bluuebunny/crossref_metadata_2025 huggingface dataset:
Time to treatment initiation in a retrospective cohort of patients with advanced lung cancer treated with an immune checkpoint inhibitor.
Authors: Quattlebaum Alexander M. , Faucheux Andrew T. , Russell Greg B. , Duckworth Christopher , Hunting John , Elko Catherine A. , Khoury Lara M. , Bloomer Chance H. , Ruiz Jimmy , Lycan Thomas William
Published: June 2023

e21199

Background: Advanced lung cancer is diagnosed by imaging through screening, incidental findings, or during the workup of symptoms. Historically, there was no apparent benefit in expediting the times to biopsy, staging, and chemotherapy initiation. However, the widespread first-line use of immune checkpoint inhibitors (ICIs) can introduce delays such as biomarker testing and financial approval. We aimed to test whether the time to ICI treatment initiation was associated with worse clinical outcomes. Methods: We created a retrospective registry of all patients with advanced lung cancer who received at least one dose of an ICI for any first-line indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics and made a validated database. We defined the time to biopsy as the interval between the initial diagnostic imaging of the index cancer and the biopsy. We defined time to treatment initiation (TTI) as the interval between initial imaging and the first dose of ICI. Overall survival was the interval from the biopsy date to death. We used a Cox multivariate regression to model the continuous association of each additional month of TTI with survival. Confidence intervals (CI) were calculated to 95%, and p-values < 0.05 were considered significant. The study had institutional IRB approval. Results: Our cohort consisted of 472 patients diagnosed with advanced lung cancer and treated with first-line ICI. The median time to biopsy was 15.5 days with an interquartile range (IQR) of 5-29 days, median TTI was 51 days (IQR 35-79), and median overall survival was 14.3 months (CI 11.5-16.6). TTI was not associated with survival by unadjusted or multivariate analysis (HR 0.98, CI 0.95-1.01 and HR 1.02, CI 1.00-1.05, respectively). Smoking history (HR 1.011, CI 1.00-1.02 per pack-year) and higher pre-treatment ECOG performance scores (p < 0.01) were associated with worse survival. Tumor histologic subtype, autoimmune comorbidities, and toxic dust exposure were not associated with survival. The time to biopsy was not associated with survival by unadjusted or multivariate analysis (HR 0.97, CI 0.95-1.01, and HR 1.02, CI 0.97-1.07, for each additional week). Among the subset of patients with a symptomatic presentation of cancer (n = 363, 77%), longer TTI was associated with improved survival, but this effect became non-significant in multivariate analysis (HR 0.94, CI 0.89-0.99 and HR 0.96, CI 0.86-1.08, respectively). Conclusions: We did not find evidence that a shorter TTI is associated with improved survival among patients with advanced lung cancer starting first-line ICI. Additional studies are needed to test if baseline disease burden or other clinical factors can identify patients who would benefit from expedited initiation of treatment.
The impact of COVID-19 on the survival outcome of lung cancer at a Canadian academic centre: A real-world data analysis.
Authors: Agulnik Jason S. , Kasymjanova Goulnar , Pepe Carmela , Friedmann Jennifer , Small David I. , Sakr Lama , Wang Hangjun , Spatz Alan , Cohen Victor
Published: June 2023

e21200

Background: The Covid-19 pandemic directly affected the screening, diagnosis, and treatment of lung cancer patients. Our group recently reported that the rate of new lung cancer diagnoses declined during the first year and significantly increased during the second of COVID-19 pandemic. The effect of COVID-19 on lung cancer treatment outcomes in literature is still limited and mostly reported either as predictive survival using prioritization and modeling techniques. In this study, we aimed to quantify the effect of COVID-19 on lung cancer survival using real world data collected at the Jewish General Hospital, Montreal. Methods: This is a retrospective chart review study including patients diagnosed with lung cancer between March 2019 and March 2022. We compared 3 cohorts: Cohort1: 2019 (pre-COVID) Cohort2: 2020 (1st year of COVID) Cohort3: 2021 (2nd year of COVID). Results: A total of 417 patients were diagnosed and treated with lung cancer at our centre throughout the three-year study: 130 in 2019, 103 in 2020 and 184 in 2021. Although the proportion of advanced/metastatic stage lung cancer remained the same for the three cohorts, there was a significant increase in the late-stage presentation during the pandemic. The proportion of M1c (multiple extrathoracic sites) cases in Cohorts 2 and 3 was 57% and 51% respectively compared to 31% in cohort 1 (p < 0.05). Median survival for early and locally advanced stages of lung cancer was similar in the 3 cohorts. However, the subgroup of patients diagnosed in the advanced/metastatic stage had a significantly increased risk of death during the pandemic (cohorts 2 and 3). The 6-month mortality rate was 53% in 2021 compared to 47% in 2020 and 29% in 2019 (p = 0.004). The median survival in this subgroup of patients decreased significantly from 13 months in 2019 to 6 months in 2020 and 5 months in 2021 (Table 1). Conclusions: The present study represents the impacts of the COVID-19 on lung cancer survival outcome. The COVID-19 pandemic potentially caused the significant shift to M1c stage and contributed to an increase 6 month mortality rate and poorer overall survival in the advanced/metastatic lung cancer patients diagnosed and treated during the pandemic.[Table: see text]
Liquid and tissue profiling of somatic mutational landscape of non-small cell lung cancer from an Indian cohort.
Authors: Limaye Sewanti Atul , Disel Umut , Plowman Nick , Rohatgi Nitesh , Syed Nelofer , Limited Datar , Datta Vineet , Patil Darshana , Raut Nirmal Vivek , Raja Dr T , Kurzrock Razelle
Published: June 2023

