Adolfo Murias

Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer

Treatment with fluororacil, epirubicin, and cyclophosphamide followed by weekly paclitaxel (FEC-P) yielded superior disease-free survival than FEC in the adjuvant breast cancer trial GEICAM 9906. We evaluate molecular subtypes predictive of prognosis and paclitaxel response in this trial. Two molecular subtype classifications based on conventional immunohistochemical and fluorescent in situ hybridization determinations were used: #1: Four groups segregated according to the combination of hormone receptor (HR) and HER2 status; #2: Intrinsic subtype classification (Triple Negative (TN), HER2, Luminal B and Luminal A). Results: Both subtype classifications yielded prognostic and predictive information. HR +/HER2− patients (and Luminal A patients) had a significantly better outcome than the other subgroups of patients. The superiority of FEC-P over FEC was clearly more marked in HR−/HER2− patients (TN patients), particularly in the subset with basal phenotype (TN and either EGFR+ or cytokeratins 5/6+). The Luminal A subtype also achieved a significant benefit with FEC-P. The molecular-defined subgroup of TN was clearly predictive of better response to treatment with FEC-P. Luminal A patients had the best prognosis and also have a better outcome with weekly paclitaxel.

Usefulness of bone turnover markers as predictors of mortality risk, disease progression and skeletal-related events appearance in patients with prostate cancer with bone metastases following treatment with zoledronic acid: TUGAMO study

Background:Owing to the limited validity of clinical data on the treatment of prostate cancer (PCa) and bone metastases, biochemical markers are a promising tool for predicting survival, disease progression and skeletal-related events (SREs) in these patients. The aim of this study was to evaluate the predictive capacity of biochemical markers of bone turnover for mortality risk, disease progression and SREs in patients with PCa and bone metastases undergoing treatment with zoledronic acid (ZA).Methods:This was an observational, prospective and multicenter study in which ninety-eight patients were included. Patients were treated with ZA (4 mg every 4 weeks for 18 months). Data were collected at baseline and 3, 6, 9, 12, 15 and 18 months after the beginning of treatment. Serum levels of bone alkaline phosphtase (BALP), aminoterminal propeptide of procollagen type I (P1NP) and beta-isomer of carboxiterminal telopeptide of collagen I (β-CTX) were analysed at all points in the study. Data on disease progression, SREs development and survival were recorded.Results:Cox regression models with clinical data and bone markers showed that the levels of the three markers studied were predictive of survival time, with β-CTX being especially powerful, in which a lack of normalisation in visit 1 (3 months after the beginning of treatment) showed a 6.3-times more risk for death than in normalised patients. Levels of these markers were also predictive for SREs, although in this case BALP and P1NP proved to be better predictors. We did not find any relationship between bone markers and disease progression.Conclusion:In patients with PCa and bone metastases treated with ZA, β-CTX and P1NP can be considered suitable predictors for mortality risk, while BALP and P1NP are appropriate for SREs. The levels of these biomarkers 3 months after the beginning of treatment are especially important.

Bone turnover markers as predictive indicators of outcome in patients with breast cancer and bone metastases treated with bisphosphonates: results from a 2-year multicentre observational study (ZOMAR study).

BACKGROUND We evaluated the evolution and predictive value of bone turnover markers (BTMs) and circulating tumor cells (CTCs) with respect to mortality, disease progression (DP) and skeletal-related events (SREs), in patients with bone metastatic breast cancer (BmBCa). The correlation between BTMs and CTCs was also studied. METHODS In a 2-year observational, multicenter study, the levels of three BTMs (N- and C-terminal telopeptides of collagen I [NTX and αα-CTX], and bone-specific alkaline phosphatase [BSAP]) and CTCs were analyzed every three months. Patients received zoledronic acid (4mg every 28days) from the baseline visit. RESULTS 234 patients were analyzed. The levels of the BTMs were increased at baseline and significantly decreased after 3months (P<0.05). In the Cox regression univariate analyses significant hazard ratios (HRs) for death were found for pathological BSAP values at baseline (5.03 [95% CI: 1.214-20.839; P=0.0259]) and at 3months (3.41 [95% CI: 1.367-8.498; P=0.0085]). HRs >2 were found for increased baseline and 3-month levels of NTX and CTC (P<0.05). Only increased baseline BSAP levels were associated with DP (HR=2.25 [95% CI: 1.391-3.626; P=0.0009]). No biomarker was associated with SREs. In the multivariate analysis, pathologic levels at 3months of NTX and BSAP were significantly associated with mortality (HRs=3.59 [95% CI: 1.375-9.382; P=0.0091] and 3.25 [95% CI: 1.293-8.189; P=0.0120], respectively). CTC and BSAP were correlated during all study timepoints (P<0.05). CONCLUSIONS Baseline levels of NTX, BSAP and CTCs, and changes after treatment initiation with bisphosphonates, may be useful for the prognostic assessment of patients with BmBCa. BSAP showed the strongest prognostic value.

Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: The TUGAMO study.

Background:Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL).Methods:This observational, prospective, and multicenter study analysed BTM and clinical outcome in these patients. Serum levels of bone alkaline phosphatase (BALP), procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxy-terminal telopeptide of type I collagen (β-CTX) were analysed.Results:Patients with RCC who died or progressed had higher baseline β-CTX levels and those who experienced SRE during follow-up showed high baseline BALP levels. In BC, a poor rate of survival was related with high baseline β-CTX and BALP levels, and new SRE with increased PINP levels. Cox univariate analysis showed that β-CTX levels were associated with higher mortality and disease progression in RCC and higher mortality in BC. Bone alkaline phosphatase was associated with increased risk of premature SRE appearance in RCC and death in BC.Conclusion:Beta-isomer of carboxy-terminal telopeptide of type I collagen and BALP can be considered a complementary tool for prediction of clinical outcomes in patients with BC and RCC with BM treated with ZOL.

Prognostic value of the quantitative measurement of the oncoprotein p185Her‐2/neu in a group of patients with breast cancer and positive node involvement

Our study attempts to determine the prognostic value of the quantitative measurement of the oncoprotein p185Her‐2/neu in a group of patients with breast cancer and positive node involvement. In a series of 217 patients with breast cancer and positive nodes in whom the oncoprotein p185 was quantitatively determined by ELISA, we analyzed the clinico‐pathological variables including age, menopausal status, tumor size, number of affected nodes, type and histology grade and the molecular variables such as the oestrogen and progesterone receptors (ER and PR, respectively), pS2 and Cathepsin D (CD). Using 260 fmol/mg protein as a cut‐off point, 18% of the tumors presented as overexpressing p185. The p185 showed no relationship with any of the clinico‐pathological variables studied except that its concentration was elevated in ductal and lobular histology types and in the moderate and poorly differentiated histology grades. With a median follow‐up of 50 months (range 1–90), the univariate analysis of disease‐free survival (DFS) and overall survival (OS) showed that the histology grade, tumor size, the number of infiltrated nodes, the p185 and the ER were the variables associated with the clinical course of the disease in the patients. In the multivariate analysis, however, only the tumor size, number of affected ganglia, the p185 and the ER remained associated with the clinical progression of the disease. The patients with p185 overexpression had a risk, not only of relapse but also death from the disease, of more than twice that of the patients who had normal p185 concentrations. When the p185 was divided into 3 categories based on ±1 × SD above or below the mean, the patients with high and low p185 showed, in the univariate analysis, a similar relationship with DFS but not with OS. In the multivariate analysis, both with the DFS as with the OS, only a high p185 concentration retained its association with the clinical course of the disease in the patients. Our results suggest that by quantitatively determining (using ELISA) the p185 oncoprotein, groups of cancer patients of high risk could be better identified for more effective clinical management.

Abstract P1-07-18: Association between Bone Turnover Markers in patients with breast cancer and bone metastases on treatment with bisphosphonates (ZOMAR study)

Background: The presence of bone metastases (BMe) alters the balance of bone remodeling and consequently, levels of bone turnover markers (BTM). Increased levels of these biomarkers are related to the risk of skeletal-related events (SREs), disease progression and death. Treatment with bisphosphonates reduces the probability of SREs through osteoclastic activity inhibition. The aim of this study was to determine the relation between BTM, bone metastasis development and SREs, disease progression and death in patients with breast cancer (BC) and BMe. Patients and methods: Observational, prospective and multicenter study. Patients with BC and BMe; no previous bone treatment in the last 6 months prior to study entry. Urinary aminoterminal telopeptide of collagen I (NTX, Osteomark NTx Urine, Wampole Laboratories, USA); urinary alpha-alpha-isomer of carboxyterminal telopeptide of collagen I (αα-CTX, ALPHA Crosslaps EIA, ids, UK) and serum bone alkaline phosphatase (BALP, OSTASE BAP, ids, UK) were determined at baseline (V0) and every 3 mo along 18 months (V6). Patients were treated with zoledronic acid (ZA) at inclusion and every 3–4 weeks. Results: 234 patients with BC and BMe were analyzed. BTM results were available for 219 patients at basal visit (V0) and every 3 mo of treatment along 18 months (V6). Population basal characteristics (234 patients): mean age: 59.8 years; ER+: 80.3%; PR+: 64.9%; HER 2+: 18.3%. Patients with pathologic baseline levels were: 49.8% NTX, 39.6% αα-CTX and 83.4% BALP. A significant decrease was observed in BTM at V2 vs V0 after 6 months: 13.7%, 8.4% and 58.4% presented pathologic values of NTX, αα-CTX and BALP respectively. Normalized levels remained steady throughout 18 mo follow-up, finding significant decrease for each BMT for each time point except at V6 for αα-CTX. Regarding association between BTM and SREs, progression and exitus, a significant association was observed between pathologic levels of BTM throughout follow-up: with SRE at V3, V4 for NTX; with disease progression at V3, V4, V5, V6 for NTX, at V2 for αα–CTX and at each follow up visit for BALP; and with death at V1,4,5 for NTX, at V5 for αα–CTX and at V1,2,3,4,5 for BALP. Conclusions: Addition of ZA to standard systemic therapy reduced BTM levels during the first 3 months of treatment and normalized levels remained steady throughout 18 months follow up except at Month 18 for αα-CTX. Pathological levels of BTM were significantly associated with SRE, disease progression and death. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-18.

