Breast Neoplasms: Láng I

Pestalozzi BC, Francis P, Quinaux E, Dolci S, Azambuja E, Gelber RD, Viale G, Balil A, Andersson M, Nordenskjöld B, Gnant M, Gutierrez J, Láng I, Crown JP, Piccart-Gebhart M, Anonymous00063. · Department of Oncology, University Hospital, Zurich, Switzerland. · Ann Oncol. · Pubmed #18562328 No free full text.

Abstract: BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. RESULTS: CNS relapse occurred in 4.0% of control patients and 3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. CONCLUSION: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse.

Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. · IBCSG Coordinating Center, Effingerstrasse 40, CH-3008 Bern, Switzerland. · J Clin Oncol. · Pubmed #18332471 No free full text.

Abstract: PURPOSE: To explore potential differences in efficacy, treatment completion, and adverse events (AEs) in elderly women receiving adjuvant tamoxifen or letrozole for five years in the Breast International Group (BIG) 1-98 trial. METHODS: This report includes the 4,922 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial. The median follow-up was 40.4 months. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to examine the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categoric age groups were defined: "younger postmenopausal" patients were younger than 65 years (n = 3,127), "older" patients were 65 to 74 years old (n = 1,500), and "elderly" patients were 75 years of age or older (n = 295). RESULTS: Efficacy results for subpopulations defined by age were similar to the overall trial results: Letrozole significantly improved disease-free survival (DFS), the primary end point, compared with tamoxifen. Elderly patients were less likely to complete trial treatment, but at rates that were similar in the two treatment groups. The incidence of bone fractures, observed more often in the letrozole group, did not differ by age. In elderly patients, letrozole had a significantly higher incidence of any grade 3 to 5 protocol-specified non-fracture AE compared with tamoxifen (P = .002), but differences were not significant for thromboembolic or cardiac AEs. CONCLUSION: Adjuvant treatment with letrozole had superior efficacy (DFS) compared with tamoxifen in all age groups. On the basis of a small number of patients older than 75 years (6%), age per se should not unduly affect the choice of adjuvant endocrine therapy.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD, Anonymous00191. · Medicine Department, Jules Bordet Institute, Blvd. de Waterloo 125, 1000 Brussels, Belgium. · N Engl J Med. · Pubmed #16236737 links to  free full text

Abstract: BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)

Boér K, Láng I, Juhos E, Pintér T, Szántó J. · Onkológiai Osztály, Szent Margit Kórház, Budapest, 1032 Hungary. · Magy Onkol. · Pubmed #12975660 links to  free full text

Abstract: AIM: The authors present the Hungarian interim analysis and experience with the BCIRG 001 randomized, multicentric, phase III clinical trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) and FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients. The results are presented according to international data. PATIENTS AND METHODS: Three Hungarian centers - St. Margit Hospital, Budapest, National Institute of Oncology, Budapest, Petz Aladár Hospital, Gyôr - participated in the international trial. Between June 1997 and June 1999, 61 patients with node positive breast cancer were enrolled in the study after the surgery. Thirty-four patients were randomized to TAC (75/50/500 mg/m2 6x q3wk) and 27 patients were randomized to FAC (500/50/500 mg/m2 6x q3wk) chemotherapy, with prospective stratification by node (1-3, 4+). In the case of patients with ER and/or PR positive tumours 5 years tamoxifen treatment was started. Radiotherapy was performed after the 6th cycle of chemotherapy. RESULTS: 36 months of follow up was performed. In both arms the hematological toxicity was more frequent. The TAC group showed a higher incidence of neutropenia (76%) compared to the FAC (22%), as well as a higher incidence of febrile neutropenia (26%), without grade 3-4 infection and there were no cases of septic death. Regarding non-hematological toxicity more grade 3-4 nausea and vomiting was observed in the FAC group. At three years follow up, the international results show statistically significant improvement in disease-free survival (82% vs. 74%, p=0.0011) in favour of TAC, and similar tendency was observed in the case of overall survival (92% vs. 87%, p=0.11). This benefit with TAC was seen regardless of hormone receptor status. Due to the low number of Hungarian patients we cannot declare the same results. CONCLUSIONS: Based on the international analysis TAC was superior to FAC chemotherapy. Additional follow up data will evaluate the role of TAC in the adjuvant setting of early breast cancer treatment. The results indicate that TAC has the potential to be incorporated in the new strategies of adjuvant breast cancer treatments.

Wapnir IL, Aebi S, Gelber S, Anderson SJ, Láng I, Robidoux A, Mamounas EP, Wolmark N. · National Surgical Adjuvant Breast and Bowel Project Operations and Biostatistics Center, Pittsburgh, PA, USA, · Ann Surg Oncol. · Pubmed #18784962 No free full text.

