Min HY, Lee SC, Woo JK
… +14 more, Jung HJ, Park KH, Jeong HM, Hyun SY, Cho J, Lee W, Park JE, Kwon SJ, Lee HJ, Ni X, Shin YK, Johnson FM, Duvic M, Lee HY
Clin Cancer Res
· 2026 Mar · PMID 41834508
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Chen J, Nelson C, Wong M
… +35 more, Tee AE, Liu PY, La T, Fletcher JI, Kamili A, Mayoh C, Bartenhagen C, Trahair TN, Xu N, Jayatilleke N, Wong M, Peng H, Atmadibrata B, Cheung BB, Lan Q, Bryan TM, Mestdagh P, Vandesompele J, Combaret V, Boeva V, Wang JY, Janoueix-Lerosey I, Cowley MJ, MacKenzie KL, Dolnikov A, Li J, Polly P, Marshall GM, Reddel RR, Norris MD, Haber M, Fischer M, Zhang XD, Pickett HA, Liu T
Clin Cancer Res
· 2026 Mar · PMID 41834507
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Martin-Broto J, Martinez-Trufero J, Diaz-Beveridge R
… +18 more, Gutierrez A, Carrasco I, Lopez-Jimenez C, Sebio A, González-Billalabeitia E, Ramos R, Romagosa C, Merino J, Fernandez-Jara J, Hernandez-Vargas L, Garmendia MD, Cruz-Jurado J, Valverde C, Mondaza-Hernandez JL, Carrera MA, Ledesma P, Hindi N, Moura DS
Clin Cancer Res
· 2026 Jun · PMID 41817407
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PURPOSE: This single-arm, phase Ib trial aimed to evaluate the safety and preliminary efficacy of epirubicin, ifosfamide, and nivolumab as first-line treatment for advanced undifferentiated pleomorphic sarcoma (UPS). PAT...PURPOSE: This single-arm, phase Ib trial aimed to evaluate the safety and preliminary efficacy of epirubicin, ifosfamide, and nivolumab as first-line treatment for advanced undifferentiated pleomorphic sarcoma (UPS). PATIENTS AND METHODS: Adult patients with a centrally confirmed diagnosis of advanced UPS were eligible. Patients received epirubicin 60 mg/m2 (days 1-2), ifosfamide 3 g/m2 (days 1-3) every 21 days for up to six cycles, and nivolumab 360 mg flat dose intravenously (day 3/each cycle), followed by maintenance nivolumab for one year. The primary endpoint was the determination of the recommended phase II dose (RP2D). RESULTS: Sixteen patients were enrolled with no dose-limiting toxicities observed; the RP2D was established at full-dose epirubicin, ifosfamide, and nivolumab 360 mg. Grade 3 to 4 treatment-related adverse events included neutropenia (62.5%) and anemia (43.8%). The overall response rate was 68.8%, with 94% of patients experiencing tumor shrinkage. The median progression-free survival was 9.9 months (95% confidence interval, 7-12.7), and the median overall survival was not reached. CONCLUSIONS: The combination of epirubicin, ifosfamide, and nivolumab is a safe, feasible, and highly active treatment for advanced UPS.