Abstract P2-01-06: Association between Circulating Tumor Cells and Bone Turnover Markers in patients with breast cancer and bone metastases on treatment with bisphosphonates (ZOMAR study)

Background: Quantification of Circulating Tumor Cells (CTC) has demonstrated an important role in assessing disease progression and outcomes, and pathological CTC levels are an independent prognostic factor of disease progression. High CTC levels may be associated with bone turnover markers (BTM) levels and have also been associated with the risk of skeletal-related events (SREs), disease progression and death. The aim of this study was to determine the relation between CTC, BTM, and SREs, disease progression and death in patients in patients with breast cancer (BC) and bone metastasis (BMe) treated with zoledronic Acid. Patients and methods: Observational, prospective and multicenter study. Patients with BC and BMe; no previous bone treatment in the last 6 months prior to study entry. CTC (fluorescently labelled with nucleic acid dye 4,6-diamidino-2-phenylindole DAPI, monoclonal antibodies specific for leukocytes CD45-allophycocyanin and epithelial cells cytokeratin 8,18,19–phycoerythrin; Cell Search System Veridex); urinary aminoterminal telopeptide of collagen I (NTX, Osteomark NTx Urine, Wampole Laboratories, USA); urinary alpha-alpha-isomer of carboxyterminal telopeptide of collagen I (αα-CTX, ALPHA Crosslaps EIA, ids, UK) and serum bone alkaline phosphatase (BALP, OSTASE BAP, ids, UK) were determined at baseline (V0) and every 3 mo along 18 months (V6). Patients were treated with zoledronic acid (ZA) at inclusion and every 3–4 weeks. Results: 234 patients with BC and BMe were analyzed, being available CTC results for 114 patients and BTM results for 219 patients at basal visit (V0) and every 3 mo of treatment along 18 months (V6). Population basal characteristics (234 patients): mean age: 59.8 years; ER+: 80.3%; PR+: 64.9%; HER 2+: 18.3%. 55.3% of patients (n = 114) had detectable CTC (CTC≥1) at V0, and 32.5% of them presented pathological (CTC≥5) at V0. A significant decrease was observed at V1, with 39.8% of patients with detectable CTC levels and 14.0% of patients with pathologic CTC levels (p Conclusion: Over 30% of mBC patients presented pathological levels of CTC. Addition of ZA to standard systemic therapy significantly reduced CTC levels after 3 mo of treatment and normalized levels remained steady throughout 18 months follow up. A significant correlation was observed between CTC and BTM after 18 months of treatment with ZA. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-06.

812 Non-Hodgkin's lymphoma of intermediate degree. 13-year follow-up of 89 patients treated with chop

From January 981 to January 1993, 89 patients with non-Hodgkins lymphoma of intermediate degree were treated with 6 courses of CHOP chemotherapy. The median age of these patients was 57 years and male/female ratio was 1.53. 8 of the patients were large-cell follicular lymphomas, 33 diffuse small-cell, 25 diffuse mixed and 22 diffuse large cell. The lymphatic areas most affected were: para-aortic 16%, left cervical 14%, right cervical 13% and mesenteric 11%. The number of lymphatic areas affected were: 1 (31%) 2 (29%) and 3 (16%). 24% of the patients were Stage I, 19% Stage II, 17% Stage III and 28% Stage IV. Bulky disease was present in 19% of the patients. The extra-nodal localizations most frequently affected were: Waldeyer ring 22%, followed by Spleen, Liver and Bone. Marrow with the percentage in each been 11%. 70% CR was achieved and 12% PR. More than 50% of the patients have had more than an 8-year follow-up and the disease-free survival rate at 13 years is 32%. A multivariant analysis, according to histological degree, primary localization and stage, will be presented.