JCO precision oncology最新文献

Purpose: The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes.

Methods: Resected patients with IHC at two institutions with genomic data were included. Sites of first recurrence (SOFR) were classified as liver only (LO), extrahepatic (EH) only, or simultaneous liver and extrahepatic (SIM). Overall survival (OS) was calculated from the time of recurrence.

Results: Between 1993 and 2021, 318 patients met inclusion criteria; 232 (73%) recurred. SOFR were LO = 93 (40%), EH = 80 (34%), and SIM = 59 (26%). Median OS from recurrence was similar in the LO (33 [26, 42] months) and EH groups (33 [23, 46] months) but much lower in SIM (12 [9.8, 18] months; P < .001). Moderate/poor tumor differentiation, lymphovascular invasion, N1 disease, perineural invasion, and time to recurrence (all P < .05) were associated with SIM; only positive resection margin predicted LO (P = .007). No individual genomic or pathway alterations predicted SOFR; however, for all recurrers, TP53mut (n = 51, 22%; hazard ratio [HR], 2.0 [1.4 to 2.9]; P = .002), CDKN2Adel (n = 34, 15%; HR, 3.4 [95% CI, 2.2 to 5.3]; P < .001), CDKN2B (n = 25, 11%; HR, 3.2 [95% CI, 2.0 to 5.0]; P < .001), and KRASmut (n = 25, 11%; HR, 2.5 [95% CI, 1.6 to 4.0]; P = .002) were associated with worse OS. On multivariable analysis, SIM (HR, 2.5 [95% CI, 1.7 to 3.5]; P < .001), N1 status (HR, 1.8 [95% CI, 1.2 to 2.6]; P = .004), and alterations in the high-risk genotype (TP53mut, CDKN2Adel or KRASmut; n = 84, 36%; HR, 2.4 [95% CI, 1.7 to 3.3]; P < .001) were independent predictors of poor OS.

Conclusion: Recurrence after resection of IHC is common, and the liver was the most common site (66%). Clinicopathologic and genomic factors had limited ability to predict SOFR. Although LO and EH were associated with similar OS, SIM recurrences had dramatically worse OS. Adjuvant strategies targeting liver recurrence may improve outcomes after resection of IHC.

Purpose: Translocation-associated sarcomas (TASs) encompass a wide spectrum of pathologic entities and clinical behavior. Driven by the oncogenic fusion, TASs typically show a stable genome and a low tumor mutational burden (TMB), with infrequent secondary genetic alterations (SGAs). Although oncogenic/likely oncogenic SGAs have been associated with an aggressive clinical course in certain histotypes, a comprehensive comparative study of their clinical impact across TAS histotypes has not been performed to date.

Materials and methods: Herein, we investigate the genomic landscape of 632 TASs, spanning the most common histotypes: Ewing sarcoma (ES, n = 196), desmoplastic small round cell sarcoma (DSRCT, n = 115), solitary fibrous tumor (SFT, n = 87), synovial sarcoma (SS, n = 75), etc. All tumors were tested on a clinically validated, matched tumor-normal DNA-targeted next-generation sequencing panel, with confirmed gene fusion partners. Both gene-level and arm-level copy number alterations were assessed and correlated with survival.

Results: Overall, oncogenic SGAs were detected in 51% of patients, with the highest incidence in myxoid liposarcoma (MLS, 88%). Patients with oncogenic SGA had a higher TMB and were associated with distant metastasis and/or progression-free survival (PFS) in ES, SFT, SS, and MLS in the localized group. TP53 mutations were the most common oncogenic SGAs across histotypes, with SFT and ES showing the highest rate (26% and 11%) and associated with worse PFS and disease-specific survival (P < .01). TP53 mutations in ES (P < .01) and SFT (P = .045) and TERT promoter mutations in SFT (P < .001) and MLS (P = .049) correlated with metastasis in the localized group.

Conclusion: Overall, oncogenic SGA correlated with a worse survival in certain TAS types.

Purpose: Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy associated with an exceptionally poor prognosis. A limitation in its standard-of-care management is the absence of practical molecular tools for monitoring disease progression. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker with potential applications in prognostication, early detection of cancer recurrence, refined evaluation of treatment response, and improved disease surveillance.

Materials and methods: We analyzed serial plasma samples from 81 patients with SCLC using a 105-gene hybrid capture-based next-generation sequencing liquid biopsy assay at three key time points: diagnosis, postchemotherapy, and clinical relapse.

Results: Extensive-stage (ES) patients demonstrated significantly higher median baseline maximum variant allele frequency (VAF_max) compared with limited-stage cases. Notably, limited-stage patients with VAF_max >40% experienced outcomes similar to those with ES disease. Across the cohort, median VAF_max values declined from 53.30% at baseline to 0.15% during remission and then rose to 38.65% at relapse, reflecting initial therapeutic sensitivity followed by disease recurrence that remained unremitting. Baseline VAF_max correlated with the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Moreover, disease-free survival (DFS), defined as the time to relapse from the date of clinical response (evaluated post-4-cycle chemotherapy), was significantly associated with baseline VAF_max and a decline in VAF_max of <99.89% at remission. Relapse genomic profiles largely mirrored baseline alterations, although some patients showed novel mutations.

Conclusion: Median ctDNA VAF_max was strongly associated with OS, PFS, DFS, and ORR. Importantly, patients with detectable residual alterations at completion of prescribed chemotherapy exhibited a markedly shorter DFS, less than that of patients with lower detectable residual alterations, highlighting the potential utility of ctDNA in risk stratification and the value of early trial enrollment for high-risk subgroups.

