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

Toni T. Seppala; Aysel Ahadova; Mev Dominguez-Valentin; Finlay Macrae; D. Gareth Evans; Christina Therkildsen; Julian Sampson; Rodney Scott; John Burn; Gabriela Moeslein; Inge Bernstein; Elke Holinski-Feder; Kirsi Pylvanainen; Laura Renkonen-Sinisalo; Anna Lepisto; Charlotte Kvist Lautrup; Annika Lindblom; John-Paul Plazzer; Ingrid Winship; Douglas Tjandra; Lior H. Katz; Stefan Aretz; Robert Hueneburg; Stefanie Holzapfel; Karl Heinimann; Adriana Della Valle; Florencia Neffa; Nathan Gluck; Wouter H. de Vos Tot Nederveen Cappel; Hans Vasen; Monika Morak; Verena Steinke-Lange; Christoph Engel; Nils Rahner; Wolff Schmiegel; Deepak Vangala; Huw Thomas; Kate Green; Fiona Lalloo; Emma J. Crosbie; James Hill; Gabriel Capella; Marta Pineda; Matilde Navarro; Ignacio Blanco; Sanne ten Broeke; Maartje Nielsen; Ken Ljungmann; Sigve Nakken; Noralane Lindor; Ian M Frayling; Eivind Hovig; Lone Sunde; Matthias Kloor; Jukka-Pekka Mecklin; Mette Kalager; Pål Møller

doi:10.1186/s13053-019-0106-8

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

Toni T. Seppala^*, Aysel Ahadova, Mev Dominguez-Valentin, Finlay Macrae, D. Gareth Evans, Christina Therkildsen, Julian Sampson, Rodney Scott, John Burn, Gabriela Moeslein, Inge Bernstein, Elke Holinski-Feder, Kirsi Pylvanainen, Laura Renkonen-Sinisalo, Anna Lepisto, Charlotte Kvist Lautrup, Annika Lindblom, John-Paul Plazzer, Ingrid Winship, Douglas TjandraLior H. Katz, Stefan Aretz, Robert Hueneburg, Stefanie Holzapfel, Karl Heinimann, Adriana Della Valle, Florencia Neffa, Nathan Gluck, Wouter H. de Vos Tot Nederveen Cappel, Hans Vasen, Monika Morak, Verena Steinke-Lange, Christoph Engel, Nils Rahner, Wolff Schmiegel, Deepak Vangala, Huw Thomas, Kate Green, Fiona Lalloo, Emma J. Crosbie, James Hill, Gabriel Capella, Marta Pineda, Matilde Navarro, Ignacio Blanco, Sanne ten Broeke, Maartje Nielsen, Ken Ljungmann, Sigve Nakken, Noralane Lindor, Ian M Frayling, Eivind Hovig, Lone Sunde, Matthias Kloor, Jukka-Pekka Mecklin, Mette Kalager, Pål Møller

^*Corresponding author af dette arbejde

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Abstract

BackgroundRecent 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.MethodsTo 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.ResultsStage 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 3.5years 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 2.5years after the last colonoscopy were not more advanced than those diagnosed earlier (p=0.14).ConclusionsThe 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.

Originalsprog	Engelsk
Artikelnummer	8
Tidsskrift	Hereditary Cancer in Clinical Practice
Vol/bind	17
Nummer	1
Antal sider	8
ISSN	1731-2302
DOI	https://doi.org/10.1186/s13053-019-0106-8
Status	Udgivet - 28 feb. 2019

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10.1186/s13053-019-0106-8

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Seppala, T. T., Ahadova, A., Dominguez-Valentin, M., Macrae, F., Evans, D. G., Therkildsen, C., Sampson, J., Scott, R., Burn, J., Moeslein, G., Bernstein, I., Holinski-Feder, E., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Lautrup, C. K., Lindblom, A., Plazzer, J.-P., Winship, I., ... Møller, P. (2019). 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. Hereditary Cancer in Clinical Practice, 17(1), Artikel 8. https://doi.org/10.1186/s13053-019-0106-8

@article{5e68558868dd4773aeff5d891bcb370f,

title = "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",

abstract = "BackgroundRecent 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.MethodsTo 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.ResultsStage 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 3.5years 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 2.5years after the last colonoscopy were not more advanced than those diagnosed earlier (p=0.14).ConclusionsThe 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.",

keywords = "Mismatch repair, Microsatellite instability, Lynch syndrome, Hereditary cancer, Colorectal cancer, Hereditary nonpolyposis colorectal cancer, Colonoscopy, Endoscopy, Surveillance, Screening, Over-diagnosis, COLORECTAL-CANCER, COLONOSCOPIC SURVEILLANCE, RISK, FAMILIES, MUTATION, ADENOMA",

