Naoki Niikura

Loss of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Metastatic Sites of HER2-Overexpressing Primary Breast Tumors

PURPOSEnWe evaluated whether patients with human epidermal growth factor receptor 2 (HER2) -positive primary breast tumors had metastatic tumors that were HER2 positive (concordant) or HER2 negative (discordant). We then evaluated whether treatment with trastuzumab or chemotherapy before biopsy of the metastasis had any effect on the rate of HER2 discordance. We also compared the overall survival durations of patients with HER2-concordant and -discordant tumors.nnnPATIENTS AND METHODSnWe retrospectively identified all patients who initially had been diagnosed with HER2-positive (immunohistochemistry 3+ and/or fluorescent in situ hybridization positive) primary breast cancer between 1997 and 2008 at MD Anderson Cancer Center who also had metastatic tumor biopsy results available for review.nnnRESULTSnWe included 182 patients who met our criteria. Forty-three (24%) of the 182 patients with HER2-positive primary tumors had HER2-negative metastatic tumors. The HER2 discordance rates differed significantly on the basis of whether patients received chemotherapy (P = .022) but not on the basis of whether patients received trastuzumab (P = .296). Patients with discordant HER2 status had shorter overall survival than did patients with concordant HER2 status (hazard ratio [HR], 0.43; P = .003). A survival difference remained among the 67 patients who received trastuzumab (HR, 0.56; P = .083) and 101 patients who did not (HR, 0.53; P = .033) before their metastasis biopsies.nnnCONCLUSIONnWe confirmed that loss of HER2-positive status in metastatic tumors can occur in patients with primary HER2-positive breast cancer. Our data strongly support the need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of targeted therapy.

FDG-PET/CT Compared with Conventional Imaging in the Detection of Distant Metastases of Primary Breast Cancer

PURPOSEnEvidence from studies with small numbers of patients indicates that (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) accurately detects distant metastases in the staging of primary breast cancer. We compared the sensitivity and specificity of PET/CT and conventional imaging (CT, ultrasonography, radiography, and skeletal scintigraphy) for the detection of distant metastases in patients with primary breast cancer.nnnPATIENTS AND METHODSnWe performed a retrospective review that identified 225 patients with primary breast cancer seen from January 2000 to September 2009 for whom PET/CT data were available for review. Imaging findings were compared with findings on biopsy, subsequent imaging, or clinical follow-up. Sensitivity and specificity in the detection of distant metastases were calculated for PET/CT and conventional imaging. Fishers exact tests were used to test the differences in sensitivity and specificity between PET/CT and conventional imaging.nnnRESULTSnThe mean patient age at diagnosis was 53.4 years (range, 23-84 years). The sensitivity and specificity in the detection of distant metastases were 97.4% and 91.2%, respectively, for PET/CT and 85.9% and 67.3%, respectively, for conventional imaging. The sensitivity and specificity of PET/CT were significantly higher than those of conventional imaging (p = .009 and p < .001, respectively). Eleven cases of distant metastases detected by PET/CT were clinically occult and not evident on conventional imaging.nnnCONCLUSIONnPET/CT has higher sensitivity and specificity than conventional imaging in the detection of distant metastases of breast cancer. A prospective study is needed to determine whether PET/CT could replace conventional imaging to detect distant metastases in patients with primary breast cancer.

A prospective study of bone tumor response assessment in metastatic breast cancer.

BACKGROUNDnIn our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases.nnnMETHODSnWe prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions.nnnRESULTSnThe median follow-up period was 26.7 months (range, 6.1-53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases.nnnCONCLUSIONnMDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA criteria in predicting bone tumor response by incorporating 18-fluorodeoxyglucose ((18)F) positron emission tomography (FDG-PET)/CT to see if findings using this modality are earlier than those with WHO criteria.

Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases.

Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression‐free survival (PFS) and overall survival (OS) of patients with bone‐only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases.

Initial Staging Impact of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Locally Advanced Breast Cancer

PURPOSEnFluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may reveal distant metastases more accurately than conventional imaging (CT, skeletal scintigraphy, chest radiography). We hypothesized that patients diagnosed with stage III noninflammatory breast cancer (non-IBC) and IBC by conventional imaging with PET/CT have a better prognosis than patients diagnosed without PET/CT.nnnPATIENTS AND METHODSnWe retrospectively identified 935 patients with stage III breast cancer in 2000-2009. We compared the relapse-free survival (RFS) and overall survival (OS) times of patients diagnosed by conventional imaging with those of patients diagnosed by conventional imaging plus PET/CT. Univariate and multivariate Cox proportional hazards regression models were used to assess associations between survival and PET/CT.nnnRESULTSnRFS and OS times were not significantly different between patients imaged with PET/CT and those imaged without PET/CT. However, the RFS time in IBC patients was significantly different between patients imaged with PET/CT and those imaged without PET/CT on both univariate (hazard ratio [HR], 0.43; p = .014) and multivariate (HR, 0.33; p = .004) analysis. There was a trend for a longer OS duration in IBC patients imaged with PET/CT.nnnCONCLUSIONnAmong IBC patients, adding PET/CT to staging based on conventional imaging might detect patients with metastases that were not detected by conventional imaging. The use of conventional imaging with PET/CT for staging in non-IBC patients is not justified on the basis of these retrospective data. The use of conventional imaging plus PET/CT in staging IBC needs to be studied prospectively to determine whether it will improve prognosis.

