Clinicopathological and surgical factors associated with long-term survival in patients with HER2-positive metastatic breast cancer.

Trastuzumab-based treatment has dramatically improved the outcomes of HER2-positive (HER2+) metastatic breast cancer (MBC) patients, with some patients achieving prolonged survival times. In this study, we aim to identify factors that are associated with long-term survival. Patients with HER2+ MBC treated with anti-HER2 target therapy were identified. Patients were grouped according to overall survival (OS) and categorized as long-term survivors (LTS, OS ≥ 5 years), or non-long-term survivors (non-LTS, OS < 5 years). Descriptive statistics and multivariable logistic regression modeling were used. A sensitivity analysis was carried out, including only patients diagnosed before 2007; therefore, 5 years of potential follow-up was possible. 1063 patients with HER2+ MBC diagnosed between 1994 and 2012 and treated with anti-HER2 therapy were identified. Among them, 154 (14.5 %) patients were categorized as LTS (median OS 92.2 months). Among LTS, 63.4 % were HR-positive and 32 % had de novo stage IV disease. Hormone receptor positivity (OR) 1.69; 95 % CI 1.17-2.44), resection of metastases (OR 2.38; 95 % CI 1.53-3.69), and primary breast surgery in patients with de novo stage IV (OR 2.88; 95 % CI 1.47-5.66) were associated with improved long-term survival. Greater number of metastatic sites (≥3 vs. 1, OR 0.41; 95 % CI 0.23-0.72) and visceral metastases (OR 0.61; 95 % CI 0.4-0.91) were associated with poor survival. Hormone receptor positivity, low burden of disease, metastasis to soft and bone tissues, and surgical management with resection of the metastatic site and the primary tumor were associated with long-term survival in patients with MBC who received anti-HER2 treatment.

A preoperative nomogram to predict the risk of synchronous distant metastases at diagnosis of primary breast cancer.

BACKGROUND: The detection of synchronous metastases at primary diagnosis of breast cancer (BC) affects its initial management. A risk calculator that incorporates many factors to evaluate an individual's risk of harbouring synchronous metastases would be useful to adapt cancer management. PATIENTS AND METHODS: Patients with primary diagnosis of BC were identified from three institutional databases sharing homogeneous work-up recommendations. A risk score for synchronous metastases was estimated and a nomogram was constructed using the first database. Its performance was assessed by receiver characteristic (ROC) analysis. The nomogram was externally validated in the two independent cohorts. RESULTS: A preoperative nomogram based on the clinical tumour size (P<0.001), clinical nodal status (P<0.001), oestrogen (P=0.17) and progesterone receptors (P=0.04) was developed. The nomogram accuracy was 87.3% (95% confidence interval (CI), 84.45-90.2%). Overall, the area under the ROC curve (AUC) was 86.1% for the validation set from the Institut Curie-René Huguenin, and 63.8% for the MD Anderson validation set. The negative predictive value (NPV) was high in the three cohorts (97-99%). CONCLUSIONS: We developed and validated a strong metastasis risk calculator that can evaluate with high accuracy an individual's risk of harbouring synchronous metastases at diagnosis of primary BC. CONDENSED ABSTRACT: A nomogram to predict synchronous metastases at diagnosis of breast cancer was developed and externally validated. This tool allows avoiding unnecessary expensive work-up.

Effect of adjuvant trastuzumab among patients treated with anti-HER2-based neoadjuvant therapy.

