Reporting and interpreting adjuvant therapy clinical trials. International Breast Cancer Study Group (formerly Ludwig Group).

Identifying effective adjuvant treatments for patients with node-negative breast cancer is made difficult by the heterogeneity of the disease, the relatively low event rate and long follow-up time required, and the small magnitude of effects of current therapies. Several aspects of clinical trials that influence the appropriate reporting and interpretation of statistical results are discussed. We point out that the P value is a measure of the statistical uncertainty of an observed outcome and depends on the number of events available for analysis; it is not a measure of the magnitude of a treatment effect. We recommend that the relative reduction in the risk of an event and its 95% confidence interval be presented as an estimate of the treatment effect size, and that absolute improvements be used to judge whether treatment benefits outweigh the costs for the patient population. We suggest that subgroup analyses are important to define treatment effects within groups with different prognoses, and should be used with the understanding that multiple comparisons increase the chance of a false-positive result. Subgroup analysis should rely on the estimates of relative treatment effect and should avoid the use of the P value to declare incorrectly that "treatment is effective for one subgroup but not for another." We present the meta-analysis (overview) as a powerful method to demonstrate the statistical significance of a modest treatment effect by increasing the number of events available for analysis. The interpretation of overviews should consider the potential for treatment interactions and the validity of indirect comparisons that are not protected by a randomized design.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prognostic value of Helix pomatia in breast cancer. International (Ludwig) Breast Cancer Study Group.

Six hundred and eighty-four primary breast cancers from the International (Ludwig) Breast Cancer Study Group (IBCSG) were studied for Helix pomatia lectin (HPA) binding. There was a weak correlation between lymph node-positive and HPA positive (P = 0.04). In our series there was a large advantage in disease-free survival (DFS) and overall survival (OS) for node-negative patients (P < 0.0001 DFS and OS). However, there was no such advantage for HPA-negative patients (P = 0.23 DFS and P = 0.32 OS). We conclude that in this randomised patient group HPA is of no clinical predictive value.     

Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. The International (Ludwig) Breast Cancer Study Group.

PURPOSE: An international trial (formerly Ludwig Trial V) has been conducted in 1,275 subjects to ascertain if perioperative chemotherapy is beneficial for node-negative breast cancer patients and to identify subgroups of patients who benefit from this therapy. PATIENTS AND METHODS: Node-negative breast cancer patients were randomized to receive either one cycle of perioperative chemotherapy or no adjuvant treatment. A detailed pathology review was conducted in 1,203 of the 1,275 patients enrolled. Stepwise Cox regression analysis was used to search for factors either predicting chemotherapeutic responsiveness and/or influencing disease-free survival (DFS). RESULTS: As expected, primary tumor size, grade, and the presence of peritumoral vascular invasion are the most important prognostic factors. Perioperative chemotherapy provides a DFS advantage at 5 years of median follow-up and such treatment is more effective for estrogen receptor-negative than for estrogen receptor-positive tumors, for histologic grade 2 and 3 than for grade 1 tumors, and for patients in whom no axillary lymph node metastases were found even after serial sectioning and review by the Central Pathology Laboratory. CONCLUSION: Hormone receptor status and tumor grade are important factors for predicting responsiveness to perioperative chemotherapy in node-negative breast cancer.     

Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group.

