bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of BRAF mutation and effectiveness of BRAF inhibitor on the brain metastases in patients with metastatic melanoma.
Authors: Gummadi Tulasi , Dronca Roxana Stefania , Kim Chul , Kottschade Lisa A. , Mittapalli Rajendar K , Elmquist William F. , Dudek Arkadiusz 
Published: March 2020

9048 Background: Brain metastases continue to be the major cause of morbidity and mortality in patients with metastatic melanoma. The impact of BRAF mutations and effectiveness of BRAF inhibitors on the brain metastases in these patients is lacking. Methods: Preclinical studies were conducted to assessthe steady-state brain and plasma distribution of vemurafenib, a BRAF inhibitor in FVB wild-type and Mdr1a/b-/-Bcrp1-/- mice deficient in the drug efflux transporters, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). A retrospective analysis of patients with metastatic melanoma treated at University of Minnesota from August 2011 to December 2012 was conducted. A similar analysis of cases treated at Mayo Clinic is underway. Results: The preclinical studies in mice show that both P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib. Retrospective analysis was performed on 57 patients with Stage IIIc /IV cutaneous and mucosal melanoma. Patients with BRAF mutation had a higher incidence rate of brain metastases compared to patients without BRAF mutation, although it was not statistically significant (Incidence ratio=1.56; 95% CI=0.70-3.48; P=0.27). Vemurafenib neither reduced the incidence of brain metastases (Incidence ratio = 0.89; 95% CI: 0.30-2.60; P=0.83) nor made significant difference in overall survival. It was observed that treatment with BRAF inhibitor led to improvement in extracranial disease but did not affect progression of intracranial disease. Conclusions: In concordance with preclinical data which indicates that P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib, the retrospective analysis shows that there is improvement in extracranial disease but progression in intracranial disease with treatment with BRAF inhibitor in patients with metastatic malignant melanoma with BRAF mutation. Development of BRAF inhibitors that are not substrates for P-gp and BCRP or concomitant use of P-gp and BCRP inhibitors with vemurafenib, may be needed in order to control or prevent intracranial disease in these patients. Further analysis to improve statistical power of our observation is underway.
Impact of age on treatment of primary melanoma patients.
Authors: Fleming Nathaniel H. , Tian Jiaying , Vega-Saenz de Miera Eleazar , Gold Heidi L. , Darvishian Farbod , Pavlick Anna C. , Berman Russell S. , Shapiro Richard L. , Polsky David , Osman Iman 
Published: March 2020

9054 Background: Although patient age at diagnosis is not currently included in guidelines for treatment of primary melanoma, several lines of evidence suggest that patient age is an important, yet understudied, factor when considering treatment options. Here, we attempt to address the limited knowledge of the impact of age on primary melanoma treatment. Methods: In a prospectively enrolled and followed-up cohort of melanoma patients at NYU, we used logistic regression models to evaluate the association between patient age at diagnosis, tumor baseline characteristics, including BRAF and NRAS mutation status, and likelihood of receiving and responding to adjuvant therapy. We examined adjuvant therapy effectiveness using recurrence and melanoma-specific survival as endpoints. Results: 444 primary melanoma patients were included in the study (median follow-up: 6.3 years; age range: 19-95 years). Age was categorized into three groups spanning the range of age at presentation: younger (19-45 years; 24%), middle (46-70 years; 50%), and older (71-95 years; 26%). Older patients were significantly more likely to have advanced stage, nodular subtype (P < 0.01, both variables), and BRAF wildtype tumors (P = 0.04). Controlling for these factors as well as gender, older patients experienced a higher risk of recurrence (HR older vs. younger 3.34, 95% CI 1.53-7.25; P < 0.01). Of the 128/444 (29%) patients who were eligible for adjuvant treatment (clinical stage ≥ IIB), only 67/128 (52%) received treatment. Using a propensity score that accounts for stage at presentation, patients in the middle age group were more likely to receive adjuvant therapy than those in the older group (OR 2.61, 95% CI 1.12-6.08; P = 0.03). In addition, a trend suggesting benefit from adjuvant therapy (defined as longer melanoma-specific survival) was observed only in the middle age group (P = 0.07). Conclusions: Our data suggest that older melanoma patients, despite having a significantly worse prognosis, are less likely to receive and benefit from adjuvant therapy. Further work is needed to understand the biological variables contributing to the limited response to treatment in elderly primary melanoma.
Vemurafenib (VEM) in patients (pts) with BRAF-mutant melanoma and brain metastases (mets).
Authors: Harding James J. , Catalanotti Federica , Yaqubie Amin , McDermott Gregory C. , Kersellius Romona , Merghoub Taha , Carvajal Richard D. , D'Angelo Sandra P. , Dickson Mark Andrew , Schwartz Gary K. , Wolchok Jedd D. , Berger Michael F. , Solit David B. , Chapman Paul B. 
Published: March 2020