e21202

Background: Circulating tumor DNA (ctDNA) encompasses spatial and temporal heterogeneity, tumor evolution, and is ideal for repeat sampling and predictive therapeutic course corrections whereas tissue is the first choice for molecular profiling. We report the mutational landscape of an Indian NSCLC cohort, with focus on liquid biopsy and value addition offered by paired tissue and liquid profiling. Methods: The study comprised 507 tumor tissue and 1271 liquid biopsies from NSCLC patients. Evaluation of single nucleotide alterations, copy number alterations and fusions was conducted using targeted next generation sequencing with paired tissue and liquid profiling in a sub cohort (n = 45). Results: In tissue based analysis (n = 507), EGFR-sensitizing mutations were the most common alterations, detected in 41.4% of samples. Among these, Exon 19 deletion was seen in 46.3%, Exon 21 L858R in 23.9%, Exon 20 insertion in 4.6%, Exon 18 G719X in 3.7% and compound mutations in 5%. TP53, KRAS and PIK3CA mutations were detected in 34.5%,13.4% and 6.3% respectively. MYC was commonly amplified (15.4%) gene followed by PIK3CA (4.1%), CCNE1 (3.3%), EGFR (2.9%), and MET (2.9%) amplifications. Tissue fusion analysis (n = 398) detected ALK in 6.3%, ROS1 in 3.3%, and RET in 1.8%. METEx14 was detected in 4.5%. Liquid biopsy (n = 1271) showed comparable mutation spectrum as tissue, with the EGFR gene being the most altered (32.9%). Mutations in TP53 were observed in 26.4%, KRAS in 7.4%, PIK3CA in 4.4% and BRAF in 3%. In EGFR positive individuals, EGFR T790M was detected at higher frequency in liquid (16.7%) than tissue (8.6%), indicating this acquired resistance alteration being better captured in liquid biopsy than tissue due to tumor heterogeneity and tumor evolution. 2 liquid biopsy samples identified additional KRAS driver mutations not seen in the paired tissue analysis, highlighting the utility of simultaneous tissue and liquid analysis. Concurrent actionable alterations were detected in 11% of tissue and 5% of liquid samples. Conclusions: We report the largest liquid biopsy study reporting the genomic landscape from NSCLC cases of Indian origin along with tissue based molecular landscape. Presence of alterations like KRAS and EGFR T790M in liquid but absence in concurrent tissue biopsy shows utility of paired tissue and liquid biopsy profiling. Higher incidence of targetable and co-existing alterations in the Indian population highlight the utility of broad molecular profiling for successful utilization of targeted therapies. [Table: see text]
Class II and class III BRAF mutations in patients with advanced non-small cell lung cancer (NSCLC): Clinical characteristics, mutation patterns, and survival outcomes.
Authors: Rasokat Anna , Kron Anna , Nogova Lucia , Siebolts Udo , Scharpenseel Heather , Riedel Richard , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Eisert Anna , Prang Darinka , Beckers Frank , Kambartel Kato , Kaminsky Britta , Schaaf Bernhard , Schulte Wolfgang , Serke Monika Heidi , Merkelbach-Bruse Sabine , Buettner Reinhard , Wolf Juergen , Scheffler Matthias
Published: June 2023

e21204

Background: Class II and class III BRAF mutations (i. e., non-V600X) in NSCLC differ from V600E in terms of dimerization and KRAS-dependency. Whereas V600X is effectively targetable by combined BRAF- and MEK-inhibition, no specific targeted approach for non-V600X exists, and a comprehensive description of the patient group is lacking. This retrospective cohort analysis presents clinical and genomic characteristics of a large cohort of patients with advanced BRAF nonV600X mutant lung cancer. Methods: Molecular data of 1411 lung cancer patients staged IIIb/IV and harboring BRAF mutations were linked to hospital registry data in the NGM (Network Genomic Medicine) database. Biospecimens were analyzed using next-generation sequencing (NGS). Results: 721 patients with BRAF non-V600X mutations were identified, of whom 10.5% had been diagnosed with squamous cell carcinoma (SCC) and 89.5% had non-squamous histology. Median age at diagnosis was 66 years (range: 34-81) and the cohort comprised 409 (56.7%) men and 312 (43.3%) women. 301 (41.8%) of the BRAF non-V600X alterations detected in this cohort are “activators” in the MAPK pathway (class II, including G469A/V/R, G464A/E/L/V, K601E/N, L597Q/R/V), while 310 (43.0%) function as “amplifiers” (class III, including mutants such as D594A/G/H/N, G466A/E/V, G469E, N581I/S/T in this cohort). While 21.5 % (155; SCC: 12.3%; non-SCC: 22.9%) of patients did not have any co-occurring mutations (55.6% of SCC and 37.1% of non-SCC patients respectively), TP53 was the most frequent co-mutation, detected in 56.6% (SCC: 74.0%; non-SCC: 53.8%) of patients. 16.4% (118) exhibited a KRAS co-mutation (SCC: 4; non-SCC: 109). A preliminary survival analysis suggests no significant difference in overall survival between these broad classes (HR 0.92, 95%-CI 0.62, 1.36). Conclusions: The study highlights the heterogeneity of patients with BRAF class II and class III regarding histology and co-mutational status, with both classes equally frequent. A more granular investigation of non-V600X alterations and their associated clinical outcomes under different treatment approaches is ongoing.
Patterns of actionable biomarker testing in lung cancer patients: Disparity or an opportunity for improvement.
Authors: Horn Robert Asa , Pawar Dushyant , Bharathidasan Kavya , Sekhon Jasmine Kaur , Rehman Shabnam
Published: June 2023