Fukumura K, Jiang P, Yeboa DN
… +10 more, Singareeka Raghavendra A, Gubbiotti MA, Andersen CR, Ferguson SD, Duose DY, Kudo Y, Arun B, Reuben A, Huse JT, Ibrahim NK
Clin Cancer Res
· 2026 Jun · PMID 41817317
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PURPOSE: Brain metastasis (BM) is a deadly complication of systemic malignancy that has been associated with defective cellular immunity. We sought to characterize the foundational elements and clinical relevance of BM-a...PURPOSE: Brain metastasis (BM) is a deadly complication of systemic malignancy that has been associated with defective cellular immunity. We sought to characterize the foundational elements and clinical relevance of BM-associated immunosuppression using integrated molecular profiling in primary patient material. EXPERIMENTAL DESIGN: Retrospective patient tissue cohorts of breast (n = 153) and lung (n = 153) cancer BM were stratified by histopathologic scoring of tumor-infiltrating lymphocytes (TIL) and clinical outcome, with a large subset of breast cancer samples further analyzed by T-cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq). An ongoing clinical trial comparing pre- and postoperative stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) in BM management was then leveraged to dissect radiation-induced immune responses by TCR- and RNA-seq. RESULTS: Patients with high-grade histopathologic TIL infiltration and enriched TCR diversity demonstrated favorable prognoses in breast and lung cancer BM. Moreover, SRS/SRT treatment enhanced TCR diversity in the BM microenvironment, along with signatures of antigen processing and presentation. Finally, integrated analysis demonstrated that IR seemed to reactivate immune microenvironmental signatures normally suppressed in BM and upregulate immune signaling pathways correlated with favorable outcomes in patients with breast cancer BM. CONCLUSIONS: High TCR diversity in BM is associated with improved prognosis and highlights therapeutically tractable targets within the immune microenvironment. Moreover, we show in a prospective clinical trial that IR enhances T-cell-mediated immune responses, upregulating antigen presentation and enhancing TCR diversity in BM. These results argue for increased therapeutic investigations of radiation-induced immunomodulatory effects in BM, potentially in association with immune checkpoint inhibition.
McKay RR, Nazari SS, Elliott A
… +14 more, Smith N, Barata P, Kilari D, Garje R, Haffner MC, Morrissey C, Rupnow BA, Basu S, Drake C, Rose B, Bagrodia A, Agarwal N, Antonarakis ES, Beltran H
Clin Cancer Res
· 2026 Jun · PMID 41817312
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PURPOSE: KLK2 is an androgen-regulated gene critical in prostate cancer biology with multiple KLK2-targeted therapies in clinical development. We investigated KLK2 RNA expression patterns and associations with molecular...PURPOSE: KLK2 is an androgen-regulated gene critical in prostate cancer biology with multiple KLK2-targeted therapies in clinical development. We investigated KLK2 RNA expression patterns and associations with molecular features to provide context for emerging KLK2-targeted treatments. EXPERIMENTAL DESIGN: DNA/RNA next-generation sequencing was performed on 7,078 prostate cancer specimens. KLK2-high/low RNA expression was defined as ≥75th/<25th percentiles (transcripts per million, TPM). KLK2 expression was evaluated across histologic subtypes, disease states, and metastatic sites, with correlative analyses of genomic alterations, RNA signatures, and clinical outcomes. RESULTS: KLK2 gene expression varied significantly by histology, with highest levels in adenocarcinoma [8.79 log2(TPM + 1)] and minimal expression in histologic neuroendocrine prostate cancer [0.33 log2(TPM + 1)]. Expression was significantly higher in androgen deprivation therapy (ADT)/androgen receptor pathway inhibitor (ARPI)-sensitive versus ADT/ARPI-exposed tumors [8.97 vs. 8.38 log2(TPM + 1), q < 0.001]. Localized tumors demonstrated higher expression than lymph node [8.93 vs. 8.76 log2(TPM + 1)] or distant metastases [8.23 log2(TPM + 1)], with visceral metastases showing the lowest levels. In the overall cohort, KLK2 expression correlated positively with androgen receptor signaling (r = 0.25-0.47) and negatively with neuroendocrine signaling. High KLK2 expression was associated with significantly improved overall survival (93.9 vs. 74.4 months, hazard ratio 0.68, P < 0.001) in the total cohort, with similar patterns in patients with ADT/ARPI-sensitive and ADT/ARPI-exposed disease. CONCLUSIONS: This large-scale clinico-genomic analysis reveals distinct KLK2 expression patterns across prostate cancer histologies, tumor sites, and clinical states. These findings provide a molecular framework understanding KLK2 as a therapeutic target in prostate cancer.