9060 Background: Emerging data suggest that RAF inhibitors are an effective therapy for pts with BRAF-mutant melanoma and brain mets. Although reported efficacy is encouraging, these data are derived from case reports or early stage trials enriched with physiologically fit pts. It is therefore of interest to assess the “real world” experience of VEM in this population. Methods: Records of all BRAF-mutant melanoma pts treated with RAF inhibitors at our center from 2007 to 2012 were reviewed retrospectively. We determined the best overall response rate (BORR) and, when applicable, the overrall intracranial response rate (OIRR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) to RAF inhibition. Pretreatment formalin-fixed, paraffin-embedded tumor was assessed using an exon capture assay able to sequence coding exons of 279 cancer-associated genes. Results: 21 (18%) of 119 pts with BRAF-mutant melanoma treated with VEM had active brain mets (age range: 25-86, sex: 52% men, median ECOG PS: 1, proportion with extracranial mets: 90%, BRAF mutation: 86% V600E and 14% V600K). 10/21 pts had no prior intracranial (IC) therapy; 11/21 pts received whole brain radiotherapy (WBRT, 7/21), stereotactic radiosurgery (1/21), metastasectomy (2/21) or multimodality therapy (1/21) prior to VEM. 12/21 pts received ipilimumab sometime during their disease course. For radiographically evaluable pts (N=17), the BORR was 65% (95% CI: 43-88) and the OIRR was 40% (95% CI: 15-65). For 4 pts, the BORR and OIRR were discordant−3 pts had IC progression but visceral tumor shrinkage, 1 pt had IC disease control but visceral progression. VEM was effective in pts whether or not they had received prior local brain therapy. The estimated median PFS and OS for all brain mets pts (N=21) were 4 and 8 months, respectively. Pretreatment tumor is available for exon sequencing in approximately half of these patients. This analysis is ongoing. Conclusions: In routine clinical practice, the OIRR to VEM was 40% which is higher than historical response rates to WBRT. VEM may be preferable to WBRT as a first-line therapy for pts with BRAF-mutant melanoma and brain mets. Whether RAF inhibitor treatment improves OS in this population will require further study.
Survival patterns following brain metastases for patients with melanoma in the targeted therapy era.
Authors: Wattson Daniel A. , Shih Helen Alice , Niemierko Andrzej , Merritt Ryan M. , Lawrence Donald P. , Oh Kevin S. , Sullivan Ryan J. , Flaherty Keith 
Published: March 2020

