Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial.

BACKGROUND: Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). METHODS: The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase 3 trial was conducted in hospitals in nine countries. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. FINDINGS: 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. INTERPRETATION: Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. FUNDING: Pfizer.

Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial.

Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers. Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided. Results: In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P < .001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy. Conclusions: The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.

Pathway-based subnetworks enable cross-disease biomarker discovery.

Biomarkers lie at the heart of precision medicine. Surprisingly, while rapid genomic profiling is becoming ubiquitous, the development of biomarkers usually involves the application of bespoke techniques that cannot be directly applied to other datasets. There is an urgent need for a systematic methodology to create biologically-interpretable molecular models that robustly predict key phenotypes. Here we present SIMMS (Subnetwork Integration for Multi-Modal Signatures): an algorithm that fragments pathways into functional modules and uses these to predict phenotypes. We apply SIMMS to multiple data types across five diseases, and in each it reproducibly identifies known and novel subtypes, and makes superior predictions to the best bespoke approaches. To demonstrate its ability on a new dataset, we profile 33 genes/nodes of the PI3K pathway in 1734 FFPE breast tumors and create a four-subnetwork prediction model. This model out-performs a clinically-validated molecular test in an independent cohort of 1742 patients. SIMMS is generic and enables systematic data integration for robust biomarker discovery.

Duration of chemotherapy with topotecan influences survival in recurrent ovarian cancer: a meta-analysis.

OBJECTIVE: This meta-analysis compares the feasibility, safety and clinical outcome of long-term therapy with topotecan vs. standard treatment duration in patients with recurrent ovarian cancer. MATERIALS AND METHODS: Data of 523 patients from five clinical trials were reviewed and retrospectively allocated into two groups. Those patients who received 6 or fewer courses were compared to those with 7 or more courses of intravenous topotecan. Response rates, overall survival and toxicity profiles were compared between these groups. RESULTS: One hundred and fifty-two (29%) patients received 7 or more courses and 371 patients (71%) received up to 6 courses of topotecan. Hematological toxicity was significant but similar in both treatment groups and was not cumulative. Non-hematological toxicity was generally mild. Eighty-seven (17%) patients responded to topotecan treatment, 66 of these patients received 7 or more courses of therapy. In total, 14 patients experienced their initial response at or after course 6 of therapy. Within the subset of patients with response or disease stabilization at course 6, those who stopped treatment at course 6 for reasons other than progressive disease or adverse events had a median survival of 83.6 weeks and those who continued treatment for longer than 6 courses had a significantly longer median survival of 107.0 weeks. CONCLUSION: Chemotherapy with 7 or more courses of topotecan in recurrent ovarian cancer is feasible with no evidence of cumulative toxicity. The results of this retrospective analysis suggest a potential for late response and a survival benefit for those patients without disease progression who continue topotecan therapy beyond 6 cycles of treatment.

Molecular stratification of early breast cancer identifies drug targets to drive stratified medicine.

Many women with hormone receptor-positive early breast cancer can be managed effectively with endocrine therapies alone. However, additional systemic chemotherapy treatment is necessary for others. The clinical challenges in managing high-risk women are to identify existing and novel druggable targets, and to identify those who would benefit from these therapies. Therefore, we performed mRNA abundance analysis using the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial pathology cohort to identify a signature of residual risk following endocrine therapy and pathways that are potentially druggable. A panel of genes compiled from academic and commercial multiparametric tests as well as genes of importance to breast cancer pathogenesis was used to profile 3825 patients. A signature of 95 genes, including nodal status, was validated to stratify endocrine-treated patients into high-risk and low-risk groups based on distant relapse-free survival (DRFS; Hazard Ratio = 5.05, 95% CI 3.53-7.22, p = 7.51 × 10-19). This risk signature was also found to perform better than current multiparametric tests. When the 95-gene prognostic signature was applied to all patients in the validation cohort, including patients who received adjuvant chemotherapy, the signature remained prognostic (HR = 4.76, 95% CI 3.61-6.28, p = 2.53× 10-28). Functional gene interaction analyses identified six significant modules representing pathways involved in cell cycle control, mitosis and receptor tyrosine signaling; containing a number of genes with existing targeted therapies for use in breast or other malignancies. Thus the identification of high-risk patients using this prognostic signature has the potential to also prioritize patients for treatment with these targeted therapies.

