Real world data on the demographic and clinicopathological profile and management of patients with early-stage HER2-positive breast cancer and residual disease treated with adjuvant trastuzumab emtansine (KARMA study).

INTRODUCTION: Trastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain. MATERIAL AND METHODS: We conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients. RESULTS: A total of 114 patients were included (March-July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1-3 N0-1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment. CONCLUSION: The KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data.

SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer (2022)

Breast cancer is the leading cause of cancer in women in Spain and its annual incidence is rapidly increasing. Thanks to the screening programs in place, nearly 90% of breast cancer cases are detected in early and potentially curable stages, despite the COVID-19 pandemic possibly having impacted these numbers (not yet quantified). In recent years, locoregional and systemic therapies are increasingly being directed by new diagnostic tools that have improved the balance between toxicity and clinical benefit. New therapeutic strategies, such as immunotherapy, targeted drugs, and antibody–drug conjugates have also improved outcomes in some patient subgroups. This clinical practice guideline is based on a systematic review of relevant studies and on the consensus of experts from GEICAM, SOLTI, and SEOM (AU)

Targeting carcinoma-associated mesothelial cells with antibody-drug conjugates in ovarian carcinomatosis.

Ovarian carcinomatosis is characterized by the accumulation of carcinoma-associated mesothelial cells (CAMs) in the peritoneal stroma and mainly originates through a mesothelial-to-mesenchymal transition (MMT) process. MMT has been proposed as a therapeutic target for peritoneal metastasis. Most ovarian cancer (OC) patients present at diagnosis with peritoneal seeding, which makes tumor progression control difficult by MMT modulation. An alternative approach is to use antibody-drug conjugates (ADCs) targeted directly to attack CAMs. This strategy could represent the cornerstone of precision-based medicine for peritoneal carcinomatosis. Here, we performed complete transcriptome analyses of ascitic fluid-isolated CAMs in advanced OC patients with primary-, high-, and low-grade, serous subtypes and following neoadjuvant chemotherapy. Our findings suggest that both cancer biological aggressiveness and chemotherapy-induced tumor mass reduction reflect the MMT-associated changes that take place in the tumor surrounding microenvironment. Accordingly, MMT-related genes, including fibroblast activation protein (FAP), mannose receptor C type 2 (MRC2), interleukin-11 receptor alpha (IL11RA), myristoylated alanine-rich C-kinase substrate (MARCKS), and sulfatase-1 (SULF1), were identified as specific actionable targets in CAMs of OC patients, which is a crucial step in the de novo design of ADCs. These cell surface target receptors were also validated in peritoneal CAMs of colorectal cancer peritoneal implants, indicating that ADC-based treatment could extend to other abdominal tumors that show peritoneal colonization. As proof of concept, a FAP-targeted ADC reduced tumor growth in an OC xenograft mouse model with peritoneal metastasis-associated fibroblasts. In summary, we propose MMT as a potential source of ADC-based therapeutic targets for peritoneal carcinomatosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Usefulness and real-world outcomes of next generation sequencing testing in patients with cancer: an observational study on the impact of selection based on clinical judgement.