9064 Background: Survival from metastatic melanoma (MM) has been significantly prolonged with the introduction of molecularly targeted therapy, including BRAF inhibitors (BRAFi) for patients (pts) with the V600E mutation. Here, we present the first data describing patterns of survival after diagnosis of brain metastases (BM) in a large cohort of these pts with long follow-up. Methods: A retrospective review of 191 MM pts accrued on multiple prospective trials between 2008–2012 was conducted. These trials assessed novel immunologic and targeted therapies in pts with both BRAF mutant (n=70) and wild type/unknown (n=121) tumors. We evaluated pt characteristics and the impact of systemic and BM-directed treatments. Results: Of 98 pts who developed BM, median follow-up after first BM was 7.7 months (15.5 months for the 25 living pts), and 33 were treated with BRAFi. Median duration of BRAFi use was 5.9 months (range 0.7–27.1), which preceded BM in 30%, was concurrent with first BM in 18%, and followed first BM in 52%. Ipilimumab or anti–PD-1/PD-L1 immunotherapy was given to 58% of pts who received a BRAFi and 95% of those who did not. Limited intracranial disease on initial BM presentation (defined as ≤3 lesions) occurred in 70% of BRAFi-treated pts and 74% of non-BRAFi pts, and 70% of BRAFi pts received at least one focal BM treatment (stereotactic radiosurgery or resection) compared to 75% of non-BRAFi pts. As shown in the Table, actuarial survival after BM diagnosis was prolonged among pts treated with a BRAFi. This is due primarily to the nearly 2-year median survival of pts for whom a BRAFi was initiated after BM were diagnosed. Conclusions: Survival for pts with BM from BRAF mutant MM can significantly exceed the often anticipated 4–6 months, particularly if a BRAFi is initiated after BM arise. This supports BRAFi activity in intracranial disease, and helps to inform trials currently under way testing BRAFi use among MM pts with previously diagnosed BM. [Table: see text]
Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access programme (EAP).
Authors: Di Giacomo Anna Maria , Grimaldi Antonio M , Ascierto Paolo Antonio , Queirolo Paola , Del Vecchio Michele , Ridolfi Ruggero , De Rosa Francesco , De Galitiis Federica , Testori Alessandro , Cognetti Francesco , Bernengo Maria Grazia , Savoia Paola , Guida Michele , Strippoli Sabino , Galli Luca , Mandala Mario , Parmiani Giorgio , Rinaldi Gaetana , Aglietta Massimo , Chiarion-Sileni Vanna 
Published: March 2020

9065 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Early clinical studies explored the potential relationship between immune-related adverse events (irAEs) associated with ipilimumab and antitumor activity but no definitive conclusion has been reached. Here, we evaluated the possible correlation between efficacy of ipilimumab treatment and irAEs in patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Pts were monitored for adverse events (AEs), including immune-related AEs (irAEs), using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to April 2012 across 55 centres. Among 833 evaluable pts, 278 pts (33.4%) reported an irAE and 555 (66.6%) did not. As of December 2012, the disease control rates among pts with or without irAEs were 35.3% and 33.9% respectively. We noted that there was a difference in the distribution of pts with or without irAEs among pts who experienced a fast progression, thus not being able to receive at least 3 cycles, and pts with slow progression. In fact, due to the mechanism of action of the drug and consequent delayed onset of irAEs, pts with irAEs among fast and slow progressors were 22% and 37% respectively. Therefore, median overall survival was evaluated by adjusting the 2 groups for this factor and results showed a comparable survival between pts who reported an irAE and pts who did not (10.0 vs 9.7 months respectively). Conclusions: This exploratory analysis of EAP data suggest that activity and efficacy of ipilimumab is not related with the occurrence of irAEs.
The clinical and biologic impact of PPP6C mutations in melanoma.
Authors: Gold Heidi L. , Wengrod Jordan , Tian Jiaying , Vega-Saenz de Miera Eleazar , Nadeem Zaineb , Fleming Nathaniel H. , Shapiro Richard , Hernando-Monge Eva , Gardner Lawrence , Osman Iman 
Published: March 2020