Chen F, Zhou S, Ma J
… +8 more, Tao H, Jing P, Liu X, Shen Z, Liu Z, Wei Y, Lv Z, Xu W
Clin Cancer Res
· 2026 Jun · PMID 41817286
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PURPOSE: Hypopharyngeal squamous cell carcinoma (HPSCC) has a poor prognosis. Although neoadjuvant chemoimmunotherapy (nCIT) is promising, responses are heterogeneous, and the PD-L1 combined positive score (CPS) inadequa...PURPOSE: Hypopharyngeal squamous cell carcinoma (HPSCC) has a poor prognosis. Although neoadjuvant chemoimmunotherapy (nCIT) is promising, responses are heterogeneous, and the PD-L1 combined positive score (CPS) inadequately stratifies benefit. We sought biomarkers to guide patient selection. PATIENTS AND METHODS: In this prospective, single-center, single-arm phase II trial, patients with resectable locally advanced HPSCC received two cycles of neoadjuvant toripalimab, albumin-bound paclitaxel, and nedaplatin. The primary endpoint was the pathologic complete response (pCR) rate. Pretreatment tumor biopsies from a subset of patients (n = 13) were analyzed by single-cell RNA sequencing to identify determinants of response. Findings were validated in a larger cohort (n = 60) using bulk RNA-seq and immunohistochemistry. RESULTS: Among 70 evaluable patients, the objective response rate was 82.7%. Of the 64 patients who underwent surgery, the pCR rate was 29.7% (95% confidence interval, 18.9%-42.7%). Baseline PD-L1 CPS was not associated with pathologic response (P = 0.313). Single-cell analysis revealed that the pretreatment tumor microenvironment of responders was significantly enriched with a proinflammatory neutrophil subset characterized by high expression of CCL3 (Neu_CCL3). A gene signature score derived from this subset was a strong and independent predictor of pCR (AUC = 0.788), significantly outperforming PD-L1 CPS (AUC = 0.621). CONCLUSIONS: The efficacy of nCIT in HPSCC is predetermined by a baseline immune architecture orchestrated by a CCL3+ neutrophil subset. The Neu_CCL3 gene signature is a promising, clinically translatable biomarker that can fill a critical gap in precision immunotherapy for HPSCC.
Sierra-Rodero B, Gil-González Á, Molina-Alejandre M
… +27 more, Nadal E, Calvo V, Lázaro M, Insa A, Massuti B, Martinez Marti A, de Castro J, García Campelo R, González Larriba JL, Bernabé R, Dómine M, Ponce Aix S, Cobo M, Camps C, Reguart N, Bosch-Barrera J, Majem M, Aguilar A, Palmero R, Blanco Clemente M, Martín-López J, Muñoz-Viana R, Megías D, Gutiérrez-Escobedo JM, Martínez-Toledo C, Cruz-Bermúdez A, Provencio M
Clin Cancer Res
· 2026 Apr · PMID 41805895
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PURPOSE: Complete pathologic response (CPR) correlates with long-term survival after perioperative chemoimmunotherapy (ChIO) in resectable non-small cell lung cancer (NSCLC). We provide a multiomic characterization of B...PURPOSE: Complete pathologic response (CPR) correlates with long-term survival after perioperative chemoimmunotherapy (ChIO) in resectable non-small cell lung cancer (NSCLC). We provide a multiomic characterization of B cells and tertiary lymphoid structures (TLS) to dissect the immune landscape associated with CPR. EXPERIMENTAL DESIGN: We integrated B-cell receptor (BCR) repertoire profiling (n = 87 tissue, n = 25 blood), multiplex immunofluorescence (n = 67), and bulk (n = 15), spatial (n = 12), and single-cell transcriptomics (n = 15) from tumor tissue and blood (baseline, surgery, and at 6 months of adjuvant therapy) in 123 patients (NADIM/NADIM II trials, NCT03081689/NCT03838159). RESULTS: CPR tumors exhibited a more clonal baseline BCR repertoire (AUC 0.775; P = 0.030) that was better conserved and reinvigorated during neoadjuvant ChIO. In blood, patients with CPR tumors displayed a repertoire enriched in class-switched clones (AUC 0.833; P = 0.008), characterized by higher diversity, lower clonality, and upregulation of activation-related transcriptional programs. Neoadjuvant ChIO was associated with the induction of B-cell-related genes within TLS regions and with higher TLS density at surgery compared with Ch (P = 0.034). TLS density was not associated with CPR (P = 0.129); however, mature TLS in CPR tumors were enriched in immune activation and antigen-presenting pathways, estimated T follicular helper cells, plasmacytoid dendritic cells, and plasma cells, whereas low B-cell regions from CPR tumors displayed higher inferred infiltration of CD8+ T cells, NK cells, and macrophages, with reduced neutrophils and Tregs. CONCLUSIONS: Patients with CPR tumors exhibit a preexisting and more mature B-cell response that develops further during neoadjuvant ChIO. Our findings link B-cell-related features to CPR and highlight BCR metrics as promising predictive biomarkers in NSCLC.
