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Clinical validation of droplet digital PCR assays in detecting BRAFV600-mutant circulating tumour DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomised phase 3 trial
Syeda, Mahrukh M; Long, Georgina V; Garrett, James; Atkinson, Victoria; Santinami, Mario; Schadendorf, Dirk; Hauschild, Axel; Millward, Michael; Mandala, Mario; Chiarion-Sileni, Vanna; Smylie, Michael; Manikhas, Georgy M; Dummer, Reinhard; Wiggins, Jennifer M; Ali, Saim; Adnaik, Sachin Bajirao; Tan, Monique; Dajee, Maya; Polsky, David
BACKGROUND:Cell-free, circulating tumour DNA (ctDNA) is an established measure of minimal residual disease; however, it is not utilised in melanoma management. We investigated whether ctDNA measurements could predict survival outcomes during adjuvant targeted therapy or placebo treatment in stage III melanoma, thereby identifying patients at high risk and low risk of recurrence. METHODS:-mutant stage III melanoma. Patients were screened for enrolment between Jan 31, 2013, and Dec 11, 2014, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and were randomly assigned (1:1) to the two treatment groups. The primary endpoint was recurrence-free survival, and the results from final analysis have been previously published and will not be described here. Biomarker analysis was a prespecified exploratory endpoint and performed in the intention-to-treat population. We compared associations between survival outcomes and baseline (post-resection) ctDNA copies per mL, tumour mutational burden and interferon gamma (IFNG) gene expression. In a subset of patients, ctDNA quantities during follow-up or at recurrence were measured. The trial is registered with ClinicalTrials.gov, NCT01682083, and has been completed. FINDINGS/RESULTS:Baseline plasma samples were available for 597 of 870 patients (331 male patients and 266 female patients) and samples for assessing the ctDNA positivity rate at landmark follow-up timepoints of 3 months, 6 months, 9 months, and 12 months after treatment initiation were available for 94 of 870 patients. Additionally, samples were available from 118 of 870 patients within a 2-month timeframe before or after clinical or radiographic recurrence. Median follow-up for the biomarker analyses was 60 months (IQR 39-66) in the combination therapy group and 58 months (21-66) for the placebo group. ctDNA was detectable in 79 (13%) of 597 baseline samples. ctDNA positivity rate and mutant copies per mL plasma were significantly higher in patients with higher disease substages. As a binary variable, ctDNA detection was associated with worse recurrence-free survival (placebo group: median 3·71 months [95% CI 2·39-6·89] vs 24·41 months [17·28-43·13]; hazard ratio [HR] 2·91 [95% CI 1·99-4·25], p<0·0001); combination therapy group: median 16·59 months [95% CI 12·02-26·80] vs 68·11 months [50·36-not reached]; HR 2·98 [1·95-4·54], p<0·0001) and overall survival (placebo group: median 33·90 months [13·96-not reached] vs not reached; HR 3·35 [2·01-5·55], p<0·0001); combination therapy group: median 40·31 months [24·90-not reached] vs not reached; HR 4·27 [2·50-7·27], p<0·0001) in the placebo group and combination therapy groups. Baseline ctDNA was more strongly associated with survival outcomes than IFNG gene expression or tumour mutational burden. Patients with adverse longitudinal ctDNA kinetics (molecular relapse or persistently positive) had markedly shorter median recurrence-free survival (8·31 months [95% CI 5·39-12·20] and 5·32 months [2·79-not reached], respectively) compared with patients with favourable kinetics (ie, undetectable after positive baseline result: 19·25 months [16·39-not reached]; and durable undetectable: not reached [38·44-not reached], p<0·0001). INTERPRETATION/CONCLUSIONS:Droplet digital PCR measurements of ctDNA to assess minimal residual disease before adjuvant targeted therapy and during follow-up can identify patients at high risk of early recurrence. Additional studies using ctDNA measurements to guide therapeutic interventions might lead to improvements in the management of resected stage III melanoma. FUNDING/BACKGROUND:Novartis.
PMID: 40250457
ISSN: 1474-5488
CID: 5829102
Recent Developments in Targeting the Cell Cycle in Melanoma
Hung, Christie; Nguyen, Trang T T; Poulikakos, Poulikos I; Polsky, David
Melanoma is an aggressive cancer with rising incidence, particularly among older individuals. Despite advancements in targeted therapies for BRAF and MEK proteins and immunotherapies, many patients either fail to respond or develop resistance. For those progressing on immunotherapy, limited treatment options remain. The Cyclin D-CDK4/6-RB pathway is commonly dysregulated in melanoma, with up to 90% of cases showing alterations that activate it. Although targeting Cyclin-CDK complexes has shown promise in preclinical models, clinical responses have been suboptimal. This review explores the molecular mechanisms behind Cyclin-CDK dysregulation in melanoma and the challenges of targeting this pathway. It also discusses strategies to improve the efficacy of CDK4/6 inhibitors, including combination therapies to overcome resistance and enhance patient outcomes. Understanding these mechanisms can guide the development of more effective treatments for melanoma.