9067 Background: PP6C binds to regulatory units to affect a number of important pathways including cell proliferation and DNA repair. Recently two independent groups reported for the first time the presence of somatic mutations in the PPP6C gene in ~10% of short term cultures and limited number of human melanoma tissues. However, the clinical or biological relevance of PPP6C mutations in melanoma patients is unknown. Our objectives were to examine the clinical relevance of PPP6C mutations in a well characterized cohort of melanoma specimens linked to extensive, prospectively-collected clinical information and to explore the functional consequence of different categories of mutations. Methods: Sanger dideoxy sequencing was performed on PCR-amplified DNA from macro-dissected FFPE tumors. Associations between PPP6C mutations and baseline characteristics, recurrence, survival, and BRAF/ NRAS mutational status were examined. The impact of mutations on binding PP6C regulatory units was assessed as well as the effect on additional downstream pathways. Results: 308 primary melanoma patients (118 Stage I, 92 Stage II, and 98 Stage III) were examined (median follow up: 5.3 years). 50 PPP6C mutations in 33 patients (10.7%) were identified with 11 tumors harboring more than one mutation. One mutation (R301C) was identified in 6 patients. PPP6C mutations occurred with similar frequencies across stages and showed no association with BRAF or NRAS mutations. Mutations were categorized into 3 groups: Mutations resulting in premature stop codon (n=9), those occurring in the active site (n=16) and others (n=8). 8/9 (89%) patients with stop mutations recurred and developed visceral metastases. Functional studies revealed that PPP6C mutants also behaved differently; some PPP6C mutations led to decreased binding to regulatory subunits, others, including the R301C mutation did not. Conclusions: Our data suggest that PPP6C mutation is an early event in melanoma progression and independent of BRAF or NRAS mutations. Data also suggest different biologic and clinical impact of PPP6C mutations, with stop mutations showing association with development of visceral metastases that requires further clinical and functional study.
Personal melanoma risk awareness versus intrinsic risk.
Authors: Robert Caroline , Lebbé Céleste , Ricard Sevrine , Saiag Philippe , Grange Florent , Mortier Laurent , Lhomel Christine , Sassolas Bruno 
Published: March 2020

9069 Background: Intrinsic risk factors for melanoma include personal and family history of the condition, a high number of naevi and a light skin phototype (I or II). The objective of this study was to evaluate the correlation between personal awareness of melanoma risk and objective risk factors and to analyze the elements associated with under-or over-evaluation of the actual risk. Methods: EDIFICE melanoma, a nationwide French observational survey, was conducted through phone interviews on a representative sample of 1502 subjects aged ≥ 18 using typical quotas. The survey took place from 28th Sept 2011 to 20th Oct 2011. Results: 393 subjects (26%) had at least one melanoma risk factor: personal: 1%; family history: 11%; high number of naevi: 8% and phototype I-II: 11%. 1109 (74%) had no risk factor. 1029 (73%) had a correct perception of their risk level, 135 (10%) overestimated their risk and 241 (17%) underestimated it. Compared to the control group (correct perception), the population overestimating the melanoma risk is characterised by a higher percentage of individuals living alone (32% vs. 24%, p<0.05), socio-professional category + (38% vs. 28%, p<0.01) and greater alcohol consumption (45% vs. 34%, p<0.02). They are also more likely to expose themselves to the sun (89% vs. 78%, p<0.004) and less likely to use sunscreen protection (58% vs. 44%, p<0.003). A greater proportion of them participates in melanoma screening programmes (21% vs. 14%, p<0.04). The population that underestimates the risk is characterised by lower educational attainment (11% vs. 7%, p<0.05), greater use of high SPF sunscreen (41% vs. 29%, p<0.0004) and a more frequent use of UV sunbeds (9% vs. 6%, p<0.06). Conclusions: Overall, the French have a fair perception of their personal likelihood of developing melanoma. Interestingly, subjects overestimating their intrinsic risk do not behave appropriately with respect to sun protection measures (more sun exposure and less sunscreen protection). On the other hand, subjects underestimating their risk use UV sunbeds more extensively.
Italian cohort of ipilimumab expanded access programme (EAP): Efficacy, safety, and correlation with mutation status in metastatic melanoma patients.
Authors: Queirolo Paola , Spagnolo Francesco , Altomonte Maresa , Chiarion-Sileni Vanna , Pigozzo Jacopo , Del Vecchio Michele , Di Guardo Lorenza , Ridolfi Ruggero , Scoppola Alessandro , Ferrucci Pier Francesco , Ferraresi Virginia , Bernengo Maria Grazia , Guida Michele , Marconcini Riccardo , Mandalà Mario , Parmiani Giorgio , Rinaldi Gaetana , Aglietta Massimo , Simeone Ester , Ascierto Paolo Antonio 
Published: March 2020

