Browsing by Author "Grande-Pulido, E."
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Item Activity and safety of sunitinib in patients with advanced radioactive iodine-refractory differentiated thyroid carcinoma in clinical practice.(Endocrine, 2015) Díez, Juan J.; Iglesias, Pedro; Alonso, Teresa; Grande-Pulido, E.Our aim was to evaluate the effectiveness of off-label use of sunitinib in patients with advanced differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) therapy. We performed a retrospective analysis of patients treated in the setting of clinical practice in a University General Hospital. Eleven consecutive patients (5 women, 6 men, mean age 63.0 ± 12.9 year) with advanced papillary (n = 7) or follicular (n = 4) thyroid carcinoma not suitable for curative surgery or RAI therapy were studied. Two patients were treated with one line of tyrosine kinase inhibitors before sunitinib therapy. All patients had evidence of objective progressive disease (PD). We analysed the objective response rate (ORR) and changes in thyroglobulin levels during therapy. Complete response was achieved in 1 patient (9 %) and partial response (PR) in 2 patients (18 %). Five patients (45 %) had stable disease (SD). Therefore, ORR was 27 % and disease control rate was 72 %. We found that the decrement in thyroglobulin concentrations was significantly higher in patients with radiological disease control than in patients with PD. Most frequent grade 1 and 2 adverse events were fatigue, mucositis, hand-and-foot syndrome, hyporexia, rash, hypertension, and edema. In routine clinical practice, sunitinib appears to be effective and feasible in patients with advanced RAI-refractory DTC. Most patients achieved SD or PR, despite having PD at the start of treatment, and safety profile was consistent with that reported in previous clinical trials.Item Cancer and Immune Response: Old and New Evidence for Future Challenges.(The Oncologist, 2008) De la Cruz-Merino, Luis; Grande-Pulido, E.; Albero-Tamarit, Ana; Codes-Manuel de Villena, Manuel EduardoCancer may occur as a result of abnormal host immune system tolerance. Recent studies have confirmed the occurrence of spontaneous and induced antitumor immune responses expressed as the presence of tumor-infiltrating T cells in the tumor microenvironment in some cancer models. This finding has been recognized as a good prognostic factor in several types of tumors. Some chemotherapy agents, such as anthracyclines and gemcitabine, are effective boosters of the immune response through tumor-specific antigen overexpression after apoptotic tumor cell destruction. Other strategies, such as GM-CSF or interleukin-2, are pursued to increase immune cell availability in the tumor vicinity, and thus improve both antigen presentation and T-cell activation and proliferation. In addition, cytotoxic T lymphocyte antigen 4 – blocking monoclonal antibodies enhance immune activity by prolonging T-cell activation. Strategies to stimulate the dormant immune system against tumors are varied and warrant further investigation of their applications to cancer therapy in the future.Item Experience in the use of sunitinib given as a single agent in metastatic chemoresistant and castration-resistant prostate cancer patients.(Expert Opinion on Pharmacotherapy, 2011) Castellano, Daniel; González-Larriba, José L.; Antón-Aparicio, Luis M.; Cassinello, Javier; Grande-Pulido, E.; Esteban, Emilio; Sepúlveda, JuanObjective: Vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) correlate with poor prognosis in castration-resistant prostate cancer (CRPC). Sunitinib has shown activity in CRPC and at the time of this analysis there was no standard therapy for docetaxel-refractory CRPC. Methods: We present a case series data collection of 19 patients with a median age of 73 years, CRPC and rising prostate-specific antigen (PSA). Patients received sunitinib 37.5 mg continuous daily dose. One cycle comprised a 4-week period. Patients were evaluated by CT scan every 8 weeks and PSA was monitored every 4 weeks. Results: Median Eastern Cooperative Oncology Group (ECOG) performance status score was 2. Patients received a median of two previous treatment lines for the hormone-refractory setting. Baseline median PSA