Precision Oncology doi: 10.3390/precisoncol1020009

Authors: Alicia Y. Lefas Hazel Lote Ian Chau

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with rising incidence and a 5-year survival rate of 13%. Late presentation, early metastasis, and intrinsic resistance constrain the efficacy of cytotoxic chemotherapy, which remains the backbone of PDAC treatment, with only modest survival gains and resistance nearly universal. Although KRAS mutations dominate tumour biology (~90% of cases), PDAC is a heterogeneous disease with distinct molecular subtypes that confer differential therapeutic vulnerabilities. Advances in comprehensive molecular profiling have catalysed a paradigm shift toward precision oncology in PDAC. In KRAS-mutant PDAC, mutation-specific inhibitors have established proof-of-concept, particularly in KRAS G12C disease, while next-generation approaches including KRAS G12D inhibitors, RAS-“ON” inhibitors, proteolysis-targeting chimeras (PROTACs), and KRAS-targeted vaccine strategies are expanding the therapeutic landscape. Combination strategies targeting upstream and downstream effectors of the RAS–MAPK pathway are also being explored to enhance the depth and durability of response. In parallel, KRAS-wild-type PDAC has emerged as a molecularly distinct subgroup enriched for rare but actionable alternative oncogenic fusion drivers including NRG1, NTRK, RET, ALK, and FGFR. Additional molecularly directed strategies targeting HER2 alterations, BRAF mutations, EGFR-dependent signalling, and tumour-selectively exposed surface antigens such as CLDN18.2 are under investigation across PDAC irrespective of KRAS mutation status. Synthetic lethal approaches, including targeting the PRMT5/CDKN2A/MTAP axis, represent a further emerging therapeutic strategy. Germline homologous recombination repair defects, particularly involving BRCA1/2 and PALB2, further define clinically important subsets with sensitivity to platinum chemotherapy and PARP inhibition. This review summarises current and emerging targeted and molecularly directed therapeutic strategies in PDAC, emphasising the importance of molecular stratification and recent advances shaping precision oncology in this historically treatment-refractory disease.

Precision Oncology doi: 10.3390/precisoncol1020008

Authors: Andreia Bilé-Silva Mehmet Özalevli Gabriel Chan Syed Ahmed Zafer Tandoğdu

Background/Objectives: Prostate cancer (PCa) incidence is rising, with radical prostatectomy (RP) as the main curative surgery for localised cases, which includes removing seminal vesicles (SV). SV invasion (SVI) predicts poor oncological outcomes, making accurate preoperative staging to identify SVI crucial for surgical planning. This ensures oncological safety by enabling wide excision when needed, while preserving tissue to maintain function. This review synthesises current evidence on pre-biopsy MRI findings and/or clinicopathological parameters to diagnose SVI in PCa. Methods: A literature search (2005–2025) using OVID for studies assessing pre-biopsy MRI findings, with a priori eligibility for clinicopathological or combined MRI–clinicopathological models (index tests), for detecting SVI (outcome) compared to RP histopathology (standard reference) in patients with primary localised PCa (patients). This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias was evaluated with QUADAS-2, and pooled diagnostic accuracy metrics and study heterogeneity were analysed. Results: Five studies qualified, while three used binary mpMRI classification and were quantitatively analysed. No eligible studies assessed clinicopathological predictors or combined MRI–clinicopathological models; all included studies evaluated pre-biopsy MRI findings only, and none included high-dimensional radiomics. The pooled sensitivity was 0.66 (95% CI: 0.52–0.78), specificity 0.94 (0.89–0.97), positive predictive value (PPV) 0.76 (0.60–0.87), negative predictive value (NPV) 0.92 (0.85–0.94), and diagnostic odds ratio 30.13 (12.36–73.47), with moderate heterogeneity. All included studies were retrospective cohorts with considerable risk of bias. Conclusions: In the small number of heterogeneous, single-centre retrospective studies available, pre-biopsy MRI findings show high specificity and NPV for preoperative detection of SVI but only moderate sensitivity, which limits its reliability as a standalone tool. The pooled diagnostic accuracy estimates should be interpreted as exploratory. These findings should therefore be interpreted cautiously. Future studies must integrate MRI with clinicopathological data, addressing this key evidence gap before firm conclusions can be drawn or clinical practice changed.

