Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
verfasst von:
Pål Møller, Toni Seppälä, James G. Dowty, Saskia Haupt, Mev Dominguez-Valentin, Lone Sunde, Inge Bernstein, Christoph Engel, Stefan Aretz, Maartje Nielsen, Gabriel Capella, Dafydd Gareth Evans, John Burn, Elke Holinski-Feder, Lucio Bertario, Bernardo Bonanni, Annika Lindblom, Zohar Levi, Finlay Macrae, Ingrid Winship, John-Paul Plazzer, Rolf Sijmons, Luigi Laghi, Adriana Della Valle, Karl Heinimann, Elizabeth Half, Francisco Lopez-Koestner, Karin Alvarez-Valenzuela, Rodney J. Scott, Lior Katz, Ido Laish, Elez Vainer, Carlos Alberto Vaccaro, Dirce Maria Carraro, Nathan Gluck, Naim Abu-Freha, Aine Stakelum, Rory Kennelly, Des Winter, Benedito Mauro Rossi, Marc Greenblatt, Mabel Bohorquez, Harsh Sheth, Maria Grazia Tibiletti, Leonardo S. Lino-Silva, Karoline Horisberger, Carmen Portenkirchner, Ivana Nascimento, Norma Teresa Rossi, Leandro Apolinário da Silva, Huw Thomas, Attila Zaránd, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepisto, Päivi Peltomäki, Christina Therkildsen, Lars Joachim Lindberg, Ole Thorlacius-Ussing, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Robert Hüneburg, Aída Falcón de Vargas, Andrew Latchford, Anne-Marie Gerdes, Ann-Sofie Backman, Carmen Guillén-Ponce, Carrie Snyder, Charlotte K. Lautrup, David Amor, Edenir Palmero, Elena Stoffel, Floor Duijkers, Michael J. Hall, Heather Hampel, Heinric Williams, Henrik Okkels, Jan Lubiński, Jeanette Reece, Joanne Ngeow, Jose G. Guillem, Julie Arnold, Karin Wadt, Kevin Monahan, Leigha Senter, Lene J. Rasmussen, Liselotte P. van Hest, Luigi Ricciardiello, Maija R. J. Kohonen-Corish, Marjolijn J. L. Ligtenberg, Melissa Southey, Melyssa Aronson, Mohd N. Zahary, N. Jewel Samadder, Nicola Poplawski, Nicoline Hoogerbrugge, Patrick J. Morrison, Paul James, Grant Lee, Rakefet Chen-Shtoyerman, Ravindran Ankathil, Rish Pai, Robyn Ward, Susan Parry, Tadeusz Dębniak, Thomas John, Thomas van Overeem Hansen, Trinidad Caldés, Tatsuro Yamaguchi, Verónica Barca-Tierno, Pilar Garre, Giulia Martina Cavestro, Jürgen Weitz, Silke Redler, Reinhard Büttner, Vincent Heuveline, John L. Hopper, Aung Ko Win, Noralane Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane Figueiredo, Daniel D. Buchanan, Stephen N. Thibodeau, Sanne W. ten Broeke, Eivind Hovig, Sigve Nakken, Marta Pineda, Nuria Dueñas, Joan Brunet, Kate Green, Fiona Lalloo, Katie Newton, Emma J. Crosbie, Miriam Mints, Douglas Tjandra, Florencia Neffa, Patricia Esperon, Revital Kariv, Guy Rosner, Walter Hernán Pavicic, Pablo Kalfayan, Giovana Tardin Torrezan, Thiago Bassaneze, Claudia Martin, Gabriela Moslein, Aysel Ahadova, Matthias Kloor, Julian R. Sampson, Mark A. Jenkins, The European Hereditary Tumour Group (EHTG) and the International Mismatch Repair Consortium (IMRC)
To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants.
Methods
CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands.
Results
In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups.
Conclusions
Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abkürzungen
LS
Lynch syndrome
CRC
colorectal cancer
Path_MMR
pathogenic or likely pathogenic variant of one of the MLH1, MSH2, MSH6 or PMS2 genes
Path_MLH1
pathogenic or likely pathogenic variant of one of the MLH1 gene
Path_MSH2
pathogenic or likely pathogenic variant of one of the MLH1 gene
Path_MSH6
pathogenic or likely pathogenic variant of one of the MLH1 gene
Path_PMS2
pathogenic or likely pathogenic variant of one of the MLH1 gene
PLSD
The Prospective Lynch Syndrome Database
IMRC
The International Mismatch Repair Consortium
Background
In 1995, a study in Finland found that colonoscopy with polypectomy conducted every three to five years was associated with a reduced CRC incidence in Lynch syndrome (LS) when compared to LS patients who did not have colonoscopy [1]. It was stated that ‘The recommended surveillance protocol for HNPCC is based on the hypothesis that the adenoma-carcinoma sequence, which is generally accepted in sporadic colorectal cancer, is also applicable in HNPCC’ [2] and relatives of LS cases were thereafter widely subjected to surveillance with colonoscopy every three years. However, continued occurrence of CRC was noted despite this surveillance and, in response, the recommended interval between colonoscopies was reduced [3, 4]. Despite this change, continuing occurrence of CRC was still observed and in some centres the interval between colonoscopies was therefore reduced further, to one year [5] or even less. Surprisingly, since the initial Finnish report in 1995 that did not control for lead-time bias and was not randomized, there has been no confirmatory study to show that colonoscopy surveillance with polypectomy significantly reduces CRC incidence in LS.
The earliest published reports of LS families [6] suggest that in previous generations, most individuals who developed a first cancer died from that cancer. By contrast, more recently, LS patients diagnosed with a non-colorectal cancer at a young age usually survive and often develop CRC later in life [7]. The extent to which this time-trend (survivor bias) has influenced the outcomes of interventions that aim to prevent occurrence of CRC and improve its prognosis through early detection and treatment, is not known.
Anzeige
No single institution nor country had the resources needed to resolve these issues, leading the European Hereditary Tumour Group in 2012 (www.ehtg.org, that at the time was known as the Mallorca group) to invite pooling of international results of prospective follow-up of LS families in a single shared database, the Prospective Lynch Syndrome Database (PLSD). The goal of PLSD was to describe cancer incidences in all organs in carriers of path_MMR variants who were undergoing follow-up according to the internationally advocated clinical guidelines and to stratify these by age, gene and gender. Once sufficient numbers of carriers and follow-up years were collated, the intention was to use the information obtained to assess whether the results were compatible with current assumptions about carcinogenesis and the expected effects of interventions in LS. This paper reports the results of one such assessment. Because neither randomized trials of colonoscopy versus no-colonoscopy, nor open trials with a non-intervention control arm are likely to be undertaken in LS, a separate goal of PLSD is to produce the information needed to inform development of alternative randomized trials, for example of different surveillance intervals, in the future.
Around the same time as the PLSD was developed, an initiative aiming to compile data on as many LS families as possible for a retrospective segregation analysis was established by the International Mismatch Repair Consortium (IMRC) (https://www.sphinx.org.au/imrc ). Its primary aim was to determine the cumulative CRC incidences in path_MMR carriers by retrospective analysis including family members in former generations who were not subject to the same degree of CRC preventive surveillance with colonoscopy as contemporary patients followed in PLSD [5].
There is limited information on survival following CRC detected during surveillance with colonoscopy in path_MMR carriers, other than reports from the PLSD [8] and the recent IMRC report did not include data on survival [5].
Here, we compare prospective CRC incidences in an updated version of PLSD that includes 8,153 path_MMR carriers aged from 25 to 70 years and subjected to regular follow-up with colonoscopy for a total of 67,604 years with retrospective CRC incidences calculated from path_MMR carriers from 5,255 families collected by the IMRC.
The IMRC used a segregation analysis to study a retrospective family cohort of first- and second-degree relatives, including 31,944 first-degree relatives and 47,865 second-degree relatives of path_MMR probands in 5,585 families. Most probands were path_MLH1 or path_MSH2 carriers, and the methods were discussed previously. Pedigree data of path_MMR families was sought from clinicians and researchers worldwide between July 11, 2014 and December 31, 2018 [5]. Observation time for all individuals included their lifetime risk of first colorectal cancer from birth to their age at death or last known age at latest update to the cohort in 2018. In summary, standard methods correcting for ascertainment bias and then calculating cumulative incidences of CRC by age, gene and gender were applied. The results were reported by continent. To allow for direct comparison with the PLSD, the results of IMRC segregation analyses for the current study were not right-censored at polypectomy (as had been done in the previously published IMRC report [5]) and consequently the results presented here may differ slightly from those previously published. The overall (global) averages were calculated as a weighted mean of the results from the different continents that were previously reported.
