Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND: In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS: Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS: Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS: The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study.

Chemotherapy remains as the only systemic treatment option available for basal-like breast cancer (BC) patients. Preclinical models and several phase II studies suggested that platinum salts are active drugs in this BC subtype though there is no randomized study supporting this hypothesis. This study investigates if the addition of carboplatin to a combination of an alkylating agent together with anthracyclines and taxanes is able to increase the efficacy in the neoadjuvant treatment context. Patients with operable breast cancer and immunophenotypically defined basal-like disease (ER-/PR-/HER2- and cytokeratin 5/6+ or EGFR+) were recruited. Patients were randomized to receive EC (epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) for 4 cycles) followed either by D (docetaxel 100 mg/m(2) × 4 cycles; EC-D) or DCb (docetaxel 75 mg/m(2) plus carboplatin AUC 6 × 4 cycles; EC-DCb). The primary end point was pathological complete response (pCR) in the breast following the Miller and Payne criteria. Ninety-four patients were randomized (46 EC-D, 48 EC-DCb). pCR rate in the breast was seen in 16 patients (35 %) with EC-D and 14 patients (30 %) with EC-DCb (P value = 0.61). pCR in the breast and axilla was seen in 30 % of patients in both arms. The overall clinical response rate was 70 % (95 % CI 56-83) in the EC-D arm and 77 % (95 % CI 65-87) in the EC-DCb arm. Grade 3/4 toxicity was similar in both arms. The addition of carboplatin to conventional chemotherapy with EC-D in basal-like breast cancer patients did not improve the efficacy probably because they had already received an alkylating agent. These findings should be taken into consideration when developing new agents for this disease.

Electronic health records and patient registries in medical oncology departments in Spain.

PURPOSE: We aimed to evaluate the current situation of electronic health records (EHRs) and patient registries in the oncology departments of hospitals in Spain. METHODS: This was a cross-sectional study conducted from December 2018 to September 2019. The survey was designed ad hoc by the Outcomes Evaluation and Clinical Practice Section of the Spanish Society of Medical Oncology (SEOM) and was distributed to all head of medical oncology department members of SEOM. RESULTS: We invited 148 heads of oncology departments, and 81 (54.7%) questionnaires were completed, with representation from all 17 Spanish autonomous communities. Seventy-seven (95%) of the respondents had EHRs implemented at their hospitals; of them, over 80% considered EHRs to have a positive impact on work organization and clinical practice, and 73% considered that EHRs improve the quality of patient care. In contrast, 27 (35.1%) of these respondents felt that EHRs worsened the physician-patient relationship and conveyed an additional workload (n = 29; 37.6%). Several drawbacks in the implementation of EHRs were identified, including the limited inclusion of information on both outpatients and inpatients, information recorded in free text data fields, and the availability of specific informed consent. Forty-six (56.7%) respondents had patient registries where they recorded information from all patients seen in the department. CONCLUSION: Our study indicates that EHRs are almost universally implemented in the hospitals surveyed and are considered to have a positive impact on work organization and clinical practice. However, EHRs currently have several drawbacks that limit their use for investigational purposes. CLINICAL TRIAL REGISTRATION: Not applicable.

Review of concepts in therapeutic decision-making in HER2-negative luminal metastatic breast cancer.

PURPOSE: Hormone receptor (HR)-positive, Human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) requires a therapeutic approach that takes into account multiple factors, with treatment being based on anti-estrogen hormone therapy (HT). As consensus documents are valuable tools that assist in the decision-making process for establishing clinical strategies and optimize the delivery of health services, this consensus document has been created with the aim of developing recommendations on cretiera for hormone sensitivity and resistance in HER2-negative luminal MBC and facilitating clinical decision-making. METHODS: This consensus document was generated using a modification of the RAND/UCLA methodology, which included the definition of the project and identification of issues of interest, a non-exhaustive systematic review of the literature, an analysis and synthesis of the scientific evidence, preparation of recommendations, and external evaluation with a panel of 64 medical oncologists specializing in breast cancer. RESULTS: A Spanish panel of experts reached consensus on 32 of the 32 recommendations/conclusions presented in the first round and were accepted with an approval rate of 100% about definition of metastatic disease not susceptible to local curative treatment, definition of hormone sensitivity and hormone resistance in metastatic luminal disease and therapeutic decision-making. CONCLUSION: We have developed a consensus document with recommendations on the treatment of patients with HER2-negative luminal MBC that will help to improve therapeutic benefits.