PURPOSE: To evaluate the prognostic importance of immunocytochemically determined c-erbB-2 overexpression in the primary tumors of patients with breast cancer. PATIENTS AND METHODS: Primary tumors from 1,506 breast cancer patients (760 node-negative and 746 node-positive) who were treated in the International (Ludwig) Breast Cancer Study Group Trial V were studied. Node-negative patients were allocated randomly to either a single cycle of perioperative chemotherapy (PeCT) or no adjuvant treatment, and node-positive patients received either a prolonged chemotherapy (with tamoxifen for postmenopausal patients) or a single perioperative cycle. RESULTS: Tumors from 16% of the node-negative patients and 19% of the node-positive patients were found to be c-erbB-2-positive. In both groups c-erbB-2 positivity correlated with negative progesterone receptors (PR), negative estrogen receptors (ER), and high tumor grade. Lobular carcinomas were all negative, and, thus support the view that such tumors represent a defined subtype of breast carcinoma. The expression of c-erbB-2 was prognostically significant for node-positive but not for node-negative patients. However, in both subgroups, the prognostic significance was greater for patients who had received more adjuvant therapy. For node-positive patients, the effect of prolonged-duration therapy on disease-free survival (DFS) was greater for patients without c-erbB-2 overexpression (hazards ratio [HR], = 0.57; 95% confidence interval [CI], 0.46 to 0.72) than for those with c-erbB-2 overexpression (HR, 0.77; 95% CI, 0.51 to 1.16). Similarly, for node-negative patients, the effect of PeCT on DFS was greater for those without c-erbB-2 overexpression (HR, 0.82; 95% CI, 0.61 to 1.09) than for those with c-erbB-2 overexpression (HR, 1.22; 95% CI, 0.66 to 2.25). CONCLUSION: We conclude that tumors with overexpression of the c-erbB-2 oncogene are less responsive to cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant therapy regimens than those with a normal amount of gene product.     

Quality of life in clinical trials of adjuvant therapies. International Breast Cancer Study Group (formerly Ludwig Group).

Clinical trials of adjuvant therapies usually measure the effectiveness of treatments by comparing disease-free survival or overall survival. These take into consideration only indirectly the quality of life experienced by the patients. We present some approaches that were developed to assess the impact of adjuvant therapy on the quality of life of breast cancer patients, as well as new methods created to compare treatments based on time spent without symptoms and toxicity (TWiST). The integration of these two methods (measuring quality and comparing duration of time) will provide a new tool for evaluating benefits from treatments given in the adjuvant setting.     

Clinical trial update: International Breast Cancer Study Group

The International Breast Cancer Study Group (IBCSG) has been conducting large, phase III clinical trials since 1978. Prior to 1986, these activities were carried out under the name of Ludwig Breast Cancer Study Group. Seven trials of adjuvant therapies are currently open for patient accrual, five of which are described in this report. The IBCSG has been a leader in the field of tailored treatment approaches for specific subpopulations of patients with breast cancer, believing that what is best for the majority may not be best for a defined minority.     

Sequential estrogen receptor determinations from primary breast cancer and at relapse: prognostic and therapeutic relevance. The International Breast Cancer Study Group (formerly Ludwig Group).

We retrospectively evaluated 401 selected patients who had estrogen receptor (ER) assays both at primary surgery and at relapse in an accessible site to determine the clinical relevance of the subsequent ER determination. The median time between ER assessments was 27 months (range: 2-122 months). The median follow-up time from diagnosis was 6 years (range: 2-12 years). For patients with ER+ tumors at primary diagnosis, 29% (76/261) had ER- tumors at relapse, while for ER- primaries, the conversion rate was 33% (46/140). Conversions from ER+ to ER- occurred more often when the time interval between assays was less than one year (p = 0.004), while conversions from ER- to ER+ tended to occur late (beyond three years; p = 0.0003). Treatments received between assays (usually adjuvant therapy) had only a slight influence on ER status conversion. Post-relapse survival was poor for patients who had the biopsy accessible recurrence within one year; an expression of the aggressive nature of the disease. Among patients whose accessible relapse was beyond one year, those with ER- primaries who converted to ER+ had a longer survival than those whose recurrence was classified again as ER- (p = 0.006). This group of patients with ER- primaries who recurred beyond one year with an ER+ tumor in an accessible site represented 29% (40/140) of all patients with ER- primaries and had an estimated overall survival rate of more than 60% at 6 years from the accessible relapse. ER determination upon relapse within one year has very little clinical relevance.(ABSTRACT TRUNCATED AT 250 WORDS)     

A single perioperative adjuvant chemotherapy course for node-negative breast cancer: five-year results of trial V. International Breast Cancer Study Group (formerly Ludwig Group).

