Hannah M. Linden

HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab

Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer. Experimental Design: We enrolled patients with metastatic HER2+ breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 17 months (95% CI: 16–28). Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR.

Quantitative Fluoroestradiol Positron Emission Tomography Imaging Predicts Response to Endocrine Treatment in Breast Cancer

PURPOSE In breast cancer, [(18)F]fluoroestradiol (FES) positron emission tomography (PET) correlates with estrogen receptors (ER) expression and predicts response to tamoxifen. We tested the ability of FES-PET imaging to predict response to salvage hormonal treatment in heavily pretreated metastatic breast cancer patients, predominantly treated with aromatase inhibitors. PATIENTS AND METHODS Initial FES uptake measurements in 47 patients with ER-positive tumors were correlated with subsequent tumor response to 6 months of hormonal treatment. Most patients had bone dominant disease and prior tamoxifen exposure. Response was compared to initial FES-PET uptake, measured qualitatively and quantitatively using standardized uptake value (SUV) and estradiol-binding flux. RESULTS Eleven of 47 patients (23%) had an objective response. While no patients with absent FES uptake had a response to treatment, the association between qualitative FES-PET results and response was not significant (P = .14). However, quantitative FES uptake and response were significantly associated; zero of 15 patients with initial SUV less than 1.5 responded to hormonal therapy, compared with 11 of 32 patients (34%) with SUV higher than 1.5 (P < .01). In the subset of patients whose tumors did not overexpress HER2/neu, 11 of 24 patients (46%) with SUV higher than 1.5 responded. CONCLUSION Quantitative FES-PET can predict response to hormonal therapy and may help guide treatment selection. Treatment selection using quantitative FES-PET in our patient series would have increased the rate of response from 23% to 34% overall, and from 29% to 46% in the subset of patients lacking HER2/neu overexpression. A multi-institutional collaborative trial would permit definitive assessment of the value of FES-PET for therapeutic decision making.

Androgen Receptor Expression in Estrogen Receptor-Negative Breast Cancer Immunohistochemical, Clinical, and Prognostic Associations

We sought to determine the prevalence of androgen receptor (AR) expression in a predominantly estrogen receptor (ER)-negative subset of breast cancers and delineate the immunohistochemical and clinical associations, including whether AR expression has prognostic significance in ER-negative tumors. We identified 69 ER-negative and 19 ER-positive breast cancer cases with concurrent immunohistochemical prognostic panels (ER, PR, HER-2/neu, Ki-67, and p53); immunohistochemical analysis was performed for AR using standard techniques. Clinical data were extracted from medical records. chi 2 tests were used to assess associations between variables. AR was found in 49% (34/69) of ER-negative and 89% (17/19) of ER-positive cases. In ER-negative tumors, AR was associated with increased age (P = .02), postmenopausal status (P < .001), tumor grade (P = .03), tumor size (P = .03), and HER-2/neu overexpression (P = .003). In ER-positive tumors, AR was associated with progesterone receptor expression (P < .03). In univariate analysis of ER-negative tumors, patients with AR-positive tumors had significantly better disease-free survival (P = .049). AR is expressed in a significant number of ER-negative cases and shows significant associations with important clinical and pathologic prognostic factors.

Racial inequities in the timing of breast cancer detection, diagnosis, and initiation of treatment.

