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.

Challenges in radiological evaluation of brain metastases, beyond progression.

MRI is the cornerstone in the evaluation of brain metastases. The clinical challenges lie in discriminating metastases from mimickers such as infections or primary tumors and in evaluating the response to treatment. The latter sometimes leads to growth, which must be framed as pseudo-progression or radionecrosis, both inflammatory phenomena attributable to treatment, or be considered as recurrence. To meet these needs, imaging techniques are the subject of constant research. However, an exponential growth after radiotherapy must be interpreted with caution, even in the presence of results suspicious of tumor progression by advanced techniques, because it may be due to inflammatory changes. The aim of this paper is to familiarize the reader with inflammatory phenomena of brain metastases treated with radiotherapy and to describe two related radiological signs: "the inflammatory cloud" and "incomplete ring enhancement", in order to adopt a conservative management with close follow-up.

Management of the toxicity of chemotherapy and targeted therapies in elderly cancer patients.

The elderly form a very heterogeneous group in relation to their general health state, degree of dependence, comorbidities, performance status, physical reserve and geriatric situation, so cancer treatment in the older patient remains a therapeutic challenge. The physiological changes associated with aging increase the risk of developing a serious toxicity induced by chemotherapy treatment, as well as other undesirable consequences as hospitalizations, dependence and non-compliance with treatment, that can negatively affect survival, quality of life and treatment efficacy. The use of hematopoietic growth factors and other active supportive interventions in the elderly can help prevent and/or alleviate these toxicities. However, we have little data on the efficacy and tolerance of support treatments in the older patient. The objective of this work is to review the most frequent toxicities of oncological treatments in the elderly and their management.

The "El Alamo" project (1990-1997): two consecutive hospital-based studies of breast cancer outcomes in Spain.

BACKGROUND: The "Alamo" project is a retrospective analysis of 14,854 patients diagnosed of breast cancer between 1990 and 1997 in 50 Spanish hospitals. METHODS: Alamo I (AI) consisted of 4,532 patients diagnosed with breast cancer between 1990 and 1993. Data were collected in 2000. Alamo II (AII) consisted of 10,322 patients diagnosed between 1994 and 1997. Data were collected in 2003. RESULTS: At presentation, there were (AI vs. AII) 17.6% vs. 24.3% at stage I; 55.5% vs. 53.1% at stage II; 18.7% vs. 15% at stage III; 7.2% vs. 5.9 at stage IV. Median age was 57 (AI) vs. 58 years (AII) and 65.9% vs. 67.2% (AI vs. AII) were post-menopausal. Firstline treatment for disease stages I, II and III was surgery in 91% of patients in both studies. Breast conserving surgery rate increased from 20.2% (AI) to 32.7% (AII). Adjuvant systemic treatments were administered to 87.6% (AI) and 92.8% (AII) of patients. Recurrence rate diminished from 36.6% (AI) to 22.5% (AII) and the 9-year survival rate increased from 63.2% (95% CI: 61.5-64.9) to 70.1% (95% CI: 68.5-71.8). CONCLUSION: Breast cancer outcomes in Spain have improved from 1990-1993 to 1994-1997, likely because of breast cancer screening program implementation and new therapies.

Randomised comparison of ceftazidime and imipenem as initial monotherapy for febrile episodes in neutropenic cancer patients.