Comparison of ID8 MOSE and VEGF-modified ID8 cell lines in an immunocompetent animal model for human ovarian cancer.

Attempts to develop novel immunotherapeutic mouse models have been hampered by the lack of an adequate in vivo system. This study was performed to establish an immunocompetent mouse model for the testing of immunotherapy concepts. The in vivo system was based on a svngeneic mouse ovarian surface epithelium (MOSE) cancer, physiologically and biologically closely resembling human epithelial ovarian cancer. In addition, a more aggressive variant containing a mutated form of vascular epithelial growth factor was also evaluated. The growth patterns of these ovarian cancer cells in mice were compared to the established, highly aggressive 4T1 breast cancer model. A clinically-relevant tool for the study of different growth patterns in ovarian cancer, with potential significance for the development of novel immunological methods, was successfully developed.

Combination of local, non-viral IL12 gene therapy and systemic paclitaxel chemotherapy in a syngeneic ID8 mouse model for human ovarian cancer.

The in vivo feasibility of the previously established ID8 and ID8-VEGF ovarian cancer models for non-viral IL-12 gene delivery by itself or in combination with paclitaxel chemotherapy, was investigated in C57BL/6 black mice. The syngeneic mouse ovarian epithelium (MOSE) cancer cell line and its more aggressive variant, a VEGF-modified strain, were used to perform these experiments. Tumor growth and survival were observed in C57/BL6 mice, inoculated with both ID8 substrains. The superiority of IL-12 gene therapy in comparison to conventional paclitaxel chemotherapy in terms of tumor size and survival was demonstrated.

Validation of the IHC4 Breast Cancer Prognostic Algorithm Using Multiple Approaches on the Multinational TEAM Clinical Trial.

CONTEXT: Hormone receptors HER2/neu and Ki-67 are markers of residual risk in early breast cancer. An algorithm (IHC4) combining these markers may provide additional information on residual risk of recurrence in patients treated with hormone therapy. OBJECTIVE: To independently validate the IHC4 algorithm in the multinational Tamoxifen Versus Exemestane Adjuvant Multicenter Trial (TEAM) cohort, originally developed on the trans-ATAC (Arimidex, Tamoxifen, Alone or in Combination Trial) cohort, by comparing 2 methodologies. DESIGN: The IHC4 biomarker expression was quantified on TEAM cohort samples (n = 2919) by using 2 independent methodologies (conventional 3,3'-diaminobezidine [DAB] immunohistochemistry with image analysis and standardized quantitative immunofluorescence [QIF] by AQUA technology). The IHC4 scores were calculated by using the same previously established coefficients and then compared with recurrence-free and distant recurrence-free survival, using multivariate Cox proportional hazards modeling. RESULTS: The QIF model was highly significant for prediction of residual risk (P < .001), with continuous model scores showing a hazard ratio (HR) of 1.012 (95% confidence interval [95% CI]: 1.010-1.014), which was significantly higher than that for the DAB model (HR: 1.008, 95% CI: 1.006-1.009); P < .001). Each model added significant prognostic value in addition to recognized clinical prognostic factors, including nodal status, in multivariate analyses. Quantitative immunofluorescence, however, showed more accuracy with respect to overall residual risk assessment than the DAB model. CONCLUSIONS: The use of the IHC4 algorithm was validated on the TEAM trial for predicting residual risk in patients with breast cancer. These data support the use of the IHC4 algorithm clinically, but quantitative and standardized approaches need to be used.

Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors.

