bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning (ML)-based quantification of tumor-infiltrating lymphocytes (TIL) and clinical outcomes of patients with melanoma treated with immune-checkpoint inhibitors (ICI).
Authors: Adib Elio , Rakaee Mehrdad , Nassar Amin , Bou Farhat Elias , Hodi F. Stephen , Kwiatkowski David J.
Published: June 2023

9560

Background: TIL quantification has shown promising prognostic and predictive impact in various tumors treated with ICI. More recently, TIL therapy has become an emerging treatment agent for ICI-refractory melanoma. In this work, we studied the effect of intrinsic TILs on clinical outcomes of patients with melanoma treated with ICI and quantified its utility as a biomarker in combination with tumor mutational burden (TMB). Methods: We applied a previously developed ML model to process digital whole-slide images of hematoxylin and eosin slides to quantify TIL density (TIL/mm2) in 182 metastatic melanoma samples treated with ICI at the Dana-Farber Cancer Institute. All samples underwent next-generation targeted-panel sequencing and had available TMB data (mutations/megabase). Overall survival (OS) was calculated from the data of ICI initiation to the date of death. TTF was calculated from the data of ICI initiation to the date of next line treatment or death. Alive patients were censored at the date of last follow-up. Multivariable cox regression was used to estimate adjusted hazard ratios (adj-HR) and p-values (adj-p), with TMB, prior lines of treatment and regimen type (single vs. combination ICI) used as covariates. TMB-high (TMB-H) group was defined as samples with TMB≥10. TIL-high (TIL-H) group was defined as samples with TIL density higher than the median. Results: Of 182 patients, 60% (110/182) were male and the median age at ICI start was 65.5 years. 63% (115/182) of patients received single-agent ICI (anti-PD1 or anti-CTLA4). Of 182 tumor specimens assessed for TILs, 47 (25.8%) were obtained from the primary site. There was no difference in TIL density (medians 583 vs. 817 TILs/mm2, p=0.57; 709 TIL/mm2 for full cohort) or TMB (medians 11.4 vs 12.2 mutations/megabase) between primary and metastatic samples, respectively. Moreover, there was no correlation between TIL density and TMB (pearson’s correlation coefficient = 0.92, p=1) across all samples. Compared to patients in the TIL-low (TIL-L) category, patients in TIL-H had significantly longer median TTF (33.9 [15.9-NR] versus 13.0 [7.8-18.6] months, adj-HR: 0.53 (95% CI: 0.36-0.78); adj-P=0.0012), while there was no difference in OS (P=0.57). In fact, patients in the TMB-H/TIL-H group had the longest TTF, followed by TMB-H/TIL-L, TMB-L/TIL-H then TMB-L/TIL-L (table). Conclusions: Our results support the potential use of ML-based TIL scoring as a novel and independent biomarker to predict time to failure on ICI. There is ongoing effort to validate our findings in an external dataset. [Table: see text]
Transforming growth factor-b1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in advanced basal cell carcinoma.
Authors: Rapoport Bernardo Leon , Anderson Ronald , Malinga Nonkululeko , Steel Helen C. , Meyer Pieter , Smit Teresa , Kgokolo Mahlatse
Published: June 2023

9567

Background: BCC rarely metastasizes and the mortality rate is low; however, the disease is associated with substantial morbidity. Transforming growth factor-b1 (TGF-b1) is a key player in cell proliferation, differentiation, apoptosis, and immune regulation. TGF-b1 is associated with immunosuppression and resistance to immunotherapeutic drugs. Immune checkpoint proteins (ICMs) maintain self-tolerance and modulate the immune responses of effector cells. The current study compared the levels and possible associations between systemic soluble ICMs (sICMs) and a group of humoral modulators of immune suppressor cells in a cohort of patients with advanced basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). Methods: We measured sICMs and immunosuppressive humoral modulators by using multiplex bead array or ELISA procedures, with plasma as the matrix. The sICMs comprised seven co-inhibitory (CTLA-4, BTLA, LAG-3, PD-1, PDL-1, PDL-2, and TIM-3) and eight co-stimulatory (CD27, CD28, CD40, CD80, CD86, GITR, GITRL, and ICOS) proteins, as well as the two dual-active sICPs, HVEM and TLR2. The seven humoral modulators of immunosuppressor cells included arginase 1, fibroblast activation protein (FAP), RANTES (Regulated upon Activation Normal T Cell Expressed and Presumably Secreted) also known as CCL5, interleukin-10 (IL-10), TGF-b1, and the M2-type macrophage biomarkers, soluble CD163 (sCD163) and sCD206. Ethics approval was granted by The Research Ethics Committee, Faculty of Health Sciences, University of Pretoria (Ethics Committee Approval Numbers 356/2020. Results: The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, and sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients ( p< 0.001- p< 0.00001), while that of sBTLA was significantly decreased ( p< 0.006). Of the co-stimulatory sICPs, sCD27 was significantly increased ( p <0.0002) in the cohort of BCC patients, with the levels of the others essentially comparable with those of the control patients; of the dual active sICPs, sHVEM, sTLR2 was significantly elevated ( p< 0.00001) and TLR2 comparable with the control group. Although the plasma levels of the seven modulators of immune suppressor function were not significantly different between the BCC and control groups, correlation heat maps revealed selective, strong associations of TGF-b1 with seven co-stimulatory (z = 0.618468-0.768131) and 4 co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Conclusions: Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-b1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells.
Overall survival after the introduction of adjuvant treatment in stage III melanoma: A nationwide registry based study.
Authors: Helgadottir Hildur , Ny Lars , Ullenhag Gustav J. , Falkenius Johan , Mikiver Rasmus , Olofsson Bagge Roger , Isaksson Karolin
Published: June 2023

