Expression of ER, PgR, HER1, HER2, and response: a study of preoperative chemotherapy.

PURPOSE: To identify the role of estrogen (ER), progesterone (PgR), epidermal growth factor 1 (HER1), and HER2 receptors in predicting response to preoperative chemotherapy. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer.

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.

Lower costs associated with hematopoietic cell transplantation using reduced intensity vs high-dose regimens for hematological malignancy.

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.

Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG).

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Quantifying trade-offs: quality of life and quality-adjusted survival in a randomised trial of chemotherapy in postmenopausal patients with lymph node-negative breast cancer.

We evaluated quality of life (QL) and quality-adjusted survival in International Breast Cancer Study Group Trial IX, a randomised trial including 1669 eligible patients receiving tamoxifen for 5 years or three prior cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 57 months tamoxifen. During the time with CMF toxicity (Tox), without symptoms and toxicity (TWiST), and following relapse (Rel), patients scored their QL indicators and a utility indicator for subjective health estimation between 'perfect' and 'worst' health. Scores were averaged within Tox, TWiST and Rel and transformed to utilities. Mean durations for the three transition times were weighted with utilities to obtain mean quality-adjusted TWiST (Q-TWiST). Patients receiving CMF reported significantly worse scores for most QL domains at month 3, but less hot flushes. After completing chemotherapy, there were no differences by treatment groups. Benefits evaluated by Q-TWiST favoured the additional chemotherapy. CMF provided 3 more months of Q-TWiST for patients with ER-negative tumours, but CMF provided no benefit in Q-TWiST for patients with ER-positive tumours. Q-TWiST analysis based on patient ratings is feasible in large-scale cross-cultural clinical trials.

Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome.

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.

Preoperative systemic treatment: prediction of responsiveness.

The use of predictive factors allows a more effective use of available therapies by enabling clinicians to distinguish patients likely to obtain substantial benefit from treatment from those for whom the same therapy is less likely to be effective. A most relevant aspect of clinical research is thus to develop alternative therapeutic approaches which are more efficacious for this latter group, particularly important since treatment effects are likely to be small. In the preoperative setting several predictors of response were identified. They include: diameter of the lesion (larger lesions respond less than smaller lesions), MIB-1 increased expression associated with increased response to chemotherapy, and estrogen receptor (ER) and progesterone receptor (PgR) expression in the tumor typically associated with increased response to endocrine therapies. Other factors include HER-2/neu overexpression, which is a target for treatment with the humanized monoclonal antibody against its extracellular domain, is hypothesized to increase response to anthracycline combination chemotherapy and to lead to an improved response to some endocrine agents (e.g. letrozole) rather than to others. Although primary endocrine therapy demonstrated activity and low profile of side effects in selected populations of older patients, it is infrequently used. On the other hand, chemotherapy remains the mainstay of treatment being considered to be a more active and better documented option. Experience at the European Institute of Oncology on 399 patients with large or locally advanced breast cancer (cT2-T4, N0-2, M0) treated with primary chemotherapy, indicated that a proper selection of primary treatment should be based on tumor characteristics such as ER and PgR status. In particular, patients with tumors with no ER and PgR expression (endocrine-unresponsive disease) at the baseline core-biopsy had a significantly higher response rate to chemotherapy if compared with tumors with some ER/PgR expression. In fact, the absence of ER and PgR expression was the strongest predictors of pCR at the multivariate analysis (P<0.0001). Information on endocrine responsiveness before primary systemic therapy will lead to better tailoring of treatment modalities, thus avoiding chemotherapy in selected populations where other approaches (e.g. endocrine primary therapy) might be more useful.