Suhail M. Ali

Elevated Serum HER-2/neu Level Predicts Decreased Response to Hormone Therapy in Metastatic Breast Cancer

PURPOSE To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001). CONCLUSION Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.

Potential Clinical Utility of Serum HER-2/neu Oncoprotein Concentrations in Patients with Breast Cancer

BACKGROUND The HER-2/neu oncogene and its p185 receptor protein are indicators of a more aggressive form of breast cancer. HER-2/neu status guides Herceptin therapy, specifically directed to the extracellular domain (ECD) of the HER-2/neu oncoprotein. The HER-2/neu ECD is shed from cancer cells into the circulation and is measurable by immunoassay. METHODS We performed a systematic review of the peer-reviewed literature on circulating ECD with respect to prevalence, prognosis, prediction of response to therapy, and monitoring of breast cancer. RESULTS The prevalence of increased ECD in patients with primary breast cancer varied between 0% and 38% (mean, 18.5%), whereas in metastatic disease the range was from 23% to 80% (mean, 43%). Some women with HER-2/neu-negative tumors by tissue testing develop increased ECD concentrations in metastatic disease. Increased ECD has been correlated with indicators of poor prognosis, e.g., overall survival and disease-free survival. Increased ECD predicts a poor response to hormone therapy and some chemotherapy regimens but can predict improved response to combinations of Herceptin and chemotherapy. Many studies support the value of monitoring ECD during breast cancer progression because serial increases precede the appearance of metastases and longitudinal ECD changes parallel the clinical course of disease. CONCLUSIONS The monitoring of circulating HER-2/neu ECD provides a tool for assessing prognosis, for predicting response to therapy, and for earlier detection of disease progression and timely intervention with appropriate therapy.

Serum HER-2/neu and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen

PURPOSE To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen. PATIENTS AND METHODS Five hundred sixty-two estrogen receptor-positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu. RESULTS For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P =.008), clinical benefit (CB; 57% v 45%; P =.016), time to progression (TTP; median, 12.2 v 8.5 months; P =.0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P =.0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P =.45) or CB (33% v 26%; P =.31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P =.0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P =.0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP. CONCLUSION Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.

Quantitation of p95HER2 in Paraffin Sections by Using a p95-Specific Antibody and Correlation with Outcome in a Cohort of Trastuzumab-Treated Breast Cancer Patients

Purpose: p95HER2 is an NH2-terminally truncated form of HER2 that lacks the trastuzumab binding site and is therefore thought to confer resistance to trastuzumab treatment. In this report, we introduce a new antibody that has enabled the first direct quantitative measurement of p95HER2 in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. We sought to show that quantitative p95HER2 levels would correlate with outcome in trastuzumab-treated HER2-positive metastatic breast cancer. Experimental Design: The novel p95HER2 antibody used here was characterized for sensitivity, specificity, and selectivity over full-length HER2. Quantitative p95HER2 levels were measured in 93 metastatic breast tumors using a VeraTag FFPE assay to determine the correlation of p95HER2 levels with outcomes. Results: Within a cohort of trastuzumab-treated metastatic breast cancer patients, high levels of p95HER2 were found to correlate with shorter progression-free survival [hazard ratio (HR), 1.9; P = 0.017] and overall survival (HR, 2.2; P = 0.012) in patients with tumors selected to be HER2 positive by the VeraTag HER2 assay. For those with tumors found to be fluorescence in situ hybridization positive, elevated p95HER2 correlated similarly with shorter progression-free survival (HR, 1.8; P = 0.022) and overall survival (HR, 2.2; P = 0.009). Conclusions: We have successfully generated an antibody that can specifically detect p95HER2, and developed an assay to quantify expression in FFPE tumor specimens. Using this novel assay, we have identified a group of HER2-positive patients expressing p95HER2 that have a worse outcome while on trastuzumab. As p95HER2 retains sensitivity to kinase inhibitors, measurement of p95HER2 in breast tumor sections may be useful in guiding treatment for patients with HER2-positive breast cancer. Clin Cancer Res; 16(16); 4226–35. ©2010 AACR.

Safety and Efficacy of Bisphosphonates Beyond 24 Months in Cancer Patients

PURPOSE Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. PATIENTS AND METHODS Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. RESULTS We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy. CONCLUSION Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.

Serum HER‐2/neu and relative resistance to trastuzumab‐based therapy in patients with metastatic breast cancer

Previous reports based on small patient numbers suggested that changes in serum HER‐2/neu levels may predict response or lack of response to trastuzumab‐based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER‐2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff.

Phase II Trial of Gemcitabine, Irinotecan, and Celecoxib in Patients With Advanced Pancreatic Cancer

Goals and Background Cyclooxygenase-2 (COX-2) has been shown to be expressed in a variety of tumors including pancreatic cancer. The combination of gemcitabine and irinotecan is active in pancreatic cancer. The purpose of this study is to determine the toxicity and response rate to the addition of the selective oral COX-2 inhibitor, celecoxib, to gemcitabine and irinotecan in patients with inoperable pancreatic cancer. Study Twenty-one patients with previously untreated inoperable pancreatic cancer were entered on this trial. Seven patients had localized disease, 8 had metastatic disease, and 6 patients were inevaluable. Results Twenty percent of the patients had a partial response and 80% of the patients had a stable response with a median response rate of 9 months. The median overall survival was 18 months with 80% of the patients achieving 1-year survival and 20% achieving 2-year survival. Using the FACT-PA scale to measure the quality of life (QOL), 13 of the 15 patients reported an improvement in their QOL and 2 patients reported no change. The median CA19-9 levels for the 13 patients with measurable CA19-9 values, decreased by 71% by cycle 2. Adverse events were acceptable and included neutropenia, thrombocytopenia, nausea, fatigue, and anemia. Conclusions The combination of gemcitabine, irinotecan, and celecoxib is an active therapy for inoperable pancreatic cancer. A marked reduction in CA19-9 is observed in all evaluable patients by cycle 2. Toxicity is tolerable and a majority of patients reported a decrease in pain and a significant improvement in their QOL.

Elevated plasma tissue inhibitor of metalloproteinase-1 level predicts decreased response and survival in metastatic breast cancer.

Tissue inhibitors of metalloproteinase (TIMPs) have at least 2 different functions. They inhibit the catalytic activity of matrix metalloproteinases, and they act as growth factors.

HER-2 therapy. HER-2/neu diagnostics in breast cancer

HER-2/neu status of the primary breast cancer (PBC) is determined by immunohistochemistry and fluorescent in situ hybridization. Because of a variety of technical factors, however, the PBC may not accurately reflect the metastatic tumor in terms of HER-2/neu status. Recently published guidelines recommend that tumors be defined as HER-2/neu positive if 30% or more of the cells are 3+. Circulating levels of the HER-2 extracellular domain can be measured in serum using a test cleared by the US Food and Drug Administration, and increased serum HER-2/neu levels to above 15 ng/ml can reflect tumor progression. Studies comparing tissue HER-2/neu status of the PBC and HER-2/neu levels above 15 ng/ml in metastatic breast cancer patients are also reviewed.

Quantitative HER2 protein levels predict outcome in fluorescence in situ hybridization‐positive patients with metastatic breast cancer treated with trastuzumab

Only a portion of breast cancer patients currently selected for trastuzumab therapy respond.