9570

Background: Adjuvant treatments with PD-1 and BRAF+MEK inhibitors significantly prolong recurrence-free survival in stage III cutaneous melanoma. However, the effect on overall survival is still unclear. After the approval of adjuvant treatments with PD-1 inhibitors and BRAF+MEK inhibitors, based on recurrence-free survival data, these treatments have been widely implemented. However, there are significant side effects and costs of the treatment, and the overall survival effect remains a highly anticipated outcome. Methods: Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry that covers nearly all (99%) primary cutaneous melanomas diagnosed. Information on deaths was received from the Cause of Death Registry, a virtually complete register of all deaths in Sweden. Patients diagnosed with stage III melanoma between 2016 and 2020 were included and divided depending on if they were diagnosed before or from July 2018, the timepoint when adjuvant treatment was introduced in Sweden (designated as pre- and post-cohorts). In Sweden, approved treatments are freely available for all residents and there is a high-adherence to national treatment guidelines. Data was retrieved for the age and sex of the patients, the site, histopathological subtype, Breslow thickness and ulceration of the primary melanoma, type of locoregional spread and numbers of affected lymph nodes. Patients were followed until the end of 2021. Melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox regression analyses. Results: There were 1371 patients diagnosed with stage III melanoma in Sweden in 2016-2020. The median time of follow-up in the pre-cohort was 57 months (range 42-72 months) and in the post-cohort 27 months (range 12-42 months). The 2-year overall survival rates, comparing the 634 patients in the pre-cohort and the 737 in the post-cohort, were 84.3% (95% CI 81.4-87.3) and 86.1% (95% CI 83.4-89.0), respectively, with an adjusted HR 0.91 (95% CI 0.70-1.19, P= 0.51). Further, no significant overall or melanoma-specific survival differences were seen when comparing the pre- and the post-cohort in different subgroups depending on the age, sex or tumor characteristics. Conclusions: To our knowledge, this study is the first to assess the impact on overall survival from a national introduction of adjuvant treatment in stage III melanoma. In this nationwide, population and registry-based study, no survival benefit was detected in the cohort receiving adjuvant therapy. Considering also the significant side effects and costs, these findings encourage a careful assessment of the current recommendations on adjuvant treatment. To offer close follow-up, and only treat if relapse occurs, should be an option discussed with patients with fully resected stage III melanoma.
Intralesional therapy, limb infusion/perfusion, and immune checkpoint inhibitors as first-line therapy in surgically unresectable melanoma in-transit metastases.
Authors: DePalo Danielle K , Naqvi Syeda Mahrukh Hussnain , Ollila David W. , Hieken Tina J. , Block Matthew Stephen , van Houdt Winan J. , Wouters Michel W.J.M. , Asher Nethanel , Broman Kristy Kummerow , Duncan Zoey , Anderson Matilda , Gyorki David E. , Vetto John T. , Hui Jane Yuet Ching , Saw Robyn P.M. , Lo Serigne N. , Kim Youngchul , Van Akkooi Alexander Christopher Jonathan , Olofsson Bagge Roger , Zager Jonathan S.
Published: June 2023

9574

Background: Surgery remains the gold standard for resectable melanoma in-transit metastases (ITM). Unresectable ITM is a heterogenous disease with multiple treatment (tx) options including systemic therapies such as immune checkpoint inhibitors (ICI), regional therapies such as isolated limb infusion or perfusion (ILI/P), and intratumoral therapies such as talimogene laherparepvec (IT). Until now, there has been no direct comparison of these first-line tx for unresectable ITM. Methods: A retrospective chart review of patients (pts) with ITM treated first-line with IT, ILI/P, or ICI was performed at 11 institutions. Pts with unresectable ITM, synchronous nodal or distant metastatic disease were excluded. Results: 560 pts (54% women) were identified, 86 received IT, 353 received ILI/P, and 121 received ICI from 1990-2022. ICI pts were youngest, IT pts were oldest (p<0.001). Limb was the most common site of ITM. There was no difference in largest ITM size, but number of lesions (burden of disease (BOD)) was highest in ILI/P pts and lowest in IT pts (p=0.003). Toxicity (tox) requiring <90 days (p<0.001) or > 90 days (p=0.034) of pharmacologic tx as well as tox requiring hospitalization (p<0.001) was greatest in ICI pts. Lymphedema was more likely in ILI/P pts (p=0.016). Median follow-up was much longer for ILI/P pts at 8.0 yrs compared to 2.5 yrs for IT pts and 3.1 yrs for ICI pts. Overall response rate (ORR) was 82.2% in ILI/P pts, significantly higher than IT (72.1%, p=0.047) or ICI pts (63.6%, p<0.001). Overall survival was similar between modalities (p=0.167); however, ILI/P pts had worse progression-free survival (PFS) (p<0.0001) and melanoma-specific survival (MSS) (p=0.003). On multivariable analysis of MSS by number of ITM present, MSS remained worst if ILI/P was used for low BOD, ≤3 ITM (p=0.005), but no difference was seen between tx modalities for higher BOD, >3 ITM (p=0.211). Conclusions: ICI was used more often in younger pts with less BOD, IT in older pts with less BOD, and ILI/P in older pts with high BOD. Short and long-term tox was greater in ICI. ILI/P had the best ORR, but ICI and IT resulted in greater overall MSS. Multidisciplinary consideration of risks and benefits of each modality should guide ITM tx selection. [Table: see text]
Nature and management of melanoma recurrences following adjuvant anti-PD-1 (PD1) therapy.
Authors: Woodford Rachel , McKeown Janet , Hoeijmakers Lotte , Mangana Joanna , Lebbe Celeste , Zaman Farzana Yasmin , Aya Francisco , Marsiglio John , Goodman Rachel S , Rayson Victoria , Placzke Joanna , Kessels Jolien Isabel , Ramelyte Egle , Haque Waqas , Wilson Isabella , Trojaniello Claudia , Roberts-Thomson Rachel , Robert Caroline , Long Georgina V. , Menzies Alexander M.
Published: June 2023

