We sought to determine whether a high-risk group could be defined among patients with operable breast cancer in whom a search of occult central nervous system (CNS) metastases was justified.
We ...evaluated data from 9524 women with early breast cancer (42% node-negative) who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1999, and treated without anthracyclines, taxanes, or trastuzumab. We identified patients whose site of first event was CNS and those who had a CNS event at any time.
Median follow-up was 13 years. The 10-year incidence (10-yr) of CNS relapse was 5.2% (1.3% as first recurrence). Factors predictive of CNS as first recurrence included: node-positive disease (10-yr = 2.2% for > 3 N+), estrogen receptor-negative (2.3%), tumor size > 2 cm (1.7%), tumor grade 3 (2.0%), < 35 years old (2.2%), HER2-positive (2.7%), and estrogen receptor-negative and node-positive (2.6%). The risk of subsequent CNS recurrence was elevated in patients experiencing lung metastases (10-yr = 16.4%).
Based on this large cohort we were able to define risk factors for CNS metastases, but could not define a group at sufficient risk to justify routine screening for occult CNS metastases.
To identify the role of estrogen (ER), progesterone (PgR), epidermal growth factor 1 (HER1), and HER2 receptors in predicting response to preoperative chemotherapy.
We reviewed the pretreatment ...biopsies of 485 patients with locally advanced breast cancer (cT2-T4, N0-2, M0) treated with preoperative chemotherapy. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to clinical and pathological findings including ER/PgR status (absent versus expressed), HER1 (absent versus expressed) and HER2 (overexpressed versus none) expression.
Patients with ER/PgR-absent tumors were 12.0 times 95% confidence interval (CI) 4.93–29.28 more likely to achieve a pCR (P<0.0001). Predictors of disease-free survival (DFS) at the univariate analysis included HER1 hazards ratio (HR) 1.6, 95% CI 1.04–2.32, P=0.03 and HER2 (HR 1.6, 95% CI 1.08–2.38, P=0.02) expression. A statistically significant difference in DFS was confirmed at the multivariate analysis for patients with ER/PgR-absent disease (HR 2.1, 95% CI 1.41–2.99, P=0.0002).
The pCR rate is higher and outcome worse for patients with ER/PgR-absent tumors. HER1 and HER2 expression may have a prognostic role in locally advanced breast cancer and warrant further studies.
Older patients with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (aMDS) must decide between receiving intensive induction chemotherapy (IC) or nonintensive chemotherapy/best ...supportive care (NIC). Little information exists about what factors influence treatment decisions and what quality of life (QOL) is associated with treatment choices. We prospectively examined 43 patients 60 years or older who were interviewed at diagnosis and periodically over 1 year. IC choice was associated with younger age (66 vs 76 years, P=0.01) and AML diagnosis, but not with performance status, comorbidities, or QOL. In total, 63% of all patients reported not being offered other treatment options despite physician documentation of alternatives. Patient and physician estimates of cure differed significantly: 74% of patients estimated their chance of cure to be 50% or greater, yet for 89% of patients physician estimates of cure were 10% or less. IC patients experienced decreased QOL at 2 weeks, but rebounded to baseline and to NIC levels by 6 weeks. Initial QOL is not associated with treatment choice in older AML and aMDS patients. Regardless of treatment choice, patients report not being offered treatment options and overestimate their chances of cure. In IC patients, QOL decreases during hospitalization but rebounds after discharge.
We compared inpatient and outpatient costs alongside clinical outcomes associated with hematopoietic cell transplantation between 2000 and 2003 with high-dose regimens (HDCT, n=185) and with reduced ...intensity regimens (RICT, n=90) from human leukocyte antigen (HLA)-matched donors for patients with hematological malignancies. With a comparable median follow-up of 3 years, long-term clinical outcomes, including cumulative incidence of chronic graft-vs-host disease, disease-free survival and overall survival, were similar between the two groups. In the univariate analysis, median costs for the first 100 days ($104,380 vs $42,149) and 1 year ($128,253 vs $80,499) in the HDCT group were higher than those in the RICT group. Median days of hospitalization are also higher for HDCT recipients (39 vs 21), although the number of outpatient clinic visits for HDCT recipients were fewer compared to that for RICT recipients (16 vs 25) during the first year. Adjusting for patient characteristics, RICT recipients had approximately 16 fewer days of hospitalization and cost $53,030 less than HDCT recipients within the first year after transplantation. Our data suggest that substantially lower costs and fewer days of hospitalization within the first year after RICT procedures can be obtained with no compromise of long-term clinical outcomes compared to HDCT procedures.
To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic ...leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In coculture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity.
Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among ...patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, -2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.
The purpose of this research was to identify factors predicting response to preoperative chemotherapy.
