Precision medicine advances in pancreatic cancer driven by genomic and molecular alterations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with limited treatment efficacy. Advances in precision oncology, enabled by next-generation sequencing, have highlighted key molecular targets. Kirsten rat sarcoma viral oncogene homolog mutations, present in up to 90% of cases, drive aggressive biology, though most variants remain undruggable; allele-specific inhibitors and exosome-based RNA interference are under exploration. Breast cancer susceptibility gene 1/2 mutations occur in 4%-7% of patients, conferring sensitivity to platinum agents and poly(ADP-ribose) polymerase inhibitors. Other rare but actionable alterations - such as v-raf murine sarcoma viral oncogene homolog B1 (V600), neurotrophic tyrosine receptor kinase, fibroblast growth factor receptor 2, and RET fusions - show benefit in tumor-agnostic trials, broadening options for selected subgroups. Immunotherapy is limited, as high tumor mutational burden and mismatch repair deficiency are uncommon in PDAC, though predictive when present. Co-mutations in tumor protein p53, cyclin-dependent kinase inhibitor 2A, and SMAD4 further stratify prognosis and influence therapy response. Cross-cancer analyses underscore the necessity of PDAC-specific strategies despite shared genomic drivers. Collectively, these insights support routine germline and somatic testing, enrollment in biomarker-matched trials, and rational combination strategies, establishing molecular profiling as central to advancing precision treatment in pancreatic cancer.

Key Words: Pancreatic ductal adenocarcinoma; Precision medicine; Kirsten rat sarcoma viral oncogene homolog mutation; Breast cancer susceptibility gene mutation; Genomic profiling; Targeted therapy; Tumor mutational burden

Core Tip: This review highlights the transformative impact of precision medicine in pancreatic ductal adenocarcinoma by focusing on clinically relevant genomic and molecular alterations such as Kirsten rat sarcoma viral oncogene homolog and breast cancer susceptibility gene mutations, rare actionable fusions, and co-mutational signatures. It emphasizes the importance of integrating routine molecular profiling into clinical workflows to guide targeted therapies and personalized treatment strategies.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal five-year survival rate of less than 10%. Despite modest advances in surgical and chemotherapeutic approaches, overall outcomes remain poor, especially in advanced stages[1]. In recent years, the advent of precision medicine - driven by high-throughput genomic sequencing and integrated molecular characterization - has led to a paradigm shift in oncology[2]. In PDAC, while challenges persist due to its complex tumor microenvironment and low immunogenicity, actionable genomic and molecular alterations are being increasingly recognized as important tools to guide targeted therapies and individualized treatment strategies (Table 1).

Table 1 Key genomic alterations in pancreatic ductal adenocarcinoma and associated targeted therapies.

Gene/alteration	Prevalence in PDAC	Associated targeted therapy/clinical implication
KRAS (G12D, G12V, G12R)	Approximately 80%-90%	Allele-specific inhibitors under development; RNAi strategies in preclinical models
KRAS G12C	< 2%	Sotorasib, adagrasib (limited efficacy in PDAC)
BRCA1/2	Approximately 4%-7%	PARP inhibitors (e.g., olaparib); platinum-based chemotherapy
BRAF (V600)	< 1%	BRAF/MEK inhibitors (e.g., dabrafenib + trametinib; off-label use)
NTRK fusions	< 1%	TRK inhibitors (larotrectinib, entrectinib)
FGFR2 fusions	Rare	FGFR inhibitors (e.g., pemigatinib; in clinical trials)
RET fusions	Rare	RET inhibitors (e.g., selpercatinib; in clinical trials)
dMMR/MSI-H	< 2%	Immune checkpoint inhibitors (e.g., pembrolizumab)
High TMB	Rare	Potential responsiveness to ICIs
TP53/CDKN2A/SMAD4 (co-mutations)	> 50%	Prognostic markers; may influence resistance and response to combination therapies

KRAS: Kirsten rat sarcoma viral oncogene homolog; BRCA: Breast cancer susceptibility gene; BRAF: V-raf murine sarcoma viral oncogene homolog B1; NTRK: Neurotrophic receptor tyrosine kinase; FGFR: Fibroblast growth factor receptor; dMMR: Deficient mismatch repair; MSI-H: Microsatellite instability-high; TMB: Tumor mutational burden; TP53: Tumor protein p53; CDKN2A: Cyclin-dependent kinase inhibitor 2A; PDAC: Pancreatic ductal adenocarcinoma; RNAi: RNA interference; PARP: Poly(ADP-ribose) polymerase; MEK: Mitogen-activated protein kinase; TRK: Tropomyosin receptor kinase; ICIs: Immune checkpoint inhibitors.

KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG MUTATIONS IN PANCREATIC CANCER

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are present in approximately 80%-90% of PDAC cases, as identified in multiple cohort studies including a large-scale analysis of 1000+ patients from The Cancer Genome Atlas[3,4]. These alterations, predominantly at codon 12, including G12D, G12V, and G12R, drive constitutive activation of the Ras-mitogen-activated protein kinase signaling pathway, promoting tumor growth, survival, and resistance to therapy. KRAS mutations are strongly associated with poor prognosis, and certain variants such as G12D and G12V correlate with worse overall survival compared to wild-type KRAS, while G12R may be linked to relatively better outcomes[5,6]. In addition to primary oncogenic activation, emerging data indicate that resistance to KRAS-targeted therapies can arise from secondary mutations in KRAS (e.g., Y96D), amplification of downstream effectors such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF), or activation of bypass signaling through the phosphatidylinositide 3-kinases-protein kinase B-mammalian target of rapamycin pathway, thereby diminishing the efficacy of KRAS inhibition strategies.

Despite their prevalence, KRAS mutations have historically been considered “undruggable” due to the protein’s small, smooth surface and high affinity for guanosine triphosphate. However, recent breakthroughs have introduced novel strategies targeting KRAS, particularly the G12C variant. While KRAS G12C-specific inhibitors like sotorasib and adagrasib have shown promising efficacy in non-small cell lung cancer, their applicability in PDAC is limited due to the rarity of this variant in pancreatic tumors[4]. Meanwhile, innovative approaches such as exosome-mediated delivery of KRAS-targeted small interfering RNA and short hairpin RNA have demonstrated preclinical potential in suppressing KRAS-driven tumorigenesis[7].

BRCA MUTATIONS AND HOMOLOGOUS RECOMBINATION DEFICIENCY

Breast cancer susceptibility gene 1 (BRCA1) and BRCA2 mutations, although less frequent, represent one of the most actionable targets in PDAC. These alterations are detected in approximately 4%-7% of patients and are more common in those with a family history of breast, ovarian, or pancreatic cancer[8]. Loss-of-function mutations in BRCA genes compromise homologous recombination repair, making tumor cells vulnerable to DNA-damaging agents.

This genomic vulnerability can be therapeutically exploited using platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib. Clinical studies have shown that BRCA-mutant pancreatic cancers demonstrate improved response rates and prolonged progression-free survival with these agents[9,10]. Moreover, the tumor-agnostic efficacy of PARP inhibitors across BRCA-mutated malignancies has reinforced the principle of biomarker-guided treatment and the importance of routine germline testing in patients with PDAC.

EMERGING TARGETABLE ALTERATIONS BEYOND KRAS AND BRCA

In addition to KRAS and BRCA mutations, a subset of PDAC tumors harbor other potentially actionable genomic alterations. BRAF (V600) mutations, although rare, may respond to combination therapies targeting the mitogen-activated protein kinase pathway[11]. Neurotrophic receptor tyrosine kinase gene fusions have also emerged as important pan-cancer biomarkers, with Food and Drug Administration-approved tropomyosin receptor kinase inhibitors such as larotrectinib and entrectinib demonstrating tumor-agnostic efficacy, including in rare PDAC cases[12]. Similarly, fusions involving fibroblast growth factor receptor 2 and RET, though infrequent, are targetable with selective kinase inhibitors currently being evaluated in clinical trials[4].

The rarity of these mutations necessitates broad molecular profiling to identify eligible patients. With the growing availability of multiplex sequencing and basket trials, even low-prevalence alterations are becoming actionable within individualized treatment frameworks. These findings support the routine implementation of next-generation sequencing in clinical practice, particularly for patients with advanced or treatment-refractory disease.

TUMOR MUTATIONAL BURDEN AND IMMUNE CHECKPOINT INHIBITOR SENSITIVITY

Pancreatic cancer is generally considered immunologically “cold” due to its low tumor mutational burden (TMB), dense stromal reaction, and immunosuppressive microenvironment. Nevertheless, a small subset of PDAC cases exhibit high TMB or mismatch repair deficiency, making them more likely to respond to immune checkpoint inhibitors such as anti-programmed death protein 1/programmed death ligand-1 agents[13]. While the prevalence of TMB-high or microsatellite instability-high (MSI-H) PDAC is low (< 2%), patients in this category may derive substantial clinical benefit from immune checkpoint inhibitors.