e21211

Background: In 2018, lung cancer represented about 13% of new cancer diagnosis but was still the leading cause of cancer deaths at 25%. In the last five years, rates of new cases of lung cancer have decreased by 11% and survival has increased 21% nationally; largely due to advancements in screening, diagnosis and expanding treatment modalities, including targeted therapies geared toward specific molecular alterations. Despite these advancements, there are still shortcomings in terms of next generation sequencing (NGS) utilization for detection of molecular aberrations. A recent query of 37,925 patients with stage IV non-small cell lung cancer (NSCLC), diagnosed between 2010 and 2018 discovered that only 22% of all patients had any molecular testing. Only 3% of these patients received any form of targeted therapy. This further illustrates the ongoing gap between molecular diagnostics and its clinical utilization. Methods: Our project serves to assess this shortcoming in our patient population. In this retrospective chart review and quality improvement project, the goal was to identify the limitations that led to delays or omittance of timely NGS in patients with newly diagnosed NSCLC. Under an IRB approval, a system was created where once a biopsy was confirmed to be NSCLC, tissue was sent for NGS. Prior to this intervention, molecular testing had to be ordered by an Oncologist after the patient was seen in clinic, generally during their first outpatient appointment or when discussed in multidisciplinary meetings. Additionally, testing was shifted from individual molecular studies, which would frequently exhaust tissue sample, to only comprehensive panels. Results: The charts of 194 patients with newly diagnosed NSCLC between 2014 and 2022 were analyzed. Of these patients, 125 patients (64.4%) had completion of at least one molecular test. 36 patients (18.6%) had only been tested for programmed death-ligand 1 (PDL1) and 33 patients (17.0%) had no immunohistochemical or molecular testing following biopsy results. The time from biopsy to completion of molecular testing was compared to 34 patients following implementation of our protocol. The median time from biopsy to availability of results was 29 days before our intervention and decreased to 23 days afterwards. Additionally, molecular testing increased to 100% in our newly diagnosed NSCLC patient population. Conclusions: As the genomic revolution continues and the importance of targeted therapy for NSCLC in both the adjuvant and metastatic setting progresses, timely next generation sequencing will be paramount for optimal treatment selection. Our project shows that through the implementation of systems codeveloped between medical oncology and anatomic pathology, turnaround times of molecular testing can be greatly improved and widely implemented.
Oncomine Dx Express CE-IVD liquid biopsy assay for non-small cell lung cancer: Performance review and analytical validation.
Authors: Schageman Jeoffrey
Published: June 2023

e21218

Background: Clinical diagnostics assays for oncology are becoming more readily available due to the advancement and democratization of Next-Generation Sequencing (NGS). Additionally, liquid biopsy can be used in NGS to detect genetic variants in circulating tumor DNA and RNA. Liquid biopsy is a less invasive option compared to traditional biopsy methods for early detection and continuous monitoring of cancer treatment outcomes. Here, we discuss screening of over 3,500 non-small cell lung cancer (NSCLC) samples, and the analytical validation of the Oncomine Dx Express Test (ODxET) and Genexus Dx Integrated Sequencer for detection of clinically significant variants in liquid biopsy samples. Methods: Our team screened over 3,500 NSCLC liquid biopsy samples in search of high priority clinical variants. Variants selected for analytical validation studies included ERBB2 exon 20 insertion, EGFR exon 20 insertion, EGFR exon 19 deletion, EGFR T790M, KRAS G12C, BRAF V600E, and RNA fusion isoforms including ALK, NTRK1/2/3, RET, and ROS1 oncogenic drivers. Over 550 screened samples were found to be positive for these variants of interest. This screening was performed on the Genexus Dx Integrated Sequencer according to the user guide. Results: The Genexus Dx Integrated Sequencer automates library preparation, sequencing, analysis, and reporting QC metrics and variant calls. Sequencing run setup is quick and straightforward, taking less than 15 minutes to start a run and just over 24 hours to go from nucleic acid to report. Limit of detection (LoD) for DNA SNVs, insertions, and deletions at 5 ng DNA input level ranged from 0.65% to 1.82% allelic frequency (AF), depending on the variant. The higher DNA input of 30 ng resulted in a lower LoD range, from 0.31% to 0.42% AF. RNA fusion and splice variant LoD at 5 ng sample input ranged from 9.9 to 19.6 molecular counts. The higher 30 ng input resulted in a lower LoD range for RNA variants as well, ranging from 6.4 to 8.0 molecular counts. In the analytical accuracy study, the false positive rate was found to be 0.2% for SNVs, 0% for insertions/deletions, and 0% for fusion targets. In the analytical reproducibility study, the average with-in run repeatability call rate (No Calls excluded) was 99.64% for DNA variants and 98.75% for RNA variants. Conclusions: Here, we demonstrated that the ODxET workflow on Genexus Dx Integrated Sequencer is a fast and efficient tool for testing clinical NSCLC liquid biopsy samples with high sensitivity and specificity.
Association of immune-related adverse events and improved treatment outcomes across race/ethnicity in a diverse patient population.
Authors: Jani Chinmay , Radwan Amr , Al Omari Omar , Patel Mohini , Burns Laura , Mackay Zoe , Li Liuping , Mahdaviani Kiana , Weinberg Janice , Everett Peter C. , Suzuki Kei , Mak Kimberley , Kulke Matthew H. , Tapan Umit
Published: June 2023