PURPOSE: To study the impact of adjuvant trastuzumab among patients achieving a pathologic complete response (pCR) after trastuzumab-based neoadjuvant systemic therapy (NST). PATIENTS AND METHODS: Patients with primary HER2-positive breast cancer treated with trastuzumab-based NST were categorised according to adjuvant trastuzumab administration and pCR status. Adjuvant trastuzumab became standard of care in 2006, this was the main reason patients in our cohort did not receive adjuvant trastuzumab. Kaplan-Meier was used to estimate survival. A test for interaction between adjuvant trastuzumab and pCR was completed. FINDINGS: Of 589 patients, 203 (34.5%) achieved a pCR. After surgery, 109 (18.5%) patients in the entire cohort did not receive adjuvant trastuzumab. Among patients achieving a pCR, 31.3% received adjuvant trastuzumab compared with 68.8% among those who did not achieve a pCR (P=0.0006). Among patients achieving pCR, adjuvant trastuzumab did not further improve overall survival (OS) or relapse-free survival (RFS) (P=0.35 and P=0.93, respectively). Any benefit of adjuvant trastuzumab in OS and RFS among patients without a pCR did not achieve statistical significance (P=0.3 and P=0.44, respectively). CONCLUSIONS: In this cohort, patients treated with trastuzumab-based NST who achieved a pCR have excellent outcome regardless of whether they received adjuvant trastuzumab.

Survival of women with inflammatory breast cancer: a large population-based study.

BACKGROUND: Our group has previously reported that women with inflammatory breast cancer (IBC) continue to have worse outcome compared with those with non-IBC. We undertook this population-based study to see if there have been improvements in survival among women with stage III IBC, over time. PATIENT AND METHODS: We searched the Surveillance, Epidemiology and End Results Registry to identify female patients diagnosed with stage III IBC between 1990 and 2010. Patients were divided into four groups according to year of diagnosis: 1990-1995, 1996-2000, 2001-2005, and 2006-2010. Breast cancer-specific survival (BCSS) was estimated using the Kaplan-Meier method and compared across groups using the log-rank test. Cox models were then fit to determine the association of year of diagnosis and BCSS after adjusting for patient and tumor characteristics. RESULTS: A total of 7679 patients with IBC were identified of whom 1084 patients (14.1%) were diagnosed between 1990 and 1995, 1614 patients (21.0%) between 1996 and 2000, 2683 patients (34.9%) between 2001 and 2005, and 2298 patients (29.9%) between 2006 and 2010. The 2-year BCSS for the whole cohort was 71%. Two-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990-1995, 1996-2000, 2001-2005, and 2006-2010, respectively (P < 0.0001). In the multivariable analysis, increasing year of diagnosis (modeled as a continuous variable) was associated with decreasing risks of death from breast cancer (HR = 0.98, 95% confidence interval 0.97-0.99, P < 0.0001). CONCLUSION: There has been a significant improvement in survival of patients diagnosed with IBC over a two-decade time span in this large population-based study. This suggests that therapeutic strategies researched and evolved in the context of non-IBC have also had a positive impact in women with IBC.

Long-term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes.

BACKGROUND: Subtypes defined by hormonal receptor (HR) and HER2 status have not been well studied in inflammatory breast cancer (IBC). We characterized clinical parameters and long-term outcomes, and compared pathological complete response (pCR) rates by HR/HER2 subtype in a large IBC patient population. We also compared disease-free survival (DFS) and overall survival (OS) between IBC patients who received targeted therapies (anti-hormonal, anti-HER2) and those who did not. PATIENTS AND METHODS: We retrospectively reviewed the records of patients diagnosed with IBC and treated at MD Anderson Cancer Center from January 1989 to January 2011. Of those, 527 patients had received neoadjuvant chemotherapy and had available information on estrogen receptor (ER), progesterone receptor (PR), and HER2 status. HR status was considered positive if either ER or PR status was positive. Using the Kaplan-Meier method, we estimated median DFS and OS durations from the time of definitive surgery. Using the Cox proportional hazards regression model, we determined the effect of prognostic factors on DFS and OS. Results were compared by subtype. RESULTS: The overall pCR rate in stage III IBC was 15.2%, with the HR-positive/HER2-negative subtype showing the lowest rate (7.5%) and the HR-negative/HER2-positive subtype, the highest (30.6%). The HR-negative, HER2-negative subtype (triple-negative breast cancer, TNBC) had the worst survival rate. HR-positive disease, irrespective of HER2 status, had poor prognosis that did not differ from that of the HR-negative/HER2-positive subtype with regard to OS or DFS. Achieving pCR, no evidence of vascular invasion, non-TNBC, adjuvant hormonal therapy, and radiotherapy were associated with longer DFS and OS. CONCLUSIONS: Hormone receptor and HER2 molecular subtypes had limited predictive and prognostic power in our IBC population. All molecular subtypes of IBC had a poor prognosis. HR-positive status did not necessarily confer a good prognosis. For all IBC subtypes, novel, specific treatment strategies are needed in the neoadjuvant and adjuvant settings.

Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer†.

BACKGROUND: Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. RESULTS: Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. CONCLUSION: The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group. CLINICAL TRIAL NUMBER: NCT00499603.

Functional proteomics characterization of residual triple-negative breast cancer after standard neoadjuvant chemotherapy.

BACKGROUND: In this study, we used functional proteomics to determine the molecular characteristics of residual triple receptor-negative breast cancer (TNBC) patients after neoadjuvant systemic chemotherapy (NCT) and their relationship with patient outcomes in order to identify potential targets for therapy. PATIENTS AND METHODS: Protein was extracted from 54 residual TNBCs, and 76 proteins related to breast cancer signaling were measured by reverse phase protein arrays (RPPAs). Univariable and multivariable Cox proportional hazard models were fitted for each protein. Survival outcomes were estimated by the Kaplan-Meier product limit method. Training and cross validation were carried out. The coefficients estimated from the multivariable Cox model were used to calculate a risk score (RS) for each sample. RESULTS: Multivariable analysis using the top 25 proteins from univariable analysis at a false discovery rate (FDR) of 0.3 showed that AKT, IGFBP2, LKB1, S6 and Stathmin were predictors of recurrence-free survival (RFS). The cross-validation model was reproducible. The RS model calculated based on the multivariable analysis was -1.1086 × AKT + 0.2501 × IGFBP2 - 0.6745 × LKB1+1.0692 × S6 + 1.4086 × stathmin with a corresponding area under the curve, AUC = 0.856. The RS was an independent predictor of RFS (HR = 3.28, 95%CI = 2.07-5.20, P < 0.001). CONCLUSIONS: We found a five-protein model that independently predicted RFS risk in patients with residual TNBC disease. The PI3 K pathway may represent potential therapeutic targets in this resistant disease.

Functional proteomics characterization of residual breast cancer after neoadjuvant systemic chemotherapy.

BACKGROUND: The purpose of this study was to determine the functional proteomic characteristics of residual breast cancer and hormone receptor (HR)-positive breast cancer after neoadjuvant systemic chemotherapy, and their relationship with patient outcomes. METHODS: Reverse phase protein arrays of 76 proteins were carried out. A boosting approach in conjunction with a Cox proportional hazard model defined relapse predictors. A risk score (RS) was calculated with the sum of the coefficients from the final model. Survival outcomes and associations of the RS with relapse were estimated. An independent test set was used to validate the results. RESULTS: Test (n = 99) and validation sets (n = 79) were comparable. CoxBoost revealed a three-biomarker (CHK1pS345, Caveolin1, and RAB25) and a two-biomarker (CD31 and Cyclin E1) model that correlated with recurrence-free survival (RFS) in all residual breast cancers and in HR-positive disease, respectively. Unsupervised clustering split patients into high- and low risk of relapse groups with different 3-year RFS (P ≤ 0.001 both). RS was a substantial predictor of RFS (P = 0.0008 and 0.0083) after adjustment for other substantial characteristics. Similar results were found in validation sets. CONCLUSIONS: We found models that independently predicted RFS in all residual breast cancer and in residual HR-positive disease that may represent potential targets of therapy in this resistant disease.

Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer.

BACKGROUND: We sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab. PATIENTS AND METHODS: Two hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (

The prognostic impact of age in patients with triple-negative breast cancer.

