tbuckley/cabot-search huggingface dataset:
Gene signature to predict hypophysitis in patients with melanoma treated with anti-PD-1 in adjuvant setting.
Authors: Ester Simeone, Domenico Mallardo, Lucia Festino, Vito Vanella, Claudia Trojaniello, Maria Grazia Vitale, Margaret Ottaviano, Francesca Sparano, Bianca Arianna Facchini, Eleonora Cioli, Antonio Isaja, Corrado Caraco, Paolo Antonio Ascierto
Journal: Journal of Clinical Oncology (2024)

e21562 Background: Adjuvant anti-PD-1 treatment has shown to improve recurrence free survival and distant metastases free survival in melanoma patients from stage II to IV. Until now ,we have no data about overall survival of these patients nor biomarkers to select them to the best therapy , avoiding in this way severe and some times durable toxicities.Hypophysitis is a rare immune-related adverse event (irAE) and in adjuvant setting may represent a chronic irAE that may affect quality of life , such as fertility in young people.There are no clinical factors able to predict hypophysitis due to adjuvant anti-PD-1 therapy. Methods: Gene profiling analysis was performed using NanoString IO360 panel from basal PBMCs of patients treated with anti-PD1 in adjuvant setting. Patient’s characteristics are reported in table1. ROC curves were used to determine the best cut off. Survival rates were evaluated and compared using the Kaplan–Meier method. Results: Eighty pts treated with adjuvant anti-PD-1were included in a retrospective analysis from December 2019 to September 2021. Among which 12 pts developed hyphosytis. Ten pts completed treatment regularly, while two were discontinued both at week 12 due to metastatic disease. A pts developed liver metastases, the other one liver, multiple lymph nodes and soft tissues metastases. Grade 2 hypophysitis was diagnosed as the only irAE in all pts (100%). Median time of onset was 3 months (9 pts ≤6 months and 7 pts ≤3 months). A specific gene signature for predicting the onset of hypophysitis has been identified and characterized with 4 genes: IFITM2,CTSS,DUSP1,HLA-B that are mainly involved in the activation of innate-like lymphocyte populations, such as natural killer (NK) cells and innate lymphoid cells (ILCs), and adaptive immune cells, such as T helper 1 (T H 1) cells and CD8 + cytotoxic T lymphocytes (CTLs). High gene signature was mostly related to hypophysitis event than lower group (HR: 0.11 95%IC 0.03-0.39, p = 0,0007). Moreover, at data lock all pts who developed hypophysitis were censored with mean overall survival of 35.60 months, 95%CI 30,86-40, 41. Conclusions: A predictive gene signature of hypophysitis was found in melanoma patients treated with adjuvant anti-PD1.Moreover, hypophysitis seems to correlate to better outcome. [Table: see text]
CD44 and CD271 expression and chemoresistance in BRAF V600E/K mutation–positive melanoma.
Authors: Erin Hyde, Madison J Reed, Robert W. Baer
Journal: Journal of Clinical Oncology (2024)

e21542 Background: Melanoma stem cells (MSC) are thought to play a role in cellular proliferation, migration, and chemotherapeutic resistance. We investigated native expression of several putative MSC biomarkers in human BRAF V600E/K mutation positive melanoma cell lines of different phases—radial growth phase (WM35), vertical growth phase (WM278)—and metastatic (LM-Mel-45, LM-Mel-71) cell lines. We examined cell viability of select cell subpopulations during in vitro treatment with BRAF and MEK inhibitor monotherapy and combination therapy. Methods: Using flow cytometry, we assessed surface expression of putative MSC biomarkers: CD44, CD271, CD133, CD186, and CD20. We sorted each cell line by CD44 and CD271 expression with a predetermined hierarchical gating strategy and compared 4 chemotherapy conditions: control, BRAF inhibition with 1.25 µM dabrafenib, MEK inhibition with 0.125 µM trametinib, and combination therapy. Cells (25,000) were collected directly into chemotherapy treated media and incubated for 72 hours. Cell viability was measured by MTT assay. Statistical analysis used mixed-effects ANOVA and Tukey HSD. Results: No significant expression of CD133, CD186, or CD20 was found in any cell line. Over 99% of live cells were CD44+ in all 4 cell lines. Only WM35 and LM-Mel-71 had both CD44+/CD271+ and