Annals of Case Reports

Introduction

Pancreatic adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality. While the majority of cases are sporadic, approximately 10% harbor a hereditary component involving genes such as BRCA1, BRCA2, PALB2, and ATM. The BLM gene encodes a RecQ DNA helicase essential for maintaining genomic stability. Biallelic mutations in BLM result in Bloom Syndrome, an autosomal recessive disorder characterized by short stature, photosensitivity, and a marked predisposition to early-onset malignancies. However, the contribution of monoallelic (heterozygous) BLM mutations to PDAC risk and treatment response is less defined.

Identifying defects in homologous recombination repair (HRR) is critical, as these tumors may exhibit synthetic lethality when exposed to DNA-damaging agents like platinum salts or PARP inhibitors. This report describes a patient with metastatic PDAC and a history of small cell lung cancer (SCLC) who harbored a germline BLM mutation and a somatic ATM mutation.

Case Presentation

A 73-year-old Caucasian female presented for surveillance following treatment for a prior malignancy. Her medical history was significant for limited-stage small cell lung cancer (SCLC) diagnosed 2 years ago, for which she completed four cycles of cisplatin and etoposide with concurrent radiation therapy. She had been without evidence of disease (NED) on recent imaging. Relevant comorbidities included type 2 diabetes, hypertension, hyperlipidemia, a recent acute lacunar cerebrovascular accident (CVA), and a 35-pack-year history of tobacco use (quit 2 years prior to presentation).

Her family history was notable for malignancy. Her father died of prostate cancer at age 93. Two sisters were diagnosed with breast cancer, one in her 50s and the other in her 60s. Additionally, the maternal grandmother had a cancer of unknown primary, which the family suspected was pancreatic in origin.

At presentation, surveillance imaging revealed a 2 cm nodule at the pancreatic head. Subsequent imaging a month later demonstrated rapid progression with new liver metastases, confirming Stage IV pancreatic adenocarcinoma. The patient developed obstructive jaundice, which was resolved via ERCP stenting.

Next-generation sequencing (NGS) was performed to guide therapy. Testing identified a pathogenic germline heterozygous variant in BLM (p.Q645*) and a pathogenic somatic mutation in ATM (p.R3008H), along with a somatic KRAS (p.G12D) mutation.

Clinical Course Due to the presence of DDR gene mutations (BLM and ATM), a platinum-based regimen was favored. The patient initiated first-line palliative chemotherapy with mFOLFOX6 (oxaliplatin 85 mg/m², fluorouracil 1800 mg/m², and leucovorin). Irinotecan was omitted from the standard FOLFIRINOX regimen due to the patient's severe baseline fatigue and recent stroke history.

Following the initiation of therapy, the patient tolerated the regimen with manageable toxicities. Due to persistent fatigue, a 20% dose reduction was implemented for subsequent cycles to preserve quality of life while maintaining platinum exposure. Follow-up evaluation showed stabilization of liver enzymes and stable disease on imaging, validating the decision to pursue a DNA-damaging strategy despite her complex medical history [1-3].

Discussion

This case illustrates the diagnostic and therapeutic nuances of treating PDAC in the context of hereditary cancer syndromes. The patientʼs germline BLM mutation, combined with a somatic ATM mutation, likely compromised the tumorʼs homologous recombination repair capacity, rendering it susceptible to oxaliplatin.

The BLM gene functions as a "caretaker" of the genome. Loss of BLM function leads to increased sister chromatid exchanges and genomic instability. While Bloom Syndrome is rare, carriers of heterozygous BLM mutations may have an increased risk of colorectal and other cancers, though specific screening guidelines for PDAC in carriers are not yet established.

Regarding the tumor immune microenvironment, emerging research suggests a link between BLM expression and immune infiltration. High BLM expression has been regulated by the LINC01133/miR-30b-5p axis, which modulates immune cell infiltration in pancreatic cancer models. Consequently, BLM status may serve as a potential biomarker not only for chemotherapy sensitivity but also for determining the immunogenicity of the tumor, which could influence future immunotherapy strategies.

The molecular profile of this patient parallels other cases of HRR-deficient PDAC. Case reports involving somatic or germline ATM mutations have documented favorable responses to platinum-based chemotherapy and PARP inhibitors, similar to BRCA-mutated phenotypes. The stabilization of disease seen in this patient aligns with literature suggesting that defects in ATM and BLM confer a synthetic lethality vulnerability that can be exploited clinically.

Future management for this patient, should progression occur, may involve clinical trials targeting DNA damage response pathways, such as those utilizing ATR inhibitors or antibody-drug conjugates [4,5].

Conclusion

This case emphasizes the value of germline and somatic testing in pancreatic cancer. The identification of BLM and ATM mutations provided a clear rationale for optimizing platinum-based therapy in an elderly patient with significant comorbidities.

Funding

The NIH grant number for Subhrajith Saha (co-author) is NIAID 5U01AI138323-05, NIAID 5U01AI170036-02.

References

1. World Health Organization. (2019). Classification of tumours of the digestive system. 5th ed. Lyon: IARC. Available from online.
2. Tempero MA, Malafa MP, Al-Hawary M, Behrman SW, Benson AB, et al. (2023). National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Pancreatic adenocarcinoma. Version 2. 19: 439-457.
3. Cunniff C, Bassetti JA, Ellis NA. (2017). Bloom’s syndrome: Clinical spectrum, molecular pathogenesis, and cancer predisposition. Molecular Syndromology. 8:4–23.
4. Fares F, Fares B, Fares J, et al. (2022). LINC01133 regulates the miR-30b-5p/BLM axis to control pancreatic cancer progression and tumor immune infiltration. Cancer Cell International.
5. Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, et al. (2014). Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. British Journal of Cancer. 111: 1132-1138.
6. Li Q, Zhang P, Zhang YN, Hu HX, Yan JF, et al. (2023). Aberrant expression of BLM correlates with malignant progression and immune infiltration in pancreatic adenocarcinoma. Cancer Screening and Prevention. 2: 14-29.