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Hereditary cancer management strategy in Pskov region
Developed within the framework of the project
“Development of Hereditary Cancer Prevention Measures in Pskov Region”
This document has been produced with the financial assistance of the Estonia – Latvia – Russia Cross Border Cooperation Programme within
European Neighbourhood and Partnership Instrument 2007 – 2013. The contents of this document are the sole responsibility of Riga Stradins
University and can under no circumstances be regarded as reflecting the position of the Programme, Programme participating countries, alongside
with the European Union.
Estonia – Latvia – Russia Cross Border Cooperation Programme within the European Neighbourhood and Partnership Instrument 2007-2013
financially supports joint cross border development activities for the improvement of the region’s competitiveness by utilising its potential and
beneficial location on the crossroads between the EU and Russian Federation. The Programme web-site is www.estlatrus.eu.
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Contents
Description and analysis of present situation .....................................................................................................3
Political background ......................................................................................................................................3
Population ......................................................................................................................................................3
Patient flow ....................................................................................................................................................3
Human resources............................................................................................................................................7
Premises .........................................................................................................................................................7
Equipment ......................................................................................................................................................7
Processes ........................................................................................................................................................8
Data management...........................................................................................................................................8
Educational aspects ........................................................................................................................................8
Medical legislation and state funding principles............................................................................................8
Long term vision for hereditary cancer (HC) management in Pskov region (2014 - 2024) ............................10
Early diagnosis measures for high cancer risk groups .................................................................................13
Regional Hereditary Cancer centre development concept ...............................................................................15
Human resources, training ...........................................................................................................................15
Premises .......................................................................................................................................................15
Equipment ....................................................................................................................................................15
High risk person identification and management system ................................................................................17
Model of collaboration among different health care professionals (surgeons, gynaecologists, medical
oncologists etc.) ...............................................................................................................................................18
Economical aspects of the programme ............................................................................................................19
Legal issues of Hereditary cancer management ...............................................................................................20
Assessment of individual risks, advantages and disadvantages .......................................................................21
Appendix ..........................................................................................................................................................22
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Description and analysis of present situation
Political background
Development of cancer molecular testing in order to improve the results of cancer management is
one of the National priorities of Russian Federation and development of hereditary cancer
prevention and management programme in Pskov region is in concordance with that.
Population
There are around 700 000 inhabitants in Pskov region. This number of population justifies the
development of hereditary cancer centre. One could expect at least 1 500 BRCA1 mutation carriers
in the Pskov region as well at least several hundreds of persons with other hereditary cancer
susceptibility gene mutations. Those are numbers of potentially preventable cancers or cancers with
possibilities for early diagnosis and better treatment results. Average age of hereditary breast and
colorectal cancer patients is around 45. This emphasise the importance of problem – hereditary
cancer programme could prevent not only the premature death of many hundreds of working age
citizens, but also will help to keep them active economically and socially.
Patient flow
Pskov regional oncology hospital (PROH) has longstanding experience in diagnosis and
management of cancer since 1946. In 2012 the branch of Pskov Regional Oncology Hospital was
organized in Velikiji Luki. Such a structure will facilitate the availability of hereditary cancer
services across the Pskov region, including more rural areas.
Every year inpatient treatment receives more than 6000 persons. There are more than 1 600 cancer
surgeries performed every year. There are more than 4 500 chemotherapy courses and more than
55 000 radiotherapy procedures administered yearly. More than 44 000 visits are taking place in
outpatient clinic. During last years Pskov region has best cancer management indicators within
North western part of Russia. Total cancer prevalence in Pskov region is 2172 cases per 100 000
population. Total cancer incidence is 42,3 cases per 10 000 inhabitants. Cancer mortality is 19,8
cases per 10 000.
3
The mortality from breast cancer rate trend in age group from 45
to 74 years is diametrically opposed: in many Western European
countries, there is a steady decrement. In the countries of Eastern
Europe, except Bulgaria and Romania - the relative stabilization of the signs of modest mortality
growth, and in Russia, Belarus and Ukraine, there is a steady growth. Analysis of 5 years specific
mortality rates from breast cancer groups in Russia showed that the favourable trends in mortality
are observed only in age from 40 to 49 years (see Tab. 1). In 2004, the mortality rate of women
aged 45-49 years was lower by 14% compared to 1996. Perhaps it is the result of targeted
preventive measures, including the introduction of mandatory mammography screening of women
40 years and older. Probably, this fact is also the cause of some stabilization of mortality in age
from 50 to 54 years.