Efforts are ongoing to convert immunologically inert tumors into immune checkpoint inhibitor-responsive ones through combination approaches that include chemotherapy, radiation, or stromal modulation. Nonetheless, the use of immunotherapy in PDAC remains largely limited to biomarker-selected populations. Moreover, the dense desmoplastic stroma and extracellular matrix in PDAC act as physical and biochemical barriers, impeding T-cell infiltration and reducing drug penetration, thereby contributing to immunotherapy resistance even in TMB-high or microsatellite instability-high subsets. Overexpression of immunosuppressive cytokines and recruitment of myeloid-derived suppressor cells further compound this resistance.

CO-MUTATIONAL PATTERNS AND PROGNOSTIC IMPLICATIONS

The co-occurrence of mutations in key tumor suppressor genes - such as tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A, and SMAD4 - alongside KRAS mutations, is common in PDAC and carries significant prognostic implications. TP53 mutations, for example, are associated with enhanced genomic instability and tumor progression. The concurrent presence of KRAS and TP53 mutations correlates with more aggressive disease and worse overall survival[6,14]. In contrast, specific combinations of genetic alterations may identify subsets of patients who are more likely to benefit from particular therapies or trial enrollment. Understanding these co-mutational signatures not only enhances prognostic stratification but also facilitates the design of tailored combination regimens. Future studies may refine risk models based on integrated genomic profiling, guiding more personalized treatment decisions.

CROSS-TUMOR COMPARISONS AND THE RELEVANCE OF CONTEXT

Although many genomic alterations found in PDAC are also present in other cancers, their therapeutic relevance is context-dependent. For instance, KRAS G12C inhibitors have demonstrated efficacy in non-small cell lung cancer but limited activity in PDAC, possibly due to different downstream signaling dynamics and tumor microenvironments. Similarly, BRCA mutations are a well-established therapeutic target in breast and ovarian cancers, but their impact in PDAC has only recently been recognized. These differences underscore the importance of pancreas-specific translational studies, rather than extrapolating directly from other tumor types. Nevertheless, the concept of tumor-agnostic treatment based on shared genomic drivers continues to gain traction, particularly in the context of Food and Drug Administration-approved indications for agents like PARP inhibitors and tropomyosin receptor kinase inhibitors.

FUTURE DIRECTIONS AND CLINICAL INTEGRATION

As precision oncology evolves in PDAC, routine germline and somatic testing is critical for identifying actionable targets and guiding therapy. Beyond genomic alterations, epigenomics, proteomics, and metabolomics offer new insights into drug response and resistance, enabling personalized treatment strategies. Despite progress, real-world implementation of molecular profiling is hindered by cost, reimbursement issues, and limited infrastructure, particularly outside academic centers. Overcoming these barriers is essential for equitable access to precision medicine. Liquid biopsy techniques like circulating tumor DNA and exosomal RNA are promising for monitoring tumor evolution, minimal residual disease, and early relapse. Methylation assays are also being explored for early detection. Proteolysis-targeting chimeras (PROTACs), particularly for KRAS G12C degradation, represent a new frontier. Recent preclinical studies have demonstrated the feasibility of PROTAC-based KRAS degradation using von Hippel-Lindau-recruiting PROTACs like YF135[15], with efforts underway to develop BRCA-targeting PROTACs for homologous recombination-deficient tumors. Ultimately, improving outcomes in pancreatic cancer requires integrating molecular data with clinical features and addressing resistance mechanisms.

CONCLUSION

Incorporating genomic and molecular profiling into the management of PDAC has opened new avenues for personalized therapy, offering hope in a disease historically characterized by limited treatment responsiveness and poor survival. KRAS and BRCA mutations remain the most clinically relevant alterations, guiding the development of targeted therapies and informing treatment selection. Although the majority of pancreatic cancers lack high-frequency actionable mutations, emerging targets such as neurotrophic receptor tyrosine kinase fusions, BRAF (V600) mutations, and homologous recombination deficiencies illustrate the growing relevance of precision oncology. Moreover, the prognostic impact of co-occurring alterations in TP53, cyclin-dependent kinase inhibitor 2A, and SMAD4 highlights the importance of a comprehensive genomic context. As sequencing technologies become more accessible, routine germline and somatic testing should be integrated into standard clinical workflows to identify therapeutic vulnerabilities and facilitate enrollment in biomarker-driven clinical trials. Continued research into the functional consequences of rare mutations, innovative delivery platforms, and combination strategies will be critical to overcoming resistance and expanding treatment options in this challenging malignancy.