Defective DNA Mismatch Repair in Long-Term (≥3 Years) Survivors with Pancreatic CancerMaple J.T.a, b · Smyrk T.C.c, d · Boardman L.A.a, b · Johnson R.A.c, e · Thibodeau S.N.c, e · Chari S.T.a, b
aDepartment of Internal Medicine, bDivision of Gastroenterology, cDepartment of Laboratory Medicine and Pathology, dDivision of Anatomic Pathology, and eDivision of Experimental Pathology and Laboratory Medicine, Mayo Clinic and Foundation, Rochester, Minn., USA
Background/Aims: Defective DNA mismatch repair (MMR) in pancreatic cancer, reported in up to 13% of sporadic pancreatic cancers, may predict a good prognosis. To determine if long-term survival in pancreatic cancer could be attributed to defective DNA MMR, we ascertained its prevalence in 35 pancreatic cancer patients who survived ≧3 years after surgery. Methods: We performed immunohistochemistry (IHC) for MMR proteins hMLH1, hMSH2, and hMSH6 in all 35 tumors and microsatellite instability (MSI) studies in 34/35 tumors using 10 microsatellite markers in paired normal and tumor DNA. Defective DNA MMR was defined as absence of protein expression on IHC and/or MSI in ≧30% of markers studied. Results: On IHC, 3/35 (8.6%) tumors had defective DNA MMR. All 3 had absent expression of a DNA MMR protein (hMLH1 in 2 and hMSH2) and 2/3 also had MSI; the third could not be tested. Definitely 2, and probably all 3 patients had hereditary nonpolyposis colon cancer as determined by clinical and genetic profiles. Conclusion: Defective DNA MMR is uncommon in long-term survivors of pancreatic cancer and does not account for the survival benefit in those with sporadic pancreatic cancer.
© 2005 S. Karger AG, Basel and IAP
Francisco X. Real
Institut Municipal d’Investigació Mèdica, Universitat Pompeu Fabra, Barcelona, Spain
Pancreatic ductal adenocarcinoma (PDA) remains a formidable clinical challenge [1, 2]. Over the past 50 years, the prognosis of patients with PDA has remained essentially unchanged. The impact of advances leading to an early diagnosis (i.e. identification of tumors of 2 cm diameter) would likely be relatively small given that approximately two thirds of such tumors involve lymph nodes. The impact of therapeutic advances may also be limited due to age at presentation and poor condition of patients. However, there is room for optimism: (1) there have been major advances in the understanding of the biology of the gland , the molecular mechanisms involved in PDA , and in the development of mouse models of disease ; (2) the study of selected subsets of patients (i.e. hereditary PDA) may provide opportunities for improved prospects for a few individuals ; and (3) randomized trials support the notion that adjuvant chemotherapy provides a clinical benefit .
In this issue of Pancreatology, Maple et al.  analyze microsatellite instability (MI) in ‘long-term’ survivors (>3 years) with PDA. MI is the molecular hallmark of the inactivation of genes involved in mismatch repair, a characteristic of hereditary nonpolyposis colorectal cancer (HNPCC) as well as of some sporadic tumors . The genes most commonly implicated in HNPCC, MLH1 and MSH2, are mainly inactivated through mutation and epigenetic silencing. The work of Maple et al. was prompted by prior reports suggesting that: (1) in PDA, MI is associated with medullary histology and wild-type K-ras [10, 11], (2) patients with MI+ tumors may have a stronger history of familial cancer , and (3) MI is associated with an improved prognosis [12, 13]. Maple et al. conclude that MI+ tumors are not over-represented among long-term survivors with PDA, that such tumors are commonly associated with a personal or familial history of cancer – possibly in the context of HNPCC – and that there is no straightforward association between MI+ tumors and medullary histology .
It is likely that the controversial findings on the subject can be accounted in part by undesired selection biases: the report of Goggins et al.  dealt with human PDA xenografted in nude mice; a subsequent report from the same group reported an analysis of 18 cases with medullary histology drawn from a series of ‘450 randomly chosen pancreatic cancers’ ; Yamamoto et al.  analyzed 100 cases undergoing surgical resection, not all of which had curative intent; and Nakata et al.  reported on 46 cases undergoing surgical resection. Now, Maple et al.  analyze 35 ‘long-term survivors’ drawn from a series of 373 patients undergoing surgical resection at a single institution. The scenario is reminiscent of the story of the blind men and the elephant: the subject of study is complex, the approach is fragmentary, and we lack a global view of the problem that can provide real understanding and progress.
The overall evidence reported in the literature strongly suggests that the identification of subgroups of PDA (i.e. MI+, medullary) may have clinical relevance. However, none of the reports published provides sufficient evidence to justify changes in clinical management.
We do not yet know why a few patients with PDA become long-term survivors. Such information may prove invaluable in designing strategies applicable in the future to many patients. What we now need are not a few more reports adding to the controversy but, rather, definitive studies. They should prospectively define the patient population, collect precise data on surgery, staging and therapy, determine the reproducibility of pathologists’ assessment of medullary carcinoma of the pancreas, carefully select the most appropriate molecular studies that need to be performed, and analyze the data with appropriate statistical tools.
There is now substantial evidence that adjuvant chemotherapy may improve the long-term survival of patients with PDA . Such progress is facilitating recruitment of patients into clinical trials at a rapid pace: more than 600 cases have already entered the ESPAC-3 protocol. Such trials provide an exceptional opportunity to determine the value of molecular prognostic markers in well-characterized series of patients treated in a homogeneous manner.
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