Precision Oncology doi: 10.3390/precisoncol1020007

Authors: Shuhei Suzuki Manabu Seino Hidenori Sato Yosuke Saito Koki Saito Yuta Yamada Koshi Takahashi Ryosuke Kumanishi Tadahisa Fukui Masanobu Takahashi

Background/Objectives: The anti-CLDN18.2 antibody zolbetuximab has emerged as a novel therapeutic option for advanced gastric adenocarcinoma. However, robust predictive biomarkers for its efficacy remain an unmet need. Methods: Utilizing the Japanese Center for Cancer Genomics and Advanced Therapeutics database, we retrospectively analyzed the clinical and genomic profiles of 49 patients with gastric adenocarcinoma who received zolbetuximab-containing regimens. In line with Japanese health insurance regulations, these patients were deemed to have CLDN18.2-positive tumors. We explored the association between the objective response rate (ORR) and concurrent genomic alterations, focusing on tumor mutational burden (TMB) and major mutations (TP53, ARID1A, CDH1). Results: The ORR to zolbetuximab-based therapy in this cohort was 22.2%. Statistical analysis revealed a trend toward higher clinical response in patients with lower TMB (median 1.82 in responders vs. 4.0 in non-responders; p = 0.050). Furthermore, patients without a CDH1 single-nucleotide variant also showed a suggestive trend toward better response (p = 0.086). No significant associations were found with TP53 or ARID1A alterations (p = 0.787 and p = 0.239, respectively). Conclusions: Our findings suggest that low TMB and the absence of CDH1 variants may serve as potential predictive biomarkers for response to zolbetuximab in CLDN18.2-positive gastric cancer. Prospective validation is warranted to maximize patient selection for this targeted therapy.

Precision Oncology doi: 10.3390/precisoncol1010006

Authors: Ángeles Sánchez-Gálvez Ana María Serradilla-Gil Ana Illescas-Vacas Antonio Lazo-Prados M. Cristina Nuño-Rodriguez Mariana Teresa Peña-Perea Nuria-Azahara Linares-Mesa Raquel Correa-Generoso Sonia García-Cabezas Manuel Luis Blanco-Villar

Prostate cancer (PCa) is a prevalent malignancy in men worldwide, and both androgen deprivation therapy (ADT) and radiotherapy (RT) are key components of its management. However, these treatments significantly affect bone health by inducing bone mineral density (BMD) loss, osteopenia, osteoporosis and increased fracture risk. ADT promotes a high bone turnover state through hormonal suppression and molecular mechanisms involving increased RANKL expression and osteoclast activation. RT generates direct cytotoxic damage and inflammatory changes that compromise bone microarchitecture. Combined ADT + RT exerts synergistic detrimental effects. This narrative review synthesizes the molecular basis, clinical evidence, preventive strategies and emerging technologies related to bone health in men with PCa undergoing ADT and/or RT.

Precision Oncology doi: 10.3390/precisoncol1010005

Authors: Cynthia Lilieholm Adedamola O. Adeniyi Ohyun Kwon Jen Zaborek Caroline P. Kerr Hansel Comas Rojas Malick Bio Idrissou Carolina A. Ferreira Paul A. Clark Won Jong Jin Joseph J. Grudzinski Amy K. Erbe Reinier Hernandez Bryan Bednarz Zachary S. Morris Jamey P. Weichert

Rationale: Radium-223 dichloride (223RaCl2) is an FDA-approved alpha-emitting radiopharmaceutical that targets bone metastases in metastatic castration-resistant prostate cancer (mCRPC). This study investigates the therapeutic and immunological effects of combining 223RaCl2 with immune checkpoint inhibitors (ICIs) in a clinically relevant, immunocompetent murine model of prostate cancer bone metastasis. Methods: Luciferase-expressing MyC-CaP prostate cancer cells were implanted intratibially into FVB mice to establish bone metastases. Mice were treated with escalating doses of 223RaCl2 (0.04–0.27 µCi) alone or a single dose combined with anti-CTLA-4 and anti-PD-L1 ICIs. Tumor growth was monitored using bioluminescence imaging. Micro-CT, alpha camera imaging, histology, and qPCR were used to assess bone remodeling, radiopharmaceutical distribution, immune infiltration, and gene expression. Ex vivo biodistribution and blood analyses quantified tissue uptake and toxicity. Results: Escalating doses of 223RaCl2 did not significantly inhibit tumor growth or improve survival. Biodistribution and imaging showed preferential localization of 223RaCl2 to tumor-adjacent bone, with minimal signal in isolated tumor tissue. Immunohistochemistry revealed increased CD4+ and CD8α+ T-cell infiltration in regions of high γH2AX expression, indicating localized immune modulation. However, combination therapy with ICIs did not enhance tumor control or immune infiltration beyond monotherapy. qPCR demonstrated significant upregulation of Mhc1 only in the combination group, suggesting localized immune activation. Toxicity profiles remained acceptable. Conclusions: 223RaCl2 localizes primarily to bone surfaces, limiting direct cytotoxic and immunomodulatory effects within the tumor microenvironment. While combination with ICIs did not improve efficacy, these findings provide a platform for studying spatial dose distribution and support future development of tumor-targeted alpha therapies to potentiate immunotherapy in mCRPC.