Tab.1 Trends in mortality from breast cancer
of women of different ages in Russia (per 100,000 women of the same age)
Trends in mortality rates in older age groups continue to be unfavourable. It seems that reducing
mortality from breast cancer in women over the age of 55 years in Russia is yet not possible.1
Статистико-демографический анализ смертности от рака молочной железы в России. Е.А. Кваша, Т.Л.
Харькова (Опубликовано в журнале "Вопросы статистики", 2006, №8, с. 25-33)
1
4
Tab.2 Main causes of morbidity in Pskov region 2
In total
Main causes of morbidity in Pskov region
(registered patients diagnosed for the first time in
2011
2012
their life)
All diseases
of which:
tumors
For 1000 people
2011
2012
452329
451692
676,0
680,0
6046
5961
9,0
9,0
Hereditary cancer high risk person identification and management in Pskova region has been
started only within framework of ELRI – 097 project.
In table 3. Additional data on breast cancer statistics in Russia are provided.
2
http://pskovstat.gks.ru/wps/wcm/connect/rosstat_ts/pskovstat/resources/ad45ed804de3e496b412fc440b9ac47d/n
as130905_7.htm
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Table nr. 3. Breast cancer statistics in Russia.
Percentage
of patients
Patients having
at the end stage III
of 2004 ( and IV
per
disease
100,000 among all
women) new
identified
in 2004
Amount of
mammographies
per 1000 women
older than 35
years
The overall
mortality rate
from breast
cancer
(per 100,000
women)
Increase (+) or
decrease (-) in 2004
compared with
2003,%
2003
2004
2003
The overall
Amount
mortality
of
2004
rate from
mammog
breast
raphies
cancer
74,56
79,82
40,23
41,00 7,1
1,9
Central Federal District
Moscow
686,82
36,2
North-West Federal District
Pskov city
and Pskov 538,17
district
35,4
14,49
13,64
28,13
29,72 -5,9
5,7
Saint
Petersbur 887,35
g
47,9
30,86
37,16
44,68
46,49 20,4
4,1
The unfavorable situation with mortality from breast cancer can be described with the percentage of
deaths in the first year after the detection of the disease. Therefore, 11.5% of registered deaths
across the whole of Russia in 2004 occurred one year after initial diagnosis. A variation of this
percentage by federal districts was 2.4 % (from 10.4 % in the Central Federal District to 12.8 % in
the South and Far Eastern Federal Districts) In conclusion, I would like to stress once again that the
death rate from breast cancer - is one of the possible causes of preventable death in women and
measures for its reduction should be a priority to reduce the mortality rate of the female population
of Russia.3
3
Статистико-демографический анализ смертности от рака молочной железы в России Е.А. Кваша, Т.Л.
Харькова (Опубликовано в журнале "Вопросы статистики", 2006, №8, с. 25-33)
6
Human resources
PROH has very experienced multidisciplinary team. There are 36 physicians in Pskov regional
oncology hospital and in its branch in Velikeji Luki, including general oncologists, surgeons,
gynaecologists, radiotherapists, medical oncologists as well more than 100 nurses, specialized in
cancer management. However there is no clinical geneticist available and neither multidisciplinary
team had training in management of hereditary cancer patients and high risk individuals. During the
project several educational conferences and training visits took place, which initiated the
competence of PROH staff in all aspects of hereditary cancer management.
Premises
At the present moment PROH is located in the old historical buildings of monastery and there is a
shortage of premises and many of them are temporarily adapted for different clinical applications.
However it was not an obstacle to launch the hereditary cancer programme within the framework of
project and to perform successful family cancer history and blood sample collection as well high
risk person consultations.
However there are no premises available for molecular laboratory, which is very important for the
identification of high risk individuals.
From January, 2014 transfer to completely renovated and appropriate premises is expected. There
will be separate rooms for the hereditary cancer centre and molecular laboratory.