Background: Next Generation Sequencing (NGS) panels are increasingly used in advanced patients with cancer to guide therapy. There is, however, controversy about when should these panels be used, and about their impact on the clinical course. Methods: In an observational study of 139 patients with cancer having an NGS test [from January 1st, 2017 to December 30th, 2020, in two hospitals (Hospital Universitario de La Princesa and Hospital Universitario Quironsalud Madrid) from Spain], we evaluated whether the clinical course (progression-free survival, PFS) was influenced by drug-based criteria [druggable alterations, receiving a recommended drug, having a favourable ESCAT category (ESMO Scale for Clinical Actionability of molecular Targets)] or clinical judgement criteria. Findings: In 111 of 139 cases that were successfully profiled, PFS was not significantly influenced by either having druggable alterations [median PFS for patients with druggable alterations was 170 (95% C.I.: 139-200) days compared to 299 (95% C.I.: 114-483) for those without; p = 0.37], receiving a proposed matching agent [median PFS for patients receiving a genomics-informed drug was 195 days (95% C.I.: 144-245), compared with 156 days for those that did not (95% C.I.: 85-226); p = 0.50], or having favourable ESCAT categories [median PFS for patients with ESCAT I-III was 183 days (95% C.I.: 104-261), compared with 180 (95% C.I.:144-215) for patients with ESCAT IV-X; p = 0.87]. In contrast, NGS testing performed within clinical judgement showed a significantly improved PFS [median PFS for patients that were profiled under the recommended scenarios was 319 days (95% C.I.: 0-658), compared to 123 days (95% C.I.: 89-156) in the non-recommended categories; p = 0.0020]. Interpretation: According to our data, real-world outcomes after NGS testing provide evidence of the benefit of clinical judgement in patients with either advanced cancers that routinely need multiple genetic markers, patients with advanced rare cancers, or patients that are screened for molecular clinical trials. By contrast, NGS does not seem to be valuable when performed in cases with a poor PS, rapidly progressing cancer, short expected lifetime, or cases with no standard therapeutic options. Funding: RC, NR-L and MQF are recipients of the PMP22/00032 grant, funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF). The study also received funds from the CRIS Contra el Cancer Foundation.

SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer (2022).

Breast cancer is the leading cause of cancer in women in Spain and its annual incidence is rapidly increasing. Thanks to the screening programs in place, nearly 90% of breast cancer cases are detected in early and potentially curable stages, despite the COVID-19 pandemic possibly having impacted these numbers (not yet quantified). In recent years, locoregional and systemic therapies are increasingly being directed by new diagnostic tools that have improved the balance between toxicity and clinical benefit. New therapeutic strategies, such as immunotherapy, targeted drugs, and antibody-drug conjugates have also improved outcomes in some patient subgroups. This clinical practice guideline is based on a systematic review of relevant studies and on the consensus of experts from GEICAM, SOLTI, and SEOM.

Correlation between late gadolinium enhancement sequences in MRI and pathologic response after neoadjuvant chemotherapy in breast cancer / Correlación entre secuencias de realce tardío de gadolinio en RM y respuesta patológica tras quimioterapia neoadyuvante en cáncer de mama

Objectives: To study the correlation between radiologic response observed by late enhancement sequences in MRI and pathologic response after neoadjuvant chemotherapy in patients with breast cancer. Material and methods: Retrospective observational study of 132 patients with 136 tumors (4 with bilateral disease), treated consecutively with neoadjuvant chemotherapy at our institution between 2011 and 2017. In all cases, we performed 3 breast MRI's, using late enhancement gadolinium sequences: the first prior to neoadjuvant chemotherapy, the second half way through treatment, and the third at the completion of therapy. Following treatment, contrast medium uptake in tumor bed was evaluated based on the Response Evaluation Criteria for Solid Tumors (RECIST). All patients underwent conservative or radical surgery. We compared the radiologic response estimated by MRI, with the pathologic response observed in the surgical specimen, according to Miller and Payne grading system. We calculated the sensitivity, specificity, and predictive values of the test, and used the Spearman correlation coefficient to stablish correlations between the parameters analyzed. Results: Complete pathologic response (pCR) was observed in 58.1% (79/136). The percentage of global radio-pathologic correlation was 88.97%. MRI showed a sensitivity of 78.9%, a specificity of 79.7%, a positive-predictive value (PPV) of 73.8% and a negative-predictive value (NPV) of 84%. In patients with partial response, the Spearman correlation was positive (rho = 1, P < .001). According to surrogate subtypes of breast cancer, we observed moderate correlation for luminal tumors (rho = 0.63, P < .001) and poor correlation for non-luminal types (rho = 0,4, P < .01). (AU)

