Predictive Value of Molecular Subtypes in Premenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the ABCSG Trial 5.

PURPOSE: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. EXPERIMENTAL DESIGN: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors. RESULTS: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). CONCLUSIONS: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.See related commentary by Hunter et al., p. 5543.

Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone.

PURPOSE: EndoPredict (EPclin) is a prognostic test validated to inform decisions on adjuvant chemotherapy to endocrine therapy alone for patients with oestrogen receptor-positive, HER2-negative breast cancer. Here, we determine the performance of EPclin for estimating 10-year distant recurrence-free interval (DRFI) rates for those who received adjuvant endocrine therapy (ET) alone compared to those with chemotherapy plus endocrine therapy (ET + C). METHODS: A total of 3746 women were included in this joint analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET + C (GEICAM 2003-02/9906). The primary objective was to evaluate the ability of EPclin to provide an estimate of the 10-year DR rate as a continuous function of EPclin separately for ET alone and ET + C. Cox proportional hazard models were used for these analyses. RESULTS: EPclin was highly prognostic for DR in women who received ET alone (HR 2.79 (2.49-3.13), P < 0.0001) as well as in those who received ET + C (HR 2.27 (1.99-2.59), P < 0.0001). Women who received ET + C had significantly smaller increases in 10-year DR rates with the increasing EPclin score than those receiving ET alone (EPclin = 5; 12% ET + C vs. 20% ET alone). We observed a significant positive interaction between EPclin and treatment groups (P-interaction = 0.022). CONCLUSIONS: In this comparative non-randomised analysis, the rate of increase in DR with EPclin score was significantly reduced in women who received ET + C versus ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease.

Cost-effectiveness analysis of prognostic gene expression signature-based stratification of early breast cancer patients.

BACKGROUND: The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict(®) (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer. OBJECTIVE: Using a life-long Markov state transition model, we determined the health economic impact and incremental cost effectiveness of EPclin-based risk stratification in combination with clinical guidelines [German-S3, National Comprehensive Cancer Center Network (NCCN), and St. Gallen] to decide on chemotherapy use. METHODS: Information on overall and metastasis-free survival came from Austrian Breast & Colorectal Cancer Study Group clinical trials 6/8 (n = 1,619) and published literature. Effectiveness was assessed as quality-adjusted life-years (QALYs). Costs (2010) were assessed from a German third-party payer perspective. RESULTS: Lifetime costs per patient ranged from 28,268 (St.Gallen and EPclin) to 33,756 (NCCN). Due to an imperfect prognostic value and differences in chemotherapy use, strategies achieved between 13.165 QALYs (NCCN) and 13.173 QALYs (EPclin alone) per patient. Using German-S3 as reference, three strategies showed dominant results (St. Gallen and EPclin, German-S3 and EPclin, EPclin alone). Compared to German-S3, the addition of EPclin saved 3,388 and gained 0.002 QALYs per patient. Combining guidelines with EPclin remained preferable in sensitivity analysis. CONCLUSION: Our study suggests that molecular markers can be sensibly combined with clinical guidelines to determine the risk profile of adjuvant breast cancer patients. Compared with the current German best practice (German-S3), combinations of EPclin with the St. Gallen, German-S3 or NCCN guideline and EPclin alone were dominant from the perspective of the German healthcare system.

Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1.

Surgical excision of colorectal cancer at early clinical stages is highly effective, but 20-30% of patients relapse. Therefore, it is of clinical relevance to identify patients at high risk for recurrence, who would benefit from adjuvant chemotherapy. The objective of this study was to identify prognostic and/or predictive methylation markers in stage II colorectal cancer patients. Therefore, we selected six gene promoters (FZD9, PCDH10 (protocadherin 10), SFRP2, SPARC (secreted protein acidic and rich in cysteine), UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), and WIF1) for methylation analysis in formalin-fixed, paraffin-embedded primary tumor samples of colorectal cancer patients (n=143) who were enrolled in a prospective randomized phase III trial of the Austrian Breast and Colorectal cancer Study Group. Patients were randomized to adjuvant chemotherapy with 5-fluorouracil and leucovorin or surveillance only. Survival analyses revealed that combined evaluation of three promoters (PCDH10, SPARC, and UCHL1) showed differential effects with regard to disease-free survival and overall survival in the two treatment groups (significance level 0.007). In the chemotherapy arm, a statistically insignificant trend for patients without methylation toward longer survival was observed (P=0.069 for disease-free survival and P=0.139 for overall survival). Contrary, patients in the surveillance arm without methylation in their gene promoters had shorter disease-free survival and overall survival (P=0.031 for disease-free survival and P=0.003 for overall survival), indicating a prognostic effect of methylation in this group (test for interaction, P=0.006 for disease-free survival and P=0.018 for overall survival). These results indicate that promoter methylation status of PCDH10, SPARC, and UCHL1 may be used both as prognostic and predictive molecular marker for colorectal cancer patients and, therefore, may facilitate treatment decisions for stage II colorectal cancer.

Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy.

PURPOSE: The objective of our study was to determine the clinical relevance of cyclin D1 expression in hormone receptor-positive breast cancer patients who were treated with tamoxifen-based therapy. EXPERIMENTAL DESIGN: We assessed expression of cyclin D1 in surgical specimens of breast carcinoma by means of immunohistochemistry. Patients had been enrolled in either Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 05 or ABCSG Trial 06 and received tamoxifen as part of their adjuvant treatment. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathologic factors. RESULTS: Cyclin D1 was expressed in 140 of 253 (55%) tumors of ABCSG Trial 05 and in 569 of 948 (60%) tumors of ABCSG Trial 06. Expression of cyclin D1 was associated with poor outcome in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors compared with patients with cyclin D1-negative tumors [adjusted hazard ratio (HR) for death (ABCSG Trial 05), 2.47; 95% confidence interval (95% CI), 1.08-5.63; P = 0.03; adjusted HR for death (ABCSG Trial 06), 1.78; 95% CI, 1.36-2.34; P < 0.0001]. Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors [adjusted HR for relapse (ABCSG Trial 05), 2.73; 95% CI, 1.50-4.96; P = 0.001; adjusted HR for relapse (ABCSG Trial 06), 1.52; 95% CI, 1.14-2.04; P = 0.005]. CONCLUSION: Cyclin D1 expression is an independent poor prognostic factor in women with early-stage, hormone receptor-positive breast cancer who received adjuvant tamoxifen-based therapy.

Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group.

PURPOSE: The multidrug resistance protein 1 (MRP1) is expressed in human breast cancer cells and may contribute to the clinical drug resistance of breast cancer patients. Therefore, we determined the impact of MRP1 expression on the clinical outcome of adjuvant therapy in patients with early-stage breast cancer. PATIENTS AND METHODS: Immunostaining for MRP1 was performed on tissue sections from 516 premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease. Statistical analyses were performed to assess the effect of MRP1 expression on survival and to test for interaction between MRP1 expression and treatment. RESULTS: MRP1 expression independently predicted shorter relapse-free survival (RFS) and overall survival (OS) in patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF; RFS: hazard ratio [HR] = 1.48; 95% CI, 1.16 to 1.88; P = .002; OS: HR = 1.82; 95% CI, 1.10 to 3.01; P = .02), but it did not predict shorter RFS and OS in patients who received tamoxifen plus goserelin (RFS: HR = 0.99; 95% CI, 0.74 to 1.31; P = .9; OS: HR = 0.68; 95% CI, 0.40 to 1.15; P = .1). Tests for interaction between MRP1 expression and treatment were statistically significant for both RFS (P = .04) and OS (P = .006). CONCLUSION: Our data suggest that MRP1 expression plays an important role in the clinical resistance to adjuvant CMF chemotherapy but does not seem to affect response to adjuvant endocrine treatment with tamoxifen plus goserelin. Thus, MRP1 may be a useful marker for the selection of patients with early-stage breast cancer for the appropriate adjuvant therapy after prospective confirmatory evaluation.

Expression of cell cycle regulatory proteins in breast carcinomas before and after preoperative chemotherapy.

Molecular markers predicting response to preoperative chemotherapy would be of major clinical relevance in breast cancer. Therefore, we studied the relationship between the expression of cell cycle regulatory proteins and clinical outcome in breast cancer patients receiving preoperative chemotherapy. Expression of p2lWaf1, p27KiP1, p53, cyclin D3 and Ki-67 was determined in breast carcinomas by means of immunohistochemistry both prior and after preoperative chemotherapy. Expression data were compared with both clinical parameters and response to preoperative chemotherapy with either cyclophosphamide/methotrexate/5-fluorouracil (CMF, n = 29) or epirubicin/docetaxel (ED, n = 36). In paired samples before and after preoperative chemotherapy, the percentage of p21Waf1, p27Kip1, p53 and cyclin D3 positive nuclei of tumor cells in postchemotherapy specimens was significantly higher than the percentage in prechemotherapy samples but no change in Ki-67 expression was observed. High Ki-67 expression (p = 0.02), negative estrogen receptor status (p = 0.01) and negative progesterone receptor status (p = 0.04) were associated with complete pathologic response to chemotherapy, whereas the other markers did not predict response. In conclusion, expression levels of p21Waf1, p27Kip1, p53 and cyclin D3 significantly increased after preoperative chemotherapy in breast carcinomas but only high Ki-67 expression, negative estrogen receptor status and negative progesterone receptor status were associated with complete pathologic response to preoperative chemotherapy.