JCO precision oncology最新文献

Purpose: Mixed phenotype acute leukemia (MPAL) is a rare clinical entity with historically poor outcomes.

Methods: We conducted a retrospective analysis of adults 18 years and older with newly diagnosed B-cell (B/M) or T-cell/myeloid (T/M) MPAL treated at our institution between 2017 and 2024.

Results: We identified 42 patients (median age 70 years); 20 (48%) had B/M MPAL, and 22 (52%) had T/M MPAL; 57% of patients had adverse risk cytogenetics, and 41% had a TP53 mutation. Sixty-two percent of patients were treated with a hybrid regimen, and 45% of patients received intensive therapy. A composite complete remission (CRc; CR + CRi) was achieved in 57% of patients (86% measurable residual disease [MRD]-negative). After a median follow-up of 27.9 months, the median relapse-free survival in patients achieving an overall response (CRc + morphological leukemia-free state) was 10.1 months, 17.8 months in those who achieved a CRc, and not reached (NR) in patients with MRD-negative CRc. The median overall survival (OS) for all patients was 9.5 months and NR for patients achieving a CRc. Although patients with T/M MPAL had a trend toward improved survival compared with those with B/M MPAL (median OS of 9.1 v 25 months P = .28), this difference abrogated when comparison was stratified by treatment intensity. Twelve patients (29%) underwent allogeneic hematopoietic stem-cell transplantation (HSCT); on landmark analysis, HSCT trended to improve OS (NR v 22.8, P = .12). Multivariate Cox analysis demonstrated that TP53 mutation was associated with increased hazards for death (hazard ratio [HR], 3.5, P = .01), whereas the use of intensive chemotherapy trended to be favorable (HR, 0.45, P = .11).

Conclusion: Overall, these data demonstrate the need for treatment intensification in MPAL with HSCT in first remission for best outcomes.

Purpose: Pathologic complete response (pCR) is a surrogate end point for prognosis in rectal cancer, yet a subset of pCR patients still face recurrence or poor outcomes. The identification of high-risk pCR patients and the effectiveness of adjuvant therapy remain contentious. This study aimed to evaluate pretreatment magnetic resonance imaging (MRI) markers, identify high-risk pCR patients, and assess the benefit of adjuvant therapy.

Materials and methods: This retrospective multicenter study analyzed 384 pCR patients (2010-2019) to assess pretreatment MRI markers' prognostic value. Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan-Meier curves, with group differences evaluated via the log-rank test.

Results: Among the MRI markers evaluated, magnetic resonance with tumor deposits (mrTD) emerged as the strongest prognostic factor. Positive mrTD was associated with a five-fold increased risk of recurrence (adjusted hazard ratio, 5.16 [95% CI, 2.67 to 9.97]; P < .001) and significantly reduced OS (5.04 [1.80 to 14.1]; P = .002). Patients with mrTD⁺ had a 3-year DFS of 74.5% and a 5-year OS of 83.6%, compared with 96.6% and 98.6%, respectively, in mrTD^- patients. Notably, adjuvant therapy did not improve prognosis in pCR patients, regardless of their MRI marker status.

Conclusion: Positive mrTD is a critical prognostic marker in pCR patients. Adjuvant therapy did not confer benefits, highlighting the need for personalized treatment strategies.

Purpose: Cancer predisposition syndromes caused by germline pathogenic variants (GPV) in adult-onset cancer predisposition genes (aoCPG) are those for which there is low risk of cancer in children, with genetic testing and screening for these conditions typically deferred until adulthood. GPV in aoCPG have been identified in pediatric oncology patients, but in these cases the potential contribution of the aoCPG to cancer development is often unknown. We investigated the role GPV in aoCPG may play in childhood cancer development.

Methods: Results of paired tumor-germline sequencing from pediatric oncology patients enrolled from May 2012 to October 2023 were analyzed for frequency of GPV in aoCPG. Germline testing included analysis of up to 182 cancer predisposition genes. Tumor loss-of-heterozygosity, presence of second somatic pathogenic variant, immunohistochemical stain for protein expression, and/or tumor mutation burden were used to determine possible causation.