With the availability of new, broad-spectrum antibiotics, initial therapy with a single agent has become an alternative to classic combinations in the management of febrile, neutropenic cancer patients. The aims of this study were to compare the efficacy of ceftazidime and imipenem as empirical monotherapy of febrile episodes in neutropenic patients, and to examine the frequency with which second-line antibiotics (amikacin, vancomycin, or both) were required. A prospective clinical trial was carried out in a single centre. Eligible patients with solid tumours or lymphoma were randomised to receive monotherapy with ceftazidime or imipenem. In the event of no response, amikacin and/or vancomycin were added in 48-72 h intervals (sequentially, or according to clinical or microbiological data). Efficacy was evaluable for 111 assessable episodes. Median neutrophil count at entry was 100 cells/microliters and median duration of neutropenia was 4 days. Febrile episodes were classified as microbiologically (34%) or clinically documented (42%), and fever of unknown origin (24%). Gram-negative infections (57%) predominated over gram-positive isolates (30%). The overall success rate with monotherapy (69% versus 70%), or with modification (20% versus 23%) were equivalent for ceftazidime and imipenem (P = 0.75). The mortality in this series was 5%. Single-agent therapy with either ceftazidime or imipenem is effective for the empirical treatment of febrile episodes in neutropenic patients with solid tumours. Early addition of amikacin and/or vancomycin resolves most failures of the first step.

Prognostic significance of c-erbB-2/neu amplification and epidermal growth factor receptor (EGFR) in primary breast cancer and their relation to estradiol receptor (ER) status.

The aim of this study is to evaluate the prognostic significance of c-erbB-2/neu amplification and epidermal growth factor receptor (EGFR) expression in primary breast cancer (BC) and their prognostic implications when combined with estradiol receptor (ER) status. In this work, 825 BCs were studied. Neu amplification was evaluated by dot-blot and EGFR expression was evaluated by ligand binding assay using I125-EGF. Neu, EGFR, estradiol and progesterone receptors (ER and PR) had a marked influence on disease free survival (DFS) in univariate analysis. In node-negative (NO) cases only neu was associated with short DFS (p = 0.005). However, in node-positive (N+) cases both EGFR (p = 0.005) and neu (p = 0.002) influenced DFS. None of the biological markers were significant predictors for overall survival (OS) in NO/BC. On the contrary, in N+/BC, EGFR + (p = 0.003) was associated with short OS. The EGFR + /neu/phenotype represented a sub-group with an even worse prognosis with respect to DFS (p = 0.0034) as well as EGFR + /ER-tumors (p = 0.005). Moreover, neu + /ER-patients also had a high probability of relapse (p = 0.0000) and death (p = 0.006). C-erbB-2/neu, EGFR, histological grade, pN, pT and ER were subjected to a Cox multivariate regression analysis: neu was the most important parameter in predicting recurrence, and EGFR was a significant predictor for OS.

Specific oncological contribution of cathepsin D and pS2 in human breast cancer: their relationship with TNM status, estradiol receptors, epidermal growth factor receptor and neu amplification.

The present study attempts to clarify the specific contribution of cathepsin D (CD) and pS2 to the progression of breast cancer (BC) by examining the relationship between these two factors and TNM status, tumour grade, estradiol receptors (ER) and the prognosis factors epidermal growth factor receptor (EGFR) and neu amplification in a group of 270 BC patients. CD and pS2 were determined by an immunoradiometric procedure in tumour cytosols obtained for ER. Neu amplifications were evaluated by dot-blot, in tumour DNA. EGFR was determined in membrane tumour preparations obtained from ER cytosols by a two-point radiometric saturation assay. CD is basically related to bad prognosis factors and has a direct correlation with tumour size (P = 0.025) and EGFR content (P = 0.007) and is associated with the presence of metastases (P = 0.000). pS2 is mostly related to good prognosis factors and showed an inverse correlation with the Scarff-Bloom Index (P = 0.011) and a direct correlation with ER content (P = 0.014). Finally, pS2 and CD also showed a strong mutual association (P = 0.009) and the fact that both correlated with ER content confirms in tumours the experimental finding that they are estrogen-induced proteins.

Hepatic resection in breast cancer metastases: should it be considered standard treatment?

