A Phase Ib/II study of IGF-neutralising antibody xentuzumab with enzalutamide in metastatic castration-resistant prostate cancer.

BACKGROUND: This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC). METHODS: The trial included Phase Ib escalation and expansion parts and a randomised Phase II part versus enzalutamide alone. Primary endpoints in the Phase Ib escalation, Phase Ib expansion and Phase II parts were maximum tolerated dose (MTD), prostate-specific antigen response and investigator-assessed progression-free survival (PFS), respectively. Patients in the Phase Ib escalation and Phase II parts had progressed on/after docetaxel/abiraterone. RESULTS: In the Phase Ib escalation (n = 10), no dose-limiting toxicities were reported, and xentuzumab 1000 mg weekly plus enzalutamide 160 mg daily (Xe1000 + En160) was defined as the MTD and recommended Phase 2 dose. In the Phase Ib expansion (n = 24), median PFS was 8.2 months, and one patient had a confirmed, long-term response. In Phase II (n = 86), median PFS for the Xe1000 + En160 and En160 arms was 7.4 and 6.2 months, respectively. Subgroup analysis suggested trends towards benefit with Xe1000 + En160 in patients whose tumours had high levels of IGF1 mRNA or PTEN protein. Overall, the combination was well tolerated. CONCLUSIONS: Xentuzumab plus enzalutamide was tolerable but lacked antitumour activity in unselected patients with mCRPC. CLINICAL TRIAL REGISTRATION: EudraCT number 2013-004011-41.

Prevalence of pathogenic germline variants in patients with metastatic renal cell carcinoma.

PURPOSE: Germline pathogenic variants are estimated to affect 3-5% of renal cell carcinoma (RCC) patients. However, higher mutational prevalence in non-clear cell RCC (non-ccRCC) and advanced disease has been suggested. METHODS: To clarify the prevalence of pathogenic germline variants in metastatic RCC, we sequenced 29 cancer susceptibility genes in 294 unselected metastatic RCC cases plus 21 patients with clinical hereditary features. In 145 tumors, genes frequently mutated in RCC were sequenced and methylation was assessed in selected cases. RESULTS: Germline variants in RCC predisposition genes (FH, VHL) were detected in 1.4% of the unselected metastatic patients, with higher frequency in non-ccRCC versus ccRCC (6.4% and 0.4%; P = 0.0025) and in younger patients (P = 0.036). Among the 315 studied patients, 14% of non-type 1 papillary cases (4 of 28), all metastatic <1 year after diagnosis, carried a FH germline variant with loss of heterozygosity and tumor genome hypermethylation. Variants in other cancer-associated genes (e.g., MUTYH, BRCA2, CHEK2) occurred in 5.1% of the unselected series, with unclear significance for RCC. CONCLUSION: Our findings confirm a high prevalence of pathogenic germline variants in RCC predisposition genes in metastatic non-ccRCC, and highlight that metastatic patients with papillary type 2 or unconventional histologies compatible with FH would benefit from genetic screening.

Controversies in the treatment of invasive urothelial carcinoma: a case report and review of the literature.

BACKGROUND: More than 429,000 patients worldwide are diagnosed with bladder cancer each year and muscle-invasive bladder cancer has an especially poor outcome. The median age at diagnosis is over 70 years, and many patients also have a substantial number of age-associated impairments that need to be considered when planning therapeutic interventions. CASE PRESENTATION: Here, we report the case of a 63-year-old man with a cT3b urothelial carcinoma which was surgically removed. No neoadjuvant or adjuvant chemotherapy was administered. After 18 months a lung metastasis was confirmed and resected but no chemotherapy was given after surgery. Twelve months later, the patient relapsed and was treated with a combination of gemcitabine and cisplatin and after a decline in renal function the treatment was changed to a combination of carboplatin and gemcitabine which resulted in a partial response which lasted 8 months. Following this vinflunine was administered as a second line treatment. Here we review the evidence available in the literature regarding the suitability of different treatment options for managing muscle-invasive bladder cancer at each step of the case presentation. CONCLUSION: Bladder cancer treatment requires a multidisciplinary approach. Although, depending on the clinical characteristics of the patient, there are some controversial points in the management of this pathology we hope that the scientific data and the clinical trials reviewed in this case report, can help to guide physicians to make more rational decisions regarding the management of these patients.

Efficacy and safety of neoadjuvant chemotherapy with concurrent liposomal-encapsulated doxorubicin, paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive breast cancer in clinical practice.