Results
Cumulative incidences at ages 30, 40, 50, 60 and 70 years for male and female carriers by MMR gene are detailed in Table 1. For the PLSD series, numbers of carriers included and follow-up years by country are given in the supplementary Table 1.
Table 1
Percent cumulative incidences (with 95% confidence intervals in parentheses) of CRC at ages 30, 40, 50, 60 and 70 years by gender and genetic variant for both series for European path_MMR carriers separately and for all carriers irrespective of residence, and overall cumulative incidence at 25 years in the IMRC series
Prospective PLSD series under colonoscopy surveillance
In total 8,153 carriers were subject to follow-up with colonoscopy for 67,604 years with mean follow-up time of 8.3 years, including 6,266 carriers followed-up for 53,559 years with mean follow-up time 8.5 years in Europe. Five-hundred and seventy-eight carriers had CRC diagnosed. Average cumulative incidences of CRC (with 95% confidence intervals in parentheses) in path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers at 70 years of age were 52 (45-59)%/ 41 (35-48)%, 50 (42-58)%/ 39 (33-46)%, 13 (7-25)%/ 17 (11-26)% and 11 (3-37)%/ 8 (2-29)% in male/female carriers in the total cohort, respectively. For carriers followed-up in Europe, the corresponding cumulative incidences at 70 years were 49 (42-57)% / 41 (35-48)%, 46 (37-57)%/ 39 (31-47) %, 12 (6-24)%/ 15 (9-24)% and 12 (3-40) %/ 3 (1-22)%, respectively.
Retrospective IMRC series
The corresponding average calculated cumulative incidences up to 70 years of age based on all carriers from the IMRC cohort were 40 (34-47)%/ 27 (22-33)%, 34 (28-40)%/ 23 (19-29)%, 16 (12-24)%/ 8 (6-13)% and 7 (6-8)%/ 6 (5-6)%, respectively. The cumulative incidences in families from Europe were 36 (27-48)%/ 22 (15-32)%, 28 (21-38)%/ 17 (11-27)%, 14 (8-24)%/ 6 (3-11)% and 8 (6-10)%/ 5 (4-7)%, respectively. Cumulative incidences at 25 years of ages were < 1.0% in all of the groups considered. Sixty percent of the carriers were right-censored after 1980.
As seen in Table 1 and Fig. 1, the cumulative incidences of CRC in path_MLH1 and path_MSH2 carriers of both genders were significantly higher in the prospective PLSD cohort in which all were subjected to regular colonoscopy surveillance than in the IMRC cohort (95% confidence intervals do not overlap). No significant differences were observed for MSH6, for which fewer patients and events were available in both cohorts (95% confidence intervals of the one series overlap the mean of the other). The point estimates for the mean for path_PMS2 carriers below 50 years of age indicated a lower CRC incidence in the PLSD cohort when compared to the IMRC cohort, but this was not statistically significant.
Fig. 1
Cumulative incidences of CRC by genetic variant and gender in PLSD (the prospective series with colonoscopy) and IMRC (the retrospective series) in European path_MLH1, path_MSH2 and path_MSH6 carriers. Broken lines indicate 95% confidence intervals
×
Discussion
Prospectively observed incidences of CRC in path_MLH1, path_MSH2 and path_MSH6 carriers of both genders in the PLSD cohort, in which all patients were subject to colonoscopy surveillance, were up to twice as high as in the retrospective IMRC series that included carriers who did not all receive regular surveillance colonoscopy.
Consideration of the methodologies used and the associated statistical concepts and confounders is indicated to explore the possibility that the results we obtained might reflect methodological biases, particularly as they were the opposite of what was expected. The PLSD methods have been described previously [9] and the IMRC results were produced using commonly accepted methods, as previously described [5]. Assuming the PLSD mean observation time (8.3 years) to be applicable to IMRC cases right-censored after 1980 (when surveillance with colonoscopy was introduced) as a maximum estimate of the fraction of IMRC cases subjected to colonoscopy, at least 85% of the IMRC observation years would have been completed without colonoscopy. The main finding of the current study would not, anyway, be confounded if a fraction of cases in the IMRC cohort underwent colonoscopy. We recognize that some individuals will have been included in the PLSD as well as the IMRC cohort, but we cannot identify them and their inclusion in both cohorts will not have contributed to the differences in observed CRC incidences. It is possible that CRC was under-reported in the pedigrees obtained by clinical teams, the details of which constituted the primary data source for the IMRC analysis. By contrast, under-reporting of CRC is unlikely in the PLSD cohort whose subjects were under regular surveillance at the contributing centres. It is unlikely that the lower CRC incidences estimated in the IMRC cohort are due to differing frequencies of lower penetrance path_MMR variants or modifying genes in former generations because there have been no known major fluctuations (bottlenecks) in population sizes or structures over the last three generations to cause such changes. As 60% of IMRC cases were right-censored after 1980, possible lower CRC incidence in previous generations (time-trend bias) can not explain the results. However, Lynch syndrome colorectal cancer incidence is associated with lower physical activity [10], and higher body mass index [11]. Temporal changes in such factors could explain some of the observed differences in colorectal cancer incidences between the two cohorts.
Anzeige
In a previous retrospective study, segregation analyses describing cumulative incidences of CRC in French path_MLH1, path_MSH2 and path_MSH6 carriers [12] were not restricted to first and second degree relatives. This helped to avoid simply returning the criteria used to identify families for genetic testing as the results of the study, and to minimize the effects of removing young affected carriers when considering a family to have a hypergeometric distribution of events. Observation time was right-censored at the diagnosis of any cancer in order to avoid survival bias when deaths from other cancers were caused by the same genetic variant. Additional family members were tested and demonstrated to carry the genetic variant in question in order to minimize the confounder of there being additional inherited causes of cancer within the family. Observation time was also right censored if the carrier was subjected to surveillance colonoscopy in order to avoid the confounder of colonoscopy modifying CRC incidence. The point estimates of cumulative CRC incidence at 70 years in that report for both genders combined were 41% for path_MLH1 carriers, 48% for path_MSH2 carriers and 12% for path_MSH6 carriers, very close to the observed incidences in the PLSD series in the current report. The number of cases included was, however, limited and the confidence intervals correspondingly wide – a reason why the PLSD waited for the IMRC results to be available before making a comparison of its prospective data with results of retrospective segregation analyses. While the French report could suggest that the IMRC segregation analyses have underestimated CRC incidence, comparing the current PLSD results with the point estimates in the French series does not demonstrate any reduction in CRC incidence associated with colonoscopy surveillance in the PLSD cohort.
A European multicentre segregation analysis that estimated CRC incidence in path_PMS2 carriers [13] demonstrated an increased incidence in carriers under 50 years of age, similar to the findings reported in the IMRC series. In a subsequent report [14] the same group confirmed that the apparent anticipation observed was a statistical artifact caused by birth cohorts. The PLSD design eliminates such artificial anticipation. The path_PMS2 carriers in the PLSD cohort had lower incidence of CRC before 50 years of age than those reported by the IMRC, but not significantly so. That is, the assumption that colonoscopy reduces CRC incidence may be true for younger adult path_PMS2 carriers. If this finding is confirmed, the recently revised clinical guidelines for path_PMS2 carriers [15] that advocate postponing surveillance compared to other groups with LS would need to be reconsidered. Observations in larger numbers of path_PMS2 carriers are needed to clarify this.
A recent overview of current knowledge on carcinogenetic mechanisms in LS CRCs [16] reported that in addition to the traditional adenoma-carcinoma pathway [2], other carcinogenetic mechanisms also need to be considered. Five hypotheses were described. including 1) adenomas that are overlooked during colonoscopy, 2) fast progression of adenomas to carcinomas [2], 3) CRCs developing without a macroscopically visible adenoma phase 4) over-diagnosis / disappearing cancers [17] and 5) colonoscopy inducing cancer in path_MMR carriers via damage of the colonic epithelium. Hypothesis 1 and 2 cannot explain the results described in this paper as we found higher rates of CRC incidence in those receiving colonoscopy. Although hypothesis 5 is consistent with our results, we have no method to evaluate this. We are left with hypotheses 3 and 4, that CRC may develop directly from MMR deficient crypts without a macroscopically visible precursor and that microsatellite instable crypts, or more advanced cancers, may be invaded by immunocompetent cells leading to their eradication. The latter underlies the principle of neoadjuvant checkpoint inhibitor therapy that has shown marked success in recent trials in MMR deficient CRCs [18, 19] and current studies exploring the feasibility of vaccines to prevent or cure LS cancers [20]. An adult path_MLH1 or path_MSH2 carrier is thought to have > 1000 microsatellite instable crypts in his/her colon [21‐24]. It is known that apparently healthy path_MMR carriers have measurable immune responses against frameshift-induced neo-peptides, suggesting their immune systems can detect and potentially attack microsatellite instable crypts [25]. The probabilities for such crypts persisting, disappearing or developing into infiltrating cancers are not known. The biology of CRC in path_PMS2 carriers may be different from carriers of the pathogenic variants of the other genes [26, 27].