Precision Oncology doi: 10.3390/precisoncol1010004

Authors: Nicole A. Lisek John L. Villano Derek B. Allison Lowell B. Anthony

Undifferentiated melanoma (UM) is a rare and diagnostically challenging subtype of malignant melanoma that often lacks traditional histological features and immunophenotypic expression. We report the case of a 58-year-old man with a history of a previously excised melanoma in-situ (lentigo maligna type) of the scalp who later developed a painful chest wall mass. Subsequent workup revealed a high-grade malignant neoplasm with only focal weak S100P positivity while molecular analysis with next-generation sequencing (NGS) revealed an ultra-high TMB tumor mutational burden (>150 mut/Mb), NF1 mutation, TERT promoter mutation, TP53 mutations, PTPRD mutations, and a UV mutational signature (100% SBS7a), supportive of a diagnosis of UM. This case highlights the diagnostic value of comprehensive molecular testing in UM and its role in informing immunotherapy decisions.

Precision Oncology doi: 10.3390/precisoncol1010003

Authors: Raul A. Urrutia

It is with great honor and satisfaction that I write this introductory Editorial for the launch of Precision Oncology, focused on a transformational discipline in the field of precision medicine for cancer [...]

Precision Oncology doi: 10.3390/precisoncol1010002

Authors: Marie Fusella Giuntini Cyril Voyant David Taieb Dominique Barbolosi

Background/Objectives: Radioactive iodine (RAI) therapy is widely used to treat metastatic differentiated thyroid cancer. To investigate physiological determinants of treatment response, a mechanistic model was developed, formulated as a system of coupled ordinary differential equations. Methods: The model captures the interactions between tumor burden, thyroglobulin (Tg) production and clearance, and radioactive iodine activity within a pharmacokinetic–pharmacodynamic framework. Model parameters were estimated using the Monte Carlo Stochastic Approximation Expectation–Maximization (MCMCSAEM) algorithm, based on clinical data from a cohort of 50 patients. Results: Tumor radiosensitivity (ρ) and initial tumor burden (N0) consistently emerged as the most influential factors in both responder and non-responder groups classified by disease doubling time under RAI (Td). A reduced model using only these two parameters preserved the principal response patterns of the full model. Other parameters influenced transient dynamics but had limited effect on overall Tg variance. Conclusions: These results support the use of a reduced calibration approach focused on ρ, N0, and the effective doubling time Td. The findings establish a theoretical foundation for developing tractable dynamic surrogates that reproduce the main treatment kinetics and support model-based clinical decision-making in RAI therapy.

Precision Oncology doi: 10.3390/precisoncol1010001

Authors: Leonardo Simonelli Sebastian James Khairkhahan Francesco Alessandrino Elizabeth Anne Montgomery Gina D’Amato

Background and Clinical Significance: Inflammatory myofibroblastic tumors (IMTs) are rare neoplasms with low metastatic potential but a high recurrence rate. Approximately 60–80% of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, making ALK inhibitors (ALKis) a key therapeutic option. However, resistance to ALKis remains a significant clinical challenge, necessitating alternative treatment strategies. Case Presentation: We report the case of a 23-year-old woman diagnosed with a metastatic TPM3::ALK fusion-positive IMT, initially managed with crizotinib and ceritinib. Disease progression prompted a switch to alectinib, followed by lorlatinib in combination with immune checkpoint inhibitors (nivolumab + ipilimumab). The patient tolerated this regimen well, with manageable side effects, and has remained progression-free for over three years, demonstrating the potential efficacy of ALK-ICI combination therapy. Conclusions: This case highlights the rapid development of resistance to first- and second-generation ALKis and the emerging role of immune checkpoint inhibitors (ICIs) in IMT treatment. PD-L1 expression in ALK-positive IMTs suggests an immune escape mechanism, supporting combination ALK-ICI therapy as a viable approach. The successful long-term disease control achieved in this case underscores the importance of molecular profiling in guiding personalized treatment strategies for IMT. This report contributes to the growing body of evidence supporting precision medicine and immunotherapy in rare sarcomas.