Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A.

Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel.

Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER).

BACKGROUND: The potential benefit of adding palbociclib to fulvestrant as first-line treatment in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive advanced breast cancer (ABC) patients remains uncharacterized. PATIENTS AND METHODS: In this randomized (1:1), double-blind, phase II study, postmenopausal women with HR-positive, HER2-negative ABC with de novo metastatic disease or those who relapsed after >12 months of adjuvant endocrine therapy received palbociclib/fulvestrant or placebo/fulvestrant. Stratification was based on recurrent versus de novo metastatic disease and visceral involvement. The primary objective was one-year progression-free survival (PFS-1y) rate. The sample size was 190 patients. The two-sided alpha of 0.2, 80% of power to detect a difference between the arms, assuming PFS rates of 0.695 and 0.545 for palbociclib/fulvestrant and placebo/fulvestrant, respectively. RESULTS: In total, 189 patients were randomized to palbociclib/fulvestrant ([n = 94] or placebo/fulvestrant [n = 95]). 45.5% and 60.3% of patients had de novo metastatic disease and visceral involvement, respectively. PFS-1y rates were 83.5% and 71.9% in the palbociclib/fulvestrant and placebo/fulvestrant arms, (HR 0.55, 80% CI 0.36-0.83, P = 0.064). The median PFS were 31.8 and 22.0 months for the palbociclib/fulvestrant and placebo/fulvestrant arms (aHR 0.48, 80% CI 0.37-0.64, P = 0.001). The most frequent grade 3-4 adverse events were neutropenia (68.1% vs. 0%), leucopenia (26.6% vs. 0%), anemia (3.2% vs. 0%), and lymphopenia (14.9% vs. 2.1%) for the palbociclib/fulvestrant and placebo/fulvestrant, respectively. The most frequent non-hematologic grade 3-4 adverse event was fatigue (4.3% vs. 0%). CONCLUSIONS: Palbociclib/fulvestrant demonstrated better PFS-1y rates and median PFS than placebo/fulvestrant in HR-positive/HER2-negative endocrine-sensitive ABC patients.

Patrones de recaída y respuesta patológica según tipo subrogado en pacientes con cáncer de mama y axila negativa al inicio tratadas con quimioterapia neoadyuvante / Patterns of relapse and pathological response according to surrogate type in breast cancer patients treated with neoadjuvant chemotherapy and negative axillary involvement

Objetivos: Determinar los patrones de recaída y la respuesta patológica en relación con los diferentes tipos subrogados de cáncer de mama tras tratamiento neoadyuvante para analizar supervivencia y optimizar la vigilancia. Material y métodos: Análisis retrospectivo de 112 pacientes con 116 tumores, con axila clínicamente negativa, tratados con quimioterapia neoadyuvante en nuestro Centro entre 2008 y 2014, y operadas posteriormente con cirugía conservadora o radical. Analizamos respuesta patológica en función de los tipos subrogados, tasas de recurrencia y sus patrones, supervivencia libre de enfermedad (SLE) y supervivencia global (SG). Resultados: Se logró una respuesta patológica completa (RPC) en el 52,6%, constatando que estas pacientes tenían mejor supervivencia (p<0,05). En cuanto a los tipos subrogados, observamos RPC en el 85% de los tumores Her-2/neu positivos puros, el 65,6% de los triple negativos, el 43,8% de Luminal B Her-2 positivo, el 40% de Luminal B Her-2 negativo y en el 25% de Luminal A (p<0,05). Con un tiempo medio de seguimiento de 53 meses encontramos una tasa de recaídas del 9%. Los tipos menos agresivos tenían un tiempo a recaída loco-regional de 38,5 meses y a recurrencia sistémica de 74 meses. Los tipos más agresivos mostraron un tiempo medio a recaída loco- regional de 36,2 meses y a recurrencia sistémica de 8 meses. Conclusiones: La quimioterapia neoadyuvante adaptada al tipo subrogado es una estrategia válida para intentar alcanzar una RPC. Las diferencias observadas en el patrón de recurrencia permiten optimizar el seguimiento.(AU)