In a large volume laboratory using standard immunohistochemical methods, we reviewed the ...pretreatment biopsies and histologic specimens at final surgery of 399 patients with large or locally advanced breast cancer (cT2-T4, N0-2, M0) who were treated with preoperative chemotherapy. The incidence of pathological complete remission and the incidence of node-negative status at final surgery were assessed with respect to initial pathological and clinical findings. Menopausal status, estrogen receptor status, progesterone receptor status absent (0% of the cells positive) versus expressed, clinical tumor size, histologic grade, Ki-67, Her-2/neu expression, and type and route of chemotherapy were considered.
High rates of pathological complete remission were associated with absence of estrogen receptor and progesterone receptor expression (P < 0.0001), and grade 3 (P = 0.001). Significant predictors of node-negative status at surgery were absence of estrogen receptor and progesterone receptor expression (P < 0.0001), clinical tumor size <5 cm (P < 0.001), and use of infusional regimens (P = 0.003). The chance of obtaining pathological complete remission or node-negative status for patients with endocrine nonresponsive tumors compared with those having some estrogen receptor or progesterone receptor expression was 4.22 (95% confidence interval, 2.20-8.09, 33.3% versus 7.5%) and 3.47 (95% confidence interval, 2.09-5.76, 42.9% versus 21.7%), respectively. Despite the significantly higher incidence of pathological complete remission and node-negative status achieved by preoperative chemotherapy for patients with estrogen receptor and progesterone receptor absent disease, the disease-free survival was significantly worse for this cohort compared with the low/positive expression cohort (4-year disease-free survival %: 41% versus 74%; hazard ratio 3.22; 95% confidence interval, 2.28-4.54; P < 0.0001).
Response to preoperative chemotherapy is significantly higher for patients with endocrine nonresponsive tumors. New chemotherapy regimens or combinations should be explored in this cohort of patients with poor outcome. For patients with endocrine responsive disease, the role of preoperative endocrine therapies should be studied.
Primary human tissues are an invaluable widely used tool for discovery of gene expression patterns which characterize disease states. Tissue processing methods remain unstandardized, leading to ...unanswered concerns of how to best store collected tissues and maintain reproducibility between laboratories. We subdivided uterine myometrial tissue specimens and stored split aliquots using the most common tissue processing methods (fresh, frozen, RNALater) before comparing quantitative RNA expression profiles on the Affymetrix U133 human expression array. Split samples and inclusion of duplicates within each processing group allowed us to undertake a formal genome-wide analysis comparing the magnitude of result variation contributed by sample source (different patients), processing protocol (fresh vs. frozen vs. 24 or 72 hours RNALater), and random background (duplicates). The dataset was randomly permuted to define a baseline pattern of ANOVA test statistic values against which the observed results could be interpreted.
14,639 of 22,283 genes were expressed in at least one sample. Patient subjects provided the greatest sources of variation in the mixed model ANOVA, with replicates and processing method the least. The magnitude of variation conferred by processing method (24 hours RNALater vs 72 hours RNALater vs. fresh vs frozen) was similar to the variability seen within replicates. Subset analysis of the test statistic according to gene functional class showed that the frequency of "outlier" ANOVA results within each functional class is overall no greater than expected by chance.
Ambient storage of tissues for 24 or 72 hours in RNALater did not contribute any systematic shift in quantitative RNA expression results relative to the alternatives of fresh or frozen tissue. This nontoxic preservative enables decentralized tissue collection for expression array analysis without a requirement for specialized equipment.
Gemtuzumab ozogamicin (GO), a monoclonal antibody used in the treatment of acute myelogenous leukemia (AML) has been linked to the development of venoocclusive disease (VOD). We conducted a ...retrospective study of 62 patients with previously treated AML/MDS (myelodysplastic syndrome) who underwent allogeneic stem cell (SC) transplantation at our institution from December 2000 to October 2002 to determine whether GO exposure prior to allogeneic SC transplantation increases the risk of developing VOD. Fourteen patients received GO prior to SC transplantation. Of 62 patients, 13 (21%) developed VOD; 9 (64%) of 14 with prior GO exposure developed VOD compared with 4 (8%) of 48 without prior GO exposure (P < .0001). Logistic regression controlling for sex, disease status, donor type, and graft-versus-host disease prophylaxis identified prior treatment with GO as a significant risk factor for VOD (odds ratio OR, 21.6; 95% confidence interval CI, 4.2-112.2. Nine of 10 patients who underwent SC transplantation 3.5 months or less following GO developed VOD compared with none of 4 patients who underwent SC transplantation more than 3.5 months from GO administration. Three of 14 patients who received GO prior to SC transplantation died of VOD. We conclude that patients undergoing SC transplantation within a short interval from GO administration are at increased risk of developing VOD.
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