Crowell C, Mankuzhy NP, Bennett J
… +60 more, Bandopadhayay P, Sturm D, Green AL, Gupta T, Chatterjee A, Epari S, Chinnaswamy G, Prasad M, Patel SH, MacNeil M, Vanan MI, Larouche V, Renzi S, Jones J, Perreault S, Mata-Mbemba D, Sangatsuda Y, Yoshimoto K, Lin E, Feddersen C, Cruz O, Pavon-Mengual M, Vizzini O, Zápotocký M, Popovacki A, Klawinski D, Hansford JR, Schlosser MP, Omene E, Alexander KL, Satgunaseelan L, Williams A, Yao K, Ronsley R, Cheng S, Ludlow L, Eisenstat D, Khuong-Quang DA, Tabouret E, André N, Matheson K, Chan A, Lim-Fat MJ, Lapointe S, Cayrol R, Coleman C, Juretic N, McThenia S, Khan S, Wright-Nadkarni M, Salloum R, Galvin RT, Sener U, Hawkins C, Imber BS, Karajannis MA, Jones DTW, Ligon KL, Jabado N, Erker C
Clin Cancer Res
· 2026 Jun · PMID 41801141
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PURPOSE: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34-mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. EXPERIMENTAL DESIGN: This ret...PURPOSE: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34-mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. EXPERIMENTAL DESIGN: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. RESULTS: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2-45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22-28] with a median PFS of 14 months (IQR, 12-19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033-0.17] and achieving GTR/NTR compared with < NTR (HR, 0.51; 95% CI, 0.33-0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57-0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15-0.96), and initial GTR/NTR compared with < NTR (HR, 0.60; 95% CI, 0.37-0.97). CONCLUSIONS: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.
Lin Q, Morales-Giron AA, Sander C
… +9 more, Curtis JM, Barnes H, Patel PS, Fece de la Cruz F, Riedl JM, Matsubara H, Nakamura H, Liss AS, Corcoran RB
Clin Cancer Res
· 2026 Jun · PMID 41801133
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PURPOSE: Oncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC), with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial...PURPOSE: Oncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC), with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, in which EGFR-mediated RAS-MAPK pathway reactivation can be targeted to improve response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear. EXPERIMENTAL DESIGN: Mechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG12D-mutant PDAC models. RESULTS: We observed receptor tyrosine kinase (RTK)-driven adaptive reactivation of RAS pathway signaling following KRASiG12D in PDAC models. EGFR was a primary driver of adaptive RAS-MAPK reactivation in some models but was limited to those with epithelial differentiation. Conversely, adaptive RAS-MAPK reactivation in models with mesenchymal differentiation was primarily driven by FGFR signaling. In clinical PDAC specimens from The Cancer Genome Atlas, EGFR and ERBB3 expression was highly correlated with the expression of epithelial markers, whereas the expression of FGFR1 and mesenchymal markers was correlated. Notably, a RAS(ON) multi-selective inhibitor, which inhibits both wild-type and mutant RAS, abrogated RAS-MAPK reactivation in combination with KRASi in both epithelial and mesenchymal models and led to more consistent antitumor activity compared with combinations of KRASi and EGFR blockade. CONCLUSIONS: In PDAC, adaptive RAS-MAPK reactivation following KRASG12D inhibition can be mediated by different RTKs and influenced by cell state. Combinations of mutant-selective KRASi and RAS(ON) multi-selective inhibitors may represent a promising universal strategy to surmount adaptive resistance in patients with PDAC.