Purpose: To determine relapse patterns and pathological response in relation to surrogate types of breast cancer after neoadjuvant treatment to analyse survival and optimize surveillance. Material and methods: Retrospective analysis of 112 patients with 116 tumours, with negative axillary involvement, treated with neoadjuvant chemotherapy at our hospital, between 2008 and 2014, who systematically underwent surgery. We analysed pathological response according to surrogate subtypes, rates and patterns of recurrence, disease free survival (DFS) and overall survival (OS). Results: Pathological complete response (pCR) was achieved in 52.6%, finding that these patients had better survival (p<.05). Looking at surrogate subtypes, we observed a pCR in 85% of pure Her-2/neu positive tumours, 65.6% of triple negatives, 43.8% of Her -2 positive Luminal B, 40% of Luminal B and 25% of Luminal A (p<.05). With a median follow-up of 53 months, we found a 9% rate of relapses. The less aggressive types had a median loco-regional relapse time of 38.5 months and a systemic recurrence time of 74 months. The more aggressive types showed a loco-regional relapse time of 36.2 months and systemic recurrence time of 8 months. Conclusions: Neoadjuvant chemotherapy according to surrogate type is a useful strategy to attempt pCR. Loco-regional relapse and systemic recurrence patterns allow surveillance adjustments.(AU)

MRI guided ROLL/SNOLL in breast cancer patients treated with neoadjuvant chemotherapy. / ROLL/SNOLL guiado por resonancia magnética en pacientes con cáncer de mama tratadas con quimioterapia neoadyuvante.

PURPOSE: To describe the results of MRI (magnetic resonance image) guided ROLL (radioguided occult lesion localization) and SNOLL (sentinel node occult lesion localization) in the localization of residual disease after neoadjuvant chemotherapy for breast cancer, as well as assessing the surgical results obtained and disease free survival. METHODS: Prospective observational analysis of 132 patients with 136 tumors, treated with neoadjuvant chemotherapy at our hospital between 2011-2017. Residual disease was located presurgically with MRI guided ROLL/SNOLL technique. We analyzed technical aspects of localization, and variables corresponding to surgical procedures and events occurred during follow-up. RESULTS: The median tumor size was of 20.5mm (interquartilic range [IQR]: 14-28). The majority (96.3%) were invasive ductal carcinomas. Sentinel lymph node detection rate was 98.9%. Complete pathological response (CPR) in the breast was achieved in 58.1% of cases. The rate of affected margins in 89 cases operated by conservative surgery was 2.2%. With a median follow-up of 50 months (IQR: 37-61) we found a 7.4% rate of relapses. Of these, seven were loco-regional and three at distant sites. The estimated mean of disease-free survival time was 83.2 months (Confidence Interval [CI] 95%: 79.6-86.6). CONCLUSIONS: MRI guided ROLL/SNOLL is a great tool for breast cancer residual disease localization following neoadjuvant chemotherapy. In addition, this technique attains good loco-regional control of the diseases and has excellent surgical results.

Indications for adjuvant radiotherapy treatment after surgery and novel modalities for treatment.

Carcinoma of the uterine cervix is a frequent common cancer in women. Patients diagnosed with early stage cervix cancer are managed with surgery. Overall survival for stage IB (IB1-IB2) and IIA, is in the range of 80-90% at 5 years. Only patients with poor prognostic factors as: large tumors (>or=4 cm), positive lymph nodes, positive and/or close margins <3 mm; can benefit from adjuvant radiotherapy. Radiotherapy has been also recommended for a subgroup of patients with intermediate-risk factors as: large tumor diameter, deep stromal invasion and presence of tumor in capillary lymphatic space adjuvant. In the presence of 2 of the 3 adverse risk factors, radiotherapy reduces tumor recurrence in stage IB cervical cancer with negative lymph nodes. Radiotherapy plays an important role in the management of cervical cancer. Conventional radiotherapy may treat a large amount of normal tissue resulting in acute toxicity. The most frequent acute adverse events after external three-dimensional radiotherapy are bowel, bladder and hematological side effects. With standard doses of external beam radiotherapy 45 Gy-50 Gy (1.8 Gy-2 Gy) grade 3-4 late toxicity occurs in about 10%-12%. Intensity modulated radiation therapy (IMRT) represents an advance in treatment delivery with doses that conform tightly to the target, and may reduce the acute gastrointestinal and chronic toxicity when compared with conventional 3D radiotherapy. Also IMRT treats less bone marrow and may lead to a better tolerance of chemotherapy.