A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression.

Capecitabine is a drug that requires the consecutive action of three enzymes: carboxylesterase 2 (CES 2), cytidine deaminase (CDD), and thymidine phosphorylase (TP) for transformation into 5-fluorouracil (5FU). The metabolism of 5FU requires the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) among other enzymes. The present study prospectively examined the possible relationship between the toxicity and efficacy of capecitabine and 14 different polymorphisms in CES 2, CDD, TS and DPD. Between 2003 and 2005, a total of 136 patients with advanced breast or colorectal cancer treated with capecitabine were prospectively enrolled. The presence of two polymorphisms (CDD 943insC and CES 2 Exon3 6046 G/A) were associated with a non-statistically significant higher incidence of grade 3 hand-foot syndrome (HFS) (p=0.07) and grade 3-4 diarrhoea (p=0.09), respectively. Patients heterozygous or homozygous for the polymorphism CES 2 5'UTR 823 C/G exhibited a significantly greater response rate to capecitabine, and time to progression of disease (59%, 8.7 months) than patients with the wild type gene sequence (32%, p=0.015; 5.3 months, p=0.014). For the first time, an association between a polymorphism in the CES2 gene and the efficacy of capecitabine has been described, providing preliminary evidence of its predictive and prognostic value.

Six cycles of ABVD in the treatment of stage I and II Hodgkin's lymphoma: a pilot study.

PURPOSE: Chemotherapy is the standard treatment in advanced Hodgkin's lymphoma and a therapeutic alternative for early stages. Although polychemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is equivalent or superior to mechloretamine, vincristine, procarbazine, and prednisone (MOPP) in advanced disease, no series have been published using ABVD without associated radiotherapy in early stages. We report the results obtained with the administration of six cycles of ABVD alone in clinical stage I and II disease. PATIENTS AND METHODS: From January 1990 to October 1994, 23 patients with stage I or II Hodgkin's lymphoma were treated with six cycles of ABVD; six patients who met the criteria for mediastinal bulky disease also received radiotherapy to the mediastinum. RESULTS: After six cycles, 20 complete responses (CRs) and three partial responses (PRs), which became CRs after radiotherapy, were obtained. Toxicity was moderate and manageable. With a median follow-up duration of 37 months (range, 12 to 75), three patients have relapsed and one has died. Overall and progression-free survival rates at 42 months are 95% and 84%, respectively. CONCLUSION: Six cycles of ABVD are effective and safe in the treatment of stage I and II Hodgkin's lymphoma, at least in the short term, but long-term observation data are not yet available.

Comparison of three protracted antiemetic regimens for the control of delayed emesis in cisplatin-treated patients.

Antiemetic activity of three protracted regimens for the control of cisplatin-evoked delayed emesis was explored. 63 patients were randomly assigned to receive one of three protracted antiemetic schedules over 4 days. Group C patients received dexamethasone 8 mg twice daily on days 2 and 3, then 4 mg twice daily on days 4 and 5; in group B, alizapride 2.5 mg/kg four times daily on days 2-5 plus dexamethasone as in group C was administered; and in group A, metoclopramide 0.5 mg/kg four times daily on days 2-5 plus dexamethasone was given at the same dose-schedule as in groups C and B. Complete protection from delayed vomiting was achieved in 44% of group C, 30% of B and 70% of group A (P = 0.02). Mild side-effects were noted in all three groups. A higher complete protection for delayed emesis was obtained in metoclopramide-dexamethasone-treated patients. Neither of the regimens used in the protection of delayed emesis controlled late nausea.

Secondary prophylactic G-CSF (filgrastim) administration in chemotherapy of stage I and II Hodgkin's lymphoma with ABVD.

UNLABELLED: The purpose of this study was to determine the effect of granulocyte colony-stimulating factor (filgrastim, G-CSF) for maintenance of chemotherapy dose-intensity in patients with stage I or II Hodgkin's lymphoma treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Fifty-six patients with stage I or II Hodgkin's lymphoma treated with ABVD were eligible for secondary prophylactic G-CSF administration because of neutropenia (absolute neutrophil count < 1 x 10(9) /L) causing treatment delay or febrile neutropenia. Patients received 300 microg (total dose) of G-CSF (filgrastim) subcutaneously on days 3 to 7 and 17 to 21 of each cycle in order to prevent dose reduction or delay in subsequent cycles of treatment continuing the G-CSF until completion of chemotherapy. Results showed that 30 (54%) of the patients required the use of G-CSF, 26 (47%) during the first or second cycle. After G-CSF administration delay in chemotherapy did not occur in 25 patients, whereas delays in the fifth or sixth cycle occurred in four patients. Despite treatment with G-CSF, one patient had febrile neutropenia. Dose intensity greater than 90% of that planned was delivered to more the 85% of patients. IN CONCLUSION: Secondary prophylactic G-CSF administration was necessary in more than half of patients with stage I or II Hodgkin's lymphoma during chemotherapy with ABVD. The use of G-CSF allowed maintenance of chemotherapy schedule and dose intensity in the majority of patients.