9575

Background: Despite improved outcomes with the use of adjuvant PD1 therapy, approximately 50% of patients (pts) develop recurrent disease by 5 years. Data to define best management of recurrences is lacking, including whether retreatment with PD1 has benefit. Methods: This was a multicentre, international retrospective study of pts with resected stage II-IV melanoma who commenced adjuvant PD1 therapy before January 2022 and then recurred. Demographics, disease characteristics, treatment, toxicity, recurrence patterns, management and outcomes were collected. Results: 711 pts from 17 sites were included. Med age was 60 [range 16-92], 64% (N=451) were male. 641 (91%) pts were stage III (A 7%, B 24%, C 54%, D 3%), 18 (2%) stage II, 51 (7%) stage IV. 80% (N=536) underwent SLNB prior to PD1, of which 44% (N=236) went onto CLND. 635 pts (90%) received PD1, 74 (10%) PD1 + other. Med time to recurrence was 6.2 months (m) (0-68.5); 63% (N=444) recurred ON PD1, while 36% (N=257) recurred OFF. 338 pts (48%) recurred within 6m of starting adjuvant, 166 (23%) between 6-12m, 140 (20%) 12-24m and 59 (8%) after 24m. Initial recurrences were locoregional (LR) alone in 315 (44%), 307 (43%) distant alone, and 78 (11%) both. Patients with LR recurrences alone underwent definitive surgery, or surgery + radiation in 98 (31%) and 42 (13%) respectively. After initial LR management, 164 (52%) had a further local and 129 (41%) distant recurrence. Those with initial distant recurrences were managed with definitive surgery (21, 7%), surgery + radiation (8, 3%) and radiation alone (14, 5%). Further ‘second’ adjuvant therapy was given in 27% (N=86) of LR and 6% (N=25) of distant recurrences. Definitive systemic therapy at first recurrence was given in 77% (N=296) distant and 23% (N=73) LR recurrences (Table). Conclusions: Patients recurring after adjuvant PD1 therapy do so early, and often while on drug. Patients with resected recurrences often receive “second adjuvant” therapy, although whether adjuvant or definitive, outcomes are poor. Novel drug therapies and clinical trials are required for those who recur despite PD1 therapy. [Table: see text]
Association of circulating tumor DNA kinetics with disease recurrence in patients with stage IIIB/C/IV melanoma treated with adjuvant immunotherapy in Checkmate 238.
Authors: Syeda Mahrukh M. , Wiggins Jennifer M , Alegun Josephine , Ali Saim , Tang Hao , Wang Sheen , Tsai Kao-Tai , Desai Keyur , Dolfi Sonia , Tenney Daniel J. , Ascierto Paolo Antonio , Larkin James , Del Vecchio Michele , Weber Jeffrey S. , Polsky David
Published: June 2023

9577

Background: In patients (pts) with resected, stage III/IV melanoma receiving adjuvant immunotherapy, pre-treatment (pre-Tx) and on-treatment (on-Tx) circulating tumor DNA (ctDNA) combined with tumor features were evaluated to predict recurrence risk. Methods: We used analytically validated, mutation-specific droplet digital PCR (ddPCR) assays to measure ctDNA in pre- and on-Tx plasma samples from pts with resected stage IIIB/C/IV melanoma enrolled in CheckMate 238 (NCT02388906) receiving either adjuvant Nivolumab (NIVO) or Ipilimumab (IPI). Assay choice was based on detection of one of the 7 melanoma hot-spot mutations in pt tumors: BRAF V600E/K, NRAS Q61R/L/K, or TERT C228T/C250T. We evaluated associations between ctDNA detection, recurrence free survival (RFS), distant metastasis free survival (DMFS), and known immunotherapy tumor biomarkers including PD-L1, IFNg gene signature, CD8, and tumor mutational burden. Associations between ctDNA kinetics and RFS/DMFS were analyzed using Kaplan-Meier and Cox regression models. Results: Mutations were identified in 87% of tumors. ctDNA was detected in pre-Tx samples from 94/753 (12.5%) pts. Pre-Tx ctDNA was significantly associated with higher stage of disease, LDH ≥ ULN, PD-L1 < 5%, and tumor IFNg-RNA signature expression below the median. Detection of pre-Tx ctDNA was associated with shorter RFS and DMFS in both NIVO and IPI arms compared to undetectable ctDNA (Table). ctDNA detection on-Tx (week (w) 3, 7, 13, 25, 37, 49) was also associated with shorter RFS. Refined subgroup predictions that potentially impact therapy were achieved by incorporating pre- and on-Tx time points. Of those with baseline and w7 ctDNA results, pts in the NIVO arm with undetectable pre-Tx ctDNA (n=308) that became positive at w7 (n=22) had shorter RFS (median RFS 20.68 mos [95% CI, 2.79, NR]) than pts in whom on-Tx ctDNA remained undetectable (n=286) (median RFS, NR [95% CI, 61.1, NR]). Pts with positive pre-Tx ctDNA (n=42) that remained positive at w7 (n=23) had markedly shorter RFS (median RFS, 3.35 mos [95% CI, 2.73, 20.44]) vs pts in whom on-Tx ctDNA became undetectable (n=19) (median RFS, NR [95% CI, 14, NR]). Similar results were observed in the IPI arm. Conclusions: Pre- and on-Tx ctDNA measurements are associated with melanoma recurrence risk during adjuvant checkpoint inhibitor therapy. Incorporation of ctDNA with other tumor molecular features may improve prediction of RFS and DMFS in this setting. Clinical trial information: NCT02388906 . [Table: see text]
[18F]FDG-PET to identify pathological responses upon neoadjuvant immune checkpoint blockade in cutaneous squamous cell carcinoma.
Authors: Breukers Sabine , Crommelin Robert D. , Smit Laura , De Boer J.P. , Navran Arash , van Houdt Winan J. , de Bree Remco , Devriese Lot A. , Haanen John B. A. G. , Zuur Charlotte L. , Wondergem Maurits
Published: June 2023

