REPORT THIRD MEETING OF THE ICG-HNPCC
TORINO, SEPTEMBER 22, 1991

1. Introduction

Henry Lynch (chairman) opened the meeting and made some remarks regarding the successful development of the collaborative group. Meera Khan (secretary) elaborated and conducted the programme.

2. Reports of the ongoing collaborative studies

2a. Mucinous colorectal cancer in HNPCC
Lemuel Herrera reported the preliminary results of 2 collaborative studies. The aims of the study were to find out whether the Dukes stage is usefull in predicting survival in patients with familial colon cancer of mucinous type. Data were collected from 299 patients from seven centers with colorectal cancer diagnosed before their 40th birthday. In 64 patients the tumor was located in the right colon. The patients are being allocated to four groups: (1) patients with an autosomal dominant pattern of transmission of cancer of the right colon; (2) patients with hereditary tendency to colon cancer; (3) familial clusters of cancer and (4) patients without a family history for cancer. The preliminary results showed that about half of the patients in the "heredofamilial" group had mucinous cancer vs 10 % reported for sporadic cases of colorectal cancer. The results suggested that survival of these cases is not predicted by the Dukes stage but that the mucinous component of the tumor is the most important prognostic parameter. Currently, all pedigrees continue to be ascertained, survivals are being completed and paraffin blocks have been requestedfor quantification of mucin for immunocytochemistry. All centers are invited to contribute their cases.

2b. Extracolonic cancers in HNPCC
Patricia Watson said that she distributed data forms among the members of the group recently.
Vasen asked whether she is interested in data from families which met the Amsterdam Criteria; or whether she want to have data from more extended pedigrees. She answered that she want to have data of families which met the "Amsterdam Criteria". Mecklin want to know the exact objective of her study because in his opinion it is already clear from earlier reports that certain tumors occur with an increased frequency in HNPCC families. Watson explained that she want to investigate the heterogeneity of the Lynch syndrome. To be able to give recommendations for screening it should be known which patterns of tumors there are in HNPCC families. To answer this question she need the data of a large number of families.

2c. Inventarization study on surveillance
Vasen stated the objectives of this study: (1) to assess the number of families being followed in the centers; (2) to assess the recommended screening procedures; (3) to determine the age at diagnosis of colorectal cancer (CRC) and the proportion of patients with their first CRC diagnosed at the age of 60 or later and (4) to assess the occurrence of interval cancers. Families were selected which met the "Amsterdam criteria". Vasen said that there was a very good response. He got data on 165 families from nine centers ( 7 countries). Regarding the screening protocol, most centers advise colonoscopy as a single procedure. Two centers (Finland and Holland) recommend as an alternative, bariumenema with sigmoidoscopy. In Italy, fecal blood testing is also advised as a screening procedure. The recommended interval between examinations varies between 1 and 3 years. In two centers the interval depends on the age of the at riskindividual. For persons younger than 35 years of age an interval of 2 years is advised, for those older than 35 years an interval of one year. Regarding the age limits of screening the advised lower age limit of screening varies in most centers from 20 to 25 years. With respect to the upper age limit of screening, three centers recommend life-long screening, the other centers advise to discontinue screening at 60, 65, 70 and 75 years, respectively. The family material included 840 patients. The mean age at diagnosis of CRC was 45 years. Fourteen percent of the CRC was diagnosed at the age of 60 or later. A total number of 682 high risk relatives are being followed in the centers. The mean follow-up varies from 1 to 10 years. Six cases were reported to have an interval cancer. Five of them had a Dukes B cancer, one a Dukes A cancer. In five of the patients, the last screening examination was 36 months before detection of the cancer, in the other patient 60 months. On the basis of these results the following conclusions were drawn: (1) the present number of HNPCC registries all over the world is limited; (2) the most common recommended screeningprocedure is colonoscopy with an interval of one to three years; (3) the mean age at diagnosis in 840 patients was 45 years; because in 14 % of these patients CRC was detected beyond 60 years, surveillance should be continued lifelong; (4) the occurrence of interval cancers appear to be low, however the follow-up in most centers is short.

3. Experience with the the new definition

St John presented the results of a study on the family history of patients with CRC. This study resulted in the finding of two HNPCC-families. He divided the probands according to the number of relatives with CRC and compared them with respect to the location of the tumor in the colon and the occurrence of multiple primary cancers. He reported that there were no differences with respect to these features. Bishop reported the results of segregation analysis of this family material. He divided the probands according to their risk of being a gene carrier and compared these groups for the same features. Also he didn't find any differences in location of CRC, histology, the occurrence of multiple cancers, and survival time.
Ponz de Leon said that when he applied the "Amsterdam Criteria" some families of which he was sure that they were HNPCC-families could not be classified as such (he gave an example of a family with three cases of an endometrial cancer diagnosed at a young age and two with a colon cancer) . He suggested to adjust the criteria so that these families could be included. Vasen showed the effect of using the "Amsterdam Criteria" on the Dutch family material: sofar he analyzed 60 families; 50 of these families had three or more relatives with CRC; six of the 50 had to be excluded because of the age criterion; eight because not all data were confirmed by histology; in three families the colon cancers were diagnosed only in one generation; three other families had to be excluded because a key patient with an extracolonic cancer was the family member between relatives with colorectal cancers. Thus he selected the remaining 30 families which met all criteria) for his studies. The application of the criteria has no implications for the screening protocol recommended by him. Mecklin stated that it is not possible to solve all the problems with respect to the definition. He is satisfied with the criteria since they did effectively maintained a standard and uniformity in the collaborative studies. Bulow and several of the participants expired the opinion that the criteria are very useful.

