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Figure.
Long-term Outcomes of Patients With Mismatch Repair Deficient Pancreatic Ductal Adenocarcinoma
Long-term Outcomes of Patients With Mismatch Repair Deficient Pancreatic Ductal Adenocarcinoma

Six patients had localized disease and 4 patients had metastatic disease.

Table.  
Complete Clinical, Genetic, and Outcomes Information for Patients With Mismatch Repair Deficient Pancreatic Ductal Adenocarcinoma
Complete Clinical, Genetic, and Outcomes Information for Patients With Mismatch Repair Deficient Pancreatic Ductal Adenocarcinoma
1.
Le  DT, Uram  JN, Wang  H,  et al.  PD-1 blockade in tumors with mismatch-repair deficiency.  N Engl J Med. 2015;372(26):2509-2520.PubMedGoogle ScholarCrossref
2.
Nakata  B, Wang  YQ, Yashiro  M,  et al.  Prognostic value of microsatellite instability in resectable pancreatic cancer.  Clin Cancer Res. 2002;8(8):2536-2540.PubMedGoogle Scholar
3.
Kastrinos  F, Mukherjee  B, Tayob  N,  et al.  Risk of pancreatic cancer in families with Lynch syndrome.  JAMA. 2009;302(16):1790-1795.PubMedGoogle ScholarCrossref
4.
Neoptolemos  JP, Stocken  DD, Bassi  C,  et al; European Study Group for Pancreatic Cancer.  Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.  JAMA. 2010;304(10):1073-1081.PubMedGoogle ScholarCrossref
5.
Conroy  T, Desseigne  F, Ychou  M,  et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.  N Engl J Med. 2011;364(19):1817-1825.PubMedGoogle ScholarCrossref
6.
Knudsen  ES, O’Reilly  EM, Brody  JR, Witkiewicz  AK.  Genetic diversity of pancreatic ductal adenocarcinoma and opportunities for precision medicine.  Gastroenterology. 2016;150(1):48-63.PubMedGoogle ScholarCrossref
Research Letter
November 2017

Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Patients With Pancreatic Ductal Adenocarcinoma

Author Affiliations
  • 1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston
  • 2Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston
JAMA Surg. 2017;152(11):1086-1088. doi:10.1001/jamasurg.2017.2631

DNA mismatch repair status is a well-established biomarker in colorectal cancer and is associated with both a favorable prognosis and excellent response to immunotherapy.1 However, the influence of deficient DNA mismatch repair (dMMR) and microsatellite instability in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The prognosis of PDAC is typically dismal and treatment options are limited, but previous research has suggested that microsatellite instability in resected PDAC specimens may be associated with improved survival.2 Because patients with Lynch syndrome harbor germline defects in mismatch repair genes and have significantly elevated lifetime risks of malignant neoplasms, including PDAC,3 we used this unique patient cohort to establish the clinical behavior and outcomes of dMMR PDAC.

Methods

The prospectively maintained Familial High-Risk Gastrointestinal Cancer Clinic and Genetic Counseling databases were queried to identify all patients with PDAC who were evaluated at the University of Texas MD Anderson Cancer Center from January 1, 2006, to December 31, 2016. Patients whose tumors showed evidence of dMMR by results of immunohistochemical analysis and/or who carry germline mutations in MLH1 (GenBank NG_007109), MSH2 (GenBank NG_007110), MSH6 (GenBank NG_007111), or PMS2 (GenBank NG_008466) were included. Clinicopathologic and genetic features as well as long-term follow-up were reviewed.

The MD Anderson Cancer Center Institutional Review Board approved this retrospective study and waived the individual informed consent requirement.

Results

Among 821 patients included in the registry, 10 (1.2%) patients with PDAC were identified (Table). Seven patients had pathogenic germline mutations in MLH1 (n = 4) and MSH2 (n = 3). The mean (SD) age of all patients was 57.2 (15.0) years, 7 patients were men, and 8 had a personal history of Lynch syndrome–associated cancers. Six patients presented with localized disease and underwent either pancreatoduodenectomy (n = 4) or distal pancreatectomy (n = 2) with curative intent. Among these 6 patients, adjuvant or neoadjuvant chemotherapy was delivered to 3 and chemoradiotherapy was provided to 2. The 5-year overall survival rate of these patients was 100% after a median follow-up of 93.1 months (95% CI, 52.5-201.7). Four patients who presented with metastatic disease and were treated with systemic chemotherapy alone had a median overall survival of 16.5 months (95% CI, 7.2-24.0) and a 5-year overall survival rate of 25% (Figure).