Objetivos: Estudiar la correlación entre la respuesta radiológica observada mediante secuencias de realce tardío en resonancia magnética y la respuesta patológica después de quimioterapia neoadyuvante en pacientes con cáncer de mama. Material y métodos: Estudio observacional retrospectivo de 132 pacientes con 136 tumores (cuatro con enfermedad bilateral), tratados consecutivamente con quimioterapia neoadyuvante en nuestra Institución entre 2011 y 2017. En todos los casos se realizaron tres resonancias magnéticas de mama, utilizando secuencias de realce tardío de gadolinio: la primera antes de la quimioterapia neoadyuvante, la segunda a mitad del tratamiento y la tercera al finalizar la terapia. Después del tratamiento, la captación media de contraste en el lecho tumoral se evaluó en función de los Criterios de Evaluación de la Respuesta para Tumores Sólidos (RECIST). Todas las pacientes se sometieron a cirugía conservadora o radical. Comparamos la respuesta radiológica estimada por resonancia magnética, con la respuesta patológica observada en la pieza quirúrgica, valorada según clasificación de Miller y Payne. Se calcularon sensibilidad, especificidad, valores predictivos y correlacion de Spearman para establecer correlaciones entre los parametros analizados. Resultados: Se observó respuesta patológica completa (pCR) en el 58,1% (79/136). El porcentaje de correlación radiopatológica global fue del 88,97%. La RM mostró una sensibilidad del 78,9%, una especificidad del 79,7%, un valor predictivo positivo (VPP) del 73,8% y un valor predictivo negativo (VAN) del 84%. En pacientes con respuesta parcial, la correlación de Spearman fue positiva (rho = 1, p < 0,001). De acuerdo con los tipos subrogados de cáncer de mama, observamos una correlación moderada para los tumores luminales (rho = 0,63, p < 0,001) y una correlación deficiente para los tipos no luminales (rho = 0,4, p < 0,01). (AU)

Defining a Standard Set of Patient-Reported Outcomes for Patients With Advanced Ovarian Cancer.

Purpose: Advanced ovarian cancer (AOC) and its treatment cause several symptoms and impact on patients' health-related quality of life (HRQoL). We aim to reach a consensus on the most relevant patient-reported outcome (PROs), the corresponding measures (PROMs), and measurement frequency during AOC patients' follow-up from patients' and healthcare professionals' (HCP) perspective. Methods: The project comprised five steps: 1) a literature review, 2) a focus group with patients, 3) a nominal group with HCP, 4) two round-Delphi consultations with patients and HCP, and 5) a final meeting with HCP. Delphi questionnaire was elaborated based on literature review, focus group (n=5 patients), and nominal group (n=16 HCP). The relevance of each PRO and the appropriateness (A) and feasibility (F) of the proposed PROM were assessed (Likert scale 1=strongly agree; 9=strongly disagree). The consensus was reached when at least 75% of the panelists rated it as 'relevant', 'appropriate', or 'feasible' (score 7-9). Results: A total of 56 HCP [51.8% Hospital Pharmacy; 41.1% Oncology; 3.6% Nursing; and 3.6% Psycho-oncology; mean time in specialty 12.5 (8.0) years] and 10 AOC patients [mean time diagnosis 5.4 (3.0) years] participated in the 1st round. All PROs achieved consensus regarding their relevance, except dry skin (58.0%). Agreement was reached for PRO-CTCAE to be used to assess fatigue (A:84.9%; F:75.8%), neuropathy (A:92.4%; F:77.3%), diarrhea (A:87.9%; F:88.7%), constipation (A:86.4%; F:75.8%), nausea (A:89.4%; F:75.8%), insomnia (A:81.8%; F:88.7%), abdominal bloating (A:82.2%; F:82.2%) and sexuality (A:78.8%; F:88.6%); EQ-5D to determine patients' HRQoL (A:87.9%; F:80.3%), pain (A:87.9%; F:75.8%) and mood (A:77.7%; F:85.5%); to assess treatment adherence the Morisky-Green (A:90.9%; F:84.9%) and the dispensing register (A:80.3%; F:80.3%) were chosen. It was agreed to note in the medical record whether the patient's treatment preferences had been considered during decision-making (A:78.8%; F:78.8%) and to use a 5-point Likert scale to assess treatment satisfaction (A:86.4%; F:86.4%). Panelists agreed (A:92.4%; F: 77.3%) to collect these PROs (1) at the time of diagnosis/relapse; (2) one month after starting treatment/change therapeutic strategy; (3) every three months during the 1st-year of treatment; and later (4) every six months until treatment completion/change. Conclusions: The consensus reached represents the first step towards including the patient's perspective in AOC follow-up. The standardized collection of PROs in clinical practice may contribute to optimizing the follow-up of these patients and thus improving the quality of care.