Gray JE, Laktionov K, Kim SW
… +15 more, Kato T, Wang J, Han Z, Mitchell P, Kuyama S, Tan Chun Bing J, Cundom J, Pinto G, Shepherd FA, Poole L, Lai R, Albayaty M, Amin NP, Kobayashi K, Lee CK
Clin Cancer Res
· 2026 Jun · PMID 41801128
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PURPOSE: In FLAURA2, first-line osimertinib plus platinum-pemetrexed induction, with osimertinib plus pemetrexed maintenance, improved progression-free survival versus osimertinib alone in epidermal growth factor recepto...PURPOSE: In FLAURA2, first-line osimertinib plus platinum-pemetrexed induction, with osimertinib plus pemetrexed maintenance, improved progression-free survival versus osimertinib alone in epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer (NSCLC; hazard ratio, 0.62; P < 0.001). Combining osimertinib with chemotherapy increased induction grade ≥3 adverse event rates, which reduced during maintenance. We report FLAURA2 patient-reported outcomes (PRO). PATIENTS AND METHODS: Health-related quality of life (HRQoL) was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core 30 (baseline, week 4, week 7, week 10, then every 6 weeks until progression) and QLQ Lung Cancer 13 (baseline, weekly until week 10, then every 3 weeks until progression). Score changes (baseline to progression/19 months) were analyzed by mixed models for repeated measures. Within-patient ≥10-point changes from baseline were considered clinically meaningful. Tolerability was assessed by PRO-Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: Patients had intermediate-to-high baseline functioning and global health status (GHS)/QoL (mean scores ≥63), with mild symptomatology (≤35). Most key scales showed nonclinically meaningful improvements; average least-squares mean (LSM) changes [95% confidence interval (CI)] for GHS/QoL and physical function, respectively, were 3.32 (1.67-4.98) and 2.37 (0.70-4.04) with combination therapy and 7.38 (5.70-9.07) and 6.74 (5.04-8.43) with monotherapy. Improvements in cough were clinically meaningful with combination therapy and monotherapy from week 5 (except monotherapy at week 73); average LSM changes (95% CI) were -13.23 (-14.85 to -11.62) and -11.19 (-12.83 to -9.55), respectively. Nonclinically meaningful deteriorations in fatigue and appetite loss were seen with the combination during induction. Both treatments were similarly well tolerated (PRO-CTCAE). CONCLUSIONS: In FLAURA2, osimertinib monotherapy and combination with platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC had nonclinically meaningful impacts on HRQoL in mildly symptomatic patients.
Clin Cancer Res
· 2026 May · PMID 41801052
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The results of a recent trial undoubtedly contribute a vital element to the overarching management of rare tumors and offer new treatment hopes for patients with brain metastases, thereby paving the way for future resear...The results of a recent trial undoubtedly contribute a vital element to the overarching management of rare tumors and offer new treatment hopes for patients with brain metastases, thereby paving the way for future research in immunotherapy. See related article by Ahluwalia et al., p. 1928.
Casak SJ, Zhang Y, Song C
… +6 more, Mishra-Kalyani PS, Tang S, Auth D, de Claro RA, Pazdur R, Lemery SJ
Clin Cancer Res
· 2026 May · PMID 41790455
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On May 5, 2021, and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval, respectively, for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or me...On May 5, 2021, and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval, respectively, for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval (AA) was granted based on the overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, P = 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months [95% confidence interval (CI), 17.8-22.1] and 16.8 months (95% CI, 14.9-18.7) in the pembrolizumab and placebo arms, respectively [hazard ratio (HR), 0.80 (95% CI, 0.67-0.94); P = 0.004]. However, in exploratory subgroup analyses, treatment benefit seemed to be driven by the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 population [85% of patients, with an OS HR of 0.79 (95% CI, 0.66-0.95)], whereas in the PD-L1 CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement [HR, 1.10 (95% CI, 0.72-1.68)]. These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a "one-trial" approach allowing AA based on the response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a first-line metastatic setting, following FDA's Project FrontRunner approach.
Yu HA, Tang KH, Markovets AA
… +11 more, Hartmaier R, Smith PE, Cho BC, De Langen AJ, Goldberg SB, Goldman JW, Le X, Iwama E, Cosaert J, Riess JW, Piotrowska Z
Clin Cancer Res
· 2026 Mar · PMID 41790029
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PURPOSE: Osimertinib is standard-of-care for first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following pr...PURPOSE: Osimertinib is standard-of-care for first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. PATIENTS AND METHODS: ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFR-mutated NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile post-progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a pre-specified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS was also assessed. RESULTS: The study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histo-genomic landscape post-first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 85% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. CONCLUSIONS: This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes.