Although the focus of this paper is on CRC incidence, we consider prevention of death due to CRC to be the ultimate goal of surveillance colonoscopy, and the good prognosis of CRC detected in path_MMR carriers who are subjected to colonoscopy every three years or more frequently has been described in previous PLSD reports [8]. This is a strong argument to continue surveillance of path_MMR carriers by colonoscopy. The current paper does not call this into question, but its findings do support a change in the message to be communicated to path_MMR carriers, namely that the purpose of surveillance colonoscopy is not to prevent CRC from occurring but to detect it early. The authors of the current study have previously examined the relationship between colonoscopy interval and CRC incidence, stage at diagnosis, and survival [18, 28‐30] without finding evidence of lower CRC incidence, less advanced stage or better survival when the interval between colonoscopies is shortened to less than three years.
Anzeige
Lastly, the very low incidence of CRC before 25 years of age that was found in the IMRC cohort indicates that the PLSD methodology of setting CRC incidence to zero at 25 years of age was justified. Indeed, without extensive genetic testing, one cannot exclude the possibility that occurrence of CRC before 25 years of age may, in some cases, have been due to inclusion of unrecognized biallelic path_MMR carriers (i.e. individuals who were affected by constitutional mismatch repair deficiency syndrome) or the presence of pathogenic germline variants in other co-existing CRC predisposition genes [31].
The strength of the current study is that it compares the results of the two largest studies to date on CRC incidences in path_MMR carriers. One weakness is the lack of information on colonoscopy in the IMRC series: contributors to IMRC were asked to provide information on colnosocpy sceeening and polypectomy, however this was not provided for the vast majority of submitted individuals. Another weakness is lack of information on the degree to which follow up for cases included in the PLSD complied with recommendations. The effects of non-compliance would be to diminish the differences between the two series and could not explain the increased CRC incidence in the PLSD series compared to the IMRC series.
Conclusions
We found a higher incidence of CRC in the carriers reported to PLSD, all of whom received colonoscopic surveillance. However, as the details of colonoscopies that will have been undertaken in some of the IMRC cohort are not available, we cannot quantify the magnitude of this effect. Although these findings could reflect differences in the fidelity of recording of CRC in the retrospective and prospective cohorts, the findings could also be explained by the occurrence of carcinogenetic mechanisms in LS CRC that override the preventive effect of colonoscopy [16].
Acknowledgments
Harsh Sheth contributed with support from Gujarat State Biotechnology Mission grant GSBTM/JD(R&D)/604/2018-2019/7 and clinical oncologists Prof. Suresh h Advani, Dr. Pankaj Shah and Dr. Abhinav Jain. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016 – Framework Partnership Agreement 2017–2021”. Funding bodies had no role in the study design, collection, analysis or interpretation of the data.
Anzeige
Declarations
Ethics approval and consent to participate
All contributors to the PLSD and IMRC have declared ethics approval and have obtained consents for participations.
Consent for publication
There is no further need for consent for publication of categorized data.