Mesothelial-to-Mesenchymal Transition and Exosomes in Peritoneal Metastasis of Ovarian Cancer.

Most patients with ovarian cancer (OvCA) present peritoneal disseminated disease at the time of diagnosis. During peritoneal metastasis, cancer cells detach from the primary tumor and disseminate through the intraperitoneal fluid. The peritoneal mesothelial cell (PMC) monolayer that lines the abdominal cavity is the first barrier encountered by OvCA cells. Subsequent progression of tumors through the peritoneum leads to the accumulation into the peritoneal stroma of a sizeable population of carcinoma-associated fibroblasts (CAFs), which is mainly originated from a mesothelial-to-mesenchymal transition (MMT) process. A common characteristic of OvCA patients is the intraperitoneal accumulation of ascitic fluid, which is composed of cytokines, chemokines, growth factors, miRNAs, and proteins contained in exosomes, as well as tumor and mesothelial suspended cells, among other components that vary in proportion between patients. Exosomes are small extracellular vesicles that have been shown to mediate peritoneal metastasis by educating a pre-metastatic niche, promoting the accumulation of CAFs via MMT, and inducing tumor growth and chemoresistance. This review summarizes and discusses the pivotal role of exosomes and MMT as mediators of OvCA peritoneal colonization and as emerging diagnostic and therapeutic targets.

Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial.

BACKGROUND: Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. METHODS: Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. RESULTS: Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline-post-bevacizumab-tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. CONCLUSIONS: This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. TRIAL REGISTRATION: (www.clinicaltrials.gov): NCT02802098 . Registered on June 16, 2020.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

BACKGROUND: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. PATIENTS AND METHODS: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. RESULTS: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. CONCLUSIONS: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

Clinical characteristics and outcomes among hospitalized adults with severe COVID-19 admitted to a tertiary medical center and receiving antiviral, antimalarials, glucocorticoids, or immunomodulation with tocilizumab or cyclosporine: A retrospective observational study (COQUIMA cohort).

BACKGROUND: The COVID-19 outbreak challenges the Spanish health system since March 2020. Some available therapies (antimalarials, antivirals, biological agents) were grounded on clinical case observations or basic science data. The aim of this study is to describe the characteristics and impact of different therapies on clinical outcomes in a cohort of severe COVID-19 patients. METHODS: In this retrospective, single-center, observational study, we collected sequential data on adult patients admitted to Hospital Universitario Quironsalud Madrid. Eligible patients should have a microbiological (positive test on RT-PCR assay from a nasal swab) or an epidemiological diagnosis of severe COVID-19. Demographic, baseline comorbidities, laboratory data, clinical outcomes, and treatments were compared between survivors and non-survivors. We carried out univariate and multivariate logistic regression models to assess potential risk factors for in-hospital mortality. FINDINGS: From March 10th to April 15th, 2020, 607 patients were included. Median age was 69 years [interquartile range, {IQR} 22; 65% male). The most common comorbidities were hypertension (276 [46·94%]), diabetes (95 [16·16%]), chronic cardiac (133 [22·62%]) and respiratory (114 [19·39%]) diseases. 141 patients (23·2%) died. In the multivariate model the risk of death increased with older age (odds ratio, for every year of age, 1·15, [95% CI 1·11 - 1·2]), tocilizumab therapy (2·4, [1·13 - 5·11]), C-reactive protein at admission (1·07, per 10 mg/L, [1·04 - 1·10]), d-dimer > 2·5 µg/mL (1·99, [1·03 - 3·86]), diabetes mellitus (2·61, [1·19 - 5·73]), and the PaO2/FiO2 at admission (0·99, per every 1 mmHg, [0·98 - 0·99]). Among the prescribed therapies (tocilizumab, glucocorticoids, lopinavir/ritonavir, hydroxychloroquine, cyclosporine), only cyclosporine was associated with a significant decrease in mortality (0·24, [0·12 - 0·46]; p<0·001). INTERPRETATION: In a real-clinical setting, inhibition of the calcineurin inflammatory pathway, NF-κΒ, could reduce the hyperinflammatory phase in COVID-19. Our findings might entail relevant implications for the therapy of this disease and could boost the design of new clinical trials among subjects affected by severe COVID-19. FUNDING: Hospital Universitario Quironsalud Madrid. Own fundings for COVID-19 research.

