Better translation from bench to bedside: breakthroughs in the individualized treatment of cancer.

This article reflects on progress made in recent years with respect to bench-to-bedside research in breast cancer. It shows how the advent of molecular oncology-accompanied by high-throughput experimental methods and "omics" technologies-has led researchers to realize that breast cancer is a heterogeneous disease for which a "one size fits all" approach to patient treatment is no longer optimal. This, in turn, has contributed to a change in thinking about clinical trial design. Using several examples of clinical trials being run under the umbrella of the Breast International Group, including the recently launched Microarray In Node-negative Disease may Avoid ChemoTherapy study and Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization study, the article looks at how translational research and biological specimen collection has become a central component of clinical research design in a relatively short period of time. This, plus an evolution in research culture that has resulted in increased international collaboration among research networks, groups, and centers, will arm researchers with the tools needed to develop truly individualized cancer treatments for patients in the future.

Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial.

BACKGROUND: Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. METHODS: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. RESULTS: Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. CONCLUSION: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil.

PURPOSE: The purpose of this study is to evaluate HER-2 and topoisomerase IIalpha (topo IIalpha) as candidates for predicting the activity of anthracyclines in the adjuvant treatment of breast cancer patients. EXPERIMENTAL DESIGN: In this study, we evaluated HER-2 and topo IIalpha gene aberrations by fluorescence in situ hybridization in a series of 430 primary breast cancer samples. Samples came from node-positive breast cancer patients randomly treated either with one of two anthracycline-based regimens [full-dose epirubicin-cyclophosphamide (HEC) and moderate-dose epirubicin-cyclophosphamide (EC)] or with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in the context of a Phase III adjuvant therapy trial. Event-free survival comparisons were performed between the three study arms in the subgroups of HER-2-amplified and nonamplified tumors. An explorative analysis was also performed to evaluate the predictive value of topo IIalpha in the cohort of HER-2-amplified patients. RESULTS: HER-2 amplification was observed in 73 of the 354 evaluable samples (21%), whereas topo IIalpha amplification was found in 23 of the 61 evaluable HER-2-amplified tumors (38%). The three event-free survival comparisons were CMF versus HEC, CMF versus EC, and EC versus HEC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were as follows: (a) CMF versus HEC, HR = 1.42 for HER-2-amplified tumors (95% CI, 0.54-3.76; P = 0.48) and 0.84 for HER-2-nonamplified tumors (95% CI, 0.49-1.44; P = 0.53); (b) CMF versus EC, HR = 1.65 for HER-2-amplified tumors (95% CI, 0.66-4.13; P = 0.29) and 0.66 for HER-2-nonamplified tumors (95% CI, 0.39-1.10; P = 0.11); and (c) EC versus HEC, HR = 0.93 for HER-2-amplified tumors (95% CI, 0.31-2.77, P = 0.90) and 1.33 for HER-2-nonamplified tumors (95% CI, 0.82-2.14; P = 0.25). Observed HRs suggest that the anthracycline-based therapy could be more effective than CMF in the subgroup of HER-2-amplified patients, whereas treatments could be equally active in the HER-2-nonamplified cohort. topo IIalpha evaluation suggests that the superiority of anthracyclines over CMF in HER-2-amplified patients could be confined to the subgroup of topo IIalpha-amplified tumors. CONCLUSIONS: HER-2 could have a predictive value for the activity of anthracycline-based regimens in the adjuvant therapy of breast cancer patients. The predictive value of HER-2 would most likely be related to the concomitant amplification of the topo IIalpha gene.

Potential predictive value of Bcl-2 for response to tamoxifen in the adjuvant setting of node-positive breast cancer.

Approximately 50% of patients with estrogen receptor (ER)-positive breast cancer (BC) and 70%-80% of patients with ER-positive and progesterone receptor (PgR)-positive BC respond to hormonal therapy. Additional predictive markers are needed. A group of 287 patients with ER- and/or PgR-positive tumors was selected from 804 patients previously enrolled in a multicenter phase III trial. Bcl-2 expression was evaluated and correlated with response to adjuvant tamoxifen and survival. Estrogen receptor and PgR were determined by biochemical means and Bcl-2 by immunohistochemistry. With a median follow-up of 76 months (95 relapses and 60 deaths), of the 287 patients with, 187 (65%) had Bcl-2-positive tumors and 78 of these patients received tamoxifen. Of the 100 patients with Bcl-2-negative disease, 51 received tamoxifen and 49 regular follow-up. Using patients treated with tamoxifen as a reference, a univariate analysis of disease-free interval for patients who did not receive tamoxifen showed a hazard ratio (HR) of 1.42 (95% CI, 0.82-2.44; P = 0.21) for patients with Bcl-2-positive disease and a HR of 1.05 (95% CI, 0.55-1.99; P = 0.89) for patients with Bcl-2-negative disease (P = 0.48). After adjusting for number of positive lymph nodes, degree of receptor and PgR positivity, and type of surgery, the HRs were 1.54 (95% CI, 0.87-2.73; P = 0.14) for Bcl-2-positive disease and 1.05 (95% CI, 0.52-2.11; P = 0.88) for Bcl-2-negative disease. Despite its being a retrospective nonrandomized study with a relatively low number of patients, our results suggest that Bcl-2 deserves further evaluation as a predictive factor of sensitivity to tamoxifen.