e21220

Background: The development of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs) has been associated with improved clinical outcomes in advanced non-small cell lung cancer (NSCLC). However, how this association extends across race and ethnicity remains uncertain. In this study, we evaluated the association between the development of irAEs and treatment outcomes across different racial and ethnic groups treated at a single institution. Methods: We performed a retrospective chart review to identify irAEs and treatment outcomes in patients with advanced NSCLC who had received treatment with ICIs at our institution between 2015-2020. The incidence of irAEs across racial subgroups was compared using logistic regression analysis. Cox regression analysis was carried out to evaluate the associations between the development of irAEs and treatment outcomes [Overall Survival (OS) and Progression Free Survival (PFS)] in these subgroups. Results: We identified a total of 138 NSCLC patients who received treatment with ICIs, of whom 50% (69) identified as non-Hispanic Black (NHB) and 50% (69) as others, including 34% (47) as non-Hispanic White. The overall incidence of irAEs in the cohort was 28%, with no significant difference between NHB and other racial groups (29% vs. 27.5%). However, females [OR 2.3 (1.1-4.8)] and patients who did not have Medicare or private insurance (i.e had Medicaid or MassHealth) were found to have a higher incidence of irAEs [OR 2.7 (1.2-5.7)]. With a median follow-up time of 363 days, the proportion of patients who were progression-free was greater in patients who had experienced irAEs than in those who did not experience irAEs [HR for time to progression 0.46 (0.23 – 0.92)]. The association between irAEs and improved PFS in NHB patients was similar to the overall population [median PFS 246 vs. 181; HR 0.87 (0.58-1.29)]. Higher ECOG status, higher Charlson Comorbidity Index and receiving ICIs as 2nd or subsequent line therapy were independently associated with worse PFS. Conclusions: Our single-institution study demonstrated a similar incidence of irAEs in patients with NSCLC across different racial and ethnic groups. As in prior studies, patients undergoing treatment with ICIs and experiencing irAEs had significantly better outcomes. We found that the association between the development of irAEs and improved treatment outcomes was independent of race and ethnicity, supporting the importance of making unbiased treatment recommendations without regard to these factors. [Table: see text]
piRNA-14633 underexpression as an independent prognostic marker in non-small cell lung cancer.
Authors: Peng Wei , Mei Jingfeng , Feng Jifeng
Published: June 2023

e21223

Background: To determine the expression and function of piRNA-14633 in non-small cell lung cancer (NSCLC) samples were taken from cancer lesions (n = 30) and adjacent normal tissue (n = 30) in NSCLC patients. Methods: piRNA-14633 expression was determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The effect of piRNA-14633 overexpression was examined in vitro utilizing a human NSCLC cell line H1650 stably transfected with a recombinant lentivirus and compared to empty vector-transfected controls. piRNA-14633 overexpression was verified by RT-PCR. The expression of proteins involved in cell cycle regulation (CDK4) and apoptosis (Bcl-6) and cell migration (MMP-9) in cells was analyzed by Western blot. The effect of piRNA-14633 overexpression on cell viability and proliferation was assessed by an MTT assay cells. Flow cytometric analyses were used to evaluate the effect of piRNA-14633 expression on cell cycle distribution and apoptosis. The migration and invasion potential of piRNA-14633 cells was examined by plating cells in Matrigel-coated chambers. Results: The level of piRNA-14633 expression was found to be significantly lower in NSCLC tissue than normal tissues (P < 0.05). Decreased expression of piRNA-14633 was significantly correlated with lymph node metastasis, clinical stage, and histological grade of patients with NSCLC (P < 0.05). Meanwhile, loss of piRNA-14633 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function shown that H1650 cell-transfected piRNA-14633 had a lower survival fraction, higher percentage of the G0/G1 phases, higher cell apoptosis, significant decrease in migration and invasion, and lower CDK4, Bcl-6, and MMP-9 expression compared with H1650 cell without piRNA-14633 (P < 0.05). Conclusions: Reduced piRNA-14633 expression is associated with increased disease severity, suggesting it is a negative regulator of NSCLC and can serve as a prognostic indicator.
Key factors associated with response in the treatment of liver metastatic melanoma by cryoablation combined with PD-1 blockade therapy: The Cryo-Fire-001 study.
Authors: Shen Lujun , Zhang Xiaoshi , Fan Weijun
Published: June 2023

e21500

Background: Liver metastasis remains a challenge in the treatment of advanced stage melanoma through immunotherapy. Although our previous study showed cryoablation could enhance the efficacy of PD-1 blockade therapy in the treatment of melanoma patients with liver metastasis, the key factors correlated with survival and treatment response remains unknown. Methods: Between 2018 and 2022, 45 melanoma patients receiving combined PD-1 blockade therapy and cryoablation of liver metastasis were retrospectively analyzed. The technical parameters of cryoablation, the sequence of the combined treatment, tumor characteristics, important immune markers and their correlations with treatment response were evaluated. The associations between key factors and overall survival (OS) were determined by Cox regression. Results: Of the 45 patients, the 3-month overall response rate (RECIST 1.1 criteria) is 26.7%. Multivariate analysis showed the number of metastatic organs ( > 2 vs ≤2; HR 3.54; 95% CI 1.32-9.49; P = 0.012), pretreatment LDH level ( > 300 vs ≤300 U/L; HR 4.59; 95% CI 1.78-11.85; P = 0.002) and diameter of ablated lesion ( > 30 vs ≤30 mm; HR 3.27; 95% CI 1.17-9.15; P= 0.024) were independent unfavorable prognostic factors for OS. Further analysis showed patients with larger intrahepatic tumors ablated had larger tumor size (P < 0.001). A scatter plot by the two key variables showed patients with intrahepatic tumor size less than 45 mm and size of ablated lesion less than 30 mm had a marginally higher rate of 3-month response (10/28, 35.7%) compared to those not (2/17, 11.7%; P = 0.076). Large diameter of ablated lesion ( > 30 mm) require more ablation needles and cause greater elevation in the level of IL-6, CD8+T cell to Treg cell ratio and neutrophil to lymphocyte ratio after cryoablation while these changes disappeared when tested one month later. Conclusions: Fine selection based on baseline characteristics of patients and size of intrahepatic lesion for cryoablation are essential to achieve a high response rate during cryoablation-PD-1 combination treatment for liver metastatic melanoma.
Socioeconomic and demographic factors on academic center accessibility in sebaceous adenocarcinoma: An NCDB analysis.
Authors: Wu Xinxin , Swedek Michelle , Silberstein Peter T. , Vardell Victoria
Published: June 2023

e21501

Background: Sebaceous adenocarcinoma (SA) is a rare, aggressive adnexal tumor shown to have both local and distant metastatic potential. The 5-year overall survival rate for this cancer is 78% for localized/regional disease and 50% for metastatic disease. Improved survival in other skin malignancies, such as melanoma, has been previously linked to treatment at academic cancer centers. The National Cancer Database (NCDB) was analyzed to determine variables impacting treatment at academic versus non-academic facility types in SA. Methods: A retrospective cohort analysis using the NCDB from 2004 to 2019 included patients diagnosed with histologically confirmed SA (N = 3,378). Socio-demographic factors (sex, age, race, Hispanic status, insurance type, urban/rural designation, facility location, education, income, distance from facility, and Charlson-Deyo score) were analyzed using Pearson Chi-squared tests and multivariate analysis of factors on academic center accessibility (facility type) was performed via binary logistic regression. A significance level of 0.05 was used. Results: The number of cases diagnosed with SA has steadily increased from 2004 to 2019 (152 and 287, respectively, R2 = 0.894). Most patients were male (59.1%), White (89.8%), not Hispanic (89.6%), insured (95.7%), and lived in an urban area (98.4%). There was a statistically significant difference between sex, race, insurance type, urban/rural designation, facility location, education, income, and distance from residence to the facility on academic facility type. Male patients were 1.3 times more likely to access academic centers compared to female patients (p < 0.001, CI = [0.681 - 0.911]). Patients with median household incomes in the top quartile were also 2.2 times more likely than those in the bottom quartile to receive treatment at an academic center (p < 0.001, CI = [1.676 - 2.992]). Conclusions: There has been an upward trend in the diagnosis of SA since 2004 with a predilection for White males. Female patients and patients with a lower income are less likely to receive treatment at an academic center. Given the rarity of the disease, this study serves as a valuable tool for understanding the factors associated with facility-type access. Future studies aim to determine the effect of academic center type on overall survival. Additional research is needed to understand the difference in treatment at academic versus non-academic facilities.
Survival in patients with unresectable melanoma: To infinity and beyond?
Authors: van Not Olivier Jules , van den Eertwegh Alfonsus Johannes Maria , Haanen John B. A. G. , Blank Christian U. , Aarts Maureen J.B. , van den Berkmortel Franchette , de Groot Jan Willem , Hospers Geke , Kapiteijn Ellen , Bloem Manja , Piersma Djura , van Rijn Rozemarijn , Stevense - den Boer Marion , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Boers-Sonderen Marye J. , Blokx Willeke , Wouters Michel , Suijkerbuijk Karijn
Published: June 2023

e21504

Background: The introduction of checkpoint inhibitors and targeted treatment has led to significant improvements in prognosis for melanoma patients over the last years. We aimed to evaluate the survival per year of diagnosis. Methods: All systemically treated patients diagnosed with advanced melanoma from 2013 to 2021 were included from the nationwide Dutch Melanoma Treatment Registry. Baseline characteristics, overall survival (OS), and melanoma-specific survival (MSS) were compared between the different years of diagnosis of unresectable melanoma. Results: In total, 6324 patients were included. Over the years, the age at start of treatment gradually increased. Patients treated in 2020 and 2021 more often had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2 and synchronous metastatic disease (table). The percentage of patients receiving systemic treatment did not change over the years. Median OS gradually increased from 11.3 months (95%CI 10.1-12.5) for patients diagnosed in 2013 to 33.3 months (95%CI 28.8-37.4) for patients diagnosed in 2019. Remarkably however, median OS was lower for patients diagnosed in 2020 and 2021 (24.8 months; 95%CI 21.1-28.2 and 18.8 months; 95%CI 17.6-NR). When excluding previously adjuvant-treated patients or looking at synchronous metastatic melanoma only, the same trends were seen. Similarly, differences in MSS mirrored our OS findings. Median OS and MSS can be found in the table. Conclusions: After a continuous survival improvement for advanced melanoma patients between 2013-2019, outcomes in 2020 and 2021 are remarkably poorer. The decreased performance status at the start of systemic treatment suggests that COVID-related delays might have played a role. [Table: see text]
Trends in overall survival in 133 cases of balloon cell melanoma: An NCDB analysis.
Authors: Wu Xinxin , Keirns Darby , Hsia Beau , Silberstein Peter T.
Published: June 2023