PURPOSE: The feasibility and utility of assessing quality of life (QoL) and disease-related symptoms in patients with advanced cancer have been evaluated in two Phase I clinical trials of p.o. administered ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced cancer. EXPERIMENTAL DESIGN: Functional Assessment of Cancer Therapy (FACT) questionnaires, including disease-specific subscales for lung, head and neck, colorectal, prostate, and ovarian cancer, were completed by patients in two open-label, Phase I, escalating multiple-dose safety and tolerability trials. RESULTS: In 157 patients, 92% of whom had received prior therapy, compliance in returning FACT questionnaires was 87% (European/Australian trial) and 57% (United States trial). This did not appear to be influenced by dose level or tumor type. For patients with colorectal, prostate, or ovarian cancer, median QoL [FACT and Trial Outcome Index (TOI)] scores deteriorated over time. In contrast, for patients with non-small cell lung cancer (NSCLC) or head and neck cancer, median FACT and TOI scores did not deteriorate significantly, and in the United States trial, head and neck cancer scores improved significantly over time. In patients with NSCLC, symptom-related scores measured by the Lung Cancer Subscale of FACT-L appeared sensitive to clinical change. CONCLUSIONS: QoL (FACT-L) questionnaires were used successfully in the Phase I clinical trials of ZD1839. They appeared to be a sensitive tool to monitor clinical changes for the five tumor types in these trials and showed that ZD1839 has the potential to improve patients' QoL.

A germline variation in the progesterone receptor gene increases transcriptional activity and may modify ovarian cancer risk.

Recently, we and others have detected a haplotype of the human progesterone receptor gene (PR). This haplotype consists of a 320-bp insertion in intron G together with point mutations in exons 4 and 5 and was named PROGINS. Whereas the exon 5 mutation is silent, the mutation in exon 4 results in a V660L substitution. Interestingly, this genetic polymorphism was seen to cosegregate with an increased risk of sporadic ovarian cancer in different ethnic groups. Our data provide evidence for the existence of an epidemiological link between a mutated progesterone receptor allele and ovarian cancer (odds ratio, 3.02; 95% confidence interval, 1.86-4.91). Functional characterization of the mutated receptor protein revealed a greater transcriptional activity compared with the wild-type receptor. By contrast, hormone binding and hormone dissociation rates were similar in both receptor proteins. We found that the increased transcriptional activity was due to increased stability resulting in higher expression of the mutant protein. Thus, the long-lasting hyperactivation of progesterone receptor-driven genes secondary to the increased transcriptional activity of the mutated progesterone receptor may participate in ovarian carcinogenesis. This is of special interest, because only a few genetic markers are available for the majority of women diagnosed with sporadic ovarian cancer.

Intraperitoneal adenovirus-mediated suicide gene therapy in combination with either topotecan or paclitaxel in nude mice with human ovarian cancer.

A mouse model of human ovarian cancer was used to investigate the effect of adenovirus-mediated thymidine kinase gene therapy (gt) in combination with chemotherapy. One hundred sixty female CD-1 nu/nu mice were injected intraperitoneally with Ov-ca-2774 cells. Onset of intraperitoneal treatment with either topotecan (6 or 12 mg/kg) or paclitaxel (18 or 36 mg/kg) was on day 4 or 8 and was repeated once after 4 days. Animals scheduled for gt received intraperitoneal application of adv/rsv-tk 1 day prior to chemotherapy and were subsequently treated with ganciclovir (gcv; 10 mg/kg, every 12 hours for 6 days). Survival was chosen as study endpoint. Whereas tumor burden had hardly any effect on survival, the lower dose of either cytotoxic agent was seen to be more effective than the higher one. In the topotecan group, an interaction between topotecan and gt was present. Survival was best for animals treated with low dose of topotecan only, the addition of gt reduced survival time significantly. With the higher dose, gt did not affect survival time. With paclitaxel, only slight effects of gt on the survival times were seen. Due to treatment toxicity, this animal model may be problematic for the evaluation of gt and chemotherapy combinations. The effect of dose varied strongly with time. Mice treated with high-dose chemotherapy had a substantially increased risk of dying in the time period following application, whereas this advantage of the lower dose disappeared later.

Expression of splicing factors in human ovarian cancer.

Alternative splicing represents an important nuclear mechanism in the post-transcriptional regulation of gene expression, which is frequently altered during tumorigenesis. Previously, we have described marked changes in alternative splicing of the CD44 gene in ovarian and breast cancer. In the latter one we described also a specific induction of splicing factors during tumor development. Now we have focussed our studies on the expression profiles of splicing factors, including classical SR proteins, Tra2 and YB-1 in physiological and malignant ovarian tissues by RT-PCR and Western blot analysis. We detected changed expression pattern with higher levels of phosphorylated 30 kDa SR proteins as well as relatively high concentrations of hyperphosphorylated Tra2 protein isoforms in ovarian cancer. RT-PCR analysis revealed a marked induction of SC35 and ASF/SF2 as well as mRNA levels in malignant ovarian tissue. These results suggest gene-specific alterations of expression rather than a general induction of the splicing machinery. Together with previously performed functional studies of CD44 splicing these findings implicate that altered expression profiles of SR proteins, Tra2beta and YB-1 might be responsible for the known changes of alternative CD44 splicing in ovarian cancer.