author = "Seppala, {Toni T.} and Aysel Ahadova and Mev Dominguez-Valentin and Finlay Macrae and Evans, {D. Gareth} and Christina Therkildsen and Julian Sampson and Rodney Scott and John Burn and Gabriela Moeslein and Inge Bernstein and Elke Holinski-Feder and Kirsi Pylvanainen and Laura Renkonen-Sinisalo and Anna Lepisto and Lautrup, {Charlotte Kvist} and Annika Lindblom and John-Paul Plazzer and Ingrid Winship and Douglas Tjandra and Katz, {Lior H.} and Stefan Aretz and Robert Hueneburg and Stefanie Holzapfel and Karl Heinimann and {Della Valle}, Adriana and Florencia Neffa and Nathan Gluck and Cappel, {Wouter H. de Vos Tot Nederveen} and Hans Vasen and Monika Morak and Verena Steinke-Lange and Christoph Engel and Nils Rahner and Wolff Schmiegel and Deepak Vangala and Huw Thomas and Kate Green and Fiona Lalloo and Crosbie, {Emma J.} and James Hill and Gabriel Capella and Marta Pineda and Matilde Navarro and Ignacio Blanco and {ten Broeke}, Sanne and Maartje Nielsen and Ken Ljungmann and Sigve Nakken and Noralane Lindor and Frayling, {Ian M} and Eivind Hovig and Lone Sunde and Matthias Kloor and Jukka-Pekka Mecklin and Mette Kalager and P{\aa}l M{\o}ller",

year = "2019",

month = feb,

day = "28",

doi = "10.1186/s13053-019-0106-8",

language = "English",

volume = "17",

journal = "Hereditary Cancer in Clinical Practice",

issn = "1731-2302",

publisher = "BioMed Central Ltd.",

number = "1",

}

Seppala, TT, Ahadova, A, Dominguez-Valentin, M, Macrae, F, Evans, DG, Therkildsen, C, Sampson, J, Scott, R, Burn, J, Moeslein, G, Bernstein, I, Holinski-Feder, E, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Lautrup, CK, Lindblom, A, Plazzer, J-P, Winship, I, Tjandra, D, Katz, LH, Aretz, S, Hueneburg, R, Holzapfel, S, Heinimann, K, Della Valle, A, Neffa, F, Gluck, N, Cappel, WHDVTN, Vasen, H, Morak, M, Steinke-Lange, V, Engel, C, Rahner, N, Schmiegel, W, Vangala, D, Thomas, H, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Capella, G, Pineda, M, Navarro, M, Blanco, I, ten Broeke, S, Nielsen, M, Ljungmann, K, Nakken, S, Lindor, N, Frayling, IM, Hovig, E, Sunde, L, Kloor, M, Mecklin, J-P, Kalager, M & Møller, P 2019, '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', Hereditary Cancer in Clinical Practice, bind 17, nr. 1, 8. https://doi.org/10.1186/s13053-019-0106-8

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. / Seppala, Toni T.; Ahadova, Aysel; Dominguez-Valentin, Mev et al.
I: Hereditary Cancer in Clinical Practice, Bind 17, Nr. 1, 8, 28.02.2019.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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 - Seppala, 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 - Moeslein, Gabriela

AU - Bernstein, Inge

AU - Holinski-Feder, Elke

AU - Pylvanainen, Kirsi

AU - Renkonen-Sinisalo, Laura

AU - Lepisto, 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 - Hueneburg, Robert

AU - Holzapfel, Stefanie

AU - Heinimann, Karl

AU - Della Valle, Adriana

AU - Neffa, Florencia

AU - Gluck, Nathan

AU - Cappel, Wouter H. de Vos Tot Nederveen

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 M

AU - Hovig, Eivind

AU - Sunde, Lone

AU - Kloor, Matthias

AU - Mecklin, Jukka-Pekka

AU - Kalager, Mette

AU - Møller, Pål

PY - 2019/2/28

Y1 - 2019/2/28

N2 - BackgroundRecent 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.MethodsTo 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.ResultsStage 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 3.5years 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 2.5years after the last colonoscopy were not more advanced than those diagnosed earlier (p=0.14).ConclusionsThe 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 - BackgroundRecent 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.MethodsTo 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.ResultsStage 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 3.5years 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 2.5years after the last colonoscopy were not more advanced than those diagnosed earlier (p=0.14).ConclusionsThe 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 - Mismatch repair

KW - Microsatellite instability

KW - Lynch syndrome

KW - Hereditary cancer

KW - Colorectal cancer

KW - Hereditary nonpolyposis colorectal cancer

KW - Colonoscopy

KW - Endoscopy

KW - Surveillance

KW - Screening

KW - Over-diagnosis

KW - COLORECTAL-CANCER

KW - COLONOSCOPIC SURVEILLANCE

KW - RISK

KW - FAMILIES

KW - MUTATION

KW - ADENOMA

UR - http://www.scopus.com/inward/record.url?scp=85062324759&partnerID=8YFLogxK

U2 - 10.1186/s13053-019-0106-8

DO - 10.1186/s13053-019-0106-8

M3 - Journal article

C2 - 30858900

SN - 1731-2302

VL - 17

JO - Hereditary Cancer in Clinical Practice

JF - Hereditary Cancer in Clinical Practice

IS - 1

M1 - 8

ER -

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

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