CD44+/CD271- subpopulations. CD271 expression was restricted to CD44+ cells. Among live cells, the CD44+/CD271+ subpopulation was 31.2% for WM35 and 14.4% for LM-Mel-71. For WM35, cell viability in CD44+/CD271+ cells was greater than CD44+/CD271- cells for all treatments (p &lt; 0.001). For LM-Mel-71 cells, CD271 expression did not affect cell viability within any treatment (p = 0.64). For chemotherapeutic treatments, cell viability in CD44+/CD271- subpopulation was higher in LM-Mel-45 cells than WM278 (p &lt; 0.03) or LM-Mel-71 (p &lt; 0.002), but not WM35 cells (p &gt; 0.05). Trametinib monotherapy and combination therapy had similar cell viability in all 4 cell lines (p &gt; 0.05). Conclusions: To our knowledge, our study is the first to show differences in phenotypic expression of CD44 and CD271 across nonmetastatic and metastatic melanoma cell lines and suggests co-expression of CD44 and CD271 confers increased chemotherapeutic resistance to in vitro BRAF and MEK inhibitor treatment in radial growth phase but not metastatic melanoma. More research is needed to better understand the role of CD44 and CD271 co-expression in melanoma initiation, progression, and chemotherapeutic resistance. CD271 remains a potential immunotherapeutic drug target in the treatment of BRAF V600E/K mutation positive melanoma.
RNA expression-based risk stratification of stage III cutaneous melanoma.
Authors: Donghyun Kim, Yeonhwa Yu
Journal: Journal of Clinical Oncology (2024)

e21551 Background: Prognostication of locally advanced cutaneous melanoma (CM) relies on accurate assessment of primary tumor invasion depth and extent of lymph node involvement. However, precision is often limited by detection limits of positron emission computed tomography and sentinel lymph node biopsy, and the estimated disease-specific survival (DSS) can vary widely. In this study, we explored tumor gene expression-based risk stratification strategies and found that CDH1 (E-cadherin) and BRAF transcript level profiles can predict DSS in stage III CM. Methods: The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) project’s normalized RNA-Seq transcriptome profile (n = 288) was analyzed with MATLAB software. TCGA-SKCM adopted AJCC 7 th edition staging. "High” or “low” level of each gene was determined by the median FPKM of the cohort used as cutoff. P-values were obtained from Cox proportional hazards regression model. Results: In stage III (n = 96), 3-year DSS for high- and low-CDH1 groups were 45% and 75%, respectively (p = 1.5x10 -5 ). High-BRAF group was weakly associated with superior 3-year DSS compared to low-BRAF group (75% vs. 55%; p = 0.06), although high-BRAF group was composed of more BRAF hotspot mutants compared to low-BRAF group (56% vs. 30%). The 3-year DSS for high-CDH1/low-BRAF and low-CDH1/high-BRAF groups were 28% and 84%, respectively (p = 4.4x10 -5 ). Composition of stages [IIIA, IIIB, IIIC, IIINOS] in high-CDH1/low-BRAF and low-CDH1/high-BRAF groups were [5%, 18%, 45%, 32%] and [23%, 13%, 37%, 27%], respectively. For high-CDH1/high-BRAF group, 3-year DSS was 54% with stage composition [6%, 33%, 39%, 22%]. DSS was not associated with CDH1/BRAF levels in stage I and II. Stage IV was not analyzed due to the small sample size. Conclusions: We demonstrate CDH1/BRAF transcript level-based prognostication of CM cases with regional metastasis (metastatic node, in-transit or satellite metastasis) defined as stage III. Our findings are contrary to the notion that CDH1 is a tumor/invasion suppressor gene, although we note the emerging evidence that CDH1 expression boosts establishment of cancer at a secondary site once they escape from the primary site 1) . The association between high BRAF level and superior survival may also seem counterintuitive given the well-accepted oncogenicity of activating BRAF mutations in variety of malignancies. However, we speculate that wild-type and oncogenic BRAF, which RNA-Seq cannot easily differentiate, may play independent roles in tumorigenesis similar to what has been previously reported in wild-type and oncogenic RAS 2) . References: 1) Padmanaban, et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019 Sep;573(7774):439-444 2) Young, et al. Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. Cancer Discov. 2013 Jan;3(1):112-23.