BACKGROUND: Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II-III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR. METHODS: Patients received six cycles of TLC-D99 (50 mg/m(2) every 3 weeks), paclitaxel (80 mg/m(2) weekly) and trastuzumab (4 mg/kg initial dose and 2 mg/kg weekly). All patients underwent surgery after treatment. pCR was defined as the absence of invasive cancer cells in the breast and the axilla. RESULTS: Sixty-two patients with a median age of 46.6 years were analyzed. Stage IIIA was diagnosed in 43.5% of patients and 14.5% had inflammatory BC. Conservative surgery was performed in 46.8% of the patients and pCR was achieved in 63% (95% CI 50.5-75.5). Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors (74.4 vs 43.5%; P = 0.028). Forty-five patients (72.6%) completed study treatment and 80.6% received at least five treatment cycles. No patients developed congestive heart failure and 14.5% of patients showed a ≥ 10 % decrease in the left ventricular ejection fraction. CONCLUSION: The triple combination therapy assessed is effective and safe, offering a high pCR rate in patients with HER2-positive BC.

Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort.

BACKGROUND: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy. METHODS: We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495. FINDINGS: Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5.4 years (IQR 3.1-6.8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0.64 (95% CI 0.44-0.93; two-sided log-rank p=0.016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0.29 (95% CI 0.11-0.78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group). INTERPRETATION: These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.

Exploratory analyses of treatment subgroup interaction by PD-L1 status and according to PD-L1 expression in the JAVELIN Bladder 100 trial.

PURPOSE: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC). METHODS: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay). RESULTS: No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff. CONCLUSIONS: These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels.

Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients.

BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

Evaluation of patients with metastatic renal cell carcinoma after failure of first-line treatment.

The approval and use of molecular targeted agents for the first-line treatment of metastatic renal cell carcinoma (mRCC) has substantially improved the clinical outcome of patients. Although eventually all patients progress, hopes have been renewed with the approval of everolimus for patients who progress on or after treatment with tyrosine kinase inhibitors. In order to improve the prognosis for these patients, it is imperative to understand the reasons why patients with mRCC fail on first-line treatment. Currently, progression is assessed on the basis of the Response Evaluation Criteria in Solid Tumors, but it is known that targeted agents tend to cause disease stabilization rather than a significant decrease in tumor mass. Therefore, it may be time to evaluate the need to incorporate additional diagnostic methods in the assessment of disease response. Equally important is the study of the factors that determine the success or failure of second-line therapy in order to increase the chances of delivering the most effective and personalized therapy possible. In this article, we review the evidence related to the evaluation of patients with mRCC who fail on first-line treatment with targeted agents, including the systems to assess response and progression, the prognostic factors, the prognostic models that have been created based on these factors, and what is known about predictive biomarkers of disease outcome.

Early colonization of sessile megabenthos on electrolytic carbonated structures (Alicante's harbor, Western Mediterranean).

Biofouling of different artificial substrates was studied to determine the differences in biofouling assemblages among different substrates. However, studies on biofouling on natural substrates like electrolytic carbonated ones are lacking. These substrates have a great potential for coral reef restoration in tropical areas and for biofilter construction. Thus, this study was developed to examine the colonization of sessile macrofouling in the port of Alicante (SE Spain, Western Mediterranean) on two types of substrates: electrolytic carbonated and bare steel (as control) over three months of immersion (October 2019-January 2020). The community diversity was studied through different biotic parameters and abundance of assemblages, and preference of organisms according to their status and functional group (active filter feeders). Univariate and multivariate analyses (PERMANOVA and SIMPER) were also applied to examine the differences between carbonate and control substrates. The carbonated substrate had a more structured community and higher abundance, recruitment, and diversity indexes than the bare steel. Moreover, filter feeders (Porifera, Bivalvia, and Ascidiacea) were more abundant, and most of them only appeared in the carbonated substrate. These results show the potential of carbonated structures as biofilters.

Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study.

BACKGROUND: Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. METHODS: In our observational, prospective study we enrolled previously untreated adults (≥ 18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. FINDINGS: We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75-7·30; p(unadjusted)=0·00049, p(adjusted)=0·0079) and rs307821 (3·31, 1·64-6·68; p(unadjusted)=0·00085, p(adjusted)=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67-8·41; p(unadjusted)=0·0014, p(adjusted)=0·022). No other SNPs were associated with sunitinib response or toxicity. INTERPRETATION: Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants. FUNDING: Pfizer.

