Eva Muñoz

A rare case of malignant solitary fibrous tumor of the spinal cord.

Study Design. Case report. Objective. We present a case of an ambulatory patient with a solitary fibrous tumor of the spinal cord. Summary of Background Data. Solitary fibrous tumor (SFT) is an uncommon mesenchymal tumor of the pleural cavity, increasingly recognized at numerous extrathoracic sites, including, among others, prostate, kidney, and thyroid. The spinal cord is an extremely rare localization of SFTs with only 17 cases reported in the literature since 1996. Although SFTs are usually indolent neoplasms that are cured with complete surgical resection, malignant transformation has been described within histologically benign SFTs. However, no cases of malignant dissemination have been described in this localization. Methods. Discussion of the patients clinical and radiologic history with a review of the relevant background literature. Results. We report the first case of spinal cord SFT with visceral dissemination years after the primary diagnosis, despite benign histologic features of the primary tumor. Conclusion. This finding may indicate that long-term follow-up might be necessary in these patients. In addition, metastatic radical surgery of SFTs should be considered to achieve long-term survival since there are no currently available effective systemic therapies.

Ipilimumab for advanced melanoma: experience from the Spanish Expanded Access Program

Ipilimumab, a fully human, recombinant, monoclonal antibody to cytotoxic T-lymphocyte antigen 4 improves overall survival (OS) in previously treated and untreated metastatic melanoma. This retrospective analysis reports data gathered by a questionnaire on the demographics, outcomes, and toxicity of ipilimumab administered through an Expanded Access Program (EAP). Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for four cycles to adults with metastatic melanoma. Efficacy outcomes included complete response, partial response (PR), progressive disease, stabilized disease, and OS. EAP data were collected from EAP physicians. A subgroup analysis examined efficacy in elderly patients (≥70 years) and factors predictive of survival were identified. Of 355 requests for ipilimumab, resulting in 288 treatments, completed questionnaires were received for 153 ipilimumab recipients (median age 58 years, 57.2% men). Efficacy was evaluated in 144 patients: complete response in 1.3%, PR in 9.6%, PR with previous progression 8.4%, stabilized disease in 14.5%, and progressive disease in 66.2%. The median OS was 6.5 months (199 days); 1-year survival was 32.9%. Predictive survival factors included lymphocytes over 1000/ml (P=0.0008) and lactate dehydrogenase more than 1.5×upper limit of normal (P=0.003). Cutaneous, hepatic, and gastrointestinal toxicities were mild. In 30 patients aged more than 70 years, ipilimumab efficacy and tolerability was similar to that of the overall population. In the clinical practice setting, ipilimumab is effective and well tolerated in patients with advanced melanoma, including elderly patients, when administered at the recommended dosage. Ipilimumab improves treatment options for patients who, until recently, have had little hope of an improved prognosis.

Molecular basis for the treatment of renal cell carcinoma

Renal cell carcinoma (RCC) is a heterogeneous malignancy whose incidence rate has notably increased in recent years without any evident reason. Traditionally, RCC has been resistant to classic treatments (chemotherapy, radiotherapy and hormonal therapy), with only a small percentage of patients benefiting from cytokine therapy. Different hereditary syndromes have been associated with RCC, Von Hippel Lindau (VHL) being the most important syndrome. Understanding key molecular pathways implicated in the tumorigenesis of RCC has crystallised in the development of more effective therapies. Specifically, drugs targeting VEGF (bevacizumab, sunitinib, sorafenib, axitinib, pazopanib) and PI3K-mTOR (temsirolimus and everolimus) have become the cornerstone of renal cancer treatment.

Management of the axilla in early breast cancer patients in the genomic era

Management of the axilla in early breast cancer (EBC) patients has dramatically evolved in recent years from more radical to increasingly conservative approaches. Classically, the EBC patients with a clinically positive axilla are offered axillary lymph node dissection (ALND) and those with a clinically negative axilla (cN0) are offered sentinel lymph node (SLN) biopsy, which obviates the complications related to ALND and provides adequate surgical staging and comparable locoregional control and survival. The need for performing ALND when the SLN is positive and contemporary adjuvant treatment is delivered has been questioned in recent years. On the other hand, ongoing trials are testing whether node-positive patients can be spared chemotherapy, based on intrinsic primary tumor biology. Because the integration of novel surgical management and tumor biology is needed, this article provides an overview of the current challenges that a more detailed knowledge of tumor biology has brought to EBC staging and treatment. We propose that breast cancer oncologists (surgeons, radiation therapists, and medical oncologists) should focus their efforts on offering therapy tailored to each patients needs in such a way that no matter which treatment is used, no overtreatment occurs.