Ge H, Li H, Kulkarni A
… +4 more, Chen Z, Upadhyay P, Ferris RL, Wang JH
Clin Cancer Res
· 2026 Jun · PMID 41785014
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PURPOSE: Immune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathologic responses (MPR) remain poorly defined. We sought to evaluate...PURPOSE: Immune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathologic responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR. PATIENTS AND METHODS: We analyzed high-resolution single-cell T-cell receptor (TCR) sequencing data from paired pretreatment and posttreatment CD8 tumor-infiltrating lymphocytes obtained from patients with HNSCC treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG3. RESULTS: Contrary to the clonal replacement hypothesis, posttreatment CD8 T-cell pools were dominated by preexisting TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of super-expanded clones. We developed the TCR adaptivity index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pretreatment and posttreatment time points; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was uncoupled from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the tumor-reactive signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR. CONCLUSIONS: Dual-ICI drives MPR predominantly through the adaptivity and functional reprogramming of preexisting immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.
Wu X, Sun K, Zhang J
… +13 more, Hou S, Yuan Z, Ju Y, Deng J, Zhao J, Jin Y, She J, Du M, Qiu M, Yang F, Li H, Li X, Yang E
Clin Cancer Res
· 2026 Jun · PMID 41784525
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PURPOSE: Despite the clinical adoption of immunotherapy in small cell lung cancer (SCLC), reliable biomarkers predicting clinical benefit are limited. Although the HERV-K (HML-2) subfamily has been reported to modulate t...PURPOSE: Despite the clinical adoption of immunotherapy in small cell lung cancer (SCLC), reliable biomarkers predicting clinical benefit are limited. Although the HERV-K (HML-2) subfamily has been reported to modulate the tumor immune response in multiple malignancies, its functional role in SCLC remains poorly defined, particularly the association with an inflamed microenvironment and favorable immunotherapy outcomes. EXPERIMENTAL DESIGN: The expression profile of locus-specific HERV-K was identified by TELESCOPE in the IMpower133 (n = 271) and PKUPH cohort (n = 40). IHC and RNA-fluorescence in situ hybridization were performed on a tissue microarray (n = 48) to validate the expression of HERV-K transcripts. Single-cell RNA sequencing and multiplex IHC, including PhenoCycler-Fusion, were used to characterize the tumor immune microenvironment. RESULTS: Although the HERV-K subfamily as a whole lacked prognostic value for immunotherapy in SCLC, a locus-specific HERV-K transcript, ERVK18, was associated with improved outcomes and exhibited the strongest positive correlation with immune-related signatures, representing multiple immune-activated pathways and increased immune cell infiltration. Single-cell and spatial analysis further revealed that high ERVK18 expression indicated elevated cytotoxicity signatures in T cells, along with enhanced spatial proximity between tumors and T cells. In the IMpower133 cohort, high ERVK18 expression was not only associated with better prognosis within the atezolizumab + chemotherapy group but also predicted improved overall survival in patients treated with atezolizumab + chemotherapy versus chemotherapy alone, confirming ERVK18 as a dual prognostic and predictive biomarker for first-line PD-L1 inhibitor response in SCLC. CONCLUSIONS: Elevated expression of ERVK18 represents an inflamed microenvironment and indicates a favorable immunochemotherapy prognosis for patients with SCLC.