9584

Background: To improve clinical prospects of patients with locally advanced cutaneous SCC (CSCC), we tested the efficacy of neoadjuvant nivolumab with or without ipilimumab prior to standard of care curative surgery ± radiotherapy; the MATISSE trial (NCT04620200). Neoadjuvant immunotherapy-response prediction via FDG-PET imaging was demonstrated feasible in the IMCISION trial (PMID 34937871), where a decrease of ≥12.5% in total-lesion glycolysis (TLG) upon immunotherapy identified deep pathological responders to immunotherapy in head and neck SCC prior to surgery with 95% accuracy. The current research investigates the predictive power of FDG-PET to identify deep pathological responses to neoadjuvant immunotherapy in MATISSE patients. Methods: 26 patients with primary CSCC (stage I‒IVa) were treated with neoadjuvant nivolumab with (n = 14) or without (n = 12) ipilimumab (weeks 0 and 2). FDG-PET/CT scans were evaluable at baseline and shortly before surgery (week 4) in 20 patients. Images were analysed for SUVmax, metabolic tumor volume (MTV), and TLG. Responders to immunotherapy were defined as having a major or partial pathological response to immunotherapy (MPR and PPR, showing ≤ 10% and 11-50% remaining viable cancer cells at time of surgery, respectively). Results: Overall, median SUVmax, MTV, and TLG decreased upon immunotherapy at the primary tumor site in responders (n = 15),whereas median SUVmax, MTV and TLG increased in non-responders (Table). Three patients with stable or increased SUVmax, MTV and TLG, also showed a pathological response and were classified as pseudo-progressive. Another patient with a MPR had an increase in SUVmax, but a decrease in MTV and TLG. All patients with any decline in SUVmax, MTV or TLG at the primary tumor site showed a pathological response (PPV 100%) and none of them developed a relapse at median follow-up 9.0 months. Conclusions: Primary tumor response assessment using FDG-PET-based ΔSUVmax, ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant immunotherapy in cutaneous SCC. FDG-PET could, upon validation, select CSCC patients for response-driven treatment adaptation in future trials. FDG-PET-CT upon neoadjuvant immunotherapy in CSCC, changes in PET-parameters and predictive values of any decline in SUVmax, MTV or TLG. Clinical trial information: NCT04620200 . [Table: see text]
FDG-PET/CT response and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.
Authors: De Barros E Silva Milton Jose , Tavares Monique Celeste , Lima Joao Paulo S. N. , Buzaid Antonio C. , Garcia Daniel , Camargo Veridiana Pires De , Molina Andre , Bertolli Eduardo , Lobo Matheus , Van Akkooi Alexander Christopher Jonathan , Pinto Clovis , De Paula Rafaela Brito , Lima Eduardo , Rinck José Augusto , Duprat Joao
Published: June 2023

9585

Background: Neoadjuvant immunotherapy with nivolumab 3mg/kg and ipilimumab 1 mg/kg (N3+I1) for two cycles for clinical stage III melanoma have shown rates of major pathological response (MPR) of approximately 60%.The prognosis of this group seems to be excellent so far. On the other hand, patients classified as pathological non-responders have a worse outcome and early identification of this group may allow us to tailor the treatment before surgery. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant N3+I1 for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. The total number of FGD avid lesions and the percentual difference between the maximum SUV per lesion was calculated. The pathological results were correlated to FGD-PET/CT findings. Results: Between January 2019 and January 2023, 28 patients with clinical stage III melanoma treated with N3+I1 who had baseline and preoperative 18F-FDG PET were identified. Gender: 20 (71%) males, median age (range):55 (34-78), BRAFV600E/K mut: 15(53%), positive nodes on baseline PET/CT:1 = 26 (92%), 2 = 1(4%), and 3 = 1(4%). All known lesions identified by CT scan were also captured by FGD-PET/CT. Site of node(s): axilla = 12 (43%), cervical = 10 (36%), and inguinal = 6(21%). All but one patient received 2 cycles of N3+IP1(1 patient had grade 3 toxicity and received only one cycle). Pathological response: MPR = 19(68%), non-MPR: 8 (28%), and 1(4%) did not undergo surgery due to widespread progression. An increase in maximum SUV and/or appearance of new lesion(s), n = 8(28%), was correlated to non-MPR or metastatic disease in all cases, including a patient who developed sarcoidosis-like reaction with increase of SUV in the index lesion (+68%) and appearance of inflammatory mediastinal lymph-nodes. The median increase was (range): +73% (+11% to 483%). Reduction or stable maximum SUV with no appearance of new lesion, n = 20 (72%), was associated with MPR in 19 patients (95%). One patient,who had G3 colitis (with the need of infliximab), had 32% of reduction in maximum SUV but 100% of viable tumor cells on pathological report. The median decrease (range) was -76% (-1.2% to -100%). Conclusions: FGD-PET/CT may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.
Survival outcomes associated with liver-directed therapies in patients with metastatic uveal melanoma.
Authors: Caplan Michael M , Chen Lanyi Nora , Krishnasamy Venkatesh , Sperling David , Weintraub Joshua , DeStephano David , Pan Samuel M , McDonnell Diana , Marr Brian P , Carvajal Richard D. , Khan Shaheer
Published: June 2023

