Durable Response to Olaparib in Pancreatic Duct Adenocarcinoma with Deleterious ARID1A Mutation
Pancreatic cancer remains one of the most lethal malignancies worldwide, with pancreatic ductal adenocarcinoma (PDAC) being the most common histological subtype. The disease is often diagnosed at an advanced stage due to the lack of early symptoms, leading to limited treatment options and poor prognosis. Systemic therapy for advanced PDAC is particularly challenging, with few effective medications available. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), has emerged as a promising therapeutic agent for cancers with defects in homologous recombination-DNA damage repair (HR-DDR). This case report highlights the durable response to olaparib in a PDAC patient with a deleterious ARID1A mutation, providing new insights into the potential efficacy of PARPi in HR-defective PDAC beyond the BRCA-mutated population.
The patient, a 50-year-old male, presented with a one-month history of dull pain in the lumbar and abdominal area. Initial evaluation revealed elevated serum levels of carbohydrate antigen 19-9 (CA 19-9) at 334.10 U/mL. Imaging studies, including enhanced MRI and positron emission tomography (PET), identified a 3.0 cm by 3.4 cm mass at the body-tail junction of the pancreas, suggestive of malignancy. The patient declined fine-needle aspiration, and surgical exploration was performed. Intraoperative findings confirmed a 2.0 cm by 1.5 cm mass with invasion of the splenic vein, prompting a distal pancreatectomy with splenic resection. Pathological assessment confirmed a well-differentiated PDAC with negative margins and one positive lymph node out of eleven, staging the disease as T1N1M0 (stage IIb).
Post-surgery, the patient received six cycles of adjuvant chemotherapy with gemcitabine plus S-1, resulting in a reduction of CA 19-9 levels to 21.85 U/mL. However, a follow-up MRI two months post-chemotherapy revealed a new 1.3 cm lesion in a lymph node behind the pancreatic resection margin, accompanied by a rise in CA 19-9 to 77.31 U/mL, indicating disease progression. Given the failure of the initial adjuvant therapy, the multidisciplinary team (MDT) decided to pursue further genomic analysis of the surgical specimen. Targeted sequencing identified four somatic mutations: ARID1A (c.3979C>T, p.Q1327*), KRAS (c.43G>C, p.G12R), TP53 (c.817C>T, p.R273C), and CBL (c.1388C>T, p.A463V). Microsatellite instability testing confirmed microsatellite stability (MSS).
The ARID1A mutation, a nonsense mutation leading to a premature stop codon, was of particular interest. ARID1A is a component of the SNF/SWI chromatin remodeling complex, and its loss of function is associated with HR-DDR deficiency. Preclinical studies have suggested that ARID1A-deficient cancer cells may be sensitized to PARPi. Based on this rationale, the patient was started on olaparib monotherapy at a dose of 300 mg twice daily. After six months of treatment, MRI demonstrated a 40% reduction in the size of the lymph node lesion, from 1.3 cm to 0.6 cm. Liquid biopsy for circulating tumor DNA (ctDNA) revealed no detectable somatic mutations, suggesting limited disease progression. The olaparib dose was subsequently increased to 400 mg twice daily. As of July 21, 2019, the patient had achieved a progression-free survival (PFS) of 13.0 months, with ongoing follow-up.
Olaparib has been approved for the treatment of breast and ovarian cancers with deleterious or suspected deleterious germline BRCA1/2 mutations (gBRCAm). In PDAC, a basket trial involving gBRCAm-associated cancers reported a response rate of 21.7% in recurrent PDAC patients, indicating the potential efficacy of PARPi in HR-defective PDAC. However, the response to PARPi in PDAC with non-BRCA HR-DDR defects, such as ARID1A mutations, remains underexplored. This case provides evidence that ARID1A-deficient PDAC may also benefit from PARPi therapy, expanding the potential patient population for this treatment.
The ARID1A mutation in this patient likely results in either nonsense-mediated mRNA decay or a truncated protein lacking the SNF/SWI-like complex subunit, both of which could impair HR-DDR. This defect in DSB repair may underlie the observed response to olaparib. The case underscores the importance of next-generation sequencing (NGS) in identifying potential therapeutic targets in PDAC and highlights the need for further research to validate the efficacy of PARPi in ARID1A-mutant PDAC.
In conclusion, this report describes a durable response to olaparib in a PDAC patient with a deleterious ARID1A mutation, suggesting that PARPi may be effective in HR-defective PDAC beyond the gBRCAm population. The findings emphasize the role of genomic profiling in guiding personalized treatment strategies for PDAC and warrant further investigation into the therapeutic potential of PARPi in ARID1A-deficient cancers.
doi.org/10.1097/CM9.0000000000000550
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