Twelve hundred seventy-five patients who were defined as having node-negative breast cancer were evaluated in a randomized trial that compared a single cycle of combination chemotherapy started within 36 hours of surgery (848 patients) with no adjuvant treatment (427 patients). The chemotherapy consisted of intravenous cyclophosphamide, methotrexate, and fluorouracil given on days 1 and 8. Leucovorin (given on days 2 and 9) was added to the regimen to decrease severe toxic effects attributed to drug interaction between nitrous oxide used in anesthesia and methotrexate given in the immediate postoperative period. At a median follow-up of 60 months, the 5 year disease-free survival (DFS) percentages (+/- SE) were 74% +/- 2% for the treated group, and 68% +/- 2% for the no adjuvant therapy group. The estimated hazard ratio [95% confidence interval (CI)] was 0.78 (0.63 to 0.96); P = .02, representing a 22% +/- 9% relative reduction in the risk of relapse. The overall survival (OS) difference was not statistically significant with 5-year OS percentages of 88% +/- 1% for the treated group, and 85% +/- 2% for the control group [estimated hazard ratio (95% CI) = 0.85 (0.62 to 1.16); P = .31]. A subgroup analysis by menopausal status and by estrogen-receptor (ER) status revealed that the treatment effect was largest among the postmenopausal women with ER-negative tumors. The 5-year DFS percentages were 79% +/- 4% and 56% +/- 7%, and the OS percentages were 91% +/- 3% and 70% +/- 6%, for the treated and control groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up

BackgroundThe role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established.Patients and methodsThree hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m² plus cyclophosphamide 4 mg/m² with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features.ResultsAt 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58–1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03).ConclusionsAfter prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encouraged.     

Impact of SERM adherence on treatment effect: International Breast Cancer Study Group Trials 13-93 and 14-93

The degree of adherence to oral anticancer agents may influence treatment efficacy. Tamoxifen and toremifene usage data from two International Breast Cancer Study Group (IBCSG) studies were used to evaluate the impact of treatment adherence on the efficacy of these two selective estrogen receptor modulators (SERMs). Between 1993 and 1999, IBCSG Trial 13-93 randomized premenopausal women with node-positive disease to tamoxifen or no endocrine therapy and IBCSG Trial 14-93 compared tamoxifen and toremifene in postmenopausal women with node-positive disease. 690 women with estrogen-receptor positive enrolled in these two trials were alive and disease-free 4 years after the start of SERM. The median follow up for this analysis was 9.0 years. Using a Kaplan–Meier landmark analysis at 4 years, the 609 women completing at least 4 years of SERM had improved 10-year disease-free survival (DFS) (71 %) compared with the 81 women taking less than 4 years (64 %), but these differences did not reach statistical significance [DFS hazard ratio (<4 year/4+ year) 1.31, 95 % CI 0.86–1.98), p value = 0.20]. Women who completed less than 4 years of SERM treatment (12 %) appeared not to have achieved the full benefit from their therapy. These results suggest that more effort should be made to educate women regarding the benefits of a full course of treatment. This is especially important in light of the results of the recently reported ATLAS and aTTom trials which suggest a benefit of 10 years of tamoxifen.     

Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII.

PURPOSE: To explore prognostic factors for locoregional failures (LRF) among women treated for invasive breast cancer within clinical trials of adjuvant therapies. PATIENTS AND METHODS: The study population consisted of 5,352 women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group randomized trials. A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy, and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months' duration and/or tamoxifen. Median follow-up is 12 to 15.5 years. RESULTS: In women with node-negative disease, factors associated with increased risk of LRF were vascular invasion (VI) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients. Of the 1,275 patients, 345 (27%) met criteria for the highest risk groups, and the 10-year cumulative incidences of LRF with or without distant metastases were 16% for premenopausal and 19% for postmenopausal women. For the node-positive cohort, number of nodes and tumor grade were factors for both menopausal groups, with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients. Of the 4,077 patients, 815 (20%) met criteria for the highest risk groups, and 10-year cumulative incidences were 35% for premenopausal and 34% for postmenopausal women. CONCLUSION: LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer, as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease. In addition to number of positive lymph nodes, predictors of LRF include tumor-related factors, such as vascular invasion, higher grade, and larger size.     

