TY - JOUR
T1 - Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; A prospective Lynch syndrome database report
AU - Seppälä, Toni T.
AU - Ahadova, Aysel
AU - Dominguez-Valentin, Mev
AU - Macrae, Finlay
AU - Evans, D. Gareth
AU - Therkildsen, Christina
AU - Sampson, Julian
AU - Scott, Rodney
AU - Burn, John
AU - Möslein, Gabriela
AU - Bernstein, Inge
AU - Holinski-Feder, Elke
AU - Pylvänäinen, Kirsi
AU - Renkonen-Sinisalo, Laura
AU - Lepistö, Anna
AU - Lautrup, Charlotte Kvist
AU - Lindblom, Annika
AU - Plazzer, John Paul
AU - Winship, Ingrid
AU - Tjandra, Douglas
AU - Katz, Lior H.
AU - Aretz, Stefan
AU - Hüneburg, Robert
AU - Holzapfel, Stefanie
AU - Heinimann, Karl
AU - Valle, Adriana Della
AU - Neffa, Florencia
AU - Gluck, Nathan
AU - De Vos Tot Nederveen Cappel, Wouter H.
AU - Vasen, Hans
AU - Morak, Monika
AU - Steinke-Lange, Verena
AU - Engel, Christoph
AU - Rahner, Nils
AU - Schmiegel, Wolff
AU - Vangala, Deepak
AU - Thomas, Huw
AU - Green, Kate
AU - Lalloo, Fiona
AU - Crosbie, Emma J.
AU - Hill, James
AU - Capella, Gabriel
AU - Pineda, Marta
AU - Navarro, Matilde
AU - Blanco, Ignacio
AU - Ten Broeke, Sanne
AU - Nielsen, Maartje
AU - Ljungmann, Ken
AU - Nakken, Sigve
AU - Lindor, Noralane
AU - Frayling, Ian
AU - Hovig, Eivind
AU - Sunde, Lone
AU - Kloor, Matthias
AU - Mecklin, Jukka Pekka
AU - Kalager, Mette
AU - Møller, Pål
N1 - Funding Information:
TTS is supported by the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Instrumentarium Science Foundation and Sigrid Juselius Foundation. DGE and EJC are both supported through the National Institute for Health Research Manchester Biomedical Research Centre (IS-BRC-1215-20007). The Finnish contribution: The Finnish Cancer Foundation, Jane and Aatos Erkko foundation and State Research Funding. The Spanish contribution: Spanish Ministry of Economy and Competitiveness, the Carlos III Health Institute, the Scientific Foundation Asociación Española Contra el Cáncer and the Government of Catalonia. The Welsh Contribution: Wales Gene Park. The Norwegian contribution: Norwegian Cancer Society, contract 194751–2017 for funding. The study sponsors did not have a role in planning the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/2/28
Y1 - 2019/2/28
N2 - Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path-MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path-MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path-MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path-MLH1, 45 path-MSH2, 10 path-MSH6 and 1 path-PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path-MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path-MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path-MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path-MMR carriers.
AB - Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path-MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path-MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path-MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path-MLH1, 45 path-MSH2, 10 path-MSH6 and 1 path-PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path-MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path-MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path-MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path-MMR carriers.
KW - Colonoscopy
KW - Colorectal cancer
KW - Endoscopy
KW - Hereditary cancer
KW - Hereditary nonpolyposis colorectal cancer
KW - Lynch syndrome
KW - Microsatellite instability
KW - Mismatch repair
KW - Over-diagnosis
KW - Screening
KW - Surveillance
U2 - 10.1186/s13053-019-0106-8
DO - 10.1186/s13053-019-0106-8
M3 - Article
AN - SCOPUS:85062324759
SN - 1731-2302
VL - 17
JO - HEREDITARY CANCER IN CLINICAL PRACTICE
JF - HEREDITARY CANCER IN CLINICAL PRACTICE
IS - 1
M1 - 8
ER -