JCO precision oncology最新文献

The presence of circulating tumor DNA (ctDNA) in patients indicates post-treatment molecular residual disease (MRD). Given the complexity of ctDNA-based MRD detection tests, consensus on analytical validation (AV) criteria is needed. To address this, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium's MRD AV Working Group evaluated existing protocols to develop standardized guidance for tumor-informed assays. Protocols pertaining to blood collection tube types, quantitative output, tissue processing, tumor or matched normal sequencing, software, and clinical validation were considered out of scope. After alignment on objectives and assumptions, study designs on the basis of best practices in the field, available assay validation guidance documents, and unique performance challenges for tumor-informed MRD assays were authored. Each protocol contains introduction, experimental design, statistical analysis, and an example data presentation per the US Food and Drug Administration (FDA) Center for Devices and Radiological Health standard format. Biostatisticians were consulted to define minimal test requirements, sample size, and appropriate statistical analyses. The protocols were submitted to the FDA via the presubmission process for formal written feedback followed by a meeting. BLOODPAC's generic protocols for the AV of tumor-informed ctDNA assays for MRD are designed to provide test developers with a core baseline of standardized AV protocols such that methods described can be adapted and applied for any tumor-informed MRD assay irrespective of technology, panel design algorithm, or workflow component. These protocols aim to optimize test developers' presubmission reviews with the FDA, ensuring productive meetings while enabling reviewers to streamline feedback. As always, test developers are encouraged to communicate with FDA directly around their particular AV methods.

Purpose: RAS mutation is a key biomarker of anti-epidermal growth factor receptor (EGFR) antibody resistance in colorectal cancer (CRC). However, the clinical impact of RAS amplification on the efficacy of anti-EGFR therapy remains unclear. This study aimed to characterize RAS-amplified CRC and evaluate the sensitivity of these tumors to anti-EGFR antibodies.

Methods: We conducted a retrospective observational study using the Center for Cancer Genomics and Advanced Therapeutics database in Japan, which includes clinical and genomic data from patients who underwent comprehensive genomic profiling. We analyzed the data from 9,135 patients with unresectable colorectal adenocarcinoma (CRA) who underwent FoundationOne CDx testing.

Results: RAS amplification was identified in 2.1% (188/9,135) of patients with CRA. Among 1,649 patients with RAS wild-type CRA who received first-line chemotherapy with anti-EGFR antibodies, those with RAS amplification had a lower overall response rate (ORR) and a shorter time to treatment failure (TTF) compared with those without RAS amplification (ORR, 37.5% [21/56] v 52.9% [843/1,593]; median TTF, 195 days [95% CI, 129 to 224] v 274 days [95% CI, 258 to 293]; P = .023 and P = .005, respectively). By contrast, among 4,858 patients treated with bevacizumab, no significant differences were observed in ORR (37.3% [31/83] v 37.1% [1,772/4,775]; P = .964) or TTF (median, 231 days [95% CI, 175 to 273] v 259 days [95% CI, 252 to 270]; P = .445).

Conclusion: RAS amplification is a rare alteration that may confer resistance to anti-EGFR antibodies. Assessing RAS amplification status may help guide the appropriate use of anti-EGFR antibodies in clinical practice.

Purpose: High levels of DNA replication stress and defects in the DNA damage response (DDR) pathways are vulnerabilities of many poor prognosis childhood malignancies. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of these pathways and constitutes an attractive target, especially in combination. However, the malignancies where ATR inhibitors have maximum benefit and synergistic combinations differ between adults and children.

Design: ACCELERATE convened a multistakeholder meeting and conducted review and analysis to propose the optimal pathway for the development of ATR inhibitors in pediatric malignancies.

Results: Considering the lack of identified biomarkers, the initial evaluation of ATR inhibitors should focus on Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma in view of their high levels of DNA replication stress and defects in DDR pathways. Early phase trials of ATR inhibitors should be iterative, based on a clear hypothesis with responders and nonresponders undergoing detailed molecular analysis and a revised new hypothesis generated. Trial designs should restrict monotherapy evaluation to a brief exposure in a small number of patients and progress rapidly to combinations. Highlighted combination partners are poly(ADP-ribose) polymerase inhibitors and antibody drug conjugates with topoisomerase I inhibitor payloads. Combinations with ALK inhibitors (in ALK/MYCN-aberrant neuroblastoma) and aurora A kinase (in MYCN-amplified) are supported by robust mechanisms of action and preclinical data. Early interactions with regulators are crucial, and early phase clinical trials should be conducted in regulatory-approved, academic-sponsored, industry-supported, platform trials.

Conclusion: ATR inhibitors are a prototype for the development of medicinal products in a limited pediatric population. For the substantial potential of ATR inhibitors in children with malignancy to be realized, strategic planning between academia, industry, regulators, and patient advocates is vital.

Purpose: This study evaluates deep learning (DL) approaches, particularly long short-term memory (LSTM) networks, for analyzing dynamic changes in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) to improve disease understanding and treatment prediction.

Materials and methods: Multimodal HCC TME data (high-throughput sequencing, protein expression, and time-series imaging) were integrated. Spatial features were extracted using convolutional neural networks (CNNs), while temporal patterns were modeled with LSTMs. Generative adversarial networks (GANs) augmented data for robust training. Model performance was assessed on the basis of dynamic TME characterization and outcome prediction accuracy.

Results: LSTMs demonstrated superior performance in analyzing TME time-series data, effectively capturing long-term dependencies and predicting cellular interactions (accuracy: 92.3% v 85.7% for CNNs alone). The integrated DL framework successfully characterized spatiotemporal TME evolution and treatment response patterns.

Conclusion: This study demonstrates that LSTMs are powerful tools for analyzing and understanding the dynamic changes in the HCC immune microenvironment. Their strong capability in time-series data analysis provides new opportunities for uncovering the mechanisms of HCC progression and optimizing therapeutic strategies. However, because of the lack of detailed etiological information, stratified validation across different etiologies such as hepatitis B virus, hepatitis C virus, and non-alcoholic steatohepatitis has not yet been conducted in this study and should be addressed in future work. The findings highlight the important role of DL technologies in future research and treatment of HCC.

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.