was 280 ng/ml. Patients received a median of 16 weeks of therapy (4 – 48+). One patient achieved a partial response (5%) and 12 (66.7%) achieved stable disease for at least 3 months according to RECIST criteria. Median progression-free survival was 4 months. PSA declined > 50% in 5/19 (26.3%) and stabilized in 7/19 (37%) patients. Frequent adverse events were grade 3 asthenia (21%), grade 3 diarrhea (10%) and grade 3 hand-foot syndrome (15.7%). Conclusions: Activity with sunitinib was observed in highly pretreated docetaxel-refractory CRPC with acceptable tolerability. Additional studies should confirm the role of antiangiogenic agents in this setting.Item GEP–NETs UPDATE: Biotherapy for neuroendocrine tumours.(European journal of endocrinology, 2015) Alonso-Gordoa, T.; Capdevila, J.; Grande-Pulido, E.Neuroendocrine tumours (NETs) represent a less frequent and heterogeneous group of tumours, which has experienced, in recent years, a significant increase in effective therapeutic possibilities overcoming the disappointing results from chemotherapy. Initial improvements in treatment strategies came from somatostatin analogues (SSAs) that have widely demonstrated a significant improvement in symptomatic relief and tumour control growth by a complex mechanism of action over cell survival, angiogenesis and immunomodulation. Recent investigations have pointed out novel SSAs with a wider binding profile (pasireotide), chimeric molecules against somatostatin receptors and dopamine receptors and the combination with targeted agents, such as mTOR inhibitors or antiangiogenic agents. Immunotherapy is the second cornerstone in NET treatment and has been represented with interferon alpha for a long time, with a demonstrated activity on tumour and clinical response. Its less manageable adverse events have limited its usage. However, different checkpoints in immune system regulation have been effectively targeted in different solid tumours, and novel approaches are currently arising in NETs. In conclusion, biotherapy remains an active treatment strategy for initial approach in patients with NETs. Further investigation on patients' selection, molecular profiles, treatment sequence or combination and optimisation of current and novel biotherapy agents is required.Item Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array.(British Journal of Cancer, 2009) Pérez-Gracia, J. L.; Prior, C.; Guillén-Grima, F.; Segura, V.; González, A.; Panizo, A.; Melero, I.; Grande-Pulido, E.; Gurpide, A.; Gurpide, A.; Gil-Bazo, I.; Calvo, A.BACKGROUND: Several drugs are available to treat metastatic renal-cell carcinoma (MRCC), and predictive markers to identify the most adequate treatment for each patient are needed. Our objective was to identify potential predictive markers of sunitinib activity in MRCC. METHODS: We collected sequential serum samples from 31 patients treated with sunitinib. Sera of six patients with extreme phenotypes of either marked responses or clear progressions were analysed with a Human Cytokine Array which evaluates 174 cytokines before and after treatment. Variations in cytokine signal intensity were compared between both groups and the most relevant cytokines were assessed by ELISA in all the patients. RESULTS: Twenty-seven of the 174 cytokines varied significantly between both groups. Five of them (TNF-a, MMP-9, ICAM-1, BDNF and SDF-1) were assessed by ELISA in 21 evaluable patients. TNF-a and MMP-9 baseline levels were significantly increased in nonresponders and significantly associated with reduced overall survival and time-to-progression, respectively. The area under the ROC curves for TNF-a and MMP-9 as predictive markers of sunitinib activity were 0.83 and 0.77. CONCLUSION: Baseline levels of TNF-a and MMP-9 warrant further study as predictive markers of sunitinib activity in MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response.Item Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes.(British Journal of Cancer, 2009) Alfaro, C.; Suárez, N.; González, A.; Solano, S.; Erro, L.; Dubrot, J.; Palazón, A.; Hervas-Stubbs, S.; Gurpide, A.; López-Picazo, J.M.; Grande-Pulido, E.; Melero, I.; Pérez-Gracia, J. L.Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.Item Interstitial Pneumonitis and Lung Fibrosis during Adjuvant Treatment of Melanoma with Interferon Alpha according to the Kirkwood Schedule.(Dermatology, 2005) Puente Vázquez, J.; Moreno Antón, F.; Grande-Pulido, E.; López Tarruella-Cobo, S.; Pérez Segura, P.; Díaz-Rubio, E.Item MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines.(British Journal of Cancer, 2011) Arriola, E.; Cañadas, I.; Arumí-Uría, M.; Dómine, M.; Grande-Pulido, E.; Albanell, J.Background: Small cell lung carcinoma (SCLC) has poor prognosis and remains orphan from targeted therapy. MET is activated in several tumour types and may be a promising therapeutic target. Methods: To evaluate the role of MET in SCLC, MET gene status and protein expression were evaluated in a panel of SCLC cell lines. The MET inhibitor PHA-665752 was used to study effects of pathway inhibition in basal and hepatocyte growth factor (HGF)-stimulated conditions. Immunohistochemistry for MET and p-MET was performed in human SCLC samples and association with outcome was assessed. Results: In MET mutant SCLC cells, HGF induced MET phosphorylation, increased proliferation, invasiveness and clonogenic growth. PHA-665752 blocked MET phosphorylation and counteracted HGF-induced effects. In clinical samples, total MET and p-MET overexpression were detected in 54% and 43% SCLC tumours (n = 77), respectively. MET phosphorylation was associated with poor median overall survival (132 days) vs p-MET negative cases (287 days) (P < 0.001). Phospho-MET retained its prognostic value in a multivariate analysis. Conclusions: MET activation resulted in a more aggressive phenotype in MET mutant SCLC cells and its inhibition by PHA-665752 reversed this phenotype. In patients with SCLC, MET activation was associated with worse prognosis, suggesting a role in the adverse clinical behaviour in this disease.Item Patient-reported outcomes in a phase III, randomized study of sunitinib versus interferon-a as first-line systemic therapy for patients with metastatic renal cell carcinoma in a European population.(Annals of Oncology, 2009) Castellano, D.; García del Muro, X.; Pérez-Gracia, J. L.; González-Larriba, J. L.; Abrio, M. V.; Ruiz, M. A.; Pardo, A.; Guzmán, C.; Díaz Cerezo, S.; Grande-Pulido, E.Background: The purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-a) treatment in patients with metastatic renal cell carcinoma (mRCC). Patients and methods: In all, 304 mRCC patients (European cohort) were randomized 1 : 1 to receive sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off) or IFN-a (9 million units s.c. injection three times/week). The following questionnaires were completed (days 1 and 28 per cycle): Functional Assessment of Cancer Therapy-General (FACTG), the FACT-Kidney Symptom Index and the EuroQol Group’s EQ-5D self-report questionnaire (EQ-5D). Results correspond to an ongoing trial with progression-free survival time as primary end point, and patients were still being followed up. Data were analyzed using repeated measures mixed effects models (MEMs) that allow the inclusion of initial differences and uncompleted repeated measures, with the assumption of data missing at random. Six-cycle results were included. Results: Results consistently showed that patients in sunitinib group experienced statistically significantly milder kidney-related symptoms, better cancer-specific HRQoL and general health status (in social utility scores) during the study period as measured by these patient-reported outcome end points. No statistical differences between groups were found on the FACT-G physical well-being subscale or the EQ-5D VAS values. Conclusions: Results from MEM showed the sunitinib’s benefit on HRQoL compared with IFN-a.Item Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE).(Annals of Oncology., 2015) Grande-Pulido, E.; Capdevila, J.; Castellano, D.; Díez, J.J.; Carrato Mena, A.; García-Carbonero, R.Background: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. Methods: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. Results: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]. Conclusions: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). Clinical trial number: NCT01280201.Item Phase II Study of Pegylated Liposomal Doxorubicin plus Vinorelbine in Breast Cancer with Previous Anthracycline Exposure.