Bi-weekly chemotherapy with medium-dose docetaxel for advanced and recurrent breast cancers (The 15th study of Keiji Breast Cancer Study Group)

The efficacy and safety of bi-weekly administration of medium-dose docetaxel (TXT) were evaluated in patients with advanced and recurrent breast cancers. The additional effect of 5'-DFUR for non-responders was also evaluated. Forty patients with advanced and recurrent breast cancers were treated and 38 cases of 40 were evaluated (34 with recurrent cases and 4 with advanced cases). All cases were female, and their mean age was 56.0 (38-74). TXT of 60 mg/body, which was equivalent to 30-50 mg/m2 for standard-sized Japanese women, was administered every two weeks. 5'-DFUR of 800 mg/body was added for non-responders after 5 weeks. The response rate was calculated from the data of 32 cases with measurable lesions, and side effects were evaluated in about 34 cases with exact records. Two hundred seventy-one courses were performed for 38 patients (4-24 courses per person, average 7.13 courses). The mean dosage per course of TXT was 58.4 mg/body (38.3 mg/ m2). Three complete and 7 partial responses were observed (overall response rate: 31.3%). Ten non-responders were evaluated for the additional effect of 5' DFUR, and one case reached PR. Grade 3/4 bone marrow suppression occurred in 9 patients, and Grade 3/4 general malaise was observed in two patient. According to the results, bi-weekly administration of medium dose TXT is an active and safe regimen in patients with advanced and recurrent breast cancers. The additional effect of 5'-DFUR was observed in one of 10 non-responders of bi-weekly chemotherapy with medium-dose TXT.     

Mutational analysis of triple-negative breast cancers within the International Breast Cancer Study Group (IBCSG) Trial 22-00

Purpose

We investigated the occurrence and the prognostic and predictive relationship of a selected number of somatic mutations in triple-negative breast cancer (TNBC) patients having known clinical outcomes treated within the IBCSG Trial 22-00.

Methods

A matched case–control sampling selected patients enrolled in the IBCSG Trial 22-00 who had TNBC tumors, based on local assessment. Cases had invasive breast cancer recurrence (at local, regional, or distant site) according to the protocol definition. Matched controls had not recurred. Mutational analysis was performed with OncoCarta panel v1.0 using Mass Array System. The panel includes 19 genes belonging to different functional pathways as PI3K pathway, receptor tyrosine kinase, and cell cycle-metabolic group. Conditional logistic regression assessed the association of mutation status with breast cancer recurrence.

Results

Mutation assessment was successful for 135 patients (49 cases, 86 controls). A total of 37 (27.4%) of the 135 patients had at least one mutation in the selected genes. PIK3CA was the most common mutated gene (18/135; 13.3%), followed by BRAF, KIT and PDGFRA (each 4/135, 3.0%) and AKT1 (3/135; 2.2%). TNBC patients with at least one mutation had increased odds of recurrence compared with those with wild-type tumors (odds ratio (OR) 2.28; 95% CI 0.88–5.92), though this difference was not statistically significant (p?=?0.09). We found no evidence that these mutations were predictive for the value of maintenance metronomic chemotherapy.

Conclusions

Mutations in the tested oncogenes were not associated with breast cancer recurrence in this TNBC subset of patients. The question of whether any of these mutated genes (e.g., PIK3CA) may represent a useful therapeutic target in TNBC may be answered by ongoing clinical trials and/or larger dataset analysis.

     

Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93.

BACKGROUND: The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials to assess whether a treatment-free gap during adjuvant chemotherapy influenced outcome. PATIENTS AND METHODS: From 1993 to 1999, IBCSG Trials 13-93 and 14-93 enrolled 2215 premenopausal and postmenopausal women with axillary node-positive, operable breast cancer. All patients received cyclophosphamide (Cytoxan, C) plus either doxorubicin (Adriamycin, A) or epirubicin (E) for four courses followed immediately (No Gap) or after a 16-week delay (Gap) by classical cyclophosphamide, methotrexate, and fluorouracil (CMF) for three courses. The median follow-up was 7.7 years. RESULTS: The Gap and No-Gap groups had similar disease-free survival (DFS) and overall survival (OS). No identified subgroup showed a statistically significant difference, but exploratory subgroup analysis noted a trend towards decreased DFS for Gap compared with No Gap for women with estrogen receptor (ER)-negative tumors not receiving tamoxifen, especially evident during the first 2 years. CONCLUSIONS: A 16-week gap between adjuvant AC/EC and CMF provided no benefit and may have increased early recurrence rates in patients with ER-negative tumors.     