3-year results of docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer: a pilot study.

BACKGROUND: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF. RESULTS: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%). CONCLUSION: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

Prognostic, predictive abilities and concordance of BCL2 and TP53 protein expression in primary breast cancers and axillary lymph-nodes: a retrospective analysis of the Belgian three arm study evaluating anthracycline vs CMF adjuvant chemotherapy.

Given recent data on genetic heterogeneity within and individual's tumor, we investigated if there were differences in the prognostic and predictive abilities of BCL2 and TP53 protein expression in primary breast cancer (TU) and corresponding axillary lymph-nodes (LN). We used patient samples from the adjuvant Belgian three-arm study which randomized between anthracycline containing regimens and traditional CMF. The endpoints analyzed were overall survival (OS), event-free survival (EFS) and interactions between chemotherapy regimens. At a median follow-up of 15.6 years, BCL2 and TP53 (in both TU and LN) were significantly associated with OS but only in the first 5 years. Likewise, BCL2 and TP53 (in both TU and LN) were associated with EFS in the first 2 years after randomization, with no association after 2 years. BCL2 and TP53 remained statistically significant after adjustment for the standard clinical-pathological characteristics in regard to OS and EFS in the respective first years after randomization, (p value < 0.001 for both markers). Furthermore, an interaction was found between high BCL2 expression in the TU (but not in LN) and benefit to CMF over anthracycline-based chemotherapy (interaction p value EFS: 0.042; OS = 0.01). No interaction was found for TP53 expression neither in TU nor in LN. We conclude that BCL2 and TP53 were predictive biomarkers for better and worse survival respectively, but only in the first two to five years after diagnosis. BCL2 expression in the TU but not in the LN was predictive of increased benefit to CMF vs anthracycline-based chemotherapy.

Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial.

PURPOSE: To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. PATIENTS AND METHODS: IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up. RESULTS: Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab. CONCLUSION: There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.

Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study.

PURPOSE: The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide (HEC) is superior to a lower dose of epirubicin, 60 mg/m(2) (EC), for event-free survival (EFS; 27% reduction), but is not superior to classical oral cyclophosphamide, methotrexate, and fluorouracil (CMF) in the adjuvant treatment of node-positive breast cancer. Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial. PATIENTS AND METHODS: Between March 1988 and December 1996, 777 eligible patients were randomly assigned to six cycles of CMF, eight cycles of EC, or eight cycles HEC. RESULTS: The 15-year EFS was 45% for patients who received CMF, 39% for patients who received EC, and 50% for patients who received HEC. The hazard ratios (HR) were 0.77 for HEC versus EC (95% CI, 0.60 to 0.98; P = .03), 0.90 for HEC versus CMF (P = .39), and 0.86 for EC versus CMF (P = .21). No difference in overall survival (OS) was seen. Cardiac toxicity was more frequent with HEC than with CMF (11 patients v 1 patient; P = .006), but no more than with EC (P = .21). CONCLUSION: Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin. However, we do not recommend the use of HEC regimen in daily clinical practice, mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study.

[The new generation of breast cancer clinical trials: the right drug for the right target]. / La nouvelle génération des études cliniques sur le cancer du sein: la bonne drogue et la bonne cible.

The principal mission of the Breast International Group (Big), Transbig, and the Breast European Adjuvant Study Team (Breast), all located at the Jules Bordet Institute in Brussels, is to accelerate and facilitate the initiation and conduct of large and difficult breast cancer clinical trials. This is made possible through the excellent network of research groups, scientists, physicians and many other collaborators deeply committed to academic clinical and translational research. A clear example of this collaboration is the HERA trial (Herceptin Adjuvant trastuzumab in HER2 positive early breast cancer) that contributed to a change of clinical practice and improved the prognosis for this particular patient population. In addition, there is an important new generation of adjuvant trials, for example, Mindact, which is evaluating the use of microarray technology in treatment decision making, and the Altto and Neo-Altto studies, which have just started and are evaluating lapatinib, a small tyrosine kinase molecule given either adjuvantly or neo-adjuvantly, alone, sequentially or in combination with trastuzumab, in patients with HER2 positive early breast cancer. The latter studies, with their strong translational research component, aim to determine which tumour profiles will best benefit from lapatinib as opposed to treatment with trastuzumab alone.

Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial.

BACKGROUND: Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. METHODS: Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF); 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF); 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. RESULTS: Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00; P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). CONCLUSIONS: Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy.