Faculty Bibliography

IMPORTANCE/UNASSIGNED:There exists substantial heterogeneity in outcomes within T stages for patients with cutaneous squamous cell carcinoma (cSCC). OBJECTIVE/UNASSIGNED:To determine whether a customized generative pretrained transformer model, trained on a comprehensive dataset with more than 1 trillion parameters and equipped with relevant focused context and retrieval augmented generation (RAG), could excel in aggregating and interpreting vast quantities of data to develop a novel class-based risk stratification system that outperforms the current standards. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:To build the RAG knowledge base, a systematic review of the literature was conducted that addressed risk factors for poor outcomes in cSCC. Using the RAG-enabled generative pretrained transformer (GPT) model, we developed a novel class-based risk stratification system that assigned point values for risk factors, culminating in a GPT-based prognostication system called the artificial intelligence-derived risk score (AIRIS). The system's performance was validated on a combined prospective and retrospective cohort of 2379 primary cSCC tumors (1996-2023) with at least 36 months of follow-up, against Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer Staging Manual, eighth edition (AJCC8) systems in stratifying risk for locoregional recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). MAIN OUTCOMES AND MEASURES/UNASSIGNED:Performance metrics evaluated included distinctiveness, homogeneity, and monotonicity, as defined by the AJCC8, as well as sensitivity, specificity, positive predictive value, negative predictive value, accuracy, the area under the receiver operating characteristic curve, and concordance. RESULTS/UNASSIGNED:The median age at diagnosis was 73 (IQR, 64-81) years, with 38.5% female patients and 61.5% male patients. The AIRIS prognostication system demonstrated superior sensitivity across all outcomes (LR, 49.1%; NM, 73.7%; DM, 82.5%; and DSD, 72.2%) and the highest area under the receiver operating characteristic curve values (LR, 0.69; NM, 0.81; DM, 0.85; and DSD, 0.80), indicating significantly enhanced discriminative capability compared with the BWH and AJCC8 systems. While all systems were comparably distinctive, the AIRIS prognostication system consistently demonstrated the lowest proportion of tumors exhibiting poor outcomes in low-risk categories, suggesting its improved homogeneity and monotonicity. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The results of this diagnostic study suggest that the AIRIS system outperforms the existing BWH and AJCC8 prognostication systems, potentially providing a more effective tool for predicting poor outcomes in cSCC. This study illustrates the potential of large language models in refining prognostic tools, offering implications for treating patients with cancer.

Targeted therapies and immunotherapy have improved treatment outcomes for many melanoma patients. However, patients whose melanomas harbor driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene often lack effective targeted treatment options when their tumors do not respond to immunotherapy. In this study, we utilized patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could inform the development of therapies for patients with NF1 mutant melanoma. Differential gene expression analysis revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, where it hyper-activates ERK and AKT, leading to increased tumor cell proliferation, survival, and growth. In contrast, genetic or pharmacological inhibition of EGFR hindered cell proliferation and survival and suppressed tumor growth in patient-derived NF1 mutant melanoma models but not in NF1 wild-type models. These results reveal a connection between NF1 loss and increased EGFR expression that is critical for the survival and growth of NF1 mutant melanoma cells in patient-derived culture and xenograft models, irrespective of their BRAF and NRAS mutation status.

Response to immune checkpoint inhibitors (ICIs) in metastatic melanoma (MM) varies among patients, and current baseline biomarkers predicting treatment outcomes are limited. As mitochondrial (MT) metabolism has emerged as an important regulator of host immune function, we explored the association of host MT genetics (MT haplogroups) with ICI efficacy in 1,225 ICI-treated patients with MM from the clinical trial CheckMate-067 and the International Germline Immuno-Oncology Melanoma Consortium. We discovered and validated significant associations of MT haplogroup T (HG-T) with resistance to anti-programmed cell death protein-1-based ICI (both single-agent and combination) and have shown that HG-T is independent from established tumor predictors. We also found that patients belonging to HG-T exhibit a unique nivolumab-resistant baseline peripheral CD8⁺ T cell repertoire compared to other MT haplogroups, providing, to our knowledge, the first link between MT inheritance, host immunity and ICI resistance. The study proposes a host blood-based biomarker with stand-alone clinical value predicting ICI efficacy and points to an ICI-resistance mechanism associated with MT metabolism, with clinical relevance in immuno-oncology.