The purpose of this study was to assess the prognostic impact of age in patients with triple-negative breast cancer (TNBC). 1,732 patients with primary TNBC were analyzed. Five age cohorts (≤30, 31-40, 41-50, 51-60, and >60 years) at diagnosis were correlated with clinical/pathological parameters. Univariate and multivariate analyses were used to examine the effect of age on disease-free (DFS), distant disease-free (DDFS), and overall survival (OS). In patients with TNBC, increasing age at diagnosis was inversely correlated with tumor grade (P < 0.0001); likelihood of being non-Caucasian (P = 0.0001); likelihood of getting chemotherapy (P < 0.0001); and positively correlated with DFS (P = 0.0003); DDFS (P < 0.0001); and OS (P < 0.0001). The median DFS for patients 31-40 and older than 60 years was 4 years [95 % confidence interval (95 % CI) 2-5] and 8 years (95 % CI 5-14, respectively, P = 0.0003). The DDFS and OS were also statistically significantly shorter for younger patients. In multivariate analysis, tumor size, nodal stage, tumor grade, and age remained significant independent prognostic variables. Clinical characteristics of TNBC differ by age group, patients ≤40 years have poorer survival despite more aggressive systemic therapy.

Identifying factors that impact survival among women with inflammatory breast cancer.

BACKGROUND: The objective of this retrospective study was to determine factors impacting survival among women with inflammatory breast cancer (IBC). METHODS: The Surveillance, Epidemiology and End Results Registry (SEER) was searched to identify women with stage III/IV IBC diagnosed between 2004 and 2007. IBC was identified within SEER as T4d disease as defined by the sixth edition of the American Joint Committee on Cancer. The Kaplan-Meier product-limit method was used to describe inflammatory breast cancer-specific survival (IBCS). Cox models were fitted to assess the multivariable relationship of various patient and tumor characteristics and IBCS. RESULTS: Two thousand three hundred and eighty-four women with stage IIIB/C and IV IBC were identified. Two-year IBCS among women with stage IIIB, IIIC and IV disease was 81%, 67% and 42%, respectively (P < 0.0001). In the multivariable model, patients with stage IIIB disease and those with stage IIIC disease had a 63% [hazard ratio (HR) 0.373, 95% confidence interval (CI) 0.296-0.470, P < 0.001] and 31% (HR 0.691, 95% CI 0.512-0.933, P = 0.016) decreased risk of death from IBC, respectively, compared with women with stage IV disease. Other factors significantly associated with decreased risk of death from IBC included low-grade tumors, being of white/other race, undergoing surgery, receiving radiation therapy and hormone receptor-positive disease. Among women with stage IV disease, those who underwent surgery of their primary had a 51% decreased risk of death compared with those who did not undergo surgery (HR = 0.489, 95% CI 0.339-0.704, P < 0.0001). CONCLUSIONS: Although IBC is an aggressive subtype of locally advanced breast cancer, it is heterogeneous with various factors affecting survival. Furthermore, our results indicate that a subgroup of women with stage IV IBC may benefit from aggressive combined modality management.

Multifocality and multicentricity in breast cancer and survival outcomes.

BACKGROUND: The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established. PATIENTS AND METHODS: MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. RESULTS: Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS. CONCLUSIONS: MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.

Metaplastic sarcomatoid carcinoma of the breast appears more aggressive than other triple receptor-negative breast cancers.

Metaplastic sarcomatoid carcinoma (MSC) of the breast is usually triple receptor (ER, PR, and HER2) negative and is not currently recognized as being more aggressive than other triple receptor-negative breast cancers. We reviewed archival tissue sections from surgical resection specimens of 47 patients with MSC of the breast and evaluated the association between various clinicopathologic features and patient survival. We also evaluated the clinical outcome of MSC patients compared to a control group of patients with triple receptor-negative invasive breast carcinoma matched for patient age, clinical stage, tumor grade, treatment with chemotherapy, and treatment with radiation therapy. Factors independently associated with decreased disease-free survival among patients with stage I-III MSC of the breast were patient age > 50 years (P = 0.029) and the presence of nodal macrometastases (P = 0.003). In early-stage (stage I-II) MSC, decreased disease-free survival was observed for patients with a sarcomatoid component comprising ≥ 95% of the tumor (P = 0.032), but tumor size was the only independent adverse prognostic factor in early-stage patients (P = 0.043). Compared to a control group of triple receptor-negative patients, patients with stage I-III MSC had decreased disease-free survival (two-sided log rank, P = 0.018). Five-year disease-free survival was 44 ± 8% versus 74 ± 7% for patients with MSC versus triple receptor-negative breast cancer, respectively. We conclude that MSC of the breast appears more aggressive than other triple receptor-negative breast cancers.