Equipment
Description of equipment, which will be used for hereditary cancer identification and management:
1. At the present moment in the use of PROH there are mammography
machine, breast ultrasound and core biopsy device for the early
diagnosis of hereditary breast cancer cases. New laparoscopy
equipment is available to perform risk reducing adnexectomies in
BRCA1 mutation carriers, but there is no breast MRI available for the
screening of high risk individuals.
7
2. There are fibrocolonoscopy in place
for the diagnosis, prevention and
surveillance
of
high
hereditary
colorectal cancer risk persons with Hereditary nonpolyposis
colorectal cancer predisposing gene mutations (HNPCC or so called
Lynch syndrome) and APC gene carriers from families with Familial
adenomatous polyposis syndrome.
3. There were no equipment for molecular laboratory within the PROH
and during the project essential technologies will be obtained in order
to launch the identification of high cancer risk persons successfully.
Processes
Before the year 2012 there were only non systematic family cancer history collection for every
cancer patient, but the information acquired was difficult to use for practical purposes because of
absence of hereditary cancer programme.
Data management
There is regional cancer registry on the basis of PROH, which provides excellent basis for
integrated cancer data base. At the present moment there are more than 14 000 patients, which are
alive, recorded in the cancer register of PROH and 60% of patients have survived more than 5
years. It is also very important tool in the verification of family cancer history data because very
frequently persons are not aware about the diagnosis of malignant tumours in their relatives.
Educational aspects
Cancer genetics is very new (about 20 years) and fast developing field of medicine, but physicians
have very considerable shortage of information regarding this important subject. Continuous
hereditary cancer educational training concept applicable for the local situation will be very
important to run successfully hereditary cancer programme.
Medical legislation and state funding principles
Should be analyzed and possible necessary corrections recommended. Present state health care
insurance covers 3000 RUB per night inpatient and 300 RUB outpatients. Cancer predisposing gene
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mutation detection as well risks reducing salpingoophorectomy is
included in national guidelines. Special issue is risk reducing
bilateral mastectomy with immediate reconstruction, which is not
accepted in national guidlines so far.
9
Long term vision for hereditary cancer
management in Pskov region (2014 - 2024)
Main objective: PROH hereditary cancer centre provides high quality hereditary cancer
identification, prevention and management services for the population of Pskov region, which
results in decreased cancer mortality and morbidity. A clear goal and well described measurable
tasks and activities of hereditary cancer management are described below.
There are several approaches worldwide used for hereditary cancer high risk person identification.
And each approach partialy reflects the local clinical and molecular features of hereditary cancers.
In the largest part of Western world there are no strong founder effect observed for the most
frequent hereditary cancer predisposing gene mutations particularly in BRCA1/2 genes and strict
family cancer history and clinical diagnostic criteria are used to select patients for molecular
testing. Generally threshold for public health care funded BRCA1/2 mutation testing is at least 10%
of probability to find the mutation. Mutations are rather evenly distributed in many fragments of
both genes (altogether more than 1000 different BRCA mutations published worldwide) and testing
requires complete sequencing of the genes, which is not inexpensive procedure. In such
circumstances molecular hereditary cancer population screening is not justified and identification of
high risk families have been done in the primary health care level largely by family cancer history
criteria or in the hospital setting, if breast or ovarian cancer affected person raise suspicion about
BRCA genes mutations by special clinical and pathological features like young age, medullar
pathology of breast cancer etc.
However there are also countries with strong BRCA1/2 founder effect like Iceland, Norway,
Poland, Belarus, Lithuania, Latvia. In addition contrary to Nordic countries with good population
registries and medical records, there are very poor family cancer history data in Eastern Europe and
as much as 50% of BRCA1 carriers do not know any blood relative with breast or ovarian cancer.
In those countries different approaches have been tested to screen as much person as possible in
order to identify high risk individuals.
Historically the first approach is so called hospital screening, where all affected breast and ovarian
cancer cases are tested for BRCA1 gene founder mutations. This is economically the most effective
10
approach with the lowest costs per one mutation detected. After
identification of index mutation carrier or proband, other family
members at risk are invited for testing. Major disadvantage of the
approach is detection of many mutation carriers, when they already affected with cancer and
ovarian cancer in 90% is in late stage with poor prognosis.