e21508

Background: Balloon cell melanoma (BCM) is a rare, malignant subtype of melanoma characterized by large, foamy melanocytes lacking pigmentation with a low overall 5-year survival rate of 37.5%. The incidence of melanoma is increasing at a greater rate than other types of cancer, but the cases of this subtype remain low. Demographic factors were analyzed via the National Cancer Database (NCDB) in an attempt to mitigate the knowledge gap in BCM diagnoses. The primary site at presentation and the effects of demographic factors on overall survival are described. Methods: A retrospective cohort analysis utilizing the NCDB from 2004 to 2020 included patients diagnosed with histologically confirmed BCM (N = 133). Socio-demographic factors (sex, age at diagnosis, race, facility type, and insurance type) were analyzed for frequency. A multivariate analysis of factors was performed on overall survival via the Kaplan–Meier Method (p = 0.05). Results: Since 2004, the number of cases diagnosed with BCM has steadily decreased (R2 = 0.204). The average age at diagnosis was 58.17 years (SD = 17.3). Most patients were male (63.9%), White (94.0%), treated at a non-academic center (56.4%), and had government insurance (96.1%). On multivariate analysis, age, race, and insurance type had statically significant effects on overall survival (p < 0.001). Patients that were older at diagnosis had poorer overall survival (p < 0.001, CI = [1.022 - 1.075]). Black patients were 4.6 times more likely than White patients to have suffered death (p < 0.001, CI = [23.586 - 450.230]). Patients without insurance were more likely to die than patients with government insurance (p < 0.001, CI = [0.026 - 0.229]). The average time from diagnosis until death was 143.1 months (SD = 8.0) with a 1-year and 5-year survival rate of 92.0% and 72.2%, respectively. Conclusions: This is the first study analyzing trends and demographic features relating to BCM in the NCDB. Due to the low survival rate of this cancer, understanding the risk factors affecting overall survival serve as a valuable clinical tool for prognostic evaluation. This database analysis suggests that the survival rate of BCM might be higher than previous literature suggests. The differences in BCM treatment on overall survival were not described in this study. Future research should aim to evaluate other prognostic factors, such as treatment, on survival.
Outcomes of patients with advanced NF1-mutant melanoma treated with MEK inhibitors.
Authors: Wang Lin , Kim Kevin B. , Kashani-Sabet Mohammed , Dighe Prasad R. , Aboosaiedi Ali
Published: June 2023

e21513

Background: Mutations in neurofibromin 1 ( NF1) constitute the third most frequent driver mutation in melanoma, occurring in approximately 15% of patients. NF1 is a tumor suppressor gene that negatively regulates the MAPK pathway by inactivating RAS through the hydrolysis of RAS-GTP to the inactive form, RAS-GDP. Preclinical studies have demonstrated that NF1 mutations induce the activation of the MAPK pathway through constitutively maintaining the active form of RAS protein, and that MEK inhibitors cause growth arrest of NF1-mutant melanoma in vitro and tumor regressions in vivo. Methods: We conducted a retrospective analysis to evaluate the outcomes of patients with NF1-mutant melanoma who were treated with MEK inhibitors using our institutional melanoma database. We searched for all melanoma patients whose melanoma was analyzed with next generation sequencing (NGS), and their clinical, pathological and molecular characteristics were examined along with the details of MEK inhibitor treatment and clinical outcomes. Results: Among 229 patients whose melanoma was analyzed with the NGS, we identified 32 patients whose melanoma harbored a pathogenic or likely pathogenic NF1 mutation, of which four were treated with trametinib. The clinical, molecular characteristics and the outcomes of the 4 patients are summarized in the table. All had previously experienced disease progression following anti-PD1 antibody therapy. One patient with metastatic mucosal melanoma had a confirmed partial response to trametinib treatment with time to progression of 18 months. Two patients had regression of the metastatic lesions at the initial tumor response evaluation, but due to significant toxicity, treatment was discontinued. Their disease progressed within 3 months after treatment discontinuation. Two patients with initial tumor regression had a mucosal primary melanoma. Interestingly, the patient with a prolonged response had the highest variant allele frequency (VAF) of NF1 whereas the early progressor had the lowest VAF (Table). All responders (including the unconfirmed responders) had a VAF of >35%. Conclusions: Despite the small sample size, our findings suggest a potential promising efficacy of trametinib in the setting of NF1-mutant melanoma, particularly those with high allelic frequency, thereby providing a strong rationale for a prospective study to evaluate the clinical efficacy of MEK inhibitors in this molecular subtype of melanoma. [Table: see text]
A dual institution real-world study of avelumab for advanced Merkel cell carcinoma.
Authors: Miller David Michael , Wright Kayla , Silk Ann W. , Thakuria Manisha , Shalhout Sophia
Published: June 2023