Results: Of the 954 participants, 42 (4.4%) had GPV in aoCPG. Six (14.3%) of these 42 participants had tumor findings indicating their GPV in an aoCPG likely contributed to cancer development: three patients with Lynch syndrome (two anaplastic astrocytomas, one giant cell glioblastoma) and one each with GPV in ATM (craniopharyngioma and diffuse high-grade glioma), BRIP1 (atypical teratoid rhabdoid tumor), and CHEK2 (mixed germ cell tumor of pineal gland).

Conclusion: These findings contribute to the literature suggesting that, rarely, GPV in aoCPG may contribute to cancer diagnoses in children, raising the question of how tumors in these cases may present differently in children than adults. Increased knowledge about potential childhood cancer risks related to what have historically been considered aoCPG could modify predictive genetic testing recommendations for children and enhance existing cancer screening protocols.

Purpose: Clear cell renal cell carcinoma (ccRCC) is characterized by marked intratumor heterogeneity (ITH), which contributes to therapeutic resistance and poor clinical outcomes. We aimed to develop a robust prognostic model for stratifying patients with ccRCC on the basis of ITH.

Methods: RNA-seq data from 522 patients with ccRCC in TCGA-KIRC were analyzed using the DEPTH algorithm to quantify ITH, with external validation in the E-MTAB-1980 cohort (N = 101). Differentially expressed genes between high and low DEPTH tumors were identified, and a machine learning framework was applied to develop the ITHscore. The ITHscore was compared with other published signatures in literature for ccRCC.

Results: The random survival forest model on the basis of three genes (UBE2C, MOCOS, and MELTF) was selected to compose the ITHscore, showing high accuracy in the development (5-year AUC = 0.957) and in the validation cohorts (5-year AUC = 0.82). The ITHscore had the best performance across all 45 retrieved signatures in both development and validation data sets. High-ITHscore tumors exhibited immunosuppressive microenvironments and were associated with immune checkpoint blockade (ICB) resistance signatures. The ITHscore was significantly associated with poor overall survival in five distinct tumor types across a meta-analysis of 104 independent data sets comprising 18,004 patients.

Conclusion: We developed and validated the ITHscore, a three-gene expression-based model with superior prognostic performance in ccRCC. The ITHscore reflects key features of aggressiveness in tumor biology, including immune evasion and ICB resistance. Its minimal gene set and consistent performance across data sets support its potential for clinical implementation in ccRCC stratification.

Purpose: Although adjuvant chemotherapy is standard for locally advanced colon cancer, defective mismatch repair (dMMR)/microsatellite instability (MSI) tumors show high sensitivity to immune checkpoint inhibitors. We aimed to investigate the efficacy of the PD-1 inhibitor prolgolimab in this setting.

Methods: We conducted phase II nonrandomized open-label clinical trial (ClinicalTrials.gov identifier: NCT06428487) in patients with locally advanced colorectal cancer (CRC) and dMMR/MSI. Prolgolimab (1 mg/kg) was administered once every 2 weeks, and surgery was performed after 6 months of immunotherapy. In case of surgical treatment refusal, the systemic treatment proceeded for 1 year. The primary end point was the rate of pathologic complete response (pCR, in operated cases) + clinical complete response (cCR, in nonoperated cases). Secondary end points included pCR, major pathologic response (MPR), objective response (ORR) rates, safety, disease-free survival (DFS), and overall survival.

Results: Of the 30 enrolled, 26 (86.6%) patients underwent surgery after the end of immunotherapy. The study met its primary end point, with 17 (56.7%) of 30 patients achieving pCR (n = 16) + cCR (n = 1 as nonoperated case). According to histologic examination, an MPR (TRG 1-2) was observed in 21 (80.8%) of 26 patients, including 16 (61.6%) patients with pCR. Radiographic ORR was 89.7%, and cCR was observed in six cases (20.7%, five patients underwent surgery further). Three patients with low rectal primary tumors refused to undergo a surgical treatment. The median follow-up was 19 months (range, 13-32). The 18-month DFS was 90%: two progressions and one unrelated death were detected. Grade 3-4 immune-related adverse effects were recorded in one (3.3%) patient.