A 34-year-old woman was diagnosed in October 1994 with a stage I breast cancer and treated with conservative surgery, locoregional radiotherapy and adjuvant chemotherapy. Nonetheless, 47 months after the initial diagnosis, an isolated liver metastasis was diagnosed in segments VII and VIII. A subsegmentectomy was performed, and chemotherapy with doxorubicin and paclitaxel was given for five cycles. High-dose chemotherapy with peripheral stem cell rescue was then administered and tamoxifen hormonal therapy was begun. Now, 54 months after the liver recurrence, the patient remains free of disease. Isolated liver metastases from breast cancer are rare and should be treated with surgical resection if possible, in the context of multimodality programs with hormonal and chemotherapy. According to the small series published in the literature, an improvement of 27-57 months in median survival rates can be expected when such treatment replaces standard therapies, although a selection bias cannot be excluded.

Long-term results after combined modality treatment for non-metastatic osteosarcoma.

Since the introduction of multimodality treatment, the prognosis of patients with high-grade non-metastatic osteosarcoma has significantly improved. A retrospective review was performed to assess the long-term results of this approach in a single centre setting, and to investigate the impact of potential clinical prognostic factors. Between 1985 and 1993, 35 patients with stage II-A and II-B osteosarcoma underwent preoperative chemotherapy (high-dose methotrexate), wide surgery, and adjuvant chemotherapy (cisplatin-doxorubicin/bleo-mycin-cyclophosphamide-dactinomycin) (modified T-10A protocol). There were 19 males and 16 females. Median patient age was 17 y (range 12-42). Primary tumour sites were the extremities (83%) and axial bones (17%). In spite of an unfavourable grade 3-4 histologic response rate to high-dose methotrexate of 12%, 31 (88%) patients were able to undergo limb-sparing surgery and 28 (80%) were rendered disease free after the planned therapy. Median follow-up was 8 y. The actuarial overall survival and disease-free survival rates were 64% and 49% at 5 y, and 59% and 49% at 10 y, respectively. Tumour size and primary site were significant prognostic factors for survival in univariate analyses. In conclusion, long-term survival after combined modality treatment can be achieved in more than 60% of patients with localised osteosarcoma, including non-appendicular lesions. Limb-sparing surgery is a realistic goal for most cases. The prognostic value of tumour necrosis and the efficacy of neoadjuvant chemotherapy should be interpreted according to individual high-dose methotrexate scheduling.

[Hipercalcemia and non-Hodgkin's lymphomas. Report of three patients (author's transl)]. / Hipercalcemia en linfomas no hodgkinianos: a propósito de tres observaciones.

Three out of 140 patients with non-hodgkin's lymphoma treated in a Department of Internal Medicine showed hypercalcemia during their clinical course. Hypercalcemia was symptomatic in two patients causing renal failure in one of them and a metabolic encephalopathy in the other. In the third case hypercalcemia was a casual finding. Serum calcium levels varied between 14.8 and 16.6 mg/100 ml; serum phosphate and tubular reabsorption of phosphate were normal. Alkaline phosphatase were high in the three cases. Bone disease was present in two cases. Transient responses were obtained with the administration of prednisone and calcitonin associated to forced diuresis. Indomethacin was ineffective. Pathogenesis of hypercalcemia could be related to the release of an osteoclastic activator factor. The role of prostaglandins and the presence of PTH-like mechanisms were discarded in our cases by indirect methods. The poor prognosis of patients with non-hogkin's lymphoma and hypercalcemia in stressed.

[Infections due to herpes-varicella viruses in Hodgkin's disease (author's transl)]. / Infecciones por herpes virus-varicela en la enfermedad de Hodgkin.

The infections due to herpes-varicella viruses occurring in 191 patients with Hodgkin's disease form the basis of this report. There were overall 41 episodes (26.7%) in 40 patients, distributed as follows: varicella in three cases, atypical herpes-varicella in two cases, and herpes zoster in 36 cases, the latter showing systemic spread in seven instances, one to the central nervous system (myelitis) and six to the skin. The mortality was 2.5% of all infections, and 33% of the varicella cases. Morbidity was apparent as postherpetic neuralgia in seven patients (19.4%), postherpetic paraplegia in one case (2.5%), and severe thrombocytopenia in another case (2.5%). The statistical study of the factors contributing to the development of reactivation episodes demonstrated that neither age, sex, or previous splenectomy were influential. The results obtained in relation to the stage and histologic type of Hodgkin's disease can not be fully evaluated because of the artifact introduced by other variables such as type of therapy and observation time. There was a clear relationship with the aggressiveness of therapy, because 81.7% of the viral episodes occurred in patients submitted to total radiotherapy with or without chemotherapy, or with partial radiotherapy plus chemotherapy. In the patients with systemic spread there was a clear relationship with prior splenectomy (p less than 0.005). The clinical features of these patients are commented upon.