Purpose: Despite recent advances in anti-human epidermal growth factor receptor 2 (HER2) treatments for HER2-positive biliary tract cancer (BTC), current guidelines lack clear thresholds for defining HER2 positivity in BTC. This study investigated the use of artificial intelligence (AI) to analyze HER2 expression and immune phenotypes (IP) in patients with HER2-positive BTC treated with anti-HER2 therapy.

Materials and methods: We conducted a post hoc analysis of a phase II trial (KCSG HB19-14) of trastuzumab plus folinic acid, fluorouracil, and oxaliplatin (FOLFOX) for HER2-positive BTC. AI-powered HER2 quantification and IP analyses were performed on whole-slide images of pretreatment samples. Clinical outcomes were analyzed on the basis of HER2 positivity using a continuous AI-based HER2 immunohistochemistry scoring system. Additionally, we evaluated the spatial distribution of tumor-infiltrating lymphocytes using AI-based IP analysis.

Results: Among 29 patients, the overall concordance rate between pathologists and the HER2-AI analyzer was 79.1%. AI-defined HER2-positivity status, characterized by a ≥30% H3 tumor cell proportion threshold, significantly predicted improved outcomes with trastuzumab plus FOLFOX (progression-free survival: 6.7 v 4.9 months, P = .039; overall survival: not reached v 8.4 months, P = .018). By contrast, traditional pathologist-based scoring did not stratify outcomes. AI-powered immune profiling revealed that HER2 3+ tumors predominantly exhibited immune-desert phenotypes, whereas HER2 2+ tumors displayed more inflamed phenotypes, potentially limiting the efficacy of current immunotherapy regimens for HER2 3+ BTC.

Conclusion: AI-powered HER2 quantification provides a refined biomarker for predicting the response to HER2-targeted therapies in BTC, proposing a ≥30% HER2 3+ tumor cell proportion threshold. Our findings highlight the potential of combining anti-HER2 therapy with immune checkpoint inhibitors on the basis of IP profiles.

Purpose: Pancreatic cancer (PC) surveillance is increasingly recommended for high-risk individuals, but there are remaining areas of uncertainty that are not consistently addressed by guidelines contributing to heterogeneity in clinical practice. Herein, we compare PC surveillance practices across sites in the international Pancreatic Cancer Early Detection (PRECEDE) Consortium to understand the application of eligibility criteria and testing strategies among experienced PC surveillance centers.

Methods: This analysis represents a cross-sectional survey administered in 2024 to PRECEDE institutions. The site principal investigator (or designee) completed the survey reflecting PC surveillance practices of their site, with one response per institution. Survey questions were related to surveillance eligibility for carriers of BRCA1/2, ATM, PALB2, and Lynch syndrome along with imaging approaches.

Results: Of the 57 PRECEDE sites, 54 (95%) completed the survey. For high-risk gene carriers, there was heterogeneity among sites with respect to whether family history of PC was used when assessing eligibility for surveillance. In the absence of family history, 44.4% and 35.2% of sites would offer PC surveillance to BRCA2 and BRCA1 carriers, respectively, whereas 31.5% and 13% would offer surveillance to PALB2/ATM and Lynch syndrome carriers, respectively. There was general consensus that surveillance should start at age 50 for men and women across all included genes. Magnetic resonance imaging with magnetic resonance cholangiopancreatography was used by 64.8% of sites as index imaging. The majority recommended an alternative modality if index imaging was unremarkable, and recommended annual surveillance imaging.

Conclusion: This is the largest assessment of global PC surveillance practices to date, showing variability in practice patterns. Additional investigation is needed to refine risk stratification for gene carriers without a family history of PC and address optimal imaging strategies.

Purpose: Individuals with Lynch syndrome (LS) predominantly develop mismatch repair-deficient/microsatellite-unstable (MMR-D/MSI-H) cancer, for which immunotherapy can yield long-term disease control, even in the metastatic setting, leading to tissue-agnostic US Food and Drug Administration approval for pembrolizumab for any advanced MMR-D/MSI-H cancer in May 2017. The primary aim of this study was to assess the causes of death in individuals with LS in the era of immunotherapy.

Methods: We performed a retrospective cohort study of individuals with LS seen at a single academic cancer center for oncology-/genetics-related care, who died between May 30, 2017, and December 20, 2024. An expert panel adjudicated the cause of death after a detailed review of the electronic medical record (EMR). Data regarding personal cancer history, germline and somatic testing, and treatment were obtained from the EMR.

Results: Fifty-four individuals with LS were known to have died since May 2017 (52% female; median age at death 64 years; IQR, 51-75), of whom 44 were determined to have died of cancer and/or cancer treatment toxicities/complications. Of these, 19 of 44 (43%) died of MMR-proficient/MS-stable cancer (five because of pancreatic cancer, four because of colorectal cancer), 20 of 44 (46%) died of MMR-D/MSI-H cancer (six because of colorectal cancer, four because of pancreatic cancer), and 5 of 44 (11%) died of cancer with unknown/indeterminate MMR/MSI status. Among those who died with MMR-D/MSI-H cancer, 14 of 20 (70%) had disease progression on immunotherapy, 2 of 20 (10%) died of immunotherapy toxicity, and 3 of 20 (15%) died of other treatment complications. Deaths from MMR-proficient/MS-stable cancer were seen among patients with MSH2-, MSH6-, and PMS2-associated LS, but not MLH1-associated LS.

Conclusion: In this single-center analysis, MMR-proficient/MS-stable cancers were a frequent cause of death among individuals with LS. MMR-D/MSI-H cancers resistant to immunotherapy and treatment-associated deaths were other significant contributors to mortality. Larger, multicenter studies are warranted to validate these findings.