Second approach for high risk person identification is so called population screening, when all
adults are screened for BRCA founder mutations by family cancer history, by molecular testing or
both. This approach has much higher direct costs per one mutation detected, but has much higher
potential of risk reduction and primary prevention. There are different approaches to population
screening. In Poland, Estonia and Latvia family cancer histories were collected in primary health
care level for all adults, BRCA testing was done only in selected cases. However in Latvia and
Estonia it was performed as a two years long pilotproject and there was no system established for
continuous screening.
In Pskov region we recommend to develop innovative approach, which consist of all adult women
hereditary cancer clinical and molecular population screening in combination with cervical cancer
screening done by gynaecologists, which in European countries usually starts at age 25 and with 3
year interval are continued until age 70. In the first stage of hereditary cancer population screening
in Pskov region within first 3 years all women aged 25-70 could be screened clinically (family
cancer history) and molecullary (BRCA1 founder testing). Thereafter (second stage) only those
women, who visit gynaecologist for first cervical cancer screening visit at age 25, are screened
clinically and molecularly for hereditary cancer. In such a way maximal coverage of women
population will be reached. In case of limited funding and resources molecular testing could be
performed only in cases selected by family cancer history, but it will decrease the number of
identified high risk individuals around 3 times.
Hereditary cancer screenings for men could be performed in collaboration with primary health care
specialists.
In table Nr. 4 summary of activities have been described.
11
10
20
8
3
1500
48 000(30%)
400
1920/24000
38
20
20
19/60
Clinical geneticist
12
for mutation carriers
200
HC consultations outpatient
400
for mutation carriers
preparations
HC consultations inpatient
1500
MSH6, APC)
Hereditary colorectal cancer
2
testing (MLH1, MSH2,
BRCA1/2 complete testing
4
screening)***
20
outpatient (population
10
BRCA1/2 founder tests
10
BRCA1/2 founder tests
100
(population screening)**
400
collected outpatient
preparations
Family cancer histories
1500
screening)*
Family cancer histories
1
collected inpatient (hospital
Year
inpatient (hospital screening)
Table Nr.4 Summary of activities and timesheet
Out –
sourced.
Consul tation
number is
4
1500
80 000(50%)
400
3200/40000
64
30
20
32/100
5
1500
112 000(70%)
400
4480/56000
90
40
20
45/140
6
1500
4 900(70%)
400
2450
49
20
20
10
10
1500
4 900(70%)
400
2450
49
20
20
10
not
sufficient
*Within hospital screening family cancer history is collected for all incident breast cancer, lung
cancer, colorectal cancer, prostate cancer, stomach cancer, endometrial cancer, ovarian cancer,
pancreas cancer, kidney cancer, thyroid cancer and melanoma cases. 95-100% coverage is
expected.
**Within population screening family cancer history is collected for all adult inhabitants. For
woman family cancer history is collected during the visit to gynaecologist within three yearly
cervical cancer screening visit. During first 3 years family cancer history is collected from all
women invited to the screening (age 25-70, around 240 000 women altogether, 80 000 yearly given
100% response rate, but in practice expected response rate dynamics could be from 30-70%)
Starting from year 4 it is collected only from women, who undergo initial cervical cancer screening
visit (age 25, around 3500 women yearly given 100% response rate, but in practice expected
response rate dynamics could be from 30-70% ).
12
In the most optimistic scenario response rate for cervical
screening could be 30% in year one and 70% in year 3 and
thereafter. However one have to admit that in several countries of
former USSR like Latvia, cervical cancer screening response rate is only 26,7% in year 4 (2012)
and this is one of the risks factors for the ineffectiveness of the cancer prevention programme.
Family cancer history collection from men could be organized in collaboration with general
practitioners starting from age 20-25. Also for men response rate for the collection of family cancer
histories have been calculated in range of 70%, but exact numbers are difficult to predict.
