Alvaro Pinto

Prognostic Impact of Pregnancy After Breast Cancer According to Estrogen Receptor Status: A Multicenter Retrospective Study

PURPOSE We questioned the impact of pregnancy on disease-free survival (DFS) in women with history of breast cancer (BC) according to estrogen receptor (ER) status. PATIENTS AND METHODS A multicenter, retrospective cohort study in which patients who became pregnant any time after BC were matched (1:3) to patients with BC with similar ER, nodal status, adjuvant therapy, age, and year of diagnosis. To adjust for guaranteed time bias, each nonpregnant patient had to have a disease-free interval at least equal to the time elapsing between BC diagnosis and date of conception of the matched pregnant one. The primary objective was DFS in patients with ER-positive BC. DFS in the ER-negative cohort, whole population, and overall survival (OS) were secondary objectives. Subgroup analyses included DFS according to pregnancy outcome and BC-pregnancy interval. With a two-sided α = 5% and β = 20%, 645 ER-positive patients were required to detect a hazard ratio (HR) = 0.65. RESULTS A total of 333 pregnant patients and 874 matched nonpregnant patients were analyzed, of whom 686 patients had an ER-positive disease. No difference in DFS was observed between pregnant and nonpregnant patients in the ER-positive (HR = 0.91; 95% CI, 0.67 to 1.24, P = .55) or the ER-negative (HR = 0.75; 95% CI, 0.51 to 1.08, P = .12) cohorts. However, the pregnant group had better OS (HR = 0.72; 95% CI, 0.54 to 0.97, P = .03), with no interaction according to ER status (P = .11). Pregnancy outcome and BC-pregnancy interval did not seem to impact the risk of relapse. CONCLUSION Pregnancy after ER-positive BC does not seem to reduce the risk of BC recurrence.

Targeting the endothelin axis in prostate carcinoma

Prostate cancer is the most common malignancy in men in Western countries. Until the last decade, the main available therapeutic options were based on hormonal therapy. For castration-refractory prostate carcinoma, from 2004, the combination of chemotherapy with docetaxel and prednisone has shown to improve survival in this subset of patients. Many agents have been tested either alone or in combination with this standard therapy, trying to find synergistic effects between drugs, and to target specific pathways that influence tumor growth, invasiveness, angiogenesis, and the development of distant metastasis. Endothelin antagonists have been recently studied, as they can get involved in many of these oncogenic pathways, and results are encouraging; nevertheless, the right setting to use them, whether to use them in monotherapy or in combination with other agents, and if they really improve the survival of our patients, are questions that remain to be addressed. In this review, we summarize the role of endothelins in tumoral biology and specifically in prostate carcinoma natural history, and the results obtained in the clinical trials involving this new therapeutic group.

An 8-gene qRT-PCR-based gene expression score that has prognostic value in early breast cancer

BackgroundGene expression profiling may improve prognostic accuracy in patients with early breast cancer. Our objective was to demonstrate that it is possible to develop a simple molecular signature to predict distant relapse.MethodsWe included 153 patients with stage I-II hormonal receptor-positive breast cancer. RNA was isolated from formalin-fixed paraffin-embedded samples and qRT-PCR amplification of 83 genes was performed with gene expression assays. The genes we analyzed were those included in the 70-Gene Signature, the Recurrence Score and the Two-Gene Index. The association among gene expression, clinical variables and distant metastasis-free survival was analyzed using Cox regression models.ResultsAn 8-gene prognostic score was defined. Distant metastasis-free survival at 5 years was 97% for patients defined as low-risk by the prognostic score versus 60% for patients defined as high-risk. The 8-gene score remained a significant factor in multivariate analysis and its performance was similar to that of two validated gene profiles: the 70-Gene Signature and the Recurrence Score. The validity of the signature was verified in independent cohorts obtained from the GEO database.ConclusionsThis study identifies a simple gene expression score that complements histopathological prognostic factors in breast cancer, and can be determined in paraffin-embedded samples.

The present and future of gene profiling in breast cancer.

Gene signatures can provide prognostic and predictive information to help in the treatment of early-stage breast cancer. Although many of these signatures have been described, only a few have been properly validated. MammaPrint and OncoType offer prognostic information and identify low-risk patients who do not benefit from adjuvant chemotherapy. With regard to prediction of response, molecular subtypes of breast cancer differ in their sensitivity to chemotherapy, although further studies are needed in this field. Cost, small sample size, and the need to use central laboratories are common limitations to the widespread use of these tools.

Angiogenesis as a therapeutic target in urothelial carcinoma.