Experience with the Advanced Breast Biopsy Instrumentation (ABBI) system.

BACKGROUND: The Advanced Breast Biopsy Instrumentation (ABBI) System is designed to excise nonpalpable breast lesions under stereotactic control. We report our experience with special regard to the histological evaluation of margins. PATIENTS AND METHODS: Breast biopsies using the ABBI system were performed on 101 patients with microcalcifications. In histologically-proven breast cancer, a re-excision was performed. RESULTS: Malignant lesions were found in thirteen patients (3 CLIS, 5 DCIS, 5 invasive ductal carcinoma). The margins were positive in two specimens with DCIS. In subsequent lumpectomies one patient with invasive cancer had residual intraductal cancer. All the patients with DCIS had residual cancer, even those with negative margins of the ABBI-specimen. Only minor complications were observed with the ABBI procedure. CONCLUSION: The ABBI system is a safe, minimally invasive stereotactic breast biopsy technique. It saves open biopsies in atypical hyperplasia and CLIS. In cases of DCIS or invasive cancer re-excision is inevitable.

Effect of prior chemotherapy regimens on the efficacy of endocrine therapy within a German cohort of the TEAM trial.

PURPOSE: Prior chemotherapy may affect the efficacy of endocrine therapy. METHODS: The tamoxifen exemestane adjuvant multinational (TEAM) trial compared 5 years of adjuvant exemestane with the sequence of tamoxifen followed by exemestane in postmenopausal women with hormone-receptor-positive breast cancer. A total of 1,502 patients were enrolled in Germany (739 received tamoxifen followed by exemestan and 610 exemestan alone). A retrospective analysis of the German cohort of TEAM was conducted to determine whether prior chemotherapy affected clinical outcome of endocrine therapy. RESULTS: Overall survival, disease-free survival and distant recurrence were similar between patients who received sequential therapy and those who received exemestane monotherapy, irrespective of prior chemotherapy. Overall survival was not significantly different between patients who had received prior chemotherapy and those who had not (P = 0.2836). Disease-free survival and distant recurrence were significantly better in patients who had not received prior chemotherapy versus those who had (P = 0.0308 and P = 0.0001). In patients receiving sequential therapy, there were no significant differences in overall survival according to prior chemotherapy use (P = 0.1812). However, disease-free survival and distant recurrence were significantly different dependent on prior chemotherapy (P = 0.0143 and P = 0.0053). CONCLUSION: In conclusion, there was no difference in overall survival between breast cancer patients who did receive prior chemotherapy before endocrine therapy and those who had not. Patients who had not received prior chemotherapy had significantly improved disease-free survival and less distant recurrence versus those who had received chemotherapy.

Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study.

PURPOSE: Deregulation of key PI3K/AKT pathway genes may contribute to endocrine resistance in breast cancer (BC). PIK3CA is the most frequently mutated gene in luminal BC (35%); however, the effect of mutations in helical versus kinase domains remains controversial. We hypothesize that improved outcomes occur in patients with estrogen receptor­positive (ER positive) BC receiving endocrine therapy and possessing PIK3CA mutations. MATERIALS AND METHODS: DNA was extracted from 4,540 formalin-fixed paraffin-embedded BC samples from the Exemestane Versus Tamoxifen-Exemestane pathology study. Mutational analyses were performed for 25 mutations (PIK3CAx10, AKT1x1, KRASx5, HRASx3, NRASx2 and BRAFx4). RESULTS: PIK3CA mutations were frequent (39.8%), whereas RAS/RAF mutations were rare (1%). In univariable analyses PIK3CA mutations were associated with significantly improved 5-year distant relapse-free survival (DRFS; HR, 0.76; 95% CI, 0.63 to 0.91; P = .003). However, a multivariable analysis correcting for known clinical and biologic prognostic factors failed to demonstrate that PIK3CA mutation status is an independent prognostic marker for DRFS (HR, 0.92; 95% CI, 0.75 to 1.12; P = .4012). PIK3CA mutations were more frequent in low-risk luminal BCs (e.g., grade 1 nodev 3, node-negative v -positive), confounding the relationship between mutations and outcome. CONCLUSION: PIK3CA mutations are present in approximately 40% of luminal BCs but are not an independent predictor of outcome in the context of endocrine therapy, whereas RAS/RAF mutations are rare inluminal BC. A complex relationship between low-risk cancers and PIK3CA mutations was identified. Although the PI3K/AKT pathway remains a viable therapeutic target as the result of ahigh mutation frequency, PIK3CA mutations do not seem to affect residual risk following treatment with endocrine therapy.