Stability of HER2-positive status in breast carcinoma: a comparison between primary and paired metastatic tumors with regard to the possible impact of intervening trastuzumab treatment.

BACKGROUND: To date, the stability of human epidermal growth factor receptor 2 (HER2)-positive primary breast carcinomas during disease progression and the role of intervening trastuzumab treatment in the loss of HER2-positive status in paired metastases remain under-investigated. MATERIALS AND METHODS: Sixty-six patients with HER2-positive primary carcinoma and paired metastasis were evaluated. We examined the overall agreement of the HER2 status and compared the status agreement between 38 trastuzumab-treated patients and 28 trastuzumab-naive control patients. The impact of chemotherapy, endocrine therapy, metastatic site (locoregional or distant), and time to relapse (≥5 or <5 years) on the HER2 status change was assessed. RESULTS: Fifty-six (84.9%) patients had HER2 status agreement between paired tumors; 10 patients had HER2-positive-to-negative conversion. The agreement rate in the trastuzumab-treated group and in the control group was comparable (86.8% versus 82.1%) (P = 0.858). Chemotherapy, endocrine therapy, metastatic site, and time to relapse did not significantly affect HER2 stability in either group. In the discordant tumor pairs, variations in testing methods and borderline scores were common. CONCLUSIONS: HER2-positive status remained unchanged in most paired metastases. Loss of HER2-positive status did not seem to be affected by trastuzumab treatment. Differences in testing and interpretation may account for the discordance in some cases.

Addition of GM-CSF to trastuzumab stabilises disease in trastuzumab-resistant HER2+ metastatic breast cancer patients.

BACKGROUND: One of the proposed mechanisms of trastuzumab-induced regression of human epidermal growth factor receptor 2-positive (HER2+) tumours includes facilitation of antibody-dependent cell-mediated cytotoxicity (ADCC). Granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates ADCC. We presented our pilot study of adding GM-CSF to trastuzumab in patients with trastuzumab-resistant HER2+ metastatic breast cancer. METHODS: Patients with HER2+ metastatic breast cancer that progressed after trastuzumab +/- chemotherapy were continued on trastuzumab 2 mg kg(-1) intravenous weekly and GM-CSF 250 µg m(-2) subcutaneous daily. Patients were assessed for response every 8 weeks. Treatment was continued until disease progression or intolerable toxicity. RESULTS: Seventeen patients were evaluable (median age 48 years, range 27-75 years). The median number of metastatic sites was 2 (range 1-3); the most common site was the liver (n=10). The median number of prior regimens for metastatic disease was 2 (range 1-5). No objective disease response was observed, but five patients (29%) had stable disease for a median duration of 15.8 (range 10-53.9) weeks. The most common adverse event was rash at the injection site. No grade 4 or irreversible adverse event was seen. CONCLUSION: The addition of GM-CSF to trastuzumab alone had a modest clinical benefit and acceptable safety profile in heavily pretreated patients with trastuzumab-resistant HER2+ metastatic breast cancer.

Chemokine receptors in advanced breast cancer: differential expression in metastatic disease sites with diagnostic and therapeutic implications.