Phase III study to evaluate patient's preference of subcutaneous versus intravenous trastuzumab in HER2-positive metastatic breast cancer patients: Results from the ChangHER study (GEICAM/2012-07).

OBJECTIVE: We compared patients' preferences for intravenous (IV-t) versus subcutaneous (SC-t) trastuzumab administration. METHODS: Phase III, open-label, multicentre study in HER2-positive metastatic breast cancer. Patients were receiving IV-t for at least 4 months without progression. Randomisation was 1:1 to administer 2 cycles of SC-t with vial followed by 2 cycles with single injection device (SID) or the reverse sequence (600mg SC-t every 3 weeks for 4 cycles). PRIMARY OBJECTIVE: patients' preference for IV-t versus SC-t; secondary objectives: patients' preference for vial versus SID, healthcare professional (HCP) preference and safety. RESULTS: We randomised 166 patients in 26 sites. Median number of previous lines of chemotherapy and/or endocrine therapy was 1 (1-7). Median duration of prior IV-t was 1.8 years (0.3-14). Of the159 patients completing the questionnaires, 86.2% preferred SC-t, 6.9% preferred IV-t, and 6.9% had no preference. Patients preferred SID (59.2%) over vial (26.3%). Most (87.2%) HCP preferred SC-t of whom 51.3% and 28.2% preferred SID and vial respectively. Related adverse events included G1-2 injection site reactions in 18 patients (10.8%), G1 pain in 8 (4.8%), G1-2 allergic reaction in 2 (1.2%), one G3 heart failure and 1 G2 ejection fraction decrease. CONCLUSIONS: SC-t is preferred with no safety impact.

Biopsia selectiva de ganglio centinela tras quimioterapia neoadyuvante en pacientes con axila negativa al inicio / Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with negative axillary involvement at initial diagnosis

OBJETIVO: valorar la tasa de detección de ganglio centinela tras quimioterapia neoadyuvante en pacientes con cáncer infiltrante de mama y axila clínicamente negativa previa al tratamiento y analizar su supervivencia global y supervivencia libre de enfermedad. MATERIAL Y MÉTODOS: estudio observacional retrospectivo. Se incluyeron las pacientes con cáncer de mama tratadas con quimioterapia neoadyuvante en el Hospital Universitario Quironsalud Madrid entre los años 2008-2014. A todas se les practicó cirugía conservadora o radical junto con biopsia selectiva de ganglio centinela posneoadyuvancia. Se recogió información correspondiente a características sociodemográficas, variables relacionadas con el tratamiento quirúrgico y médico, evolución, características del tumor, supervivencia global y supervivencia libre de enfermedad. RESULTADOS: se incluyeron en el estudio 112 pacientes (116 tumores, 4 de ellos bilaterales). De los 112 tumores unilaterales, 98 (84,5%) estaban en estadios iniciales. La mediana de tamaño tumoral fue 20 mm (15-30). La práctica totalidad (97,4%) eran carcinomas ductales infiltrantes. La quimioterapia se basó en antraciclinas y taxanos con adición de carboplatino en los casos triple negativo y de trastuzumab en Her-2/neu sobreexpresado. Se realizó cirugía conservadora en el 59,5%. La tasa de detección de ganglio centinela fue del 100% con un valor predictivo negativo del 99,1% (110/111), al encontrar una sola recidiva axilar en los 111 ganglios centinela negativos, y se obtuvo respuesta completa patológica en el 52,6%, mayoritariamente en los tumores Her-2 puros y triples negativos con diferencia estadísticamente significativa (p:0.018). La supervivencia global fue del 99,1% con mediana de seguimiento de 53 meses, observando eventos de recaída en 10 pacientes de las cuales solo 2 fueron axilares. CONCLUSIONES: en nuestra experiencia, la biopsia selectiva de ganglio centinela sistemática posneoadyuvancia en pacientes con axila negativa al inicio presenta una excelente tasa de detección, sin aumentar el número de recidivas axilares de forma significativa ni la supervivencia global de estas pacientes. Consideramos, por tanto, esta estrategia la mejor opción para la estadificación quirúrgica de estos tumores