BACKGROUND:Lymphovascular invasion (LVI) is regarded as a high-risk feature of cutaneous squamous cell carcinoma (CSCC) but is currently absent from CSCC staging systems. OBJECTIVE:To assess whether LVI serves as an independent predictor of major poor outcomes in CSCC. METHODS:Twelve centers contributed to a multinational CSCC database. Clinical and pathologic risk factors, treatment, and patient outcomes were retrospectively collected. CSCCs were stratified based on LVI status. Tumors that developed major poor outcomes defined as nodal metastasis, in-transit metastasis, distant metastasis, and disease-specific death were identified. RESULTS:A total of 23,166 CSCCs were identified, 179 were LVI+ tumors (0.8%). LVI+ tumors had a higher cumulative incidence of major poor outcomes than those without LVI (33.5% vs. 3.2% at 3 years; overall cumulative incidence function p < 0.001). In an adjusted analysis, LVI+ tumors had an 82% increase in the rate of developing major poor outcomes when compared to LVI- tumors (subdistribution hazard ratio (SHR) = 1.82; p = 0.002). Notably, LVI+ low-stage BWH tumors (T1 or T2a) had a greater cumulative incidence of major poor outcomes compared to LVI- BWH low-stage tumors (20.7% vs. 1.61% at 3 years, overall cumulative incidence function p < 0.001). LIMITATIONS/CONCLUSIONS:Retrospective study design CONCLUSION: The presence of LVI in CSCC is a high-risk feature that is an independent predictor of metastasis and disease-specific death in both low and high BWH stage tumors.

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.

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.

IMPORTANCE/UNASSIGNED:Cutaneous squamous cell carcinoma (CSCC) risk stratification is central to management, and physicians rely on tumor staging systems to estimate risk. The Brigham and Women's Hospital (BWH) T staging system predicts risk based on 4 tumor risk factors (RFs). However, stage is not precisely associated with the number of RFs, as BWH stage T2b includes CSCCs with 2 and 3 RFs. OBJECTIVE/UNASSIGNED:To determine how RF number is associated with the risk of recurrence, metastasis, and disease-related death. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective multination cohort study of CSCCs diagnosed between October 1, 1991, and July 19, 2023, was conducted at 12 centers in the US (10), Spain (1), and Brazil (1). Invasive CSCCs with confirmed negative margins longer than 14 days were included. Tumors were excluded if they were metastatic at presentation or received adjuvant therapy. Data were analyzed from October 2023 to August 2024. INTERVENTIONS OR EXPOSURES/UNASSIGNED:CSCCs were stratified by the number of the following RFs (0, 1, 2, 3, or 4): a diameter of 2 cm or larger, poorly differentiated histology, tumor extension beyond subcutaneous fat, and large caliber nerve invasion. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Five-year cumulative incidences of local recurrence, nodal metastasis, distant metastasis, and disease-specific death. RESULTS/UNASSIGNED:A total of 16 844 CSCCs were included (5978 female individuals [35.5%]; median [IQR] age, 73.9 [65.7-81.8] years), with 0 (12 657 [75.1%]), 1 (2892 [17.2%]), 2 (1015 [6.0%]), 3 ( 225 [1.3%]) or 4 (55 [0.3%]) RFs. Median (IQ) follow up time was 33.6 (14.5-60.3) months. For local recurrence, the risk increased as the number of RF increased from 0 (1.7%; 95% CI, 1.5%-2.0%) to 1 (5.0%; 95% CI, 4.1%-5.9%) to 2 (8.8%; 95% CI, 7.0%-11.0%) to 3 (16.0%; 95% CI, 11.0%-22.0%) to 4 (33.0%; 95% CI, 19.0%-47.0%; P < .001 for between-group differences). This increase was also observed for nodal metastasis (0.6% [95% CI, 0.4%-0.7%] vs 3.6% [95% CI, 2.9%-4.4%] vs 11.0% [95% CI, 9.2%-13.0%] vs 20.0% [95% CI, 15.0%-26.0%] vs 28.0% [95% CI, 15.0%-42.0%], respectively; P < .001), distant metastasis (0.2% [95% CI, 0.1%-0.3%] vs 1.1% [95% CI, 0.7%-1.6%] vs 2.3% [95% CI, 1.4%-3.4%] vs 7.9% [95% CI, 4.6%-12.0%] vs 8.4% [95% CI, 2.6%-19.0%], respectively; P < .001), and disease-specific death (0.3% [95% CI, 0.2%-0.4%] vs 1.9% [95% CI, 1.4%-2.7%] vs 5.4% [95% CI, 4.0%-7.0%] vs 11.0% [95% CI, 6.7%-16.0%] vs 25% [95% CI, 12%-39%], respectively; P < .001). CSCCs with 3 RFs had higher cumulative incidences of local recurrence (1.6-fold), nodal metastasis (1.9-fold), distant metastasis (4.3-fold), and disease-specific death (1.9-fold) compared with those with 2 RFs. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The results of this cohort study suggest that the number of RFs is an indicator of risk, and among BWH T2b tumors, those with 3 RFs represent a higher risk subset.