In the last few years, angiogenesis has confirmed its critical role in the development of malignant neoplasms. Antiangiogenic drugs, mainly bevacizumab, sorafenib, or sunitinib, are currently approved in a wide number of tumor types, such as breast, colorectal, liver, or kidney cancer, and have changed dramatically the evolution of our patients. Unfortunately, in urothelial carcinoma, which is a very common neoplasm, antiangiogenic agents are still in a very preliminary phase of clinical research. In this study, we focus on the biological basis of angiogenesis in urothelial tumors, its influence in the prognosis of these malignancies, and the available evidence about the use of antiangiogenic drugs in urothelial carcinoma.

Continuation of bevacizumab and addition of hormone therapy following weekly paclitaxel therapy in HER2-negative metastatic breast cancer.

Background Bevacizumab plus taxane chemotherapy improves progression-free survival (PFS) versus taxane monotherapy in the first-line treatment of HER2-negative metastatic breast cancer (MBC) and appears promising in the second-line setting. This retrospective analysis evaluated the efficacy and safety of this combination in a real-world setting. Patients and methods Eligible patients received bevacizumab (10 mg/kg days 1 and 15, every 28 days) plus paclitaxel (80 mg/m2 days 1, 8, and 15, every 28 days) as first-line therapy for MBC, or as subsequent lines, including bevacizumab continuation therapy, at La Paz University Hospital between August 2007 and October 2012. End points included objective response rate (ORR), PFS, overall survival (OS), and safety. Results Seventy-eight patients were included. Median PFS was 12.8 months for patients receiving first-line treatment and 9.3 months for subsequent lines. Forty-five patients (57.7%) continued bevacizumab after stopping paclitaxel, and had significantly longer PFS and OS than those who did not (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.248–0.653, P<0.001; HR 0.39, 95% CI 0.218–0.710, P=0.002; respectively). In the continuation phase, estrogen receptor-positive patients had longer PFS and OS when receiving hormone therapy plus bevacizumab versus patients receiving only bevacizumab (HR 0.50, 95% CI 0.24–1.04, P=0.06; HR 0.43, 95% CI 0.16–1.16, P=0.09; respectively). Thirty-five patients (44.9%) reported grade 3–4 adverse events. Conclusion Bevacizumab plus paclitaxel was effective in HER2-negative MBC. Continuation of bevacizumab and addition of hormone therapy following paclitaxel therapy could be beneficial.

Recent advances in genitourinary tumors: A review focused on biology and systemic treatment

Updated information published up to 2016 regarding major advances in renal cancer, bladder cancer, and prostate cancer is here presented. Based on an ever better understanding of the genetic and molecular alterations that govern the initial pathogenic mechanisms of tumor oncogenesis, an improvement in the characterization and treatment of urologic tumors has been achieved in the past year. According to the Cancer Genome Atlas (ATLAS) project, alterations in the MET pathway are characteristics of type 1 papillary renal cell carcinomas, and activation of NRF2-ARE pathway is associated with the biologically distinct type 2. While sunitinib and pazopanib continue to be the standard first-line treatment in metastatic renal cell carcinoma of clear cell histology, nivolumab and cabozantinib are now the agents of choice in the second-line setting. In relation to urothelial bladder carcinoma, new potential molecular targets such as FGFR3, PI3K/AKT, RTK/RAS, CDKN2A, ARIDIA, ERBB2 have been identified. Response to adjuvant cisplatin-based chemotherapy appears to be related to basal, luminal, and p53-like intrinsic subtypes. A phase II study with eribulin and a maintenance phase II trial with vinflunine have shown promising results. Similarly, the use of the check point inhibitors in advanced disease is likely to revolutionize the management of patients who have progressed after cisplatin-based chemotherapy. In prostate cancer, seven mutually exclusive molecular subtypes have been identified by the TCGA project. Chemotherapy has been consolidated as a key treatment for castration-sensitive metastatic prostate cancer, and abiraterone, enzalutamide, cabazitaxel, and radium-223 remain standard therapeutic options for men with metastatic castration-resistant prostate cancer. All this progress will undoubtedly contribute to the development of new treatments and therapeutic strategies that will improve the survival and quality of life of our patients.