9590

Background: Metastatic uveal melanoma (mUM) is characterized by a hepatotropic pattern of spread and poor outcomes. Tebentafusp, the only FDA approved therapy, is restricted to patients (pts) with the HLA-A*02:01 genotype. As a result, a variety of liver-directed therapies (LDT) are commonly used for management of hepatic metastases. Methods: Pts with mUM with hepatic metastases who underwent LDT, including radiofrequency ablation, microwave ablation, hepatic metastatectomy, Yttrium-90 radioembolization (SIRT), transarterial chemoembolization (TACE), bland embolization, and immunoembolization (IE), were identified from an institutional database. Data collected included: age, gender, tumor location and size, baseline liver function tests (LFT) and lactate dehydrogenase (LDH), molecular tumor characteristics (where available), type(s) of LDT received, systemic therapies received, and vital status. Time from onset of hepatic metastasis until death (Liver-OS), as well as time from initial diagnosis of primary uveal melanoma until death (Ocular-OS) were calculated. Results: A total of 119 pts were identified. The median age at diagnosis was 53.8 years (range 26-83), 47% were female. At the time of LDT initiation, 33% had bilobar disease and 16% had extrahepatic metastasis. 18% pts had elevated LFTs and 55% had elevated LDH. 72% of pts had M1a disease, 24% had M1b and 4% had M1c disease. 45% of pts received more than one form of LDT. SIRT (31%) was the commonly administered initial LDT, followed closely by IE (26%) and TACE (9%). 86% of pts received systemic therapy including 42% who received immune checkpoint blockade overlapping with LDT. Molecular profiling in 26 pts revealed recurrent mutations in BAP1 (n = 18) and SF3B1 (n = 8). The median ocular-OS across all pts was 71.0 months (95% confidence intervals (CI), 62.8-99.4). The median liver-OS across all pts was 31.8 months (95% CI 25.2-35.3). In pts who received TACE, IE, or SIRT exclusively (n = 44), the median Liver-OS was 15.2 months (95% CI 12.8-NA) for TACE (n = 8), 23.3 months (95% CI 15.8-NA) for SIRT (n = 28), and 28.2 months (95% CI 22.6-NA) for IE (n = 8). Conclusions: Our results provide additional support for the utilization of LDT in pts with mUM, as demonstrated by improved OS compared to historical survival data.
Long-term outcomes of chronic immune-related adverse events from adjuvant anti-PD-1 therapy for high-risk resected melanoma.
Authors: Goodman Rachel S , Lawless Aleigha , Woodford Rachel , Fa'ak Faisal , Tipirneni Asha , Patrinely James Randall , Yeoh Hui-Ling , Rapisuwon Suthee , Haydon Andrew , Osman Iman , Mehnert Janice M. , Long Georgina V. , Sullivan Ryan J. , Carlino Matteo S. , Menzies Alexander M. , Johnson Douglas Buckner
Published: June 2023

9591

Background: Adjuvant anti-PD1 improves relapse-free survival in high-risk, resected melanoma, but can lead to irAEs, which become chronic in up to 41% of patients (Patrinely et al, JAMA Onc 2021). Given the expanding use of anti-PD-1 in earlier settings in many tumors, it is imperative to assess their long-term effects. We aimed to determine the incidence, characteristics, and long-term outcomes, including resolution vs persistence, of chronic irAEs from adjuvant anti-PD1. Methods: We retrospectively analyzed patients (pts) treated with adjuvant anti-PD1 for resected stage III-IV melanoma from 2015-2022 from 6 institutions; all pts had at least 18 month follow up post-anti-PD1 discontinuation. Demographics, disease characteristics, treatment and recurrence details, and outcomes were collected. Type, grade, duration, treatment, and resolution of acute (onset during treatment) and chronic irAEs (defined as those extending 6+ months after treatment cessation) were characterized. Results: Among 318 pts, 226 (64%) developed acute irAEs arising during treatment, including 44 (20%) with grade 3-5 irAEs. Chronic irAEs developed in 147 (46%) pts, of which 74 (50%) were grade 2+, 6 (4%) were grade 3-5, and 100 (68%) were symptomatic. With long-term follow-up (median 35 months), 52 (35%) pts experienced resolution of chronic irAEs while 95 (30% of the full cohort) had persistent chronic irAEs at last follow-up. Among these 95 pts with persistent chronic irAEs, 43 (45%) were grade 2+, 42 (44%) were symptomatic, 24 (16%) were on steroids, and 42 (29%) were on other management. The most common persistent chronic irAEs were hypothyroid (n = 38), arthritis (n = 18), dermatitis (n = 9), and adrenal insufficiency (n = 8). Of 37 pts with chronic irAEs who received additional immunotherapy, 12 (32%) had a flare, 10 (27%) had no effect, and 20 (54%) had a distinct irAE. Conclusions: In this large cohort of anti-PD1 treated pts, chronic irAEs were common (46%) and frequently were persistent with long-term follow up (30%, most often hypothyroid and arthritis). Prolonged monitoring and management are needed for these long-term survivors. [Table: see text]
Treatment pattern of early-stage premenopausal breast cancer patients with low Oncotype DX score: Single center experience.
Authors: Al Saheli Zaid Ihab , Ammari Omar , Albusoul Linda , Dabak Vrushali S.
Published: June 2023