(Clinical Breast Cancer, 2004) Martín, Miguel; García-Donas, Jesús; Casado, Antonio; Moreno, Fernando; Grande-Pulido, E.; Díaz-Rubio, E.Thirty-five patients with metastatic breast cancer (MBC) entered a phase II study of pegylated liposomal doxorubicin 35 mg/m2 intravenously (I.V.) on day 1 plus vinorelbine 30 mg/m2 I.V. on day 1 every 4 weeks. Patients were required to have measurable disease, previous chemotherapy with an anthracycline-containing regimen, and a normal left ventricular ejection fraction (LVEF). Thirty-four patients were assessable for response and toxicity. The overall response rate (on an intent-to-treat basis) was 35% (12 of 34; 95% CI, 20%-54%). One complete response and 11 partial responses were noted. In addition, 14 patients (41%) had stable disease of > 4 months duration, and 7 patients (20.5%) had disease progression. The response rates to the combination when it was used as first- and second-line chemotherapy were 31% (4 of 13) and 38% (8 of 21), respectively. Median time to disease progression was 7 months (range, 1–35 months) and median overall survival was 13 months (range, 2 to > 62 months). Neutropenia was the most frequent toxicity (grade 4 in 44% of patients and 19% of cycles), but neutropenic fever was seen in only 3 cases. No septic deaths occurred. Nonhematologic grade 3 side effects included skin toxicity (palmar-plantar erythrodysesthesia syndrome, 6%) and mucositis (15%). Late alopecia was seen in 53% of patients (grade 1 in 41%, and grade 2 in 12%). The median LVEFs were 64% (range, 50%-81%) at baseline and 62% (range, 37%–70%) after treatment. Three patients presented an LVEF decrease to < 50%; however, no clinical heart failure was noted, and 2 of these patients recovered normal values after cessation of therapy. The combination of pegylated liposomal doxorubicin and vinorelbine can be safely administered to patients with anthracycline-pretreated MBC and is active in this population.Item Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract after failure of one platinum-based systemic therapy in clinical practice.(BMC Cancer, 2014) Castellano, Daniel; Puente, Javier; De Velasco, Guillermo; Chirivella, Isabel; López-Criado, Pilar; Mohedano, Nicolás; Fernández, Ovidio; García-Carbonero, Icíar; González, María Belén; Grande-Pulido, E.Background: Patients with transitional cell carcinoma of the urothelial tract (TCCU) who fail initial platinum-based chemotherapy for advanced disease represent a challenge in daily clinical practice. Vinflunine is approved by the European Medicine Agency (EMA) but, up to now, limited experience has been reported outside clinical trials. Methods: We assessed the efficacy and safety of vinflunine in an unselected group of 102 consecutive patients with metastatic TCCU. Results: The median age was 67 years (range 45–83). Among the most common comorbidities that patients presented at baseline were hypertension (50.5%) and diabetes (20.7%). Distant metastases were present in retroperitoneal nodes (58%), lung (29.3%), and bone (20.2%). The ECOG 0, 1 and 2 performance status at the start of vinflunine were 31.3%, 60.6% and 8.1%, respectively. The most commonly reported adverse events of any grade were constipation 70.6% (5.9% grade 3–4), vomiting 49.1% (2% grade 3–4), neutropenia 48.1% (12.8% grade 3–4) and abdominal pain 34.3% (4.9% grade 3–4). A median of 4 cycles of vinflunine was administered per patient (range 1–18). Median progression free and overall survival for all patients (N = 102) were 3.9 months (2.3-5.5) and 10 months (7.3-12.8), respectively. Time to tumor progression was 4.3 months (2.6-5.9). Two patients (2%) achieved CR, 23 (22.5%) patients had PR, and 42 (41.2%) presented SD as best response. The clinical benefit rate with vinflunine was 65.7%. Conclusions: Our results show that the behavior of vinflunine in routine clinical practice resembles that of the pivotal phase III randomized study.Item Targeting oncogenic ALK: a promising strategy for cancer treatment.