***Calculations for BRCA1/2 founder tests in population screening have been taken from the
results of population screening in Latvia and Estonia 2005-2007, (Vanags et al. 2010) as well in
Poland (Gronwald et al., 2006, Brozek et al., 2011). Full text of the publications please find
enclosed in appendix nr. 1. From those studies we can speculate that frequency of BRCA1 founder
mutation carriers could be around 1% (range 1-2%), if preselection by family cancer history is
performed, involving persons, who have at least one breast cancer before age 50 or ovarian cancer
at any age among first degree relatives (second degree through male). Accordingly without any
preselection BRCA1 founder mutation frequency could be estimated around 0,25% in general
population. Such approach increase expenses considerably, but also the number of mutation carriers
identified is more than three times higher. It is related to low sensitivity of family cancer history in
the countries of former USSR. Epidemiological numbers have been calculated in their lowest
ranges in order to avoid overestimation of hereditary cancer programme results.
Early diagnosis measures for high cancer risk groups
PROH should provide these actions for patients included in high cancer risk group. European
guidelines for cancer population screening could be used for more details.
1.
Yearly cancer screening visits - physical examination of the breast,
rectum, prostate, skin and screening for other cancer symptoms by
specialists;
2.
Breast cancer screening with mammography;
3.
Colorectal cancer screening with occult blood tests;
13
4.
Cervical
cancer
screening
with
cytological examination;
5.
Lung cancer screening with X-ray examination;
6.
Prostate and ovarian cancer screening with PSA and CA 125
respectively.
14
Regional Hereditary Cancer centre
development concept
The proposed patient flow can be seen in table nr. 4.
Human resources, training
Hereditary cancer prevention programme could be done on the basis of available human resources
within PROH and in the Pskov region generally. Probably during year 3-5 temporary employees
should be attracted, when the activity plan is the most intensive. Family cancer history collection
and blood sample collection could be done by the nurse of gynaecologist or general practitioner.
Family cancer history analysis could be done by the oncologists of PROH. Molecular tests will be
performed in the newly established molecular lab of the PROH and one laborant and one laboratory
physician could secure the demand. Consultations for BRCA1 carriers could be done by specially
trained oncologists of PROH and in more difficult cases outsourced clinical geneticist could be
invited.
Premises
From January, 2014 transfer to completely renovated and appropriate premises is expected. There
will be separate rooms for the hereditary cancer centre and molecular laboratory.
Equipment
Description of equipment, which will be used for hereditary cancer identification and management:
1. mammography,
2. breast ultrasound
3. core biopsy, laparoscopy.
During the project completely new molecular laboratory will be established and equipped with –
Solid-state thermostat, Centrifuge MiniSpin, Pipette variable volume for nucleonic acids zone,
Pump for suctioning, PCR cycler, Laminar box, Centrifuge microspin, Digital photo camera,
Freezer -80C 200 litres, Laptop computer, universal nozzles for dosing devices with filers,
Abaclerial environment box 1-2 proteclicn class, Fidge with a freezer-20C, Thermo container for
transportation of biological materials etc.
15
Not later than year 4 MRI for breast with biopsy possibilities
would be recommended in order to provide effective early
diagnostics of breast cancer for BRCA mutation carriers. Also
stereotactic biopsy device for nonpalpable breast cancers would be recommended.
Processes
Family cancer history and blood sample collection will be available for every woman, visiting
surgeon, gynaecologist or medical oncologist in PROH.
Development of integrated data base
On the basis of regional cancer registry integrated data base have to be developed, which includes
hereditary cancer centre as well all inpatient departments, including radiology, surgery, pathology,
chemotherapy, radiotherapy. Data base have to be at least 3-monthly updated with information
from population registry, regarding the alive or dead status.
Dedicated data manager should be employed in order to set and run the data base.
In yearly scientific meeting of hereditary cancer centre all the information regarding hereditary
cancer cases and high hereditary cancer risk individuals should be discussed.
16
High risk person identification and
management system
The most ambitious goal would be population molecular screening for BRCA1 founder mutations,
which could be done in combination with first cervical smear for all women, who reach 20-25 years
of age and with written consent agree to undergo testing. It means around 40 000 molecular tests
avaregely in first 3 years annually and 3 500 tests every year thereafter if the model of organized
population screening for BRCA1 mutations will be chosen. Probably the most efficient way would
be to organize it in collaboration with gynaecologist from whole region. Exact numbers are shown
in Table nr. 4.
Family cancer history collection from men population could be performed in collaboration with
general practitioners.