PMID: 40282469
ISSN: 2072-6694
CID: 5830832
SpotCheck: A Skin Cancer Diagnostic Accuracy Study Comparing Teledermoscopy with and without Electrical Impedance Spectroscopy to In-Person Dermatologist Evaluation of Patient-Identified Lesions Concerning them for Skin Cancer
Ingrassia, Jenne P; Bajaj, Shirin; Kolla, Avani; Li, Vivienne; Shah, Payal; Gulati, Nicholas; Criscito, Maressa C; Xing, Yiping; Lopez, Adriana; Tran, Duy C; Ramachandran, Vignesh; Kakpovbia, Efe; Meehan, Shane; Shao, Yongzhao; Lo Sicco, Kristen; Milam, Emily C; Bieber, Amy K; Levine, Amanda; Liebman, Tracey N; Stein, Jennifer A; Polsky, David
PMID: 39528165
ISSN: 1097-6787
CID: 5752722
Dermoscopic Features of Ethnic Acral Melanosis in Fitzpatrick Skin Types IV-VI
Rodriguez, Elijah; Sher, Elizabeth F; Juarez, Michelle; Polsky, David; Johnson, James; Stein, Jennifer A; Adotama, Prince
PMID: 39937665
ISSN: 1365-2230
CID: 5793572
Association of MC1R variants with melanoma risk and interaction with sun exposure: An M-SKIP project [Letter]
Stefanaki, Irene; D'Ecclesiis, Oriana; Vignati, Silvano; Gaeta, Aurora; Kypreou, Katerina; Caini, Saverio; Gandini, Sara; Nagore, Eduardo; Sera, Francesco; Botta, Francesca; Newton-Bishop, Julia; Polsky, David; Lazovich, DeAnn; Kanetsky, Peter A; Puig, Susana; Gruis, Nelleke A; Landi, Maria Teresa; Fargnoli, Maria Concetta; Stratigos, Alexander; Guida, Gabriella; Ghiorzo, Paola; Menin, Chiara; GarcÃa-Borrón, José C; Little, Julian; Nan, Hongmei; Raimondi, Sara; ,
PMID: 39425518
ISSN: 1468-3083
CID: 5718982
Evaluating the support of pigmented lesion expert dermatologists for the use of skin self-examinations [Letter]
Ingrassia, Jenne P; Swearingen, Alyssa; Levine, Amanda; Liebman, Tracey N; Stein, Jennifer A; Polsky, David; Adotama, Prince
PMID: 39133325
ISSN: 1432-069x
CID: 5697102
Cutaneous Melanoma Incidence - Evidence of a Flattening Curve
Berk-Krauss, Juliana; Sharma, Medha; Polsky, David; Geller, Alan C
PMID: 38086518
ISSN: 1097-6787
CID: 5589212
Re-examining melanoma secondary prevention and the role of skin self-examination
Ingrassia, Jenne P; Adotama, Prince; Stein, Jennifer A; Polsky, David
PMID: 37385450
ISSN: 1097-6787
CID: 5540512
Human TLR8 induces inflammatory bone marrow erythromyeloblastic islands and anemia in SLE-prone mice
Maria, Naomi I; Papoin, Julien; Raparia, Chirag; Sun, Zeguo; Josselsohn, Rachel; Lu, Ailing; Katerji, Hani; Syeda, Mahrukh M; Polsky, David; Paulson, Robert; Kalfa, Theodosia; Barnes, Betsy J; Zhang, Weijia; Blanc, Lionel; Davidson, Anne
Anemia commonly occurs in systemic lupus erythematosus, a disease characterized by innate immune activation by nucleic acids. Overactivation of cytoplasmic sensors by self-DNA or RNA can cause erythroid cell death, while sparing other hematopoietic cell lineages. Whereas chronic inflammation is involved in this mechanism, less is known about the impact of systemic lupus erythematosus on the BM erythropoietic niche. We discovered that expression of the endosomal ssRNA sensor human TLR8 induces fatal anemia in Sle1.Yaa lupus mice. We observed that anemia was associated with a decrease in erythromyeloblastic islands and a block in differentiation at the CFU-E to proerythroblast transition in the BM. Single-cell RNAseq analyses of isolated BM erythromyeloblastic islands from human TLR8-expressing mice revealed that genes associated with essential central macrophage functions including adhesion and provision of nutrients were down-regulated. Although compensatory stress erythropoiesis occurred in the spleen, red blood cell half-life decreased because of hemophagocytosis. These data implicate the endosomal RNA sensor TLR8 as an additional innate receptor whose overactivation causes acquired failure of erythropoiesis via myeloid cell dysregulation.
PMCID:10372407
PMID: 37495396
ISSN: 2575-1077
CID: 5592342
Early Detection and Prognostic Assessment of Cutaneous Melanoma: Consensus on Optimal Practice and the Role of Gene Expression Profile Testing
Kashani-Sabet, Mohammed; Leachman, Sancy A; Stein, Jennifer A; Arbiser, Jack L; Berry, Elizabeth G; Celebi, Julide T; Curiel-Lewandrowski, Clara; Ferris, Laura K; Grant-Kels, Jane M; Grossman, Douglas; Kulkarni, Rajan P; Marchetti, Michael A; Nelson, Kelly C; Polsky, David; Seiverling, Elizabeth V; Swetter, Susan M; Tsao, Hensin; Verdieck-Devlaeminck, Alexandra; Wei, Maria L; Bar, Anna; Bartlett, Edmund K; Bolognia, Jean L; Bowles, Tawnya L; Cha, Kelly B; Chu, Emily Y; Hartman, Rebecca I; Hawryluk, Elena B; Jampel, Risa M; Karapetyan, Lilit; Kheterpal, Meenal; Lawson, David H; Leming, Philip D; Liebman, Tracey N; Ming, Michael E; Sahni, Debjani; Savory, Stephanie A; Shaikh, Saba S; Sober, Arthur J; Sondak, Vernon K; Spaccarelli, Natalie; Usatine, Richard P; Venna, Suraj; Kirkwood, John M
IMPORTANCE:Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. OBJECTIVE:To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM. EVIDENCE REVIEW:Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). FINDINGS:The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. CONCLUSIONS AND RELEVANCE:For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.
PMID: 36920356
ISSN: 2168-6084
CID: 5502422