e12510

Background: The predictive value of Oncotype DX in early-stage node negative breast cancer had been previously well established. As per TAILORx, patients with a low Oncotype DX Recurrence Score RS (0–25) did not benefit from chemotherapy. Premenopausal patients are a crucial subgroup for which recommendations based on Oncotype DX are imprecise. Those with Oncotype DX RS 16-25 are thought to have a small benefit from chemotherapy. Our goal was to study the treatment pattern for this group of patients managed at our institution. Methods: We conducted a retrospective analysis to assess premenopausal patients with early-stage breast cancer who had Oncotype DX testing done. All eligible patients were compared based on whether chemotherapy was given or not. The primary endpoint evaluated was the rate of local recurrence. Univariate comparisons were assessed using t-tests or ANOVA for continuous variable & chi-square for categorical variable. Results: A total of 506 patients younger than 50 years diagnosed between 01/2018 and 12/2020 who had an Oncotype DX available were identified. Of these, 344 were White, 137 were Black and 23 identified as another race. The average age of patients was 42.7 ± 5.5 years. Patients treated with chemotherapy were found to be on average younger than those who did not receive chemotherapy (42 years old vs 43.6 years old, P < 0.0001). The average tumor size for patients who got chemotherapy was 3.26 cm compared to an average size of 2.78 cm for patients who avoided chemotherapy. 72.1% of patients with stage 2 disease had received chemotherapy compared to 38.1 % of patient with stage 1. There were 462 patients with RS < 16, 28 patients with RS 16-25, and 16 patients with RS > 25 as illustrated. Patients were followed from a range of 1.8 months to 30.7 months. There were 6 patients who had local recurrences identified, all of which had RS scores < 16. Conclusions: In our study, 91.3% had RS < 16 and generally should have avoided chemotherapy, however 35% of these patients continued to receive chemotherapy. Only 5.5% of our population had RS 16-25, a quarter of which (n = 7) received chemotherapy. Of those 7 patients, 3 had positive lymph node disease. None of these patients had disease recurrence to date. Patients with RS >25 made up 3.2% of the population and would generally benefit from chemotherapy, however 12.5% of these patients did not end up receiving it. Using Oncotype DX in early-stage breast cancer helps avoid chemotherapy safely in majority of patients. [Table: see text]
The safety of breast reconstruction: The impact of breast reconstruction surgery on postoperative adjuvant therapy for breast cancer.
Authors: Nagura Naomi , Ogiya Akiko , Nogi Hiroko , Narui Kazutaka , Mori Hiroki , Sasada Shinsuke , Ishitobi Makoto , Kondo Naoto , Yamauchi Chikako , Koike-Shimo Ayaka , Saiga Miho , Seki Hirohito , Sakurai Teruhisa , Shien Tadahiko
Published: June 2023

e12511

Background: Postoperative adjuvant therapy is very important in treating breast cancer, and increasing numbers of patients are undergoing immediate breast reconstruction (IBR) at the same time as breast cancer surgery. However, the impact of breast reconstruction surgery on adjuvant therapy is controversial. In this multicenter cohort study led by the Japanese Breast Cancer Society, we examined the impact of reconstructive surgery on postoperative adjuvant therapy in breast cancer patients who underwent IBR. Methods: We examined the association between adjuvant therapy and complications of reconstructive surgery in 4726 patients with primary breast cancer who underwent IBR during the period from January 1, 2008 to December 31, 2016. Statistical analysis employed the χ2 test. Results: Of the 1044 patients who received adjuvant chemotherapy, the median time from the date of surgery to the start of chemotherapy was 51.0 days, with 65 patients (6.2%) starting more than 90 days after surgery. 66 IBR complications required surgery, including infections and tissue expander (TE) removal. Of the 65 patients for whom chemotherapy was initiated 90 days or more after surgery, 9 patients (13.8%) had complications requiring surgery, significantly more than the 57 patients (5.8%) in the < 90 days group (P = 0.010). Post-mastectomy radiation therapy (PMRT) was performed after breast cancer surgery in 359 cases: 69 cases received autologous tissue irradiation, 46 TE irradiation, 241 silicone breast implant (SBI) irradiation, and 3 removal before irradiation. 5 cases given autologous tissue irradiation and 30 receiving artificial material irradiation required surgery within 1 year after the cancer surgery due to complications of IBR. There was no significant difference in the frequency of complications requiring surgery between autologous tissue irradiation and artificial material irradiation (P = 0.422). There were 35 complications (9.7%) requiring surgery in the irradiated group, significantly more than the 118 cases (2.7%) in the non-irradiated group (P < 0.001). Conclusions: Adjuvant chemotherapy was generally not delayed, but complications requiring surgery related to IBR were more frequent in those with delay beyond 90 days, suggesting that postoperative complications from breast reconstruction may have influenced the delay in initiating chemotherapy. Therefore, in cases for whom postoperative chemotherapy is anticipated, complications from breast reconstruction may have impacted outcomes, making preoperative risk assessment even more important. There was no difference in the frequency of reconstructive complication surgery according to whether autologous tissue irradiation or artificial material irradiation had been used, but further investigation is needed.
An analysis of National Cancer Data Base: Male breast cancer and overall survival.
Authors: Albagoush Sara , Masih Durva , Wu Xinxin , Swedek Michelle , Randhawa Saboor Ejaz , Silberstein Peter T.
Published: June 2023