Genetic profile of GNAQ-mutated blue melanocytic neoplasms reveals mutations in genes linked to genomic instability and the PI3K pathway.

Melanomas arising in association with a common or cellular blue nevus (MABN) comprise a relatively rare and heterogeneous group of lethal melanomas. Although GNAQ is known to be frequently mutated in common blue nevus, cellular blue nevus (CBN) and MABN and these malignant lesions present gross chromosome alterations harboring BAP1 mutations, little is known about other mutations that contribute to the development and progression of these neoplasms. Thus, the genetic profile of these tumors is important to increase the number of intervention and treatment modalities. Here, we characterized and genetically profiled two different sections of a rare MABN and two CBNs from three different patients. All of the samples harbored a GNAQ mutation, exhibited RAS pathway activation, and harbored additional mutations in genes associated with genomic instability and epigenetic regulation (KMT2C, FANCD2, ATR, ATRX, NBN, ERCC2, SETD2, and WHSC1). In addition, all neoplasms harbored mutations that directly or indirectly affected either the regulation or activation of the PI3K pathway (PIK3CA, NF1, INPP5B and GSK3B). Our results not only help understand the genetic complexity of these blue melanocytic lesions but provide a rationale to use the combination of PI3K/MTOR and MEK1/2 inhibitors against these types of tumors.

Genetic Evolution of Nevus of Ota Reveals Clonal Heterogeneity Acquiring BAP1 and TP53 Mutations

Melanoma presents molecular alterations based on its anatomical location and exposure to environmental factors. Due to its intrinsic genetic heterogeneity, a simple snapshot of a tumors genetic alterations does not reflect the tumor clonal complexity or specific gene–gene cooperation. Here, we studied the genetic alterations and clonal evolution of a unique patient with a Nevus of Ota that developed into a recurring uveal‐like dermal melanoma. The Nevus of Ota and ulterior lesions contained GNAQ mutations were c‐KIT positive, and tumors showed an increased RAS pathway activity during progression. Whole‐exome sequencing of these lesions revealed the acquisition of BAP1 and TP53 mutations during tumor evolution, thereby unmasking clonal heterogeneity and allowing the identification of cooperating genes within the same tumor. Our results highlight the importance of studying tumor genetic evolution to identify cooperating mechanisms and delineate effective therapies.

Abstract 468: BRAF mutation analysis in cell free tumoral DNA (cfDNA) of melanoma patients: results from the prospective study GEM1304 (Spanish Melanoma Group)

Backgroud: Tumor-derived circulating cell-free DNA (cfDNA) is a dynamic source for determination of tumor mutation status. We have previously demonstrated the prognostic value of BRAFV600 mutation status in pretreatment cfDNA (BRAF pre-cfDNA) in advanced melanoma patients (p) treated with BRAF inhibitors (median overall survival [OS] 7 months [m] vs 22m for BRAF pre-cfDNA positive and negative p, respectively p = 0.017)1. Based on these results, the Spanish Melanoma Group conducted a prospective study in 13 centers to determine the prognostic value of BRAFV600 mutation in pre-cfDNA, the change in mutation status at time of first evaluation (BRAF early-cfDNA), and the correlation of BRAF cfDNA dynamics with clinical evolution (GEM1304) (ClinicalTrials.gov Identifier: NCT01960634). Methods: One hundred and fifty nine plasma and serum samples from 66 stage IV BRAF mutant melanoma p were collected before and during treatment, until disease progression. A quantitative 5’-nuclease PCR based assay was used to determine BRAFV600 mutation status in cfDNA. Results: Most p were stage M1c (62%), treated with BRAF inhibitors (53%), and not previously treated (67%). BRAF pre-cfDNA was positive in 42 p (64%). Median OS was 6.4 m (95% CI: 10.9-23.6) and 17 m (95% CI: 3.5-9.2) for p with positive and negative BRAF pre-cfDNA, respectively (p = 0.06). Significant differences in OS were observed according to BRAF early-cfDNA negativization: 4.7 m (95%CI: 1.2-8.1) in those with persistence of BRAF in cfDNA (12 p), not reached (NR) in p with BRAF early-cfDNA negativization (11 p), and 22 m (95%CI:0.6-43.9) in those who continued to be negative (17 p) (p Conclusions: Patients with early negativization of BRAFV600 in cfDNA have excellent prognosis, at least as good as those with negative BRAF in pre-cfDNA. Gonzalez-Cao et al. Mel Res 2015; 25:486 Citation Format: Maria Gonzalez Cao, Jose Luis Manzano, Virtudes Soriano, Teresa Puertolas, Ainara Soria, Clara Mayo, Margarita Magem, Miguel Angel Molina, Clara Montagut, Eva Munoz, Delvys Rodriguez, Elizabeth Perez, Almudena Garcia, Javier Cortes, Nuria Jordana, Jordi Rodon, Niki Karachaliou, Rafael Rosell. BRAF mutation analysis in cell free tumoral DNA (cfDNA) of melanoma patients: results from the prospective study GEM1304 (Spanish Melanoma Group). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 468.