BACKGROUND: We investigated the expression of CXCR4, CCR7, estrogen receptor (ER), progesterone receptor (PR) and HER2-neu in human metastatic breast cancers to determine whether these biological biomarkers were preferentially expressed in any organ-specific metastases. MATERIALS AND METHODS: CXCR4, CCR7, ER, PR and HER2-neu expression levels were evaluated by immunohistochemical staining using paraffin-embedded tissue sections of metastatic breast cancers (n = 41) obtained by either diagnostic biopsy or surgical resection. RESULTS: The metastatic sites included the following: bone (n = 15), brain (n = 14), lung (n = 6), liver (n = 2), and omental metastases (n = 2). CXCR4 was expressed in 41% of cases, CCR7 expression was demonstrated in 10%, and HER2-neu overexpression was present in 27%. CXCR4 was more likely to be expressed in bone metastases than visceral metastases (67% versus 26%, P = 0.020). Visceral sites demonstrated a lower rate of CXCR4 positivity (33% and 23%, respectively, for lung and brain metastases). Similarly, CCR7 was more likely to be found in bone metastases than visceral sites (27% versus 0%, P = 0.037). CONCLUSIONS: These results indicate that CXCR4 can contribute to the homing of breast cancer cells to the bone. This finding might have important clinical implications since patients with metastatic bone disease may achieve the highest benefit from a CXCR4-targeted therapy.

Survival among women with triple receptor-negative breast cancer and brain metastases.

BACKGROUND: The purpose of this study was to determine the incidence of and survival following brain metastases among women with triple receptor-negative breast cancer. PATIENTS AND METHODS: In all, 679 patients with nonmetastatic triple receptor-negative breast cancer diagnosed from 1980 to 2006 were identified. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for development of brain metastases. Survival was computed using the Kaplan-Meier product limit method. RESULTS: Median follow-up was 26.9 months. In all, 42 (6.2%) patients developed brain metastases with a cumulative incidence at 2 and 5 years of 5.6% [95% confidence interval (CI) 3.8% to 7.9%] and 9.6% (95% CI 6.8% to 13%), respectively. A total of 24 (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2 and 5 years of 2.0% (95% CI 2.6% to 6.0%) and 4.9% (95% CI 3.2% to 7.0%), respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases. Median survival for all patients who developed brain metastases and those who developed brain metastases as the first site of recurrence was 2.9 months (95% CI 2.0-7.6 months) and 5.8 months (95% CI 1.7-11.0 months), respectively. CONCLUSION: In this single-institutional study, patients with nonmetastatic triple receptor-negative breast tumors have a high early incidence of brain metastases associated with poor survival and maybe an ideal cohort to target brain metastases preventive strategies.

Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer.

BACKGROUND: We evaluated discordance in expression measurements for estrogen receptor (ER), progesterone receptor (PR), and HER2 between primary and recurrent tumors in patients with recurrent breast cancer and its effect on prognosis. METHODS: A total of 789 patients with recurrent breast cancer were studied. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Repeat markers for ER, PR, and HER2 were available in 28.9%, 27.6%, and 70.0%, respectively. Primary and recurrent tumors were classified as triple receptor-negative breast cancer (TNBC) or receptor-positive breast cancer (RPBC, i.e. expressing at least one receptor). Discordance was correlated with clinical/pathological parameters. RESULTS: Discordance for ER, PR, and HER2 was 18.4%, 40.3%, and 13.6%, respectively. Patients with concordant RPBC had significantly better post-recurrence survival (PRS) than discordant cases; patients with discordant receptor status had similarly unfavorable survival as patients with concordant TNBC. IHC scores for ER and PR showed weak concordance between primary and recurrent tumors. Concordance of HER2-FISH scores was higher. CONCLUSIONS: Concordance of quantitative hormone receptor measurements between primary and recurrent tumors is modest consistent with suboptimal reproducibility of measurement methods, particularly for IHC. Discordant cases have poor survival probably due to inappropriate use of targeted therapies. However, biological change in clinical phenotype cannot be completely excluded.

Defining prognosis for women with breast cancer and CNS metastases by HER2 status.

BACKGROUND: The purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease. METHODS: Five hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan-Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics. RESULTS: In the multivariable model, patients with HER2-negative disease [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15-1.95, P = 0.003] and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51-3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31-2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78-2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis. CONCLUSION: In our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.

Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab.

BACKGROUND: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status. PATIENTS AND METHODS: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease. RESULTS: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR-) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%). CONCLUSIONS: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR-/HER2+ breast cancers.