Long-term follow-up of patients in four prospective studies of the German Breast Cancer Study Group (GBSG): A summary of key results

Evaluation of treatment modalities and prognostic factors in early breast cancer requires a long-term follow-up of patients in prospective studies. The German Breast Cancer Study Group (GBSG) started four nationwide studies in 1983 in which a total of 2,746 patients have been enrolled and followed for about 10 years. Questions that have been addressed in these studies are still relevant today and comprise the role of breast-conserving therapy, the duration of adjuvant chemotherapy, and whether adjuvant radiotherapy is needed. The key results of these studies are highlighted including some important findings on prognosis, e.g., the role of isolated locoregional recurrence and the prognosis of patients with 10 or more positive lymph nodes. The data of all randomized patients were regularly included into the overviews of the Early Breast Cancer Trialists' Collaborative Group; the data of the nonrandomized patients have been used to examine the external validity of treatment comparisons. Overall, it can be concluded that the GBSG studies have made valuable and internationally recognized contributions to the prognosis and treatment of patients with early breast cancer.     

Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group.

In 1985 a second randomisation was initiated for women in the treatment arm of the Scottish Tamoxifen Trial either to stop tamoxifen at 5 years or to continue indefinitely. A preliminary analysis of outcome in 342 patients at a median follow-up of 6 years suggests that a worthwhile gain in disease control from continuing adjuvant tamoxifen beyond 5 years is unlikely. [Hazard ratio for events (relapse or death without relapse) is 1.27, 95% CI = 0.87 - 1.85.] There is a suggestion that therapy for longer than 5 years may increase the risk of endometrial carcinoma (P = 0.064).     

The EORTC Breast Cancer Group: major achievements of 50 years of research and future directions

The EORTC Breast Cancer Group (BCG), created in 1962, is a multidisciplinary group involving surgeons, medical oncologists, radiation oncologists, pathologists, basic scientists, and clinical research fellows. Currently, more than 80 member's institutions across Europe are participating in the group studies. The main goal of the BCG is to conduct high-quality international clinical trials covering all areas of breast cancer care: from loco-regional to systemic disease control, and from in situ carcinoma to metastatic disease. Over 50 years, the BCG has performed dozens of clinical studies including several thousands of patients. Many practice-changing trials and major achievements were conducted optimizing local control, improving systemic therapy in early and metastatic breast cancer, pioneering work in clinical-translational trials and collaboration within intergroup trials. The strategic plan of the BCG for future research includes three distinct albeit overlapping areas: loco-regional therapy, (neo-)adjuvant systemic therapy, trials in the metastatic setting, and niche population studies. For each of these areas the group has considered the prevailing EORTC strategy of focusing on practice-changing studies and translational research, with an emphasis on niche trials. During five decades, the BCG has successfully performed a series of practice-changing trials enrolling several thousands of patients. These studies have contributed to the clinical knowledge on the treatment of breast cancer and have influenced clinical practice and breast cancer patients' outcome worldwide.     

The EORTC Breast Cancer Group: 40 years of research contributing to improve breast cancer management

The EORTC Breast Cancer Group (EBCG) is a multidisciplinary international group created in 1962 in conjunction with the EORTC. This group has always focused its activities on the development of new cancer treatments and strategies for all categories of breast cancer. It has been active both in drug development, as well as in the development of new radiotherapy and surgical techniques to attempt to improve cure rates and loco-regional control. Over 40 years, the EBCG has performed dozens of clinical studies including several thousands of patients. Many of these studies have contributed to the clinical knowledge on the treatment of breast cancer and have influenced the standard management of this tumour. Beside its clinical research activities, the Group has also been very active in developing guidelines for breast cancer research, promoting high standards of care in conferences, as well as in fellowships and quality assurance programmes. EBCG is a founding member of the Breast InterGroup (BIG).