Conservative management of patients with early endometrial carcinoma: a systematic review

OBJECTIVE: To know the characteristics of endometrial adenocarcinoma in young patients and to review the published experience in patients with endometrial adenocarcinoma that were conservatively managed with hormonal therapy to spare their fertility. METHODS: We carried out a search in the Survey conducted by the Section of Oncologic Gynecology of SEGO (Spanish Society of Gynecologists) to identify the characteristics of young patients with endometrial adenocarcinoma. In addition we searched MEDLINE and other databases for English-language articles describing patients with endometrial adenocarcinoma who were treated with hormonal therapy. The search included articles published between January 1966 and January 2007. RESULTS: Endometrial carcinoma in patients under 45 years old is an unusual condition that shows a more favourable pattern than in older patients. One hundred and thirty-three patients were found in the search. The average duration of hormonal therapy was approximately six months. The average response time was 12 weeks; 76% of patients treated with hormonal therapy had a complete response and the other 24% never responded to treatment. Of those who initially responded, 66% percent did not show recurrence of disease. The other 34% had a relapse. There have been 4 published deaths of conservatively managed patients. CONCLUSION: 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 (AU)

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Randomized study of cefepime versus ceftazidime plus amikacin in patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia.

OBJECTIVE: This randomized clinical trial evaluated the efficacy and safety of monotherapy with cefepime for patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia. SUBJECTS: Patients with solid tumors treated with HDC and PBSCS, that developed fever and neutropenia (absolute neutrophil count < 500 cells/microL) were eligible, and randomly assigned to receive ceftazidime plus amikacin or cefepime. RESULTS: Fifty-one episodes were randomized, and all were evaluable (27 received ceftazidime plus amikacin arm, and 24 cefepime). Major efficacy endpoints did not show significant differences, with success rates of 44.4% and 54.2% (p = 0.481) for the combination arm and the monotherapy arm, respectively. The proportion of patients that became afebrile in the first 24 hours was significantly higher in the cefepime group (41.7% vs 11.1%, respectively; p = 0.012). However, due to its premature closure and small sample size, this study lacks the adequate power to definitely address this question. CONCLUSIONS: Cefepime monotherapy appeared to have an equivalent efficacy and safety as empiric treatment in febrile neutropenia episodes in a highrisk population compared with ceftazidime and amikacin. Nevertheless, this study is not adequately powered to answer this question. Given the small number of patients randomized and the single-center nature of this study, these results must be cautiously interpreted.

Randomized study of cefepime versus ceftazidime plus amikacin in patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia

OBJECTIVE: This randomized clinical trial evaluated the efficacy and safety of monotherapy with cefepime for patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia. SUBJECTS: Patients with solid tumors treated with HDC and PBSCS, that developed fever and neutropenia (absolute neutrophil count < 500 cells/microL) were eligible, and randomly assigned to receive ceftazidime plus amikacin or cefepime. RESULTS: Fifty-one episodes were randomized, and all were evaluable (27 received ceftazidime plus amikacin arm, and 24 cefepime). Major efficacy endpoints did not show significant differences, with success rates of 44.4% and 54.2% (p = 0.481) for the combination arm and the monotherapy arm, respectively. The proportion of patients that became afebrile in the first 24 hours was significantly higher in the cefepime group (41.7% vs 11.1%, respectively; p = 0.012). However, due to its premature closure and small sample size, this study lacks the adequate power to definitely address this question. CONCLUSIONS: Cefepime monotherapy appeared to have an equivalent efficacy and safety as empiric treatment in febrile neutropenia episodes in a highrisk population compared with ceftazidime and amikacin. Nevertheless, this study is not adequately powered to answer this question. Given the small number of patients randomized and the single-center nature of this study, these results must be cautiously interpreted (AU)