Abstract: BACKGROUND: The utility of chemotherapy for women who experience a locoregional recurrence after primary treatment of early breast cancer remains an open question. An international collaborative trial is being conducted by the Breast International Group (BIG), the International Breast Cancer Study Group (IBCSG), and the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine the effectiveness of cytotoxic therapy for these patients, either alone or in addition to selective use of hormonal therapy and trastuzumab. METHODS: The trial population includes women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery, but subsequently develop an isolated local and/or regional ipsilateral invasive recurrence. Excision of all macroscopic tumor without evidence of systemic disease is required for study entry. Patients are randomized to receive chemotherapy or no chemotherapy; type of chemotherapy is not protocol-specified. Radiation, hormonal therapy, and trastuzumab are given as appropriate. The primary endpoint is disease-free survival (DFS). Quality-of-life measurements are collected at baseline, and then at 9 and 12 months. The accrual goal is 977 patients. RESULTS: This report describes the characteristics of the first 99 patients. Sites of recurrence at study entry were: breast (56%), mastectomy scar/chest wall (35%), and regional lymph nodes (9%). Two-thirds of patients have estrogen-receptor-positive recurrences. CONCLUSION: This is the only trial actively investigating the question of "adjuvant" chemotherapy in locally recurrent breast cancer. The case mix of accrual to date indicates a broad representation of this patient population.

Horváth Z, Farkas P, Ganofszky E, Hitre E, Juhos E, Nagy T, Rubovszky G, Szabó E, Láng I. · Országos Onkológiai Intézet, Kemoterápia B Belgyógyászati Onkológiai és Klinikai Farmakológiai Osztály, Budapest. · Magy Onkol. · Pubmed #18403297 links to  free full text

Abstract: Renal function aberrations during bisphosphonate treatment is a well-known phenomenon. In our retrospective study we examined renal functions of 97 breast cancer patients with bone metastasis during their first year of bisphosphonate treatment i.e. (1) frequency of initial renal function alterations; (2) frequency of decreasing renal function during bisphosphonate treatment; (3) the connection between the laboratory findings and the renal function parameters measured at the beginning of bisphosphonate treatment. At the beginning of bisphosphonate treatment we found a surprisingly high rate (26.80%) of decreased creatinine clearance calculated by the Cockcroft-Gault formula. Decreased creatinine clearance at least once during bisphosphonate treatment has been found in 32.99% of the patients, and in 13.4% of the patients with decreased renal function parameters before bisphosphonates it remained decreased during the one-year period. Expected normal renal function is prognosticated by the renal function parameters and serum calcium level measured before starting bisphosphonate treatment. However, we could not demonstrate any connection between decreasing renal function and either the route of administration or the generation or type of bisphosphonates or the previous use of platinum compounds. Our analysis confirms the necessity of monitoring renal function before and during bisphosphonate treatment, and it is advisable to calculate the creatinine clearance in the upper quarter of the normal range of creatinine levels. In case of decreased renal function, change to a less nephrotoxic bisphosphonate or discontinuing the treatment is suggested. While our results are at variance with the published literature, the above-mentioned questions should be examined in a prospective trial.

Mauriac L, Keshaviah A, Debled M, Mouridsen H, Forbes JF, Thürlimann B, Paridaens R, Monnier A, Láng I, Wardley A, Nogaret JM, Gelber RD, Castiglione-Gertsch M, Price KN, Coates AS, Smith I, Viale G, Rabaglio M, Zabaznyi N, Goldhirsch A, Anonymous00032, Anonymous00033. · French Breast Cancer Group, Institut Bergonié Bordeaux, France. · Ann Oncol. · Pubmed #17301074 links to  free full text

Abstract: BACKGROUND: Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. PATIENTS AND METHODS: Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. RESULTS: Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. CONCLUSION: Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors.

Láng I, Hitre E. · Országos Onkológiai Intézet, Budapest 1122, Hungary. · Magy Onkol. · Pubmed #17216002 links to  free full text

Abstract: The prognosis of HER-2-positive breast cancer (characterized by amplification of the HER-2 oncogene and/or overexpression of HER-2 receptor) is unfavourable. Trastuzumab (Herceptin), a monoclonal antibody against HER-2 receptor can improve the outcome of HER-2-positive breast cancer. Up to now this was proven only in advanced disease. Recently five large multicentric phase III adjuvant trials gave level one evidence on the benefit of adjuvant treatment with Herceptin, concerning disease-free survival (DFS) and overall survival (OS). Herceptin has decreased the relative risk of recurrence with about 50% and that of death with nearly 30% in HER-2-positive early breast cancer. Based on these results Herceptin, together with chemotherapy, has been recently approved for the adjuvant treatment of HER-2-positive breast cancer.

Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. · International Breast Cancer Study Group (IBCSG), IBCSG Coordinating Center, Bern, Switzerland. · J Clin Oncol. · Pubmed #17200148 No free full text.

Abstract: PURPOSE: Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results. PATIENTS AND METHODS: Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point. RESULTS: At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. CONCLUSION: The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.

Dubecz S, Csuka O, Török K, Vasas N, Péley G, Doleschal Z, Sulyok Z, Láng I, Köves I. · Altalános- és Mellkassebészeti Osztály, Országos Onkológiai Intézet, Budapest. · Magy Seb. · Pubmed #14619093 No free full text.

Abstract: Detection of hematogenous micrometastases (MM) in bone marrow might play important role in determining stage, prognosis and multimodality treatment strategy of invasive breast cancer. Therefore we studied the presence of occult tumor cells in bone marrow of outpatients operated on with breast cancer by detecting cytokeratin 20 mRNA using the RT-PCR method. In 182 primary breast cancer patients 54 (29.7%) micrometastases were detected while in 128 patients (70.3%) no tumor cells were found in the bone marrow aspirates. Correlation of MM with HER-2, c-met, nm23, p53 and estrogen receptor (ER) were studied. The presence of MM was correlated with HER-2, nm23- and p53 positivity and with low frequency of nm23 and ER. The possible role of bone marrow MM in selecting node negative breast cancer patients for adjuvant therapy should be tested in randomized prospective clinical trials.

Láng I. · Kemoterápia B Belgyógyászati Onkológiai Osztály, Országos Onkológiai Intézet, Budapest, 1122, Hungary. · Magy Onkol. · Pubmed #12202900 links to  free full text

Abstract: Taxol (paclitaxel) and Herceptin (trastuzumab) are two milestones in the treatment of metastatic breast cancer. Accordingly it was feasible to study the combination of these two highly active drugs (with different toxicity profiles and mechanisms of action) in the treatment of metastatic breast cancer. In multicentric phase III trial performed in the US the combination of Herceptin with either taxane or anthracyclin was investigated. It was established that the combination of Herceptin with Taxol treatment significantly improves the overall response rate, increases the time to progression and the overall survival. These effects are more pronounced in patients characterized with HER/2 +++ overexpression. Based on these evidences the Herceptin-Taxol combined treatment protocol was introduced in Hungary for the treatment of Stage IV breast cancer patients.

Boér K, Láng I, Juhos E, Pintér T, Szántó J. · V. Department of Internal Medicine - Oncology, Szent Margit Hospital, Budapest, H-1032, Hungary. · Pathol Oncol Res. · Pubmed #14530809 links to  free full text

Abstract: The adjuvant chemotherapy of breast cancer changed in the past two decades. Docetaxel containing regimens are highly active in metastatic breast cancer. A logical approach was their incorporation into trials of early breast cancer adjuvant therapy. The authors present the Hungarian interim analysis and experience with the BCIRG 001 randomized, multicentric, phase III clinical trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) and FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients. The results are presented compared to the international data. Three Hungarian centers - Szt. Margit Hospital, Budapest, National Institute of Oncology, Budapest, Petz Aladár Hospital, Gyôr - participated in the international trial. Between June 1997 and June 1999, 61 patients with node positive breast cancer were enrolled in the study after the surgery. Thirty-four patients were randomized to TAC (75/50/500 mg/m2 6xq3wk) and 27 patients were randomized to FAC (500/50/500 mg/m2 6x q3wk) chemotherapy, with prospective stratification by node (1-3, 4+). Patients with hormone receptor positive tumors received tamoxifen for 5 years after the chemotherapy. Radiotherapy was performed after the 6th cycle of chemotherapy. 33 months of follow up was performed. In both arms the hematological toxicity was more frequent. The TAC group showed a higher incidence of neutropenia (76%) compared to the FAC (22%), as well as a higher incidence of febrile neutropenia (26 % versus none), without grade 3-4 infection and there was no cases of septic death. More grade 3-4 nausea and vomiting was observed in the FAC group. At three years follow up, results indicated improvement in disease-free survival (88% vs. 76%) in favour of TAC, and similar tendency was observed in the case of overall survival (97% vs. 88%). Based on the international data analysis TAC was superior to FAC chemotherapy, the results show statistically significant differences between the two arms. This benefit with TAC was seen regardless of hormone receptor status. Additional follow up data will evaluate the role of TAC in the adjuvant setting of early breast cancer treatment.