Compliance, analgesic use and side-effect protection within a German cohort of the TEAM trial.

BACKGROUND: Compliance is an essential aspect for the success of any medical intervention. Adverse events (AEs) contribute significantly to non-compliance with endocrine treatment. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial compared five years of adjuvant exemestane therapy with the sequence of tamoxifen followed by exemestane. PATIENTS AND METHODS: A retrospective analysis of the German cohort of TEAM was conducted to determine the effects of prior tamoxifen on the tolerability profile of exemestane in both treatment arms. RESULTS: Fracture incidence was significantly higher during the first 30 months of exemestane versus the 30 months of exemestane following tamoxifen for 2-3 years; however, the incidence of AEs was not significantly different. With regard to compliance, the use of analgesics did not influence overall or disease-free survival (DFS) nor the incidence of distant recurrence in both treatment groups. CONCLUSION: Tamoxifen has a boneprotective effect when applied before exemestane treatment. Intake of analgesics (or pain medication) does not influence compliance or treatment outcome.

Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the tamoxifen versus exemestane adjuvant multicenter trial pathology study.

PURPOSE: Some postmenopausal patients with hormone-sensitive early breast cancer remain at high risk of relapse despite endocrine therapy and, in addition, might benefit from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk and may inform treatment decisions. We tested the efficacy of this panel in the Tamoxifen versus Exemestane Adjuvant Multicenter (TEAM) trial. PATIENTS AND METHODS: Pathology blocks from 4,598 TEAM patients were collected, and tissue microarrays (TMAs) were constructed. The cohort was 47% node-positive, and 36% of patients in the cohort were treated with adjuvant chemotherapy. Triplicate 0.6-mm(2) TMA cores were stained, and positivity for p53, HTF9C, CEACAM5, NDRG1, and SLC7A5 was assessed. Cases were assigned a Mammostrat risk score, and distant relapse-free survival (DRFS) and disease-free survival (DFS) were analyzed. RESULTS: In multivariate regression analyses, which were corrected for conventional clinicopathologic markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in estrogen receptor (ER) -positive node-negative patients (n = 1,226) who did not receive chemotherapy (P = .004). Additional analyses in all patients not exposed to chemotherapy, irrespective of nodal status (n = 2,559) and in the entire cohort (n = 3,837) showed Mammostrat scores provided additional information on DRFS in these groups (P = .001 and P < .001, respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens. CONCLUSION: The Mammostrat score predicts DRFS for patients treated with exemestane and patients treated with tamoxifen followed by exemestane irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data after treatment provides additional evidence of its use in risk stratification of ER-positive postmenopausal patients with breast cancer.

Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial.

PURPOSE: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen. PATIENTS AND METHODS: Pathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment. RESULTS: Of 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred < 4) and 77% were PgR- rich (Allred ≥ 5). No treatment-by-marker effect for PgR was observed for exemestane versus tamoxifen (PgR-rich hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.05; PgR-poor HR, 0.85; 95% CI, 0.61 to 1.19; P = .88 for interaction). Both PgR and ER expression were associated with patient prognosis in univariate (PgR HR, 0.53; 95% CI, 0.43 to 0.65; P < .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P = .002), and multivariate analyses (P < .001 and P = .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed. CONCLUSION: Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression; conversely, patients with ER-rich tumors may derive additional benefit from exemestane. Quantitative analysis of ER and PgR expression provides highly significant information on risk of early relapse (within 1 to 3 years) during treatment.