OBJECTIVE: To assess sentinel lymph node biopsy rate after neoadjuvant chemotherapy in breast cancer patients with negative axillary nodes at diagnosis and to analize their disease free interval and overall survival. MATERIAL AND METHODS: Retrospective observational study including breast cancer patients with neoadjuvant chemotherapy at the Hospital Universitario Quironsalud Madrid between 2008-2014. Post chemotherapy, all patients underwent conservative or radical surgery along with a systematic sentinel lymph node biopsy. Patients data was collected and included sociodemographic characteristics, variables regarding surgical and medical treatment, follow-up, tumor characteristics, overall and disease-free survival. RESULTS: The study included 112 patients (116 tumors, 4 of them bilateral). Of the 112 unilateral tumors, 98 (84.5%) were early stages. The median tumor size was 20 mm (15-30) and the majority (97,4%) were invasive ductal carcinoma chemotherapy was based on anthracyclines and taxanes with addition of carboplatin in triple negative cases and trastuzumab in Her-2/neu positive tumors. Conservative procedures were performed in 59,5% of cases. Sentinel lymph node detection rate reached 100% with a negative predictive value of 99,1% (110/111) finding only one axillary recurrence among 111 SLNB. We achieved pathological complete response in 52,6% of tumors in the breast, and more specifically in pure Her2/neu positive and triple negative surrogates (p:0.018). Overall survival was 99,1% with median follow-up of 53 months and 10 patients had a relapse, with only two patients with axillary involvement. CONCLUSIONS: In our experience, sentinel lymph node biopsy performed systematically after neoadjuvant treatment in clinically node negative patients have an excellent detection rate without increasing the axillary recurrence rate nor decreasing overall survival in this group of patients. We consider this strategy the best option for the surgical staging of this tumors after chemotherapy

Nintedanib plus letrozole in early breast cancer: a phase 0/I pharmacodynamic, pharmacokinetic, and safety clinical trial of combined FGFR1 and aromatase inhibition.

BACKGROUND: The combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole. PATIENTS AND METHODS: Women with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150 mg/bid) plus letrozole (2.5 mg/day) administered for a single 28-day cycle (DLT assessment period), followed by a classic 3 + 3 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6 cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level). RESULTS: A total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200 mg/bid plus letrozole 2.5 mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). Nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period. CONCLUSION: Combined treatment with nintedanib (200 mg/bid) plus letrozole (2.5 mg/day) effectively suppressed FGFR1 and aromatase activity, and these respective doses can be used as starting doses in any subsequent trials. However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6 months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions. TRIAL REGISTRATION: This trial was registered at www.clinicaltrials.gov under reg. # NCT02619162, on December 2, 2015.