e21514

Background: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neoplasm with an increasing incidence rate and poor prognosis. The treatment landscape has changed dramatically over the last half decade, beginning with the 2017 approval of the anti-programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Accelerated approval for avelumab was based on data from the JAVELIN Merkel 200 study, which demonstrated an objective response rate (ORR) of 33% in previously treated subjects (≥2L). In the first-line (1L) clinical-trial setting, avelumab was associated with an ORR of 40% and a durable response rate (DRR) of 30%. There are limited data regarding the efficacy of avelumab in the real-world setting. Methods: We performed a Mass General Brigham (MGB) Institutional Review Board-approved retrospective study of patients with advanced MCC. Clinical data regarding the disease course, including diagnosis and treatment, were collected from the Electronic Health Record and stored in a REDCap database. Response category was assigned based on the text of the radiology reports and clinician notes. Analysis was performed in R. Results: 1249 patients with MCC were identified; 260 received systemic therapy; 54 were treated with avelumab (our primary analysis cohort, PAC). Median age of the PAC was 74 years. 80% were male. 83% had an initial ECOG of 0 or 1. 20% were immunosuppressed at the time of MCC diagnosis. The real-world response rate (rwORR) for all patients treated with avelumab was 45.83%. rwORR in the 1L was 53.57% and 35% in the second line and beyond. The median duration of treatment response in the 1L was 518 days and 144 days for ≥2L. Median progression-free survival was 158 days and 95 days, and median overall survival was 553 days and 323 days for 1L and > 2L, respectively. Conclusions: Our study provides important data about the real-world treatment of patients with advanced MCC. The response rate and progression-free survival were consistent with those observed in other real-world studies as well as the clinical trials. While the subjects studied in previously published studies differ from that in MGB cohort, the overall body of literature continues to demonstrate positive outcomes attributable to avelumab monotherapy in both the 1L as well as second-line or beyond and in patients with competent, as well as compromised, immune systems. Limitations of this study include its retrospective nature. Furthermore, given the small sample size, we are limited in making statistical inferences from the current data set and specific results may not be generalizable to all patients with MCC.
Multi-modal and longitudinal characterization of the tumor and immune microenvironment from primary to in-transit and distant metastasis in acral melanoma.
Authors: Tarantino Giuseppe , Zaremba Anne , Vallius Tuulia , Rambow Florian , Pelletier Roxanne , Makhzami Samira , Zimmer Lisa , Sucker Antje , Livingstone Elisabeth , Hadaschik Eva , Lian Christine , Murphy George , Sorger Peter , Liu David , Schadendorf Dirk
Published: June 2023

e21518

Background: Patients with in-transit metastases (ITM) in melanoma are a heterogeneous subset of patients where melanoma recurrence is anatomically detected between the site of the primary tumor and the draining lymph node. Notably, a significant subset of those patients has locoregional recurrences with long-term survival without progression to distant sites. The underlying mechanisms responsible for these distinct phenotypes are unknown. Methods: To understand the evolution from primary melanoma to in-transit and distant metastasis, we characterized the tumor and immune microenvironment among 9 patients with acral lentiginous melanoma using whole exome sequencing (WES), bulk RNAseq, snRNAseq and high-plex Cyclic Immunofluorescence (CyCIF) imaging. We further profiled the dynamics and the evolution of the tumor and immune compartments using 28 tumor samples obtained longitudinally over 9 years from a single patient (pt222) with recurrent in-transit and distant metastases undergoing CDK4/6, MEK inhibition and immune checkpoint blockade. Results: Our cohort included 5 patients that progressed from ITM to distant disease and 4 patients with only local recurrence and without distant progression (Table). WES profiling identified enriched RAS mutations (5 out of 9), independent of progression and treatment response. Pt222 showed multiple morphological features related to aggressive tumor growth and high risk of recurrence such as clefting, ulceration detected within the primary tumor by the histopathological assessment of the H&E section. Phylogenetic analysis revealed co-evolution of 7 genetic lineages that shared 35 clonal mutations, including NRAS p.Q61H, with independent resistance-associated alterations. The metastases at distant sites emerged from a lineage featured with high aneuploidy and tumor mutational burden (TMB). The brain metastasis showed the highest TMB and aneuploidy. Bulk RNAseq deconvolution, snRNAseq, CyCIF and H&E revealed low and heterogeneous immune composition among different samples and lineages with macrophages and DCs as dominant populations. Interestingly, we did not observe the lineage characterized by the highest absolute immune infiltrates after ICB treatment. Another specific lineage that disappeared after the treatment with ICB showed angiotropic growth and the over-expression of a WNT-betacatenin transcriptional signature linked with T cell exclusion. An orthogonal validation using bulk RNAseq, snRNAseq and CyCIF confirmed these findings. Conclusions: This study helps define a high-resolution map of the evolutionary dynamics from primary to in-transit and distant metastasis. [Table: see text]
Immune checkpoint inhibitors in advanced cutaneous squamous cell carcinoma: Real-world evidence.
Authors: Koch Hein Erica C. , Vilbert Maysa , Hirsch Ian , Ribeiro Mauricio Fernando , Mantle Luke , Fournier Cynthia , Butler Marcus O. , Spreafico Anna , Saibil Samuel
Published: June 2023

e21519

Background: Immune checkpoint inhibitors (ICI) Cemiplimab and Pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate efficacy and safety of ICI in a real-world cSCC population, including patients with conditions which would exclude trial participation. Methods: In this single-center retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We aimed to assess efficacy outcomes according to age, comorbidities, and immune-related adverse events (irAE). Best overall response (BOR) was investigator-assessed. X2, Fisher’s exact, and Mann-Whitney U tests were used to compare subgroups of interest, and Cox proportional hazards models were fitted. The log-rank test was used to assess progression free survival (PFS) and overall survival (OS). Results: We identified 35 patients. Characteristics are displayed in the table. Median follow-up was 21.8 months (95% CI 19.3-24.4). BOR to ICI was partial response (PR) in 42.9%, complete response (CR) in 28.6%, and stable disease in (SD) 14.3% of patients. Main reasons for discontinuation of treatment were progression of disease (PD) in 20%, achievement of maximum benefit in 17.1%, and toxicities in 14.3%. Treatment beyond progression was given to 22.9% patients. The PFS rate at 1 year was 62%; median PFS was not reached (NR). PFS and OS were similar between patients with or without comorbidities, ECOG performance status 0-1 versus 2-3, or between age groups ≥75 years versus <75. IrAE grade 1-2 and 3-4 were seen in 80% and 14.3% of patients, respectively. Patients with grade 1-2 irAE had greater PFS than those without toxicities (HR 0.16; 95%CI 0.045-0.567, p=0.005). The OS rate at 1 year was 76%, with a median OS of 38.57 months (95% CI 19.4-57.7). Responders (CR+PR) had a prolonged median OS compared to non-responders (SD+PD): 38.57 months versus 9 months (HR 0.083; 95%CI 0.17-0.406, p=0.002). Conclusions: ICI were effective and safe among real-world cSCC patients, independent of age, comorbidities or ECOG. Our BOR was higher than in the published clinical trials, which might reflect the subjective nature of investigator-assessed response or the small sample size assessed. [Table: see text]
Meta-analysis of efficacy outcome measures across immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) in melanoma to guide future clinical trial design.
Authors: Ousey James , Ahadieh Sima , Di Pietro Alessandra , Sturtz Keren , Williams Jason H. , Fetterly Gerald
Published: June 2023