Validation of breast cancer prognostic models.

Besides classic prognostic factors in breast cancer, there are numerous variables without fully established prognostic value. The use of all these factors in daily clinical practice may prove difficult. In this study we investigated the validity of certain reported prognostic models in our own population of patients. In a retrospective series of 244 breast cancer patients, we determined certain clinical, morphological and immunohistochemistry variables. Validity analysis of the prognostic models reported by other authors was performed by the use of their corresponding Cox equations calculated from the data published. The validation made with the Paik model without prognostic value has obtained statistical significance in our series, and variables predicting the evolution of their patients was not confirmed. The application of the Lovekin prognostic model did appear to be valid in our group of patients. It has not been possible to verify as prognostic in our patients all the models proposed by other authors.

The quotient of number of nodes and tumour size (N/T) from primary breast cancer predicts the clinical course after diagnosis of distant relapse.

INTRODUCTION: Breast cancer is a disease with a very variable progression. Primary tumour size and metastatic lymph node involvement are the best indicators of the likelihood of relapse. However, their value in predicting progression following relapse is not clear. AIM: The aim of this study was to asses whether the relationship between tumour size and the number of lymph nodes involved had any value as predictive factors of post-relapse progression. METHOD: We established an index defined as the quotient between the number of diseased lymph nodes and the tumour size (in cm). RESULTS: Applying this index in 230 consecutive patients with metastatic breast cancer, we observed that there was a significant inverse relation between the index and post-relapse progression. CONCLUSION: We conclude that, at the time of initial diagnosis, the quotient of tumour size and the number of diseased lymph nodes could be a good predictor of time-to-progression following the diagnosis of the metastatic disease.

Cisplatin, 5-fluorouracil, and high-dose folinic acid in patients with advanced unresectable head and neck cancer.

For patients with advanced, unresectable head and neck (HN) cancer, surgery and/or radiotherapy are the standard treatments but have poor results. A phase II trial of a continuous infusion of cisplatin, 5-FU, and high dose folinic acid (PFL) as induction chemotherapy in patients with previously untreated, locally advanced HN cancer was performed in an attempt to confirm the encouraging results reported by Dana Farber investigators using an identical regimen. Forty-five consecutive patients with unresectable HN cancer were treated every 28 days with a continuous infusion of cisplatin 25 mg/m(2)/day (days 1-5), 5-FU 800 mg/m(2)/day (days 2-6), and folinic acid 500 mg/m(2)/day (days 1-6). After three courses of chemotherapy, patients were treated with surgery and/or radiotherapy. Objective responses were observed in 26 of 38(69%) evaluable patients with 14(37%) clinical complete responses. Grade III-IV toxicity was important and consisted mainly of mucositis and neutropenia that were found in 47 and 18%, respectively , of patients after the first course. There was one toxic death. PFL is an active, toxic induction regimen for far-advanced HN cancer, yielding a response rate in the range of the widely used cisplatin and 5-FU (PF) schedule; a comparative trial is warranted before concluding that PFL is superior to the latter combination.

Sequential combination of methotrexate (MTX), 5-fluorouracil (FU), and high-dose folinic acid (FA) in advanced colorectal cancer: double biochemical modulation?

Thirty evaluable patients were treated with methotrexate (MTX) 200 mg/m2, i.v. infusion over 60 minutes, 24 hours prior to the administration of 5-fluorouracil 600 mg/m2, and folinic acid 200 mg/m2, i.v. infusion over 60 minutes, every 2 weeks. A partial or complete response was achieved in 12 patients (40%), and disease stable in 10 patients (33%). Median actuarial survival was 18 months. Side effects, which were within acceptable limits, included 11 cases of stomatitis (5 Grade 3), 3 cases of leukopenia (Grade 2) and 12 cases of mild nausea and vomiting. We conclude that the present combination is active in metastatic colorectal cancer with mild toxicity. These results are being confirmed and a randomized trial is being carried out to prove that this combination holds therapeutic advantage.