Abstract P5-19-21: TRASTYVERE study: A retrospective analysis of HER2-positive metastatic breast cancer (MBC) patients treated in Spain with lapatinib (L) plus trastuzumab (T)

Background: Vertical dual blockade with L and T in heavily pretreated HER2+ MBC patients has shown consistent survival gain in a phase III trial (Blackwell KL et al. 2012), justifying an EMA approval for the hormone-negative subgroup. However, there is very limited information about the futility of the combination in clinical practice, mostly in patients progressing also on prior L regimens. Methods: We conducted a retrospective analysis among patients treated in Spain by compassionate uses for the combination of T-L. The study was approved by the regulatory authorities and ethics committees from the 14 participating centers. Major inclusion criteria were (1) HER2+ MBC; (2) progression on at least one prior line of T for advanced disease; and (3) T-L treatment started between JAN/2005 and DEC/2012. Concomitant endocrine therapy for HR+ patients as well as prior exposure to L was allowed. Chemotherapy combinations were excluded. A total of 111 patients were predefined for the primary outcome: clinical benefit rate (CBR). Secondary endpoints included time to progression (TTP), overall survival (OS) and toxicity. 114 women were included and externally monitored. Results: The median age was 60 years (34 - 89); 64% HR+; 77% visceral disease; 32% CNS disease (37 patients); 47% with ≥3 organs involved. Mean number of prior T lines 4 (range 0-13); 64% previously treated with L. A total of 40 patients (35%) achieved a CBR (95%CI 26–44%); 6 CR, 19 PR and 15 SD lasting >24 weeks. The median time to progression was 3.8 months (95%CI 3.3–5.1) and the median overall survival 21.6 months (95%CI 17.1–27.3). CBR, median TTP and median OS achieved in patients with CNS disease were 32.4% (95%CI 17.3–47.5%), 3.6 (95%CI 2.8–5.9) and 15.4 (95%CI 10.9–27.3) months, respectively. The CBR was independent of L treatment (41.5% L naive vs. 31.5% L pretreated, p=0.285) and HR status (39% HR- vs. 32.9% HR+, p=0.509). Patients with Conclusions: The combination of T-L seems safe and active in heavily pretreated patients. The combination remains active among patients progressing on prior L. Future research may focus on the ability of endocrine therapy to increase activity among HER2+/HR+ patients. REFERENCES: 1 Blackwell KL, Burstein HJ, Storniolo AM, et al: Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 2012;30(21):2585-2592. Citation Format: Joaquin Gavila, Begona Bermejo, Alvaro Rodriguez-Lescure, Juan Lao Romera, Luis Manso, Joan Brunet, Eva Munoz, Marta Santisteban, Cesar A Rodriguez, Ana Santaballa, Juan de la Haba, Pedro Sanchez-Rovira, Manuel Ruiz-Borrego, Jose Angel Garcia-Saenz, Javier Cortes, Antonio Llombart. TRASTYVERE study: A retrospective analysis of HER2-positive metastatic breast cancer (MBC) patients treated in Spain with lapatinib (L) plus trastuzumab (T) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-21.