9070 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma to show a survival benefit in randomised phase III trials. Efficacy and safety of ipilimumab treatment outside of clinical trials and the correlation with BRAF and NRAS mutation status were evaluated. Methods: Ipilimumab was available upon physician request for patients (pts) aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. BRAF and NRAS mutation status was retrospectively collected for all available pts. Patients were monitored for adverse events, including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. With a median follow-up of 6.5 months (range 0.5-30), the disease control rate among 833 pts evaluable for response was 34.3%: 28 pts (3.4%) with complete response, 83 (10.0%) with partial response and 175 (20.9%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.3 months and 7.2 months respectively, with 1-year survival rate of 36%. The Table shows mutation status for available patients. Disease control rates were comparable among pts with BRAF positive tumors and BRAF wild-type (37.5% vs 39.5%) and among pts with NRAS positive tumors and NRAS wild-type (57.1% vs 49.3%). Survival curves were also comparable between groups. 399 pts (46.7%) had a AEs of any grade, with 286 (33.5%) considered IrAEs. IrAEs were reversible with protocol specific guidelines. Conclusions: Based on EAP data, ipilimumab is an effective and safe treatment for pretreated pts with metastatic melanoma regardless BRAF and NRAS mutation status. [Table: see text]
Dissection of anti-CTLA4-induced cytotoxic T-cell responses in melanoma.
Authors: Haanen John B. A. G. , Kvistborg Pia , Philips Daisy , Kelderman Sander , Heemskerk Bianca , Ottensmeier Christian , Speiser Daniel E , Michielin Olivier Alain , Romano Emanuela , Blank Christian U. , Schumacher Ton 
Published: March 2020

9078 Background: There is strong evidence that melanoma-reactive T cells induced by immunotherapeutic interventions such as anti-CTLA4 therapy can exert clinically effects. However, there is very little information on how these therapies influence tumor-specific T cell responses. Furthermore, as the number of potential melanoma-associated antigens to which these responses can be directed is very high, classical strategies to map cytotoxic T cell reactivity do not suffice. Knowledge of such reactivities would be useful to design targeted strategies, selectively aiming to induce immune reactivity against these antigens. Methods: We have addressed these issues by designing MHC class I molecules occupied with UV-sensitive ‘conditional’ ligands, thereby allowing the production of very large collections of pMHC complexes for T cell detection. Secondly, we have developed a ‘combinatorial coding’ strategy that allows parallel detection of dozens of different T cell populations within a single sample. The combined use of MHC ligand exchange and combinatorial coding allows the high-throughput dissection of disease- and therapy-induced CTL immunity. We have used this platform to monitor immune reactivity against a panel of 145 melanoma-associated epitopes in patients receiving Ipilimumab treatment. Results: Comparison of PBMC samples from 32 melanoma patients pre- and post-therapy indicated a significant increase in the number of detectable melanoma-associated T cell responses (p=0.004). Furthermore, kinetic data on T cell responses during therapy suggests that this broadening generally occurs within weeks after start of therapy. The magnitude of melanoma-specific T cell responses that was detectable prior to start of therapy was not significantly altered (p=0.8). Conclusions: These results establish the pattern of melanoma-specific T-cell reactivity induced by anti-CTLA4 treatment and form a benchmark for evaluation of other immunotherapeutic interventions, like anti-PD1 treatment, that are currently undergoing clinical evaluation. Furthermore, our data suggests that the clinical activity of Ipilimumab may be mostly due to epitope spreading, rather than through enhancement of pre-existing immune activity.