[The description of a new cellular type, Pinocchio cells, induced during the treatment of solid tumors with interleukin-2]. / Descripción de un nuevo tipo celular, células Pinocho, inducido en el curso del tratamiento de tumores sólidos con interleucina-2.

Three patients with renal adenocarcinoma and one with metastatic malignant melanoma were treated with continuous intravenous infusion of 18 x 10(6) IU/m2/day interleukin-2 during 5 days per week (2 weeks). Overall 60% of the calculated dose was administered owing to the development of severe toxicity. Among the hematological effects, eosinophilia was found in all patients, which was more marked 15-20 days after therapy was started. In addition, 15% of atypical lymphocytes were found in peripheral blood. These cells, denominated Pinocchio cells, show a cytoplasmatic prolongation with azurophilic granulation. Their cytochemical study disclosed a marked positivity for acid phosphatase and alpha-naphthyl acetate esterase, and a variable positivity for dipeptidyl-amino peptidase (DAP IV). The immunophenotype revealed that is a T lineage cell population, basically CD 3+, with small or absent positivity for the monoclonal CD 19 antibody. The presence of Pinocchio cells, which are effector cells mediating tumor destruction by an apoptosis mechanism, is related to the administered dose of interleukin-2.

Addressing critical issues in the development of an Oncology Information System.

PURPOSES: This paper presents the experience on the design and implementation of a user-centered Oncology Information System developed for the Medical Oncology Department at the "Hospital Universitario Virgen de la Victoria", in Málaga, Spain. The project focused on the aspects considered in the literature as critical factors for a successful deployment and usage of a health information system. METHODS: System usability, adequate technology, integration of clinical routines, real-time statistical analysis of data, information confidentiality and standard protocol-based external interconnection were the key aspects considered. RESULTS: The developed system is based on a web application with a modular and layered architecture accounting for usability, ease of maintenance and further system development. Evaluation of system usability was carried at three and fifteen months after system deployment to analyze the advantages/disadvantages experienced by the end-users. CONCLUSIONS: A thorough prior analysis of clinical activities and workflows, the use of the adequate technology, and the availability of data analysis tools will almost guarantee success in the deployment of an Oncology Information System.

Is it possible to increase pCR in the neoadjuvant treatment with a dose-dense/sequential combination?: results from a phase II Trial combining epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine ± trastuzumab in stage II and III breast cancer patients.

PURPOSE: To evaluate the pathologic complete response (pCR) rate of a combination of epirubicin (E) and cyclophosphamide (C) followed by paclitaxel (P) and gemcitabine (G) (+ trastuzumab[T]) in Her2+ patients) in a sequential and dose-dense schedule as neoadjuvant chemotherapy for stages II and III patients with breast cancer. Secondary endpoints: clinical response rate, disease free survival, safety and correlation between pCR and biologic markers. PATIENTS AND METHODS: Eligible patients were treated with E (90 mg/m²) and C (600 mg/m²) for 3 cycles (first sequence) followed by P (150 mg/m²) and G (2500 mg/m²) (second sequence) for 6 cycles. All drugs were administered on day 1, every 2 weeks, with prophylactic growth factor support. Weekly T (2 mg/kg [4 mg/kg first infusion]) was administered concomitantly with P and G in Her2+ patients. A core biopsy was performed before treatment for biologic markers assessment. Patients underwent surgery, radiotherapy, and adjuvant hormonal therapy according to institutional practice. RESULTS: Seventy-three patients were treated. A pCR was achieved in 27 (37%) patients (32.1%, Her2- and 50%, Her2+). pCR was significantly higher in tumors that were hormonal receptor negative, poorly differentiated and positive for Ki67 and p53. Breast-conserving surgery was performed in 47 patients (64.4%). Most frequent grade 3/4 hematologic and nonhematological toxicities included neutropenia (12%), nausea/vomiting (17%), and transient liver enzymes elevation (7%). One patient suffered an asymptomatic and reversible decrease in left ventricular ejection fraction. CONCLUSIONS: These results show a highly effective regimen in terms of pCR with a good toxicity profile in the neoadjuvant treatment of patients with breast cancer. The addition of trastuzumab increased pCR rate in Her2+ tumors.