Cost-benefit analysis of a follow-up program in patients with breast cancer: a randomized prospective study.

Increasing the number of breast cancer patients in follow-up involves increased costs and, with limited health care resources, there is a need to evaluate the cost-benefit to the patient of follow-up regimens. We present a randomized prospective study to evaluate the cost-benefit of intensive follow-up in the early detection of relapses in patients with breast cancer. One hundred and twenty-one patients were randomized to standard clinical follow-up (n=63) or to an intensive follow-up (n=58) that included diagnostic laboratory tests and imaging designed to detect early relapse following curative treatment. All patients had annual mammography. The number of scheduled outpatient appointments kept were 359 in the standard clinical follow-up and 355 in the intensive follow-up group. After a median of 3 years of follow-up, there were 28 relapses, 11 in standard clinical follow-up, and 13 in the intensive follow-up group. The overall cost of follow-up was 24,567 euros in the standard clinical follow-up group and 74,171 euros in the intensive follow-up group. Performing complimentary investigations in breast cancer follow-up is associated with higher costs without difference in early detection of relapses.

Improvement of breast cancer relapse prediction in high risk intervals using artificial neural networks.

The objective of this study is to compare the predictive accuracy of a neural network (NN) model versus the standard Cox proportional hazard model. Data about the 3811 patients included in this study were collected within the 'El Alamo' Project, the largest dataset on breast cancer (BC) in Spain. The best prognostic model generated by the NN contains as covariates age, tumour size, lymph node status, tumour grade and type of treatment. These same variables were considered as having prognostic significance within the Cox model analysis. Nevertheless, the predictions made by the NN were statistically significant more accurate than those from the Cox model (p < 0.0001). Seven different time intervals were also analyzed to find that the NN predictions were much more accurate than those from the Cox model in particular in the early intervals between 1-10 and 11-20 months, and in the later one considered from 61 months to maximum follow-up time (MFT). Interestingly, these intervals contain regions of high relapse risk that have been observed in different studies and that are also present in the analyzed dataset.

Pretreatment prognostic factors for survival in small-cell lung cancer: a new prognostic index and validation of three known prognostic indices on 341 patients.

AIMS: a) To identify which pretreatment clinical or blood parameters were predictive of patients survival in small-cell lung cancer (SCLC) in a retrospective analysis. b) To validate three known prognostic indices: Royal Marsden Model (index 1), London Group (index 2) and Manchester Score (index 3). PATIENTS AND METHODS: From 1981 to 1993, 341 SCLC patients were treated with chemotherapy with or without surgery or radiotherapy. Univariate and multiple regression analyses of survival were performed and the feasibility of these models was explored, index 1: Karnofsky index, albumin, sodium and alkaline phosphatase; index 2: ECOG performance status (PS), albumin and alanine transaminase; and index 3; lactate dehydrogenase (LDH), disease extent, sodium, Karnofsky index, alkaline phosphatase and bicarbonate. RESULTS: Significant prognostic factors for survival after univariate and multiple regression analysis were: disease extent, PS, creatine kinase, neutrophilia, LDH, hypoalbuminemia, hyperglycemia and bicarbonate. A new prognostic index was performed that included LDH, hypoalbuminemia, neutrophilia, disease extent and PS. It defined three prognostic groups (PG). Median survival and two-year survival for these PG were 12.3, 8 and 3.4 months and 16.5%, 2.3% and 0%, respectively. The following PG were identified after application of the three models proposed: Index 1 identified two PG with 0% and 16.6% two-year survival (P < 0.001); index 2 detected three PG with 0%, 5% and 15.7% two-year survival (P < 0.001) and index 3 detected three PG with 0%, 2.5% and 16.2% two-year survivals, respectively (P < 0.001). CONCLUSION: A new prognostic index is proposed allowing identification of three different PG. The feasibility of three known prognostic models was validated and demonstrated. Variables other than disease extent or PS (albumin or LDH) should be taken into account in designing future clinical trials.