(Molecular Cancer Therapeutics, 2011) Grande-Pulido, E.; Bolós, María-Victoria; Arriola, EdurneRecently, the anaplastic lymphoma kinase (ALK) has been found to be altered in several solid and hematologic tumors. Novel drugs targeting this tyrosine kinase receptor are under development, and early clinical trials are showing promising activity in non-small cell lung cancer patients with ALK+ tumors. Here, we review the structure and function of the ALK receptor, the mechanisms associated with its deregulation in cancer, methods for ALK detection in tumor samples, its potential as a new marker for candidate patient selection for tailored therapy, and novel drugs under development that target ALK.Item The potential role of sunitinib in gastrointestinal cancers other than GIST.(Critical Reviews in Oncology/Hematology, 2010) Grávalos, Cristina; Grande-Pulido, E.; Gasent, Joan ManelGastrointestinal tumors are the most frequent and lethal malignancies worldwide. The deeper knowledge in molecular biology mechanisms involved in carcinogenesis has allowed the design of new targeted drugs mainly directed against the epidermal growth factor receptor (EGFR), the vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). Sunitinib is an oral multitargeted inhibitor of the VEGF, platelet-derived growth factor (PDGF), and c-KIT, among others, tyrosine kinase receptors. Therefore, sunitinib acts in a dual mode as antiangiogenic agent and as antitumoral drug. The aim of this review is to gather the preclinical rationale behind the clinical use of sunitinib in gastrointestinal malignancies other than gastrointestinal stromal tumors (GIST) and to summarize the clinical data from phase I to III trials currently available.Item The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status.(Angiogenesis, 2014) García-Alfonso, Pilar; Grande-Pulido, E.; Polo, Eduardo; Afonso, Ruth; Reina, Juan José; Jorge, Mónica; Campos, Juan Manuel; Martínez, Virginia; Angeles, Cristina; Montagut, ClaraColorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.Item Trastuzumab Associated with Successive Cytotoxic Therapies Beyond Disease Progression in Metastatic Breast Cancer.(Clinical breast cancer, 2005) García-Sáenz, José A.; Martín, Miguel; Puente, Javier; López-Tarruella, Sara; Casado, Antonio; Moreno, Fernando; Grande-Pulido, E.; Díaz-Rubio, E.Purpose To determine the activity of successive trastuzumab-containing regimens in HER2-overexpressing metastatic breast cancer (MBC) as well as the response rate (RR), time to progression (TTP), and predictive factors for response. Patients and Methods We performed a descriptive retrospective study of trastuzumab activity in patients with HER2-overexpressing MBC treated at our hospital from October 1999 to October 2003. Results Fifty-eight patients were evaluated, in whom an overall RR (complete response plus partial response) of 39.7% was obtained for first-time administration of trastuzumab; stable disease (SD) was seen in 29.3%, and the clinical benefit rate was 69%. Median TTP was 6 months (range, 1 months to > 39 months). A total of 31 patients (53.4%) received a second trastuzumab-containing regimen, with an RR of 25.8%; SD was seen in 12.9%, and the clinical benefit rate was 38.7%. Median TTP was 3 months (range, 1 months to > 22 months). A total of 8 patients (14.3%) received a third trastuzumab-containing regimen. The RR for the third trastuzumab regimen was 12.5%; SD was seen in 12.5%, and the clinical benefit rate was 25%. Median TTP was 2 months (range, 1 months to > 12 months). A total of 4 patients (7.1%) received a fourth trastuzumab-containing regimen, with an RR of zero and SD in 25%. Predictive factors for response were disease in soft tissue or bone (P = 0.03; odds ratio [OR], 3.25; 95% confidence interval [CI], 1.08–9.8) and metastases at > 2 sites (P = 0.03; OR, 6.2; 95% CI, 1.25–30.9). We observed a better RR in the second trastuzumab-containing regimen when the patient responded to the first regimen (P = 0.03; OR, 13.2; 95% CI, 1.36–126). Conclusion Trastuzumab-containing regimens beyond disease progression in MBC show activity even in heavily pretreated patients. The activity noted does not allow us to ascertain the independent contribution of trastuzumab in this setting. There were more responses in patients with few metastases in the soft tissues or bone. Patients who have shown a previous response to trastuzumab can show a response to a second trastuzumab-containing regimen.