Prognosis and treatment-selection criteria for patients with high-grade stage IIIc-IV serous ovarian, fallopian tube or peritoneal cancer / Pronóstico y selección de tratamiento en pacientes con cáncer seroso de ovario, de trompas de Falopio o peritoneal de alto grado, estadio IIIc-IV

Objective: To determine the impact of implementing strict treatment-selection criteria on the overall outcome of women with high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma. Material and methods: We included patients treated for high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma at our Institution from January 2007 to March 2015. All other non-serous, low-grade histology tumors and secondary cytoreductions were excluded. strict treatment-selection criteria was used to decide on primary cytoreductive surgery versus neoad-juvant chemotherapy and type of adjuvant therapy. Collected data included patient and tumor characteristics, preoperative diagnostic procedures, surgical treatment, perioperative complications, and neoadjuvant and adjuvant chemotherapies. Appropriate statistical tests were used and survival analysis performed. Results: We identified 71 eligible patients. Mean age was 58.5 ± 11.8 years, 28.2% received neoadjuvant chemotherapy, and 77.5% had optimal cytoreductive surgery to < 1 cm residual disease. Major complications were observed in 16.9% of women, with no significant difference between neoadjuvant chemotherapy and primary cytoreductive surgery groups. With a median follow-up of 35.7 months, median overall survival was not achieved and 57.2% of patients were alive 54 months after surgery. A total of 24 out of 71 (33.8%) died of disease, 11 (45.8%) within two years after surgery. Median progression-free survival was 19.5 months (95% CI 14.8-24.3). Conclusions: Applying strict treatment-selection criteria for patients with high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma ensures few surgical complications and excellent survival rates for the majority of these women

Objetivo: determinar el impacto de la implementación de criterios estrictos de selección de tratamiento sobre el pronóstico de las mujeres con carcinoma seroso de ovario, trompa de Falopio o peritoneal primario en estadio avanzado y de alto grado. Material y métodos: entre enero de 2007 y marzo de 2015 se incluyeron pacientes tratadas por carcinoma ovárico seroso avanzado de alto grado, trompa de Falopio o carcinoma peritoneal primario en nuestro hospital. Se utilizaron criterios estrictos de selección de tratamiento para decidir sobre la cirugía citorreductora primaria versus quimioterapia neoadyuvante y el tipo de tratamiento adyuvante. Los datos recogidos incluyeron características del paciente y del tumor, procedimientos diagnósticos preoperatorios, tratamiento quirúrgico, complicaciones perioperatorias y quimioterapias neoadyuvantes y adyuvantes. Se utilizaron pruebas estadísticas adecuadas y se realizó un análisis de supervivencia. Resultados: se incluyeron 71 pacientes. La edad media fue de 58,5 ± 11,8 años, el 28,2% recibió quimioterapia neoadyuvante y el 77,5% tuvo una cirugía citorreductora óptima (< 1 cm de enfermedad residual). Se observaron complicaciones mayores en el 16,9% de las mujeres, sin diferencias significativas entre los grupos de quimioterapia neoadyuvante y de cirugía citorreductora primaria. Con una mediana de seguimiento de 35,7 meses, no se alcanzó la mediana de supervivencia global y el 57,2% de los pacientes estaban vivas 54 meses después de la cirugía. Un total de 24 de 71 (33.8%) murieron de enfermedad, 11 (45.8%) en los dos años después de la cirugía. La mediana de supervivencia libre de progresión fue de 19,5 meses (IC del 95%: 14,8-24,3). Conclusiones: la aplicación de criterios estrictos de selección de tratamiento para pacientes con carcinoma seroso ovárico, de trompa de Falopio o carcinoma peritoneal primario en estadio avanzado de alto grado asegura pocas complicaciones quirúrgicas y buenas tasas de supervivencia para la mayoría de estas pacientes

Prospective study of the impact of the Prosigna assay on adjuvant clinical decision-making in unselected patients with estrogen receptor positive, human epidermal growth factor receptor negative, node negative early-stage breast cancer.