Long-term follow-up and prognostic factors in Ewing's sarcoma. A multivariate analysis of 116 patients from a single institution.

The records of 116 patients from a single center (1970-1993) with newly diagnosed Ewing's sarcoma or primitive neuroectodermal tumor were reviewed retrospectively. The aim of this study was to ascertain the impact of pretreatment variables on disease-free survival. Median age was 14 years (range 1-34). Twenty patients presented with metastatic disease. Treatment consisted of systemic multiagent chemotherapy plus local irradiation (39%), wide resection (22%), or both (35%). Median potential follow-up was 10.7 years (range 2-26). Three patients developed second malignancies (1 breast carcinoma, 2 acute myeloid leukemias). Median time to relapse was 24 months (range 3-143). The actuarial disease-free survival was 37.4% at 5 years, 33.3% at 10 years and 27.8% at 15 years. Neoadjuvant chemotherapy and a therapy-induced tumor necrosis > or = 90% were associated with a better outcome. Patients undergoing surgical resection had a superior disease-free survival than those treated without surgery (45 vs. 18% at 10 years, p = 0.0009). Multiple regression analysis showed that raised serum lactate dehydrogenase levels (p < 0.001), hypoalbuminemia (p = 0.001) and distant metastases at diagnosis (p = 0.03) were independent adverse prognostic factors. In conclusion, one third of patients with Ewing's sarcoma become long-term survivors with combined modality treatment. Late relapses and second neoplasms are of concern. Prognostic factors should be considered in the selection of therapy, and the value of serum albumin warrants confirmatory studies.

Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group.

BACKGROUND: The purpose of this study was to determine the relative efficacy of doxorubicin versus methotrexate in combination with intravenous cyclophosphamide and 5-fluorouracil (FAC versus CMF) as adjuvant chemotherapy for operable breast cancer. PATIENTS AND METHODS: Over a 4-year period, 985 women undergoing curative surgery for breast cancer (T1-3 N0-2 M0, stage I-IIIA, UICC) from nine hospitals were stratified with respect to axillary node involvement (node positive versus node negative) and randomized to receive either FAC (500/50/500/m(2)) every 3 weeks for six cycles or CMF (600/60/600/m(2)) every 3 weeks for six cycles. RESULTS: The relative dose intensities of FAC and CMF were 87% and 85% of planned doses, respectively. Unadjusted data indicated a non-significant trend towards better results with FAC. In the prospectively formed subset of node-negative patients, disease-free survival and overall survival were statistically superior in the FAC treatment arm (P = 0.041 and 0.034, respectively), but this advantage was not seen in the subset of node-positive patients, probably because of a difference in the percentage of patients with four or more positive nodes. Adjusting data for size of treatment effect and potential interactions (number of positive nodes, tumor size, treatment center), the overall relative risk (RR) of disease recurrence and death were significantly lower with FAC treatment (RR 1.2, P = 0.03, and RR 1.3, P = 0.05, respectively). This result was mainly due to the difference observed in the node-negative patient population. Toxicity was mild: FAC induced more alopecia, emesis, mucositis and cardiotoxicity; this last was of clinical concern, but was infrequent and manageable. CMF induced more conjunctivitis and weight gain. There were no toxic deaths. CONCLUSIONS: Doxorubicin in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil is superior to methotrexate in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil as adjuvant chemotherapy for operable breast cancer. A treatment effect is particularly evident in the node-negative patients. Although the clinical toxicity of FAC is greater than that of CMF, the levels were manageable and clinically acceptable.