Lin Z, Tang C, Liu T
… +7 more, Wang X, Wu Z, Hu F, Gai Y, Ruan W, Zhang X, Lan X
Clin Cancer Res
· 2026 May · PMID 41779012
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PURPOSE: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]-N-(2-(diethylamino)ethyl)-5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)picolinamide ([18F]PFPN) positron emission tomography (PET...PURPOSE: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]-N-(2-(diethylamino)ethyl)-5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)picolinamide ([18F]PFPN) positron emission tomography (PET) and [18F]fluorodeoxyglucose ([18F]FDG) PET in mucosal melanoma, evaluate their impact on clinical staging, and assess correlations between imaging metrics and molecular markers. EXPERIMENTAL DESIGN: This prospective study enrolled 65 participants with histologically confirmed mucosal melanoma from February 2021 to January 2025. All participants underwent both [18F]FDG PET and [18F]PFPN PET within 1 week. Lesion- and participant-based analyses compared detection sensitivity, false-positive rate, and staging concordance. Quantitative PET parameters were analyzed, and correlations with HMB45, SOX10, MelanA, S100, and mutation status (BRAF, KIT, NRAS) were evaluated using nonparametric tests and correlation analysis with Bonferroni correction. Decision curve analysis was used to evaluate clinical benefit. RESULTS: Sixty-five participants were included. [18F]PFPN PET showed higher lesion-based sensitivity than [18F]FDG PET [363/399 (91%) vs. 332/399 (83.2%)] and no false positives [0/363 (0%) vs. 4/336 (1.2%)]. The normalized maximum standardized uptake value was significantly higher for [18F]PFPN across all lesion types (P < 0.05). PFPN-based staging was more consistent with clinical staging (6.2% vs. 18.5% discordant cases). [18F]PFPN uptake showed significant positive correlations with HMB45 and SOX10 expression, whereas [18F]FDG parameters showed no such associations. CONCLUSIONS: [18F]PFPN PET outperforms [18F]FDG PET in lesion detection and clinical staging in mucosal melanoma, especially for liver and bone metastases. Its association with melanin differentiation markers may support its use in personalized imaging strategies.
Yogo A, Akanuma N, Kim GE
… +3 more, Mäkinen N, Thirlwell C, Nakakura EK
Clin Cancer Res
· 2026 May · PMID 41779010
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PURPOSE: Small intestinal neuroendocrine tumors (SI-NET) frequently present as multifocal lesions, but the molecular mechanisms underlying their development and heterogeneity remain unclear. This study aimed to character...PURPOSE: Small intestinal neuroendocrine tumors (SI-NET) frequently present as multifocal lesions, but the molecular mechanisms underlying their development and heterogeneity remain unclear. This study aimed to characterize the phenotypes of tumor cell populations across anatomic sites in patients with multifocal SI-NET and identify local microenvironmental factors influencing tumor development. EXPERIMENTAL DESIGN: Spatial transcriptomics was performed on 72 tissue microarray cores derived from 4 patients with multifocal SI-NETs that included tumoral and nontumoral tissues from various anatomic layers of the small intestine and regional metastatic sites. Unsupervised clustering, overrepresentation analysis, and ligand-receptor (L-R) pair analysis were used to define the tumor cell subtypes and associated signaling networks. External datasets were used for validation. Protein expression of selected genes was evaluated by immunohistochemistry and immunofluorescence. RESULTS: Unsupervised clustering revealed four major tumor cell subtypes: "mucosal," "mesenteric," "lymphatic," and "deep," based on their anatomic location and transcriptomic profiles. Each subtype exhibited distinct gene expression patterns and L-R interactions. The "mesenteric" and "lymphatic" subtypes exhibited distinct L-R pairs, such as NRG1-ERBB3 (HER3) and CXCL12-CXCR4, respectively. 5HT-HTR1D was found in all subtypes except "mucosal." Across the four subtypes, SST-SSTR1/2, PTN-NCL, MDK-NCL, and GJD2-GJD2 were consistently detected, suggesting fundamental roles in SI-NET biology. CONCLUSIONS: Although further validation is needed, our findings indicate that multifocal SI-NETs consist of spatially distinct tumor cell subtypes affected by local cellular interactions, providing insight into SI-NET intratumoral heterogeneity, possible microenvironment-triggered tumorigenesis, and potential subtype-targeted therapeutic strategies.
