Pancreatic cancer is a deadly disease and it is usually diagnosed at an advanced stage. Chemotherapy plays a key role in the treatment of pancreatic cancer, often producing a temporary clinical benefit (1,2). Genomic aberrations in breast cancer 1 (BRCA1) and BRCA2 genes, which are components of a common DNA repair pathway, are inherited in an autosomal dominant pattern (3,4). A number of studies have demonstrated that BRCA mutations, particularly those in BRCA2, increase the risk of developing pancreatic adenocarcinoma (5). It has been suggested that DNA-damaging agents, such as platinum salts or poly(ADP-ribose) polymerase (PARP) inhibitors, may be used in patients with pancreatic cancer carrying BRCA mutations (6,7). In the present study, genomic evolution was investigated in a patient with stage IV pancreatic cancer bearing a germline BRCA2 mutation.

A 60-year-old male patient carrying a known deleterious BRCA2 mutation (1153insT) presented with locally advanced pancreatic cancer. The patient underwent surgery, and the subsequent pathological analysis revealed pancreatic adenocarcinoma. Two months later, prior to commencing adjuvant chemotherapy, the patient developed liver metastasis. He received a cisplatin-based regimen and rapidly achieved a complete response that lasted for 18 months. When relapse occurred in the liver, the patient resumed the same protocol, achieving a partial response for an additional 20 months. At that point, disease progression was detected in the brain. The patient received multidisciplinary treatment that included resection of one lesion and stereotactic radiosurgery (SRS) for the second lesion. Subsequently, he received irinotecan and bevacizumab, which resulted in a response that lasted for 7 months.

The patient provided written informed consent, in accordance with the Hadassah Institutional Review Board-approved protocol.

In order to identify biomarkers for response and resistance to platinum-based therapy in exceptional responder, parallel genomic molecular characterization of the primary and metastatic tumors was conducted. Genetic sequencing indicated that selective therapeutic pressure did not lead to any significant genomic alternation in the brain metastasis, which suggests that the isolated relapse in the brain was instead due to pharmacological sanctuary at this site. This hypothesis was confirmed by the clinical observation that the patient also responded well to SRS and irinotecan administered to treat the brain recurrence, suggesting that the therapeutic sensitivity to DNA-damaging agents was retained.

Moreover, a BRCA1 gene mutation was identified in both the primary tumor tissue and the brain metastasis, in addition to the germline BRCA2 mutation. Such dual BRCA1/2 loss of function may be the cause of the exceptional clinical sensitivity to DNA-damaging agents throughout the treatment of this patient.

In light of the role of BRCA in DNA repair, it is suggested that BRCA1 or BRCA2 mutations result in increased sensitivity to DNA-damaging agents (9,10). Indeed, mounting evidence suggests a better response to PARP inhibitors or cisplatin in BRCA-associated malignancies (11–16). However, over time, BRCA-deficient tumors become resistant and disease progression may occur.

The ‘synthetic lethality’ concept has provided new opportunities for drug development (17). For example, in cancer cells with loss of function of BRCA, treatment with PARP inhibitors leads to an accumulation of single-strand breaks that subsequently develop into double-strand breaks, which cannot be fixed by homologous recombination (18,19).

A mutation in the CHEK2 gene in the primary tumor and brain metastatic tissues was also detected. CHEK2 is an important regulator of cellular response to DNA damage, and has been identified as tumor-suppressor gene in various human malignancies (20,21). This CHEK2 mutation may also contribute to the defects in DNA repair mechanisms in the described tumor.

To conclude, the findings of the present study suggest that loss of BRCA1, BRCA2 and CHEK2 function may result in greater sensitivity of cancer cells to DNA-damaging agents compared with the loss of function of only one of these genes (Fig. 1). If such a strategy becomes pharmacologically applicable, it may represent a novel synthetic effective approach to the treatment of pancreatic cancer, as well as other malignancies.