In parallel hospital screening is performed, but unfortunately it identifies BRCA1 mutation carrier
only when she is already affected by breast or ovarian cancer. However it is reasonable to perform
hospital screening anyway because with 400 tests yearly is not putting a considerable pressure on
the budget. Molecular testing will be performed both on site as well outsourced for more
complicated and rare tests.
Hospital screening will be performed also in Velikiji Luki branch. Blood samples will be taken on
place and forwarded to Pskov for molecular tests. If high risk individual will be identified, patient
will be invited to Pskov for hereditary cancer consultation.
High risk individuals will be involved in early cancer detection programme. In our opinion one of
the guidelines to be followed are the British ones. NICE guidelines for familial breast cancer and
related risks please find in appendix nr. 2.
The single most effective measure to reduce mortality of BRCA1 mutation carriers is risk reducing
salping ophorectomy. It will be performed in BRCA1 mutation carriers at the age 35-40, who will
decide on this measure
For familial colorectal cancer guidelines please follow link
http://www.cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/page1/AllPages
17
Model of collaboration among different health
care professionals (surgeons, gynaecologists,
medical oncologists etc.)
Surgical oncologists and gynaecological oncologists will provide hereditary cancer consultations in
PROH.
In collaboration with nearest competent Medical University postgraduate training programme for
cancer genetic consultants have to be developed and each involved physician have to pass exam
before starting his/her praxis.
Ideally training programme has to be optimal in terms of academic hours and availability for
clinical specialists of PROH, who are very busy and overloaded in their daily activities.
Nurses of the oncology hospital will provide family cancer history collection and blood sample
collection for molecular tests inpatient.
18
Economical aspects of the programme
Financial aspects of the programme is the most difficult part to estimate as not only local salary
levels, local price of primers, but also rapidly developing technologies, which could influence the
cost of the service, have to be taken into account in the long term. At the present moment with the
technologies proposed within the project (multiplex PCR), the cost of three BRCA1 founder
mutations c.181T >G (300T >G), c.4034delA (4153delA) and c.5266dupC (5382insC) could be
estimated around 50 euro per case. If so, cost of molecular testing for hospital patients will be at
least 20 000 euro per year. Accordingly cost of molecular testing for population screening in year 6
could be at least 122 500 euro per year, but in year 5 expenses could be as high as 2 800 000 euro
per year. This is rather large investment in population health care, but the potential expenses of the
state could be estimated even much higher taking into account the treatment costs of BRCA1
positive breast or ovarian cancer patients, which includes pre-treatment diagnosis and staging,
surgery, chemotherapy, irradiation, sick leave more than half a year as well potential death of
economically active women, if treatment is unsuccessful. More precise localized cost-benefit
evaluation should be done within separate project, but previously performed similar study in Poland
revealed clear cost benefit of the preventive programme. Calculations please find in appendix nr. 3.
In order to realize the strategy it is necessary to apply for special state funding as there are no
enough funds within the existing state health care funding system.
19
Legal issues of Hereditary cancer management
Collaboration with responsible institutions is necessary to include in the guidelines risk reductive
mastectomies. Other legal issues should be resolved during daily clinical practice if they arise.
20
Assessment of individual risks, advantages and
disadvantages
Decrease in number of population could decrease the patient flow and decrease the experience and
competence accordingly. As well economical effectiveness of the programme could decrease
because of smaller patient flow. However decrease is not expected considerably large in a short run.
Problem of not having clinical geneticist in nearest 5 years could impose some competence
problems, but from another hand in several European countries (The Netherlands, Poland and
others) specially trained nurse or physician performs the primary cancer genetic counselling and
only more complicated cases have been addressed to certified clinical geneticist, potentially in St.
Petersburg.
Clear advantage of PROH is centralized cancer management systems, which enables easy access to
all newly diagnosed as well surveillance programmes undergoing malignant tumours patients.
Separate training have to be elaborated for other team members, particularly nurses, because in
largest proportion of cases the nurse will be the only medical person, who will be met by the
patient, including blood sample uptake and disclosure of negative tests results.
21
Appendix
Nr. 1. Articles on hereditary cancer population screening.
Nr. 2. NICE guidelines.
Nr. 3. Study on economical effectiveness of the hereditary cancer screening programme.
22