e21520

Background: Systemic treatments (Tx) for unresectable or metastatic melanoma include TTs and ICIs, with TT+ICI combinations under exploration. Heterogeneity in clinical trial sample size and subject characteristics pose obstacles for treatment class comparisons. We applied meta-analysis to elucidate Tx and covariate effects on efficacy outcomes in melanoma. Methods: A PICOS-guided literature search was conducted from 2000-2022 for TT or ICI given as monotherapy or in combination for unresectable or metastatic melanoma. Median progression-free survival (mPFS), median overall survival (mOS), and overall response rate (ORR) were recorded. Random-effects models were fit to endpoints with study arms weighted by variance. Covariate inclusion was based on likelihood-ratio tests (P < 0.05). For simulation, parameter distributions from weighted linear regression (wi ~ nstudy) of mPFS to ORR were sampled (N = 5000) with residual error scaled by mean Phase 3 arm size. ORR uncertainty was modeled by normal approximation. Results: From 134 publications, 100 (mPFS), 73 (mOS), and 111 (ORR) outcomes were retained, from 53, 44, and 63 studies, respectively, and classified by treatment. For all endpoints, Tx classification was an outcome predictor (P< 0.001). BRAFi+MEKi+PD-1 combination therapy had the greatest predicted duration of mPFS (16.7 months [11.8, 23.6]) and ORR (62.8% [53.7%, 71.1%]). mPFS and mOS outcomes were reduced by prior Tx failure and evidence of brain metastases, with mOS also impacted by elevated lactate dehydrogenase. I2 statistics for the final models were 89.0% (mPFS), 73.9% (mOS), and 51.8% (ORR). A robust correlation between ORR and mPFS (R2= 0.77, P < 0.001) was observed across all treatment classes. The predictive power of this relationship was demonstrated by simulating the probability of achieving target Phase 3 mPFS outcomes from ORR derived from as few as 20 patients. Conclusions: This meta-analysis characterizes the shifting space of Tx in unresectable or metastatic melanoma and provides a model-based framework for simulation of efficacy endpoints and trial designs for TT+ICI combinations. ORR-based predictions of trial success illustrate the value of utilizing early endpoints to inform decisions in drug development, across all Tx options in melanoma. Further investigation will include longitudinal PFS and OS modeling and refinement of PFS predictions from tumor growth metrics and clinical benefit rate.
Trends, predictors and impact of atrial fibrillation on inpatient outcomes among malignant melanoma patients: A 5-year National Inpatient Sample (NIS) study.
Authors: Olafimihan Ayobami Gbenga , Kanemo Philip Onyekaoso , Jackson Inimfon , Litvin Rafaella , Turk Ekrem , Vakil Jay , Cuartas Mesa Maria Cristina , Ibrahim Muhammad Bilal , Batra Kunnal
Published: June 2023

e21525

Background: Malignant melanoma (MM), a very aggressive cancer, is associated with the highest mortality rate among dermatologic malignancies. Atrial fibrillation (AF) is the most common cardiac arrhythmia. Very little is reported in the literature on the association between both diseases, and there is marked paucity of studies comparing outcomes in patients with concomitant MM and AF. Methods: Retrospective cohort analyses were performed using the National Inpatient Sample (NIS) data collected between 2016 and 2020. Multivariable logistic and linear regression models were used to examine the predictors of AF and inpatient outcomes among MM patients. Results: Out of 9,760 hospitalizations with a diagnosis of MM, the overall prevalence of AF was 13.3% with an increasing trend from 10.1% in 2016 to 16.4% in 2020. MM patients with AF had similar odds (adjusted odds ratio (AOR) = 0.9; 95% confidence interval (CI) = 0.451.61) of inpatient all-cause mortality when compared to those without atrial fibrillation. However, they were more likely to have longer hospital stays (beta coefficient (β) = 1.27; 95% CI = 0.392.0) and total hospital charges (β = $12,830; 95% CI: $7041.4$25426.4) when compared to their counterparts without atrial fibrillation. Furthermore, patients with AF had a double likelihood (AOR: 1.90; 95% CI: 1.252.90) of developing an acute kidney injury (AKI). We also found that female MM patients were 50% (AOR: 0.50; 95% CI: 0.360.68) less likely to have a diagnosis of AF relative to their male counterparts. Similarly, Hispanic MM patients were significantly less likely (AOR: 0.06; 95% CI: 0.0080.459) to have AF in comparison to Non-Hispanic White patients. Conclusions: There is an increasing trend of comorbid atrial fibrillation in patients hospitalized for malignant melanoma, and this is associated with longer hospital stays and higher total hospital charges. These findings highlight the need for surveillance to enable early detection of atrial fibrillation in this population.