Conclusion: The use of prolgolimab in locally advanced dMMR/MSI CRC is associated with high rates of pCR and cCR, allowing for further exploration of organ-sparing approaches in these patients.

Purpose: Homozygous deletions of methylthioadenosine phosphorylase (MTAP) enzyme are common across human cancers and are associated with poor prognoses. Currently, to our knowledge, there are no approved therapies targeting MTAP-deleted tumors, although there is significant ongoing research in this area. The aim of this study was to analyze the prevalence, clinical impacts, and comutational landscapes of patients with MTAP deletions in a network of community-based oncology clinics.

Methods: We conducted retrospective analyses of clinicogenomic data from 21 community oncology practices in the Sarah Cannon Research Institute (SCRI) network. Clinical data from electronic health record systems, including drug administration dates, diagnosis dates, and molecular data from commercial next-generation sequencing vendors, were aggregated in SCRI's web-based precision medicine platform, Genospace. Overall survival (OS) and time to next therapy (TTNT) were analyzed using Kaplan-Meier plots and Cox proportional hazards regression. Patient data were deidentified before analysis.

Results: Among 10,936 patients analyzed in this study, 9.4% had homozygous MTAP deletions (MTAP-del). MTAP-del was prevalent in glioblastoma (58.2%) and mesothelioma (40.5%) and least common in breast (4.0%) and colorectal cancers (1.4%). Overall, MTAP-del patients had diminished OS (25.4 months v 52.1 months, P < .0001), with pronounced deficits in MTAP-del mesotheliomas (12.8 months v 23.0 months, P = .0478) and urothelial carcinomas (22.9 months v 36.0 months, P = .0549). MTAP-del patients receiving chemotherapy had shortened TTNT intervals overall (8.1 months v 10.1 months, P = .0002), and for urothelial (5.4 months v 6.4 months, P = .0195) and gastroesophageal carcinomas (7.2 months v 8.8 months, P = .0412). MTAP-del patients had distinct mutational landscapes, compared with MTAP-prof patients, including lower rates of TP53 mutation.

Conclusion: MTAP is a key biomarker in precision oncology; this work describes the clinical outlook for these patients within the community-oncology setting. These insights can inform future study design, as MTAP-directed therapies continue their development.

Purpose: Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC).

Methods: Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response.

Results: Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP-mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP-mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02).

Conclusion: SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP-mutated PC support its consideration as a unique molecular subtype with prognostic implications.

Purpose: There is growing interest in multicancer detection (MCD) blood tests for diagnosing patients with cancer-related symptoms. However, recent studies suggest that MCD testing may not be sensitive enough to rule out cancer in the symptomatic population without retraining the underlying classifiers. On the basis of clinical guidelines for suspected cancer referral, here we cast these data into a formal diagnostic decision-making perspective to assess clinical utility.

Methods: Data were extracted from the SYMPLIFY study (ISRCTN10226380), which evaluated the performance of the Galleri test (GRAIL, LLC). The decision threshold for suspected cancer referral was extracted from the National Institute for Health and Care Excellence Guideline 12. Clinical utility was estimated using Bayesian decision curve analysis.

Results: For the guideline-derived decision threshold of 3%, the Galleri MCD test avoided 18,005 unnecessary suspected cancer referrals per 100,000 symptomatic patients, with a 99.4% posterior probability of clinical utility. High probabilities of clinical utility were observed for gynecologic, lower GI, and upper GI referral pathways, avoiding between 25,414 and 62,501 unnecessary referrals per 100,000 symptomatic patients. The rapid diagnostic center and lung referral pathways showed negligible probabilities of clinical utility. The minimum diagnostic performance required for clinical utility varied significantly across referral pathways. The gynecologic pathway showed the lowest sensitivity requirement (under 30% for a highly specific test) and the lung pathway the highest (over 90% for any specificity level).

Conclusion: Clinical utility of MCD testing for symptomatic patients in the United Kingdom varies substantially across referral pathways but is favorable for gynecologic and GI cancers. Future pathway-specific optimization of MCD tests must consider clinical utility explicitly and does not require retraining the underlying machine learning classifiers.