Prognostic Impact of Phosphorylated HER-2 in HER-2+ Primary Breast Cancer

PURPOSEnTyrosine 1248 is one of the autophosphorylation sites of human epidermal growth factor receptor (HER)-2. We determined the prognostic value of the expression level of tyrosine 1248-phosphorylated HER-2 (pHER-2) in patients with HER-2(+) primary breast cancer using a reverse-phase protein array.nnnPATIENTS AND METHODSnThe optimal cutoff value of pHER-2 for segregating disease-free survival (DFS) was determined by receiver operating characteristic (ROC) curve analysis. Five-year DFS for pHER-2 expression level was estimated with the Kaplan-Meier method using both derivation (n = 162) and validation (n = 227) cohorts.nnnRESULTSnOf the 162 patients in the derivation cohort, 26 had high HER-2 expression levels. The area under the ROC curve for pHER-2 level and DFS was 0.662. Nineteen of the 162 patients (11.7%) had high pHER-2 expression levels (pHER-2(high)); 143 patients (88.3%) had low pHER-2 expression levels (pHER-2(low)). Among the 26 patients with high HER-2 expression levels, the 17 pHER-2(high) patients had a significantly lower 5-year DFS rate than the nine pHER-2(low) patients (23.5% versus 77.8%). On multivariate analysis, only pHER-2(high) independently predicted DFS in the Cox proportional hazards model. In the validation cohort, among 61 patients with high HER-2 expression, the difference in 5-year DFS rates between pHER-2(high) (n = 7) and pHER-2(low) (n = 54) patients was marginal (57.1% versus 81.5%).nnnCONCLUSIONnIn patients with HER-2(+) primary breast cancer, pHER-2(high) patients had a lower 5-year DFS rate than pHER-2(low) patients. Quantification of pHER-2 expression level may provide prognostic information beyond the current standard HER-2 status.

Bone metastasis-related signaling pathways in breast cancers stratified by estrogen receptor status

Background: Breast cancer bone metastasis (BCBM)-specific genes have been reported without considering biological differences based on estrogen receptor (ER) status. The aims of this study were to identify BCBM-specific genes using our patient dataset and validate previously reported BCBM-specific genes, and to determine whether ER-status-related biological differences matter in identification of BCBM-specific genes. Methods: We used Affymetrix GeneChips to analyze 365 primary human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer specimens. Genes that were differentially expressed between patients who developed bone metastasis and those who developed non-bone metastasis were identified using Cox proportional hazards model, and differential expression of gene sets was assessed using gene set analysis. We performed gene set analysis to determine whether biological function associated with bone metastasis were different by ER status using 2,246 functionally annotated gene sets assembled from Gene Ontology data base. Results: Among 16,712 probe sets, 592 were overexpressed in the bone metastasis cohort compared to the non-bone-metastasis cohort (false discovery rate ≤ 0.05). However, no BCBM-specific genes met our significance tests when the cancers were stratified by ER status. In ER-positive and ER-negative breast cancers, 151 and 125 gene sets, respectively, were overexpressed for BCBM and the majority of BCBM-related pathways were different. Of significant gene sets, only 13 gene sets were overlapped between ER-positive and -negative cohorts. Conclusion: ER-positive and ER-negative breast cancers have different biological pathways in BCBM development. We have yet to explore BCBM-related biomarkers and targets considering the biological features associated with BCBM depending on the ER status.

Clinical significance of metastatic-tumor HER2 status in patients with HER2-positive primary breast cancer.

545 Background: Studies have suggested that trastuzumab may convert HER2-positive (HER+) primary breast tumors to HER2-negative (HER2-). Whether this conversion happens between primary and metastatic lesions is unknown. We tested the hypothesis that trastuzumab increases the number of patients with HER2+ primary tumors and HER2- metastases (HER2 discordance). We assessed the same effect of chemotherapy. We also compared overall survival (OS) durations of patients with HER2 discordance and patients with HER2 concordance (ie, HER2+ primary and metastatic tumors).nnnMETHODSnWe retrospectively identified 182 patients who had been diagnosed with HER2+ (IHC 3+ and/or FISH+) primary breast cancer in 1997-2008 at MD Anderson Cancer Center and had known HER2 status of the metastasis. Median follow-up was 18 (1-90) months. OS rates were determined using the log-rank test and Cox proportional regression models.nnnRESULTSnOf 182 patients with HER2+ primary tumors, 43 (24%) had HER2- metastases (discordance). Of 76 patients who received trastuzumab before their metastasis biopsies, 15 (20%) had HER2 discordance. Similarly, of 106 patients who did not receive trastuzumab before their metastasis biopsies, 28 (26%) had discordance. There was no significant difference in discordance rates based on trastuzumab (P = .296). However, discordance rates differed significantly based on chemotherapy (P = .022); 39 (27%) of 142 patients who received chemotherapy (with or without trastuzumab) before their metastasis biopsies had discordance, compared with 4 (10%) of 40 patients who did not receive chemotherapy. Patients with HER2 discordance had shorter OS than patients with HER2 concordance (hazard ratio = .43; P= .003). A survival difference remained among the 67 patients who received trastuzumab before their metastasis biopsies (hazard ratio = .56; P = .083).nnnCONCLUSIONSnOne-fourth of primary HER2+ breast cancers converted to HER2-. Our hypothesis was rejected; trastuzumab did not affect discordance rate, although chemotherapy did. Patients with HER2 discordance had poorer prognoses than those with concordance. A prospective study is warranted to determine whether HER2 discordance affects prognosis and treatment.