Management of Patients with Metastatic Bladder Cancer in the Real-World Setting from the Multidisciplinary Team: Current Opinion of the SOGUG Multidisciplinary Working Group.

Based on the discussion of current state of research of relevant topics of metastatic bladder cancer (mBC) among a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group, a set of recommendations were proposed to overcome the challenges posed by the management of mBC in clinical practice. First-line options in unfit patients for cisplatin are chemotherapy with carboplatin and immunotherapy in PD-L1 positive patients. FDG-PET/CT may be a useful imaging technique in the initial staging or re-staging. In patients with oligometastatic disease, it is important to consider not only the number of metastatic lesions, but also the tumor biology and the clinical course. The combination of stereotactic body radiotherapy and immunotherapy with anti-PD-L1 monoclonal antibodies is under investigation and could improve the results of systemic treatment in patient with oligometastatic disease. Rescue treatment with curative intent could be considered in patients with oligometastatic disease after complete response on FDG-PET/CT. Metastatic disease should be evaluated using the same imaging modality over the course of the disease from diagnosis until rescue treatment. For improving the outcome of patients with mBC, the involvement of a dedicated multidisciplinary team, including urologists, pathologists, oncologists, radiologists and other specialists is of outmost importance in the daily care of these patients.

Recent therapeutic advances in urothelial carcinoma: A paradigm shift in disease management.

Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the administration of platinum-based chemotherapy followed by observation. Despite moderate to high response rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic developments including the paradigm shift of first-line maintenance therapy with avelumab after response or stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease.

Advances in Transversal Topics Applicable to the Care of Bladder Cancer Patients in the Real-World Setting.

Recommendations regarding transversal topics applicable to bladder cancer patients independent of tumor grade and stage were established by members of the Spanish Oncology Genitourinary Multidisciplinary Working Group (SOGUG). Liquid biopsy in urine and blood samples is useful in the surveillance of non-muscle-invasive and muscle-invasive bladder cancer, respectively. Multiparametric MRI is an accurate, faster and non-invasive staging method overcoming the understaging risk of other procedures. The combination of FDG-PET/MRI could improve diagnostic reliability, but definite criteria for imaging interpretation are still unclear. Hospital oncology pharmacists as members of tumor committees improve the safety of drug use. Additionally, safety recommendations during BCG preparation should be strictly followed. The initial evaluation of patients with bladder cancer should include a multidimensional geriatric assessment. Orthotopic neobladder reconstruction should be offered to motivated patients with full information of self-care requirements. Bladder-sparing protocols, including chemoradiation therapy and immune checkpoints inhibitors (ICIs), should be implemented in centers with well-coordinated multidisciplinary teams and offered to selected patients. The optimal strategy of treatment with ICIs should be defined from the initial diagnostic phase with indications based on scientific evidence. Centralized protocols combined with the experience of professional groups are needed for the integral care of bladder cancer patients.

Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel.

(1) Background: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3-0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4-0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2-0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1-3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX.

Update from the Spanish Oncology Genitourinary Group on the treatment of advanced renal cell carcinoma: focus on special populations.

Elderly or frail patients are often excluded from clinical trials. As a result, clinical outcome of these patients may differ from those obtained in trials. This situation may also hold true for patients who have severe concomitant diseases such as renal, hepatic, or cardiac dysfunction. Being aware of the wide range of clinical situations that a specialist may face is important to ensure that under any circumstances, the patient will receive the best treatment possible. The Spanish Oncology Genitourinary Group issued its first public statement on recommendations for the optimal management of advanced renal cell carcinoma (RCC). However, some issues remained unsolved. In this report, we discuss the current role of Medical Oncology in the treatment of patients with advanced RCC and review the management of special patient populations, such as elderly or patients with concomitant diseases.

Updated recommendations from the Spanish Oncology Genitourinary Group on the treatment of advanced renal cell carcinoma.

The speed at which targeted therapies are being developed and incorporated into the treatment of advanced renal cell carcinoma (RCC) is surprising. After decades in which the only systemic treatment options available for advanced disease were interleukin-2 and interferon-alpha, in the last decade, six new targeted therapies have emerged showing meaningful clinical benefits to patients with advanced RCC through phase III trials. Recently, the Spanish Oncology Genitourinary Group issued its first public statement of recommendations for the optimal management of advanced RCC. However, most pivotal phase III trials on which these recommendations were based have been updated and/or fully reported. Moreover, a new multikinase inhibitor, pazopanib, has emerged with good quality clinical data. In this report, we review in depth the latest phase III data of targeted therapies for advanced RCC and update our recommendations. Furthermore, we hypothesize about the best environment for patients with advanced RCC to receive cancer therapy.

Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort.

BACKGROUND: The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab. METHODS: We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495. FINDINGS: Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61-78; n=36 events] with trastuzumab, vs 56% [46-65; n=51 events] without; hazard ratio 0.59 [95% CI 0.38-0.90]; p=0.013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs. INTERPRETATION: The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses. FUNDING: F Hoffmann-La Roche.

Recent Advances in the Management of Patients with Non-Muscle-Invasive Bladder Cancer Using a Multidisciplinary Approach: Practical Recommendations from the Spanish Oncology Genitourinary (SOGUG) Working Group.

On the basis of the discussion of the current state of research on relevant topics of non-muscle-invasive bladder cancer (NMIBC) among a group of experts of the Spanish Oncology Genitourinary (SOGUG) Working Group, recommendations were proposed to overcome the challenges posed by the management of NMIBC in clinical practice. A unified definition of the term 'microhematuria' and the profile of the patient at risk are needed. Establishing a 'hematuria clinic' would contribute to a centralized and more efficient evaluation of patients with this clinical sign. Second or repeated transurethral resection (re-TUR) needs to be defined, including the time window after the first procedure within which re-TUR should be performed. Complete tumor resection is mandatory when feasible, with specification of the presence or absence of muscle. Budding should be used as a classification system, and stratification of T1 tumors especially in extensive and deep tumors, is advisable. The percentage of the high-grade component should always be reported, and, in multiple tumors, grades should be reported separately. Luminal and basal subtypes can be identified because of possibly different clinical outcomes. Molecular subtypes and immunotherapy are incorporated in the management of muscle-invasive bladder cancer but data on NMIBC are still preliminary.

Management of Localized Muscle-Invasive Bladder Cancer from a Multidisciplinary Perspective: Current Position of the Spanish Oncology Genitourinary (SOGUG) Working Group.

This review presents challenges and recommendations on different aspects related to the management of patients with localized muscle-invasive bladder cancer (MIBC), which were discussed by a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group within the framework of the Genitourinary Alliance project (12GU). It is necessary to clearly define which patients are candidates for radical cystectomy and which are candidates for undergoing bladder-sparing procedures. In older patients, it is necessary to include a geriatric assessment and evaluation of comorbidities. The pathological report should include a classification of the histopathological variant of MIBC, particularly the identification of subtypes with prognostic, molecular and therapeutic implications. Improvement of clinical staging, better definition of prognostic groups based on molecular subtypes, and identification of biomarkers potentially associated with maximum benefit from neoadjuvant chemotherapy are areas for further research. A current challenge in the management of MIBC is improving the selection of patients likely to be candidates for immunotherapy with checkpoint inhibitors in the neoadjuvant setting. Optimization of FDG-PET/CT reliability in staging of MIBC and the selection of patients is necessary, as well as the design of prospective studies aimed to compare the value of different imaging techniques in parallel.

Expert recommendations on the management of patients with metastatic castration-resistant prostate cancer who progress after CHAARTED or LATITUDE.

OBJECTIVE: Our aim was to provide practical recommendations on the management of patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel plus androgen-deprivation therapy (ADT) or abiraterone plus ADT. METHODS: Systematic literature review (SLR), nominal group meeting, and Delphi process. A panel of 12 experts was established who defined the scope, users, and sections of the document. We performed an SLR in order to assess the efficacy and safety of available drugs in patients with mCRPC. Abstracts from the American Society of Oncology and European Society for Medical Oncology meetings were also examined. The results were discussed during an expert meeting in which 14 recommendations were generated. The level of agreement with the recommendations was also tested by 13 additional experts following the Delphi process. Recommendations were voted by means of scores ranging from 0 (total disagreement) to 10 (total agreement). We defined agreement when at least 70% of the experts voted ⩾7. Next, we assigned a level of evidence and grade to the recommendation using the Oxford Centre for Evidence-based Medicine Levels of Evidence, following which the final document was drafted. RESULTS: The literature search did not find any articles meeting the inclusion criteria. Finally, 13 out of 14 recommendations were accepted after two Delphi rounds (two were modified after the first round). They pertain to general and individual case-based treatment recommendations. CONCLUSIONS: In mCRPC patients who have progressed after docetaxel or abiraterone plus ADT in the metastatic hormone-sensitive prostate cancer setting, these recommendations may support treatment decision-making, due to the lack of evidence or other globally accepted sequencing algorithms.