Temozolomide and nivolumab in patients with refractory metastatic melanoma (MM).
Authors: Jessica Quintos, Sophie Schellhammer, Kristin Kathleen Ancell, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2024)

e21521 Background: Immune checkpoint inhibitors (ICI) are the standard treatment for patients (pts) with MM. However, only a subset of pts respond to ICIs. Temozolomide (TEM) is used in refractory settings but with low objective response rates and no clear overall survival benefit. The efficacy of combined ICI + TEM is not well described. Methods: This was a single center, retrospective study of pts with MM who received treatment with nivolumab (NIVO) and TEM or TEM alone between 11/6/2013 and 11/6/2023. Demographic information, disease characteristics, LDH, treatment, toxicity, objective response, and outcomes were collected. Results: 34 patients were included. 16 were treated with NIVO + TEM and 18 were treated with TEM alone. In the NIVO + TEM group, 81% were male (n = 13) with median age of 59.5 years (range 20-79), and in the TEM group, 56% were male with median age 61 (range 35-81). For NIVO + TEM, 31% had partial response (PR; n = 5), 6% had stable disease (SD, n = 1), and 63% had progressive disease (PD; n = 10). For TEM, 11% had PR (n = 2), 22% had SD (n = 4), and 67% had PD (n = 12) (p = 0.37). For NIVO + TEM, 2 PRs were durable, ongoing at 442 and 741 days; 3 PRs were transient (85-179 days); 1 pt had durable SD ongoing at 201 days. For TEM, PR durations were 173 and 504 days, and SD durations between 213-435 days. Five pts with PD treated with NIVO + TEM had mixed responses (31%) compared with 1 pt treated with TEM (6%). Median progression free survival (PFS) was 80 days (range 11-748) for NIVO + TEM and 55.5 days (7-415) for TEM (p = 0.31). Median overall survival (OS) was 160 days (43-363) for NIVO + TEM and 118 days (7-1938) for TEM (p = 0.15). There were 26 adverse events (AEs) for NIVO + TEM (27% grade 1, 42% grade 2, 19% grade 3, and 12% grade 4; thrombocytopenia and pneumonitis), and 25 AEs for TEM (40% grade 1, 40% grade 2, 12% grade 3, and 8% grade 4; thrombocytopenia) [p = 0.64]. Conclusions: NIVO + TEM occasionally produced durable responses, although outcome metrics were not clearly superior to TEM alone in this small study. Further studies should quantify the benefit of ICI + chemotherapy regimens in refractory MM. [Table: see text]
Sex as a predictor of progression-free survival in sentinel node-negative stage II melanoma.
Authors: George Adigbli, Fadi Issa, Oliver Cassell
Journal: Journal of Clinical Oncology (2024)

e21560 Background: Adjuvant immunotherapy can improve outcomes for resected stage IIB/C melanoma patients, but also poses challenges. Many patients are cured by surgery alone, making them susceptible to unnecessary treatment risks. Additionally, current staging may overlook some high-risk stage IIA patients who could benefit from immunotherapy. Accurate risk assessment is therefore critical to balance benefits and risks of early immunotherapy and optimise patient selection. This study sought to identify clinicopathologic predictors to refine risk stratification for sentinel lymph node-negative (SLN(-)) stage II melanoma patients, with a focus on the role of sex in prognostic accuracy and treatment personalisation. Methods: We retrospectively analysed 565 stage II melanoma patients with negative sentinel lymph node biopsies at four UK hospitals between 2004-2017. The primary outcome was progression-free survival (PFS). Analysed clinicopathologic factors included Breslow thickness, ulceration sex and tumour-infiltrating lymphocytes (TILs). Univariate and multivariate analyses were conducted. Results: Median follow-up was 9.5 years. Melanoma progression occurred in 24% of patients. Sex emerged as a significant PFS predictor. Specifically, stage IIA and IIB males had higher progression risks than females at the same stages. We also observed disparities across stages; for instance, PFS was significantly worse in stage IIA males than stage IIB females (PFS difference: χ2 = 5.629, p = 0.018), revealing gaps in the prognostic accuracy of current staging systems. Stage IIB females—identified as at risk by current standards—had 5-year PFS of 91%. This highlights potential overestimation of their treatment needs and subsequent risk of undue exposure to treatment toxicity. The sex-based discrepancies observed may be partially explained by differences in antitumor immune function, evidenced by the discovery that Non-brisk TILs-an independent predictor of high progression risk in SLN(-) stage II melanoma- were associated with a 20% reduction in PFS in males vs females (p &lt; 0.001). Conclusions: Significant sex-based PFS disparities exist among sentinel lymph node-negative stage II melanoma patients, with implications for treatment decisions. Incorporating sex enables more refined risk assessment than current substaging alone. Specifically, stage IIA males may be under-recognised for progression risks, while many stage IIB females could face overtreatment. Our findings advocate for nuanced, sex-specific approaches to enhance prognostic accuracy and optimise patient care.