4. Data collection forms

Vasen introduced this session. He said that recently a subcommittee (Patricia Watson, Lars Svendsen, Tim Bishop) was established to improve the original data forms. The aims of these forms are to promote collection of data of HNPCC-families in a uniform way to enable sharing of specific data for future collaborative studies. He said that they are not meant for setting up an international database. He emphasised that an ideal data collection form is far from reaching.
During the session there were many suggestions to improve the data sheets. Vasen said that the subcommittee will revise the forms using these comments. After that the subcommittee will explore the possibility to develop a computer programme for a HNPCC data base.

5. Proposals for new studies

The following proposals were iscussed:
Patrick Lynch suggested to perform a randomized controlled trial to investigate the appropriate interval between screening examinations. Bishop said that in fact such a study is already going on because the different centers recommend different screening protocols. The only thing we have to do is to assess the occurrence of interval cancers in the centers after 5 or 10 years. Some members were of the opinion that it would be better to perform a randomized controlled trial,
other members expect to get problems with their patients and ethical committees when they introduce an interval of screening of one year in patients who were investigated sofar every three years. Bulow suggested to establish a subcommittee to discuss this problem further.
Lemuel Herrera proposed the members of the group to report on the demographics and phenotypic tumor spectrum in their registries in reference to population based studies of prevalence of cancer in their respective regions/countries in order to segregate populations to a specific cancer risk and to interpret their results and identify possible deficits or excess rates by comparison to their regional data.
Bishop suggested to cooperate in linkage studies. In his opinion it would be usefull to have a meeting, for example, each half year and to pool and discuss the linkage data. Watson asked what his experience is with this sort of cooperation in other hereditary cancer syndromes. Bishop said that he is involved in hereditary breast cancer studies and that the cooperation in this group appeared to be very useful. Some members were more ambivalent about this sort of cooperation. It was agreed upon to establish a subcommittee of members of the group involved in linkage studies in which the possibilities of cooperation will be discussed further. Bishop agreed to write a proposal.
Mecklin presented some figures regarding the incidence of CRC cases in Finland. Every year there are about 30 patient younger than 40 years with colorectal cancer. He was wondering whether these patients represent new mutations of HNPCC. A way to find an answer to this question is to select patients diagnosed 20 -30 years ago and to find out whether they have offspring with CRC. The members of the group agreed that this would be an interesting study. The best place to perform such a study are the Scandinavian countries. It was decided to establish a subcommittee for the epidemiology of HNPCC.
Vasen said that he has sometimes problems with advising screening for endometrial cancer in his families. He has several families with only one case of this type of cancer and doesn't know whether he should recommend screening for this cancer in these families. Because there are no studies available on the epidemiology of this cancer in HNPCC and on the value of screening, he suggested to perform such a study on a collaborative basis. He proposed to establish a committee on this subject. Watson expressed her interest in such a study. Mecklin added that studies on this subject are being performed in his country by Dr. Hakala and that she also would be interested to join in such studies.
Bulow summarized that four subcommittees have been established:
(1) Surveillance for CRC (P. Lynch, Mecklin, Bishop, Vasen);
(2) Linkage studies; ( the members are yet to be nominated)
(3) Epidemiology; (Mecklin, Bulow or Svendsen or Myrhoy)
(4) Endometrial cancer (Watson, Mecklin, Hakala, Vasen).
The subcommittees are supposed to organize their studies by theirselves in the period between the meetings.

6. National initiatives

Japan (Kunitomo): see abstract International Symposium on Colorectal Cancer. Denmark (Myrhoi): see abstract. Australia (St.John): St John said that he has been following HNPCC_families in his hospital for about 10 years. He collected data of about 80 families with three or more CRC cases. The studies which he performed in these families include case control studies and linkage studies. Switserland (Weber):see abstract Israel (Rozen): Rozen said that recently a hereditary cancer registry was set up in the Tel Aviv area. A medical interviewer is connected with this registry who is inventorying all records of patients with cancer and who contacts family members when there is suspicion for a hereditary cancer syndrome. The studies he performed in the colorectal families include: calcium intervention studies and proliferation studies. Germany (M”slein): M”slein said that recently a registry for polyposis families was set up at the University of Heidelberg. United Kingdom (Bishop, Murday): Bishop said that he follows at present about 12 HNPCC-families. In addition, he mentioned two other centers in the U.K. which are interested in these families: New Castle (J.Burn) and the St Marks Hospital. In the latter center a prospective follow-up study of a large number of HNPCC-families is in progress.
Sweden (Kullander): Kullander said that he is involved only in the study of hereditary endometrium cancer. He is not aware of any groups in Sweden which are involved in HNPCC.
France (Grandjouan): In her institute in Paris an investigation is going on to identify familial cancer. So far about 25 HNPCC-families have been found.

7. ICG-HNPCC business meeting

Because of the limited time Meera khan suggested to discuss only the nomination of new members and the place and time of the next meeting. Vasen mentioned that 29 specialists from 8 countries attended the meeting in Amsterdam last year. Tor the present meeting 41 persons were invited and 32 of them were able to come. These 32 persons represent 12 countries. During the last months he received letters from 9 investigators (7 from countries not yet represented) who were interested to become a member of this group. Henry Lynch asked the members of the group their opinion on the most appropriate number of this group. Vasen said that he would prefer to restrict the number to about 50. The reason for that is that at this stage many collaborative studies are going on and a number limited would be effective in promoting fruitful discussions about these studies. In the future when the main objective of the group will be exchange of information the group could be extended. There was a general agreement on this proposal.

The next meeting will be on 21-26 October, 1992 in Crete during the IV International Congress of Anticancer Research.