Baudin L, Zanella L, Lebeau A
… +11 more, Pleyers C, Gubbels N, Blacher S, Seidel L, Kakkos A, Goffin F, Lovinfosse P, Gennigens C, Pirson S, Kridelka F, Noel A
Clin Cancer Res
· 2026 Jun · PMID 41779008
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PURPOSE: Treatment of locally advanced cervical cancer (LACC) is guided notably by the European Society of Gynaecological Oncology guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy an...PURPOSE: Treatment of locally advanced cervical cancer (LACC) is guided notably by the European Society of Gynaecological Oncology guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histologic assessment of nonmetastatic para-aortic lymph nodes (PAoLN) provides prognostic value in LACC. EXPERIMENTAL DESIGN: Primary tumor and PAoLNs from 137 patients with nonmetastatic LACC were stratified by pretherapeutic 18F-2'-deoxy-2'-fluorodeoxyglucose PET/CT into pelvic PET-positive (pPET+, n = 72) and pelvic PET-negative (pPET-, n = 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils [CD66b+, neutrophil extracellular traps (NET)], and high-endothelial venules (HEV). Associations with progression-free survival (PFS) were examined via uni- and multivariate analyses after a median follow-up of 55.4 months. RESULTS: The primary tumor profile was not associated with outcome, whereas PAoLN features were strongly predictive. In pPET- patients, higher NETs were associated with shorter PFS [P = 0.015; hazard ratio (HR) = 2.768], whereas an elevated CD4/CD8 ratio improved outcomes (P = 0.047, HR = 0.497). In pPET+ patients, shorter PFS was linked to FOXP3+ (P = 0.04, HR = 1.918) and proliferating FOXP3+ cell (P = 0.018, HR = 1.668) density. Across the full cohort, abundant germinal centers (P = 0.0355, HR = 0.273) and an elevated CD4/CD8 ratio (P = 0.001, HR = 0.490) independently correlated with lower recurrence risk. Internal validation was conducted through a bootstrap resampling method. Combinatorial analyses revealed distinct predictive signatures according to pPET status: higher NETs, fewer germinal centers, and International Federation of Gynaecology and Obstetrics IIA1 to IIIB status predicted relapse in pPET- patients. CONCLUSIONS: Integrating pPET status with PAoLN histologic analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.
Irajizad E, Fahrmann JF, Wu R
… +5 more, Rudsari H, Dennison JB, Ostrin E, Ajani J, Hanash S
Clin Cancer Res
· 2026 May · PMID 41779007
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PURPOSE: Recent evidence suggests a significant association between microplastic (MP), forever chemicals, and plasticizers and various diseases, including cancer. In this study, we evaluated circulating levels of plastic...PURPOSE: Recent evidence suggests a significant association between microplastic (MP), forever chemicals, and plasticizers and various diseases, including cancer. In this study, we evaluated circulating levels of plastic-associated chemicals in relation to lung cancer incidence and mortality among smokers in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study. EXPERIMENTAL DESIGN: Using mass spectrometry, we screened for 29 known MP, forever plastics [per- and polyfluoroalkyl substances (PFAS)], and plasticizer chemicals in 245 sera collected preceding a lung cancer diagnosis and 1,200 noncase sera from participants in the PLCO study who had a history of smoking. Five PFAS and three plasticizers were detected and quantified in sera. A PFAP model, consisting of perfluorooctane sulfonate (PFOS) + perfluorohexanesulfonic acid (PFHA) + mono-iso-nonyl phthalate, was developed for predicting lung cancer mortality and risk strata based on quantiles established. RESULTS: Higher circulating levels of PFOS, PFHA, and mono-iso-nonyl phthalate were associated with increased risk of lung cancer death (P < 0.05) but not incidence. Compared with the lowest quantile (reference), individuals with PFAP scores in the highest quantile were at markedly higher risk of death from lung cancer (P < 0.0001), with respective cause-specific and subdistributional HR of 1.86 [95% confidence interval (CI), 1.18-2.93] and 1.82 (95% CI, 1.15-2.88). Substratified analyses confirmed that the PFAP model remained an independent predictor of lung cancer-specific mortality (P < 0.05) across strata defined by age, sex, smoking history, histologic subtype, and stage at diagnosis. CONCLUSIONS: In the PLCO cohort, elevated levels of PFOS, PFHA, and mono-iso-nonyl phthalate were associated with increased lung cancer mortality among ever smokers across disease subgroups.