Discussion

In this single-institution study of dMMR PDAC, we identified patients with defects in MLH1, MSH2, MSH6, and PMS2 genes due to both germline and sporadic causes. Although patients with dMMR were not immune to nodal and distant metastases, those with localized disease who underwent surgery with curative intent had remarkably good outcomes with a 5-year overall survival rate of 100%, which is significantly better than the 25% reported in the largest randomized clinical trial of surgical resection and adjuvant chemotherapy.4 Patients who presented with metastatic disease also experienced better-than-expected outcomes, achieving a median of 16.5 months’ survival with one 5-year survivor (95% CI, 7.2-24.0) compared with a median of 11.1 months in patients treated with FOLFIRINOX (fluorouracil, leucovorin calcium, irinotecan hydrochloride, and oxaliplatin) and 6.8 months in patients treated with gemcitabine hydrochloride.5 These findings confirm those of previous studies, which suggested superior outcomes in patients with dMMR malignant neoplasms, presumably related to a more robust tumor-infiltrating immune response.2

The limitation of this study is its retrospective, single-institution design and the inclusion of only patients referred to and evaluated in our familial and high-risk cancer clinic, but these findings have several implications. First, the diagnosis of PDAC in patients with a personal history of Lynch syndrome–associated cancers should prompt dedicated tumor and germline genetic testing. Second, treatment decisions should be made in the context of these patients’ favorable tumor biological characteristics and life expectancy. In fact, 2 patients in this series underwent local therapy (surgery or chemoradiotherapy) for retroperitoneal recurrences and experienced durable responses. Finally, previous research in colorectal cancer has demonstrated the influence of dMMR status on sensitivity to specific treatments, including checkpoint inhibitors. Ongoing clinical trials in patients with PDAC and mutations in DNA damage-repair genes, such as BRCA, PALB2, ATM, and MMR, hold promise for more effective targeted treatment options.6 Given the clinical significance of the findings reported herein, routine screening of PDAC specimens for dMMR may be indicated and should be the focus of future investigations.

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Article Information

Corresponding Author: Y. Nancy You, MD, MHSc, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT 17.6058, Houston, TX 77030-4008 (ynyou@mdanderson.org).

Accepted for Publication: May 11, 2017.

Published Online: August 9, 2017. doi:10.1001/jamasurg.2017.2631

Author Contributions: Drs Cloyd and You had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cloyd, You.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Cloyd.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cloyd, You.

Administrative, technical, or material support: Wang, Cuddy.

Study supervision: Katz, You.

Conflict of Interest Disclosures: None reported.

References
1.
Le  DT, Uram  JN, Wang  H,  et al.  PD-1 blockade in tumors with mismatch-repair deficiency.  N Engl J Med. 2015;372(26):2509-2520.PubMedGoogle ScholarCrossref
2.
Nakata  B, Wang  YQ, Yashiro  M,  et al.  Prognostic value of microsatellite instability in resectable pancreatic cancer.  Clin Cancer Res. 2002;8(8):2536-2540.PubMedGoogle Scholar
3.
Kastrinos  F, Mukherjee  B, Tayob  N,  et al.  Risk of pancreatic cancer in families with Lynch syndrome.  JAMA. 2009;302(16):1790-1795.PubMedGoogle ScholarCrossref
4.
Neoptolemos  JP, Stocken  DD, Bassi  C,  et al; European Study Group for Pancreatic Cancer.  Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.  JAMA. 2010;304(10):1073-1081.PubMedGoogle ScholarCrossref
5.
Conroy  T, Desseigne  F, Ychou  M,  et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.  N Engl J Med. 2011;364(19):1817-1825.PubMedGoogle ScholarCrossref
6.
Knudsen  ES, O’Reilly  EM, Brody  JR, Witkiewicz  AK.  Genetic diversity of pancreatic ductal adenocarcinoma and opportunities for precision medicine.  Gastroenterology. 2016;150(1):48-63.PubMedGoogle ScholarCrossref
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