Abstract C41: BRAFV600 serum/plasma analysis: Predictive value of survival in melanoma treated with BRAF inhibitors.

Background: BRAF mutation is present in 50% of metastatic melanoma patients. Treatment with BRAF inhibitors improves survival of BRAF mutant melanoma patients, with a median progression free survival time of 6 months. Twenty percent of patients are refractory to BRAF inhibitors, and others have early resistance development. Pretreatment analysis of BRAFV600 mutation in cell free DNA from serum or plasma could help to select patients for BRAF inhibitor treatments. We have investigated the sensitivity of the assay and its predictive value. Methods: Analysis of BRAFV600 mutation was performed in cell free DNA (cf DNA) from serum and plasma of 22 metastatic melanoma patients before starting a BRAF inhibitor treatment. Results: Six patients were women, median age was 62 years old (58-81). Four patients (18%) had complete response to treatment. Eleven patients (50%) had partial response to treatment. Two patients (9%) had progression disease as their best response. Median progression free survival time (PFS) for patients with complete response, partial response, stable disease and progression disease were: not reached, 4.6 months, 3 months and one month, respectively (p<0.00001). Twelve patients (54.5%) had BRAF positive analysis pretreatment in serum/plasma. From BRAF serum/plasma positive patients 1 had CR (8%) and 7 PR (58%). From BRAF serum/plasma negative patients: 3 (30%) CR and 4 (40%) PR. Median PFS for patients treated with BRAF inhibitors was 3.5 months for BRAF serum/plasma positive patients and 13.57 months for BRAF serum/plasma negative patients (p=0.026) Conclusion: BRAFV600 serum/plasma analysis is a good predictor of survival for patients treated with BRAF inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C41. Citation Format: Maria Gonzalez Cao, Salvador Martin Algarra, Eva Munoz, Clara Mayo de las Casas, Jose Luis Manzano, Javier Cortes, Miguel Angel Molina-Vila, Jose Pablo Berros, Leticia De Mattos-Arruda, Miguel Sanmamed, Alvaro Gonzalez, Carlos Alvarez, Niki Karachaliou, Rafael Rosell. BRAFV600 serum/plasma analysis: Predictive value of survival in melanoma treated with BRAF inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C41.

Abstract P2-09-27: Predictive Factors of Complete Axillary Downstaging after Neoadjuvant Chemotherapy in Breast Cancer Patients

Background: The axillary status after neoadjuvant chemotherapy (NACT) is an important prognostic factor. Complete axillary downstaging (CAD) occurs in up to 20-30% of the patients, however, sentinel node biopsy after NACT is not recommended in patients with initial axillary nodal involvement and complete axillary response after NACT. Our aim was to investigate predictive factors of CAD after NACT to identify patients who could avoid an unnecessary axillary dissection. Patients and methods: From January 2004 to December 2008, 256 consecutive patients were diagnosed with invasive breast cancer and received NACT and breast surgery at our institution. Patients were eligible for this analysis if they met the following inclusion criteria: clinically and/or cytologically proven metastatic axillary nodes; complete axillary response after NACT; and complete axillary dissection after systemic treatment. CAD was defined as pN0 (isolated tumor cells and micrometastasis were excluded). Univariate and multivariate analyses were performed to assess the association between CAD and either tumor characteristics or intrinsic cancer subtypes. Results: 84 patients were included. Median age was 51.64 years. 75 (89,3%) received anthracyclines-and taxanes-based CT and 11 (13%). 38 (45,2%) had cytologically proven metastatic axillary nodes at diagnosis. According to intrinsic cancer subtypes, 22 (26%) were classified as HER2 positive, 17 (20,2%) as triple negative (ER, PR, and HER2 -), 6 (7,1%) as luminal A [estrogen receptor positive and/or progesterone receptor positive and (Ki67 Conclusions: In our cohort of breast cancer patients, HER2 status is an independent predictive factor of CAD after NACT. Clinical trials, probably according to specific breast cancer subtypes, are required to identify patients with initial axillary metastatic involvement who could avoid an axillary dissection after systemic therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-27.