Consensus Recommendations from the Spanish Germ Cell Cancer Group on the Use of High-dose Chemotherapy in Germ Cell Cancer

BACKGROUND High-dose chemotherapy (HDCT) has been studied in several clinical scenarios in advanced germ cell cancer (GCC). OBJECTIVE To establish a clinical practice guideline for HDCT use in the treatment of GCC patients. DESIGN, SETTING, AND PARTICIPANTS An expert panel reviewed information available from the literature. The panel addressed relevant issues concerning and related to HDCT. The guideline was externally reviewed by two international experts. RESULTS AND LIMITATIONS The efficacy of HDCT has been demonstrated in selected GCC patients. The most conclusive evidence comes from retrospective analyses that need to be interpreted with caution. HDCT can cure a significant proportion of heavily treated GCC patients. When indicated, sequential HDCT with regimens containing carboplatin and etoposide, as well as peripheral stem-cell support, is recommended. There is no conclusive evidence to recommend HDCT as first-line therapy. According to a multinational retrospective pooled analysis, HDCT might be superior to conventional CT as first salvage treatment in selected patients. There is an urgent need for prospective clinical trials addressing the value of HDCT in GCC patients who experience failure on first-line cisplatin-based CT. In patients who progress on conventional-dose salvage CT, HDCT should be considered. Treatment of these patients at experienced centers is strongly recommended. CONCLUSIONS It has been demonstrated that HDCT cures selected GCC patients who experience disease progression on conventional rescue regimens. The panel recommends the inclusion of GCC patients in randomized clinical trials including HDCT. PATIENT SUMMARY This consensus establishes clinical practice guidelines for the use and study of high-dose chemotherapy in patients with germ cell cancer.

SEOM Clinical Guideline for treatment of muscle-invasive and metastatic urothelial bladder cancer (2016)

The goal of this article is to provide recommendations for the diagnosis and treatment of muscle-invasive and metastatic bladder cancer. The diagnosis of muscle-invasive bladder cancer is made by pathologic evaluation after transurethral resection. Recently, a molecular classification has been proposed. Staging of muscle-invasive bladder cancer must be done by computed tomography scans of the chest, abdomen and pelvis and classified on the basis of UICC system. Radical cystectomy and lymph node dissection are the treatment of choice. In muscle-invasive bladder cancer, neoadjuvant chemotherapy should be recommended in patients with good performance status and no renal function impairment. Although there is insufficient evidence for use of adjuvant chemotherapy, its use must be considered when neoadjuvant therapy had not been administered in high-risk patients. Multimodality bladder-preserving treatment in localized disease is an alternative in selected and compliant patients for whom cystectomy is not considered for clinical or personal reasons. In metastatic disease, the first-line treatment for patients must be based on cisplatin-containing combination. Vinflunine is the only drug approved for use in second line in Europe. Recently, immunotherapy treatment has demonstrated activity in this setting.

Expert Recommendations for First-Line Management of Metastatic Renal Cell Carcinoma in Special Subpopulations.

The availability of agents targeting the vascular endothelial growth factor or mammalian target of rapamycin [mTOR] pathways has provided new treatment options for patients with metastatic renal cell carcinoma (RCC). Based on the results of pivotal randomized clinical trials, specific recommendations have been established for management of these patients in first- and second-line settings. However, certain subgroups of patients may be excluded or under-represented in clinical trials, including patients with poor performance status, brain metastases, and cardiac or renal comorbidities, elderly patients, and those with non-clear cell histology. For these subpopulations, management recommendations have emerged from expanded access programs (EAPs), small phase II studies, retrospective analysis of clinical data, and expert opinion. This paper describes recommendations from an expert panel for the treatment of metastatic RCC in these subpopulations. The efficacy of targeted agents appears to be inferior in these patient subgroups relative to the general RCC population. Tyrosine kinase inhibitors (TKIs) and mTOR inhibitors can be administered safely to elderly patients and those with poor performance status, although dose and schedule modifications are often needed, and close monitoring and management of adverse events is essential. In addition to local surgical treatment and radiotherapy for brain metastases, systemic treatment with a TKI should be offered as part of multidisciplinary care.While there are currently no data from randomized trials, sunitinib has the greatest body of evidence, and it should be considered the first choice in patients with a good prognosis. Patients with an acute cardiac event within the previous 6 months, New York Heart Association grade III heart failure, or uncontrolled high blood pressure should not be treated with TKIs. In patients with mild or moderate renal failure, there are no contraindications to TKI treatment. TKIs can be administered to patients undergoing dialysis, but other, less nephrotoxic agents and other alternatives should always be considered.In managing RCC among patients with non-clear cell histology, sunitinib seems to be more effective than everolimus for the papillary subtype, but there are no clear data to guide treatment for other subtypes. In conclusion, individualized treatment approaches are needed to manage RCC in subpopulations that are underrepresented in registration clinical trials.