Background:Recent studies suggest differences in quality and timeliness of care received may be major contributing sources to the racial disparity in breast cancer detection and related outcomes. Methods:Female patients with breast cancer diagnosed during 1985–1993 (n = 400) and followed through June 20, 2001, were included in this retrospective cohort study. Three white patients were selected randomly and matched to each black patient by year of diagnosis. Method and timing of diagnosis and timing of treatment were abstracted from medical records. Initial staging and subsequent breast cancer recurrence and vital status were obtained from the Hospital and Connecticut State Tumor Registry. Results:Black women were more likely than white women to be diagnosed after a patient-noted abnormality. Black women were less likely than white women to have completed a diagnostic evaluation within 30 days after a patient-noted abnormality (P < 0.01) or after having an abnormality noted on screening mammogram (P = 0.0001) and were less likely to have initiated treatment within 30 days of diagnosis (P = 0.0001). Women diagnosed after a patient-noted abnormality were more likely to have subsequent breast cancer recurrence and/or death due to breast cancer compared with women diagnosed after a screening mammogram (56% versus 24%, respectively, P < 0.05). Conclusions:Racial differences were identified at each step in the evaluation and treatment clinical pathway, including method of detection, timing from first symptoms of cancer to pathologic diagnosis, and timing from diagnosis to initiation of treatment. The findings highlight the need to provide equal opportunity for timely medical care and treatment.

Tumor Receptor Imaging

Tumor receptors play an important role in carcinogenesis and tumor growth and have been some of the earliest targets for tumor-specific therapy, for example, the estrogen receptor in breast cancer. Knowledge of receptor expression is key for therapy directed at tumor receptors and traditionally has been obtained by assay of biopsy material. Tumor receptor imaging offers complementary information that includes evaluation of the entire tumor burden and characterization of the heterogeneity of tumor receptor expression. The nature of the ligand–receptor interaction poses a challenge for imaging—notably, the requirement for a low molecular concentration of the imaging probe to avoid saturating the receptor and increasing the background because of nonspecific uptake. For this reason, much of the work to date in tumor receptor imaging has been done with radionuclide probes. In this overview of tumor receptor imaging, aspects of receptor biochemistry and biology that underlie tumor receptor imaging are reviewed, with the estrogen–estrogen receptor system in breast cancer as an illustrative example. Examples of progress in radionuclide receptor imaging for 3 receptor systems—steroid receptors, somatostatin receptors, and growth factor receptors—are highlighted, and recent investigations of receptor imaging with other molecular imaging modalities are reviewed.

Tumor Metabolism and Blood Flow Changes by Positron Emission Tomography: Relation to Survival in Patients Treated With Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer

PURPOSE Patients with locally advanced breast carcinoma (LABC) receive preoperative chemotherapy to provide early systemic treatment and assess in vivo tumor response. Serial positron emission tomography (PET) has been shown to predict pathologic response in this setting. We evaluated serial quantitative PET tumor blood flow (BF) and metabolism as in vivo measurements to predict patient outcome. PATIENTS AND METHODS Fifty-three women with primary LABC underwent dynamic [(18)F]fluorodeoxyglucose (FDG) and [(15)O]water PET scans before and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG) and transport (FDG K(1)) parameters were calculated; BF was estimated from the [(15)O]water study. Associations between BF, MRFDG, FDG K(1), and standardized uptake value and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. RESULTS Patients with persistent or elevated BF and FDG K(1) from baseline to midtherapy had higher recurrence and mortality risks than patients with reductions. In multivariable analyses, BF and FDG K(1) changes remained independent prognosticators of DFS and OS. For example, in the association between BF and mortality, a patient with a 5% increase in tumor BF had a 67% higher mortality risk compared with a patient with a 5% decrease in tumor BF (hazard ratio = 1.67; 95% CI, 1.24 to 2.24; P < .001). CONCLUSION LABC patients with limited or no decline in BF and FDG K(1) experienced higher recurrence and mortality risks that were greater than the effects of clinical tumor characteristics. Tumor perfusion changes over the course of neoadjuvant chemotherapy measured directly by [(15)O]water or indirectly by dynamic FDG predict DFS and OS.