e12513

Background: Male breast cancer unlike female breast cancer is rare, representing approximately 1% of cancers that occur in men and approximately 1% of all BCs worldwide. It is managed by extrapolating from breast cancer in women due to it is rarity. We aimed to perform a large retrospective study with a focus on disease characteristics and overall survival. Methods: We performed a retrospective analysis of male breast cancer patients from the National Cancer Database (2004–2020). We obtained demographic, tumor, clinical and therapy data. Kaplan-Meier survival curves were created to estimate overall survival. Cox regression analysis was used to compare the groups within each variable. Results: We identified 31348 patients with primary diagnosis of male breast cancer (median age 66 years). Patients were predominantly white (82.1%) then black (13.4%). Most of patients are located in urban or metropolitan areas (95.9%) within a median of only 8.4 miles from the hospital where they received care. Almost equal patients treated at community hospitals (48.2%) and academic hospitals (50%). Patients were mainly covered by Medicare (49.0%) then Private insurance (40.8%). Most men who diagnosed with MBC had invasive cancer (88.3%). Only 1433 (4.6%) patients presented with metastases at diagnosis. The median tumor size was 3 cm. Most of tumors were moderately differentiated (36.1%) then (24.0%) poorly differentiated. In most patients, the tumor is present in the central portion of the breast. Several treatment modalities were used, of which primary surgical resection was the most common [90.7%). Among systemic therapies, hormonal therapy was the most common (57.1%%) then chemotherapy (34.3%) then radiation therapy (30.6%) and immunotherapy (4.8%). In terms of duration, time from diagnosis to surgery was 26 days (shortest), diagnosis to immunotherapy was 57 days, diagnosis to chemotherapy was 59 days, and time from diagnosis to radiation was 145 days (longest). The overall 30-day mortality was 0.3% (75/26333), the 90-day mortality was 0.9% (224/26333). Median overall survival is 67.1% (95% CI 143.371-150.349). Using cox proportional hazards model; factors influencing survival rate including Age, race, CDS P < 0.001, tumor size, year of diagnosis P < 0.000. All treatment modalities including surgery, chemotherapy and hormonal therapy was associated with increase overall survival with P < 0.001 (95% CI 1.245-1.370). Conclusions: This is the largest study to date on epidemiology and prognostic factors for MBC using NCDB. Old age, white race, greater comorbidity index, and larger tumor size are associated with decreased survival. Surgery and adjuvant therapy are associated with increased overall survival. Further studies warranted to elucidate the causes of improved survival associated with some of these factors will help improve quality of care for patients with MBC.
Exosome-based delivery of microRNAs to confer adriamycin-resistance to sensitive cells through modulating the immune- and metabolism-related gene PTEN in HER2-negative breast cancer.
Authors: Yang Sujin , Tang Jinhai
Published: June 2023

e12518

Background: Anthracycline-based chemotherapy is frequently used to treat breast cancer. However, acquired drug-resistance remains a challenge for successful treatment. Recent evidence suggests that in addition to increased tumor cell resistance, modifications in the tumor immune microenvironment (TIME) consistently contribute to the development of chemo-resistance. Methods: TIME scores and tumor-infiltrating immune cells (TICs) scores were used to investigate clinicopathological characteristics and gene transcriptome profiling of 142 HER2-negative breast cancer patients who received anthracycline-based chemotherapy. Exosomes isolated from MCF/7-ADR (ADR-exos) and MCF/7-S (S-exos) cell lines were characterized. MiRNA microarray and TMT mass spectrometry analysis were used to identify differentially expressed miRNA and its target genes. The ability of ADR-exos to transfer drug-resistance mediated by miR-222 was assessed by immunofluorescence assay, flow cytometry and qRT-PCR. We optimized the conditions to load miR-222 mimic (or inhibitor) into exosomes produced by HBL-100 cells (H-exos). The influence of miR-222 inhibitor-containing exosomes on the downstream pathway of miR-222 and the potential therapeutic effects both in vitro and in vivo were evaluated. Results: Firstly, we discovered the complicated and heterogenous TICs subtypes and their unique biological behaviors in HER2-negative breast cancer. Gene set variation analysis (GSVA) was used to quantify 85 differentially expressed immunologic signature gene sets and 7202 corresponding immune-related genes. Using miRNA microarray analysis and TMT mass spectrometry, 45 differentially expressed immune-related proteins affected by the miR-222 level were identified, particularly PTEN, a well-known tumor suppressor factor. Furthermore, we successfully established miRNA mimic/inhibitor-containing exosomes to explore the individual function of exosomal miR-222 in promoting adriamycin-resistance both in vitro and in vivo. Conclusions: HER2-negative breast cancer patients own unique TIME subtypes, leading to different outcomes of chemotherapy. We exhibit the potential applications of miR-222-mimic/inhibitor-containing exosomes for reversing chemo-resistance. Adriamycin-resistant cells can transmit drug-resistance to sensitive cells via delivering miR-222 by modulating the immune- and metabolism-related target gene PTEN both in vitro and in vivo without interference from other relevant drug-resistance factors in exosomes. Therefore, miR-222-containing exosomes as well as the target gene PTEN may be a promising biomarker to predict the chemo-resistance and tumor immunomodulatory effects of Anthracycline-based chemotherapy in HER2-negative breast cancer patients.
HR+/HER2- Breast cancer: The effect of online education on clinician knowledge, competence, and confidence in monitoring, mitigating toxicities, and developing patient-centric plans using a team-based approach.
Authors: Patel Urvi , Dorkhom Nabil , Phoenix Victoria , Cohen Jacob
Published: June 2023

e12522

Background: CDK4/6 inhibitors provide effective treatment options for patients with HR-positive, HER2-negative breast cancer (BC), but adherence and persistence can be challenging. To address this gap, a global educational activity was developed that consisted of a 2-hour live streaming virtual meeting with interactive workshops and a 45-minute online enduring activity. The objective of this study was to assess the educational impact of the online enduring educational activity. Methods: To assess educational impact a repeated-pairs pre-/post-assessment study design using 3 knowledge/competence questions, in which everyone served as their own control. A paired samples t-test assessed mean differences in average number of correct responses pre- to post-assessment, and a McNemar’s test assessed significance of improvement in single questions from pre- to post-assessment. P values < .05 are statistically significant. Confidence was also assessed using a pre/post confidence question. The activity launched on June 4, 2021, and data was collected till March 30, 2022. Results: 80 oncologists from outside the US (OUS) and 69 oncologists from the US who answered all the assessment questions were included in the analysis. Each question assessed a learning objective. All three knowledge/competence learning objectives showed a significant improvement in the OUS oncologist group, and 2 of the 3 showed a significant improvement in the US group. Conclusions: This online enduring activity resulted in a significant improvement of oncologists’ knowledge and competence related to clinical evidence for the use of CDK4/6i, managing adverse events associated with CDK4/6i and monitoring patients on CDK4/6i. Confidence of oncologists in counselling patients on the importance of adherence to CDK 4/6 inhibitor therapy also improved in 29% of OUS oncologists and 33% of US oncologists. However, there is still a need for education in a significant percentage of both OUS and US oncologists on this topic. [Table: see text]
Longitudinal trends in serum calcium, parathormone and bone mineral density in breast cancer survivors on aromatase inhibitor therapy: A single institutional cohort study.
Authors: Sorathia Sharmeen , Ogbue Olisaemeka , Unlu Serhan , Nanah Abdel Rahman , Abdeljaleel Fatima , Alqaisi Sura , Serhal Dina , Haddad Abdo S. , Daw Hamed
Published: June 2023