Competing of interests
L Senter-Jamieson have received speaking/consultant fees from AstraZeneca in the past year. Carmen Guillén-Ponce: registrations for congresses and continuing education courses by Merck, Sanofi and Astra Zeneca. Toni T. Seppälä reports CEO and co-owner of Healthfund Finland and an interview honoraria from Boehringer Ingelheim Finland. All other authors declare no conflict of interest.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
verfasst von
Pål Møller Toni Seppälä James G. Dowty Saskia Haupt Mev Dominguez-Valentin Lone Sunde Inge Bernstein Christoph Engel Stefan Aretz Maartje Nielsen Gabriel Capella Dafydd Gareth Evans John Burn Elke Holinski-Feder Lucio Bertario Bernardo Bonanni Annika Lindblom Zohar Levi Finlay Macrae Ingrid Winship John-Paul Plazzer Rolf Sijmons Luigi Laghi Adriana Della Valle Karl Heinimann Elizabeth Half Francisco Lopez-Koestner Karin Alvarez-Valenzuela Rodney J. Scott Lior Katz Ido Laish Elez Vainer Carlos Alberto Vaccaro Dirce Maria Carraro Nathan Gluck Naim Abu-Freha Aine Stakelum Rory Kennelly Des Winter Benedito Mauro Rossi Marc Greenblatt Mabel Bohorquez Harsh Sheth Maria Grazia Tibiletti Leonardo S. Lino-Silva Karoline Horisberger Carmen Portenkirchner Ivana Nascimento Norma Teresa Rossi Leandro Apolinário da Silva Huw Thomas Attila Zaránd Jukka-Pekka Mecklin Kirsi Pylvänäinen Laura Renkonen-Sinisalo Anna Lepisto Päivi Peltomäki Christina Therkildsen Lars Joachim Lindberg Ole Thorlacius-Ussing Magnus von Knebel Doeberitz Markus Loeffler Nils Rahner Verena Steinke-Lange Wolff Schmiegel Deepak Vangala Claudia Perne Robert Hüneburg Aída Falcón de Vargas Andrew Latchford Anne-Marie Gerdes Ann-Sofie Backman Carmen Guillén-Ponce Carrie Snyder Charlotte K. Lautrup David Amor Edenir Palmero Elena Stoffel Floor Duijkers Michael J. Hall Heather Hampel Heinric Williams Henrik Okkels Jan Lubiński Jeanette Reece Joanne Ngeow Jose G. Guillem Julie Arnold Karin Wadt Kevin Monahan Leigha Senter Lene J. Rasmussen Liselotte P. van Hest Luigi Ricciardiello Maija R. J. Kohonen-Corish Marjolijn J. L. Ligtenberg Melissa Southey Melyssa Aronson Mohd N. Zahary N. Jewel Samadder Nicola Poplawski Nicoline Hoogerbrugge Patrick J. Morrison Paul James Grant Lee Rakefet Chen-Shtoyerman Ravindran Ankathil Rish Pai Robyn Ward Susan Parry Tadeusz Dębniak Thomas John Thomas van Overeem Hansen Trinidad Caldés Tatsuro Yamaguchi Verónica Barca-Tierno Pilar Garre Giulia Martina Cavestro Jürgen Weitz Silke Redler Reinhard Büttner Vincent Heuveline John L. Hopper Aung Ko Win Noralane Lindor Steven Gallinger Loïc Le Marchand Polly A. Newcomb Jane Figueiredo Daniel D. Buchanan Stephen N. Thibodeau Sanne W. ten Broeke Eivind Hovig Sigve Nakken Marta Pineda Nuria Dueñas Joan Brunet Kate Green Fiona Lalloo Katie Newton Emma J. Crosbie Miriam Mints Douglas Tjandra Florencia Neffa Patricia Esperon Revital Kariv Guy Rosner Walter Hernán Pavicic Pablo Kalfayan Giovana Tardin Torrezan Thiago Bassaneze Claudia Martin Gabriela Moslein Aysel Ahadova Matthias Kloor Julian R. Sampson Mark A. Jenkins The European Hereditary Tumour Group (EHTG) and the International Mismatch Repair Consortium (IMRC)
Immunchemischer Stuhltest positiv, Koloskopie negativ – in solchen Fällen kann die Blutungsquelle auch weiter proximal sitzen. Ein Forschungsteam hat nachgesehen, wie häufig und in welchen Lokalisationen das der Fall ist.
Frauen, die zum Zeitpunkt der Brustkrebsdiagnose eine hohe mammografische Brustdichte aufweisen, haben ein erhöhtes Risiko für ein baldiges Rezidiv, legen neue Daten nahe.
In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.
Welchen Nutzen es trägt, wenn die Strahlentherapie nach radikaler Prostatektomie um eine Androgendeprivation ergänzt wird, hat die RADICALS-HD-Studie untersucht. Nun liegen die Ergebnisse vor. Sie sprechen für länger dauernden Hormonentzug.
Update Onkologie
Bestellen Sie unseren Fach-Newsletterund bleiben Sie gut informiert.