Use of early circulating tumour DNA dynamics in patients with stage III melanoma receiving neoadjuvant combination immunotherapy.
Authors: Wei Yen Chan, Jenny Lee, Ashleigh Stewart, Russell J. Diefenbach, Maria Gonzalez, Alexander M. Menzies, Christian U. Blank, Richard A Scolyer, Georgina V. Long, Helen Rizos
Journal: Journal of Clinical Oncology (2024)

9577 Background: Neoadjuvant therapy in resectable stage III cutaneous melanoma improves relapse-free survival compared to adjuvant therapy alone and is now a standard of care.While pathological response can help predict recurrence risk and the need for further treatment, more biomarkers are required. We investigated circulating tumour DNA (ctDNA) as a predictive biomarker for recurrence in stage IIIB/C melanoma patients following neoadjuvant immunotherapy and surgery. Methods: We retrospectively analysed plasma samples collected at baseline and six weeks post-surgery from 30 patients enrolled in the OpACIN-neo and PRADO clinical trials, who received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent pre-amplification followed by tumour-informed mutation detection analysis using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system. BRAF mutations were identified in 60% of patients through tumour tissue sequencing. Following neoadjuvant therapy, 7/30 (23%) achieved complete pathological response (pCR), 5/30 (17%) near pCR, 4/30 (13%) partial response, and 14/30 (47%) non-response (pNR). Results: Baseline ctDNA was detectable in 15/30 (50%) patients using the pre-amplification ddPCR method. At median follow-up of 47 months, 9/30 (30%) patients recurred, with a median time to recurrence of 8 months (range 6 to 29 months). Post-surgery, ctDNA was detectable in 4/9 patients who recurred; all four were pathological non-responders and recurred with distant, unresectable disease. Among the 15 ctDNA-positive patients at baseline, 13/15 (87%) patients achieved ctDNA clearance while 2/15 (13%) remained persistently ctDNA-positive; with a subsequent relapse rate of 0% and 100% respectively. ctDNA detection post-surgery predicted patients at higher risk of disease recurrence [relapse-free survival (RFS) hazard ratio (HR) 7.83, 95%CI 0.82-74.48; p=0.0002] and poorer melanoma-specific survival (MSS) [HR 6.35, 95% CI 0.36-110.70; p=0.0337]. Conclusions: Post-surgery ctDNA positivity can signal imminent recurrence, thus offering a window for personalised adjuvant therapy modification.
Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years.
