Ignacio Tusquets

Bone health in a prospective cohort of postmenopausal women receiving aromatase inhibitors for early breast cancer

OBJECTIVE Baseline bone health in postmenopausal women is poorly characterized in prospective series of early breast cancer (EBC) patients candidates to aromatase inhibitor (AI) therapy. Our objective is to comprehensively evaluate bone health in a prospective clinical cohort of patients recruited prior to adjuvant AI therapy, with the aim of establishing potential AI impact on bone loss and fractures. METHODS From January 2006 to April 2010, we consecutively included 343 women with EBC who were about to start adjuvant AI therapy. Participants were assessed at baseline (before AI initiation) and at 3 months, with annual assessments thereafter. Bone mineral density (BMD), spine X-ray, bone metabolism (vitamin D [25(OH)D], bone turnover markers [BTM]), arthralgia and quality of life are measured. RESULTS Mean age was 61.9 years; 197 (57.4%) had been previously treated with tamoxifen; 145 (42.3%) were taking exemestane, 187 (54.5%) letrozole, and 11 (3.2%) anastrozole. Analysis of baseline data shows only 59 women (17.7%) had normal BMD; 200 (60.1%) had osteopenia and 74 (22.2%) had osteoporosis; 39 women (11.4%) had a prevalent fracture, 293 (89.1%) had 25(OH)D insufficiency (<30 ng/ml), and 61 (18.5%) severe deficiency (<10 ng/ml). Low 25(OH)D concentrations were associated with lower BMD and 233 (67.9%) participants had some degree of arthralgia. CONCLUSIONS Low bone mass, prevalent fractures and vitamin D insufficiency were highly prevalent among candidates to adjuvant AI for EBC. Therefore, it is crucial to assess BMD, prevalent fractures and 25(OH)D concentrations before starting AI therapy and during follow-up.

Estudio epidemiológico del grupo GEICAM sobre el cáncer de mama en España (1990-1993): proyecto «El Álamo»

Fundamento y objetivo El objetivo del proyecto «El Alamo» fue definir las caracteristicas demo-graficas y clinicas, los tratamientos y la evolucion de las mujeres diagnosticadas de cancer de mama invasivo en hospitales del Grupo Espanol de Investigacion en Cancer de Mama entre los anos 1990 y 1993. Pacientes y metodo Se incluyeron datos de 4.532 pacientes, recogidos entre diciembre de 1999 y diciembre de 2000. Los formularios completados a partir de las historias clinicas se incorporaron a una base de datos. Resultados En el estudio participaron 32 hospitales de 11 comunidades autonomas. La edad media de las 4.532 pacientes incluidas era de 56,72 anos, de las que 1.428 (31,5%) eran premenopausicas y 2.988 (65,9%) posmenopausicas. Los tumores de estadio II fueron los mas frecuentes (55,5%). Entre las enfermas con estadios I, II y III en el momento del diagnostico, la cirugia fue el tratamiento de inicio de la mayoria (90,7%), siendo la mastectomia radical la intervencion mas frecuente (79,7%). El 70,4% de las 1.941 pacientes con ganglios axilares positivos y el 37,4% de las 1.806 sin afectacion axilar recibieron quimioterapia adyuvante con o sin hormonoterapia. La mediana de supervivencia global de las 4.532 pacientes aun no se ha alcanzado. Conclusiones El proyecto «El Alamo» constituye una base de datos extensa sobre el cancer de mama en Espana. La distribucion por estadios en el momento del diagnostico fue desfavorable respecto a la observada en otros paises occidentales en el mismo periodo; sin embargo, los resultados terapeuticos por estadio son practicamente similares.

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.

Comparing Neoadjuvant Nab-paclitaxel vs Paclitaxel Both Followed by Anthracycline Regimens in Women With ERBB2/HER2-Negative Breast Cancer—The Evaluating Treatment With Neoadjuvant Abraxane (ETNA) Trial: A Randomized Phase 3 Clinical Trial

Importance Studies of neoadjuvant chemotherapy regimens using anthracyclines followed by taxanes have reported a doubling of pathological complete remission (pCR) rates compared with anthracycline-based regimens alone. A reverse sequence did not reduce activity. Nab-paclitaxel is an albumin-bound nanoparticle of paclitaxel that allows for safe infusion without premedication, and its use led to a significantly higher rate of pCR in the GeparSepto trial. Objective To determine whether nab-paclitaxel improves the outcomes of early and locally advanced human epidermal growth factor receptor 2 (ERBB2/HER2)-negative breast cancer compared with paclitaxel when delivered in a neoadjuvant setting. Design, Setting, and Participants In this multicenter, open-label study, in collaboration with Grupo Español de Investigación en Cáncer de Mama (GEICAM) and Breast Cancer Research Center–Western Australia (BCRC-WA), patients with newly diagnosed and centrally confirmed ERBB2/HER2-negative breast cancer were recruited. Participants were randomly allocated to paclitaxel, 90 mg/m2 (349 patients), or nab-paclitaxel, 125 mg/m2 (346 patients). The 2 drugs were given on weeks 1, 2, and 3 followed by 1 week of rest for 4 cycles before 4 cycles of an anthracycline regimen per investigator choice. Main Outcomes and Measures The primary end point was the rate of pCR, defined as absence of invasive cells in the breast and axillary nodes (ie, ypT0/is ypN0) at the time of surgery. A secondary end point was to assess tolerability and safety of the 2 regimens. Results From May 2013 to March 2015, 814 patients were registered to the study; 695 patients met central confirmation eligibility and were randomly allocated to receive either paclitaxel (349), or nab-paclitaxel (346) (median age, 50 years; range, 25-79 years). The intention-to-treat analysis of the primary end point pCR revealed that the improved pCR rate after nab-paclitaxel (22.5%) was not statistically significant compared with paclitaxel (18.6%; odds ratio [OR], 0.77; 95% CI, 0.52-1.13; P = .19). Overall, 38 of 335 patients (11.3%) 11.3% of patients had at least 1 serious adverse event in the paclitaxel arm and 54 of 337 patient (16.0%) in the nab-paclitaxel arm. Peripheral neuropathy of grade 3 or higher occurred in 6 of 335 patients (1.8%) and in 15 of 337 (4.5%), respectively. Conclusions and Relevance The improved rate of pCR after nab-paclitaxel was not statistically significant. The multivariate analysis revealed that tumor subtype (triple-negative vs luminal B-like) was the most significant factor (OR, 4.85; 95% CI, 3.28-7.18) influencing treatment outcome. Trial Registration clinicaltrials.gov Identifier: NCT01822314

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.