Thrombopoietin: a pan-hematopoietic cytokine

The recent discovery of thrombopoietin has enhanced our understanding of both hematopoiesis and platelet production. Thrombopoietin supports hematopoietic stem cell survival and expansion as well as promoting all aspects of megakaryocyte development. The hormone displays many structural similarities to other members of the hematopoietic cytokine family and some notable differences, and regulation of its expression requires both receptor-mediated removal and other mechanisms. Thrombopoietin induces receptor dimerization and tyrosine phosphorylation, and a series of signaling events including activation of JAK/STAT, Shc/Ras/MAPK and PI3K/Akt; these pathways overlap with those induced by other cytokines, but the differences that lead to the unique biological effects of the hormone are gradually being uncovered. Our growing appreciation of how cytokine signaling pathways are translated into megakaryocyte development is discussed.

Fluoroestradiol Positron Emission Tomography Reveals Differences in Pharmacodynamics of Aromatase Inhibitors, Tamoxifen, and Fulvestrant in Patients with Metastatic Breast Cancer

Purpose: To determine, by molecular imaging, how in vivo pharmacodynamics of estrogen-estrogen receptor (ER) binding differ between types of standard endocrine therapy. Experimental Design: The ER has been a highly successful target for breast cancer treatment. ER-directed treatments include lowering ligand concentration by using aromatase inhibitors (AI) and blocking the receptor with agents like tamoxifen (TAM) or fulvestrant (FUL). We measured regional estrogen-ER binding by using positron emission tomography with 18F-fluoroestradiol (FES PET) prior to and during treatment with AI, TAM, or FUL in a series of 30 metastatic breast cancer patients. FES PET measured in vivo estrogen binding at all tumor sites in heavily pretreated women with metastatic bone soft tissue–dominant breast cancer. In patients with uterus (n = 16) changes in uterine FES uptake were also measured. Results: As expected, tumor FES uptake declined more markedly on ER blockers (TAM and FUL, average 54% decline) compared with a less than 15% average decline on estrogen-depleting AIs (P < 0.001). The rate of complete tumor blockade [FES standardized uptake value (SUV) ≤1.5] following TAM (5/5 patients) was greater than the blockade rate following FUL (4/11; 2-sided mid P = 0.019). Percent FES SUV change in the uterus showed a strong association with tumoral change (ρ = 0.63, P = 0.01). Conclusions: FES PET can assess the in vivo pharmacodynamics of ER-targeted agents and may give insight into the activity of established therapeutic agents. Imaging revealed significant differences between agents, including differences in the efficacy of blockade by different ER antagonists in current clinical use. Clin Cancer Res; 17(14); 4799–805. ©2011 AACR.

Gene expression profiling and breast cancer care: what are the potential benefits and policy implications?

Purpose: Gene expression profiling has been proposed as an alternative to clinical guidelines to identify high-risk patients for adjuvant chemotherapy. However, the outcomes associated with gene expression profiling are not clear, and guidelines for the appropriate use of genomic technologies have not been established.Methods: We developed a decision analytic model to evaluate the incremental cost and quality-adjusted life years of gene expression profiling versus NIH clinical guidelines in a hypothetical cohort of premenopausal early stage breast cancer patients 44 years of age. We conducted empirical analyses and identified literature-based data to inform the model, and performed probabilistic sensitivity analyses to evaluate uncertainty in the results. We interpreted the implications of our findings for treatment guidelines and policies.Results: Use of gene expression profiling resulted in an absolute 5% decrease in the proportion of cases of distant recurrence prevented, 0.21 fewer quality-adjusted life years, and a cost savings of

PET Tumor Metabolism in Locally Advanced Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy: Value of Static versus Kinetic Measures of Fluorodeoxyglucose Uptake

2882. The chosen test cutoff value to identify a tumor as poor prognosis and the cost of adjuvant chemotherapy were the most influential parameters in the analysis, but our findings did not change substantially in sensitivity analyses. Regardless of the test cutoff used to identify a poor prognosis tumor, the gene expression profiling assay studied in our analysis, at its current level of performance, did not attain the threshold sensitivity (95%) necessary to produce equal or greater quality-adjusted life years than NIH guidelines.Conclusion: Although the use of gene expression profiling in breast cancer care holds great promise, our analysis suggests additional refinement and validation are needed before use in clinical practice.