Authors: Hussein A. Tawbi, F. Stephen Hodi, Evan J. Lipson, Dirk Schadendorf, Paolo Antonio Ascierto, Luis Matamala, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen Gogas, Christopher D. Lao, Juliana Menezes, Stéphane Dalle, Ana Maria Arance, Jean-Jacques Grob, Barbara Ratto, Saima Rodriguez, Antonella Mazzei, Sonia Dolfi, Georgina V. Long
Journal: Journal of Clinical Oncology (2024)

9524 Background: NIVO + RELA as a fixed-dose combination (FDC) demonstrated a statistically significant progression-free survival (PFS) benefit vs NIVO in RELATIVITY-047 (NCT03470922), with a clinically meaningful, but not statistically significant, improvement in OS and a numerically higher objective response rate (ORR), resulting in regulatory approval of the FDC. Here we report updated descriptive analyses with 3 years of follow-up. Methods: Patients (pts) were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg Q4W. PFS per RECIST v1.1 was assessed by blinded independent central review (BICR); secondary endpoints included OS and ORR per BICR. Exploratory analyses included MSS (death due to melanoma, with censoring of deaths due to other causes), CNS metastasis-free survival in specified populations, and efficacy on subsequent systemic therapy. Results: At database lock (19 Oct 2023), median follow-up was 33.8 months (mo; range, 0.3–64.2). NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS (Table). NIVO + RELA was also favored over NIVO across the majority of key subgroups. Subsequent systemic therapy was received by 135 pts (38%) on NIVO + RELA and 141 pts (39%) on NIVO. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 78 pts (22%) on NIVO + RELA and 43 pts (12%) on NIVO; TRAEs (any grade) led to treatment discontinuation in 63 pts (18%) and 35 pts (10%), respectively. No new treatment-related deaths were reported since the last analysis. Conclusions: At 3 years of follow-up, NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS. OS and MSS demonstrated sustained improvement, with the OS HR 95% CI upper bound &lt; 1. Efficacy results also continued to favor NIVO + RELA vs NIVO across the majority of prespecified subgroups. Safety of NIVO + RELA remained consistent with previous reports, with no new or unexpected safety signals. CNS metastasis-free survival and efficacy outcomes on subsequent systemic therapy will be presented. Clinical trial information: NCT03470922 . [Table: see text]
Identifying the high risk group in stage pT1bN0 cutaneous melanoma.
Authors: Pawel Teterycz, Tatsiana Sryukina, Agnieszka Kluz, Anna Ziobro, Jacek Skoczylas, Marcin Zdzienicki, Piotr Rutkowski
Journal: Journal of Clinical Oncology (2024)

9583 Background: In recent years, there has been a substantial improvement in prognosis for patients diagnosed with stage II or III melanoma due to the advent of adjuvant and neoadjuvant therapy. At the same time, significant percentage of melanoma deaths are caused by prevalent cases of thin melanoma. In this work, we aimed to identify the stage pT1bN0 melanoma subgroup with the worst prognosis. Methods: All cases of stage pT1b melanoma (with negative sentinel node biopsy) treated between 1998 and 2022 in high-throughput reference center were analyzed. Patients were followed for ten years or up to lost to follow-up or death. Patients alive at 10 year mark were censored. The patients were divided into groups with BOTH pT1b features (i.e., Breslow thickness &gt; 0.8mm AND ulceration) vs those with just ONE of those features. Additionally, patients’ sex, the tumor’s pathological subtype, and mitotic index were analyzed. The Kaplan-Meier and the Cox proportional model were used in statistical analysis. Results: There were 665 cases identified. 63% of patients were female, median age was 49 (IQR: 38-60). 70% of patients were classified as pT1b due to Breslow thickness, 21% due to ulceration and 9% due to BOTH features. 48% of patients had superficially spreading melanoma, 3% - acral, 9% - nodular while other patients had other/unspecified subtype. The median mitotic index was 1/mm2, but this feature was missing in 46% of cases. Overall, 61 patients died during the follow-up. The 10-year overall survival (OS) rate for the whole group was 86% (95% CI: 83-90%). In a multivariable model, patients with BOTH IB features (HR 2.1, 95%CI:1.1-4.2), nodular or acral melanoma (HR 2.2, 95%CI:1.2-4.1) and males (HR 2.6, 95%CI:1.6-4.4) had worse prognosis; the mitotic index was not predictive for OS in this model. In patients with BOTH pT1b features the 10 year survival rate was 75% (95%CI: 62-89) and 87% (95%CI: 84-91%) in case of just one feature (log-rank p=0.008). Conclusions: There is a specific subgroup of patients diagnosed with stage IB who have a relatively bad prognosis. Focusing on perioperative treatment or on a more strict follow-up schedule in this group may prove beneficial.