、存在淋巴结转移是PTEN、PI3K、AKT在乳腺癌组织中的阳性表达的相关因素（P﹤0.05）。结论 PI3K/AKT信号通路可能参与了乳腺癌的发生与发展,PTEN蛋白表达缺失导致AKT、PI3K蛋白的过度表达,PI3K、PTEN、AKT蛋白表达的检测可能有助于预测乳腺癌的预后。     

肿瘤相关炎性因子对曲妥珠单抗治疗HER2阳性转移性乳腺癌预后及疗效的影响

目的 研究肿瘤相关炎性因子(tumor associated inflammatory factor,TAIF)对曲妥珠单抗治疗人表皮生长因子受体2(HER2)阳性转移性乳腺癌(PMBC)预后及疗效的关系.方法 选取接受曲妥珠单抗方案治疗的HER2 PMBC患者89例纳入为试验组,选取同期接受健康体检的健康女性89例纳入为对照组,试验组所有患者均给予卡培他滨、吉西他滨联合曲妥珠单抗治疗,观察化疗前两组及试验组化疗前后的TNF-α、IL-1β、IL-6、IL-8水平,试验组的临床疗效,并对影响曲妥珠单抗治疗HER2 PMBC患者预后的因素进行多因素回归分析.结果治疗后,试验组的RR为40.45％,DCR为69.66％,1年内复发、转移率为79.78％.化疗前,试验组的TNF-α、IL-1β、IL-6、IL-8水平均明显高于对照组(P﹤0.01).试验组化疗前的TNF-α、IL-1β、IL-6、IL-8水平均明显高于化疗后(P﹤0.01).化疗前后,试验组1年内复发、转移患者的TNF-α、IL-1β、IL-6、IL-8水平均高于未复发、转移患者(P﹤0.05).年龄、身高、体重不是影响曲妥珠单抗治疗HER2 PMBC患者预后的危险因素(P﹥0.05);TNF-α、IL-1β、IL-6、IL-8是影响曲妥珠单抗治疗HER2 PMBC患者预后的危险因素(P﹤0.05).结论 TAIF可促进HER2 PMBC的进展、复发及转移,影响曲妥珠单抗治疗HER2 PMBC患者的疗效及预后.     

Serum HER2 extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ hybridization and with response rate.

PURPOSE: We explored the relationship between circulating HER2 extracellular domain (ECD) and tissue HER2 status as determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). We also examined its predictive value in a cohort of metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel. METHODS: Eligible patients had pre- and post-treatment stored serum specimens and were treated on a previously reported phase II trial. Retrospective analysis evaluated: the association between pretreatment serum HER2 ECD and tissue HER2 status by IHC and FISH; and the association between change in serum HER2 ECD after 12 weeks of therapy and response proportion. RESULTS: Stored serum samples were available for 55/95 (58%) patients. Statistically significant associations were found between HER2 status as assessed by IHC and FISH, and baseline serum HER2 ECD level. Patients whose ECD normalized after 12 weeks of therapy had a higher response proportion compared with patients with persistently high ECD levels (68% versus 15%, P=0.005). A relative decline of over 55% from baseline HER2 ECD predicted response to therapy. CONCLUSION: A statistically significant association was observed between pretreatment serum HER2 ECD and tissue HER2 status as assessed by IHC and FISH. A decrease in serum HER2 ECD level was a significant predictor of response to trastuzumab-based therapy.