e12531

Background: Aromatase inhibitors (AIs), when used as adjuvant treatment of hormone receptor positive breast cancer, have been associated with bone density loss. However, any impact on PTH and by extension calcium (Ca) homeostasis is yet to be elucidated as no study till date has investigated longitudinal trends in parathyroid hormone (PTH) while on AI therapy. We explored these to determine if long term AI therapy was associated with hyperparathyroidism. Methods: This is a retrospective study of female breast cancer patients at the Cleveland Clinic Foundation started on AIs (anastrozole, letrozole and exemestane) from January 2015 to April 2022. Included patients had both baseline and subsequent data (after starting AI therapy), on serum Ca, PTH and lumbar spine T-scores (LsTs). These values were compared using paired t-test. Results: We identified n=9657 patients on AI therapy and included n=249 with pre and post AI PTH values. Among these, n= 209 received anastrozole, n=34 received letrozole and n=6 received exemestane. Cohort median age was 68 (IQR 62-72) years and median duration of AI therapy was 3 years. While we observed a significant positive correlation between change in Ca and change in PTH (p=0.02), the differences between baseline and treatment median serum Ca and PTH were not statistically significant. There was no significant association between changes in either serum Ca or PTH and change in LsTs (p-value: 0.69 and p-value: 0.05 respectively). Notably, 4% patients had elevated PTH and Ca after AI therapy was initiated among whom n=4 had markedly elevated PTH with low urinary Ca. Three of these four patients also had a diagnosis of chronic kidney disease (CKD) with normal vitamin D levels. Two patients with elevated PTH were on biotin supplements. There was an overall downtrend in LsTs (p-value: 0.0039) with no significant difference between the three AIs (p-value 0.0613). However, in comparison to other AIs, letrozole had the least depreciation in LsTs. Conclusions: Our findings do not suggest any correlation between AI therapy and hyperparathyroidism among breast cancer survivors. No significant increase in PTH levels occurred during AI therapy and majority of patients with clinically significant PTH elevation also had CKD, which may have contributed also to elevation of PTH level and low urinary calcium excretion.[Table: see text]
Lowering the bar for consideration of neoadjuvant chemotherapy in early-stage HER2-positive breast cancers.
Authors: Godbole Manasi Manoj , Meranda Matthew , Shango Kathren , Dabak Vrushali S.
Published: June 2023

e12534

Background: The use of neoadjuvant chemotherapy (NAC) has contributed to increased rates of disease-free survival (DFS) as well as overall survival in breast cancer patients, specifically those with HER2-positive disease. Stage 2 patients with HER2-positive disease including tumors > 2cm as well as node positive disease receive neoadjuvant chemotherapy as per current NCCN guidelines. The aim of our study was to understand outcomes in patients with early breast cancer receiving chemotherapy. Methods: We extracted data on patients with initial clinical stages IA-IB breast cancer who had HER2-positive status on initial biopsy and received chemotherapy plus anti-HER2 therapy in the Henry Ford Health System between January 2016 to June 2020. Patients with T2 or above and/or node positive disease were excluded. Results: Of the 229 total patients that met eligibility criteria, 159 (71%) were white, 65 (28%) were African American. 99% were females. The median age at diagnosis was 61 years. Estrogen receptor positivity was noted in 85% (196/229) of the patients. NAC was given to 56 patients (24%) of which 26 (46%) were African American and 45 (80%) were hormone receptor positive. 5 (9%) patients achieved pathological complete remission (CR). Remaining 51 patients (91%) did not have pathological CR. Of these, 17 (33%) patients had the same stage at surgery after NAC and 34 (66%) were upstaged on final pathological evaluation. 21 patients with residual disease (41%) underwent treatment change in the form of either ado-trastuzumab emtasine (TDM-1) or additional radiation therapy or repeat surgery. Of note, 34 of the 51 patients were treated for residual disease after 2019 with TDM-1. 54 (95%) patients are alive currently. Of the 173 patients that received adjuvant chemotherapy (76%), 39 (23%) were African American and 150 (87%) had hormone receptor positive disease. 19 of these (11%) were upstaged at surgery compared to the initial biopsy requiring treatment change. 163 (94%) are alive currently with no disease recurrence. Conclusions: Our study results suggest that NAC is used in minority of breast cancer patients, especially with stages 1A and 1B. Pathological CR rate in our study population was low and majority of patients who got NAC as well as a small percent of those who received adjuvant chemotherapy had disease upstaged based on surgical pathology results. We believe that this could be because of inaccurate initial staging due to limitations of imaging techniques and our population being mostly hormone receptor positive. With approval of TDM-1 in patients with residual disease post NAC, we may be able to improve outcomes in terms of recurrences and survival in these patients. Thus, consideration of NAC for early stage HER2-positive breast cancers appears attractive and data like our study may support ongoing prospective clinical trials.