PURPOSE: Improved understanding of risk of recurrence (ROR) is needed to reduce cases of recurrence and more effectively treat breast cancer patients. The purpose of this study was to examine how a gene-expression profile (GEP), identified by Prosigna, influences physician adjuvant treatment selection for early breast cancer (EBC) and the effects of this influence on optimizing adjuvant treatment recommendations in clinical practice. METHODS: A prospective, observational, multicenter study was carried out in 15 hospitals across Spain. Participating medical oncologists completed pre-assessment, post-assessment, and follow-up questionnaires recording their treatment recommendations and confidence in these recommendations, before and after knowing the patient's ROR. Patients completed questionnaires on decision-making, anxiety, and health status. RESULTS: Between June 2013 and January 2014, 217 patients enrolled and a final 200 were included in the study. Patients were postmenopausal, estrogen receptor positive, human epidermal growth hormone factor negative, and node negative with either stage 1 or stage 2 tumors. After receiving the GEP results, treatment recommendations were changed for 40 patients (20%). The confidence of medical oncologists in their treatment recommendations increased in 41.6% and decreased in 6.5% of total cases. Patients reported lower anxiety after physicians made treatment recommendations based on the GEP results (p < 0.05). CONCLUSIONS: Though this study does not include evaluation of the impact of GEP on long-term outcomes, it was found that GEP results influenced the treatment decisions of medical oncologists and their confidence in adjuvant therapy selection. Patients' anxiety about the selected adjuvant therapy decreased with use of the GEP.

Diffusion-weighted magnetic resonance imaging evaluation of intra-abdominal sites of implants to predict likelihood of suboptimal cytoreductive surgery in patients with ovarian carcinoma.

OBJECTIVES: To analyse the diagnostic accuracy and to establish a predictive score based on diffusion-weighted magnetic resonance imaging (DWMRI) compared to exploratory laparotomy (EL) for predicting suboptimal cytoreductive surgery for different intra-abdominal sites of implants in patients with ovarian cancer. METHODS: Thirty-four patients with advanced ovarian carcinoma were studied. Preoperative DWMRI of the abdomen and pelvis was performed. DWMRI findings were compared with EL. Ten anatomical sites were selected for inclusion in the score. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for suboptimal cytoreduction were calculated for both DWMRI and EL. Receiver operating characteristic (ROC) curve analysis was used to assess the ability to predict suboptimal cytoreduction. RESULTS: Using predictive score, ROC curves were generated with an area under the curve of 0.938 for DWMRI and 0.947 for EL (P < 0.0001). For DWMRI, a score ≥6 had the highest overall accuracy at 91.1 % and identified patients with unnecessary EL with a sensitivity of 75 %. For EL, a score ≥4 had the highest overall accuracy at 88.2 % and was able to identify patients with unnecessary EL with a sensitivity of 87.5 %. CONCLUSIONS: DWMRI is an emerging technique that may be useful to predict suboptimal cytoreduction in ovarian cancer. KEY POINTS: • DWMRI is increasingly used in ovarian cancer. • DWMRI is an accurate technique for depicting intra-abdominal sites of implants • DWMRI is useful for predicting optimal cytoreductive surgical outcome. • We report a high predictive value similar to exploratory laparotomy.

Sparing fertility in young patients with endometrial cancer.

The objective of this review is to recognize the characteristics of endometrial adenocarcinoma in young patients and to evaluate the published experience with conservative approach in patients with endometrial adenocarcinoma. We searched MEDLINE articles describing patients with endometrial adenocarcinoma who were treated with hormonal therapy. The search included articles published between January 1966 and January 2007. Endometrial carcinoma in patients under 45 years of age is an unusual condition that shows a more favorable pattern than in older patients. One hundred thirty three patients were found in the search. The average duration of hormonal therapy was approximately 6 months. The average response time was 12 weeks. Seventy six percent of patients treated with hormonal therapy had a complete response and the other 24% never responded to treatment. Of those who initially responded, 66% didn't show recurrence of disease. The other 34% had a relapse. There have been published 4 deaths of patients conservatively managed. A conservative approach in these patients can offer reasonable oncological security and the opportunity of fulfilling their maternal desires in selected cases. However, consideration should be taken regarding the potential adverse outcomes that have been recently published in the literature.